Huntington's Disease

Number: 0614

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

Policy

Scope of Policy

This Clinical Policy Bulletin addresses selected interventions for Huntington's disease.

Experimental, Investigational, or Unproven

Aetna considers the following interventions experimental, investigational, or unproven for Huntington's disease because the effectiveness of these approaches has not been established:
1. Functional neuroimaging (e.g., MRI) for monitoring disease progression or predicting the onset of pre-manifest Huntington’s disease;
2. Measurement of circulating interleukins (ILs) levels (including IL-6 and IL-10) for identifying pre-symptomatic individuals with Huntington’s disease and monitoring disease progression;
3. PET imaging for evaluation of progression of HD;
4. Putaminal magnetic resonance spectroscopy measurements of myo-inositol and N-acetylaspartate for the diagnosis of Huntington's disease;
5. Sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) mRNA as molecular biomarkers for monitoring onset and/or progression of Huntington’s disease;
6. The following biomarkers for Huntington's disease:
  1. Cytokines
  2. Measurement of iron accumulation in the basal ganglia
  3. MicroRNAs
  4. Neuro-filament light chain
  5. Salivary levels of total huntingtin
  6. Tau
  7. Transcriptomic changes in blood;
7. The following interventions (not an all-inclusive list) for the treatment of Huntington's disease:
  1. Alpha-tocopherol
  2. Aminooxyacetic acid (AOAA)
  3. Cannabinoids
  4. Combination of gene therapy and stem cell therapy
  5. Dance therapy
  6. Deep brain stimulation
  7. Electro-convulsive therapy
  8. Ethyl eicosapentaenoate
  9. Fetal striatal transplantation
  10. Gene therapy including HTT-lowering therapies and gene silencing (e.g., through RNA interference)
  11. Ionis-HTTRx (an HTT-targeting anti-sense oligonucleotide)
  12. Levocarnitine
  13. Minocycline
  14. Music therapy
  15. Neural grafts
  16. Neurotrophic factors (e.g., brain-derived neurotrophic factor, ciliary neurotrophic factor, glial cell line-derived neurotrophic factor)
  17. Pallidotomy (for the treatment of dystonia associated with Huntington’s disease)
  18. Rhythmic auditory cueing
  19. Stem cell transplantation (e.g., fetal stem cell transplantation, mesenchymal stem cell transplantation, and neural stem cell transplantation)
  20. Transcranial direct current stimulation
  21. Transcranial magnetic stimulation
  22. Wearable/portable digital sensors for clinical management (e.g., detection of early disease manifestations and disease fluctuations) of individuals with Huntington's disease.
Related Policies

Table:
CPT Codes / HCPCS Codes / ICD-10 Codes
Code	Code Description
CPT codes not covered for indications listed in the CPB:
Ionis-HTTRx (an HTT-targeting anti-sense oligonucleotide), Fetal striatal transplantation, Transcriptomic changes in blood, Alpha-tocopherol, aminooxyacetic acid [AOAA], cannabinoids, rhythmic auditory cueing - no specific code
0232T	Injection(s), platelet rich plasma, any site, including image guidance, harvesting and preparation when performed
38230	Bone marrow harvesting for transplantation; allogeneic
38232	autologous
38240	Hematopoietic progenitor cell (HPC); allogeneic transplantation per donor
38241	autologous transplantation
38242	Allogeneic lymphocyte infusions
38243	Hematopoietic progenitor cell (HPC); HPC boost
61720	Creation of lesion by stereotactic method, including burr hole(s) and localizing and recording techniques, single or multiple stages; globus pallidus or thalamus
61798	Stereotactic radiosurgery (particle beam, gamma ray, or linear accelerator); 1 complex cranial lesion
61799	each additional cranial lesion, complex (List separately in addition to code for primary procedure)
61863 - 61864	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
61867 - 61868	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
61880	Revision or removal of intracranial neurostimulator electrodes
61885 - 61886	Insertion or replacement of cranial neurostimulator pulse generator or receiver, direct or inductive coupling; with connection to a single electrode array or with connection to 2 or more electrode arrays
64885	Nerve graft (includes obtaining graft), head or neck; up to 4 cm in length [neural graft]
64886	more than 4 cm length [neural graft]
70553	Magnetic resonance (eg, proton) imaging, brain (including brain stem); without contrast material, followed by contrast material(s) and further sequences
70554	Magnetic resonance imaging, brain, functional MRI; including test selection and administration of repetitive body part movement and/or visual stimulation, not requiring physician or psychologist administration
76390	Magnetic resonance spectroscopy [putaminal MRS measurements of myoinositol and N-acetylaspartate]
78608	Brain imaging, positron emission tomography (PET); metabolic evaluation
78609	perfusion evaluation
78813	Positron emission tomography (PET) imaging; whole body
78814	Positron emission tomography (PET) with concurrently acquired computed tomography (CT) for attenuation correction and anatomical localization imaging; limited area (eg, chest, head/neck)
78816	whole body
81401	Molecular pathology procedure, Level 2 (eg, 2 - 10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) [salivary levels of total Huntington]
81405	Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) [Neuro-filament light chain]
83520	Immunoassay for analyte other than infectious agent antibody or infectious agent antigen; quantitative, not otherwise specified [Tau]
83529	Interleukin-6 (IL-6)
90867 - 90869	Therapeutic repetitive transcranial magnetic stimulation (TMS) treatment
90870	Electroconvulsive therapy (includes necessary monitoring)
95836	Electrocorticogram from an implanted brain neurostimulator pulse generator/transmitter, including recording, with interpretation and written report, up to 30 days
95970 - 95971	Electronic analysis of implanted neurostimulator pulse generator system (eg, rate, pulse amplitude, pulse duration, configuration of wave form, battery status, electrode selectability, output modulation, cycling, impedance and patient compliance measurements)
95976	Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with simple cranial nerve neurostimulator pulse generator/transmitter programming by physician or other qualified health care professional
95977	Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with complex cranial nerve neurostimulator pulse generator/transmitter programming by physician or other qualified health care professional
95983	Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with brain neurostimulator pulse generator/ transmitter programming, first 15 minutes face-to- face time with physician or other qualified health care professional
95984	Electronic analysis of implanted neurostimulator pulse generator/transmitter (eg, contact group[s], interleaving, amplitude, pulse width, frequency [Hz], on/off cycling, burst, magnet mode, dose lockout, patient selectable parameters, responsive neurostimulation, detection algorithms, closed loop parameters, and passive parameters) by physician or other qualified health care professional; with brain neurostimulator pulse generator/ transmitter programming, each additional 15 minutes face-to-face time with physician or other qualified health care professional (List separately in addition to code for primary procedure)
Other CPT codes related to the CPB:
38225	Chimeric antigen receptor T-cell (CAR-T) therapy; harvesting of blood-derived T lymphocytes for development of genetically modified autologous CAR-T cells, per day
38226	preparation of blood-derived T lymphocytes for transportation (eg, cryopreservation, storage)
38227	receipt and preparation of CAR-T cells for administration
38228	CAR-T cell administration, autologous
HCPCS codes not covered for indications listed in the CPB :
Wearable/portable digital sensor, SERCA2, VEGF mRNA,ethyl eicosapent, orneurotrophic factors (e.g., brain-derived neurotrophic factor, ciliary neurotrophic factor, glial cell line-derived neurotrophic factor), MicroRNAs as biomarkers - no specific code
C1767	Generator, neurostimulator (implantable), nonrechargeable
C1778	Lead, neurostimulator (implantable)
C1816	Receiver and/or transmitter, neurostimulator (implantable)
C1883	Adaptor/ extension, pacing lead or neurostimulator lead (implantable)
C1897	Lead, neurostimulator test kit (implantable)
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)
J1955	Injection, levocarnitine, per 1 gm
J2265	Injection, minocycline HCl, 1 mg
L8680 - L8683, L8685 - L8689	Neurostimulators and accessories
L8695	External recharging system for battery (external) for use with implantable neurostimulator, replacement only
S2150	Bone marrow or blood-derived stem cells (peripheral or umbilical), allogeneic or autologous, harvesting, transplantation, and related complications; including: pheresis and cell preparation/storage; marrow ablative therapy; drugs, supplies, hospitalization with outpatient follow-up; medical/surgical, diagnostic, emergency, and rehabilitative services; and the number of days of pre-and post-transplant
ICD-10 codes not covered for indications listed in the CPB:
G10	Huntington’s disease
Z13.858	Encounter for screening for other nervous system disorders [Huntington’s disease]

Background

Huntington's disease (HD) is a progressive, fatal, autosomal dominant neuro-degenerative disease caused by increased CAG repeats in the huntington gene. It is characterized by chorea and imbalance as well as deterioration in cognitive and neuropsychiatric function. Primary pathological changes are found in the caudate-putamen (striatum), where gabaminergic neurons undergo degenerative changes. There is also evidence that HD is a multi-system degeneration. A recent study reported that cortical degeneration is present in early stages of HD and may explain at least some of the clinical symptoms (Rosas et al., 2002).

Circulating Interleukins Levels in Huntington's Disease

Corey-Bloom et al. (2020) stated that growing evidence suggests that inflammatory responses, both in the brain and peripheral tissues, contribute to disease pathology in Huntington's disease (HD). Therefore, studies of inflammation-related markers in peripheral fluids might be useful for better characterizing disease features. In this study, these researchers measured levels of C-reactive protein (CRP), interleukin-6 (IL-6), interleukin-1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from 125 subjects, including 37 manifest HD patients, 36 pre-manifest patients, and 52 healthy controls (HCs), using immunoassays. They found increases in salivary levels of IL-6, IL-1B, and CRP across different disease groups, as well as increased levels of IL-6 in the plasma of HD patients compared to pre-manifest patients and HCs. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. In addition, salivary IL-6 and IL-1B levels were significantly positively correlated with total motor score and chorea scores, and negatively correlated with total functional capacity in HD patients. In HCs, IL-6 was significantly negatively correlated with the Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations with any clinical measures in either HD patients or HCs. The authors concluded that this study was the first to measure salivary inflammation markers in the context of HD, highlighting salivary levels of IL-6 as significantly associated with prominent disease symptoms in HD mutation carriers, as well as correlated with cognitive measures in normal participants. These findings suggest that inflammatory changes detected in peripheral saliva may be biologically relevant and mirror the neurodegenerative process occurring in the central nervous system (CNS). The investigators stated that although IL-6 elevation would likely not be specific to HD compared to other neurodegenerative diseases, the advent of an effective, dependable salivary biomarker would meet the need for a less invasive means of identifying and monitoring HD disease progression.

Eide et al. (2023) stated that HD is a rare, inherited disorder with a broad spectrum of manifestations that vary with disease severity and progression. Although genetic testing can readily confirm the initial diagnosis of HD, markers sensitive to HD progression are needed to aid the development of individual treatment plans. In a systematic review and meta-analysis, these researchers identified plasma IL-6 as a marker of disease progression in HD patients. They conducted a systematic search of PubMed and Medline from inception through October 2021. Studies reporting plasma IL-6 levels of mutation-positive HD patients and HCs that met inclusion criteria were selected. The search strategy collected 303 studies, 9 of which fulfilled the inclusion criteria. From the included studies, plasma IL-6 levels of 469 individuals with the HD mutation and 206 HCs were collected. Plasma IL-6 levels were meta-analytically compared between HCs and individuals with the confirmed HD mutation at all stages of the disease and correlated with performance on standardized measures of total cognitive and motor function. Plasma IL-6 was significantly increased in HD groups compared to controls (g = 0.73, 95% CI: 0.31 to 1.16, p < 0.01) and increased significantly throughout most stages of disease progression, notably between pre-manifest and manifest (g = 0.31, 95% CI: 0.04 to 0.59, p < 0.05) and early and moderate HD stages (g = 0.52, 95% CI: 0.18 to 0.86, p < 0.01). Significant correlations between plasma IL-6 levels and HD symptomatic progression were identified, with increased cytokine levels associated with more severe motor impairments (r = 0.179, 95% CI: 0.0479 to 0.304, p = 0.008) and more extreme disabilities in activities of daily living (ADLs) and/or work tasks (r = -0.229, 95% CI: -0.334 to -0.119, p < 0.001). The authors concluded that plasma IL-6 levels correlated with disease and motor symptom progression and may act as a viable marker for clinical use. Moreover, these investigators stated that the analysis was limited by small study numbers and highlighted the need for further investigations to identify definitive ranges or rates of change of plasma IL-6 levels that correlate with progressive HD disease states.

The authors stated that future work should quantitatively define ranges of plasma IL-6 levels across states of disease progression or quantify the rate of change in plasma IL-6 levels as individuals progress through disease states. Such information could be directly applied to clinical practice and provide a framework to estimate timeframes for disease and symptom progression based on plasma IL-6. Unfortunately, the nature of pooling heterogeneous data derived from different studies did not allow for such conclusions in the current analysis. Another potential drawback of this systematic review and meta-analysis was the inclusion of HD partners, as well as ambiguous inclusion criteria that may have resulted in the inclusion of HD partners in control groups who were not confirmed to be free of psychiatric or neurological symptoms. Furthermore, these researchers stated that future investigations should focus on identifying potential sex-based differences in HD manifestations and the molecular mechanisms that lead to these alterations, including cytokine production. In addition, future studies should also examine IL-6 as a therapeutic target for HD in later stages of the disease. These studies can complement current findings to aid in the development of improved diagnostic measures and individualized treatments to ameliorate the day-to-day complications afflicting those with HD.

Khaboushan et al. (2023) noted that HD is an autosomal dominant disease caused by an abnormally high number of CAG repeats at the huntingtin-encoding gene, HTT. This genetic alteration leads to the expression of a mutant form of the protein (mHTT) and the formation of intracellular aggregates, inducing an inflammatory state within the affected areas. This dysfunction of the inflammatory response results in elevated levels of related inflammatory markers in both CNS tissue samples and body fluids. In a systematic review and meta-analysis, these investigators examined peripheral and blood concentrations of inflammatory molecules in HD. They conducted a search in Medline, Scopus, Web of Science, and Embase databases until March 30, 2023. Random-effect meta-analysis was used to examine concentrations of inflammatory molecules in HD. Subgroup and sensitivity analyses were employed to evaluate heterogeneity among the included studies. A total of 10 studies were included in the meta-analysis. Plasma levels of IL-6 and IL-10 were higher in HD compared to controls. Other biomarkers, namely complement component CRP, C3, interferon-γ (IFN-γ), IL-1, IL-2, IL-8, and tumor necrosis factor-α (TNF-α), did not show any significant differences between the two groups. Furthermore, the subgroup analysis results established no significant differences in levels of these biomarkers in body fluids among pre-manifest and manifest HD patients. The authors concluded that the findings of this study provided evidence for the presence of higher plasma levels of IL-6 and IL-10 in HD patients compared to HCs.

Morena et al. (2023) stated that HD is characterized by clinical motor impairment (e.g., involuntary movements, poor coordination, parkinsonism), cognitive deficits, and psychiatric symptoms. An inherited expansion of the CAG triplet in the huntingtin gene, causing a pathogenic gain-of-function of the mHTT protein, has been identified. Numerous efforts are underway to identify useful biomarkers for HD. In this review, these investigators focused on peripheral fluid biomarkers in the pre- and peri-manifest phases of HD. HD biomarkers have been informative for their potential predictive role in monitoring disease course and therapeutic response; however, each biomarker has certain limitations. Neurofilament light chains (NfLs) are not specific for HD but rather represent irreversible, general neuronal damage. Tau protein, while also being non-specific for HD, is not a useful biomarker because it is difficult to obtain, and its role in HD pathology remains to be elucidated. While CAG expansion in the HTT gene is a known unequivocal cause of HD, mHTT varies considerably with age of onset and clinical disease progression, suggesting that some genetic and environmental modifiers of disease may impact the effects of mHTT. Additionally, the difficulty of measuring mHTT in peripheral blood and the lack of consistent correlations with clinical assessments of manifest HD preclude the use of peripheral mHTT as a biomarker for HD. In contrast, circulating non-coding RNA (NcRNA) is highly stable in biological fluids and may mediate paracrine and endocrine effects on different tissues, modulate gene expression, and influence the function of distal cells. These features support the notion of NcRNAs as possible modifiers of HD. A clinical trial examining a specific microRNA via a viral delivery approach (rAAV5-miHTT) is currently underway with the objective of inhibiting mHTT production. However, researchers still know very little regarding NcRNAs, and studies performed so far have produced inconsistent results. These researchers noted that NcRNAs, telomere length (LTL), and damage DNA response (DDR) are under-studied; their cumulative role, along with known biomarkers, may open a window on the complex pathogenic scenario of HD. The authors concluded that future studies should focus on peripheral biomarkers and assess their ability to predict disease progression and treatment effectiveness in pre-HD. Interestingly, interleukins were not mentioned in this review.

Xia et al. (2024) examined the role of peripheral inflammation in HD by assessing the correlation of peripheral inflammatory markers with clinical manifestations and disease prognosis. This study involved 92 HD patients and 92 matched HCs. These investigators quantified various peripheral inflammatory markers and calculated their derived metrics, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII). Clinical assessments spanning cognitive, motor, and disease severity were administered. Comparative analysis of inflammatory markers and clinical correlations between HD patients and HCs was carried out. Kaplan-Meier survival analysis and Cox regression models were used to examine the effect of inflammatory markers on survival. The study revealed that HD patients had significantly reduced lymphocyte counts and LMR. Conversely, NLR, PLR, and SII were elevated compared to HCs. Lymphocyte levels inversely correlated with the age of onset, and monocyte levels inversely correlated with the UHDRS total functional capacity (TFC) scores. After adjusting for age, sex, and CAG repeat length, lymphocyte count, NLR, PLR, and SII were significantly correlated with the progression rate of TFC scores. Elevated levels of white blood cells (WBCs) and monocytes were associated with an increased risk of disability and mortality in the HD cohort. The authors concluded that these findings showed that HD patients displayed a distinct peripheral inflammatory profile with increased NLR, PLR, and SII levels compared to HCs. Peripheral inflammation appeared to be linked with accelerated disease progression and decreased survival in HD. Moreover, these researchers stated that further studies are needed to transform their findings into innovative clinical markers and potential therapeutic targets; interestingly, these investigators did not examine circulating levels of interleukins.

Furthermore, an UpToDate review on “Huntington disease: Clinical features and diagnosis” (Suchowersky, 2024) does not mention the measurement of circulating interleukins as a management option.

Complementary and Alternative Medicine

Morsy and associates (2019) stated that after MRI studies suggested the efficacy of ethyl-EPA in reducing progressive brain atrophy in Huntington's disease (HD), further studies were conducted to examine its effectiveness as a treatment for HD. Trials that continued for 6 months did not find any significant improvement, leading to the discontinuation of the drug. However, trials that continued for 12 months indicated improvements in motor functions among these patients. The investigators searched 12 electronic databases to find randomized clinical trials relevant to their inclusion criteria. After screening, only 5 studies were included. Continuous and binary variables were analyzed to compute the pooled mean difference (MD) and risk ratio (RR), respectively. A quality effect model meta-analysis was used as a post-hoc analysis for studies at 12 months. The meta-analysis indicated that ethyl-EPA had no significant effect on any scale of HD at 6 months. At 12 months, two studies suggested significant improvements in the Total Motor Score and Total Motor Score-4 in both fixed and quality effect models [MD = -2.720, 95% CI (-4.76 to -0.68), p = 0.009; MD = -2.225, 95% CI: -3.842 to -0.607, p = 0.007], respectively. The maximal chorea score showed significant results [MD = -1.013, 95% CI: -1.793 to -0.233, p = 0.011] in only the fixed-effect model, while no improvement was detected for the Stroop color naming test or symbol digit modality. The authors concluded that the findings of this meta-analysis indicated a significant improvement in motor scores only after 12 months. Moreover, these researchers stated that these findings should be interpreted cautiously because only two studies had evaluated the efficacy of ethyl-EPA after 12 months, with one of them having a 6-month open-label phase.

Yu and Bega (2019) noted that there is a lack of published guidelines related to the use of complementary and alternative medicine (CAM) for HD. These investigators conducted a review of the literature to summarize the available evidence for various mind-body practices and nutraceuticals. PubMed and Cochrane Library electronic databases were searched independently from inception to February 2019 by two independent raters. Studies were classified for the level of evidence (Class I, II, III, or IV) according to the American Academy of Neurology (AAN) classification scale. Randomized controlled trials (RCTs) in HD were reviewed for mind-body interventions (dance therapy, music therapy, and exercise), alternative systems (traditional Chinese medicine [TCM]), and nutraceuticals/diet (aminooxyacetic acid [AOAA], coenzyme Q10, creatine, cannabinoids, alpha-tocopherol, eicosapentaenoic acid, idebenone, levocarnitine, and triheptanoin). Few studies met AAN Class I or II level of evidence for benefits. The authors concluded that there is a relative paucity of clinical trials examining CAM modalities in HD compared to other neurodegenerative disorders. Currently, there is no evidence supporting disease modification or symptom improvement with any specific dietary or nutraceutical supplement for HD. Supervised exercise and contemporary dance are safe for people with HD, but more robust studies are needed to guide specific recommendations for these and other mind-body interventions.

Schwartz and colleagues (2019) noted that studies have examined the therapeutic effect of music, dance, and rhythmic auditory cueing for patients with HD. However, the synthesis of evidence supporting their positive impact on symptoms is lacking. These investigators conducted a systematic literature review to examine the potential benefits of music, dance, and rhythm on cognitive, psychiatric, and motor function in patients with HD. Two- and three-keyword searches, along with a manual search, identified medical literature published from 1999 through 2019. These researchers considered literature that assessed outcomes of art-based rehabilitation programs or individual modalities for persons with early, middle, or advanced HD. A structured analysis was conducted using data entry tables with categories for patient health status, art methods, and outcomes. A total of 7 articles and 6 abstracts met eligibility criteria, of which 9 evaluated art-based rehabilitation programs. Studies mainly assessed cognitive, psychiatric, and motor functions through music, dance, or rhythm modalities. Although results were conflicting, improvements in motor function were dependent on disease severity and were more responsive to art therapy programs than to rhythm-motor synchronization. Benefits to global cognition resulting from rhythmic training correlated with microstructural changes. Qualitative data verified a positive impact on language production, chorea, behavior, and quality of life (QoL). The authors concluded that the findings of this review demonstrated a potential benefit of music, dance, and rhythm for patients with HD, which is particularly important for a disease that has no cure. Art forms appeared to affect cognitive, psychiatric, motor, psychosocial, and neuroanatomical domains. However, the evidence is preliminary, warranting further investigation to establish a foundation for this field.

Cytokines as Biomarkers of Huntington's Disease Progression

Rocha et al. (2025) noted that HD is a neurodegenerative condition with a well-established genetic basis. The mechanisms driving neurodegeneration appear to be multi-factorial with a significant contribution from peripheral and CNS inflammation. In this scenario, cytokines, especially IL-6 and IL-8, have emerged as potential biomarkers and contributors to HD progression. These investigators provided a brief perspective on the role of inflammation in HD, highlighting peripheral cytokines as potential biomarkers for disease progression. IL-6 and IL-8 are involved in microglia activation; therefore, exacerbating neuroinflammation. This chronic inflammatory state results in excitotoxicity, oxidative damage, as well as neuronal loss. IL-6 also promotes the expression of other inflammatory mediators, including TNF-α and IL-1β, further amplifying the inflammatory response. Moreover, these investigators stated that continued research into neuroinflammation and its therapeutic modulation is vital for advancing the understanding of HD and improving clinical outcomes for patients with HD. The authors concluded that larger, longitudinal studies are needed to validate cytokines as reliable biomarkers for early diagnosis, monitoring, and evaluating therapeutic interventions. Furthermore, they stated that gaining deeper insight into the temporal dynamics of neuroinflammation and its role in HD pathophysiology could unlock new opportunities for therapeutic development

Furthermore, UpToDate reviews on “Huntington disease: Clinical features and diagnosis” (Suchowersky, 2025a), and “Huntington disease: Management” (Suchowersky, 2025b) do not mention cytokines as a management tool.

Deep Brain Stimulation

Gonzalez et al. (2014) noted that the experience of globus pallidus internus (GPi) deep brain stimulation (DBS) in the treatment of Huntington's disease (HD) has been limited to a small number of case reports. These researchers analyzed the long-term motor outcomes of a cohort of HD patients treated with GPi DBS. A total of seven patients with pharmacologically resistant chorea and functional impairment were included in a prospective open-label study from 2008 to 2011. The main outcome measure was the motor section of the Unified Huntington's Disease Rating Scale (UHDRS). The primary endpoint was the reduction of chorea. Patients underwent magnetic resonance imaging (MRI)-guided bilateral GPi implantation. The median duration of follow-up was three years. A significant reduction of chorea was observed in all patients, with a sustained therapeutic effect; the mean improvement on the chorea sub-score was 58.34% at the 12-month follow-up visit (p = 0.018) and 59.8% at the three-year visit (p = 0.040). Bradykinesia and dystonia showed a non-significant trend toward progressive worsening related to disease evolution and partly to DBS. The frequency of stimulation was 130 Hz for all patients. Deep brain stimulation-induced bradykinesia was managed by pulse-width reduction or bipolar settings. Levodopa mildly improved bradykinesia in four patients. Regular off-stimulation tests confirmed a persistent therapeutic effect of DBS on chorea. The authors concluded that GPi DBS may provide sustained chorea improvement in selected HD patients with pharmacologically resistant chorea, with transient benefits in the physical aspects of quality of life before the progression of behavioral and cognitive disorders. Moreover, DBS therapy did not improve dystonia or bradykinesia. They stated that further studies, including quality of life (QOL) measures, are needed to evaluate the impact of DBS on the long-term outcomes of HD.

Gruber et al. (2014) stated that recent case reports suggested a beneficial effect of GPi-DBS in selected patients suffering from HD with marked disabling chorea. These investigators presented a 41-year-old man with genetically confirmed HD following quadruple GPi- and subthalamic nucleus (STN)-DBS. Motor function was assessed by the Abnormal Involuntary Movement Scale (AIMS) and by UHDRS pre-surgery and post-surgery for up to four years. Furthermore, cognitive, neuropsychiatric state, and QOL, including life satisfaction (QLS), were annually evaluated. Chorea, assessed by AIMS and UHDRS sub-scores, improved by 52% and 55%, 45% and 60%, 35% and 45%, and 55% to 66% at one to four years, respectively, compared to the pre-surgical state following GPi-STN-DBS. During these time periods, bradykinesia did not increase following separate STN- and combined GPi-STN-DBS compared to the pre-surgical state. Mood, QOL, and QLS were ameliorated. However, dysexecutive symptoms increased at four years post-surgery. The present case report suggested that bilateral GPi- and STN-DBS may represent a new treatment avenue in selected HD patients. Clinically, GPi-DBS attenuated chorea and was associated with a larger effect-adverse effect window compared to STN-DBS. However, GPi-DBS-induced bradykinesia may emerge as one main limitation of GPi-DBS in HD. The authors concluded that quadruple GPi-STN-DBS may be indicated if separate GPi-DBS does not result in sufficient control of motor symptoms. Moreover, they stated that future controlled studies are needed to confirm if the present anecdotal observation of additive beneficial effects of GPi- and STN-DBS in an HD patient with severe generalized chorea and relatively intact cognitive and affective functions indeed represents a new therapeutic option.

In a systematic review, Kaczynska et al. (2022) examined available evidence on the safety and effectiveness of DBS in the management of motor, behavioral, and cognitive functions in patients with HD. This review was performed using the Scopus database and the following search criteria: TITLE (huntington*) AND TITLE-ABS-KEY (“deep brain stimulation” OR “neuromodulation”). The search criteria included original studies with at least five patients, reporting any motor, cognitive, and/or behavioral, and functional assessment data with at least a six-month follow-up. Finally, four selected studies were analyzed. In all analyzed studies, these investigators found a statistically significant improvement of the UHDRS chorea sub-score by an average of 40% to over 60% following DBS implantation. Heterogeneous results were obtained for the UHDRS total motor score. DBS did not improve the functional capacity of HD patients in the analyzed studies. These researchers found no systematic assessment concerning the effect of DBS in HD on behavior, cognition, or speech. The authors concluded that DBS implantation could be considered a therapeutic option for patients with severe, drug-resistant chorea; however, the evidence for this is limited. Currently, no high-quality data based on randomized controlled trials (RCTs) supports the long-term safety and effectiveness of DBS in HD; therefore, this therapeutic option should currently be considered investigational.

Electro-Convulsive Therapy

Cusin and colleagues (2013) noted that many patients with HD develop psychiatric symptoms such as depression and psychosis. In a retrospective chart review, these investigator identified 7 patients with HD who received electro-convulsive therapy (ECT) at Massachusetts General Hospital in the past 20 years. In all cases, ECT was well-tolerated and produced improvement in psychiatric and behavioral symptoms. The authors concluded that the findings of this case-series study supported the hypothesis of a positive risk-benefit ratio for ECT in patients with HD and severe depression or psychosis. These preliminary findings need to be validated by well-designed studies.

Fetal Striatal Transplantation

Fetal neural transplantation has been demonstrated to be a feasible treatment for patients with Parkinson's disease (PD). Embryonic mesencephalic tissue containing dopaminergic cells is implanted into the patient's striatum to modify the motor disability of patients with advanced PD. However, the effectiveness of fetal neural transplantation for the treatment of PD has yet to be established.

Recently, fetal neural transplantation has also been performed as a potential treatment for Huntington's disease (HD). While it is clear that the techniques of neural transplantation are feasible for various neurodegenerative diseases, significant problems remain in the availability of suitable donor tissues and in defining the optimal conditions for reliable survival of the implanted cells. There is insufficient data on the "progress" of HD patients following fetal striatal transplantation. Furthermore, a recent study on the use of bilateral fetal striatal transplantation for the treatment of HD found that patients with moderately advanced HD are at risk for subdural hemorrhages following transplantation surgery (Hauser et al., 2002). Thus, the safety and effectiveness of fetal striatal transplantation for the treatment of HD have yet to be established.

In an article on the safety and tolerability of intra-striatal neural allografts in patients with HD, Bachoud-Levi and colleagues (2000) called for caution regarding the involvement of HD patients in experimental surgical protocols. In an editorial on fetal striatal transplantation for the treatment of HD published in Neurology, Greenamyer and Shoulson (2002) stated that the benefits of this procedure—even the theoretical benefits—are unclear. Rosser and Dunnett (2003) noted that a small number of studies have demonstrated the feasibility and safety of transplantation in HD, but it will require several more years before the effectiveness of the procedure can be confidently established.

In a long-term follow-up study, Bachoud-Levi and colleagues (2006) stated that although they have shown in three out of five patients with HD that motor and cognitive improvements two years after intra-cerebral fetal neural grafts are correlated with recovery of brain metabolic activity in grafted striatal areas and connected regions of the cerebral cortex, neural grafts are not known to have protective effects on the host brain per se. These investigators undertook long-term follow-up of previously reported patients with the disease to ascertain the nature and extent of any secondary decline after grafting. Five patients with HD from the authors’ pilot study were assessed annually with the UHDRS, neuropsychological tests, and MRI for up to six years after neural grafting. Resting cerebral activity was recorded at two and six years. Clinical improvement reached a plateau after two years and then faded off variably four to six years following surgery. Dystonia deteriorated consistently, whereas chorea did not. Cognitive performance remained stable on non-timed tests, whereas progression of motor disability was shown by deterioration on timed tests. Hypo-metabolism also affected the brain heterogeneously, sparing the benefits in the frontal cortex and at the precise location of the grafts, but showing a progressive deterioration in other areas. Two patients who had no benefit from grafting at two years continued to decline in the same way as non-grafted patients. These researchers noted that neuronal transplantation in HD provides a period of several years of improvement and stability, but not a permanent cure for the disease. Improvement of the surgical procedure, as well as in patient selection, could enhance the therapeutic value, but neuroprotective treatment seems to be unavoidable in the disease.

Keene et al. (2007) reported the pathological findings in two patients with HD who died 74 and 79 months after transplantation. The neostriatum from both patients showed typical neuropathological changes of advanced HD. Surviving grafts were identified in both patients (6/6 sites and 7/8 sites, respectively) as well-demarcated nests within the host neostriatum with associated needle tracts. Grafted neurons adopted either dominant calbindin/parvalbumin or calretinin immunoreactivity (IR). Few neurofilament, MAP-2, DARPP-32, tyrosine hydroxylase, or calbindin IR processes traversed the host parenchyma-graft interface despite minimal junctional gliosis. Immunohistochemistry for CD68 showed microgliosis that was more pronounced in the host striatum than in the graft. Scattered CD45 and CD3 IR cells were present within grafts and host parenchyma. No ubiquitin IR neuronal intra-nuclear inclusions were identified in graft neurons, although these were prevalent in host cells. The authors concluded that these two autopsies confirm previous findings of neuronal differentiation and survival of transplanted fetal tissue from the ganglionic eminence and also demonstrate the viability of neurons from fetal transplants in human neostriatum for more than six years. Despite prolonged survival, these grafts had poor integration with the host striatum, which is likely responsible for the lack of clear clinical improvement in these patients.

In an editorial that accompanied the article by Keene et al., Frank and Biglan (2007) stated that "more work is needed in the design of trials, clinical and pathologic follow-up, and methods of transplantation of various cells. There are cell-based therapies that are commercially available, mostly outside the United States. Rather than referring patients to centers that will infuse or implant cells, these procedures should only be done in the setting of a rigorous research trial using established criteria."

Reuter et al. (2008) reported the findings of two patients with moderate HD who received bilateral fetal striatal allografts. One patient demonstrated, for the first time, increased striatal D2 receptor binding, evident with 11C-raclopride positron emission tomography, and prolonged clinical improvement over five years, suggesting long-term survival and efficacy of the graft. The other patient did not improve clinically or radiologically. The authors stated that these results indicated that striatal transplantation in HD may be beneficial, but further studies are needed to confirm this.

Gallina and colleagues (2010) reported the findings of four HD patients who underwent bilateral transplantation with human fetal striatal tissues (9 to 12 weeks gestation). Small blocks of whole ganglionic eminencies were processed to obtain cell suspension and then stereotactically grafted in the caudate head and in the putamen. The follow-up period ranged between 18 and 34 months (mean of 24.7 months). Surgery was uneventful. Starting from the fourth month after grafting, neo-generation of metabolically active tissue with striatal-like MRI features was observed in six out of eight grafts. The increase in D2 receptor binding suggested striatal differentiation of the neo-generated tissue in three patients. New tissue, connecting the developing grafts with the frontal cortex and, in one case, with the ventral striatum, was also observed. The new tissue growth halted after the ninth month post-transplantation. All patients showed stabilization or improvement in some neurological indices. No clinical and imaging signs suggestive of graft uncontrolled growth were seen. This study provided the first evidence in humans that neuroblasts of a striatal primordium can develop and move into the brain following neuro-transplantation. Primordium development resulted in the building of a new structure with the same imaging features as the corresponding mature structure, combined with short- and long-distance targeted migration of neuroblasts. The results of this study support both the reconstructive potential of fetal tissue and the remarkably retained plasticity of the adult brain. The authors stated that further studies are needed to evaluate the clinical effectiveness of human fetal striatal transplantation for the treatment of HD.

Functional Neuroimaging (e.g., MRI)

Zhang et al. (2023) stated that functional neuroimaging (e.g., MRI) could provide abundant information of underling pathophysiological mechanisms of the clinical triad including motor, cognitive and psychiatric impairment in patients with HD. These investigators carried out a voxel-based meta-analysis using the anisotropic effect size-signed differential mapping (AES-SDM) method. A total of 6 studies (78 symptomatic HD, 102 pre-manifest HD and 131 healthy controls [HC]) were included in total. Altered resting-state brain activity was primarily detected in the bilateral medial part of superior frontal gyrus, bilateral anterior cingulate/paracingulate gyrus, left insula, left striatum, right cortico-spinal projections area, right inferior temporal gyrus area, right thalamus, right cerebellum and right gyrus rectus area. Pre-manifest and symptomatic HD patients showed different alterative pattern in the subgroup analyses. The authors concluded that the robust and consistent abnormalities in the specific brain regions identified in this trial could aid in understanding the pathophysiology of HD and examine reliable neuroimaging biomarkers for monitoring disease progression, or even predicting the onset of pre-manifest HD patients. Moreover, these researchers stated that future large sample size studies are needed to further clarify the dynamic change pattern of HD.

The authors noted that this meta-analysis was a preliminary exploratory study to portray the alteration pattern of the resting-state brain activity in HD patients with several drawbacks. First, only 6 studies were included in this meta-analysis; and the sample size of the current study was relatively small. There was also heterogeneity among the studies included. The findings of the current study should be interpreted cautiously. Second, following the AES-SDM guideline and previous voxel-based meta-analysis, these investigators included all studies using resting-state neuroimaging methods focused on brain activity that might result in the heterogeneity between studies considering different physiological bases of different methods. However, in the Jack-knife sensitivity analyses, the results remained stable in the combination of resting-state functional MRI (rs-fMRI) studies. Third, these researchers also excluded all experiments applying the region-of-interest (ROI) method that may lead to a bias as a critical number of studies may not be considered in the meta-analysis. Hence, they discussed some important findings of previous ROI studies in the discussion part as recommended in the software guideline. Fourth, the AES-SDM meta-analysis was carried out based on reported results, but not original data, which may have affected the accuracy of the identified spatial location.

Gene Therapy / Gene Silencing

Rollnik (2015) noted that Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by hyperkinetic movements, psychiatric symptoms (e.g., depression and psychosis), and cognitive symptoms (frontal lobe dementia). The author reviewed the clinical course, epidemiology, genetics, differential diagnoses, pathophysiology, symptoms, and causal therapeutic options. Publications on animal and human HD studies, as well as trials and reviews available in Medline, have been taken into account. Only genetic testing allows for diagnostic certainty. The CAG repeat length influences the age of onset, disease course, and life expectancy. The mechanism by which mutant huntingtin protein (mHTT) causes HD is complex and poorly understood but leads to cell death, particularly in striatal neurons. In clinical trials, anti-oxidants (e.g., coenzyme Q10), selisistat, PBT2, cysteamine, N-methyl-D-aspartate (NMDA) receptor antagonists, and tyrosine kinase B receptor agonists have been studied in HD. The author concluded that no disease-modifying therapy is currently available for HD; however, gene silencing (e.g., through RNA interference) is a promising technique that could lead to effective therapies in the future.

Spronck and colleagues (2019) noted that HD is a fatal neurodegenerative disorder caused by an autosomal dominant CAG repeat expansion in the HTT gene. The translated expanded polyglutamine repeat in the HTT protein is known to cause a toxic gain of function. These researchers previously showed that strong HTT lowering prevented neuronal dysfunction in HD rodents and mini-pigs following a single intracranial injection of an adeno-associated viral vector serotype 5 expressing a microRNA targeting human HTT (AAV5-miHTT). To evaluate long-term efficacy, AAV5-miHTT was injected into the striatum of knock-in Q175 HD mice, and the mice were sacrificed 12 months post-injection. AAV5-miHTT caused a dose-dependent and sustained HTT protein reduction with subsequent suppression of mutant HTT aggregate formation in the striatum and cortex. Functional proof of concept was shown in transgenic R6/2 HD mice. Eight weeks after AAV5-miHTT treatment, a significant improvement in motor coordination on the rotarod was observed. Survival analysis showed that a single AAV5-miHTT treatment resulted in a significant four-week increase in median survival compared with vehicle-treated R6/2 HD mice. The combination of long-term HTT lowering, reduction in aggregation, prevention of neuronal dysfunction, alleviation of HD-like symptoms, and beneficial survival observed in HD rodents treated with AAV5-miHTT supports the continued development of HTT-lowering gene therapies for HD.

Gene Therapy In Combination With Stem Cell Therapy

Cho and colleagues (2019) stated that HD is a dominantly inherited monogenetic disorder characterized by motor and cognitive dysfunction due to neurodegeneration. The disease is caused by the polyglutamine (polyQ) expansion at the 5' terminal of the exon 1 of the HTT gene, IT15, which results in the accumulation of mHTT aggregates in neurons and cell death. The monogenetic cause and the loss of specific neural cell population make HD a suitable candidate for gene therapy and stem cell therapy. In this study, these researchers showed the efficacy of the combination of gene therapy and stem cell therapy in a transgenic HD mouse model (N171-82Q; HD mice) using rhesus monkey (Macaca mulatta) neural progenitor cells (NPCs). These investigators established monkey NPC cell lines from induced pluripotent stem cells (iPSCs) that can differentiate into GABAergic neurons in-vitro as well as in mouse brains without tumor formation. Wild-type monkey NPCs (WT-NPCs), NPCs derived from a transgenic HD monkey (HD-NPCs), and genetically modified HD-NPCs with reduced mHTT levels by stable expression of small-hairpin RNA (HD-shHD-NPCs), were grafted into the striatum of WT and HD mice. Mice that received HD-shHD-NPC grafts showed a significant increase in lifespan compared to the sham injection group and HD mice. Both WT-NPC and HD-shHD-NPC grafts in HD mice showed significant improvement in motor functions assessed by rotarod and grip strength. Furthermore, immuno-histochemistry demonstrated the integration and differentiation. The authors concluded that these findings suggested the combination of gene therapy and stem cell therapy as a viable therapeutic option for the treatment of HD. These researchers stated that to better evaluate the safety and efficacy of gene therapy and stem cell therapy, non-human primate (NHP) models, such as the HD monkey, will provide a unique pre-clinical large animal model that could facilitate clinical translation of new therapeutic approaches. Recent success in stem cell therapies in NHPs and the authors’ recent report on developing HD model of NHP will facilitate the effort for clinical translation to benefit patients in need.

Ionis-HTTRx (An HTT-Targeting Antisense Oligonucleotide) for the Treatment of Huntington's Disease

van Roon-Mom and associates (2018) stated that on December 11, 2017, Ionis Pharmaceuticals published a press release announcing dose-dependent reductions of mutant huntingtin protein in their HTTRx phase I/IIa study in HD patients. The results from this Ionis trial have gained much attention from the patient community and the oligonucleotide therapeutics field, since it is the 1st trial targeting the cause of HD, namely the mHTT, using anti-sense oligonucleotides (ASOs). The press release also stated that the primary end-points of the study (safety and tolerability) were met, but did not contain data. This news followed the approval of another therapeutic ASO nusinersen (trade name Spinraza) for a neurological disease, spinal muscular atrophy, by the FDA and European Medicines Agency, in 2016 and 2017, respectively. Combined, this offers hope for the development of the HTTRx therapy for HD patients.

Tabrizi and colleagues (2019) noted that HD is an autosomal-dominant neurodegenerative disease caused by CAG trinucleotide repeat expansion in HTT, resulting in a mHTT. Ionis-HTTRx (hereafter, HTTRx) is ASO designed to inhibit HTT messenger RNA and thereby reduce concentrations of mutant huntingtin. These researchers conducted a randomized, double-blind, multiple-ascending-dose, phase I-IIa clinical trial involving adults with early HD. Patients were randomly assigned in a 3:1 ratio to receive HTTRx or placebo as a bolus intra-thecal administration every 4 weeks for 4 doses. Dose selection was guided by a pre-clinical model in mice and non-human primates that related dose level to reduction in the concentration of huntingtin. The primary end-point was safety; secondary end-point was HTTRx pharmacokinetics in CSF. Pre-specified exploratory end-points included the concentration of mutant huntingtin in CSF. Of the 46 patients who were enrolled in the trial, 34 were randomly assigned to receive HTTRx (at ascending dose levels of 10 to 120 mg) and 12 were randomly assigned to receive placebo. Each patient received all 4 doses and completed the trial. Adverse events, all of grade 1 or 2, were reported in 98 % of the patients. No serious adverse events were seen in HTTRx-treated patients. There were no clinically relevant adverse changes in laboratory variables. Pre-dose (trough) concentrations of HTTRx in CSF showed dose dependence up to doses of 60 mg. HTTRx treatment resulted in a dose-dependent reduction in the concentration of mutant huntingtin in CSF (mean percentage change from baseline, 10% in the placebo group and -20%, -25%, -28%, -42%, and -38% in the HTTRx 10-mg, 30-mg, 60-mg, 90-mg, and 120-mg dose groups, respectively). The authors concluded that intra-thecal administration of HTTRx to patients with early HD was not accompanied by serious adverse events. These researchers observed dose-dependent reductions in concentrations of mutant huntingtin. Moreover, these researchers stated that larger studies of greater duration are needed to examine if HTTRx-mediated reduction of the concentration of mutant HTT in CSF is associated with a treatment effect on the disease course, which is typically slow, with changes on standard outcomes generally occurring over a period of years.

Magnetic Resonance Spectroscopy

Sturrock et al. (2010) evaluated in vivo brain metabolite differences in control subjects, individuals with pre-manifest Huntington's disease (pre-HD), and individuals with early HD using ^1H magnetic resonance spectroscopy (MRS) and assessed their relationship with motor performance. A total of 85 subjects (30 controls, 25 pre-HD, and 30 early HD) were recruited as part of the TRACK-HD study; 84 were scanned at 3T with single-voxel spectroscopy in the left putamen. The disease burden score was greater than 220 among pre-HD individuals. Subjects underwent TRACK-HD motor assessment, including UHDRS motor scoring and a novel quantitative motor battery. Statistical analyses included linear regression and one-way analysis of variance. Total N-acetylaspartate (tNAA), a neuronal integrity marker, was lower in early HD (approximately 15%) versus controls (p < 0.001). N-acetylaspartate (NAA), a constituent of tNAA, was lower in pre-HD (approximately 8%) and early HD (approximately 17%) versus controls (p < 0.05). The glial cell marker, myo-inositol (mI), was 50% higher in early HD versus pre-HD (p < 0.01). In early HD, mI correlated with UHDRS motor score (R² = 0.23, p < 0.05). Across pre-HD and early HD, tNAA correlated with performance on a tongue pressure task (R² = 0.30, p < 0.0001) and with disease burden score (R² = 0.17, p < 0.005). The authors demonstrated that lower putaminal tNAA in early HD compared to controls in a cross-section of subjects. A novel biomarker role for mI in early HD was also identified. These findings resolve disagreement in the literature about the role of MRS as an HD biomarker. The authors concluded that putaminal MRS measurements of NAA and mI are promising potential biomarkers of HD onset and progression.

The American College of Radiology (ACR)’s Appropriateness Criteria on "Dementia and movement disorders" (Wippold et al., 2014) rendered a "3" rating regarding the use of MR spectroscopy of the head without contrast for individuals suspected of HD (a rating scale of 1, 2, or 3 denotes “usually not appropriate”).

Measurement of Iron Accumulation in the Basal Ganglia

Domínguez and colleagues (2016) measured iron accumulation in the basal ganglia in HD using quantitative susceptibility mapping (QSM), and ascertained its relevance in terms of clinical and disease severity. In this cross-sectional investigation, weighted imaging was undertaken on 31 pre-manifest HD, 32 symptomatic HD and 30 control participants as part of the observational IMAGE-HD study. Group differences in iron accumulation were ascertained with QSM. Associations between susceptibility values and disease severity were also investigated. Compared with controls, both pre-manifest and symptomatic HD groups showed significantly greater iron content in pallidum, putamen and caudate. Additionally, iron accumulation in both putamen and caudate was significantly associated with disease severity. The authors concluded that these findings provided the first evidence that QSM is sensitive to iron deposition in subcortical target areas across pre-manifest and symptomatic stages of HD. They noted that such findings could open up new avenues for biomarker development and therapeutic intervention.

Mesenchymal Stem Cells

Clelland et al. (2008) stated that a major impetus for research into the treatment of HD has centered on cell therapy strategies to protect vulnerable neuronal cell populations or to replace dysfunctional or dying cells. The work underlying 3 approaches to HD cell therapy includes

the potential for self-repair through the manipulation of endogenous stem cells and/or neurogenesis,
the use of fetal or stem cell transplantation as a cell replacement strategy, and
the administration of neurotrophic factors to protect susceptible neuronal populations.

These approaches have shown some promising results in animal models of HD. Although striatal transplantation of fetal-derived cells has undergone clinical assessment since the 1990s, many cell therapy strategies have yet to be applied in the clinic environment. A more thorough understanding of the pathophysiology underlying HD as well as the response of both endogenous and exogenous cells to the degenerating brain will inform their merit as potential therapeutic agents and enhance the framework by which the success of such therapies are ascertained.

Sadan et al. (2012) stated that excitotoxicity and reduced availability of neurotrophic factors (NTFs) likely play roles in HD pathogenesis. These researchers developed a protocol that induces adult human bone marrow derived mesenchymal stem cells (MSCs) into becoming NTF secreting cells (NTF(+) cells). Striatal transplantation of such cells represents a promising autologous therapeutic approach whereby NTFs are delivered to damaged areas. These investigators examined the effectiveness of NTF(+) cells using the quinolinic acid (QA) rat model for excitotoxicity. They showed that NTF(+) cells transplanted into rat brains after QA injection survive transplantation (19% after 6 weeks), maintain their NTF secreting phenotype and significantly reduce striatal volume changes associated with QA lesions. Moreover, QA-injected rats treated with NTF(+) cells exhibit improved behavior; namely, perform 80% fewer apomorphine- induced rotations than phosphate-buffered saline (PBS)-treated QA-injected rats. More importantly, these researchers found that MSCs derived from HD patients can be induced to become NTF(+) cells and exert efficacious effects similarly to NTF(+) cells derived from healthy donors. To the authors' knowledge, this is the first study to take adult bone marrow derived MSCs from patients with an inherited disease, transplant them into an animal model and evidence therapeutic benefit. Using MRI the authors demonstrated in-vivo that PBS-treated QA-injected striatae exhibit increasing T(2) values over time in lesioned regions, whereas T(2) values decrease in equivalent regions of QA-injected rats treated with NTF(+) cells. The authors concluded that NTF cellular treatment could serve as a novel therapy for managing HD.

MicroRNAs as Biomarkers for Huntington’s Disease

Nguyen et al. (2022) stated that microRNAs (miRNAs) are essential post-transcriptional gene regulators involved in various neuronal and non-neuronal cell functions and play a key role in pathological conditions. Numerous studies have reported that miRNAs are dysregulated in major neurodegenerative diseases, such as Alzheimer's disease (AD), PD, multiple sclerosis (MS), ALS, or HD. These investigators constructed a comprehensive overview of individual microRNA alterations in various models of the afore-mentioned neurodegenerative diseases. They also provided evidence of miRNAs as promising biomarkers for prognostic and diagnostic approaches. Furthermore, these researchers summarized data from the literature regarding miRNA-based therapeutic applications via inhibiting or promoting miRNA expression. They identified the overlapping miRNA signature across the diseases, including miR-128, miR-140-5p, miR-206, miR-326, and miR-155, associated with multiple etiological cellular mechanisms. However, it remains to be established whether and to what extent miRNA-based therapies could be safely employed in the future as effective symptomatic or disease-modifying approaches in the different human neurodegenerative disorders. For HD, these investigators stated that there is currently an urgent need for biomarker measure methods consistent with HD pathology, and the development of miRNA biomarker assays may contribute as a significant indicator for HD progression diagnostic. Some studies focused on detecting specific miRNA; others figured out several miRNA-signature alterations. However, the general limitations of these studies were the sample size, the unknown interactions of extrinsic factors, such as nutrition, medications, ethnicity, or race, as well as technical issues, such as accurate detection methods or internal reference for miRNA expression; thus, additional analysis of larger cohorts during disease progression will undoubtedly improve the efficacy of these measures. The authors concluded that future identification and characterization of novel miRNAs involved in neurodegenerative diseases are highly desired to improve the potential of this novel and up-and-coming research field.

Music Therapy

In a randomized, controlled trial, van Bruggen-Rufi and co-workers (2017) examined the effectiveness of music therapy in comparison with recreational therapy in improving QOL of patients with advanced HD by means of improving communication. A total of 63 HD-patients with a TFC score of less than or equal to 7, admitted to 4 long-term care facilities in the Netherlands, were randomized to receive either group music therapy or group recreational therapy in 16 weekly sessions. They were assessed at baseline, after 8, 16 and 28 weeks using the Behavior Observation Scale for Huntington (BOSH) and the Problem Behavior Assessment-short version (PBA-s). A linear mixed model with repeated measures was used to compare the scores between the 2 groups. Group music therapy offered once-weekly for 16 weeks to patients with HD had no additional beneficial effect on communication or behavior compared to group recreational therapy. The authors concluded that this was the first study to evaluate the effect of group music therapy on HD patients in the advanced stages of the disease. The beneficial effects of music therapy, recorded in many, mainly qualitative case reports and studies, could not be confirmed with the design (i.e., group therapy versus individual therapy) and outcome measures that have been used in the present study.

Neural Grafts for the Treatment of Huntington’s Disease

Bachoud-Levi (2022) noted that HD is a rare, severe, and inherited neurodegenerative disorder that affects young adults. To-date, there is no treatment to stop its progression. The primary atrophy of the striatum in HD, is limited in space and centrally focalized in the brain; therefore, constituting a good candidate for graft. Transplantation of fetal cells from the ganglionic eminence, the germinal zone of the striatum, has the potential to restore disrupted fronto-cortical circuits and corresponding clinical functions. The international, multi-center intra-cerebral grafting in HD trial was not as successful as 2 pilot studies (Creteil and London) which showed promising results in the 2000s, displaying stabilization/recovery of symptoms in some patients. A point-by-point comparison of the differences between MIG-HD and the pilot trial from Creteil in which similar data were available provided lessons on the grafting procedure and allowed for strategic thinking before embarking on future trials. MIG-HD demonstrated the existence of intra-cerebral alloimmunization leading to acute or chronic graft rejection into the brain and showed the limitations of surgical standardization and immunosuppression. It has also improved the safety of the procedure and provided guidance for the follow-up of future patients. Indeed, even if disease modifiers treatments are currently the focus of intense research, they may not stop or slow the progression of the disease sufficiently, or even be administered in all patients, to prevent brain atrophy in all cases. The authors concluded that although disease-modifying therapies are currently the subject of intense research, they may not stop or slow disease progression sufficiently, or may not be given to all patients to prevent brain atrophy. A combination with intra-cerebral transplantation to repair the damaged structures may thus prove beneficial. Altogether, pursuing research in intra-cerebral transplantation remains necessary.

Neuro-Filament Light Chain and Tau as Biomarkers for Huntington's Disease

Niemela and colleagues (2017) stated that previous studies have suggested that cerebrospinal fluid (CSF) levels of neurofilament light (NF-L) and total tau are elevated in Huntington's disease (HD) and may be used as markers of disease stage. Biomarkers are needed due to the slow disease progression and the limitations of clinical assessment. These investigators validated the role of NF-L and tau as biomarkers in HD; CSF was obtained from a cohort of HD patients and pre-manifest HD mutation carriers, and UHDRS testing was performed on all subjects at the time of sampling. NF-L and tau concentrations were determined by ELISA. Spearman correlations were calculated with R version 3.2.3. A total of 11 pre-manifest HD and 12 manifest HD subjects were enrolled, and NF-L and tau levels were correlated. NF-L showed strong correlations with all items included in the clinical assessment (e.g., the Total Functional Capacity (TFC) (r = -0.70; p < 0.01) and total motor score (r = 0.83; p < 0.01)). Tau showed slightly weaker correlations (e.g., total motor score (r = 0.67; p < 0.01); TFC (r = -0.59; p < 0.01)). NF-L was significantly correlated with the five-year probability of disease onset, whereas tau was not. The authors concluded that the findings of this study strengthened the case for NF-L as a useful biomarker of disease stage; NF-L was strongly correlated to all evaluated items in the UHDRS assessment. They stated that tau also has potential for use as a biomarker, but correlations to clinical tests were weaker in this study. These researchers suggested that NF-L and possibly tau be used in clinical drug trials as biomarkers of disease progression that are potentially influenced by future disease-modifying therapies.

The authors stated that the main drawback of this study was its small sample size (n = 12 manifest HD); some trends suggested herein may prove significant in larger samples. The timing of meals and the time of day for sampling varied, but this is not likely to influence the results, at least regarding tau. To avoid such limitations, these investigators recommended the HD Clarity project, which is a new initiative for a multi-center collection of HD CSF that aims to enroll a large number of participants, allowing statistical power for multiple analyses while offering a standardized protocol for CSF collection.

In a retrospective study, Byrne and associates (2017) examined whether NF-L in blood is a potential prognostic marker of neurodegeneration in patients with HD. These researchers carried out a retrospective analysis of healthy controls and carriers of CAG expansion mutations in HTT participating in the three-year international TRACK-HD study. They studied associations between NF-L concentrations in plasma and clinical and MRI neuroimaging findings, namely cognitive function, motor function, and brain volume (global and regional). They used random effects models to analyze cross-sectional associations at each study visit and to assess changes from baseline, with and without adjustment for age and CAG repeat count. In an independent London-based cohort of 37 participants (23 HTT mutation carriers and 14 controls), these investigators further examined whether concentrations of NF-L in plasma correlated with those in CSF. Baseline and follow-up plasma samples were available from 97 controls and 201 individuals carrying HTT mutations. Mean concentrations of NF-L in plasma at baseline were significantly higher in HTT mutation carriers than in controls (3.63 [SD 0.54] log pg/ml versus 2.68 [0.52] log pg/ml, p < 0.0001), and the difference increased from one disease stage to the next. At any given time point, NF-L concentrations in plasma correlated with clinical and MRI findings. In longitudinal analyses, baseline NF-L concentration in plasma also correlated significantly with subsequent decline in cognition (symbol-digit modality test; r = -0.374, p < 0.0001; Stroop word reading; r = -0.248, p = 0.0033), TFC (r = -0.289, p = 0.0264), and brain atrophy (caudate; r = 0.178, p = 0.0087; whole brain; r = 0.602, p < 0.0001; grey matter; r = 0.518, p < 0.0001; white matter; r = 0.588, p < 0.0001; and ventricular expansion; r = -0.589, p < 0.0001). All changes except Stroop word reading and TFC remained significant after adjustment for age and CAG repeat count. In 104 individuals with pre-manifest HD, NF-L concentration in plasma at baseline was associated with subsequent clinical onset during the three-year follow-up period (hazard ratio [HR] 3.29 per log pg/ml, 95% CI: 1.48 to 7.34, p = 0.0036). Concentrations of NF-L in CSF and plasma were correlated in mutation carriers (r = 0.868, p < 0.0001). The authors concluded that NF-L in plasma showed promise as a potential prognostic blood biomarker of disease onset and progression in HD. They suggested that this approach has a potential role, once validated to regulatory standards, in facilitating the development of novel disease-modifying therapeutics and possibly guiding treatment decisions once such treatments become available. These researchers recommended that quantification of NF-L concentrations in plasma be included in future observational and therapeutic trials for HD; retrospective analysis of blood samples collected in previous trials might also be useful to test for evidence that interventions had effects on neuronal damage, even if the clinical outcomes were negative.

The authors stated that this study had several drawbacks. First, some of the cross-sectional and longitudinal correlations of NF-L with existing outcome measures were slight, probably due to both biological and measurement variability. Accurate quantification of putaminal atrophy, for example, is particularly challenging. One potential advantage of measuring NF-L is that repeated assessment is not needed to indicate the rate of change in the brain at a given time point. Thus, modest associations in a natural history study do not preclude interpretable changes in NF-L concentrations in plasma in response to an intervention that ameliorates neuronal damage. Second, the analysis of the independent CSF cohort was not powered to compare the relative effect sizes of NF-L concentrations in CSF and plasma, and therefore, these investigators could not determine whether measurement in plasma is a sufficient alternative or whether there remains additional value in quantification in CSF. Third, the authors did not yet have longitudinal data on NF-L concentrations in CSF or predictive power of this measurement for HD progression. Fourth, TRACK-HD did not include participants with advanced HD, and further study is needed to understand the patterns of NF-L concentrations across the whole disease spectrum. To address these issues and to enable head-to-head comparison of NF-L with other proposed biochemical markers, these researchers have recruited 80 participants in whom NF-L concentrations in CSF will be measured longitudinally, supported by neuroimaging, and have launched a multi-site CSF study, HDClarity (NCT02855476), that will include 600 participants with pre-manifest to advanced HD and controls. Finally, these investigators noted that although NF-L was a strong predictor of onset and progression overall in this study, its variability was too great to allow confident prediction in individuals. Moreover, the clinical relevance of any predicted changes could not be inferred from this work.

Johnson and co-workers (2018) examined the regional distribution of NF-L-associated neural pathology in HD gene expansion carriers. These investigators examined associations between NF-L measured in plasma and regionally specific atrophy in cross-sectional (n = 198) and longitudinal (n = 177) data in HD gene expansion carriers from the international multi-site TRACK-HD study. Using voxel-based morphometry, they measured associations between baseline NF-L levels and both baseline gray matter and white matter volume, as well as longitudinal change in gray matter and white matter over the subsequent three years in HD gene expansion carriers. After controlling for demographics, associations between increased NF-L levels and reduced brain volume were seen in cortical and subcortical gray matter and within the white matter. After also controlling for known predictors of disease progression (age and CAG repeat length), associations were limited to the caudate and putamen. Longitudinally, NF-L predicted subsequent occipital gray matter atrophy and widespread white matter reduction, both before and after correction for other predictors of disease progression. The authors concluded that the findings of this study provided further evidence supporting the use of NF-L as a prognostic marker of progression of neuronal damage in both HD and other neurodegenerative diseases. They stated that NF-L appeared to be a significant indicator of subsequent widespread brain changes extending beyond the striatum, particularly within the white matter. They noted that the ability to measure NF-L from plasma provides an easily accessible biomarker that has close links to the underlying pathology of HD and shows promise as a dynamic marker of ongoing neuronal change.

Silajdzic and Bjorkqvist (2018) noted that there is an unmet clinical need for objective biomarkers to monitor disease progression and treatment response in HD. These researchers provided advice for biomarker discovery and summarized studies on biofluid markers for HD. They carried out a PubMed search to review the literature regarding candidate saliva, urine, blood, and CSF biomarkers for HD. Information was organized into tables to allow a pragmatic approach to the discussion of the evidence and generation of practical recommendations for future studies. Many of the markers published converge on metabolic and inflammatory pathways, although changes in other analytes representing antioxidant and growth factor pathways have also been found. The authors concluded that the most promising markers reflect neuronal and glial degeneration, particularly NF-L. They stated that international collaboration to standardize assays and study protocols, as well as to recruit sufficiently large cohorts, will facilitate future biomarker discovery and development.

Neurotrophic Factors

Azman et al. (2025) reviewed the neurobiology of brain-derived neurotrophic factor (BDNF) in the pathogenesis and therapeutic modulation of Huntington’s disease. Huntington’s disease is described as an autosomal dominant neurodegenerative disorder caused by expansion of CAG repeats exceeding 36 in the huntingtin gene, with prevalence ranging from 5.96 to 13.7 cases per 100,000 and juvenile cases accounting for less than 5%. The authors described BDNF as a neurotrophin essential for the survival and function of striatal neurons and reported that reduced BDNF transcription and impaired transport led to decreased neurotrophic support and neuronal death, contributing to motor, cognitive, and psychiatric manifestations. Their review outlined that proBDNF signaling through p75NTR and sortilin receptors activated TRAF6/NF-κB, PI3K/AKT, and JNK pathways associated with apoptosis, whereas mature BDNF signaling through TrkB receptors activated MAPK, PLC, PI3K, and JAK/STAT pathways promoting neuronal survival and synaptic plasticity. Human studies described reductions of 53% to 82% in BDNF expression in the caudate and putamen, increased promoter methylation, and decreased cortical mRNA and protein levels, with inconsistent findings in peripheral blood and cerebrospinal fluid measurements. Animal and in vitro models demonstrated decreased BDNF levels, impaired vesicular transport, reduced TrkB signaling, and altered synaptic function associated with disease progression. Therapeutic approaches evaluated included exogenous BDNF administration, viral-mediated gene delivery, stem cell–based delivery, and pharmacologic stimulation of endogenous BDNF using agents such as cystamine at 100 mg/kg, selective serotonin reuptake inhibitors, and ampakines, alongside natural compounds, environmental enrichment, and physical exercise that increased BDNF expression and delayed disease onset in models. The authors concluded that reduced BDNF levels and disrupted signaling contributed to Huntington’s disease pathology and that restoration of BDNF expression or signaling pathways represented a potential therapeutic strategy, although delivery limitations and safety considerations required further investigation.

Non-Invasive Neuromodulation Methods to Alleviate Symptoms of Huntington's Disease

Jose et al. (2023) stated that HD is a progressive and debilitating neurodegenerative disease. There is growing evidence for non-invasive neuromodulation tools as therapeutic strategies in neurodegenerative diseases. In a systematic review, these investigators examined the effectiveness of non-invasive neuromodulation in HD-associated motor, cognitive, and behavioral symptoms. They carried out a literature search in Ovid Medline, Cochrane Central Register of Clinical Trials, Embase, and PsycINFO from inception to July 13, 2021. Case reports, case series, and clinical trials were included while screening/diagnostic tests involving non-invasive neuromodulation, review papers, experimental studies on animal models, other systematic reviews, and meta-analyses were excluded. These researchers identified 19 studies in the literature examining the use of ECT, TMS, and tDCS in the treatment of HD. Quality assessments were carried out using Joanna Briggs Institute's (JBI's) critical appraisal tools. A total of 18 studies showed improvement of HD symptoms; however, the findings were very heterogeneous considering different intervention techniques and protocols, and domains of symptoms. The most noticeable improvement involved depression and psychosis following ECT protocols. The impact on cognitive and motor symptoms was more controversial. The authors concluded that further investigations are needed to determine the therapeutic role of distinct neuromodulation techniques for HD-related symptoms.

The authors stated that this review had several drawbacks, mostly reflecting the relatively small number and quality of the available studies. It was not possible to carry out a quantitative synthesis of the data due to significant differences in intervention type, stimulation parameters, outcome measures, and most studies encompassed case reports or case series. Furthermore, there was poor evidence of blinding of staff delivering treatment in all RCT studies and of participants in 1 study, with most studies having short follow-up period (2 to 4 weeks). Thus, more rigorous and robust studies of non-invasive neuromodulation in HD with representative sample, proper randomization, blinding, and assessment alongside adequate follow-up are needed to confirm (or refute) these preliminary findings.

PET Imaging for Evaluation of Huntington’s Disease Progression

Delva et al. (2022) noted that synaptic damage has been proposed to play a major role in the pathophysiology of HD; however, in-vivo evidence in humans is lacking. In a cross-sectional study, these researchers carried out a PET imaging study to examine synaptic damage and its clinical correlates in early HD in-vivo. Pre-manifest and early manifest (Shoulson-Fahn stage 1 and 2) HD mutation carriers and age- and sex-matched healthy controls (HCs) underwent clinical assessment of motor and non-motor manifestations and time-of-flight PET with 11C-UCB-J, a radio-ligand targeting the ubiquitous pre-synaptic terminal marker synaptic vesicle protein 2A (SV2A). They also performed 18F-fluorodeoxyglucose (18F-FDG)-PET in all subjects because regional cerebral glucose consumption is thought to largely reflect synaptic activity. Volumes of interest were delineated on the basis of individual 3-dimensional T1 MRI. Standardized uptake value ratio-1 images were calculated for 11C-UCB-J with the centrum semiovale as reference region. 18F-FDG-PET activity was normalized to the pons. All PET data were corrected for partial volume effects. Volume of interest- and voxel-based analyses were performed. Correlations between clinical scores and 11C-UCB-J PET data were calculated. A total of 18 HD mutation carriers (age of 51.4 ± 11.6 years; 6 women; 7 pre-manifest, 11 early manifest) and 15 HCs (age of 52.3 ± 3.5 years; 4 women) were included. In the HD group, significant loss of SV2A binding was found in putamen, caudate, pallidum, cerebellum, parietal, and temporal and frontal cortex, whereas reduced 18F-FDG uptake was restricted to caudate and putamen. In the pre-manifest subgroup, 11C-UCB-J and 18F-FDG-PET showed significant reductions in putamen and caudate only. In the total HD group, SV2A loss in the putamen correlated with motor impairment. The authors concluded that these findings revealed loss of pre-synaptic terminal integrity in early HD, which began in the striatum in the pre-manifest phase, spread extensively to extra-striatal regions in the early manifest phase; and correlated with motor impairment. 11C-UCB-J PET was more sensitive than 18F-FDG-PET for detection of extra-striatal changes in early HD. This study provided Class III evidence that 11C-UCB-J PET accurately discriminated individuals HD from HCs. Moreover, these researchers stated that the main drawback of the study was the small sample size compared; they stated that longitudinal studies are needed to examine if 11C-UCB-J PET can provide a biomarker of disease progression.

Percutaneous Endoscopic Gastrostomy in Patients with Huntington’s Disease

In a retrospective chart review, Frank et al. (2021) examined the impact of percutaneous endoscopic gastrostomy (PEG) tubes in patients with advanced HD. These researchers evaluated the rate of pneumonia and pressure ulcer, length of life, changes in weight, and serologic nutritional measures. Surviving and deceased patients with and without PEG tubes were compared using descriptive statistical analysis. A total of 148 records were reviewed (39 patients with PEG tubes). The mean age of patients still alive and diagnosed with HD was 58.3 ± 12.7 years and age at death (n = 62) 57.7 ± 10.3 years. At the time of analysis, the mean duration of HD was 14.2 ± 7 years. Groups were similar in sex, age, and weight at admission. In those deceased, insertion of a PEG tube increased the length of life with HD by 3.6 years (16.2 ± 6.7 versus 13.2 ± 4.9 years). Placement of a PEG tube in HD patients significantly reduced cholesterol levels, increased the prevalence of skin ulcers and the rate of pneumonia; it did not significantly change weight or albumin levels. The authors concluded that PEG tube placement in advanced HD provided benefit in the length of life; however, weight and other nutritional measures, as well as the rate of pneumonia were either not impacted or worsened with the insertion of a PEG tube. These researchers stated that the impact on QOL needs further study, but providers, patients, and families should consider all options when discussing preferences for interventions. This study provides Class IV evidence that for patients with advanced HD, PEG tube placement increased the length of life but has no or negative impacts on nutritional measures. These researchers stated that future studies should be carried out to confirm these findings to help guide clinical care over the course of decades of living with HD.

Salivary Levels of Total Huntingtin as Biomarker for Huntington's Disease

Corey-Bloom and colleagues (2018) noted that patients with HD show substantial variability in age-of-onset, symptom severity and course of illness, warranting the need for biomarkers to anticipate and monitor these features. The HD gene encodes the disease protein HTT, a potentially useful biomarker for this disease. These researchers examined if total HTT protein (normal plus mutant; "tHTT") could be reliably measured in human saliva, and whether salivary levels of tHTT were clinically meaningful. They collected 146 saliva samples from manifest HD patients, early pre-manifest individuals, late pre-manifest patients, gene-negative family members and normal controls. These investigators found that tHTT protein could be reliably and stably detected in human saliva and that tHTT levels were significantly increased in saliva from HD individuals compared to normal controls. Salivary tHTT showed no gender effects, nor were levels correlated with total protein levels in saliva. Salivary tHTT was significantly positively correlated with age, but not age-of-onset or CAG-repeat length. Importantly, salivary tHTT was significantly correlated with several clinical measures, indicating relevance to disease symptom onset and/or severity. The authors concluded that measurements of salivary tHTT offer significant promise as a relevant, non-invasive disease biomarker for HD, and its use could be implemented into clinical applications.

Sarco-Endoplasmic Reticulum-Associated ATP2A2 Calcium Pump (SERCA2) and Vascular Endothelial Growth Factor (VEGF) mRNS as Molecular Biomarkers

Cesca et al. (2015) stated that abnormalities of intracellular calcium homeostasis and signaling as well as the down-regulation of neurotrophic factors in several areas of the central nervous system and in peripheral tissues are hallmarks of HD. As there is no therapy for this hereditary, neurodegenerative fatal disease, further effort should be made to slow the progression of neurodegeneration in patients through the definition of early therapeutic interventions. For this purpose, molecular biomarker(s) for monitoring disease onset and/or progression and response to treatment need to be identified. In the attempt to contribute to the research of peripheral candidate biomarkers in HD, these researchers adopted a multiplex real-time PCR approach to analyze the mRNA level of targeted genes involved in the control of cellular calcium homeostasis and in neuroprotection. For this purpose these investigators recruited a total of 110 subjects possessing the HD mutation at different clinical stages of the disease and 54 sex- and age-matched controls. This study provided evidence of reduced transcript levels of sarco-endoplasmic reticulum-associated ATP2A2 calcium pump (SERCA2) and vascular endothelial growth factor (VEGF) in peripheral blood mononuclear cells (PBMCs) of manifest and pre-manifest HD subjects. The authors concluded that these findings provided a potentially new candidate molecular biomarker for monitoring the progression of this disease and contribute to understanding some early events that might have a role in triggering cellular dysfunctions in HD.

Stem Cell Transplantation

Precious and co-workers (2017) stated that HD is a neurodegenerative disease that offers an excellent paradigm for cell replacement therapy because of the associated relatively focal cell loss in the striatum. The predominant cells lost in this condition are striatal medium spiny neurons (MSNs). Transplantation of developing MSNs taken from the fetal brain has provided proof of concept that donor MSNs can survive, integrate and bring about a degree of functional recovery in both pre-clinical studies and in a limited number of clinical trials. The scarcity of human fetal tissue, and the logistics of coordinating collection and dissection of tissue with neurosurgical procedures makes the use of fetal tissue for this purpose both complex and limiting. Alternative donor cell sources that are expandable in culture prior to transplantation are currently being sought. Two potential donor cell sources that have received most attention recently are embryonic stem (ES) cells and adult induced pluripotent stem (iPS) cells, both of which can be directed to MSN-like fates, although achieving a genuine MSN fate has proven to be difficult. All potential donor sources have challenges in terms of their clinical application for regenerative medicine, and thus it is important to continue exploring a wide variety of expandable cells. The authors discussed 2 less well-reported potential donor cell sources:

embryonic germ (EG) cells and
fetal neural precursors (FNPs),

both are which are fetal-derived and have some properties that could make them useful for regenerative medicine applications.

Tartaglione and colleagues (2017) noted that HD is an inherited neurodegenerative disorder, characterized by impairment in motor, cognitive and psychiatric domains. Currently, there is no specific therapy to act on the onset or progression of HD. The marked neuronal death observed in HD is a main argument in favor of stem cells (SCs) transplantation as a promising therapeutic perspective to replace the population of lost neurons and restore the functionality of the damaged circuitry. The availability of rodent models of HD encourages the investigation of the restorative potential of SCs transplantation longitudinally. However, the results of pre-clinical studies on SCs therapy in HD are so far largely inconsistent; this hampers the individuation of the more appropriate model and precludes the comparative analysis of transplant efficacy on behavioral end-points. The authors described the state of the art of in-vivo research on SCs therapy in HD, analyzing in a translational perspective the strengths and weaknesses of animal studies investigating the therapeutic potential of stem cell transplantation on HD progression.

Marsh and Blurton-Jones (2017) stated that neurodegenerative disorders such as AD, PD, and HD currently affect millions of people worldwide. Unfortunately, as the world's population ages, the incidence of many of these diseases will continue to rise and is expected to more than double by 2050. Despite significant research and a growing understanding of disease pathogenesis, only a handful of therapies are currently available and all of them provide only transient benefits. Thus, there is an urgent need to develop novel disease-modifying therapies to prevent the development or slow the progression of these debilitating disorders. A growing number of pre-clinical studies have suggested that transplantation of neural stem cells (NSCs) could offer a promising new therapeutic approach for neurodegeneration. While much of the initial excitement about this strategy focused on the use of NSCs to replace degenerating neurons, more recent studies have implicated NSC-mediated changes in neurotrophins as a major mechanism of therapeutic efficacy. The authors discussed recent work that examined the ability of NSCs to provide trophic support to disease-effected neuronal populations and synapses in models of neurodegeneration. They also discussed some of key challenges that remain before NSC-based therapies for neurodegenerative diseases can be translated toward potential clinical testing.

Colpo and colleagues (2019) noted that HD is an autosomal-dominant neurodegenerative disorder encoding a mHTT. Huntington disease is pathologically characterized by loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline and behavioral symptoms. Stem cell-based therapy has emerged as a feasible therapeutic approach for the treatment of neurodegenerative diseases and may be effective in alleviating and/or halting the pathophysiological mechanisms underlying HD. Several pre-clinical studies have used stem cells in animal models of HD. These researchers performed a systematic review of pre-clinical studies to estimate the treatment efficacy of stem cells in animal models of HD. Based on this systematic review, treatment with stem cells significantly improves neurological and behavioral outcomes in animal models of HD. The authors concluded that although promising results were found, the design of animal studies, the types of transplanted cells and the route of administration were poorly standardized and this greatly complicated comparative analysis.

Transcranial Direct Current Stimulation

Eddy and associates (2017) stated that transcranial direct current stimulation (tDCS) combined with a cognitive task can enhance targeted aspects of cognitive functioning in clinical populations. Huntington's disease is associated with progressive cognitive impairment. Deficits in working memory (WM) can be apparent early in the disease and impact functional capacity. In a cross-over study, these researchers examined if tDCS combined with cognitive training could improve WM in patients with HD, and if baseline clinical or cognitive measures may predict effectiveness. A total of 20 patients with HD completed this trial, undergoing 1.5 mA anodal tDCS over left dorsolateral prefrontal cortex (pFC) and sham stimulation on separate visits. Subjects and evaluator were blinded to condition order, which was randomized across subjects. All participants completed baseline clinical and cognitive assessments. Pre- and post-stimulation tasks included digit reordering, computerized n-back tests and a Stroop task. During 15-min of tDCS/sham stimulation, participants practiced 1- and 2-back WM tasks. Participants exhibited an increase in WM span on the digit re-ordering span task from pre- to post-stimulation after tDCS, but not after sham stimulation. Gains in WM were positively related to motor symptom ratings and negatively associated with verbal fluency scores. Patients with more severe motor symptoms showed greatest improvement, suggesting that motor symptom ratings may help identify patients who are most likely to benefit from tDCS. The authors concluded that dorsolateral pFC tDCS appeared well-tolerated in HD and enhanced WM span compared to sham stimulation. They stated that these findings strongly encouraged further investigation of the extent to which tDCS combined with cognitive training could enhance everyday function in HD.

Talsma and colleagues (2017) noted that tDCS is a promising tool for neurocognitive enhancement. Several studies have shown that just 1 session of tDCS over the left dorsolateral pFC (lDLPFC) can improve the core cognitive function of WM in healthy adults. Yet, recent studies combining multiple sessions of anodal tDCS over lDLPFC with verbal WM training did not observe additional benefits of tDCS in subsequent stimulation sessions nor transfer of benefits to novel WM tasks post-training. Using an enhanced stimulation protocol as well as a design that included a baseline measure each day, the current study aimed to further examine the effects of multiple sessions of tDCS on WM. Specifically, these researchers examined the effects of 3 subsequent days of stimulation with anodal (20 minutes, 1 mA) versus sham tDCS (1 minute, 1 mA) over lDLPFC (with a right supraorbital reference) paired with a challenging verbal WM task; WM performance was measured with a verbal WM updating task (the letter n-back) in the stimulation sessions and several WM transfer tasks (different letter set n-back, spatial n-back, operation span) before and 2 days after stimulation. Anodal tDCS over lDLPFC enhanced WM performance in the 1st stimulation session, an effect that remained visible 24 hours later. However, no further gains of anodal tDCS were observed in the 2nd and 3rd stimulation sessions, nor did benefits transfer to other WM tasks at the group level. Yet, post-hoc individual difference analyses revealed that in the anodal stimulation group the extent of change in WM performance on the 1st day of stimulation predicted pre- to post-changes on both the verbal and the spatial transfer task. Notably, this relationship was not observed in the sham group. Performance of 2 individuals worsened during anodal stimulation and on the transfer tasks. The authors concluded that these findings suggested that repeated anodal tDCS over lDLPFC combined with a challenging WM task may be an effective method to enhance domain-independent WM functioning in some individuals, but not others, or can even impair WM. They called for a thorough investigation into individual differences in tDCS responses as well as further research into the design of multi-session tDCS protocols that may be optimal for boosting cognition across a wide range of individuals.

Transcranial Magnetic Stimulation

Ni and Chen (2015) noted that common neurodegenerative diseases include PD, AD, amyotrophic lateral sclerosis (ALS) and HD. Transcranial magnetic stimulation (TMS) is a non-invasive and painless method to stimulate the human brain. Single- and paired-pulse TMS paradigms are powerful ways to study the pathophysiological mechanisms of neurodegenerative diseases. Motor evoked potential studied with single-pulse TMS is increased in PD, AD and ALS, but is decreased in HD. Changes in motor cortical excitability in neurodegenerative diseases may be related to functional deficits in cortical circuits or to compensatory mechanisms. Reduction or even absence of short interval intra-cortical inhibition induced by paired-pulse TMS is common in neurodegenerative diseases, suggesting that there are functional impairments of inhibitory cortical circuits. Decreased short latency afferent inhibition in AD, PD and HD may be related to the cortical cholinergic deficits in these conditions. Cortical plasticity tested by paired associative stimulation or theta burst stimulation is impaired in PD, AD and HD. Repetitive TMS (rTMS) refers to the application of trains of regularly repeating TMS pulses. High-frequency facilitatory rTMS may improve motor symptoms in PD patients whereas low-frequency inhibitory stimulation is a potential treatment for levodopa-induced dyskinesia; rTMS delivered both to the left and right dorsolateral prefrontal cortex improves memory in AD patients. The authors concluded that supplementary motor cortical stimulation in low frequency may be useful for HD patients. However, the effects of treatment with multiple sessions of rTMS for neurodegenerative diseases need to be tested in large, sham-controlled studies in the future before they can be adopted for routine clinical practice.

Latorre and colleagues (2019) stated that TMS is a safe and painless non-invasive brain stimulation technique that has been largely used in the past 30 years to explore cortical function in healthy participants and, the pathophysiology of movement disorders. The use of TMS has evolved from primarily research purposes to treatment of a large variety of neurological and psychiatric diseases. These investigators described the basic principles on which the therapeutic use of TMS is based and reviewed the clinical trials that have been performed in patients with movement disorders. A search of the PubMed database for research and review articles was performed on therapeutic applications of TMS in movement disorders. The search included the following conditions: Parkinson's disease, dystonia, Tourette syndrome and other chronic tic disorders, HD and chorea, and essential tremor. The results of the studies and possible mechanistic explanations for the relatively minor effects of TMS were discussed. Possible ways to improve the methodology and achieve greater therapeutic efficacy were discussed. The authors concluded that despite the promising and robust rationales for the use of TMS as a treatment tool in movement disorders, the results taken as a whole are not as successful as were initially expected. There is encouraging evidence that TMS may improve motor symptoms and depression in Parkinson's disease, but the efficacy in other movement disorders is unclear. Possible improvements in methodology are on the horizon but have yet to be implemented in large clinical studies.

Transcriptomic Changes in Blood as Biomarkers for Huntington's Disease

Zadel and colleagues (2018) stated that HD is a severe neurodegenerative disorder manifesting as progressive impairment of motor function, cognitive decline, psychiatric symptoms, and immunological and endocrine dysfunction. These researchers examined the consistency of blood transcriptomic biomarkers in HD based on a novel Slovene patient cohort and expert review of previous studies. HumanHT-12 v4 BeadChip microarrays were performed on the whole blood samples of a cohort of 23 HD mutation carriers and 23 controls to identify differentially expressed (DE) transcripts. In addition, they performed an expert review of DE transcripts identified in comparable HD studies from whole blood, to identify any consistent signature of HD. In the Slovene cohort, these investigators identified 740 DE transcripts (p < 0.01 and a false discovery rate (FDR) of less than 0.1) of which 414 were down-regulated and 326 were up-regulated. Pathway analyses of DE transcripts showed enrichment for pathways involved in systemic, rather than neural processes in HD. With an expert review of comparable studies, these researchers have further identified 15 DE transcripts shared by 3 studies. The authors suggested transcriptomic changes in blood reflect systemic changes in HD pathogenesis, rather than being a direct result of the neuropathological processes in the central nervous system during HD progression, and thus, have limited value as disease biomarkers.

Use of Wearable/Portable Digital Sensors in the Clinical Management of Huntington's Disease

Tortelli and colleagues (2021) noted that in chronic neurological conditions, wearable and portable devices have the potential to serve as innovative tools for detecting subtle early disease manifestations and fluctuations for the purposes of clinical diagnosis, care, and therapeutic development. Huntington's disease (HD) has a unique combination of motor and non-motor features, which, combined with recent and anticipated therapeutic progress, presents great potential for such devices to prove useful. These researchers provided a comprehensive account of the use of wearable and portable devices in HD and what they have contributed so far. They conducted a systematic review, searching Medline, Embase, and IEEE Xplore. A total of 30 references were identified; their findings revealed large variability in the types of sensors used, study designs, and measured outcomes. The authors concluded that digital technologies show considerable promise for therapeutic research and clinical management of HD; however, more studies with standardized devices and harmonized protocols are needed to optimize the potential applicability of wearable and portable devices in HD. These researchers stated that wearable and portable devices can be used to study other aspects of HD that are currently under-investigated (e.g., non-motor symptoms), and this technology may eventually be used to guide collaborative decision-making for patients and clinicians. However, much work is needed before such systems can be used as primary trial outcome measures or in clinical settings.

The authors stated that a major drawback for the applicability of wearables and portables in clinical practice and therapeutic investigations is the lack of validation of the proposed devices. The majority of them have been used in a single population, with no data on the reliability and reproducibility of the acquired data and derived results. Most studies utilized different hardware and methods, making it difficult to compare the wearable devices and acquired data, and most studies lacked a validation cohort. Another drawback is that the methodologies for analyzing the vast amount of collected data to obtain meaningful disease-related signals from background noise remain a completely open field of discussion. Furthermore, as with any rapidly growing field of interest, there is no gold standard for the validation of newly proposed monitoring systems. Quantitative motor systems, such as GAITRite mats, can serve as a good gold standard for wearable sensors that measure gait parameters; however, there are no corresponding reference electronic quantitative measures for wearables that assess other disease characteristics. On the other hand, the use of clinical scales as gold standards for validating the proposed devices and collected features has several limitations related to the discrete and rater-dependent nature of these scales, as well as their low temporal and spatial resolution. Finally, in the use of wearables and portables, selection bias must be considered. Socio-cultural factors such as age and enthusiasm for technology may influence recruitment, and there is a lack of studies concerning the influence of relatives, gender, education, and working conditions on the use of wearable and portable technologies. Furthermore, disease stage and functional status can play a role, as wearable and portable devices may not have the same applicability or tolerability across all disease stages. All these limitations, along with the lack of integration and standardization of the measured characteristics, represent major drawbacks responsible for the considerable gap between the promising role of wearable and portable sensors, as well as other digital technologies in neurodegenerative disorders, and their actual adoption in clinical practice or pharmacological studies. Despite at least 20 years of widespread use of wearables and significant advances in technology, they have only been sporadically used as surrogates or exploratory endpoints.

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