Huntington Disease Gene Expansion Carriers Research Articles

Cerebrospinal fluid glial fibrillary acidic protein, in contrast to amyloid beta protein, is associated with disease symptoms in Huntington's disease

IntroductionHuntington's disease (HD) is a hereditary neurodegenerative disease, currently lacking disease-modifying treatments. Biomarkers are needed for objective assessment of disease progression. Evidence supports both complex protein aggregation and astrocyte activation in HD. This study assesses the 42 amino acid long amyloid beta (Aβ42) and glial fibrillary acidic protein (GFAP) as potential biomarkers in the cerebrospinal fluid (CSF) of HD mutation carriers. MethodsCSF from participants was obtained from three sites in Sweden. Clinical symptoms were graded with the composite Unified Huntington's disease rating scale (cUHDRS). Protein concentrations were measured using ELISA. Pearson correlations were calculated to assess disease progression association. Results were adjusted for age and collection site. ResultsThe study enrolled 28 manifest HD patients (ManHD), 13 premanifest HD gene-expansion carriers (PreHD) and 20 controls. Aβ42 levels did not differ between groups and there was no correlation with measures of disease progression.GFAP concentration was higher in ManHD (424 ng/l, SD 253) compared with both PreHD (266 ng/l, SD 92.4) and controls (208 ng/l, SD 83.7). GFAP correlated with both cUHDRS (r = −0.77, p < 0.001), and 5-year risk of disease onset (r = 0.70, p = 0.008). ConclusionWe provide evidence that indicates CSF Aβ42 has limited potential as a biomarker for HD. GFAP is a potential biomarker of progression in HD. Validation in larger cohorts measuring GFAP in blood and CSF would be of interest.

High Levels of Mutant Huntingtin Protein in Tear Fluid From Huntington's Disease Gene Expansion Carriers.

Huntington's disease (HD) is an autosomal dominant, fully penetrant, neurodegenerative disease that most commonly affects middle-aged adults. HD is caused by a CAG repeat expansion in the HTT gene, resulting in the expression of mutant huntingtin (mHTT). Our aim was to detect and quantify mHTT in tear fluid, which, to our knowledge, has never been measured before. We recruited 20 manifest and 13 premanifest HD gene expansion carriers, and 20 age-matched controls. All patients underwent detailed assessments, including the Unified Huntington's Disease Rating Scale (UHDRS) total motor score (TMS) and total functional capacity (TFC) score. Tear fluid was collected using paper Schirmer's strips. The level of tear mHTT was determined using single-molecule counting SMCxPRO technology. The average tear mHTT levels in manifest (67,223 ± 80,360 fM) and premanifest patients (55,561 ± 45,931 fM) were significantly higher than those in controls (1,622 ± 2,179 fM). We noted significant correlations between tear mHTT levels and CAG repeat length, "estimated years to diagnosis," disease burden score and UHDRS TMS and TFC. The receiver operating curve demonstrated an almost perfect score (area under the curve [AUC] = 0.9975) when comparing controls to manifest patients. Similarly, the AUC between controls and premanifest patients was 0.9846. The optimal cutoff value for distinguishing between controls and manifest patients was 4,544 fM, whereas it was 6,596 fM for distinguishing between controls and premanifest patients. Tear mHTT has potential for early and noninvasive detection of alterations in HD patients and could be integrated into both clinical trials and clinical diagnostics.

Guided self-help for anxiety among Huntington’s disease gene expansion carriers (GUIDE-HD) compared to treatment as usual: a randomised controlled feasibility trial

BackgroundHuntington’s disease (HD) is an adult-onset genetic neurodegenerative condition associated with cognitive decline, motor impairments, and emotional difficulties. Anxiety affects up to 71% of HD gene expansion carriers (i.e., those with the version of the gene that causes HD) and can negatively impact quality of life, worsen other HD symptoms, and increase suicide risk. Therefore, helping people with their anxiety should be a clinical priority. A significant evidence base now exists for low-cost talking therapies for anxiety, such as guided self-help, and with people with other neurodegenerative conditions (e.g., Parkinson’s disease). However, this type of intervention has not been specifically assessed with HD gene expansion carriers.MethodsThis protocol describes an exploratory randomised controlled feasibility study of a psychological intervention for anxiety for HD gene expansion carriers. The 10 session guided self-help intervention ('GUIDE-HD') is based on a blend of second and third wave cognitive behavioural models of anxiety (cognitive behaviour therapy [CBT] and acceptance and commitment therapy [ACT]) and is adapted to meet the specific needs of an HD population. This study will compare guided self-help with treatment as usual (TAU), with 15 HD gene expansion carriers randomly allocated to each group. Participants will be recruited across the UK. Quantitative data will be collected pre-intervention, immediately post-intervention, 3-month post-intervention and 6-month post-intervention. Qualitative data will be collected at one month post-intervention from participants, including HD carers. The data will be analysed to assess whether the current intervention and study design are feasible to progress to a larger randomised controlled trial. Feasibility has been defined in terms of recruitment rate, retention rate to both trial arms, intervention adherence, and acceptability of the intervention and measurement tools.DiscussionGiven the lack of evidenced interventions to date to support the wellbeing of people with the expanded Huntington’s gene, this study will assess the feasibility of progressing this particular intervention to a full trial. To try and increase the acceptability of the intervention, a number of stakeholders, including those affected by HD and in caring roles, have been fundamental to the creation of the intervention (e.g., therapy manual, planned therapy process) to date.Trial registrationTrial ID: ISRCTN47330596.Date registered: 28/09/2022.Protocol version and date: Version 2, 09/06/22.Trial sponsor organisation and contact: Leicestershire Partnership NHS Trust (Dave Clarke).Role of sponsor: Overall responsibility for the conduct and governance of the trial.Role of funder: Review of initial research proposal.

A Randomized Controlled Trial of Probiotics Targeting Gut Dysbiosis in Huntington's Disease.

Gastrointestinal symptoms are clinical features of Huntington's disease (HD), which adversely affect people's quality of life. We recently reported the first evidence of gut dysbiosis in HD gene expansion carriers (HDGECs). Here, we report on a randomized controlled clinical trial of a 6-week probiotic intervention in HDGECs. The primary objective was to determine whether probiotics improved gut microbiome composition in terms of richness, evenness, structure, and diversity of functional pathways and enzymes. Exploratory objectives were to determine whether probiotic supplementation improved cognition, mood, and gastrointestinal symptoms. Forty-one HDGECs, including 19 early manifest and 22 premanifest HDGECs were compared with 36 matched-healthy controls (HCs). Participants were randomly assigned probiotics or placebo and provided fecal samples at baseline and 6-week follow-up, which were sequenced using 16S-V3-V4 rRNA to characterize the gut microbiome. Participants completed a battery of cognitive tests and self-report questionnaires measuring mood and gastrointestinal symptoms. HDGECs had altered gut microbiome diversity when compared to HCs, indicating gut dysbiosis. Probiotic intervention did not ameliorate gut dysbiosis or have any effect on cognition, mood, or gastrointestinal symptoms. Gut microbiome differences between HDGECs and HCs were unchanged across time points, suggesting consistency of gut microbiome differences within groups. Despite the lack of probiotic effects in this trial, the potential utility of the gut as a therapeutic target in HD should continue to be explored given the clinical symptomology, gut dysbiosis, and positive results from probiotics and other gut interventions in similar neurodegenerative diseases.

Speech biomarkers in Huntington's disease: A cross-sectional study in pre-symptomatic, prodromal and early manifest stages.

Motor speech alterations are a prominent feature of clinically manifest Huntington's disease (HD). Objective acoustic analysis of speech can quantify speech alterations. It is currently unknown, however, at what stage of HD speech alterations can be reliably detected. We aimed to explore the patterns and extent of speech alterations using objective acoustic analysis in HD and to assess correlations with both rater-assessed phenotypical features and biological determinants of HD. Speech samples were acquired from 44 premanifest (29 pre-symptomatic and 15 prodromal) and 25 manifest HD gene expansion carriers, and 25 matched healthy controls. A quantitative automated acoustic analysis of 10 speech dimensions was performed. Automated speech analysis allowed us to differentiate between participants with HD and controls, with areas under the curve of 0.74 for pre-symptomatic, 0.92 for prodromal, and 0.97 for manifest stages. In addition to irregular alternating motion rates and prolonged pauses seen only in manifest HD, both prodromal and manifest HD displayed slowed articulation rate, slowed alternating motion rates, increased loudness variability, and unstable steady-state position of articulators. In participants with premanifest HD, speech alteration severity was associated with cognitive slowing (r=-0.52, p < 0.001) and the extent of bradykinesia (r=0.43, p=0.004). Speech alterations correlated with a measure of exposure to mutant gene products (CAG-age-product score; r=0.60, p < 0.001). Speech abnormalities in HD are associated with other motor and cognitive deficits and are measurable already in premanifest stages of HD. Therefore, automated speech analysis might represent a quantitative HD biomarker with potential for assessing disease progression.

Study protocol of the HD-MED study aiming to personalize drug treatment in Huntington's disease: a longitudinal, observational study to assess medication use and efficacy in relation to pharmacogenetics.

Huntington's disease (HD) is a hereditary, neurodegenerative disorder characterized by motor, cognitive, and psychiatric symptoms. Currently, HD can only be managed symptomatically, including a large variety of prescribed drugs. Many HD patients experience negative medication effects (e.g. side effects or non-response). Pharmacogenetic (PGx) studies show how genetic variation affects both medication efficacy and toxicity and holds the potential to improve these outcomes of drug treatment. To classify the effect of the PGx profile of CYP2C19 and CYP2D6 in HD gene expansion carriers on negative medication effects of HD-related medication. Multicenter, observational study with 1-year follow-up. Adult HD gene expansion carriers who use one or more HD-related medications are eligible to participate. A detailed overview of medication use, medication efficacy, and side effects is retrospectively and prospectively collected via medication diaries, questionnaires, phone calls, and pharmacy medication verification schemes. PGx analysis on whole blood-extracted DNA is performed with Agena Bioscience VeriDose® Core Panel and long-range polymerase chain reaction copy number variation analysis. Per the study protocol-defined negative medication effects in HD gene expansion carriers with a genotype predicted poor or ultrarapid metabolizer phenotype will be compared with HD gene expansion carriers with a predicted intermediate and normal metabolizer phenotype. Frequencies will be analyzed via χ2 and logistic multivariate regression analysis. In addition, we summarize in this manuscript HD-relevant PGx prescription recommendations to improve drug therapy. The original study protocol was approved by the medical research ethics committee Leiden Den Haag Delft on 26 November 2019. HD-MED is a low-risk study that will generate personalized PGx results that can immediately be implemented in clinical practice, thus potentially improving pharmacovigilance and patients' quality of life. This study is registered in the International Clinical Trial Registry Platform under registration number NL8251, URL https://trialsearch.who.int/Trial2.aspx?TrialID=NL8251.

Study protocol of IMAGINE-HD: Imaging iron accumulation and neuroinflammation with 7T-MRI + CSF in Huntington’s disease

IntroductionStrong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington’s disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures. MethodsThis is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites’ level and diffusion. Age and sex matched healthy subjects are included as a control group. DiscussionResults from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other.

Pepinemab antibody blockade of SEMA4D in early Huntington’s disease: a randomized, placebo-controlled, phase 2 trial

SIGNAL is a multicenter, randomized, double-blind, placebo-controlled phase 2 study (no. NCT02481674) established to evaluate pepinemab, a semaphorin 4D (SEMA4D)-blocking antibody, for treatment of Huntington’s disease (HD). The trial enrolled a total of 265 HD gene expansion carriers with either early manifest (EM, n = 179) or late prodromal (LP, n = 86) HD, randomized (1:1) to receive 18 monthly infusions of pepinemab (n = 91 EM, 41 LP) or placebo (n = 88 EM, 45 LP). Pepinemab was generally well tolerated, with a relatively low frequency of serious treatment-emergent adverse events of 5% with pepinemab compared to 9% with placebo, including both EM and LP participants. Coprimary efficacy outcome measures consisted of assessments within the EM cohort of (1) a two-item HD cognitive assessment family comprising one-touch stockings of Cambridge (OTS) and paced tapping (PTAP) and (2) clinical global impression of change (CGIC). The differences between pepinemab and placebo in mean change (95% confidence interval) from baseline at month 17 for OTS were −1.98 (−4.00, 0.05) (one-sided P = 0.028), and for PTAP 1.43 (−0.37, 3.23) (one-sided P = 0.06). Similarly, because a significant treatment effect was not observed for CGIC, the coprimary endpoint, the study did not meet its prespecified primary outcomes. Nevertheless, a number of other positive outcomes and post hoc subgroup analyses—including additional cognitive measures and volumetric magnetic resonance imaging and fluorodeoxyglucose–positron-emission tomography imaging assessments—provide rationale and direction for the design of a phase 3 study and encourage the continued development of pepinemab in patients diagnosed with EM HD.

Decreased CSF oxytocin relates to measures of social cognitive impairment in Huntington's disease patients

ObjectiveHuntington's disease (HD) is an inherited neurodegenerative disease with motor, cognitive and psychiatric symptoms. Non-motor symptoms like depression and altered social cognition are proposed to be caused by dysfunction of the hypothalamus. We measured the hypothalamic neuropeptide oxytocin in plasma and cerebrospinal fluid (CSF) in a cohort of HD gene expansion carriers (HDGECs), compared the levels to healthy HD family controls and correlated oxytocin levels to disease progression and social cognition. MethodsWe recruited 113 HDGECs and 33 controls. Psychiatric and cognitive symptoms were evaluated, and social cognition was assessed with the Emotion Hexagon test, Reading the Mind in the Eyes and The Awareness of Social Inference Test. The levels of oxytocin in CSF and blood were analyzed by radioimmunoassay. ResultsWe found the level of oxytocin in CSF to be significantly lower by 33.5% in HDGECs compared to controls (p = 0.016). When dividing the HDGECs into groups with or without cognitive impairment, we found the oxytocin level to be significantly lower by 30.3% in the HDGECs with cognitive symptoms (p = 0.046). We found a statistically significant correlation between the level of oxytocin and scores on social cognition (Reading the Mind in the Eyes p = 0.0019; Emotion Hexagon test: p = 0.0062; The Awareness of Social Inference Test: p = 0.002). ConclusionsThis is the first study to measure oxytocin in the CSF of HDGECs. We find that HDGECs have a significantly lower level of oxytocin compared to controls, and that the level of oxytocin may represent an objective and comparable measure that could be used as a state biomarker for impairment of social cognition. We suggest treatment trials to evaluate a potential effect of oxytocin on social cognition in HD.

Safety and Feasibility of Research Lumbar Puncture in Huntington's Disease: The HDClarity Cohort and Bioresource.

Biomarkers are needed to monitor disease progression, target engagement and efficacy in Huntington's disease (HD). Cerebrospinal fluid (CSF) is an ideal medium to research such biomarkers due to its proximity to the brain. To investigate the safety and feasibility of research lumbar punctures (LP) in HD. HDClarity is an ongoing international biofluid collection initiative built on the Enroll-HD platform, where clinical assessments are recorded. It aims to recruit 1,200 participants. Biosamples are collected following an overnight fast: blood via venipuncture and CSF via LP. Participants are healthy controls and HD gene expansion carriers across the disease spectrum. We report on monitored data from February 2016 to September 2019. Of 448 participants screened, 398 underwent at least 1 sampling visit, of which 98.24% were successful (i.e., CSF was collected), amounting to 10,610 mL of CSF and 8,200 mL of plasma. In the total 572 sampling visits, adverse events were reported in 24.13%, and headaches of any kind and post-LP headaches in 14.86% and 12.24%, respectively. Frequencies were less in manifest HD; gender, age, body mass index and disease burden score were not associated with the occurrence of the events in gene expansion carriers. Headaches and back pain were the most frequent adverse events. HDClarity is the largest CSF collection initiative to support scientific research into HD and is now stablished as a leading resource for HD research. Our data confirm that research LP in HD are feasible and acceptable to the community, and have a manageable safety profile.

Intellectual Curiosity and Action Initiation are Subtypes of Apathy Affected in Huntington Disease Gene Expansion Carriers.

Apathy is a prevalent behavioral syndrome of Huntington disease (HD) that can result in severe loss of function for the individual with HD and substantial caregiver distress. Research-based evidence of apathy is characterized by methodological differences, and there is a deficiency in the evidence concerning the subtypes of apathy. To characterize apathy in premanifest and motor-manifest HD gene expansion carriers and controls using the Short Problem Behaviors Assessment for Huntington's Disease (PBA-s) and the Lille Apathy Rating Scale (LARS). We included 82 HD gene expansion carriers (premanifest and motor manifest) and 32 controls (Mini-Mental State Examination score ≥24 and Montreal Cognitive Assessment score ≥19) in the study. We quantified apathy using the PBA-s and the LARS and performed correlation analyses between the global LARS score and motor function, cytosine-adenine-guanine repeat length, cytosine-adenine-guanine Age Product score, and neuropsychiatric and cognitive symptoms. The motor-manifest HD gene expansion carriers scored significantly higher than the controls on the global score and the Intellectual Curiosity and Action Initiation subscales of the LARS. Apathy was present in 28% of the HD gene expansion carriers (including 7 premanifest). The apathetic participants had a significantly higher motor score, significantly higher scores on the neuropsychiatric instruments, and significantly lower cognitive scores compared with the controls. Apathy is a frequent syndrome that is found in individuals with HD. Apathy has a specific expression, with symptoms such as reduced initiation, voluntary actions, and interests, that might be related to the underlying neuropathology. Apathy is related to disease progression, neuropsychiatric symptoms, and cognitive impairments.

Intellectual curiosity and action initiation are subtypes of apathy affected in Huntington’s disease gene expansion carriers

AbstractBackgroundApathy is a prevalent behavioral symptom in neurodegenerative diseases. In Huntington’s Disease, apathy can result in severe loss of function for the patient and substantial caregiver distress. The research‐based evidence of apathy is characterized by a lack of generalizability due to methodological differences. In this study we wished to characterize apathy in premanifest and motor‐manifest Huntington’s Disease gene expansion carriers and controls.Method82 Huntington’s Disease gene expansion carriers (premanifest and motor‐manifest) and 32 controls were included in the study (Mini‐Mental State Examination score ≥ 24 and Montreal Cognitive Assessment score ≥ 19). Apathy was quantified using the Lille Apathy Rating Scale and the Short Problem Behaviors Assessment for Huntington’s Disease. Analyses of association were performed between apathy on the Lille Apathy Rating Scale and motor function, cytosine‐adenine‐guanine repeat length, cytosine‐adenine‐guanine age product score, neuropsychiatric and cognitive screening tests.ResultCompared to premanifest and control participants, the motor‐manifest Huntington’s Disease gene expansion carriers scored significantly higher on the global score on the Lille Apathy Rating Scale and on two subscales (Intellectual Curiosity and Action Initiation – see table 1). Likewise, motor‐manifest HD gene expansion carriers scored significantly higher on the Short Problem Behaviors Assessment for Huntington’s Disease. Significant correlations were found between apathy on the Lille Apathy Rating Scale and the motor score, the neuropsychiatric measures and the cognitive screening tests. Apathy was present in 22 % of the Huntington’s Disease gene expansion carriers (including four premanifest participants) when examined with the Lille Apathy Rating Scale. The apathetic participants had significantly higher motor score and were significantly affected on the neuropsychiatric measures and the cognitive screening tests. When entered a multiple stepwise regression model, apathy was predicted by the motor score and the depression score. No other variables could significantly predict apathy on the Lille Apathy Rating Scale.ConclusionApathy is a frequent and early symptom of disease in Huntington’s Disease gene expansion carriers, and it has a specific expression that might be related to the underlying neuropathology. Apathy is related to disease progression, cognitive decline and neuropsychiatric symptoms.

An MDS Evidence-Based Review on Treatments for Huntington's Disease.

Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. 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. 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. 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. 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.

Study Protocol for the Development of a European eHealth Platform to Improve Quality of Life in Individuals With Huntington's Disease and Their Partners (HD-eHelp Study): A User-Centered Design Approach.

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that affects the quality of life (QoL) of HD gene expansion carriers (HDGECs) and their partners. Although HD expertise centers have been emerging across Europe, there are still some important barriers to care provision for those affected by this rare disease, including transportation costs, geographic distance of centers, and availability/accessibility of these services in general. eHealth seems promising in overcoming these barriers, yet research on eHealth in HD is limited and fails to use telehealth services specifically designed to fit the perspectives and expectations of HDGECs and their families. In the European HD-eHelp study, we aim to capture the needs and wishes of HDGECs, partners of HDGECs, and health care providers (HCPs) in order to develop a multinational eHealth platform targeting QoL of both HDGECs and partners at home.Methods: We will employ a participatory user-centered design (UCD) approach, which focusses on an in-depth understanding of the end-users' needs and their contexts. Premanifest and manifest adult HDGECs (n = 76), partners of HDGECs (n = 76), and HCPs (n = 76) will be involved as end-users in all three phases of the research and design process: (1) Exploration and mapping of the end-users' needs, experiences and wishes; (2) Development of concepts in collaboration with end-users to ensure desirability; (3) Detailing of final prototype with quick review rounds by end-users to create a positive user-experience. This study will be conducted in the Netherlands, Germany, Czech Republic, Italy, and Ireland to develop and test a multilingual platform that is suitable in different healthcare systems and cultural contexts.Discussion: Following the principles of UCD, an innovative European eHealth platform will be developed that addresses the needs and wishes of HDGECs, partners and HCPs. This allows for high-quality, tailored care to be moved partially into the participants' home, thereby circumventing some barriers in current HD care provision. By actively involving end-users in all design decisions, the platform will be tailored to the end-users' unique requirements, which can be considered pivotal in eHealth services for a disease as complex and rare as HD.

Hippocampal and striatal volumes correlate with spatial memory impairment in Huntington's disease.

Spatial memory impairments are observed in people with Huntington's disease (HD), however, the domain of spatial memory has received little focus when characterizing the cognitive phenotype of HD. Spatial memory is traditionally thought to be a hippocampal-dependent function, while the neuropathology of HD centers on the striatum. Alongside spatial memory deficits in HD, recent neurocognitive theories suggest that a larger brain network is involved, including the striatum. We examined the relationship between hippocampal and striatal volumes and spatial memory in 36 HD gene expansion carriers, including premanifest (n=24) and early manifest HD (n=12), and 32 matched healthy controls. We assessed spatial memory with Paired Associates Learning, Rey-Osterrieth Complex Figure Test, and the Virtual House task, which assesses three components of spatial memory: navigation, object location, and plan drawing. Caudate nucleus, putamen, and hippocampal volumes were manually segmented on T1-weighted MR images. As expected, caudate nucleus and putamen volumes were significantly smaller in the HD group compared to controls, with manifest HD having more severe atrophy than the premanifest HD group. Hippocampal volumes did not differ significantly between HD and control groups. Nonetheless, on average, the HD group performed significantly worse than controls across all spatial memory tasks. The spatial memory components of object location and recall of figural and topographical drawings were associated with striatal and hippocampal volumes in the HD cohort. We provide a case to include spatial memory impairments in the cognitive phenotype of HD, and extend the neurocognitive picture of HD beyond its primary pathology within the striatum.

Incidence of completed suicide and suicide attempts in a global prospective study of Huntington's disease.

Risk of death from suicide in Huntington's disease is notably elevated relative to that in the general population, although the incidence within HD populations has not been precisely defined. Robust incidence estimates of suicidal behavior can serve as references for HD therapeutic research and post-marketing surveillance to help evaluate the suicidality risk of novel therapeutics. To estimate the incidence rate of completed suicide and suicide attempt in the global, prospective HD cohort study Enroll-HD that records these events per protocol. A total of 20 912 participants were available for analysis (HD gene-expansion carriers (HDGECs) n = 15 924; non-HDGECs n = 4988) representing a collective observation period of 53 390 participant-years. Each observed event was subject to clinical review and evaluation. We generated incidence rates (events per 100 000 person-years) for suicides and suicide attempts using all available data, as well as by year of study and geographical region. Proportionate mortality statistics for suicide and respective 95% confidence intervals were also generated. The overall incidence rate of suicide in HDGECs was 72 per 100 000 person-years, and 8 per 100 000 person-years in non-HDGECs. Proportionate mortality attributable to suicide in HDGECs was 4.6%. For suicide attempts, the global overall incidence rate observed in HDGECs was 306-375 per 100 000 person-years, and 23-38 per 100 000 person-years in non-HDGECs. The incidence estimates calculated here can be used as a reference to help evaluate drug safety and may also be useful in assessing progress in clinical care for HDGECs once therapeutic interventions become widely available.

Endophenotypical drift in Huntington\u2019s disease: a 5-year follow-up study

BackgroundHuntington’s disease (HD) is clinically characterized by progressing motor, cognitive and psychiatric symptoms presenting as varying phenotypes within these three major symptom domains. The disease is caused by an expanded CAG repeat tract in the huntingtin gene and the pathomechanism leading to these endophenotypes is assumed to be neurodegenerative. In 2012/2013 we recruited 107 HD gene expansion carriers (HDGECs) and examined the frequency of the three cardinal symptoms and in 2017/2018 we followed up 74 HDGECs from the same cohort to describe the symptom trajectories and individual drift between the endophenotypes as well as potential predictors of progression and remission.ResultsWe found higher age to reduce the probability of improving on psychiatric symptoms; increasing disease burden score ((CAG-35.5) * age) to increase the risk of developing cognitive impairment; increasing disease burden score and shorter education to increase the risk of motor onset while lower disease burden score and higher Mini Mental State Examination increased the probability of remaining asymptomatic. We found 23.5% (N = 8) to improve from their psychiatric symptoms.ConclusionsThere is no clear pattern in the development of or drift between endophenotypes. In contrast to motor and cognitive symptoms we find that psychiatric symptoms may resolve and thereby not entirely be caused by neurodegeneration. The probability of improving from psychiatric symptoms is higher in younger age and advocates for a potential importance of early treatment.

Utility of Huntington's Disease Assessments by Disease Stage: Floor/Ceiling Effects.

Introduction: An understanding of the clinimetric properties of clinical assessments, including their constraints, is critical to sound clinical study and trial design. Utilizing data from Enroll-HD—a global, prospective HD observational study and clinical research platform—we examined several well-established HD clinical assessments across all stages of disease for evidence of instrument constraints, specifically floor/ceiling effects, to inform selection of appropriate instruments for use in future studies/trials and identify gaps in instrument utility over the life-course of the disease.Material and Methods: Analyzing publicly available data from 6,614 HD gene-expansion carriers (HDGECs), we grouped participants into deciles based on baseline CAP score, which ranged from 26 to 229. We used descriptive statistics to characterize data distribution for 25 outcome measures (encompassing motor, function, cognition, and psychiatric/behavioral domains) in each CAP decile. A skewness statistic threshold of ±2 was defined a priori to indicate floor/ceiling effects.Results: We found evidence of floor/ceiling effects in the early premanifest stages of disease for most motor and function assessments (e.g., TMS, TFC) and select cognitive tasks (MMSE, Trail Making tests). Other cognitive assessments, and the HADS-SIS scales, performed well ubiquitously, with no evidence of floor/ceiling effects at any disease stage. Floor/ceiling effects were evident at every disease stage for certain assessments, including PBA-s measures. Ceiling effects were apparent for DCL from onset stages onwards, as expected.Discussion: Developing instruments sensitive to subtle differences in performance at the earlier stages of the disease spectrum, particularly in motor and function domains, is warranted.

Hybrid 2-[18F] FDG PET/MRI in premanifest Huntington's disease gene-expansion carriers: The significance of partial volume correction.

BackgroundHuntington’s disease (HD) is an inherited, progressive neurodegenerative disease that has no cure. Striatal atrophy and hypometabolism has been described in HD as far as 15 years before clinical onset and therefore structural and functional imaging biomarkers are the most applied biomarker modalities which call for these to be exact; however, most studies are not considering the partial volume effect and thereby tend to overestimate metabolic reductions, which may bias imaging outcome measures of interventions.ObjectiveEvaluation of partial volume effects in a cohort of premanifest HD gene-expansion carriers (HDGECs).Methods21 HDGECs and 17 controls had a hybrid 2-[18F]FDG PET/MRI scan performed. Volume measurements and striatal metabolism, both corrected and uncorrected for partial volume effect were correlated to an estimate of disease burden, the CAG age product scaled (CAPS).ResultsWe found significantly reduced striatal metabolism in HDGECs, but not in striatal volume. There was a negative correlation between the CAPS and striatal metabolism, both corrected and uncorrected for the partial volume effect. The partial volume effect was largest in the smallest structures and increased the difference in metabolism between the HDGEC with high and low CAPS scores. Statistical parametric mapping confirmed the results.ConclusionsA hybrid 2-[18F]FDG PET/MRI scan provides simultaneous information on structure and metabolism. Using this approach for the first time on HDGECs, we highlight the importance of partial volume effect correction in order not to underestimate the standardized uptake value and thereby the risk of overestimating the metabolic effect on the striatal structures, which potentially could bias studies determining imaging outcome measures of interventions in HDGECs and probably also symptomatic HD.

Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease.

Converging lines of evidence from several models, and post‐mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single‐site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high‐performance liquid‐chromatography to measure the levels of KP metabolites—tryptophan, kynurenine, kynurenic acid, 3‐hydroxykynurenine, anthranilic acid and quinolinic acid—in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short‐term stability, intergroup differences, associations with clinical and imaging measures and derived sample‐size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient‐derived biofluids.