Parkinson's Disease

Number: 0307

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses Parkinson's disease.

1. Medical Necessity

   Aetna considers the following diagnostic and treatment modalities medically necessary (unless otherwise specified) for Parkinson's disease (PD) when criteria are met:

   1. Diagnosis

      1. Levodopa or apomorphine challenge when the diagnosis of PD is in doubt;
      2. Olfactory testing by means of the University of Pennsylvania Smell Identification Test (UPSIT) or "Sniffin' Sticks" to differentiate PD from progressive supranuclear palsy and corticobasal degeneration;
      3. Neuropsychological testing for the diagnosis of PD;
      4. SPECT scanning (e.g., DaTSCAN [Ioflupane I-123 injection - a radiopharmaceutical indicated for striatal dopamine transporter visualization]) to distinguish PD from essential tremor. Aetna considers SPECT scanning experimental and investigational for distinguishing PD from other parkinsonian syndromes; and for monitoring the progression of PD;

   2. Non-surgical treatments

      1. Carbidopa and levodopa enteral suspension (Duopa)

         1. Criteria for Initial Approval of Duopa

            For the treatment of motor fluctuations in members with advanced PD when all of the following criteria are met:

            1. Member is levodopa responsive with clearly defined "on" periods; and
            2. The member has "off" periods greater than 3 hours per day despite optimization efforts; and
            3. The member must have had an inadequate response or intolerable adverse event with oral carbidopa-levodopa and one of the following anti-Parkinson agents:
               
               
               1. Catechol-O‐methyl transferase (COMT) inhibitor (e.g. entacapone, tolcapone); or
               2. Dopamine agonists (e.g. pramipexole, ropinirole); or
               3. Monoamine oxidase B (MAO)-B inhibitor (e.g. selegiline, rasagiline).

            Aetna considers Duopa experimental and investigational for all other indications.

         2. Continuation of Duopa Therapy

            For members with advanced PD who have demonstrated a positive clinical response to Duopa therapy;

      2. CADD®‐Legacy 1400 portable infusion pump for administering carbidopa and levodopa enteral suspension is considered medically necessary durable medical equipment (DME) for persons who meet criteria for carbidopa and levodopa enteral suspension (Duopa).

   3. Surgical treatment

      1. Pallidotomy for the treatment of PD when all of the following criteria are met:

         1. Individuals with idiopathic PD who have tried and failed medical therapy as indicated by worsening of Parkinsonian symptoms and/or disabling medication side effects (motor fluctuations with "wearing off", and unpredictable "on/off", as well as Sinemet-induced dyskinesia); and
         2. Members exhibit 2 of 4 major symptoms (bradykinesia, tremor, rigidity, and gait disturbance); and
         3. Members have a history of positive response to dopaminergic replacement therapy (e.g., Sinemet or bromocriptine); and
         4. Members have been screened by a neurologist who has expertise in movement disorders to ensure all reasonable forms of pharmacotherapies have been tried and failed.

      2. Pallidotomy for the treatment of PD is of no proven value in persons with the following conditions:

         1. Members with Parkinson's plus or atypical Parkinson's disorders (e.g., multi-system atrophy, striato-nigral degeneration, progressive supranuclear palsy, or combined Alzheimer's disease and PD); or
         2. Members with severe dementia or cerebral atrophy; or
         3. Members with Hoehn and Yahr Stage V Parkinson's disease (see Note below).

         Note: Hoehn and Yahr Stage V individuals exhibit the following characteristics:

         • Cachectic state
         • Can not stand or walk (need wheelchair assistance, or are unable to get out of bed)
         • Invalidism
         • Requires constant nursing care.

2. Experimental and Investigational

   Aetna considers the following diagnostic and treatment modalities experimental and investigational for Parkinson's disease (PD) (not an all-inclusive list) because the effectiveness of these approaches has not been established:

   1. Diagnosis and Monitoring

      1. Any of the following tests for differentiating PD from other parkinsonian syndromes:

         1. Electrooculography
         2. Growth hormone stimulation with clonidine
         3. Iodine-123 meta-iodobenzylguanidine cardiac imaging
         4. Magnetic resonance imaging (MRI)
         5. Tilt table testing
         6. Transcranial duplex scanning

      2. Any of the following genetic testing of PD:

         • PD (e.g., testing for alpha-synuclein, apolipoprotein E (APOE)
         • DJ1
         • Fibroblast growth factor 20 rs12720208 polymorphism
         • Glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) polymorphisms
         • Interleukin-10 polymorphisms (-1082A/G and -592C/A)
         • LRRK2/PARK8
         • Parkin/PARK2
         • PARK10 and its variants
         • PINK1
         • PITX3
         • Sphingomyelin phosphodiesterase 1 gene (SMPD1)
      3. Alpha-synuclein in CSF/salivary extracellular vesicles, and the Syn-One test (cutaneous alpha-synuclein) for the diagnosis of PD
      4. Cerebrospinal fluid (CSF) α-synuclein, heart fatty acid-binding protein, neurofilament light chain, tau (phosphorylated or total) and ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) as diagnostic biomarkers for PD
      5. CSF amyloid beta 1-42 as a biomarker for PD progression
      6. Metabolic profiling for PD
      7. Plasma neurofilament light chain (NfL) as a biomarker for disease severity and progression in PD
      8. Quantitative EEG (qEEG) measures as predictive biomarkers for the development of dementia in PD
      9. Retinal thinning as a biomarker of PD
      10. Salivary biomarkers (e.g., acetylcholinesterase, alpha-synuclein, cortisol, heme oxygenase-1, and nitric oxide) for diagnosis of PD
      11. Serum fibroblast growth factor 21 (FGF-21), serum growth differentiation factor 15 (GDF-15) and blood mitochondrial DNA (mtDNA) copy number levels as biomarkers of PD
      12. Serum leptin levels for the diagnosis of PD
      13. Submandibular gland needle biopsy for the diagnosis of PD
      14. Telomere length as a risk factor for development of PD
      15. Urinary LRRK2 phosphorylation to determine PD risk among LRRK2 mutation carriers
      16. Use of serum α-synuclein autoantibody as a biomarker“ (SYNTap Biomarker Test) for PD
      17. Use of wearable inertial sensors for home monitoring of individuals with PD;

   2. Non-surgical treatment

      1. Alpha-synuclein immunotherapy for the treatment of PD
      2. Bright light therapy for treatment of depression in PD
      3. Cala-Trio device for treatment of essential and Parkinsonian tremor
      4. Cannabinoids for the treatment of PD
      5. Cueing module device (auditory cue) for treatment of Parkinson's freezing
      6. Hyperbaric oxygen therapy (see CPB 0172 - Hyperbaric Oxygen Therapy (HBOT))
      7. Intravenous glutathione
      8. Music-based interventions for the treatment of motor and non-motor symptoms in individuals with PD
      9. Proprioceptive focal stimulation (the Equistasi device) for gait and postural balance rehabilitation in individuals with PD
      10. Robot-assisted gait training on lower extremity dyskinesia in individuals with PD
      11. Transcranial direct current stimulation/transcranial magnetic stimulation (including theta burst stimulation-patterned transcranial magnetic stimulation)
      12. Tumor necrosis factor inhibition for prevention of PD, or delay its onset;

   3. Surgical treatment

      The following surgical procedures are considered experimental and investigational for the management of PD (not an all-inclusive list) because either the long-term safety or effectiveness has not been established:

      1. Adrenal medullary transplantation
      2. Extra-dural motor cortex stimulation
      3. Gene therapy, including aromatic L-amino acid decarboxylase (AADC) gene therapy (via putaminal infusion)
      4. Intra-striatal implantation of human retinal pigment epithelial cells
      5. Magnetic resonance imaging-guided focused ultrasound neurosurgery
      6. Spinal cord stimulation for the treatment of gait disorders in individuals with PD
      7. Stem cell transplantation
      8. Subthalamotomy
      9. Transplantation of fetal mesencephalic tissue or fetal xenografts (e.g., from pigs or other animals)
      10. Vagotomy for the prevention and treatment of PD.

3. Related Policies 

   • CPB 0071 - Positron Emission Tomography (PET)
   • CPB 0153 - Thalamotomy
   • CPB 0158 - Neuropsychological and Psychological Testing
   • CPB 0168 - Tumor Scintigraphy
   • CPB 0208 - Deep Brain Stimulation
   • CPB 0221 - Quantitative EEG (Brain Mapping)
   • CPB 0390 - Smell and Taste Disorders: Diagnosis

Dosage and Administration

Carbidopa and Levodopa Enteral Suspension (Duopa)

• Enteral suspension: 4.63 mg carbidopa and 20 mg levodopa per mL in a single-use cassette. Each cassette contains approximately 100 mL of suspension.
• For treatment of motor fluctuations in advanced Parkinson’s disease, the maximum recommended daily dose of Duopa is 2000 mg of levodopa (i.e., one cassette per day) administered over 16 hours. Prior to initiating Duopa, individuals should be converted from all forms of levodopa to oral immediate-release carbidopa-levodopa tablets (1:4 ratio). The total daily dose is titrated based on the clinical response. Duopa is administered into the jejunum through a percutaneous endoscopic gastrostomy with jejunal tube (PEG-J) with the CADD-Legacy 1400 portable infusion pump. At the end of the daily 16-hour infusion, the individual will disconnect the pump from the PEG-J and take their night-time dose of oral immediate-release carbidopa-levodopa tablets. For additional dosage and administration information, please refer to the full prescribing information for Duopa.

Source: AbbVie, 2022

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Diagnostic Tests:
CPT codes covered if selection criteria are met:
96132 - 96133	Neuropsychological testing evaluation services by physician or other qualified health care professional, including integration of patient data, interpretation of standardized test results and clinical data, clinical decision making, treatment planning and report, and interactive feedback to the patient, family member(s) or caregiver(s), when performed
96146	Psychological or neuropsychological test administration, with single automated, standardized instrument via electronic platform, with automated result only
CPT codes not covered for indications listed in the CPB:
Genetic testing of fibroblast growth factor 20 rs12720208 polymorphism, plasma neurofilament light chain (NfL) as a biomarker, salivary biomarkers, serum fibroblast growth factor 21 (FGF-21), serum growth differentiation factor 15 (GDF-15) and blood mitochondrial DNA (mtDNA) copy number levels as biomarkers of PD, Measurement of serum leptin levels, Metabolic profiling, measurement of alpha-synuclein in cerebrospinal fluid/salivary extracellular vesicles, Syn-One test, aromatic L-amino acid decarboxylase (AADC) gene therapy (via putaminal infusion), theta burst stimulation-patterned transcranial magnetic stimulation - no specific code
0361U	Neurofilament light chain, digital immunoassay, plasma, quantitative
0393U	Neurology (eg, Parkinson disease, dementia with Lewy bodies), cerebrospinal fluid (CSF), detection of misfolded a-synuclein protein by seed amplification assay, qualitative
70551 - 70553	Magnetic resonance (eg, proton) imaging, brain (including brain stem) [for differentiating PD from other parkinsonian syndromes]
80428	Growth hormone stimulation panel (e.g., arginine infusion, l-dopa administration)
81330	SMPD1 (sphingomyelin phosphodiesterase 1, acid lysosomal)(eg, Niemann-Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsP330)
81401	Molecular pathology procedure level 2 [Not covered for urinary LRRK2 phosphorylation for parkinson’s disease risk]
82013	Acetylcholinesterase [salivary biomarker]
82172	Apolipoprotein, each [not covered for apolipoprotein E (APOE)]
82530	Cortisol; free [salivary biomarker]
82533	total [salivary biomarker]
88184	Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; first marker [measurement of telomere length]
88185	Flow cytometry, cell surface, cytoplasmic, or nuclear marker, technical component only; each additional marker (List separately in addition to code for first marker) [measurement of telomere length]
88341 - 88344	Immunohistochemistry or immunocytochemistry, per specimen [ICSF alpha-synuclein test as a biomarker for PD] [cerebrospinal fluid ubiquitin carboxy-terminal hydrolase L1 (UCH-L1] ], [not covered for CSF levels of heart fatty acid-binding protein, neurofilament light chain, and tau (phosphorylated or total) as biomarkers of PD]
Other CPT codes related to the CPB:
80349 - 80352	Cannabinoids, natural; synthetic
Other HCPCS codes related to this CPB:
J0135	Injection, adalimumab, 20 mg
J0717	Injection, certolizumab pegol, 1 mg
J1438	Injection, etanercept, 25 mg
J1602	Injection, golimumab, 1 mg
J1745	Injection, infliximab, excludes biosimilar, 10 mg
Q5103	Injection, infliximab-dyyb, biosimilar, (Inflectra), 10 mg
Q5104	Injection, infliximab-abda, biosimilar, (Renflexis), 10 mg
Q5109	Injection, infliximab-qbtx, biosimilar, (Ixifi), 10 mg
Q5121	Injection, infliximab-axxq, biosimilar, (Avsola), 10 mg
Q5131	Injection, adalimumab-aacf (idacio), biosimilar, 20 mg
Q5132	Injection, adalimumab-afzb (abrilada), biosimilar, 10 mg
Surgical Procedures:
CPT codes covered if selection criteria are met:
61720	Creation of lesion by stereotactic method, including burr hole(s) and localizing and recording techniques, single or multiple stages; globus pallidus or thalamus
61735	subcortical structure(s) other than global pallidus of thalamus
61863	Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), without use of intraoperative microelectrode recording; first array
+ 61864	each additional array (List separately in addition to primary procedure)
61867	Twist drill, burr hole, craniotomy, or craniectomy with stereotactic implantation of neurostimulator electrode array in subcortical site (e.g., thalamus, globus pallidus, subthalamic nucleus, periventricular, periaqueductal gray), with use of intraoperative microelectrode recording, first array
+ 61868	each additional array (List separately in addition to primary procedure)
CPT codes not covered for indications listed in the CPB:
Alpha-synuclein immunotherapy, Robot-assisted gait training – no specific code
0398T	Magnetic resonance image guided high intensity focused ultrasound (MRgFUS), stereotactic ablation lesion, intracranial for movement disorder including stereotactic navigation and frame placement when performed
38232	Bone marrow harvesting for transplantation; autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	autologous transplantation
42400	Biopsy of salivary gland; needle [submandibular]
61850	Twist drill or burr hole(s) for implantation of neurostimulator electrodes, cortical
61860	Craniectomy or craniotomy for implantation of neurostimulator electrodes, cerebral, cortical
63650	Percutaneous implantation of neurostimulator electrode array, epidural
63655	Laminectomy for implantation of neurostimulator electrodes, plate/paddle, epidural
63661	Removal of spinal neurostimulator electrode percutaneous array(s), including fluoroscopy, when performed
63662	Removal of spinal neurostimulator electrode plate/paddle(s) placed via laminotomy or laminectomy, including fluoroscopy, when performed
63663	Revision including replacement, when performed, of spinal neurostimulator electrode percutaneous array(s), including fluoroscopy, when performed
63664	Revision including replacement, when performed, of spinal neurostimulator electrode plate/paddle(s) placed via laminotomy or laminectomy, including fluoroscopy, when performed
63685	Insertion or replacement of spinal neurostimulator pulse generator or receiver, direct or inductive coupling
63688	Revision or removal of implanted spinal neurostimulator pulse generator or receiver
64760	Transection or avulsion of; vagus nerve (vagotomy), abdominal
90867	Therapeutic repetitive transcranial [direct current] magnetic stimulation treatment; planning [for the treatment of PD]
90868	Delivery and management, per session [for the treatment of PD]
90869	subsequent delivery and management, per session [for the treatment of PD]
92270	Electro-oculography with interpretation and report
93660	Evaluation of cardiovascular function with tilt table evaluation, with continuous ECG monitoring, with or without pharmacological intervention [for differentiating PD from other parkinsonian syndromes]
93890	Transcranial Doppler study of the intracranial arteries; vasoreactivity study
95961	Functional cortical and subcortical mapping by stimulation and/or recording of electrodes on brain surface, or of depth electrodes, to provoke seizures or identify vital brain structures; initial hour of attendance by a physician or other qualified health care professional
95962	each additional hour of attendance by a physician or other qualified health care professional (List separately in addition to code for primary procedure)
95970	Electronic analysis of implanted neurostimulator pulse generator system (e.g., rate, pulse amplitude and duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements); simple or complex brain, spinal cord, or peripheral (i.e., cranial nerve, peripheral nerve, autonomic nerve, neuromuscular) neurostimulator pulse generator/transmitter, without reprogramming
95971	simple spinal cord, or peripheral (i.e., peripheral nerve, autonomic nerve, neuromuscular) neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming
95972	complex spinal cord, or peripheral (ie, peripheral nerve, sacral nerve, neuromuscular) (except cranial nerve) neurostimulator pulse generator/transmitter, with intraoperative or subsequent programming
99183	Physician attendance and supervision of hyperbaric oxygen therapy, per session
HCPCS codes covered if selection criteris are met:
A9584	Iodine 1-123 ioflupane, diagnostic, per study dose, up to 5 millicuries [to distinguish PD from essential tremor]
J7340	Carbidopa 5 mg/levodopa 20 mg enteral suspension
HCPCS codes not covered for indications listed in the CPB:
Cueing module device (auditory cue), wearable inertial sensors, cannabinoids, Equistasi device - no specific code
A4290	Sacral nerve stimulation test lead, each
A4542	Supplies and accessories for external upper limb tremor stimulator of the peripheral nerves of the wrist
A4575	Topical hyperbaric oxygen chamber, disposable
C1767	Generator, neurostimulator (implantable), nonrechargeable
C1778	Lead, neurostimulator (implantable)
C1787	Patient programmer, neurostimulator
C1816	Receiver and/or transmitter, neurostimulator (implantable)
C1820	Generator, neurostimulator (implantable), non high frequency with rechargeable battery and charging system
C1822	Generator, neurostimulator (implantable), high frequency, with rechargeable battery and charging system
C1883	Adaptor/extension, pacing lead or neurostimulator lead (implantable)
C1897	Lead, neurostimulator test kit (implantable)
C9734	Focused ultrasound ablation/therapeutic intervention, other than uterine leiomyomata, with magnetic resonance (MR) guidance
E0446	Topical oxygen delivery system, not otherwise specified, includes all supplies and accessories
E0734	External upper limb tremor stimulator of the peripheral nerves of the wrist
E0745	Neuromuscular stimulator, electronic shock unit
G0176	Activity therapy, such as music, dance, art or play therapies not for recreation, related to the care and treatment of patient's disabling mental health problems, per session (45 minutes or more) [Music-based interventions]
G0277	Hyperbaric oxygen under pressure, full body chamber, per 30 minute interval
L8679	Implantable neurostimulator, pulse generator, any type
L8680	Implantable neurostimulator electrode, each [not covered for dorsal column stimulation]
L8681	Patient programmer (external) for use with implantable programmable neurostimulator pulse generator, replacement only
L8682	Implantable neurostimulator radiofrequency receiver
L8683	Radiofrequency transmitter (external) for use with implantable neurostimulator radiofrequency receiver
L8684	Radiofrequency transmitter (external) for use with implantable sacral root neurostimulator receiver for bowel and bladder management, replacement
L8685	Implantable neurostimulator pulse generator, single array, rechargeable, includes extension
L8686	Implantable neurostimulator pulse generator, single array, non-rechargeable, includes extension
L8687	Implantable neurostimulator pulse generator, dual array, rechargeable, includes extension
L8688	Implantable neurostimulator pulse generator, dual array, non-rechargeable, includes extension
L8689	External recharging system for battery (internal) for use with implantable neurostimulator, replacement only
L8695	External recharging system for battery (external) for use with implantable neurostimulator, replacement only
S8042	Magnetic resonance imaging (MRI), low-field [for differentiating PD from other parkinsonian syndromes]
Other HCPCS codes related to the CPB:
J0364	Injection, apomorphine hydrochloride, 1 mg
J0735	Injection, clonidine HCl, 1 mg
J1265	Injection, dopamine HCl, 40 mg
ICD-10 codes covered if selection criteria are met:
F06.8	Other specified mental disorders due to known physiological condition [development of dementia in parkinsonism]
G20.A1 – G20.C	Parkinson's disease
G21.0 - G21.9	Secondary parkinsonism
G23.1	Progressive supranuclear ophthalmoplegia [Steele-Richardson-Olszewski] [supranuclear palsy associated with parkinsonism] [covered for levodopa or apomorphine challenge, olfactory testing by UPSIT or Sniffin' Sticks, and neuropsychological testing]
G31.85	Corticobasal degeneration [covered for levodopa or apomorphine challenge, olfactory testing by UPSIT or Sniffin' Sticks, and neuropsychological testing]
ICD-10 codes not covered for indications listed in the CPB:
F02.80 - F02.C4	Dementia in other diseases classified elsewhere [not covered for continued use of levodopa-carbidopa intestinal gel]
F03.90 - F03.C4	Unspecified dementia [not covered for continued use of levodopa-carbidopa intestinal gel]
F06.0 - F06.4	Other mental disorders due to known physiological condition
G25.0	Essential tremor
G30.0 - G30.9	Alzheimer's disease
R26.0 – R26.9	Abnormalities of gait and mobility [Gait disorders]
R27.0 – R27.9	Other lack of coordination [Gait disorders]
R64	Cachexia
Z74.01	Bed confinement status
SPECT Scanning:
CPT codes covered if selection criteria are met:
78607	Brain imaging, tomographic (SPECT) [to distinguish PD from essential tremor]
HCPCS codes covered if selection criteria are met:
A9584	Iodine 1-123 ioflupane, diagnostic, per study dose, up to 5 millicuries [to distinguish PD from essential tremor]
ICD-10 codes covered if selection criteria are met:
G20.A1 – G20.C	Parkinson's Disease
G21.11 - G21.19	Other drug-induced secondary parkinsonism
G25.0 -G25.2	Essential, drug-induced and other specified forms of tremor
ICD-10 codes not covered for indications listed in the CPB:
H35.89	Other specified retinal disorders brackets thinning brackets [retinal thinning as a biomarker of PD]

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Background

Parkinson disease (PD) is the most common cause of parkinsonism, which is characterized by bradykinesia, rigidity, resting tremor, and postural reflex impairment.  The diagnosis of PD is based on a careful taking of medical history and a thorough physical examination.  Currently, there are no laboratory tests or imaging studies that confirm the diagnosis (Nutt and Wooten, 2005).  It is important for clinicians to understand the clinical signs that aid to differentiate PD from various parkinsonism syndromes (also known as Parkinson-plus syndromes) that include progressive supranuclear palsy (PSP), multiple system atrophy (MSA), cortico-basal degeneration (CBD), dementia with Lewy bodies (DLB), vascular parkinsonism, parkinsonism with no clear etiology, and Parkinson-dementia-amyotrophic lateral sclerosis complex.

The correct diagnosis of PD is important for prognostic as well as therapeutic reasons.  Research of the diagnostic accuracy for the disease and other forms of parkinsonism in community-based samples of patients taking anti-parkinsonian medication confirmed a diagnosis of parkinsonism in only 74 % of patients and clinically probable PD in 53 % of patients.  Clinicopathological studies based on brain bank material from the United Kingdom and Canada have revealed that clinicians diagnose the disease incorrectly in about 25 % of patients.  In these studies, the most common reasons for diagnostic errors were presence of essential tremor, vascular parkinsonism, and atypical parkinsonian syndromes.  Infrequent misdiagnosis included Alzheimer's disease (AD), DLB, and drug-induced parkinsonism.  Moreover, ancillary tests such as olfactory testing and dopamine-transporter (DAT) single photon emission computed tomography (SPECT) imaging may help with clinical diagnostic decisions (Tolosa et al, 2006).  Winogrodzka et al (2005) noted that DAT scintigraphy with SPECT has been used to evaluate the dopaminergic function in patients with PD.  Initial studies with several radioligands show significant loss of DAT binding in PD patients as compared to controls.

It should be noted that the role of neuroimaging in the differential diagnosis of PD has not been clearly established.  Piccini and Whone (2004) noted that recent improvements in the characterization of the parkinsonian syndromes have led to improvements in clinical diagnostic accuracy; however, clinical criteria alone are not always sufficient to distinguish between idiopathic PD and other parkinsonian syndromes, especially in the early stages of disease and in atypical presentations.  Thus, in addition to the development and implementation of diagnostic clinical assessments, there is a need for available objective markers to aid clinicians in the differential diagnosis of idiopathic PD (IPD).  Functional neuroimaging such as positron emission tomography (PET) and SPECT holds the promise of improved diagnosis and allows assessment in early disease.

Seibyl et al (2005) stated that the development of imaging biomarkers, which target specific sites in the brain, represents a major advance in neurodegenerative diseases and PD with the promise of new and improved approaches for the early and accurate diagnosis of disease as well as novel ways to monitor patients and assess treatment.  The 3 major applications that imaging may play a role in PD are:

1. the use of neuroimaging as a biomarker of disease in order to improve the accuracy, timeliness, and reliability of diagnosis;
2. objective monitoring of the progression of disease to provide a molecular phenotype of PD that may illuminate some of the sources of clinical variability;and
3. the evaluation of disease-modifying treatments designed to retard the progression of disease by interfering with pathways thought to be implicated in the ongoing neuronal loss or replace dopamine-producing cells.

Each of these areas has shown a numbers of critical clinical investigations that have better defined the utility of neuroimaging to these tasks.  However, current unresolved issues around the clinical role of neuroimaging in monitoring PD patients over time and validation of quantitative imaging measures of dopaminergic function are immediate issues for the field and the subject of current research efforts and the extension of the lessons learned in PD to other neurodegenerative diseases including AD.

In a review on conventional and advanced magnetic resonance imaging (MRI) techniques in the differential diagnosis of neurodegenerative parkinsonism, Seppi and Schocke (2005) noted that research findings suggest that novel MRI techniques such as magnetization transfer imaging, diffusion-weighted imaging, and magnetic resonance volumetry have superior sensitivity compared to conventional MRI in detecting abnormal features in neurodegenerative parkinsonian disorders.  They stated that whether these techniques will emerge as standard tools in the work-up of patients presenting with parkinsonism requires further prospective studies during early disease stages.

Ravina and colleagues (2005) reported that radiotracer imaging (RTI) of the nigrostriatal dopaminergic system is a widely used but controversial biomarker in PD.  These investigators reviewed the concepts of biomarker development and the evidence to support the use of four radiotracers as biomarkers in PD:

1. [18F]fluorodopa PET,
2. (+)-[11C]dihydrotetrabenazine PET,
3. [123I]beta-CIT SPECT,and
4. [18F]fluorodeoxyglucose PET.

According to the authors, biomarkers used to study disease biology and facilitate drug discovery and early human clinical trials rely on evidence that they are measuring relevant biological processes.  The 4 tracers fulfill this criterion, although they do not measure the number or density of dopaminergic neurons.  Biomarkers used as diagnostic tests, prognostic tools, or surrogate endpoints must not only have biological relevance but also a strong linkage to the clinical outcome of interest.  No radiotracers fulfill these criteria, and current evidence does not support the use of imaging as a diagnostic tool in clinical practice or as a surrogate endpoint in clinical trials.  Mechanistic information added by RTI to clinical trials may be difficult to interpret because of uncertainty about the interaction between the interventions and the tracer.

In the recent practice parameter on the diagnosis and prognosis of new onset PD (an evidence-based review) by the American Academy of Neurology (AAN), Suchowersky, et al (2006) provided the following conclusions/recommendations:

• Levodopa or apomorphine challenge should be considered for confirmation when the diagnosis of PD is in doubt.
• Olfactory testing by means of the University of Pennsylvania Smell Identification Test (UPSIT) or "Sniffin' Sticks" should be considered to differentiate PD from PSP and CBD; but not PD from MSA.
• The following tests may not be useful in differentiating PD from other parkinsonian syndromes:
  
  
  • Electrooculography
  • Growth hormone stimulation with clonidine
  • SPECT scanning
     
• There is insufficient evidence to determine if iodine-123 meta-iodobenzylguanidine cardiac imaging is useful in differentiating PD from MSA or PSP.
• In the future, there may be an increasing role for genetic testing to diagnose PD.  However, the development of any new diagnostic test will require long-term follow-up and autopsy confirmation to determine its accuracy.

de la Fuente-Fernández (2012) evalauted the role of DaTSCAN in the diagnosis of PD.  Using the sensitivity and specificity values obtained in the 2 studies that recently led the Food and Drug Administration to approve the use of DaTSCAN for the diagnosis of PD, calculations were carried out to estimate the accuracy of the clinical diagnosis taking DaTSCAN findings as the standard of truth.  In early PD, a clinical diagnosis of "possible" or "probable" PD has a sensitivity of 98 % and a specificity of 67 %.  The specificity increases to 94 % once the clinical diagnosis becomes established.  The overall accuracy of the clinical diagnosis is 84 % in early PD and 98 % at later stages.  The clinical diagnostic accuracy is mathematically identical to the diagnostic accuracy of DaTSCAN imaging.  The authors concluded that in the absence of neuropathologic validation, the overall accuracy of a clinical diagnosis of PD is very high and mathematically identical to the accuracy of DaTSCAN imaging, which calls into question the use of radiotracer neuroimaging as a diagnostic tool in clinical practice.  They stated that neuropathological studies are definitely needed to evaluate the diagnostic accuracy of radiotracer neuro-imaging compared to the clinical diagnosis.  Until these assessments are available, it may be premature to embark on a large-scale use of DaTSCAN imaging for the diagnosis of PD.

Beyer and colleagues (2007) noted that the nosologic relationship between DLB and PD with dementia (PDD) is continuously being debated.  These investigators conducted a study using voxel-based morphometry (VBM) to explore the pattern of cortical atrophy in DLB and PDD.  A total of 74 patients and healthy elderly were imaged (healthy elderly, n = 20; PDD, n = 15; DLB, n = 18, and AD, n = 21).  Three dimensional T1-weighted MRI were acquired, and images analyzed using VBM.  Overall dementia severity was similar in the dementia groups.  These researchers found more pronounced cortical atrophy in DLB than in PDD in the temporal, parietal, and occipital lobes.  Patients with AD had reduced gray matter concentrations in the temporal lobes bilaterally, including the amygdala, compared to PDD.  Compared to DLB, the AD group had temporal and frontal lobe atrophy.  The authors concluded that despite a similar severity of dementia, patients with DLB had more cortical atrophy than patients with PDD, indicating different brain substrates underlying dementia in the 2 syndromes.  Together with previous studies reporting subtle clinical and neurobiological differences between DLB and PDD, the findings of this study supported the hypothesis that PDD and DLB are not identical entities, but rather represent 2 subtypes of a spectrum of Lewy body disease.

While the AAN practice parameter on diagnosis and prognosis of new onset PD (Suchowersky et al, 2006) stated that there is insufficient evidence to support or refute the use of MRI as a means of distinguishing PD from other parkinsonian syndromes, Seppi and Rascol (2007), in an editorial that accompanied the article by Beyer et al, stated that further studies involving larger groups of patients with prospective long-term follow-up and ultimate pathologic diagnosis are needed for verifying the findings of Beyer et al.  Furthermore, while such confirmatory data might be available in the future at the level of groups of patients, it is unlikely that MRI will be sufficiently sensitive and specific to allow differential diagnosis at the level of a single patient.

Genetic causes of PD have been identified in approximately 3 % of cases with the discovery of mutations in 6 genes.  The most common of these are the gene for leucine-rich repeat kinase 2 (LRRK2 or PARK8), which is autosomal dominant, and parkin (PARK2), which is recessive.  LRRK2 produces a phenotype identical to classical PD, with age of onset at approximately 50 to 70 years.  The most common mutation (G2019S) has been reported to cause 1.5 % of all cases of PD.  Penetrance is age-dependent and is estimated to be 25 % to 35 %.  Despite LRRK2 being dominantly inherited, many people who are heterozygous for LRRK2 mutations do not develop the disease.  Homozygous or compound heterozygous mutations of parkin are the most common cause of early-onset PD (10 % to 20 % of cases).  However, because single heterozygous mutations also are seen in many people with PD, these mutations are thought to confer a risk for PD.  This idea is supported by studies of age of onset and by PET imaging of the dopamine system.  However, examinations of mutation frequency in control populations have had conflicting results.  Reduced penetrance can cause LRRK2 to act in an apparently recessive or sporadic manner, and parkin may appear to be dominant.  Hence, the distinction between dominant and recessive genes in PD is blurred, because the disease is likely multi-factorial, involving causative genes, susceptibility genes, environmental exposures that may have protective effects such as smoking and caffeine, and exposures that may induce neurodegeneration such as pesticides (Factor, 2007).

Klein et al (2007) stated that the association of 6 genes with monogenic forms of parkinsonism has unambiguously established that the disease has a genetic component.  Of these 6 genes, LRRK2, parkin, and PINK1 (PTEN-induced putative kinase 1, or PARK6) are the most clinically relevant because of their mutation frequency.  Insights from initial familial studies suggested that LRRK2-associated parkinsonism is dominantly inherited, whereas parkinsonism linked to parkin or PINK1 is recessive.  However, screening of patient cohorts has revealed that up to 70 % of people heterozygous for LRRK2 mutations are unaffected, and that more than 50 % of patients with mutations in parkin or PINK1 have only a single heterozygous mutation.  Deciphering the role of heterozygosity in parkinsonism is important for the development of guidelines for genetic testing, for the counselling of mutation carriers, and for the understanding of late-onset PD.  However, much more remains to be understood regarding the pathogenesis of PD before genetic testing can be considered definitive.

Commenting on the article by Beyer et al, Factor (2007) stated that "[b]ecause gene expression in this disease is so complex, most results will be inconclusive.  No published guidelines currently exist regarding how to test and counsel patients appropriately; the tests are costly; and the results, even if conclusive, would not change treatment for individual patients, although one hopes they soon might.  For these reasons, no good rationale yet exists for the genetic testing of PD patients".

Williams-Gray et al (2009) noted that in addition to the well-established association between apolipoprotein E (APOE) and AD, this gene has also been implicated in both susceptibility to, and dementia in, PD.  However studies to date have produced contradictory findings.  These investigators conducted a case-control study in a population of 528 PD patients and 512 healthy controls and found no significant difference in allele or genotype distribution of APOE between the 2 groups.  An updated meta-analysis showed a modest increase of APOE-epsilon2 carriers among PD patients compared to controls (p = 0.017, odds ratios [OR] = 1.16 [95 % confidence interval (CI): 1.03 to 1.31]).  A total of 107 patients were incident cases participating in a population-based epidemiological study.  Longitudinal follow-up of this cohort over a mean of 5.0 +/- 0.7 years from diagnosis revealed no significant impact of APOE-epsilon4 carrier status on risk of dementia or rate of cognitive decline.  An updated meta-analysis indicated an over-representation of APOE-epsilon4 carriers among PD dementia compared to non-dementia cases [OR 1.74 (1.36 to 2.23), p = 1 x 10(-4)], although small sample sizes, heterogeneity of OR and publication bias may have confounded this finding.  The authors concluded that these findings did not support previously reported associations between APOE genotype and susceptibility to, or cognitive decline in, PD.  An updated meta-analysis indicates any association with PD susceptibility is at most modest, an observation with important implications for further study of this issue.  They stated that large scale longitudinal studies would be best placed to further evaluate any impact of APOE genotype on cognitive decline in PD.

The findings by Williams-Gray et al (2009) are in agreement with those of Kurz et al (2009) who investigated the role of APOE alleles in PD and PD dementia.  These researchers determined APOE genotypes in a group of patients with PD (n = 95) and compared them with those of healthy control participants (n = 73).  Additionally, in 64 longitudinally followed patients with PD, the allele types were correlated to development and progression of dementia and to time from onset of PD to dementia using multi-variate and survival analyses.  The APOE e4e4 genotype was more common in patients with PD (7.4 %) than in healthy controls (1.4 %; p = 0.03).  No significant associations between the APOE genotype and development and progression of dementia or time to dementia were found.  The authors stated that more studies with larger PD samples are needed.

Riley and Chelimsky (2003) stated that formal laboratory testing of autonomic function is reported to distinguish between patients with PD and those with MSA, but such studies segregated patients according to clinical criteria that select those with autonomic dysfunction for the MSA category.  These researchers attempted to characterize the profiles of autonomic disturbances in patients in whom the diagnosis of PD or MSA used criteria other than autonomic dysfunction.  A total of 47 patients with parkinsonism and autonomic symptoms who had undergone autonomic laboratory testing were identified and their case records reviewed for non-autonomic features.  They were classified clinically into 3 diagnostic groups:

1. PD (n = 19),
2. MSA (n = 14), and
3. uncertain (n = 14).
 

The performance of the patients with PD was compared with that of the MSA patients on 5 autonomic tests:

1. R-R interval variations during deep breathing,
2. heart rate changes with the Valsalva maneuvre,
3. tilt table testing,
4. the sudomotor axon reflex test,and
5. thermoregulatory sweat testing.

None of the tests distinguished one group from the other with any statistical significance, alone or in combination.  Parkinson's disease and MSA patients showed similar patterns of autonomic dysfunction on formal testing of cardiac sympathetic and parasympathetic, vasomotor, and central and peripheral sudomotor functions.  The authors concluded that these findings supported the clinical observation that PD is often indistinguishable from MSA when it involves the autonomic nervous system.  The clinical combination of parkinsonism and dysautonomia is as likely to be caused by PD as by MSA.  Current clinical criteria for PD and MSA that direct patients with dysautonomia into the MSA group may be inappropriate.

Reimann et al (2010) stated that differential diagnosis of parkinsonian syndromes is a major challenge in movement disorders.  Dysautonomia is a common feature but may vary in clinical severity and onset.  These investigators attempted to find a pattern of autonomic abnormalities discriminative for patients with different parkinsonian syndromes.  The cross-sectional study included 38 patients with MSA, 32 patients with PSP, 26 patients with IPD, and 27 age-matched healthy controls.  Autonomic symptoms were evaluated by a standardized questionnaire.  The performance of patients and controls was compared on 5 autonomic function tests:

1. deep breathing,
2. Valsalva maneuvre,
3. tilt-table testing,
4. sympathetic skin response,
5. pupillography, as well as 24-hr ambulatory BP monitoring (ABPM).

Disease severity was significantly lower in IPD than PSP and MSA.  Except for pupillography, none of the laboratory autonomic tests distinguished one patient group from the other alone or in combination.  The same was observed on the questionnaire.  Receiver operating characteristic curve revealed discriminating performance of pupil diameter in darkness and nocturnal BP change.  The composite score of urogenital and vasomotor domains significantly distinguished MSA from IPD patients but not from PSP.  These findings supported the observation that even mild IPD is frequently indistinguishable from more severe MSA and PSP.  Thus, clinical combination of motor and non-motor symptoms does not exclusively point at MSA.  Pupillography, ABPM and the questionnaire may assist in delineating the 3 syndromes when applied in combination.

Although PD is primarily considered a movement disorder, the high prevalence of psychiatric complications suggests that it is more accurately conceptualized as a neuropsychiatric disease.  Depression, dementia, and psychosis are common manifestations of idiopathic PD; and are associated with excess disability, worse quality of life, poorer prognosis, as well as caregiver burden.  Rihmer and colleagues (2004) noted that depression is one of the most disabling symptoms of PD, with a prevalence of approximately 40 %.  Unfortunately, such depression is frequently unrecognized and untreated in patients with PD.  Papapetropoulos and Mash (2005) stated that psychotic symptoms are common in patients with PD, and occur in at least 20 % of medication-treated patients.  Benign visual hallucinations often appear earlier, while agitation, confusion, delirium, delusions, malignant hallucinations, and paranoid beliefs become more frequent with disease progression.  Nearly all anti-parkinsonian medications may produce psychotic symptoms.  Moreover, cognitive impairment, increased age, disease duration and severity, depression, as well as sleep disorders have been consistently identified as independent risk factors for their development.  Although the exact cause for the pathogenesis of psychosis in PD is not fully known, there is some evidence that links over-activity of the ventral dopaminergic pathway with the involvement of other neurotransmitter system imbalances as likely contributors.

Dementia occurs in up to 30 % of patients with PD.  Cognitive impairments involve attentional, executive, memory, and visuospatial dysfunctions (Lauterbach, 2005).  Furthermore, Levin and Katzen (2005) stated that early cognitive changes in PD patients are often subtle and influenced by factors that interact with the disease process, including medication, motor symptoms, and age of disease onset.  These factors notwithstanding, ample evidence exists that specific cognitive changes occur early in the course of PD.  The authors noted that this evidence does not imply that cognitive deficits are pervasive during the early stages. On the contrary, they are usually subtle and often difficult to detect without formal neuropsychological testing.  Executive-function deficits are the most frequently reported cognitive problems and, given that executive skills are an integral part of many tasks, it follows that subtle difficulties may be seen on a wide range of cognitive measures, especially in working memory as well as visuospatial dysfunction, two areas that rely heavily on executive skills.  Whereas apraxia and language processing deficits occur infrequently, subtle changes in olfaction and contrast sensitivity have also been repeatedly observed.

In the recent practice parameter on the evaluation and treatment of depression, psychosis, and dementia in PD (an evidence-based review) by the AAN, Miyasaki et al (2006) provided the following conclusions/recommendations:

• Tools such as the Beck Depression Inventory (BDI), the Hamilton Depression Rating Scale (HDRS-17), and the Montgomery Asberg Depression Rating Scale (MADRS) should be considered for screening depression associated with PD.
• Tools such as the Cambridge Cognitive Examination (CAMCog) and the Mini-Mental State Examination (MMSE) should be considered for screening dementia in patients with PD.
• There are no widely used, validated tools for psychosis screening in PD.

In a systematic review on transcranial duplex (TCD) scanning in the differential diagnosis of parkinsonian syndromes, Vlaar and colleagues (2009) concluded that before TCD scanning can be implicated, more research is needed to standardize the TCD technique, to investigate the TCD in non-research settings and to determine the additional value of TCD scanning compared with currently used clinical techniques.

Tokuda et al (2010) stated that to-date, there is no accepted clinical diagnostic test for PD that is based on biochemical analysis of blood or cerebrospinal fluid (CSF).  The discovery of mutations in the SNCA gene encoding α-synuclein in familial parkinsonism and the accumulation of α-synuclein in the PD brain suggested a critical role for this protein in PD etiology.  These researchers investigated total and α-synuclein oligomers levels in CSF from patients clinically diagnosed with PD, PSP, or AD, and age-matched controls, using ELISA.  The levels of α-synuclein oligomers and oligomers/total-α-synuclein ratio in CSF were higher in the PD group (n = 32; p < 0.0001, Mann-Whitney U test) compared to the control group (n = 28).  The area under the receiver operating characteristic curve (AUC) indicated a sensitivity of 75.0 % and a specificity of 87.5 %, with an AUC of 0.859 for increased CSF α-synuclein oligomers in clinically diagnosed PD cases.  However, when the CSF oligomers/total-α-synuclein ratio was analyzed, it provided an even greater sensitivity of 89.3 % and specificity of 90.6 %, with an AUC of 0.948.  In another cross-sectional pilot study, these researchers confirmed that the levels of CSF α-synuclein oligomers were higher in patients with PD (n = 25) compared to patients with PSP (n = 18; p < 0.05) or AD (n = 35; p < 0.001) or control subjects (n = 43; p < 0.05).  The authors concluded that these findings showed that levels of α-synuclein oligomers in CSF and the oligomers/total-α-synuclein ratio can be useful biomarkers for diagnosis and early detection of PD.  Moreover, the authors stated that large-scale, prospective, and well-controlled studies, especially those that include subjects with neuroimaging-supported definite PD and other synucleinopathies, as well as unrelated neurologic disorders, are necessary to validate the quantification of CSF α-synuclein oligomers as an urgently needed surrogate biomarker.  It will be critical to carry out prospective studies to examine if individuals who do not have PD, but have an elevated oligomer-to-total α-synuclein ratio in their CSF will be more prone to develop the disease in the future.

In an editorial that accompanied the afore-mentioned study, Ballard and Jones (2010) noted that there is emerging evidence that measurement of specific forms of α-synuclein in CSF may contribute to diagnosis and treatment development in PD and related disorders.  Moreover, they stated that further validation is still needed; it is too preliminary to put this forward as a diagnostic test for PD.

The policy on surgical treatment of PD is based primarily on evidence assessments by the AAN (Hallett et al, 1999), the National Institute for Clinical Excellence (NICE, 2004), the BlueCross BlueShield Association Technology Evaluation Center (BCBSA, 2001), and the Agency for Healthcare Research and Quality (AHRQ) (Levine et al, 2003).

Arle and colleagues (2008) stated that since the initial 1991 report by Tsubokawa et al, stimulation of the M1 region of the motor cortex has been used to treat chronic pain conditions and various movement disorders.  The authors reviewed the literature and found 459 cases in which motor cortex stimulation (MCS) was used.  Of these, 72 were related to a movement disorder.  More recently, up to 16 patients specifically with PD were treated with MCS, and a variety of results were reported.  In this report, the authors described 4 patients who were treated with extra-dural MCS.  Although there were benefits seen within the first 6 months in Unified Parkinson's Disease Rating Scale Part III scores (decreased by 60 %), tremor was only modestly managed with MCS in this group, and most benefits seen initially were lost by the end of 12 months.  The authors concluded that although there have been some positive findings using MCS for PD, a larger study may be needed to better determine if it should be pursued as an alternative surgical treatment to deep brain stimulation (DBS).

Martin and Teismann (2009) stated that PD is the second most common neuro-degenerative disease, affecting over a million people in the United States alone.  Its main neuro-pathological feature is the loss of dopaminergic neurons of the substantia nigra pars compacta.  However, the pathogenesis of this loss is not understood fully.  One of the earliest biochemical changes seen in PD is a reduction in the levels of total glutathione (GSH), a key cellular antioxidant.  Traditionally, it has been thought that this decrease in GSH levels is the consequence of increased oxidative stress, a process heavily implicated in PD pathogenesis.  However, emerging evidence suggests that GSH depletion may itself play an active role in PD pathogenesis.

Hauser and colleagues (2009) evaluated the safety, tolerability, and preliminary efficacy of intravenous GSH in PD patients.  This was a randomized, placebo-controlled, double-blind, pilot trial in subjects with PD whose motor symptoms were not adequately controlled with their current medication regimen.  Subjects were randomly assigned to receive intravenous GSH 1,400 mg or placebo administered 3 times a week for 4 weeks.  A total of 21 subjects were randomly assigned, 11 to GSH and 10 to placebo.  One subject who was assigned to GSH withdrew from the study for personal reasons prior to undergoing any post-randomization efficacy assessments.  Glutathione was well-tolerated and there were no withdrawals because of adverse events in either group.  Reported adverse events were similar in the 2 groups.  There were no significant differences in changes in Unified Parkinson's Disease Rating Scale (UPDRS) scores.  Over the 4 weeks of study medication administration, UPDRS ADL + motor scores improved by a mean of 2.8 units more in the GSH group (p = 0.32), and over the subsequent 8 weeks worsened by a mean of 3.5 units more in the GSH group (p = 0.54).  Glutathione was well-tolerated and no safety concerns were identified.  The authors stated that these preliminary efficacy data suggest the possibility of a mild symptomatic effect, but this remains to be evaluated in a larger study.

Sedlacková and associates (2009) examined the effects of one session of high-frequency repetitive transcranial magnetic stimulation (rTMS) applied over the left dorsal premotor cortex (PMd) and left dorsolateral prefrontal cortex (DLPFC) on choice reaction time in a noise-compatibility task, and cognitive functions in patients with PD.  Clinical motor symptoms of PD were assessed as well.  A total of 10 patients with PD entered a randomized, placebo-controlled study with a cross-over design.  Each patient received 10 Hz stimulation over the left PMd and DLPFC (active stimulation sites) and the occipital cortex (OCC; a control stimulation site) in the OFF motor state, i.e., at least after 12 hrs of dopaminergic drugs withdrawal.  Frameless stereotaxy was used to target the optimal position of the coil.  For the evaluation of reaction time, a noise-compatibility paradigm was used.  A short battery of neuropsychological tests was performed to evaluate executive functions, working memory, and psychomotor speed.  Clinical assessment included a clinical motor evaluation using part III of the UPDRS.  Statistical analysis revealed no significant effect of rTMS applied over the left PMd and/or DLPFC in patients with PD in any of the measured parameters.  In this study, these researchers did not observe any effect of 1 session of high frequency rTMS applied over the left PMd and/or DLPFC on choice reaction time in a noise-compatibility task, cognitive functions, or motor features in patients with PD; rTMS applied over all 3 stimulated areas was safe and well-tolerated in terms of the cognitive and motor effects.

In a double-blind, placebo-controlled study, Arias and co-workers (2010a) evaluated the effect of 10-day rTMS on sleep parameters in PD patients.  A total of 18 IPD patients completed the study.  Sleep parameters were evaluated through actigraphy and the Parkinson's Disease Sleep Scale (PDSS), along with depression (Hamilton Depression Rating Scale, HDS), and the UPDRS.  Evaluations were carried out before treatment with rTMS (pre-evaluation, PRE), after the rTMS treatment programme (post-evaluation, POST), and 1 week after POST (POST-2).  Nine PD patients received real rTMS and the other 9 received sham rTMS daily for 10 days, (100 pulses at 1Hz) applied with a large circular coil over the vertex.  Stimulation had no effect over actigraphic variables.  Conversely PDSS, HDS, and UPDRS were significantly improved by the stimulation.  Notably, however, these changes were found equally in groups receiving real or sham stimulation.  The authors concluded that rTMS, using these researchers' protocol, has no therapeutic value on the sleep of PD patients, when compared to appropriate sham controls.  They stated that future works assessing the possible therapeutic role of rTMS on sleep in PD should control the effect of placebo.

In a double-blind placebo-controlled trial, Arias et al (2010b) evaluated the effect of low-frequency rTMS on motor signs in PD.  Patients with PD were randomly assigned to received either real (n = 9) or sham (n = 9) rTMS for 10 days.  Each session comprises 2 trains of 50-stimuli each delivered at 1 Hz and at 90 % of daily rest motor threshold using a large circular coil over the vertex.  The effect of the stimulation, delivered during the ON-period, was evaluated during both ON and OFF periods.  Tests were carried out before and after the stimulation period, and again 1 week after.  The effect of the stimulation was evaluated through several gait variables (cadence, step amplitude, velocity, the CV(stride-time), and the turn time), hand dexterity, and also the total and motor sections of the UPDRS.  Only the total and motor section of the UPDRS and the turn time during gait were affected by the stimulation, the effect appearing during either ON or OFF evaluation, and most importantly, equally displayed in both real and sham group.  The rest of the variables were not influenced.  The authors concluded that the protocol of stimulation used, different from most protocols that apply larger amount of stimuli, but very similar to some previously reported to have excellent results, has no therapeutic value and should be abandoned.  This contrasts with the positive reported effects using higher frequency and focal coils.  These findings also reinforced the need for sham stimulation when evaluating the therapeutic effect of rTMS.

Filipović et al (2010) examined the effects of low-frequency rTMS on OFF-phase motor symptoms in patients with PD.  A total of 10 patients with PD had rTMS (1,800 stimuli at just below active motor threshold intensity) at 1Hz rate delivered over the motor cortex for 4 consecutive days on 2 separate occasions.  On 1 of these occasions, real rTMS was used and on the other sham rTMS (placebo) was used.  Evaluations with UPDRS Part 3 (Motor Scale) were done in practically defined OFF-phase at the baseline and 1 day after the end of each of the treatment series.  Neither total Motor Scale scores nor subscores for axial symptoms, rigidity, bradykinesia, and tremor showed any significant difference.  The results did not confirm presence of residual beneficial clinical after-effects of consecutive daily applications of low-frequency rTMS on motor symptoms in PD, at least when 1800 stimuli at sub-threshold intensity are applied for 4 days.

In a randomized, double-blind, sham-controlled study, Benninger et al (2011) examined the safety and effectiveness of intermittent theta-burst transcranial magnetic stimulation (iTBS), a novel type of rTMS, in the treatment of motor symptoms in PD. These researchers investigated safety and efficacy of iTBS of the motor and dorso-lateral prefrontal cortices in 8 sessions over 2 weeks (evidence Class I).  Assessment of safety and clinical efficacy over a 1-month period included timed tests of gait and bradykinesia, UPDRS, and additional clinical, neuropsychological, and neurophysiologic measures.  A total of 26 patients with mild-to-moderate PD were included in this study: 13 received iTBS and 13 sham stimulation.  These investigators found beneficial effects of iTBS on mood, but no improvement of gait, bradykinesia, UPDRS, and other measures.  EEG/EMG monitoring recorded no pathologic increase of cortical excitability or epileptic activity.  Few reported discomfort or pain and 1 experienced tinnitus during real stimulation.   The authors concluded that iTBS of the motor and prefrontal cortices appears safe and improves mood, but failed to improve motor performance and functional status in PD.  This study provided Class I evidence that iTBS was not effective for gait, upper extremity bradykinesia, or other motor symptoms in PD.

In a randomized, double-blind, sham-controlled study, Benninger and colleagues (2010) examined the effectiveness of transcranial direct current stimulation (tDCS) in the treatment of PD.  The effectiveness of anodal tDCS applied to the motor and pre-frontal cortices was investigated in 8 sessions over 2.5 weeks.  Assessment over a 3-month period included timed tests of gait (primary outcome measure) and bradykinesia in the upper extremities, UPDRS, Serial Reaction Time Task, Beck Depression Inventory, Health Survey and self-assessment of mobility.  A total of 25 PD patients were studied, 13 receiving tDCS and 12 sham stimulation.  Transcranial direct current stimulation improved gait by some measures for a short time and improved bradykinesia in both the ON and OFF states for longer than 3 months.  Changes in UPDRS, reaction time, physical and mental well being, and self-assessed mobility did not differ between the tDCS and sham interventions.  The authors concluded that tDCS of the motor and prefrontal cortices may have therapeutic potential in PD; but better stimulation parameters need to be established to make the technique clinically viable.  The findings of this preliminary study need to be validated by well-designed studies.

Klassen and colleagues  (2011) evaluated quantitative EEG (qEEG) measures as predictive biomarkers for the development of dementia in PD.  A cohort of subjects with PD in the authors' brain donation program utilizes annual pre-mortem longitudinal movement and cognitive evaluation.  These subjects also undergo biennial EEG recording.  EEG from subjects with PD without dementia with follow-up cognitive evaluation was analyzed for qEEG measures of background rhythm frequency and relative power in δ, α, and β bands.  The relationship between the time to onset of dementia and qEEG and other possible predictors was assessed by using Cox regression.  The hazard of developing dementia was 13 times higher for those with low background rhythm frequency (lower than the grand median of 8.5 Hz) than for those with high background rhythm frequency (p < 0.001).  Hazard ratios (HRs) were also significant for greater than median bandpower (HR = 3.0; p = 0.004) compared to below, and for certain neuropsychological measures.  The HRs for δ, α, and β bandpower as well as baseline demographic and clinical characteristics were not significant.  The authors concluded that qEEG measures of background rhythm frequency and relative power in the band are potential predictive biomarkers for dementia incidence in PD.  These qEEG biomarkers may be useful in complementing neuropsychological testing for studying PD-D incidence.

In a randomized clinical trial, Espay and colleagues (2011) evaluated the effectiveness of methylphenidate (MPD) for the treatment of gait impairment in PD.  A total of 27 subjects with PD and moderate gait impairment were screened for this 6-month placebo-controlled, double-blind study.  Subjects were randomly assigned to MPD (maximum, up to 80 mg/day) or placebo for 12 weeks and crossed-over after a 3-week washout.  The primary outcome measure was change in a gait composite score (stride length + velocity) between groups at 4 and 12 weeks.  Secondary outcome measures included changes in motor function, as measured by the UPDRS, Freezing of Gait Questionnaire (FOGQ), number of gait-diary freezing episodes, and measures of depression, sleepiness, and quality of life.  Three-factor repeated-measures analysis of variance was used to measure changes between groups.  Twenty-three eligible subjects with PD were randomized and 17 completed the trial.  There was no change in the gait composite score or treatment or time effect for any of the variables.  Treatment effect was not modified by state or study visit.  Although there was a trend for reduced frequency of freezing and shuffling per diary, the FOGQ and UPDRS scores worsened in the MPD group compared to placebo.  There was a marginal improvement in some measures of depression.  The authors concluded that MPD did not improve gait and tended to worsen measures of motor function, sleepiness, and quality of life.

The National Institute for Health and Clinical Excellence's clinical practice guideline on "Parkinson's disease: Diagnosis and management in primary and secondary care" (NICE, 2006) stated that "123I-FP-CIT SPECT should be considered for people with tremor where essential tremor can not be clinically differentiated from parkinsonism".  Furthermore, the Scottish Intercollegiate Guidelines Network's clinical practice guideline on "Diagnosis and pharmacological management of Parkinson's disease" (SIGN, 2010) stated that "Single photon emission computed tomography (SPECT) with (123I-labeled N-omega-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)tropane (123I-FP-CIT SPECT scanning) should be considered as an aid to clinical diagnosis in patients where there is uncertainty between Parkinson's disease and non-degenerative parkinsonism/tremor disorders.  Routine use of functional imaging is not recommended for the differential diagnosis of Parkinson's disease and Parkinson's plus disorders such as progressive supranuclear palsy and multiple system atrophy".

Also, an UpToDate review on "Diagnosis of Parkinson disease" (Chou, 2012) states that "Positron emission tomography (PET) and single photon emission computed tomography (SPECT) may be helpful for the early diagnosis of PD.  With PET, decreased tracer uptake is seen in the mid- and posterior putamen of patients with early PD when compared with controls.  Striatal dopamine transporter imaging using SPECT (e.g., 123I-FP-CIT SPECT scan or DaTscan) can reliably distinguish patients with PD and other parkinsonian syndromes from controls or patients with essential tremor, but it can not differentiate PD and the parkinsonian syndromes from one another".

Fink et al (2000) stated that the observation that fetal neurons are able to survive and function when transplanted into the adult brain fostered the development of cellular therapy as a promising approach to achieve neuronal replacement for treatment of diseases of the adult central nervous system.  This approach has been demonstrated to be effective in patients with PD after transplantation of human fetal neurons.  The use of human fetal tissue is limited by ethical, infectious, regulatory, and practical concerns.  Other mammalian fetal neural tissue could serve as an alternative cell source.  Pigs are a reasonable source of fetal neuronal tissue because of their brain size, large litters, and the extensive experience in rearing them in captivity under controlled conditions.  In phase I studies, porcine fetal neural cells grafted unilaterally into PD and Huntington's disease patients were being evaluated for safety and effectiveness.  Clinical improvement of 19 % has been observed in the Unified Parkinson's Disease Rating Scale "off" state scores in 10 PD patients assessed 12 months after unilateral striatal transplantation of 12 million fetal porcine ventral mesencephalic (VM) cells.  Several patients have improved more than 30 %.  In a single autopsied PD patient some porcine fetal VM cells were observed to survive 7 months after transplantation.  Twelve Huntington's disease patients have shown a favorable safety profile and no change in total functional capacity score 1 year after unilateral striatal placement of up to 24 million fetal porcine striatal cells.  Xenotransplantation of fetal porcine neurons is a promising approach to delivery of healthy neurons to the central nervous system.  The major challenges to the successful use of xenogeneic fetal neuronal cells in neurodegenerative diseases appear to be minimizing immune-mediated rejection, management of the risk of xenotic (cross-species) infections, and the accurate assessment of clinical outcome of diseases that are slowly progressive.

Cederfjall et al (2012) noted that it has been suggested that the beneficial effect of L-DOPA could be re-established by changing the mode of administration.  Indeed, continuous delivery of L-dopa has been shown to be an effective way to circumvent many of the side effects seen with traditional oral administration, which results in an intermittent supply of the dopamine precursor to the brain.  However, all currently tested continuous dopaminergic stimulation approaches rely on peripheral administration.  This is not ideal since it gives rise to off-target effects and is difficult to maintain long-term.  Thus, there is an unmet need for an effective continuous administration method with an acceptable side effect profile.  Viral-mediated gene therapy is a promising alternative paradigm that can meet this demand.  Encouraging pre-clinical studies in animal models of PD showed therapeutic effectiveness after expression of the genes encoding the enzymes required for biosynthesis of dopamine.  Although phase I clinical trials using these approaches have been conducted, clear positive data in placebo-controlled efficacy studies are still lacking.  The authors stated that "We are now at a critical junction and need to carefully review the preclinical data from the clinical translation perspective and identify the key factors that will determine the potential for success in gene therapy for Parkinson's disease".

Besong-Agbo et al (2013) stated that biomarkers are needed for the diagnosis and monitoring of disease progression in PD.  To date, most studies have concentrated on α-synuclein (α-Syn), a protein involved in PD pathogenesis, as a potential biomarker, with inconsistent outcomes.  Recently, naturally occurring autoantibodies against α-Syn (α-Syn-nAbs) have been detected in the serum of patients with PD.  They represent a putative diagnostic marker for PD.  These researchers established and validated an ELISA to quantify α-Syn-nAbs in serum samples.  They analyzed serum samples from 62 patients with PD, 46 healthy controls (HC), and 42 patients with Alzheimer disease (AD) using this newly established ELISA.  Additionally, serum levels of endogenous α-Syn were measured.  There was a significant difference in α-Syn-nAbs levels between the investigated groups (p = 0.005; Kruskal-Wallis test).  Levels of α-Syn-nAbs were significantly lower in patients with PD compared to HC (p < 0.05; Dunn multiple comparison post-hoc test) or patients with AD (p < 0.05).  Furthermore, these investigators detected no difference between patients with AD and HC.  The sensitivity and specificity of the assay for patients with PD versus HC were 85 % and 25 %, respectively.  The α-Syn-nAbs levels did not correlate with age, Hoehn and Yahr status, or duration of disease.  Endogenous α-Syn had no influence on α-Syn-nAbs levels in sera.  The authors concluded that using a well-validated assay, they detected reduced α-Syn-nAbs levels in patients with PD compared to patients with AD and HC.  The assay did not achieve criteria for use as a diagnostic tool to reliably distinguish PD from HC.  They stated that appropriately powered and independent investigations with validated assays are needed to further evaluate the utility of α-Syn-nAbs as a biomarker in PD.

In an editorial that accompanied the afore-mentioned study, Sharma (2013) stated that "While these data do not change the way in which patients with PD are diagnosed or treated, they do illustrate the utility of performing genetic studies in relatively ethnically homogeneous cohorts that have undergone careful clinical characterization …. The finding that a specific mutation in the SMPD1 enzyme is associated with an increased risk of PD gives further support to the hypothesis that defects in the ALP [autophagy-lysosomal pathway] play a role in the pathogenesis of PD and identifies another cellular pathway as a target for drug development".

Wang and Wang (2014) stated that the glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) genes have been studied extensively as potential candidate genes for the risk of PD; however, direct evidence from genetic association studies remains inconclusive.  These researchers performed an updated and refined meta-analysis to determine the effect of GSTM1 and GSTT1 polymorphisms on PD.  A fixed-effect model was utilized to calculate the combined OR, OR of different ethnicities, and 95 % CIs.  Potential publication bias was estimated.  Homogeneity of the included studies was also evaluated.  The pooled OR was 1.13 [95 % CI: 1.03 to 1.24)] and 0.96 [95 % CI: 0.82 to 1.12)] for GSTM1 and GSTT1 polymorphisms, respectively.  Analysis according to different races found no association between GSTM1/GSTT1 polymorphisms and PD risks except for GSTM1 variant in Caucasians, which showed a weak correlation (OR 1.16 [95 % CI: 1.04 to 1.29), I squared = 6.2 %, p = 0.384]).  Neither publication bias nor heterogeneity was found among the included studies.  The authors concluded that the results of this meta-analysis suggested that GSTM1 polymorphism is weakly associated with the risk of PD in Caucasians whereas GSTT1 polymorphism is not a PD risk factor.

Jin and colleagues (2014) noted that several studies have been conducted in recent years to evaluate the risk of PD and polymorphisms of interleukin -10 (IL-10); however, the results were conflicting.  These researchers performed a meta-analysis of published case-control studies to assess this association.  Systematic searches of electronic databases PubMed Web of Science, BIOSIS Previews, Science Direct, Chinese Biomedical Database, WANFANG Database, and Chinese National Knowledge Infrastructure with hand-searching of the references of identified articles were conducted.  Data were extracted using a standardized form and pooled ORs with 95 % CIs were calculated to evaluate the strength of the association.  A total of 7 case-control studies involving 1,912 PD cases and 1,740 controls were included, concerning 2 polymorphisms (-1082A/G and -592C/A) of IL-10 gene.  No significant associations were found in the overall analysis for both -1082A/G and -592C/A polymorphisms with PD risk.  Similar lacking associations were observed in subgroup analysis based on ethnicity and age of onset.  The authors concluded that there is inadequate evidence for association between IL-10 polymorphisms (-1082A/G and -592C/A) and risk of PD at present.  Moreover, they stated that well-designed studies with larger sample-size and multi-ethnicity studies are needed in the future.

Mondello et al (2014) stated that α-synuclein, linked to the pathogenesis of PD, is a promising biomarker candidate in need of further investigation.  The ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a pivotal component of the ubiquitin proteasome system that seems to be disturbed in PD, may also be involved in the pathogenesis of this disorder.  These researchers investigated CSF α-synuclein and UCH-L1 levels from 22 healthy controls, 52 patients with PD, 34 with MSA, 32 with PSP, and 12 with CBD.  Cerebrospinal fluid α-Synuclein levels were significantly decreased in PD and in MSA compared with controls, and in synucleinopathies compared with tauopathies; UCH-L1 levels were significantly decreased in PD, MSA as well as PSP compared with controls, and in PD compared with APD (p < 0.001).  Both markers discriminated PD well from controls (p < 0.0001; AUC = 0.82 and 0.89, respectively).  Additionally, CSF α-synuclein separated patients with synucleinopathies from those with tauopathies (p = 0.015; AUC = 0.63), whereas CSF UCH-L1 discriminated between PD and APD (p = 0.0003; AUC = 0.69).  Interestingly, α-synuclein and UCH-L1 levels were strongly correlated in PD and synucleinopathies, and weakly in tauopathies.  No correlation was found in controls.  The authors concluded that CSF levels of α-synuclein and UCH-L1 showed distinct patterns in parkinsonian syndromes.  Their combined determination may be useful in the differential diagnosis of parkinsonian disorders and provided key to understanding their pathoetiology and clinical course.  Moreover, they stated that further large studies are needed to validate these findings.

Beach and colleagues (2013) stated that the clinical diagnosis of PD is incorrect in 30 % or more of subjects particularly at the time of symptom onset.  Because Lewy-type α-synucleinopathy (LTS) is present in the submandibular glands of PD patients, these researchers assessed the feasibility of submandibular gland biopsy for diagnosing PD.  They performed immunohistochemical staining for LTS in sections of large segments (simulating open biopsy) and needle cores of submandibular glands from 128 autopsied and neuropathologically classified subjects, including 28 PD, 5 incidental Lewy body disease, 5 PSP (3 with concurrent PD), 3 CBD, 2 MSA, 22 AD with Lewy bodies, 16 AD without Lewy bodies, and 50 normal elderly.  Immunoreactive nerve fibers were present in large submandibular gland sections of all 28 PD subjects (including 3 that also had PSP); 3 AD with Lewy bodies subjects were also positive, but none of the other subjects was positive.  Cores from frozen submandibular glands taken with 18-gauge needles (total length, 15 to 38 mm; between 10 and 118 sections per subject examined) were positive for LTS in 17 of 19 PD patients.  The authors concluded that these results suggested that biopsy of the submandibular gland may be a feasible means of improving PD clinical diagnostic accuracy.

Folgoas et al (2013) evaluated the diagnostic performance of minor salivary gland biopsy for PD.  Minor salivary glands were examined for Lewy pathology using phosphorylated alpha-synuclein antibody in 16 patients with clinically diagnosed PD and 11 control subjects with other neurological disorders.  Abnormal accumulation of alpha-synuclein was found in 3 out of 16 PD patients.  Two control subjects exhibited weak phosphorylated alpha-synuclein immunoreactivity.  The authors concluded that these  results did not support the use of minor salivary glands biopsy for the detection of Lewy pathology in living subjects.

Adler et al (2014) examined salivary gland biopsies in living patients with PD.  Patients with PD for greater than or equal to 5 years underwent outpatient transcutaneous needle core biopsies (18-gauge or 16-gauge) of 1 submandibular gland.  Minor salivary glands were removed via a small incision in the lower lip.  Tissue was fixed in formalin and serial 6-µm paraffin sections were immunohistochemically stained for phosphorylated α-synuclein and reviewed for evidence of LTS.  A total of 15 patients with PD were biopsied: 9 females/6 males, mean age of 68.7 years, mean PD duration of 11.8 years.  Twelve of the needle core biopsies had microscopically evident submandibular gland tissue to assess and 9/12 (75 %) had LTS.  Only 1/15 (6.7 %) minor salivary gland biopsies were positive for LTS; 5 patients had an adverse event; all were minor and transient.  The authors concluded that this study demonstrated the feasibility of performing needle core biopsies of the submandibular gland in living patients with PD to assess LTS.  Moreover, they stated that although this was a small study, this tissue biopsy method may be important for tissue confirmation of PD in patients being considered for invasive procedures and in research studies of other PD biomarkers.  One major drawback of this study was the lack of control subjects.  Also, this study did not include patients with other parkinsonian disorders, so determination of the specificity for LTS in submandibular gland biopsies for PD will require further study.  The authors stated that future studies should include patients with early-stage PD, control subjects, subjects with other parkinsonian disorders, and when possible, longitudinal studies extended to autopsy with neuropathologic confirmation of PD.

Alpha-Synuclein Immunotherapy for the Treatment of Parkinson's Disease

Hu et al (2022) stated that there is no consensus on the effectiveness of using alpha-synuclein as the primary immunotherapy for the treatment of PD.  In a systematic review and meta-analysis, these investigators examined the safety and effectiveness of α-synuclein immunotherapy for treating patients with PD.  The databases of CNKI, CBM, Cochrane Library, PubMed, Web of Science, and Embase were searched for RCTs.  Cochrane Collaboration's bias assessment tool was employed to evaluate the risk of bias in the included articles, and the included PD patients older than 18 years adopted immunotherapy.  Stata 15.0 was employed for statistical analysis.  A total of 6 RCTs were included in the present study, entailing 606 immunotherapy recipients (using alpha-synuclein immunotherapy) and 254 control individuals (placebo).  The meta-analysis found no statistical difference in the MDS-UPDRS total score [WMD: -0.72, 95 % CI: -1.56 to 0.13, p =0.099], AE incidence [relative risk (RR): 1.06, 95 % CI: 0.98 to 1.15, p = 0.150], headache incidence (RR: 0.95, 95 % CI: 0.67 to 1.34, p = 0.773), and constipation incidence (RR: 1.47, 95 % CI: 0.77 to 2.78, p = 0.242).  However, the infection rate in the immunotherapy group was higher than in the control group (RR: 2.29, 95 % CI: 1.40 to 3.74, p = 0.003).  These findings indicated that immunotherapy was significantly different from placebo in MDS-UPDRS and AE incidence, but it could reduce the incidence of infection rate.  The authors concluded that existing results showed that alpha-synuclein immunotherapy had no significant effect on PD.  These researchers stated that high-quality, large-scale, multi-center studies are needed to corroborate these findings.

Brain SPECT for Monitoring the Progression of Parkinson’s Disease

Jeong and colleagues (2018) stated that levodopa-induced dyskinesia (LID) is a major complication of dopamine replacement drug usage in PD patients.  Since the mechanism of LID is yet unclear, these researchers analyzed serial [I-123] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (I-123 FP-CIT) SPECT images.  They examined the changes of dopaminergic innervation during the progression of PD in relation to the development of LID.  Data were obtained from the Parkinson's Progression Markers Initiative (PPMI) database.  A total of 290 PD dopamine replacement drug-naïve patients (age of 61.0 ± 9.7 years, M: F = 195: 95) were enrolled.  I-123 FP-CIT SPECT images from baseline, 12, 24, and 48 months were analyzed among with clinical factors.  Specific binding ratios (SBRs) of the striatal regions from I-123 FP-CIT SPECT images were analyzed.  These investigators used independent tests and logistic regression for analysis of LID risk association.  Among 290 patients, 36 patients developed LID after 48 months follow-up.  Baseline Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and III scores were significantly higher in the PD patients with LID, compared with the PD patients without LID.  Striatal SBRs were significantly lower in the PD patients with LID at baseline, 24 and 48 months (p < 0.001).  Multi-variate analysis revealed MDS-UPDRS Part II and putaminal SBRs at baseline and 24 months to be significantly associated with the development of LID (p < 0.001).  Furthermore, patients who developed LID at 48 months had a higher decrease rate of putaminal SBR at the 24 months (p < 0.05), and 48 months (p < 0.01) period.  The authors concluded that in this study, they demonstrated the serial changes of the nigrostriatal dopaminergic innervation in relationship to LID development for the first time.  The deterioration rate of dopaminergic innervation was significantly higher in the PD patients who developed LID, compared with the PD patients who did not develop LID.  These researchers stated that serial follow-up I-123 FP-CIT SPECT acquisition during the course of PD could be helpful in predicting the development of LID.

The authors stated that this study had  several drawbacks.  First, this study did not include the FP-CIT SPECT images of healthy controls, since the PPMI data did not provide follow-up FP-CIT SPECT images nor clinical data of healthy controls.  It remains to be seen whether the striatal neuronal loss in PD patients progress in a higher rate compared with those of age- and sex-matched healthy controls, and whether these researchers could exclude the effect of normal aging process.  Second, the PPMI data were collected from multiple institutions, and could have variations in the FP-CIT SPECT image acquisition.  In order to maintain a uniformly acquired imaging dataset, quality assurance procedures were performed.  Third, all 3 follow-up FP-CIT SPECT images were acquired in 215 patients out of 290 patients.  In 75 patients, only 2 follow-up FP-CIT SPECT images were acquired.  Finally, although these investigators have focused on the pre-synaptic hypothesis for LID development, this does not undermine the post-synaptic hypothesis.  They stated that further studies focusing on the post-synaptic striatal signal transduction are needed.

Djaldetti and co-workers (2018) stated that the role of nuclear imaging in predicting PD progression is unclear.  These investigators examined if the degree of reduced striatal DAT binding at diagnosis of PD predicts later motor complications and time to disease progression.  They retrospectively studied 41 patients with early PD who underwent 123I-FP-CIT SPECT and were followed thereafter with a mean disease duration of 9.51 ± 3.18 years.  The association of quantitatively analyzed 123I-FP-CIT binding in striatal sub-regions with the development of motor fluctuations, dyskinesia, freezing of gait (FOG), and falls as well as the time to Hoehn and Yahr (H&Y) stage 3 was evaluated.  Logistic regression models controlling for age at diagnosis, sex, disease duration, and L-dopa dose revealed that 123I-FP-CIT binding in the putamen and striatum significantly predicted FOG (OR = 0.02, p = 0.03; OR = 0.01, p = 0.04; respectively); but not falls.  Cox proportional hazard analysis did not reveal significant relationship between 123I-FP-CIT binding and motor fluctuations, dyskinesia, or H&Y stage 3.  The authors concluded that these findings suggested that a more severe depletion of pre-synaptic dopamine in early PD is a bad prognostic sign in terms of FOG development.  They stated that these findings, if replicated, may point to dopaminergic transmission as part of the mechanism underlying FOG in PD.

In a retrospective, cohort study, Kim and colleagues (2018) examined if the degree of pre-synaptic striatal dopamine depletion could predict the later development of FOG in PD.  This trial  included 390 de-novo patients with PD without FOG at baseline.  Subjects were divided into tertiles according to the baseline DAT uptake of each striatal sub-region, and the cumulative risk of FOG was compared using the Kaplan-Meier method.  Cox proportional hazard models were used to assess the predictive power of DAT uptake of striatal sub-regions for the development of FOG.  During a median follow-up period of 4.0 years, 143 patients with PD (36.7 %) developed FOG.  The severe reduction group of DAT uptake in the caudate nucleus and putamen had a significantly higher incidence of FOG than that of the mild and moderate reduction groups.  Multi-variate Cox regression analyses showed that DAT uptakes in the caudate nucleus (HR 0.551; 95 % CI: 0.392 to 0.773; p = 0.001) and putamen (HR 0.441; 95 % CI: 0.214 to 0.911; p = 0.027) predicted the development of FOG.  In addition, male sex, higher postural instability and gait difficulty score, and a lower Montreal Cognitive Assessment score were also significant predictors of FOG.  The authors concluded that these findings suggested that pre-synaptic striatal dopaminergic denervation predicted the later development of FOG in de-novo patients with PD, which may provide reliable insight into the mechanism of FOG in terms of nigrostriatal involvement.

Kuo and associates (2019) noted that quantitative assessment of DAT imaging can aid in diagnosing PD and assessing disease progression in the context of therapeutic trials.  Previously, the software program SBRquant was applied to 123I-ioflupane SPECT images acquired on healthy controls and subjects with PD.  Earlier work on optimization of the parameters for differentiating between controls and subjects with dopaminergic deficits was extended for maximizing change measurements associated with disease progression on longitudinally acquired scans.  Serial 123I-ioflupane SPECT imaging for 51 subjects with PD (conducted approximately 1 year apart) were down-loaded from the PPMI database.  The software program SBRquant calculated the SBR separately for the left and right caudate and putamen regions of interest (ROI).  Parameters were varied to evaluate the number of summed transverse slices and the positioning of the striatal ROIs for determining signal-to-noise associated with their annual rate of change in SBR.  The parameters yielding the largest change of the lowest putamen's SBR from scan 1 to scan 2 were determined.  For the change from scan 1 to scan 2 in the 51 subjects, the largest annual change was observed when the putamen ROI was placed 3 pixels away from the caudate and by summing 5 central striatal slices.  This resulted in an 11.2 ± 4.3 % annual decrease in the lowest putamen's SBR for the group.  The authors concluded that quantitative assessment of DAT imaging for assessing progression of PD requires specific, optimal parameters different than those for diagnostic accuracy.

Furthermore, UpToDate reviews on "Clinical manifestations of Parkinson disease" (Chou, 2018) and "Cognitive impairment and dementia in Parkinson disease" (Rodnitzky, 2018) do not mention SPECT scanning as a management tool.

Bright Light Therapy for the Treatment of Depression in Parkinson Disease

In a double-blind RCT, Rutten and colleagues (2019) examined the efficacy of bright light therapy (BLT) in reducing depressive symptoms in patients with PD and major depressive disorder (MDD) compared to a control light.  Patients with PD and MDD were randomized to receive treatment with BLT (± 10,000 lux) or a control light (± 200 lux); they were treated for 3 months, followed by a 6-month naturalistic follow-up.  The primary outcome of the study was the HDRS score.  Secondary outcomes were objective and subjective sleep measures and salivary melatonin and cortisol concentrations.  Assessments were repeated halfway, at the end of treatment, and 1, 3, and 6 months after treatment.  Data were analyzed with a linear mixed-model analysis.  These researchers enrolled 83 subjects; HDRS scores decreased in both groups without a significant between-group difference at the end of treatment.  Subjective sleep quality improved in both groups, with a larger improvement in the BLT group (B [SE] = 0.32 [0.16], p = 0.04).  Total salivary cortisol secretion decreased in the BLT group, while it increased in the control group (B [SE] = -8.11 [3.93], p = 0.04).  The authors concluded that BLT was not more effective in reducing depressive symptoms than a control light.  Mood and subjective sleep improved in both groups; BLT was more effective in improving subjective sleep quality than control light, possibly through a BLT-induced decrease in cortisol levels.  This study provided Class I evidence that BLT was not superior to a control light device in reducing depressive symptoms in patients with PD with MDD.

In an editorial that accompanied the afore-mentioned study, Videnovic and Messinis (2019) stated that "This trial represents an important contribution to a growing body of literature centered on chrono-therapeutics of PD.  While reported effects of LT on depressive symptoms in PD are encouraging, further studies are needed to better define the role of LT in the management of PD".

Cannabinoids for the Treatment of Parkinson's Disease

Urbi et al (2022) noted that cannabis has been proposed as a potential treatment for PD due to its neuroprotective benefits; however, there has been no rigorous review of pre-clinical studies to examine any potential treatment effect.  In a systematic review, these investigators examined available evidence in support or against a treatment effect of cannabinoids in animal models of PD.  Databases were searched for any controlled comparative studies that examined the effects of any cannabinoid, cannabinoid-based treatment or endocannabinoid transport blocker on behavioral symptoms in PD animal models.  A total of 41 studies were identified to have met the criteria for this review; 14 of these studies were included in meta-analyses of rotarod, pole and open-field tests.  Meta-analysis of rotarod tests showed a weighted mean difference (WMD) of 31.63 s for cannabinoid-treated group compared with control.  Meta-analysis of pole tests also showed a positive treatment effect, evidenced by a WMD of -1.51 s for cannabinoid treat group compared with control.  However, meta-analysis of open-field test demonstrated a SMD of only 0.36 indicating no benefit.  The authors concluded that this systematic review showed cannabinoid treatment effects in alleviating motor symptoms of PD animal models and supported the conduct of clinical trials of cannabis in PD population.  However, there is no guarantee of successful clinical translation of this outcome because of the many variables that might have affected the results, such as the prevalent unclear and high risk of bias, the different study methods, PD animal models and cannabinoids used.

Carbidopa and Levodopa Enteral Suspension (Duopa)

U.S. Food and Drug Administration (FDA)-Approved Indications

• Duopa is indicated for the treatment of motor fluctuations in patients with advanced Parkinson’s disease.

Carbidopa and levodopa enteral suspension is available as Duopa (AbbVie, Inc.). In individuals with Parkinson’s disease (PD), a loss of dopaminergic cells in the midbrain results in abnormal nerve functioning, which in turn leads to a reduced ability or loss of ability to control body movements. The combination product of carbidopa and levodopa is the most effective agent for controlling the symptoms of Parkinson’s disease. Levodopa, the precursor to dopamine, crosses the blood brain barrier while dopamine itself cannot. Levodopa is given concomitantly with carbidopa, as carpidopa inhibits the peripheral metabolism of levodopa, thus allowing a higher percentage of levodopa to cross the blood brain barrier for central nervous system effect, this also limits adverse effects. Oral carbidopa and levodopa becomes progressively less effective as the disease progresses. Motor complications occur in 80% of young patients and 44% of older patients after 5 years of oral levodopa therapy.  

Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. The goal of PD management is to improve motor and nonmotor symptoms so that patients obtain the best function for their stage of disease.

Duopa (levodopa‐carbidopa enteral suspension), FDA-approved for treatment of motor functions in advanced PD, provides continuous daily 16‐hour delivery of levodopa directly into the jejunum through a percutaneous endoscopic gastrostomy with jejunal tube (PEG‐J) with the CADD‐Legacy 1400 portable infusion pump in order to reduce the amount of motor fluctuations that patients with advanced PD currently taking oral carbidopa/levodopa are experiencing.

Duopa is administered over a 16‐hour infusion period through either a naso‐jejunal tube for short‐term administration (i.e. temporary administration of Duopa prior to PEG‐J tube placement to observe patient’ clinical response) or through a PEG‐J for long‐term administration. Each cassette is for single‐use only and should not be used for longer than 16 hours, even if some drug remains. The daily dose is determined by individualized patient titration and composed of a morning dose, a continuous dose and an extra dose.

Duopa is contraindicated in patients who are currently taking a nonselective monoamine oxidase (MAO) inhibitor (e.g., phenelzine and tranylcypromine) or have recently (within 2 weeks) taken a nonselective MAO inhibitor. Hypertension can occur if these drugs are used concurrently (AbbVie, 2020).

Most common adverse reactions (at least 7% greater than oral carbidopa-levodopa incidence) were complication of device insertion, nausea, depression, peripheral edema, hypertension, upper respiratory tract infection, oropharyngeal pain, atelectasis, and incision site erythema (AbbVie, 2020).

Orthostatic systolic hypotension (≥30 mm Hg decrease) occurred in 73% of Duopa treated patients compared to 68% of patients treated with oral immediate‐release carbidopa levodopa in the controlled clinical study.

There is an increased risk for hallucinations and psychosis while taking Duopa. In addition, patients may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications.

Monitoring for the development of depression and concomitant suicidal tendencies is recommended.

Duopa may cause or exacerbate dyskinesia. In addition, patients should have clinical assessments for the signs and symptoms of peripheral neuropathy before starting Duopa. Monitoring patients periodically for signs of neuropathy is recommended. Because Duopa is administered using a PEG‐J, gastrointestinal complications can occur. These complications include bezoar, ileus, implant site erosion/ulcer, intestinal hemorrhage, intestinal ischemia, intestinal obstruction, intestinal perforation, pancreatitis, peritonitis, pneumo‐peritoneum, and post‐operative wound infection. These complications may result in serious outcomes, such as the need for surgery or death. Gastrointestinal hemorrhage may occur in patients with a history of peptic ulcer.

Melanoma has been reported with a higher risk in patients with Parkinson’s disease, thus, close monitoring is recommended.

Duopa (carbidopa and levodopa enteral suspension) has been shown to be an effective and safe therapy compared with oral immediate release of carbidopa and levodopa tablet, but it would likely be reserved for patients with persistent, severe, on‐off fluctuations who are not candidates for deep brain stimulation (DBS).

In clinical trials, Duopa significantly reduced daily mean off time at 12 weeks by 4 hours, which resulted in an average of 1.9 fewer hours of off time compared with carbidopa‐levodopa IR tablets. Treatment with Duopa was also associated with an improved mean on time without dyskinesia by 4 hours at 12 weeks, which resulted in an average of 1.9 more hours of on time compared with carbidopa‐levodopa IR tablets.

Additionally, the mean score increase in "n" time by 1.9 hours without dyskinesia from baseline to Week 12 was statistically significant greater (p=0.0059) for Duopa than for oral immediate‐release carbidopa and levodopa. In a long‐term follow‐up study, initiation of Duopa required an average of 11‐day of hospitalization stay. The first 3 days involved placement of a nasogastric tube and dose adjustments to reach maximal motor performance without relevant dyskinesia. Then the J‐tube was placed and Duopa was converted to the J‐tube infusion. The study results showed reduction of motor fluctuations and dyskinesias along with improved quality of life. Adverse reactions are similar to oral carbidopa and levodopa (i.e. hallucinations and dyskinesias). There are few complications associated with the J‐tube such as surgical placement complications, infections, perforation, tube kinking, dislocating as well as pump programming malfunction.

Olanow et al (2014) assessed the efficacy and safety of levodopa-carbidopa intestinal gel delivered continuously through an intrajejunal percutaneous tube. In a 12-week, randomized, double-blind, double-dummy, double-titration trial, investigators enrolled adults (aged ≥ 30 years) with advanced Parkinson's disease and motor complications at 26 centers in Germany, New Zealand, and the United States. Eligible participants had jejunal placement of a percutaneous gastrojejunostomy tube and were then randomly allocated (1:1) to treatment with immediate-release oral levodopa-carbidopa plus placebo intestinal gel infusion or levodopa-carbidopa intestinal gel infusion plus oral placebo. Randomization was stratified by site, with a mixed block size of 2 or 4. The primary endpoint was change from baseline to final visit in motor off-time. Investigators assessed change in motor on-time without troublesome dyskinesia as a prespecified key secondary outcome. They assessed efficacy in a full-analysis set of participants with data for baseline and at least one post-baseline assessment, and imputed missing data with the last observation carried forward approach. They assessed safety in randomly allocated patients who underwent the percutaneous gastrojejunostomy procedure. From baseline to 12 weeks in the full-analysis set, mean off-time decreased by 4.04 h (SE 0.65) for 35 patients allocated to the levodopa-carbidopa intestinal gel group compared with a decrease of 2.14 h (0.66) for 31 patients allocated to immediate-release oral levodopa-carbidopa (difference -1.91 h [95% CI -3.05 to -0.76]; p=0.0015). Mean on-time without troublesome dyskinesia increased by 4.11 h (SE 0.75) in the intestinal gel group and 2.24 h (0.76) in the immediate-release oral group (difference 1.86 [95% CI 0.56 to 3.17]; p=0.0059). In the safety analyses 35 (95%) of 37 patients allocated to the levodopa-carbidopa intestinal gel group had adverse events (five [14%] serious), as did 34 (100%) of 34 patients allocated to the immediate-release oral levodopa-carbidopa group (seven [21%] serious), mainly associated with the percutaneous gastrojejunostomy tube. The investigators concluded that continuous delivery of levodopa-carbidopa with an intestinal gel offers a promising option for control of advanced Parkinson's disease with motor complications.

An accompanying editorial (Rascol, 2014) noted some of the limitations of the randomized controlled trial (RCT) by Olanow et al.  The editorialist noted that the trial by Olanow et al was small (71 patients) and short (3 months). This design prevented long-term conclusions and provided insufficient power to assess rare adverse events such as polyneuropathy and Guillain-Barré syndrome, or even more common ones such as impulse-control disorders. The editorialist noted that unmasking factors because of efficacy (as with any strongly efficacious intervention) or black coloration of the tube caused by levodopa oxidation might have enhanced placebo response on the active infusion. The editorialist noted that, unfortunately no formal assessment of masking was done. The editorialist noted that patients on sustained-release levodopa-carbidopa formulations had to be converted to immediate-release levodopa-carbidopa to allow double-blind adjustments during the trial. This design deprived the trial participants of the benefit of the long-term oral formulation, thus favoring the active infusion. Moreover, forbidding changes in oral dosing frequency during the titration phase might have induced similar consequences. Finally, head-to-head comparisons have not been done to assess the respective advantages and disadvantages of levodopa jejunal infusion versus the two main alternatives for management of severe problems with refractory off -time complications: continuous subcutaneous apomorphine infusion and functional surgery.

Fernandez et al (2015) reported on the results of a prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day "off" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, "on" time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. The investigators reported that most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. The investigators stated that LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function daily activities, and HRQoL sustained over 54 weeks.

Caceres-Redondo et al (2014) reported on the motor and cognitive outcome of LCIG treatment in advanced PD after a follow-up period of at least 24 months. The investigators assessed 29 patients with advanced PD who started LCIG infusion at one center between 2007 and 2013. Motor fluctuations, parkinsonian symptoms, activities of daily living and impact on quality of life were evaluated. They also evaluated the cognitive outcome using a battery of neuropsychological tests. All adverse events were recorded. Of the 29 PD patients who initiated LCIG, 16 patients reached the follow-up evaluation (24 months), after a mean time period of 32.2 ± 12.4 months. Six patients did not fulfil the 24-month follow-up visit and were evaluated after a mean time period of 8.6 ± 5.4 months. Seven patients discontinued the treatment before the scheduled visit. The authors reported that "Off" time and "On" dyskinesia duration were significantly reduced. LCIG improved quality of life and non-motor symptoms, despite overall unchanged total levodopa doses prior to LCIG beginning. Motor and cognitive decline were detected. The authors noted that a relatively high number of adverse events occurred during the follow-up, above all, technical problems with the infusion device and mild problems related with gastrostomy. There were four cases of peripheral neuropathy (PN), 2 of which were considered serious. The authors stated that their data confirm that LCIG is beneficial in the long-term treatment of advanced PD patients despite a decline in cognitive functions in a subgroup of patients, probably due to disease progression. PN in patients with LCIG may be more frequent than the published data suggest.

Zibetti et al (2014) analyzed all PD patients treated with LCIG at their center over a 7-year period to determine the duration of treatment, retention rate, reasons for discontinuation, LCIG efficacy in motor complications, modifications of concomitant therapy and adverse events. Of the 59 patients, seven subjects (12%) died of causes unrelated to LCIG infusion and 11 patients (19%) discontinued therapy prior to the cut-off date. The authors reported that Duodopa improved motor complications and over 90% of patients reported an improvement in their quality of life, autonomy and clinical global status. The most common adverse events were dislocation and kinking of the intestinal tube.

Cala-Trio Device for the Treatment of Essential Tremor

The Cala Trio is a targeted therapy designed to reduce hand tremors, and the wearable device is currently cleared by the FDA for the treatment of essential tremor (ET).  In November 2020, the FDA granted a Breakthrough Device Designation to Cala Trio for the treatment of action tremors in the hands of adults with PD.

Per the MPO webpage, the FDA has granted Breakthrough Device Designation to Cala Trio for the treatment of action tremors in the hands of adults with PD.  Cala Trio is currently FDA-cleared to relieve hand tremors from ET.  The company expects to initiate the next clinical trials evaluating the therapy in the treatment of action hand tremors in patients with PD by the end of 2020.  Breakthrough Device Designation is granted to specific medical devices that have the potential to provide a more effective treatment for life-threatening or irreversibly debilitating diseases.  The goal of the Breakthrough Devices Program is to provide patients and health care providers with timely access to these medical devices by speeding up their development, assessment, and review while preserving the statutory standards for premarket approval, 510(k) clearance, and De Novo marketing authorization.  "While hand tremor in patients living with Parkinson's disease typically occurs when the arm is at rest while sitting or walking, it is also estimated that more than half of patients also experience action tremor, which occurs when the arm is being used to perform an activity or task," said Stuart Isaacson, MD, director of the Parkinson's Disease and Movement Disorders Center of Boca Raton in Florida.  "Furthermore, published data suggest that levodopa, the primary treatment for motor symptoms of Parkinson's disease, is not usually effective in treating this type of tremor, which can negatively affect performing daily tasks like eating and writing.  For this reason, treatment for action tremor in patients with Parkinson's disease remains a significant unmet medical need that impacts their daily activities and overall quality of life".  Cala Trio, a non-invasive targeted therapy, is currently available in the U.S. by prescription.  Cala Health sought Breakthrough Device Designation for Cala Trio because many patients with Parkinson's disease experience the same action tremor as patients with essential tremor.  Physicians and their patients with Parkinson's disease-related action hand tremors interested in participating in research are encouraged to visit CalaHealth.com/research.  Virtual clinical trials will allow participants to volunteer from home, using the therapy as indicated in the study design and having telemedicine visits with a neurologist throughout the study.  "Cala Health is committed to pursuing rigorous scientific and clinical research to demonstrate the mechanism, benefits, useability, and safety of our technologies," said Kate Rosenbluth, Ph.D., founder and chief scientific officer of Cala Health.  "We are pleased to have the FDA recognize the novelty and potential for our wrist-worn neuromodulation therapy". 

Herrnstadt et al (2019) stated that there is a need for alternative treatment options for tremor patients who do not respond well to medications or surgery, either due to side effects or poor efficacy, or that are excluded from surgery.  The se researchers examined the feasibility of a voluntary-driven, speed-controlled tremor rejection approach with individuals with pathological tremor.  The suppression approach was examined using a robotic orthosis for suppression of elbow tremor.  More importantly, the study emphasized the performance in relation to the voluntary motion.  A total of 9 subjects with either ET or PD were recruited and tested off medication.  The subjects carried out computerized pursuit tracking tasks following a sinusoid and a random target, both with and without the suppressive orthosis.  The impact of the Tremor Suppression Orthosis (TSO) at the tremor and voluntary frequencies was determined by the relative power change calculated from the Power Spectral Density (PSD).  Voluntary motion was, in addition, assessed by position and velocity tracking errors.  The suppressive orthosis resulted in a 94.4 % mean power reduction of the tremor (p < 0.001) -- a substantial improvement over reports in the literature.  As for the impact to the voluntary motion, paired difference tests revealed no statistical effect of the TSO on the relative power change (p = 0.346) and velocity tracking error (p = 0.283).  A marginal effect was observed for the position tracking error (p = 0.05).  The interaction torque with the robotic orthosis was small (0.62 Nm) when compared to the maximum voluntary torque that can be exerted by adult individuals at the elbow joint.  The authors concluded that 2 key contributions of this work were: First -- a recently proposed approach was evaluated with individuals with ET demonstrating high levels of tremor suppression; and second -- the impact of the approach to the voluntary motion was analyzed comprehensively, showing limited inhibition.  This study also sought to address a gap in studies with individuals with tremor where the impact of engineering solutions on voluntary motion is unreported.  The findings of this preliminary study demonstrated feasibility of the wearable technology as an effective treatment that removes tremor with limited impediment to intentional motion.  The objective for such wearable technology is to help individuals with pathological tremor regain independence in activities affected by the tremor condition.  These researchers stated that further investigations with larger study populations are needed to validate the technology.

Castrillo-Fraile et al (2019) noted that there is a growing interest in non-pharmacological approaches for the treatment of ET, including tremor cancelation devices; however, the true efficacy of such devices in ET remains unclear.  These researchers carried out a systematic literature review using standardized criteria regarding efficacy and comfortability.  Devices focused on design or experimental testing in which tremor was simulated in a robot were excluded.  Out of 324 articles initially identified, 12 articles were included . Orthoses using biomechanical loading and neuromodulation with electrical stimulation, and external tremor cancelation devices, were the main interventions used to suppress tremor.  All devices were designed to control tremor of the upper limbs at different anatomical locations.  Overall, an average tremor attenuation of 50 to 98 % was reported (Level of Evidence = III).  Interference with voluntary movements and portability was described as the main drawback.  The authors concluded that this review highlighted the growing interest in emerging tremor control devices and the importance of assessing comfort without affecting voluntary movements; however, the level of evidence regarding the efficacy of these tremor control devices remains low.  An integrated multi-disciplinary combination approach of engineering, robotics, physiology, physiotherapy, and clinical assessment is needed to improve the quality of non-pharmacological interventions for ET.

Mo and Priefer (2021) stated that tremors are the most prevalent movement disorder that interferes with the patient's daily living, and physical activities, ultimately leading to a reduced quality of life (QOL).  Due to the pathophysiology of tremor, developing effective pharmacotherapies, which are only suboptimal in the management of tremor, has many challenges.  Therefore, a range of therapies are needed in managing this progressive, aging-associated disorder.  Surgical interventions such as deep brain stimulation (DBS) are able to provide durable tremor control; however, due to high costs, patient and practitioner preference, and perceived high risks, their use is minimized.  Medical devices are placed in a unique position to bridge this gap between lifestyle interventions, pharmacotherapies, and surgical treatments to provide safe and effective tremor suppression.  These investigators reviewed the mechanisms of action, safety and efficacy profiles, and clinical applications of different medical devices that are currently available or have been previously examined for tremor suppression.  These devices are primarily non-invasive, which can be a beneficial addition to the patient's existing pharmacotherapy and/or lifestyle intervention.  The authors concluded that based on the current evidence, some of these devices appeared to have promise as potentially safe and effective options in the medical armamentarium for tremor suppression.  Most of these devices are non-invasive and placed externally around the wrists or the upper limbs.  It is important to note that externally wearing a device could pose a cosmetic and social concern, so understanding the acceptability of tremor medical devices among patients with tremors is warranted.  Nonetheless, it is likely that the future of tremor management will benefit from the addition of medical devices into the patient’s existing pharmacotherapy and/or lifestyle intervention.  Moreover, these researchers stated that given the high variability in the quality of the current studies, future research is needed to better understand the long-term efficacy, safety, and cost-effectiveness of the tremor suppression devices to fulfill this promise.

Furthermore, an UpToDate review on “Essential tremor: Treatment and prognosis” (Deik and Tarsy, 2021) states that “Biomechanical loading refers to either the external application of force on a tremulous limb or the facilitation of antagonist muscle contraction within the limb to reduce tremor.  At least two small research projects have explored different wearable robots to effectively suppress tremor.  One of the studies examined a robotic exoskeleton that applied forces to tremulous limbs, and the other was a neuroprosthesis capable of providing transcutaneous neurostimulation”.

Cerebro-Spinal Fluid (CSF) Biomarkers

Leaver and Poston (2015) stated that cross-sectional studies have shown that certain protein levels are altered in the CSF of PD patients with dementia and are thought to represent potential biomarkers of underlying pathogenesis.  Recent studies suggested that CSF biomarker levels may be predictive of future risk of cognitive decline in non-demented PD patients.  However, the strength of this evidence and difference between specific CSF biomarkers is not well-delineated.  These investigators performed a systematic review to examine if levels of specific CSF protein biomarkers are predictive of progression to cognitive impairment.  A total of 9 articles were identified that met inclusion criteria for the review.  Findings from the review suggested a convergence of evidence that a low baseline Aβ42 in the CSF of non-demented PD patients predicts development of cognitive impairment over time.  Conversely, there is limited evidence that CSF levels of tau, either total tau or phosphorylated tau, is a useful predictive biomarker.  There are mixed results for other CSF biomarkers such as α-synuclein, neurofilament light chain, and heart fatty acid-binding protein.  Overall the results of this review showed that certain CSF biomarkers have better predictive ability to identify PD patients who are at risk for developing cognitive impairment.  The authors concluded that given the interest in developing disease-modifying therapies, identifying this group will be important for clinical trials as initiation of therapy prior to the onset of cognitive decline is likely to be more effective.

In a longitudinal, single-center, cohort study, Mollenhauer and associates (2016) examined multi-modal progression markers for PD in patients with recently diagnosed PD (n = 123) and age-matched, neurologically healthy controls (HC; n = 106).  A total of 30 tests at baseline and after 24 months covered non-motor symptoms (NMS), cognitive function, and REM sleep behavior disorder (RBD) by polysomnography (PSG), voxel-based morphometry (VBM) of the brain by MRI, and CSF markers.  Linear mixed-effect models were used to estimate differences of rates of change and to provide standardized effect sizes (d) with 95 % CI.  A composite panel of 10 informative markers was identified.  Significant relative worsening (PD versus HC) was seen with the following markers: the UPDRS I (d 0.39; 95 % CI: 0.09 to 0.70), the Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25; 95 % CI: 0.06 to 0.46), the Epworth Sleepiness Scale (ESS) (d 0.47; 95 % CI: 0.24 to 0.71), the RBD Screening Questionnaire (d 0.44; 95 % CI: 0.25 to 0.64), and RBD by PSG (d 0.37; 95 % CI: 0.19 to 0.55) as well as VBM units of cortical gray matter (d -0.2; 95 % CI: -0.3 to -0.09) and hippocampus (d -0.15; 95 % CI -0.27 to -0.03).  Markers with a relative improvement included the Non-motor Symptom (Severity) Scale (d -0.19; 95 % CI: -0.36 to -0.02) and 2 depression scales (BDI; d -0.18: 95 % CI: -0.36 to 0; MADRS; d -0.26; 95 % CI: -0.47 to -0.04).  Unexpectedly, cognitive measures and select laboratory markers were not significantly changed in PD versus HC participants.  The authors concluded that current CSF biomarkers and cognitive scales do not represent useful progression markers.  However, sleep and imaging measures, and to some extent NMS, assessed using adequate scales, may be more informative markers to quantify progression.  Moreover, they stated that future studies need to examine the validity of these proposed markers, standardize the assessment of non-motor features, and identify more sensitive and disease-specific marker candidates that reflect underlying biological processes (such as propagation of α-synuclein pathology, inflammation and neuronal death).

Hu and colleagues (2017) stated that as a biomarker of axonal injury, neurofilament light chain (NFL) in MSA patients and PD patients has been investigated by numerous studies. However, CSF NFL changes are conflicting in MSA patients relative to PD patients to date.  In a meta-analysis, these researchers attempted to find out possible heterogeneity sources. Furthermore, "neurofilament", "neurofilament light chain" and "multiple system atrophy" were employed to search "PubMed", "Springer" and "Medline" databases until August 2016 with standard mean difference (Std.MD) being calculated.  In addition, subgroup analysis and meta-regression were performed to assess possible heterogeneity sources.  A total of 9 studies were pooled, in which 212 MSA patients and 373 PD patients were involved.  Moreover, CSF NFL in MSA patients was higher than that in PD patients [pooled Std.MD = 1.56, 95 % CI: 1.12 to 2.00, p < 0.00001] with significant heterogeneity (I 2 = 76 %).  Besides, population variations, sample size, the difference in CSF phosphorylated tau (p-tau) levels between MSA patients and PD patients, and Hoehn-Yahr staging of PD patients were the main heterogeneity sources.  As shown by meta-regression, Hedges's g of CSF NFL was correlated with CSF Std.MD of α-synuclein between MSA patients and healthy controls (r = -1.34824, p = 0.00025).  Therefore, CSF NFL increased in MSA patients relative to PD patients.  Meta-regression showed that NFL was associated with α-synuclein in CSF of MSA patients relative to healthy controls.  The authors concluded that due to the influence of heterogeneity sources, more prospective large sample studies are still needed to assess CSF NFL changes in MSA patients relative to PD patients.

Mollenhauer and colleagues (2017) analyzed longitudinal levels of CSF biomarkers in drug-naive patients with PD and HC, examined the extent to which these biomarker changes relate to clinical measures of PD, and identified what may influence them.  CSF α-synuclein (α-syn), total and phosphorylated tau (t- and p-tau), and β-amyloid 1-42 (Aβ42) were measured at baseline and 6 and 12 months in 173 patients with PD and 112 matched HC in the international multi-center Parkinson's Progression Marker Initiative.  Baseline clinical and demographic variables, PD medications, neuroimaging, and genetic variables were evaluated as potential predictors of CSF biomarker changes.  CSF biomarkers were stable over 6 and 12 months, and there was a small but significant increase in CSF Aβ42 in both patients with patients with PD and HC from baseline to 12 months.  The t-tau remained stable.  The p-tau increased marginally more in patients with PD than in HC; α-syn remained relatively stable in patients with PD and HC.  Ratios of p-tau/t-tau increased, while t-tau/Aβ42 decreased over 12 months in patients with PD.  CSF biomarker changes did not correlate with changes in Movement Disorder Society-sponsored revision of the UPDRS motor scores or dopamine imaging.  CSF α-syn levels at 12 months were lower in patients with PD treated with dopamine replacement therapy, especially dopamine agonists.  The authors concluded that these core CSF biomarkers remained stable over 6 and 12 months in patients with early PD and HC; PD medication use may influence CSF α-syn.  Moreover, they stated that novel biomarkers are needed to better profile progressive neurodegeneration in PD.

Cueing Module Device (Auditory Cue) for the Treatment of Parkinson's Freezing

Lopez et al (2014) noted that evidence supports the use of rhythmic external auditory signals to improve gait in Parkinson’s disease (PD) patients.  However, few prototypes are available for daily use, and to the authors’ knowledge, none utilize a smartphone application allowing individualized sounds and cadence.  These researchers analyzed the effects on gait of Listenmee, an intelligent glasses system with a portable auditory device, and presented its smartphone application, the Listenmee app, offering over 100 different sounds and an adjustable metronome to individualize the cueing rate as well as its smartwatch with accelerometer to detect magnitude and direction of the proper acceleration, track calorie count, sleep patterns, steps count and daily distances.  The present study included patients with idiopathic PD presented gait disturbances including freezing.  Auditory rhythmic cues were delivered through Listenmee.  Performance was analyzed in a motion and gait analysis laboratory.  The results revealed significant improvements in gait performance over 3 major dependent variables: walking speed in 38.1 %, cadence in 28.1 % and stride length in 44.5 %.  The authors concluded that these findings suggested that auditory cueing through Listenmee may significantly enhance gait performance.  Moreover, these investigators stated that further studies are needed to elucidate the potential role and maximize the benefits of these portable devices.

Zhao et al (2016) stated that new mobile technologies like smart-glasses could deliver external cues that may improve gait in people with PD in their natural environment.  However, the potential of these devices must first be assessed in controlled experiments.  These researchers evaluated rhythmic visual and auditory cueing in a laboratory setting with a custom-made application for the Google Glass.  A total of 12 participants (mean age of 66.8 years; mean disease duration of 13.6 years) were tested at end of dose.  These investigators compared several key gait parameters (walking speed, cadence, stride length, and stride length variability) and freezing of gait for 3 types of external cues (metronome, flashing light, and optic flow) and a control condition (no-cue).  For all cueing conditions, the subjects completed several walking tasks of varying complexity; 7 inertial sensors attached to the feet, legs and pelvis captured motion data for gait analysis.  Two experienced raters scored the presence and severity of freezing of gait using video recordings.  User experience was evaluated through a semi-open interview.  During cueing, a more stable gait pattern emerged, particularly on complicated walking courses; however, freezing of gait (FOG) did not significantly decrease.  The metronome was more effective than rhythmic visual cues and most preferred by the participants.  Subjects were overall positive about the usability of the Google Glass and willing to use it at home.  The authors concluded that smart-glasses like the Google Glass could be used to provide personalized mobile cueing to support gait; however, in its current form, auditory cues appeared more effective than rhythmic visual cues.  These researchers stated that smart-glasses have the potential to become mobile assistive devices for on-demand cueing in daily life, but further development is needed to better accommodate the individual needs of patients with PD.

The authors stated that this study had several drawbacks.  First, out of the 12 participants, only 6 experienced FOG more than once, 4 exhibited no FOG, and 2 had a single FOG episode.  Due to this small sample size of freezers, the effect of cueing on FOG was inconclusive.  Second, a potential confound was that many of the participants have already used cues in their daily life and may be more efficient during the cued walking trials.  As the effects of cueing did not generalize well and none of the participants had prior experience using the Google Glass, these researchers did not expect that those with cueing experience would out-perform those with no previous experience during this study.  Visual inspection of individual performances also did not show consistent differences between these 2 groups.  Third, as the study was conducted at end of dose, the findings may be less applicable to daily life when people are mostly in the on state.  However, as FOG is known to be resistant to medication and deep brain stimulation and motor fluctuations -- alterations between on and off states -- are the most common complications of long-term levodopa use, cueing during the on state is still a useful strategy.  Lastly, the version of the Google Glass used in this study is no longer available for purchase, with Google pursuing a new Enterprise edition of the Glass tailored for working environments.  As numerous other augmented reality smart-glasses are appearing on the market, mobile cueing will continue to advance.

Furthermore, an UpToDate review on "Motor fluctuations and dyskinesia in Parkinson disease" (Tarsy, 2020) does not mention auditory cue as a management option.

Disease-Associated α-Synuclein Aggregates as Biomarkers of Parkinson Disease Clinical Stage

Majbour et al (2022) stated that robust biomarkers that could mirror PD are of great significance.  These investigators presented a novel approach to examine disease-associated α-synuclein (αSyn) aggregates as biomarkers of PD clinical stage.  They combined both seed amplification assay (SAA) and ELISA to provide a quantitative test read-out that reflected the clinical severity of patients with PD.  To attain this objective, these researchers initially examined the potential of their test using 2 sets of human brain homogenates (pilot and validation sets) and then verified it with 2 independent human CSF cohorts; discovery (62 patients with PD and 34 controls) and validation (49 patients with PD and 48 controls) cohorts.  These investigators showed that oligomers-specific ELISA robustly quantified SAA end product from patients with PD or dementia with Lewy bodies with high sensitivity and specificity scores (100 %).  Analysis also showed that seeding activity could be detected earlier with oligomeric ELISA as the test read-out rather than SAA alone.  Of more importance, multiplexing the assays provided robust information regarding the patients' clinical disease stage.  In the discovery cohort, levels of CSF-seeded αSyn oligomers correlated with the severity of the clinical symptoms of PD as measured by the UPDRS motor (r = 0.58, p < 0.001) and H&Y scores (r = 0.43, p < 0.01).  Similar correlations were observed in the validation cohort between the concentrations of CSF-seeded αSyn oligomers and both UPDRS motor (r = 0.50, p < 0.01) and H&Y scores (r = 0.49, p < 0.01).  At 20 hours, ROC curves analysis yielded a sensitivity of 91.9 % (95 % CI: 82.4 % to 96.5 %) and a specificity of 85.3 % (95 % CI: 69.8 % to 93.5 %), with an AUC of 0.969 for CSF-seeded αSyn oligomers differentiating those with PD from controls in the discovery CSF cohort, whereas, a sensitivity of 80.7 % (95 % CI: 69.1 % to 88.5 %), a specificity of 76.5 % (95 % CI: 60.0 % to 87.5 %), and AUC of 0.860 were generated with thioflavin T maximum intensity of fluorescence at the same time-point.  The authors concluded that these findings further supported the growing evidence of αSyn SAA as a robust clinical diagnostic tool for patients with PD.  In addition, these researchers have established and validated a novel approach to provide clinical information regarding the underlying disease severity in patients with PD; therefore, perhaps a promising tool to support clinical trials targeting αSyn aggregates in PD.  Classification of Evidence = III.

These investigators stated that although their SAA-ELISA multiplex was initially tested in post-mortem human tissues, the lack of autopsy data to provide a definitive diagnosis of PD that would help researchers better appreciate the correlation with disease severity in the CSF cohorts remains a limitation of this study.  Furthermore, analyzing longitudinal cohorts would also be essential as a next step to extract further information regarding the potential use of their approach.  These researchers stated that further studies are needed to examine if the approach of combining SAA with oligomer-specific ELISA is useful in patients with other synucleinopathies and in evaluating therapies targeting αSyn aggregation.

Gene Therapy 

Nutt and associates (2020) noted that as PD progresses, levodopa treatment loses efficacy, partly via the loss of the endogenous dopamine-synthesizing enzyme L-amino acid decarboxylase (AADC).  In the phase-I PD-1101 Trial, putaminal administration of VY-AADC01, an investigational adeno-associated virus serotype-2 vector for delivery of the AADC gene in patients with advanced PD, was well-tolerated, improved motor function, and reduced anti-Parkinsonian medication requirements.  This sub-study aimed to examine if the timing and magnitude of motor response to intravenous levodopa changed in PD-1101 patients after VY-AADC01 administration.  Subjects received 2-hour threshold (0.6 mg/kg/hour) and supra-threshold (1.2 mg/kg/hour) levodopa infusions on each of 2 days, both before and approximately 6 months after VY-AADC01.  Infusion order was randomized and double-blinded.  UPDRS motor scores, finger-tapping speeds, and dyskinesia rating scores were evaluated every 30 mins for 1 hour before and greater than or equal to 3 hours after start of levodopa infusion.  Of the 15 subjects enrolled in the PD-1101 Trial, 13 participated in the sub-study.  UPDRS motor score area under the curve responses to threshold and supra-threshold levodopa infusions increased by 168 % and 67 %, respectively, after VY-AADC01; finger-tapping speeds improved by 162 % and 113 %, and dyskinesia scores increased by 208 % and 72 %, respectively, after VY-AADC01.  AEs (mild/moderate severity) were reported in 5 subjects during levodopa infusions pre-VY-AADC01 and 2 subjects post-VY-AADC01 administration.  The authors concluded that VY-AADC01 improved motor responses to intravenous levodopa given under controlled conditions.  These researchers stated that these data and findings from the parent study supported further clinical development of AADC gene therapy for patients with PD. 

The authors stated that a drawback of this sub-study was the potential for a placebo effect following gene therapy administration; placebo effects are especially prominent after neurosurgical interventions in PD.  Furthermore, the PD‐1101 Trial had small cohort sizes that were not powered for efficacy assessments or for between‐cohort comparisons.  A lingering question is whether the administration of IV levodopa at a clinical research center would translate to the clinical setting with oral levodopa and the use of other anti-Parkinsonian medications. 

Christine and colleagues (2022) reported final, 36-month safety and clinical outcomes from the PD-1101 Trial of NBIb-1817 (VY-AADC01) in patients with moderately advanced PD and motor fluctuations.  PD-1101 was a phase-Ib, open-label, dose escalation trial of VY-AADC01, an experimental AAV2 gene therapy encoding the human aromatic AADC enzyme.  VY-AADC01 was delivered via bilateral, intra-operative MRI-guided putaminal infusions to 3 cohorts (n = 5 subjects per cohort): cohort 1, less than or equal to 7.5 × 10(11) vector genomes (vg); cohort 2, less than or equal to 1.5 × 10(12) vg; cohort 3, less than or equal to 4.7 × 10(12) vg.  No serious AEs (SAEs) attributed to VY-AADC01 were reported.  All 4 non-vector-related SAEs (atrial fibrillation and pulmonary embolism in 1 subject and 2 events of small bowel obstruction in another subject) resolved.  Requirements for PD medications were reduced by 21 % to 30 % in the 2 highest dose cohorts at 36 months.  Standard measures of motor function (PD diary, UPDRS III "off"-medication and "on"-medication scores), global impressions of improvement (Clinical Global Impression of Improvement, Patient Global Impression of Improvement), and QOL (39-item Parkinson's Disease Questionnaire) were stable or improved compared with baseline at 12, 24, and 36 months following VY-AADC01 administration across cohorts.  The authors concluded that the findings of the PD-1101 Trial supports the long-term safety and potential durability of VY-AADC01 clinical effects following a single administration.  No vector-related SAEs were reported; and clinical outcomes of motor function and QOL were stable or improved throughout the 3-year trial duration in a PD population that would otherwise be expected to decline over this time period.  PD-1101, along with a companion IV administered levodopa response sub-study and a 2nd, ongoing open-label phase-Ib trial (PD-1102, NCT03065192), suggest that AAV2-hAADC gene therapy may confer meaningful benefits to patients with PD.  Level of Evidence = IV. 

The PD-1101 Trial did not include a control group and its primary objective was to examine the safety and tolerability of AADC gene therapy.  Although there are limited data on the natural progression of motor impairment in moderately advanced PD to help contextualize the observed effects of VY-AADC01 on motor function in the current trial, long-term extension studies of therapies designed for use in moderately advanced PD can provide insight into the expected progression in such patients under medical management.

Genetic Testing of Fibroblast Growth Factor 20 rs12720208 Polymorphism

Wang and colleagues (2017) noted that many studies had examined the association between fibroblast growth factor 20 (FGF20) rs12720208 polymorphism and the susceptibility of PD.  However, published data are still controversial.  These researchers performed a meta-analysis to evaluate the association of rs12720208 polymorphism with the risk of PD.  Up to April 2016, PubMed, Embase, Web of science, the Chinese National Knowledge Infrastructure, and Wanfang Medicine were reviewed to identify appropriate documents.  A total of 7 articles involving 11 studies with 3,360 PD cases and 3,681 controls were included based on the strict inclusion and exclusion standards.  And STATA 12.0 statistics software was used to calculate available data from each study.  The pooled OR and 95 % CI were calculated to assess the association between FGF20 rs12720208 polymorphism and PD risk.  When all studies were pooled into this meta-analysis, neither the minor T allele frequencies nor the genotypic distributions were different between PD cases and controls.  But the subgroup analysis stratified by ethnicity showed FGF20 rs12720208 polymorphism was associated with increased risk in the allele model (T versus C: OR = 1.167, 95 % CI: 1.020 to 1.335) and dominant model (TT + TC versus CC: OR = 1.156, 95 % CI: 1.001 to 1.335) in Caucasians but not in Asians.  The authors concluded that the findings of this meta-analysis indicated that rs12720208 C/T variant might be associated with PD susceptibility in Caucasians.

Genetic Testing of PARK10 and Variants

Beecham et al (2015) noted that to minimize pathologic heterogeneity in genetic studies of PD, the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls.  A total of 484 cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis.  A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10(-8)).  The association peak lied within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus.  These researchers demonstrated that rs10788972 is in strong linkage disequilibrium with rs914722, the SNP defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD.  The region containing the PARK10 locus was significantly reduced from 10.6 mega-bases to 100 kilo-bases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1.  The authors concluded that they confirmed the association of a PARK10 haplotype with the risk of developing idiopathic PD.  Furthermore, they significantly reduced the size of the PARK10 region.  None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research.  They stated that the findings of this study strongly suggested that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD. 

In an editorial that accompanied the afore-mentioned study, Simon-Sanchez and Gasser (2015) stated that "although spurious associations driven by undetected population stratification remains a possibility until this findings has been replicated in other studies, another possible explanation for this discrepancy is that the PARK10 locus is only associated with a special subgroup of PD and that its effect size is strong enough to yield statistical association when a selection of LB [Lewy body] PD class is made, but not when larger series of clinical PD cases are studied …. Another limitation of this study 9and GWAS in general) is the relatively small effect size associated with the identified loci.  This precludes useful individual disease prediction, and is a problem for risk stratification and personalized medicine …. Further applications of the data derived from this and other GWAS include the possibility to build genetic risk profiles for a disease of interest.  These profiles have the potential to identify at-risk individuals and apply different therapeutic strategies depending on the specific genetic underpinnings of the disease in a given individual".

Simon-Sanchez et al (2015) stated that a recent study in autopsy-confirmed PD patients and controls revived the debate about the role of PARK10 in this disorder.  In an attempt to replicate these results and further understand the role of this locus in the risk and age at onset of PD, these researchers explored NeuroX genotyping and whole exome sequencing data from 2 large independent cohorts of clinical patients and controls from the International Parkinson's Disease Genomic Consortium.  A series of single-variant and gene-based aggregation (sequence kernel association test and combined multi-variate and collapsing test) statistical tests suggested that common and rare genetic variation in this locus do not influence the risk or age at onset of clinical PD.

Guo et al (2015) noted that PD is the second most common chronic neuronal degeneration disorder with motor and non-motor clinical features.  The rs10788972 variant of the transcription elongation factor A (SII) N-terminal and central domain containing 2 (TCEANC2) gene in the PARK10 region was recently identified to be strongly related to sporadic PD in the American population.  These researchers examined if the same variant is associated with sporadic PD in Chinese Han population.  They researched 513 sporadic PD patients and 512 normal controls of Chinese Han ethnicity in Mainland China.  No significant difference in genotypic and allelic distributions between patients and control groups for either rs10788972 (for genotypic distribution, χ(2) = 0.412, p = 0.814, and for allelic distribution, χ(2) = 0.280, p = 0.597) or its neighbor marker rs12046178 (for genotypic distribution, χ(2) = 1.500, p = 0.472, and for allelic distribution, χ(2) = 1.339, p = 0.247) was found.  The authors concluded that these findings suggested that neither variant is related to sporadic PD in Chinese Han population.

Genetic Testing of PITX3

Jimenez-Jimenez et al (2014) noted that several single nucleotide polymorphisms (SNPs) in the PITX3 gene have been associated with the risk for PD.  These investigators performed a systematic review and a meta-analysis including all the studies published on the risk of PD related with these polymorphisms.  The systematic review was carried out using several databases.  Eligible studies were included in the meta-analysis that was carried out using Meta-DiSc 1.1.1 software.  Heterogeneity between studies was tested using the Q-statistic.  The meta-analysis included 8 association studies for the PITX3 rs3758549 SNP (4,052 PD patients, 3,949 controls), 8 studies for the PITX3 rs2281983 SNP (4,309 PD patients, 4,287 controls), and 6 studies for the rs4919621 SNP (2,724 PD patients, 2,285 controls), and the risk for PD, global diagnostic ORs (95 % CIs) for rs3758549, rs2281983, and rs4919621 were, respectively, 1.00 (0.89-1.12) (p = 0.979), 0.99 (0.91-1.09) (p = 0.896), and 0.98 (0.83-1.16) (p = 0.844) for the total group.  The separate analysis in Caucasian and Chinese subjects on the frequency of the minor allele of the 3 SNPs analyzed did not show significant differences between PD patients and controls in both subgroups; rs2281983 and rs4919621 SNPs were related with early-onset PD risk in Caucasians.  The authors concluded that the findings of this meta-analysis suggested that rs3758549, rs2281983, and rs4919621 SNPs are not major determinants of the risk for PD.

Magnetic Resonance Imaging-Guided Focused Ultrasound Neurosurgery

Xu and colleagues (2021) stated that magnetic resonance imaging-guided focused ultrasound (MRgFUS) neurosurgery is a new option for medication-resistant PD, but its safety and efficacy remain elusive.  These investigators examined the safety and efficacy of MRgFUS for PD by systematically reviewing related literature.  PubMed and Embase were searched to identify related studies.  Inclusion criteria were reported the efficacy or safety of MRgFUS for PD and published in English.  Exclusion criteria were non-human study, review or meta-analysis or other literature types without original data, and conference abstract without full text.  Data on study characteristics, treatment parameters, efficacy, and As were collected.  Descriptive synthesis of data was performed.  A total of 11 studies containing 80 patients were included; 9 studies were observational studies with no controls; 2 studies included a randomized and controlled phase.  Most studies included tremor-dominant PD; 10 studies reported decline of UPDRS-III scores after MRgFUS, and 5 reported a statistically significant decline; 9 studies evaluated the quality of life (QOL).  Significant improvement of QOL was reported by 4 studies using the 39-item PD questionnaire; 4 studies examined the impact of MRgFUS on non-motor symptoms.  Most tests indicated that MRgFUS had no significant effect on neuropsychological outcomes; most AEs were mild and transient.  The authors concluded that MRgFUS is a potential treatment for PD with satisfying efficacy and safety.  Studies in this field are still limited.  These researchers stated that more studies with strict design, larger sample size, and longer follow-up are needed to further examine its safety and efficacy for PD.

Martinez-Fernandez and associates (2020) noted that the subthalamic nucleus is the preferred neurosurgical target for DBS to treat cardinal motor features of PD.  Focused US is an imaging-guided method for creating therapeutic lesions in deep-brain structures, including the subthalamic nucleus.  These researchers randomly assigned, in a 2:1 ratio, patients with markedly asymmetric PD who had motor signs not fully controlled by medication or who were ineligible for DBS surgery to undergo focused US sub-thalamotomy on the side opposite their main motor signs or a sham procedure.  The primary efficacy outcome was the between-group difference in the change from baseline to 4 months in the MDS-UPDRS motor score (i.e., part III) for the more affected body side (range of 0 to 44, with higher scores indicating worse parkinsonism) in the off-medication state.  The primary safety outcome (procedure-related complications) was examined at 4 months.  Among 40 enrolled patients, 27 were assigned to focused US sub-thalamotomy (active treatment) and 13 to the sham procedure (control).  The mean MDS-UPDRS III score for the more affected side decreased from 19.9 at baseline to 9.9 at 4 months in the active-treatment group (least-squares mean difference, 9.8 points; 95 % CI: 8.6 to 11.1) and from 18.7 to 17.1 in the control group (least-squares mean difference, 1.7 points; 95 % CI: 0.0 to 3.5); the between-group difference was 8.1 points (95 % CI: 6.0 to 10.3; p < 0.001); AEs in the active-treatment group were dyskinesia in the off-medication state in 6 patients and in the on-medication state in 6, which persisted in 3 and 1, respectively, at 4 months; weakness on the treated side in 5 patients, which persisted in 2 at 4 months; speech disturbance in 15 patients, which persisted in 3 at 4 months; facial weakness in 3 patients, which persisted in 1 at 4 months; and gait disturbance in 13 patients, which persisted in 2 at 4 months. In 6 patients in the active-treatment group, some of these deficits were present at 12 months.  The authors concluded that focused US sub-thalamotomy in 1 hemisphere improved motor features of PD in selected patients with asymmetric signs; AEs included speech and gait disturbances, weakness on the treated side, and dyskinesia.  Moreover, these researchers stated that longer-term and larger trials are needed to determine the role of focused US sub-thalamotomy in the management of PD and its effect as compared with other available treatments, including DBS.

The authors stated that this study had several drawbacks.  The small sample size (n = 27 for the focused US sub-thalamotomy group) and the enrollment of almost all the patients at 1 of the 2 trial sites (36 patients at 1 site and 4 at the other) limited the generalizability of the results because the trial approximated a single-center trial.  Patients and assessors correctly guessed the trial-group assignments, which eliminated the intended effect of blinding.  Furthermore, because of the lack of a pre-specified plan for adjustment of the 95 % CIs for multiple comparisons of secondary outcomes, no definite inferences could be made from these data.

Lennon and Hassan (2021) stated that ExAblate received FDA approval for treatment of a range of movement disorders in 2016, including tremor-dominant PD (TDPD), dyskinetic PD, and essential tremor (ET).  This incisionless device allows for MRgFUS for ablation of several regions of interest.  Current studies should aim to measure pre- and post-operative neurocognitive functioning to better understand MRgFUS in PD and how it compares to DBS, which has known cognitive risks among certain populations.  PubMed, CINAHL, PsycINFO, and Cochrane Library databases were searched from January 2016 to January 2020.  Guidelines for Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) were used to review clinical trials comprehensively assessing pre- and post-operative neurocognitive functioning in PD patients undergoing MRgFUS.  Due to limited extant literature in this area, TDPD was expanded to PD with severe dyskinesia.  A total of 22 abstracts were reviewed following removal of duplicates.  After full-text review of 8 articles, only 2 studies included comprehensive neuropsychological evaluations of PD patients undergoing MRgFUS thalamotomy or pallidotomy.  Most excluded studies used only brief cognitive screeners to evaluate functioning.  Cognitive declines appeared to be minimal following MRgFUS in PD, with exceptions in verbal fluency and inhibition.  These results were limited by sample size and sample diversity.  The authors concluded that significant methodological gaps were inadvertently discovered.  Few studies to-date have administered comprehensive neuropsychological batteries to determine MRgFUS risks to neurocognitive functioning in PD.  These researchers stated that studies must extend beyond brief screeners when evaluating PD populations vulnerable to decline.  Furthermore, consensus on a comprehensive battery would better serve replicability and the ability to engage in useful meta-analyses.

Measurement of Alpha-Synuclein in Cerebrospinal Fluid/Salivary Extracellular Vesicles for Diagnosis of Parkinson’s Disease

Cao and associates (2019) stated that detection of alpha-synuclein (α-syn) in biological fluids such as saliva may serve as potential biomarker of PD.  Recently, α-syn pertaining to extracellular vesicles (EVs) has been studied in plasma, but not in other biological fluids such as saliva.  These investigators examined the presence of exosomes in PD saliva; and examined the value of α-syn in salivary EVs as potential biomarker in PD.  Saliva samples were obtained from 74 PD and 60 healthy controls (HCs).  The EVs were extracted from saliva by XYCQ EV Enrichment KIT.  Western blot and Nanosight 300 were used to validate the existence of exosomes in EVs and to analyze the size of salivary EVs.  Salivary EVs α-syn levels, including total α-syn (α-synTotal), oligomeric α-syn (α-synOlig) and phosphorylated-ser129 α-syn (α-synPS129), were measured by electrochemiluminescence (ECL) assays.  Diagnostic value and clinical relevance of salivary EVs α-syn were assessed by Receiver Operator Characteristic (ROC) curve and Spearman correlation.  Alix and CD9 positive EVs, representing the presence of exosomes, was detected in PD salivary samples.  Size of salivary EVs was about 30 to 400 nm.  The levels of α-synOlig and α-synOlig/α-synTotal in the salivary EVs were higher in PD than in HCs (10.39 ± 1.46 pg/ng versus 1.37 ± 0.24 pg/ng, p < 0.001;1.70 ± 0.52 pg/ng versus 0.67 ± 0.26 pg/ng, p < 0.001).  There was no significant difference in α-synTotal、α-synPS129、 α-synPS129/α-synTotal ratio between PD and HCs (p = 0.723, 0.634, 0.734, respectively). α-synOlig 2.05 pg/ng distinguished PD from HCs with sensitivity 92 % and specificity 86 %; α-synOlig /α-synTotal 0.18 pg/ng differentiated PD from HCs with sensitivity 81 % and specificity 71 %.  No significant correlation between salivary EVs α-synOlig, α-synOlig/α-synTotal and disease severity was found.  The authors concluded that exosomes were present in PD saliva.  The α-synOlig and α-synOlig/α-synTotal ratio in salivary EVs may serve as potential diagnostic biomarkers for PD.

In a cross-sectional, multi-center study, Hong and colleagues (2021) developed a reliable and fast assay to quantify the α-syn-containing EVs in CSF and evaluated its diagnostic potential for PD.  This trial included 170 patients with PD and 131 HCs with a similar distribution of age and sex recruited from existing center studies at the University of Washington and Oregon Health and Science University.  CSF EVs carrying α-syn or aggregated α-syn were quantified using antibodies against total or aggregated α-syn, respectively, and highly specific, sensitive, and rapid assays based on the novel Apogee nanoscale flow cytometry technology.  No significant differences in the number and size distribution of total EVs between patients with PD and HCs in CSF were observed.  When examining the total α-syn-positive and aggregated α-syn-positive EV subpopulations, the proportions of both among all detected CSF EVs were significantly lower in patients with PD compared to HCs (p < 0.0001).  While each EV subpopulation showed better diagnostic sensitivity and specificity than total CSF α-syn measured directly with an immunoassay, a combination of the 2 EV subpopulations demonstrated a diagnostic accuracy that attained clinical relevance (AUC 0.819, sensitivity 80 %, specificity 71 %).  The authors concluded that by means of newly established, sensitive nanoscale flow cytometry assays, they have demonstrated that total α-syn-positive and aggregated α-syn-positive EVs in CSF may serve as a helpful tool in PD diagnosis.  Moreover, these researchers stated that If the performance on PD diagnosis and differential diagnosis can be improved/confirmed and validated in further independent studies, this assay could be useful to improve diagnostic accuracy of PD in clinical practice and to increase power and reduce costs in clinical trials by lowering the mis-classification rate during participant recruitment.  Level of Evidence = III.

Measurement of Serum Leptin Levels for the Diagnosis of Parkinson’s Disease

Rahnemayan and colleagues (2021) noted that the exact mechanism of PD is not fully understood yet; however, it is suggested that inflammation is one of its contributing factors.  Among several inflammatory factors, adipokines, especially leptin may have a great role in this mechanism; since it is not only causing inflammation, but it can also play other roles in the body that may contribute to the symptoms described for PD.  Regarding the contradictions in the association of serum leptin levels with PD, these investigators carried out a systematic review and meta-analysis to have a more accurate estimation of this relationship.  Published literature was obtained by searching PubMed, Embase, Cochrane Library, Scopus, Ovid, ProQuest and Google Scholar.  Random-effect model analysis was used to calculate pooled standard mean difference (SMD) with 95 % CI.  Heterogeneity was tested with the heterogeneity statistic Q and quantified using I2.  Newcastle-Ottawa scale was used to evaluate the study quality.  A total of 6 studies (198 PD patients and 182 controls) were finally included in the meta-analysis.  Serum leptin levels in PD patients were non-significantly lower than those in control group (SMD = -0.40 ng/ml, 95 % CI: -2.33 to 1.53).  Subgroup analyses revealed that serum leptin levels of PD patients and controls in either women or men didn't show any significant difference.  The authors concluded that this meta-analysis revealed that leptin level did not show any significant difference between PD patients and healthy controls, even when taking the subjects' gender into consideration.

Measurement of Telomere Length

Forero et al (2016) stated that differences in telomere length (TL) have been reported as possible risk factors for several neuropsychiatric disorders, including PD.  Results from published studies for TL in PD are inconsistent, highlighting the need for a meta-analysis.  In the current work, a meta-analysis of published studies for TL in PD was carried out.  PubMed, Web of Science and Google Scholar databases were used to identify relevant articles that reported TL in groups of PD patients and controls.  A random-effects model was used for meta-analytical procedures.  The meta-analysis included 8 primary studies, derived from populations of European and Asian descent, and did not show a significant difference in TL between 956 PD patients and 1,284 controls (p value: 0.246).  The authors concluded that the findings of this meta-analysis showed that there is no consistent evidence of shorter telomeres in PD patients and suggested the importance of future studies on TL and PD that analyze other populations and also include assessment of TL from different brain regions.

Measurement of Urinary LRRK2 Phosphorylation

Fraser and colleagues (2016) examined if phosphorylated Ser-1292 LRRK2 levels in urine exosomes predicts LRRK2 mutation carriers (LRRK2+) and non-carriers (LRRK2-) with Parkinson disease (PD+) and without Parkinson disease (PD-).  LRRK2 protein was purified from urinary exosomes collected from participants in 2 independent cohorts.  The 1st cohort included 14 men (LRRK2+/PD+, n = 7; LRRK2-/PD+, n = 4; LRRK2-/PD-, n = 3).  The 2nd cohort included 62 men (LRRK2-/PD-, n = 16; LRRK2+/PD-, n = 16; LRRK2+/PD+, n = 14; LRRK2-/PD+, n = 16).  The ratio of Ser(P)-1292 LRRK2 to total LRRK2 was compared between LRRK2+/PD+ and LRRK2- in the 1st cohort and between LRRK2 G2019S carriers with and without PD in the 2nd cohort.  LRRK2+/PD+ had higher ratios of Ser(P)-1292 LRRK2 to total LRRK2 than LRRK2-/PD- (4.8-fold, p < 0.001) and LRRK2-/PD+ (4.6-fold, p < 0.001).  Among mutation carriers, those with PD had higher Ser(P)-1292 LRRK2 to total LRRK2 than those without PD (2.2-fold, p < 0.001).  Ser(P)-1292 LRRK2 levels predicted symptomatic from asymptomatic carriers with an area under the receiver operating characteristic curve of 0.844.  The authors concluded that elevated ratio of phosphorylated Ser-1292 LRRK2 to total LRRK2 in urine exosomes predicted LRRK2 mutation status and PD risk among LRRK2 mutation carriers.  Moreover, they stated that future studies may explore whether interventions that reduce this ratio may also reduce PD risk.  In particular, they stated that larger studies that measure Ser(P)-1292 LRRK2 levels over time in asymptomatic carriers will be needed to understand the prognostic potential of this new biomarker.

In an editorial that accompanied the afore-mentioned study, Grunewald and Klein (2016) stated that "The findings by Fraser et al are exciting and promising.  However, they remain subject to independent confirmation and have been only obtained in a relatively small sample of 18 probands per group".

Metabolic Profiling for the Management of Parkinson’s Disease

Shao and colleagues (2021) stated that PD is a prevalent neurological disease in the elderly with increasing morbidity and mortality.  Despite enormous efforts, rapid and accurate diagnosis of PD is still compromised.  Metabolomics defines the final readout of genome-environment interactions via the analysis of the entire metabolic profile in biological matrices.  Recently, unbiased metabolic profiling of human sample has been initiated to identify novel PD metabolic biomarkers and dysfunctional metabolic pathways, however, it remains a challenge to define reliable biomarker(s) for clinical use.  These researchers presented a comprehensive metabolic evaluation for identifying crucial metabolic disturbances in PD using liquid chromatography-high resolution mass spectrometry (LC-hrMS)-based metabolomics approach.  Plasma samples from 3 independent cohorts (n = 460; 223 PD, 169 healthy controls (HCs), and 68 PD-unrelated neurological disease controls) were collected for the characterization of metabolic changes resulted from PD, anti-parkinsonian treatment and potential interferences of other diseases.  Unbiased multi-variate and uni-variate analyses were carried out to determine the most promising metabolic signatures from all metabolomic datasets.  Multiple linear regressions were used to examine the associations of metabolites with age, duration time and stage of PD.  The combinational biomarker model established by binary logistic regression analysis was validated by 3 cohorts.  A list of metabolites including amino acids, acylcarnitines, organic acids, steroids, amides, and lipids from human plasma of 3 cohorts were identified.  Compared with HC, these researchers observed significant reductions of fatty acids (FFAs) and caffeine metabolites, elevations of bile acids and microbiota-derived deleterious metabolites, and alterations in steroid hormones in drug-naïve PD.  Furthermore, these investigators found that L-dopa treatment could affect plasma metabolome involved in phenylalanine and tyrosine metabolism and alleviate the elevations of bile acids in PD.  Also, a metabolite panel of 4 biomarker candidates, including FFA 10:0, FFA 12:0, indole-3-lactic acid and phenylacetyl-glutamine was identified based on comprehensive discovery and validation workflow.  This panel showed favorable discriminating power for PD.  The authors concluded that the findings of this study may help improve the understanding of PD etiopathogenesis and facilitate target screening for therapeutic intervention.  The metabolite panel identified in this study may provide a novel approach for improving the understanding of PD etiopathogenesis and aid in the clinical diagnosis of PD/target screening for therapeutic intervention in the future.

The authors stated that this study had several drawbacks.  First, PD was diagnosed based on clinical criteria without laboratory confirmation.  Further studies to link peripheral metabolic changes to pathophysiology markers, genetic findings and neuroimaging profiles are recommended.  Second, these researchers only examined the effects of several commonly used anti-parkinsonian treatments, the impacts of other medications could not be clarified.  There were other factors such as genetic background, disease history, lifestyle, and diet, etc., which might influence the profiles of the metabolites in PD and controls.  To address this issue, future study is needed to calibrate the levels of metabolites with these factors in a larger cohort study.

Music-Based Interventions for the Treatment of Motor and Non-Motor Symptoms in Parkinson's Disease

In a systematic review and meta-analysis, Lee and Ko (2023) examined previous studies on music-based interventions for patients with PD.  The effectiveness of the interventions on various motor and non-motor outcomes was evaluated.  This review was conducted by searching PubMed, CINAHL, PsycINFO, and Cochrane Library CENTRAL prior to June 2022 for RCTs and controlled clinical trials (CCTs) published in English.  Data were expressed as weighted mean (WM) and SMD with 95 % CI; I2 index was used for heterogeneity.  The initial search identified 745 studies, and 13 studies entailing 417 subjects with PD that met the inclusion criteria included in this review.  The results of the meta-analysis revealed that music-based interventions could significantly improve walking velocity (MD = 0.12, 95 % CI: 0.07 to 0.16, p < 0.00001), stride length (MD = 0.04, 95 % CI: 0.02 to 0.07, p = 0.002), and mobility (MD = -1.05, 95 % CI: -1.53 to -0.57, p < 0.0001).  However, the results did not support significant effects for music-based interventions on cadence (MD = 3.21, 95 % CI: -4.15 to 10.57, p = 0.39), cognitive flexibility (MD = 20.91, 95 % CI: -10.62 to 52.44, p = 0.19), inhibition (SMD = 0.07, 95 % CI: -0.40 to 0.55, p = 0.76), and QOL (SMD = -0.68, 95 % CI: -1.68 to 0.32, p = 0.18).  The authors concluded that these findings suggested that music-based interventions were effective for the improvement of some motor symptoms, but evidence for non-motor symptoms was limited.  Moreover, these researchers stated that rigorous RCTs with larger sample sized are needed to examine the robust effects of music-based interventions on various outcomes among patients with PD.

The authors stated that this review had several drawbacks.  First, the sample size included in the meta-analysis was relatively small and varied between the studies, which may have affected the quality of the evidence.  Second, the literature included only publications written in English, which may have increased the risk of publication bias.  Furthermore, only 11 studies contributed to the meta-analysis in this review, which could not be carried out for all outcomes nor all combinations of interventions and comparators; thus, future research and evidence syntheses should include a wider range of outcomes relating to the potential benefit of various types of music-base interventions.  Those outcomes could include motor symptoms, including gait freezes and falls and upper extremity and fine motor rehabilitation, as well as non-motor symptoms, including communication and language and cognitive and psychosocial rehabilitation in patients with PD.  Additionally, owing to the insufficient number of trials included in each outcome, the confirmation of publication bias had a limited aspect.  Third, there was limitation in performing subgroup analyses on various factors including the type of interventions and the severity of disease due to the limited number of included studies.  It would be necessary to conduct a multilateral analysis of the variables that influence the results in the future.  These drawbacks may have affected the evaluated outcomes for motor and non-motor symptoms in patients with PD.

Non-Invasive Brain Stimulation (e.g., Transcranial Direct Current Stimulation/Transcranial Magnetic Stimulation)

Dinkelbach and co-workers (2017) noted that cognitive impairments and depression are common non-motor manifestations in PD, and recent evidence suggested that both partially arise via the same fronto-striatal network, opening the opportunity for concomitant treatment with non-invasive brain stimulation (NIBS) techniques (e.g., rTMS and tDCS).  In this systematic review, these investigators evaluated the effects of NIBS on cognition and/or mood in 19 placebo-controlled studies involving 561 PD patients.  Outcomes depended on the area stimulated and the technique used; rTMS over the dorsolateral-prefrontal cortex (DLPFC) resulted in significant reductions in scores of depressive symptoms with moderate-to-large effect sizes along with increased performance in several tests of cognitive functions; tDCS over the DLPFC improved performance in several cognitive measures, including executive functions with large effect sizes.  Additional effects of tDCS on mood were not detectable; however, only non-depressed patients were assessed.  The authors concluded that further confirmatory research is needed to clarify the contribution that NIBS could make in the care of PD patients.

Brabenec and associates (2017) review papers on hypokinetic dysarthria (HD) in PD with a special focus on

1. early PD diagnosis and monitoring of the disease progression using acoustic voice and speech analysis, and
2. functional imaging studies exploring neural correlates of HD in PD, and
3. clinical studies using acoustic analysis to evaluate effects of dopaminergic medication and brain stimulation.

A systematic literature search of articles written in English before March 2016 was conducted in the Web of Science, PubMed, SpringerLink, and IEEE Xplore databases using and combining specific relevant keywords. Articles were categorized into 3 groups:

1. articles focused on neural correlates of HD in PD using functional imaging (n = 13);
2. articles dealing with the acoustic analysis of HD in PD (n = 52); and
3. articles concerning specifically dopaminergic and brain stimulation-related effects as assessed by acoustic analysis (n = 31); the groups were then reviewed.

These researchers identified 14 combinations of speech tasks and acoustic features that can be recommended for use in describing the main features of HD in PD.  While only a few acoustic parameters correlate with limb motor symptoms and can be partially relieved by dopaminergic medication, HD in PD appeared to be mainly related to non-dopaminergic deficits and associated particularly with non-motor symptoms.  The authors concluded that future studies should combine NIBS with voice behavior approaches to achieve the best treatment effects by enhancing auditory-motor integration.

Liu and co-workers (2021) stated that PD is a common neurodegenerative disorder with motor and non-motor symptoms.  Recently, as adjuvant therapy, tDCS has been shown to improve the motor and non-motor function of patients with PD.  In a systematic review, these investigators examined available evidence for the effectiveness of tDCS for PD.  They included English databases (PubMed, the Cochrane Library, Embase, and Web of Science) and Chinese databases [Wanfang database, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and China Biology Medicine (CBM)] without restricting the year of publication.  A total of 21 tDCS studies (736 subjects) were included in the analysis.  Two independent researchers extracted the data and characteristics of each study.  There was a significant pooled effect size (-1.29; 95 % CI: -1.60 to -0.98; p < 0.00001; I2 = 0 %) in the UPDRS I and the Montreal cognitive assessment (SMD = 0.87, 95 % CI: 0.50 to 1.24; p < 0.00001; I2 = 0 %).  The poor effect size was observed in the UPDRS III scores (SMD = -0.13; 95 % CI: -0.64 to 0.38; p = 0.61; I2 = 77 %), and similar results were observed for the timed up and go (TUG) test, Berg balance scale, and gait assessment.  The authors concluded that the findings of this meta-analysis showed that there was insufficient evidence that tDCS improved the motor function of patients with PD; however, tDCS appeared to improve their cognitive performance.  Moreover, these researchers stated that further multi-center research with a larger sample size is needed.  In addition, future research should focus on determining the tDCS parameters that are most beneficial to the functional recovery of patients with PD.

de Oliveira and colleagues (2022) noted that clinical impact of tDCS alone for PD is still a challenge; thus, there is a need to synthesize available results, analyze methodologically and statistically, and provide evidence to guide tDCS in PD.  In a systematic review and meta-analysis, these researchers examined isolated tDCS effect in different brain areas and number of stimulated targets on PD motor symptoms.  They carried out a systematic review to February 2021, in databases: Cochrane Library, Embase, PubMed/Medline, Scopus, and Web of science.  Full text articles examining the effect of active tDCS (anodic or cathodic) versus sham or control on motor symptoms of PD were included.  A total of 10 studies (n = 236) were included in meta-analysis and 25 studies (n = 405) in qualitative synthesis.  The most frequently stimulated targets were DLPFC and PMd.  No significant effect was found among single targets on motor outcomes: UPDRS III - motor aspects (MD = -0.98 %, 95 % CI: -10.03 to 8.07, p = 0.83, I2 = 0 %), UPDRS IV - dyskinesias (MD = -0.89 %, 95 % CI: -3.82 to 2.03, p = 0.55, I2 = 0 %) and motor fluctuations (MD = -0.67 %, 95 % CI: -2.45 to 1.11, p = 0.46, I2 = 0 %), timed up and go - gait (MD = 0.14 %, 95 % CI: -0.72 to 0.99, p = 0.75, I2 = 0 %), Berg Balance Scale - balance (MD = 0.73 %, 95 % CI: -1.01 to 2.47, p = 0.41, I2 = 0 %).  There was no significant effect of single versus multiple targets in: UPDRS III - motor aspects (MD = 2.05 %, 95 % CI: -1.96 to 6.06, p = 0.32, I2 = 0 %) and gait (SMD = -0.05 %, 95 % CI: -0.28 to 0.17, p = 0.64, I2 = 0 %).  Simple univariate meta-regression analysis between treatment dosage and effect size revealed that number of sessions (estimate = -1.7, SE = 1.51, z-score = -1.18, p = 0.2, IC = -4.75 to 1.17) and cumulative time (estimate = -0.07, SE = 0.07, z-score = -0.99, p = 0.31, IC = -0.21 to 0.07) had no significant association.  The authors concluded that there was no significant tDCS alone short-term effect on motor function, balance, gait, dyskinesias or motor fluctuations in PD, regardless of brain area or targets stimulated.

Cheng and associates (2022) stated that theta burst stimulation (TBS), a type of patterned rTMS, has several advantages, such as short time of single treatment and low stimulation intensity compared with traditional rTMS.  Since the effectiveness of TBS on the symptoms of PD was inconsistent among different studies, these investigators systematically searched these studies and quantitatively analyzed the therapeutic effect of TBS for patients with PD.  They followed the recommended PRISMA guidelines for systematic reviews.  Studies from PubMed, Embase, CENTRAL, and ClinicalTrials.gov from January 1, 2005 of each database to September 30, 2021 were analyzed.  These researchers also manually retrieved studies of reference.  A total of 8 eligible studies with 189 subjects (received real TBS and/or sham TBS) were included.  This meta-analysis found that TBS did not significantly improve UPDRS-III score in the "on" medicine state (SMD = -0.06; 95 % CI: -0.37 to 0.25; p = 0.69; I2 = 0 %); however, it brought significant improvement of UPDRS-III scores in the "off" medicine state (SMD = -0.37; 95 % CI: -0.65 to -0.09; p < 0.01; I2 = 19 %).  Subgroup analysis found that merely continuous TBS (cTBS) over the supplementary motor area (SMA) brought significant improvement of UPDRS-III score (SMD = -0.63; 95 % CI: -1.02 to -0.25; p < 0.01).  TBS had insignificant effectiveness for upper limb movement disorder both in the "on" and "off" medicine status (SMD = -0.07; 95 % CI: -0.36 to 0.22; p = 0.64; I2 = 0 %; SMD = -0.21; 95 % CI: -0.57 to 0.15; p = 0.26; I2 = 0 %; respectively).  TBS significantly improved slowing of gait in the "off" medicine status (SMD = -0.37; 95 % CI: -0.71 to -0.03; p = 0.03; I2 = 0 %).  Subgroup analysis suggested that only intermittent TBS (iTBS) over the primary motor cortex (M1) + DLPFC had significant difference (SMD = -0.57; 95 % CI: -1.13 to -0.01; p = 0.04).  Furthermore, iTBS over the M1+ DLPFC had a short-term (within 2 weeks) therapeutic effect on PD depression (MD = -2.93; 95 % CI: -5.52 to -0.33; p = 0.03).  the authors concluded that the findings of this study demonstrated that cTBS over the SMA could significantly improve the UPDRS-III score for PD patients in the "off", not in the "on" medicine state.  These researchers stated that TBS could not bring significant improvement of upper limb movement dysfunction; and ITBS over the M1+DLPFC could significantly improve the slowing of gait in the "off" medicine status.  In additional, iTBS over the M1+DLPFC had a short-term (within 2 weeks) therapeutic effect on PD depression.  These researchers stated that further large sample size, multi-center studies are needed to evaluate the application prospect of TBS on invasive brain stimulation for expanding the therapeutic window and enhancing clinical benefits in PD.

The authors stated that this study had several drawbacks.  First, the total number of included subjects was small; thus, interpreting results should be performed cautiously.  Second, interpretation of changes for behavioral evaluation should be associated with reaching a level that reflected a significant clinical improvement.  Third, several uncontrolled variables, such as disease stage, side of onset, age, and sex, exist that could have confounded the results and must be acknowledged.  Lastly, these investigators did not definite the optimal iTBS/cTBS-brain targets and parameters of TBS that could bring significant therapeutic effect due to the limitation of the data in these included studies.  A further study combining TBS with different neuroimaging techniques may better discover the potential pathophysiological mechanisms of clinical benefit and optimize TBS treatment protocols.  Compared with the figure-of-8 coils mainly used in the included studies, the double-cone coil has the advantage of a stronger magnetic field with higher penetration depth, which is worthy of further study.  Furthermore, future research should try to establish a more precise relationship between the TBS effect and PD patients' clinical and demographic characteristics, such as anti-Parkinsonism medicine regimen, stage of disease, side of onset, symptom subtype (e.g., specific cognitive domain impairment), age, and gender, for finding the optimal stimulation protocols for individualized TBS treatment.

Partial Body Weight-Supported Treadmill Training

Plasma Neurofilament Light Chain (NfL) as a Biomarker for Disease Severity and Progression in Parkinson Disease

In a prospective, follow-up study, Lin and colleagues (2019) examined if plasma neurofilament light chain (NfL) levels were associated with motor and cognitive progression in PD.  This trial enrolled 178 subjects, including 116 with PD, 22 with multiple system atrophy (MSA), and 40 healthy controls.  These researchers measured plasma NfL levels with electro-chemiluminescence immunoassay.  Patients with PD received evaluations of motor and cognition at baseline and at a mean follow-up interval of 3 years.  Changes in the UPDRS part III motor score and MMSE score were used to assess motor and cognition progression.  Plasma NfL levels were significantly higher in the MSA group than in the PD and healthy groups (35.8 ± 6.2, 17.6 ± 2.8, and 10.6 ± 2.3 pg/ml, respectively, p < 0.001).  In the PD group, NfL levels were significantly elevated in patients with advanced Hoehn-Yahr stage and patients with dementia (p < 0.001).  NfL levels were modestly correlated with UPDRS part III scores (r = 0.42, 95 % CI: 0.46 to 0.56, p < 0.001).  After a mean follow-up of 3.4 ± 1.2 years, a Cox regression analysis adjusted for age, sex, disease duration, and baseline motor or cognitive status showed that higher baseline NfL levels were associated with higher risks for either motor or cognition progression (p = 0.029 and p = 0.015, respectively).  The authors concluded that these findings suggested that the plasma NfL level could serve as a non-invasive, easily accessible biomarker to evaluate disease severity and to monitor disease progression in PD.  They stated that future, large longitudinal follow-up studies that incorporate other biomarkers such as neuroimages are needed to strengthen the possible prognostic role of blood NfL levels in PD progression.  Level of Evidence = Class III.

The authors stated that this study had several drawbacks.  First, these researchers evaluated cognitive function only with MMSE, a simple measurement of global cognitive function. Detailed neuropsychological tests for evaluating individual cognitive domains are needed for further assessments of correlations between plasma NfL levels and individual cognitive domain declines in patients with PD.  Second, the clinical diagnosis of PD and MSA was not confirmed by post-mortem pathological confirmation and may be susceptible to mis-classification. However, these researchers based the final diagnosis on thorough clinical and laboratory examinations such as autonomic function tests and nuclear imaging studies, with close clinical follow-up, using the international consensus criteria in a movement disorder specialist's clinic. Third, the plasma level of NfL was checked only when the subjects were enrolled in the study. Future studies that serially follow-up plasma levels of NfL accompanied by motor and cognitive function evaluations would further delineate the changes of NfL in the disease course of PD and MSA.  Finally, although the plasma NfL level was significantly increased in patients with PD compared to controls and was correlated with disease severity (both motor and cognition) in the cross-sectional design of comparison, the Cox progression analysis revealed a modest significance of higher HRs for either motor or cognition progression in the follow-up study.  The possible reason may come from the relatively short follow-up time period for neurodegenerative disorders.  A future cohort with a larger sample size of subjects and longer follow-up is needed to confirm these findings and to validate the role of plasma NfL in predicting disease progression.

Halloway et al (2022) noted that blood biomarkers may allow earlier identification of PD, parkinsonism, and poor PD-related outcomes, such as physical functioning.  Neurofilament light (NfL) is a biomarker of neurodegeneration measurable in biofluids.  These investigators examined the association of serum NfL at baseline with clinically diagnosed PD, parkinsonian signs, and physical functioning change over 16 years in a population-based sample of older adults.  Data were derived from 1,327 older participants from the Chicago Health and Aging Project, a longitudinal population-based study.  Clinical evaluations included assessing parkinsonian signs in 4 domains-bradykinesia, parkinsonian gait, rigidity, and tremors-using a structured version of the UPDRS.  Board-certified neurologists diagnosed PD.  Physical functioning was assessed using chair stands, tandem walk, and timed walk.  An ultra-sensitive immunoassay was used to measure the concentration of NfL in blood.  Of the 1,254 participants examined for clinical PD, 77 (6.1 %) developed clinical PD and parkinsonian signs were on average 9.5 (range of 0 to 66.0).  After adjusting for demographic characteristics, APOE ε4 allele, and global cognition, a 2-fold higher concentration of serum NfL was associated with incident clinical PD (OR 2.54, 95 % CI: 1.70 to 3.81) and global parkinsonian signs (OR 2.44, 95 % CI: 1.94 to 2.94).  This association was significant more than 5 years before diagnosis.  Compared with participants with levels below 18.5 pg/ml of serum NfL at baseline, participants with levels between 18.5 and 25.4 pg/ml, between 25.4 and 37.3 pg/ml, and above 37.3 pg/ml had a higher OR of clinical PD at all time intervals from the time of diagnosis to more than 5 years before diagnosis.  A higher concentration of serum NfL was associated with a faster rate of physical functioning decline.  In participants with 2-fold higher concentrations of serum NfL, the annual rate of decline in physical functioning increased by 0.15 units (95 % CI: 0.21 to 0.08).  The authors concluded that serum NfL was associated with incident clinical PD, parkinsonian signs, and physical functioning decline in a population-based sample.  These findings suggested that NfL may serve as a potential biomarker for neurodegeneration, including PD outcomes.  Classification of Evidence = II.

The authors stated that findings from this analysis may be limited.  First, this sample represented a bi-racial population-based cohort in the Chicago metropolitan area; thus, the results may not generalize to other populations.  Second, the neuropathologic development of PD may begin in early adult or mid-life periods that were not captured in the CHAP study of older adults.  An earlier examination of blood biomarkers of PD over time would help elucidate the early stages of pre-clinical development.  Third, a potential limitation is method of diagnosing clinical PD.  At the time of the clinical evaluation, the neurologist rendered a diagnosis of clinical PD based on clinical history, evaluation of the parkinsonian signs, self-reported diagnosis for PD for which the participant received L-dopa or a dopamine agonist, and review of medications.  Because these diagnostic criteria may not wholly align with other accepted definitions, the rate of clinical PD diagnosis may differ from other reports in the general population.  In addition, the recruitment timeline of the CHAP study spanned 16 years, which may have resulted in variability of diagnosis over time.  Fourth, there was a small number of patients diagnosed with PD in this cohort (n = 77), which affected the findings with clinical PD as the outcome.  Fifth, although performance-based physical function tests were preferred over self-report measures, there still may be variation across raters.  Finally, these researchers examined only 1 biomarker of PD, which only evaluated neurodegeneration related to axonal loss and did not definitively discriminate PD from other neurodegenerative diseases in asymptomatic individuals.  In the future, other biomarkers of PD could be considered, such as α-synuclein (a marker of Lewy body neuropathology) or inflammatory factors (e.g., tumor necrosis factor–α).  This study did not obtain neuropathologic autopsy data, which should be considered for future studies.

Progressive Resistance Training

In a systematic review and meta-analysis, Saltychev and colleagues (2016) examined if there is evidence on effectiveness of progressive resistance training in rehabilitation of PD.  Data sources included Central, Medline, Embase, Cinahl, Web of Science, Pedro until May 2014.  Randomized controlled or controlled clinical trials were selected for analysis.  The methodological quality of studies was assessed according to the Cochrane Collaboration's domain-based evaluation framework.  Adults with primary/idiopathic PD of any severity, excluding other concurrent neurological condition were included in this analysis.  Progressive resistance training defined as training consisting of a small number of repetitions until fatigue, allowing sufficient rest between exercises for recovery, and increasing the resistance as the ability to generate force improves.  Of 516 records, 12 were considered relevant; 9 of them had low risk of bias.  All studies were RCTs conducted on small samples with none or 1 month follow-up after the end of intervention.  Of them, 6 were included in quantitative analysis.  Pooled effect sizes of meta-analyses on fast and comfortable walking speed, the 6-min walking test, Timed Up and Go test and maximal oxygen consumption were below the level of minimal clinical significance.  The authors concluded that there is so far no evidence on the superiority of progressive resistance training compared with other physical training to support the use of this technique in rehabilitation of PD.

Proprioceptive Focal Stimulation (Equistasi) for the Treatment of Gait and Postural Balance Rehabilitation in Patients with Parkinson's Disease

Spolaor et al (2021) examined the effects of Equistasi, a wearable device, on the relationship between muscular activity and postural control changes in a sample of 25 PD patients.  Gait analysis was performed via a 6-camera stereophotogrammetric system synchronized with 2 force plates, an 8-channel surface electromyographic (EMG) system, recording the activity of 4 muscles bilaterally: Rectus femoris, tibialis anterior (TA), biceps femoris, and gastrocnemius lateralis (GL).  The peak of the envelope (PoE) and its occurrence within the gait cycle (position of the peak of the envelope, PPoE) were calculated.  Frequency-domain posturographic parameters were extracted while standing still on a force plate in “eyes-open” and “eyes-closed” conditions for 60 s.  After the treatment with Equistasi, the mid-low (0.5 to 0.75) Hz and mid-high (0.75 to 1.0 Hz) components associated with the vestibular and somatosensory systems, PoE and PPoE, displayed a shift toward the values registered on the controls.  In addition, a correlation was found between changes in proprioception (power spectrum frequencies during the Romberg Test) and the activity of GL, BF (PoE), and TA (PPoE).  The authors concluded that findings of this study suggested that focal mechanical vibrations exerted by a wearable postural stabilizer could promote effective motor control strategies in PD patients at both levels: Balance and gait control.  Moreover, these researchers stated that future investigations should include larger sample size, a longer follow-up period, and the evaluation of the interaction of Equistasi with the proprioceptive system at both the level of frequency analysis during the Romberg Test and on tonic vibration stimulus-induced inhibition of the soleus muscle H reflex.

Alashram et al (2022) stated that gait and postural deficits are the most common impairments in patients with PD.  These impairments often reduce patients' QOL.  Equistasi is a wearable proprioceptive stabilizer that converts body thermic energy into mechanical vibration.  No systematic reviews have been published examining the influences of Equistasi on gait and postural control in patients with PD.  In a systematic review, these investigators examined the effects of proprioceptive focal stimulation (Equistasi) on gait deficits and postural instability in patients with PD.  PubMed, Scopus, PEDro, REHABDATA, web of science, CHAINAL, Embase, and Medline were searched from inception to July 2021.  The methodological quality of the selected studies was examined using the Physiotherapy Evidence Database (PEDro) scale.  A total of 5 studies met the eligibility criteria.  The scores on the PEDro scale ranged from 3 to 8, with a median score of 8.  The results showed evidence for the benefits of the proprioceptive focal stimulation on gait and postural stability in individuals with PD.  The authors concluded that proprioceptive focal stimulation (Equistasi) appeared to be safe and well-tolerated in patients with PD; it may improve gait ability and postural stability in patients with PD.  Moreover, these researchers stated that further high-quality studies with long-term follow-ups are needed to examine the long-term effects of proprioceptive focal stimulation (Equistasi) in patients with PD.

Respiratory Muscle Training

In a systematic review, Rodríguez and colleagues (2020) examined the effectiveness of respiratory muscle training in persons with PD.  PubMed/Medline, Embase, Web of Science, Scopus and PEDro electronic databases were searched until November 15, 2019.  Reference lists of included studies were hand-searched; RCTs assessing the effects of respiratory muscle training programs (both inspiratory and expiratory) in patients with PD were included.  Two reviewers independently identified eligible studies and extracted data; method quality was appraised with the PEDro scale.  A total of 5 papers including 3 RCTs with a total of 111 patients were identified.  Method appraisal showed a mean score of 5 in the PEDro scale.  One study analyzed inspiratory muscle training, 1 expiratory muscle training and 2 established a comparison between both of them.  Statistically positive results were found in maximal inspiratory pressure (p < 0.05 and d = 0.76), maximal expiratory pressure (p < 0.01 and d = 1.40), perception of dyspnea (p < 0.01), swallowing function (d = 0.55) and phonatory measures, without significant differences in spirometric indices.  The authors concluded that respiratory muscle training may be an effective alternative for improving respiratory muscle strength, swallowing function and phonatory parameters in subjects with PD.  Moreover, these researchers stated that the lack of primary studies regarding this type of training prevents obtaining robust evidence.

Retinal Thinning as a Biomarker of Parkinson Disease

Ahn and colleagues (2018) analyzed the relationship between retinal thinning and nigral dopaminergic loss in de-novo PD.  A total of 49 patients with PD and 54 age-matched controls were analyzed.  Ophthalmologic examination and macula optical coherence tomography (OCT) scans were performed with additional micro-perimetry, N-(3-[18F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane PET, and 3T MRI scans were done in patients with PD only.  Retinal layer thickness and volume were measured in sub-fields of the 1-, 2.22-, and 3.45-mm Early Treatment of Diabetic Retinopathy Study circle and compared in patients with PD and controls.  Correlation of inner retinal layer thinning with micro-perimetric response was examined in patients with PD, and the relationships between retinal layer thickness and dopamine transporter densities in the ipsilateral caudate, anterior and posterior putamen, and substantia nigra were analyzed.  Retinal layer thinning was observed in the temporal and inferior 2.22-mm sectors (false discovery rate-adjusted p < 0.05) of drug-naive patients with PD, particularly the inner plexiform and ganglion cell layers.  The thickness of these layers in the inferior 2.22-mm sector showed a negative correlation with the Hoehn and Yahr stage (p = 0.032 and 0.014, respectively).  There was positive correlation between macular sensitivity and retinal layer thickness in all 3.45-mm sectors, the superior 2.22-mm sector, and 1-mm circle (p < 0.05 for all).  There was an association between retinal thinning and dopaminergic loss in the left substantia nigra (false discovery rate-adjusted p < 0.001).  The authors concluded that retinal thinning was present in the early stages of PD, correlated with disease severity, and may be linked to nigral dopaminergic degeneration.  These researchers stated that retinal imaging may be useful for detection of pathologic changes occurring in early PD.

Robot-Assisted Gait Training on Lower Extremity Dyskinesia in Parkinson's Disease

Xue et al (2023) noted that robot-assisted training is used as a new rehabilitation training method for the treatment of motor dysfunction in neurological diseases.  Robot-assisted gait training (RAGT) has been reported to treat motor dysfunction in patients with PD.  In a systematic review and meta-analysis, these investigators examined clinical studies comparing the effectiveness of RAGT and conventional training for lower extremity dyskinesia in PD patients.  They searched PubMed, Cochrane library, Scopus, Embase, EBSCO, Web of Science, CNKI, and Wanfang databases.  This study included all RCTs compared lower extremity RAGT with conventional training on motor impairment in PD patients.  The retrieval time limit was from the establishment of the database to October 2022. T wo researchers independently screened the literature, extracted data, assessed the risk of bias of included studies, and then used RevMan 5.3 software for meta-analysis.  A total of 14 RCTs with 572 patients were included.  The results showed that compared with the control group, RAGT significantly improved the motor function evaluation-related indicators 10-meter walk test (10MWT), 6 minute walk test (6MWT), Timed Up & Go (TUG) test and UPDRS III, 10MWT [MD = 0.08, 95 % CI: 0.01 to 0.14, p = 0.03], 6MWT [MD = 42.83, 95 % CI: 22.05 to 63.62, p < 0.0001], TUG  [MD= -1.81, 95 % CI: 2.55 to -1.08, p < 0.0001], UPDRS III [MD = -3.82, 95 % CI: -4.27 to -3.37, p < 0.00001];  For the balance function evaluation index BBS [MD = 3.33, 95 % CI: 2.76 to 3.89, p < 0.00001], the above results were significantly different significance.  The authors concluded that the currently limited evidence suggested that RAGT provided evidence for the effectiveness of lower extremity motor function and balance dysfunction, and RAGT could significantly improve motor and balance function in PD patients.  Moreover, these researchers stated that future studies are needed to confirm these findings.

Salivary Biomarkers of Parkinson's Disease

Bougea and colleagues (2019) noted that the search for a reliable, early-disease biomarker for PD that reflects underlying pathology is a high priority in PD research.  Salivary alpha-synuclein (α-Syn) is an easily accessible biomarker for PD with promising results.  These researchers examined the performance of salivary α-Syn as a diagnostic biomarker of PD.  They identified 476 studies through a systematic literature review according to PRISMA guidelines.  A total of 8 studies reporting data on salivary α-Syn were included in the review (1,240 participants).  The quality of studies was assessed by Newcastle-Ottawa scale: 3 studies showed that the total α-Syn levels were significantly lower in PD patients compared to healthy controls, while in another 5 there was no significant association.  In some studies, total salivary α-Syn was associated with demographic and clinical features; however, no consistent pattern emerged.  In 1 study, total α-Syn levels were associated with poor cognitive performance in PD patients.  Four studies showed a higher salivary oligomeric α-Syn and oligomeric α-Syn/total α-Syn ratio in PD compared to healthy controls, while in another 4 there was no association.  One study concluded that genetic polymorphisms may influence total salivary α-Syn in PD patients.  The authors concluded that the potential of salivary total α-Syn as a PD biomarker is still uncertain, whereas salivary oligomeric α-Syn appeared quite promising.  Pre-analytical and analytical factors of included studies were important limitations to justify the introduction of salivary α-Syn into clinical practice.

Vivacqua and associates (2019) stated that α-Syn aggregation is the pathological hallmark of PD.  These investigators measured α-Syn total (α-Syntotal), oligomeric α-Syn (α-Synolig) and α-Synolig/α-Syntotal ratio in the saliva of patients affected by PD and in age and sex-matched healthy subjects.  They also compared salivary α-Sntotal measured in PD with those detected in progressive supranuclear palsy (PSP), in order to examine if salivary α-Syn could be used as a biomarker for PD and for the differential diagnosis between PD and PSP.  These researchers studied 100 PD patients, 20 patients affected by PSP and 80 age- and sex-matched healthy subjects; ELISA analysis was performed using 2 commercial ELISA platforms and a specific ELISA assay for α-Syn aggregates.  They detected lower α-Syntotal and higher α-Synolig in PD than in healthy subjects.  Conversely in PSP salivary α-Syntotal concentration was comparable to that measured in healthy subjects.  Receiver operating characteristic (ROC) analyses revealed specific cut-off values able to differentiate PD patients from healthy subjects and PSP patients with high sensitivity and specificity.  However, there was no significant correlation between clinical and molecular data.  The authors concluded that salivary α-Syn detection could be a promising and easily accessible biomarker for PD and for the differential diagnosis between PD and PSP.

Figura and Friedman (2020) stated that the identification of reliable biomarkers of PD is a pivotal step in the introduction of causal therapies.  Saliva is a biofluid that may be involved in synuclein pathology in PD.  These researchers have reviewed current studies on salivary proteins and compounds in PD patients and healthy controls, and their potential application as biomarkers.  They carried out a systematic literature search of the PubMed and Scopus databases.  A total of 198 studies were screened, of which 20 were included in this qualitative analysis.  The authors concluded that the oligomeric form of salivary α-Syn was higher in PD patients, and that this may serve as a potential biomarker of PD.  Salivary DJ-1 concentrations failed to differentiate PD patients from controls.  Other enzymes and substances (heme oxygenase-1, nitric oxide, acetylcholinesterase) have been assessed in single studies.  Salivary cortisol levels were higher in PD than in healthy subjects.  These researchers stated that saliva may be a promising source of biomarkers in PD; moreover, further validation of these findings is needed.

Serum FGF-21, GDF-15, and Blood mtDNA Copy Number as Biomarkers of Parkinson Disease

Davis and colleagues (2019) noted that strong evidence of mitochondrial dysfunction exists for both familial and sporadic PD.  A simple test, reliably identifying mitochondrial dysfunction, could be important for future stratified medicine trials in PD.  These researchers previously undertook a comparison of serum biomarkers in classic mitochondrial diseases and established that serum growth differentiation factor 15 (GDF-15) out-performed fibroblast growth factor 21 (FGF-21) when distinguishing patients with mitochondrial diseases from healthy controls.  These investigators evaluated serum FGF-21 and GDF-15, together with mitochondrial DNA (mtDNA) copy number levels in peripheral blood cells from patients with PD and healthy controls, to examine if these measures could act as a biomarker of PD.   A total of 121 patients with PD and 103 age-matched healthy controls were recruited from a single center.  Serum FGF-21 and GDF-15, along with blood mtDNA copy number, were quantified using established assays.  There were no meaningful differences identified for any of the measures when comparing patients with PD with healthy controls.  This highlighted a lack of diagnostic sensitivity that is incompatible with these measures being used as biomarkers for PD.  The authors concluded that in this study, serum FGF-21, serum GDF-15, and blood mtDNA levels were similar in patients with PD and healthy controls and thus unlikely to be satisfactory indicators of mitochondrial dysfunction in patients with PD.

Spinal Cord Stimulation for the Treatment of Gait Disorders in Parkinson's Disease

Opova et al (2023) noted that spinal cord stimulation (SCS) is a therapeutic procedure widely used in the management of refractory chronic pain.  Evidence from case reports and small descriptive studies has emerged suggesting a role for SCS in patients with gait dysfunction, such as freezing of gait (FoG) and postural imbalance, which are severely debilitating symptoms of advanced PD.  These researchers examined the available evidence for the potential use of SCS on gait and balance dysfunction in PD patients.  A total of 3 online databases were screened for relevant studies; 2 separate searches and 4 different search strategies were employed to yield relevant results.  The main parameters of interest were postural and gait symptoms; secondary outcomes were QOL and adverse effects.  A total of 19 studies fulfilled the inclusion criteria.  Motor improvements using section III of the UPDRS (UPDRS-III) were available in 13 studies.  Measurements to evaluate FoG reported the following improvements: FoG questionnaires (in 1/19 studies); generalized freezing parameters (2); and walkway/wireless accelerometer measurements (2).  Parameters of postural imbalance and falling improved as follows: BBS (1); posture sagittal vertical axis (1); and generalized data on postural instability (8).  Two studies reported on adverse effects.  QOL was shown to improve as follows: EQ-5D (2); ADL (1); SF-36 (1); BDI-II (1); PDQ-8 (1); HDRS (1); and VAS (5).  The authors concluded that SCS for Postural instability and gait disorder (PIGD) in PD is a therapy that is worth investigating further.  The existing evidence within this patient population, weak as it is, suggests that the procedure is relatively safe and may have beneficial effects on QOL and motor scores.  There is a pressing need for an adequately powered clinical trial with clearly described statistical analysis methods, patient cohort and tools for clinical evaluation.  This will aid researchers to draw more solid conclusions regarding the therapeutic potential of SCS in PD patients with gait complications and open new research opportunities in the field of preventative medicine or combined treatment.

The Syn-One Test (Cutaneous Alpha-Synuclein)

Gibbons et al (2017) stated that Parkinson disease (PD) is a neurodegenerative disorder characterized by tremor, rigidity and bradykinesia and pathologically by the deposition of alpha-synuclein within different tissues.  These investigators, and others, have reported the detection of cutaneous alpha-synuclein in patients with PD.  In a pilot study, these researchers detected alpha-synuclein deposition by immunohistochemical staining of skin samples in pathologically confirmed cases of PD.  Post-mortem skin biopsy samples from 11 individuals with PD, and 5 non-synucleinopathy control subjects were paraffin embedded and stained for total alpha-synuclein and protein gene product (PGP) 9.5.  Alpha-synuclein deposition was greater in both scalp and abdominal skin biopsy PD samples compared to control samples in pilomotor nerves (p < 0.05), sudomotor nerves (p < 0.05) and vasomotor nerves (p < 0.05).  Deposition of alpha-synuclein in scalp and abdominal tissue did not correlate with age, duration of PD, or severity of PD.  The authors concluded that there was greater deposition of alpha-synuclein within pilomotor, sudomotor and vasomotor nerve fibers of paraffin embedded samples from autopsy confirmed cases of PD compared to control samples; however, assessment of alpha-synuclein deposition in post-mortem paraffin embedded tissue has many limitations and the use of this technique in clinical and research studies is uncertain.  These researchers noted that these findings suggested that paraffin embedded tissue sections may have limited value as a diagnostic biomarker but are not likely to demonstrate value as a prognostic biomarker or as a biomarker for assessing therapeutic efficacy.

Wang et al (2020) noted that the detection of cutaneous phosphorylated alpha-synuclein (P-syn) in patients with PD has ranged from 30 % to 100 % across different studies.  These researchers hypothesized that part of the variability in P-syn detection was due to methodological differences using sections of different tissue thickness.  Three skin biopsies were obtained from 29 individuals with PD and 21 controls.  Tissues were cut into 10-, 20-, and 50-µm thick sections and double-stained with PGP 9.5 and P-syn.  They quantified the deposition of P-syn with and without PGP 9.5 in sweat glands, pilomotor muscle, and blood vessels using confocal digital images of autonomic structures.  Overall, the P-syn-positive rates with PGP 9.5 colocalization in subjects with PD were 100 % using 50-µm sections, 90 % using 20-µm sections, and 73 % using 10-µm sections with 100 % specificity.  No P-syn was detected within control subjects.  Without PGP 9.5, colocalization of the P-syn-positive rates was 100 % for all samples; however, specificity dropped below 70 %.  The authors concluded that in this study, double-immuno-stained 50-µm skin biopsy tissue sections were superior to 20- and 10-µm tissue sections at detecting P-syn in subjects with PD.  The increased sensitivity was likely secondary to a combination of greater volume of tissue analyzed and improved visualization of nerve fiber architecture.

Ma et al (2019) stated that PD is a common neurodegenerative disorder.  To-date, the diagnosis of PD relies mainly on clinical manifestations whereas neuropathological confirmation of the brain is only possible with post-mortem studies.  Neuronal loss in the substantia nigra pars compacta (SNc) associated with Lewy bodies/neurites is the pathological hallmark feature of PD.  The major component of Lewy pathology (LP) is misfolded alpha-synuclein (α-SYN).  There is evidence that the distribution of LP is not only limited to the brain but extends to peripheral tissues, including gastro-intestinal (GI) tract, salivary glands, olfactory mucosa, skin, retina, adrenal gland, and heart.  Sensitivity and specificity of α-SYN detection in PD vary greatly among studies due to methodological heterogeneity, such as sampling sites and size, tissue preparation, staining techniques, and antibodies used.  Of note, α-SYN has also been found in pre-clinical and prodromal PD.  The authors concluded that further in-vivo studies focusing on favorable biopsy sites and standard techniques are needed to get better understanding of α-SYN deposits in pre-clinical, prodromal, and clinical PD.

Furthermore, an UpToDate review on “Etiology and pathogenesis of Parkinson disease” (Jankovic, 2021) does not mention detection of cutaneous alpha-synuclein as a management option.

Tumor Necrosis Factor Inhibition for Prevention of Parkinson Disease or Delay its Onset

Kang and colleagues (2021) examined the effects of long-term tumor necrosis factor (TNF) inhibition on the risk and age at onset of PD.  These researchers carried out a 2-sample Mendelian randomization study using genome-wide association studies (GWAS) summary statistics.  Genetic variants in the vicinity of TNFRSF1A, the gene encoding TNF receptor 1 (TNFR1), were identified as predictive of pharmacologic blockade of TNFR1 signaling by anti-TNF therapy, based on genetic associations with lower circulating C-reactive protein (CRP; GWAS n = 204,402).  The effects of TNF-TNFR1 inhibition were estimated for PD risk (cases/controls = 37,688/981,372) and age at PD onset (n = 28,568) using GWAS data from the International Parkinson's Disease Genomics Consortium and 23andMe, Inc.  To validate variants as proxies of long-term anti-TNF treatment, these investigators also examined if variant associations reflected anticipated effects of TNFR1 inhibition on Crohn disease, ulcerative colitis, and multiple sclerosis risk (n = 38,589-45,975).  TNF-TNFR1 signaling inhibition was not estimated to affect PD risk (OR per 10 % lower circulating CRP = 0.99; 95 % CI: 0.91 to 1.08) or age at onset (0.13 years later onset; 95 % CI: -0.66 to 0.92).  In contrast, genetically indexed TNF-TNFR1 signaling blockade predicted reduced risk of Crohn disease (OR 0.75; 95 % CI: 0.65 to 0.86) and ulcerative colitis (OR 0.84; 95 % CI: 0.74 to 0.97) and increased multiple sclerosis risk (OR 1.57; 95 % CI: 1.36 to 1.81).  Findings were consistent across models using different genetic instruments and Mendelian randomization estimators.  The authors concluded that these findings did not imply that TNF-TNFR1 signaling inhibition will prevent or delay PD onset.  Level of Evidence = II.

The authors stated that this study's main drawbacks were that they could not examine if there was an interaction between inflammatory status and TNF inhibition on PD risk or index the effects of TNF inhibition on direct measures of PD progression.  Moreover, these researchers stated that future Mendelian randomization studies could use large-scale GWAS of PD progression to help examine the disease-modifying potential of selective TNFR1 inhibitors for PD treatment.

Vagotomy for the Prevention and Treatment of PD

Liu and colleagues (2017) examined if vagotomy decreases the risk of PD.  Using data from nationwide Swedish registers, these researchers conducted a matched-cohort study of 9,430 vagotomized patients (3,445 truncal and 5,978 selective) identified between 1970 and 2010 and 377,200 reference individuals from the general population individually matched to vagotomized patients by sex and year of birth with a 40:1 ratio.  Participants were followed-up from the date of vagotomy until PD diagnosis, death, emigration out of Sweden, or December 31, 2010, whichever occurred first.  Vagotomy and PD were identified from the Swedish Patient Register.  These researchers estimated HRs with 95 % CIs using Cox models stratified by matching variables, adjusting for country of birth, chronic obstructive pulmonary disease, diabetes mellitus, vascular diseases, rheumatologic disease, osteoarthritis, and co-morbidity index.  A total of 4,930 cases of incident PD were identified during 7.3 million person-years of follow-up.  PD incidence (per 100,000 person-years) was 61.8 among vagotomized patients (80.4 for truncal and 55.1 for selective) and 67.5 among reference individuals. Overall, vagotomy was not associated with PD risk (HR 0.96, 95% CI 0.78-1.17). However, there was a suggestion of lower risk among patients with truncal vagotomy (HR 0.78, 95 % CI: 0.55 to 1.09), which may be driven by truncal vagotomy at least 5 years before PD diagnosis (HR 0.59, 95 % CI: 0.37 to 0.93).  Selective vagotomy was not related to PD risk in any analyses.  The authors stated that although overall vagotomy was not associated the risk of PD; they found suggestive evidence for a potential protective effect of truncal, but not selective, vagotomy against PD development.

In an editorial that accompanied the afore-mentioned study, Borghammer and Hamani (2017) stated that "At this stage, we have insufficient knowledge to propose vagotomy as a putative treatment for PD".

Wearable Inertial Sensors for Home Monitoring of Patients with Parkinson's Disease

Sica and colleagues (2021) noted that PD is a progressive neurological disorder of the central nervous system (CNS) that deteriorates motor functions, while it is also accompanied by a large diversity of non-motor symptoms such as cognitive impairment and mood changes, hallucinations, and sleep disturbance.  Parkinsonism is evaluated during clinical examinations and appropriate medical treatments are directed towards alleviating symptoms.  Tri-axial accelerometers, gyroscopes, and magnetometers could be adopted to support clinicians in the decision-making process by objectively quantifying the patient's condition.  In this context, at-home data collections aim to capture motor function during daily living and unobstructedly examine the patients' status and the disease's symptoms for prolonged time periods.  These investigators collated existing literature on PD monitoring using inertial sensors while it focused on papers with at least 1 free-living data capture unsupervised either directly or via videotapes.  A total of 24 studies were selected at the end of the process: 14 examined gait impairments, 8 of which focused on walking, 3 on turning, 2 on falls, and 1 on physical activity; 10 articles on the other hand examined symptoms, including bradykinesia, tremor, dyskinesia, and motor state fluctuations in the on/off phenomenon.  The authors concluded that inertial sensors were capable of gathering data over a long period of time and have the potential to facilitate the monitoring of people with PD, providing relevant information regarding their motor status.  Concerning gait impairments, kinematic parameters (such as duration of gait cycle, step length, and velocity) were typically used to discern PD from healthy subjects, whereas for symptoms' assessment, researchers were capable of achieving accuracies of over 90 % in a free-living environment.  The authors concluded that further investigations should be focused on the development of ad-hoc hardware and software capable of providing real-time feedback to clinicians and patients.  Furthermore, features such as the wearability of the system and user comfort, set-up process, and instructions for use, need to be strongly considered in the development of wearable sensors for PD monitoring.

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References