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Depression is a common psychiatric disorder among individuals with Huntington's disease (HD). Depression in HD and major depressive disorder appear to have different pathophysiological mechanisms. Despite the unique pathophysiology, the treatment of depression in HD is based on data from the treatment of major depressive disorder in the general population. The objective of this systematic review was to conduct a comprehensive evaluation of the available evidence. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Studies on the treatment of depression in HD were identified by searching MEDLINE, Embase, and PsycInfo. The initial search yielded 2,771 records, 41 of which were ultimately included. There were 19 case reports, seven case series, three cross-sectional studies, one qualitative study, nine nonrandomized studies, and two randomized trials among the included studies. The most common assessment tools were the Hospital Anxiety and Depression Scale (N=8), the Beck Depression Inventory (N=6), and the Hamilton Depression Rating Scale (N=6). Only 59% of the included studies assessed depressive symptoms with a scoring system. The pharmacological options for the treatment of depression included antidepressants and antipsychotics. Nonpharmacological approaches were multidisciplinary rehabilitation, psychotherapy, and neurostimulation. Limited evidence on the treatment of depression in HD was available, and this literature consisted mainly of case reports and case series. This systematic review highlights the knowledge gap and the pressing need for HD-specific research to determine the efficacy of treatment approaches for depression in HD., Competing Interests: Dr. Furr Stimming has received research grant support from or served as a consultant, advisory board member, or speakers bureau member for the Cure Huntington’s Disease Initiative Foundation, Cures Within Reach, Genetech, the Houston Area Parkinson Society, the Huntington’s Disease Society of America, the Huntington Study Group, the Michael J. Fox Foundation, Neurocrine Biosciences, Novartis, Prilenia, Roche, Sage Therapeutics, Sunovion, Teva, uniQure, University of Iowa, and Vaccinex. The other authors report no financial relationships with commercial interests.

Obsessive-compulsive and perseverative behaviors (OCBs/PBs) are characteristic features of Huntington's Disease (HD). Although a few recent research have attempted to discriminate between OCBs and PBs, most of the available evidence on OCBs does not consistently make this distinction. In this article, we aimed to explore the current inconsistencies in assessing and reporting OCBs/PBs and map the body of existing evidence. Up to half of the patients with motor manifest HD can experience OCBs. Separate reporting of PBs in HD patients has been uncommon among the studies and was frequently reported as a part of obsessive-compulsive symptoms. The structural limitation of the currently used rating scales and the overlaps in neuropathology and definition of OCBs and PBs are among the main reasons for the mixed reporting of OCBs/PBs. Perseverative thinking or behavior as a separate item is found in a few assessment tools, such as the Problem Behaviors Assessment - Short form (PBA-s). Even when the item exists, it is commonly reported as a composite score in combination with the obsessive-compulsive item. In addition to the significant psychological burden in individuals with HD, PBs are associated with somatic effects (e.g., cardiovascular symptoms) and high-risk behaviors (e.g., suicide). Recognition and monitoring of PBs in HD can aid in early detection of concerning symptoms and differentiating overlapping illnesses., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To describe the characteristics of patients receiving a clinical referral for neuropsychological evaluation in two Huntington's Disease Society of America Centers of Excellence (HDSA COE). In this exploratory pilot study, we used an empirically supported clinical neuropsychological battery to assess differences in cognitive performance between premanifest and manifest HD patient groups (compared with each other and normative expectations)., Method: Clinical data from 76 adult genetically confirmed patients referred for neuropsychological evaluations was retrospectively collected from two HDSA COEs. ANOVA and Chi-square tests were used to compare variables between pre-manifest (n = 14) and manifest (n = 62) groups for demographic, cognitive, neuropsychiatric, and disease severity variables., Results: Our clinics serviced a disproportionate number of motor manifest patients. Six measures were excluded from analyses due to infrequent administration. The full WAIS-IV Digit Span was disproportionately administered to the manifest group. The premanifest group showed stronger cognitive performance with effect sizes in the large range on subtests of the WAIS-IV Digit Span, HVLT-R, SDMT, and verbal fluency., Conclusions: This is the first study to assess an empirically supported neuropsychological research battery in a clinical setting with a relatively large sample size given the rarity of HD. The battery adequately captured areas of impairment across the disease spectrum. Application of the current battery with larger premanifest samples is warranted., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease., Methods: KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing., Findings: KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were -4·6 for valbenazine and -1·4 for placebo (least-squares mean difference -3·2, 95% CI -4·4 to -2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine., Interpretation: In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea., Funding: Neurocrine Biosciences., Competing Interests: Declaration of interests EFS has received honoraria as an advisory board member, consulted for, received research funding from, and served on the speakers’ bureau for Cures Within Reach, the Cure Huntington's Disease Initiative, Huntington's Disease Society of America, Neurocrine Biosciences, Prilenia, Roche/Genentech, UniQure, Novartis, Teva Pharmaceuticals, Vaccinex, and Sunovion. DOC has received research funding from Vaccinex, the Cure Huntington's Disease Initiative, Huntington's Disease Society of America, Griffin Foundation, Genentech, Wave Life Sciences, Neurocrine Biosciences, Teva Pharmaceuticals, AbbVie, and Biogen. DOC has also served as a consultant to Neurocrine Biosciences, Wave Life Science, Teva Pharmaceuticals, Acadia, Alterity, Genentech/Roche, and Lundbeck. RM served as a consultant for Global Kinetic Corporation and was on the speaker bureau for Teva Pharmaceuticals, Adamas Pharmaceuticals, Kyowa Kirin, Sunovion, and Accorda Therapeutics. DOC has received research grants from Prilenia, Global Kinetic Corporation, Northera, Neurocrine Biosciences, and Cerevel. EK and JG have no conflicts to disclose. HZ, GSL, and DH are full-time employees of Neurocrine Biosciences and own stock in the company., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The Renin-Angiotensin System (RAS) is expressed in the central nervous system and has important functions that go beyond blood pressure regulation. Clinical and experimental studies have suggested that alterations in the brain RAS contribute to the development and progression of neurodegenerative diseases. However, there is limited information regarding the involvement of RAS components in Huntington's disease (HD). Herein, we used the HD murine model, (BACHD), as well as samples from patients with HD to investigate the role of both the classical and alternative axes of RAS in HD pathophysiology. BACHD mice displayed worse motor performance in different behavioral tests alongside a decrease in the levels and activity of the components of the RAS alternative axis ACE2, Ang-(1-7), and Mas receptors in the striatum, prefrontal cortex, and hippocampus. BACHD mice also displayed a significant increase in mRNA expression of the AT1 receptor, a component of the RAS classical arm, in these key brain regions. Moreover, patients with manifest HD presented higher plasma levels of Ang-(1-7). No significant changes were found in the levels of ACE, ACE2, and Ang II. Our findings provided the first evidence that an imbalance in the RAS classical and counter-regulatory arms may play a role in HD pathophysiology.

Background: Depression and suicidality are commonly experienced by Huntington disease (HD) gene carriers. Research on these behavioral symptoms is imperative, not only to increase our understanding of the symptoms and how they relate to HD, but also to contribute to improving patients' care and quality of life., Objective: To identify clinical variables associated with a history of depression and suicidality in HD gene carriers., Method: We conducted a cross-sectional study of HD gene carriers from the Enroll-HD database PDS4 (periodic data set 4; N = 11,582). Data from baseline visits were obtained, and binary logistic regression models were used to ascertain the effects of clinical variables on the likelihood that HD gene carriers would have previous depression and suicidal ideation/attempts., Results: Approximately 65% (n = 7526) of the HD gene carriers had a history of depression, and ~27% (n = 3152) had previous suicidal ideation/attempts. Female sex; diagnosis of manifest HD; history of perseverative/obsessive behavior, apathy, and psychosis; and previous suicidal ideation/attempts were significantly associated with a history of depression in the HD gene carriers. Medical history of apathy, psychosis, and depression, as well as worse scores on the Total Functional Capacity and Irritability Scales, were significantly associated with previous suicidal ideation/attempts in the HD gene carriers., Conclusion: The prevalence of depression and suicidality is high among HD gene carriers. An improved understanding of the risk factors for depression and suicide in HD gene carriers can assist providers in recognizing at-risk individuals and allow providers to implement therapeutic strategies., Competing Interests: E.F.S. has received honoraria as an advisory board member, consulted for, received research funding from, and/or served on the speakers’ bureau for Cures within Reach, CHDI, HDSA, Neurocrine Biosciences/HSG, Prilenia, Roche/Genetech, UniQure, Novartis, Teva, Vaccinex, and Sunovion. The remaining authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments., Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers., Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention., Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments., Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Objective: To define the role played by microglia in different stages of Huntington disease (HD), we used the TSPO radioligand [11C]-ER176 and PET to evaluate microglial activation in relation to neurodegeneration and in relation to the clinical features seen at premanifest and manifest stages of the disease., Methods: This is a cross-sectional study in which 18 subjects (6 controls, 6 premanifest, and 6 manifest HD gene carriers) underwent a [11C]-ER176 PET scan and an MRI for anatomic localization. Segmentation of regions of interest (ROIs) was performed, and group differences in [11C]-ER176 binding (used to evaluate the extent of microglial activation) were assessed by the standardized uptake value ratio (SUVR). Microglial activation was correlated with ROIs volumes, disease burden, and the scores obtained in the clinical scales. As an exploratory aim, we evaluated the dynamic functions of microglia in vitro, by using induced microglia-like (iMG) cells from peripheral blood monocytes., Results: Individuals with manifest HD present higher [11C]-ER176 SUVR in both globi pallidi and putamina in comparison with controls. No differences were observed when we compared premanifest HD with controls or with manifest HD. We also found a significant correlation between increased microglial activation and cumulative disease burden, and with reduced volumes. iMG from controls, premanifest HD, and manifest HD patients showed similar phagocytic capacity., Conclusions: Altogether, our data demonstrate that microglial activation is involved in HD pathophysiology and is associated with disease progression., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Huntington's disease (HD) is an inherited neurodegenerative disease. Besides the well-characterized motor symptoms, HD is marked by cognitive impairment and behavioral changes. In this study, we analyzed the blood of HD gene carries using RNA-sequencing techniques. We evaluated samples from HD gene carriers with ( n = 8) and without clinically meaningful depressive symptoms ( n = 8) compared with healthy controls ( n = 8). Groups were age- and sex-matched. Preprocessing of data and between-group comparisons were calculated using DESeq2. The Wald test was used to generate p -values and log2 fold changes. We found 60 genes differently expressed in HD and healthy controls, of which 21 were upregulated and 39 downregulated. Within HD group, nineteen genes were differently expressed between patients with and without depression, being 6 upregulated and 13 downregulated. Several of the top differentially expressed genes are involved in nervous system development. Although preliminary, our findings corroborate the emerging view that in addition to neurodegenerative mechanisms, HD has a neurodevelopmental component. Importantly, the emergence of depression in HD might be related to these mechanisms.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder encoding a mutant form of the huntingtin protein (HTT). HD 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. Here, we performed a systematic review of preclinical studies to estimate the treatment efficacy of stem cells in animal models of HD. Based on our systematic review, treatment with stem cells significantly improves neurological and behavioral outcomes in animal models of HD. Although promising results were found, the design of animal studies, the types of transplanted cells and the route of administration are poorly standardized and this greatly complicates comparative analysis., (Published by Elsevier Inc.)

Background: Prediction of motor diagnosis in Huntington's disease (HD) can be improved by incorporating other phenotypic and biological clinical measures in addition to cytosine-adenine-guanine (CAG) repeat length and age., Objective: The objective was to compare various clinical and biomarker trajectories for tracking HD progression and predicting motor conversion., Methods: Participants were from the PREDICT-HD study. We constructed a mixed-effect model to describe the change of measures while jointly modeling the process with time to HD diagnosis. The model was then used for subject-specific prediction. We employed the time-dependent receiver operating characteristic (ROC) method to assess the discriminating capability of the measures to identify high and low risk patients. The strongest predictor was used to illustrate the dynamic prediction of the disease risk and future trajectories of biomarkers for three hypothetical patients., Results: 1078 individuals were included in this analysis. Five longitudinal clinical and imaging measures were compared. The putamen volume had the best discrimination performance with area under the curve (AUC) ranging from 0.74 to 0.82 over time. The total motor score showed a comparable discriminative ability with AUC ranging from 0.69 to 0.78 over time. The model showed that decreasing putamen volume was a significant predictor of motor conversion. A web-based calculator was developed for implementing the methods., Conclusions: By jointly modeling longitudinal data with time-to-event outcomes, it is possible to construct an individualized dynamic event prediction model that renews over time with accumulating evidence. If validated, this could be a valuable tool to guide the clinician in predicting age of onset and potentially rate of progression.

Huntington's disease (HD) is a neurodegenerative disorder characterized by selective loss of neurons in the striatum and cortex, which leads to progressive motor dysfunction, cognitive decline, and psychiatric disorders. Although the cause of HD is well described-HD is a genetic disorder caused by a trinucleotide (CAG) repeat expansion in the gene encoding for huntingtin (HTT) on chromosome 4p16.3-the ultimate cause of neuronal death is still uncertain. Apart from impairment in systems for handling abnormal proteins, other metabolic pathways and mechanisms might contribute to neurodegeneration and progression of HD. Among these, inflammation seems to play a role in HD pathogenesis. The current review summarizes the available evidence about immune and/or inflammatory changes in HD. HD is associated with increased inflammatory mediators in both the central nervous system and periphery. Accordingly, there have been some attempts to slow HD progression targeting the immune system.