Disease Gene Expansion Carriers Research Articles

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.

An Exploratory Study Investigating Autonomy in Huntington's Disease Gene Expansion Carriers.

Autonomy describes a psychological state of self-regulation of motivation and action, which is a central characteristic of healthy functioning. In neurodegenerative diseases measures of self-perception have been found to be affected by the disease. However, it has never been investigated whether measures of self-perception, like autonomy, is affected in Huntington's disease. We investigated whether autonomy is affected in Huntington's disease and if the degree of autonomy is associated with motor function, neuropsychiatric symptoms, cognitive impairments, and apathy. We included 44 premanifest and motor-manifest Huntington's disease gene expansion carriers and 19 controls. Autonomy was examined using two self-report questionnaires, the Autonomy-Connectedness Scale-30 and the Index of Autonomous Functioning. All participants were examined according to motor function, cognitive impairments, and neuropsychiatric symptoms, including apathy. Statistically significant differences were found between motor-manifest Huntington's disease gene expansion carriers and premanifest Huntington's disease gene expansion carriers or controls on two measures of autonomy. Between 25-38% of motor-manifest Huntington's disease gene expansion carriers scored significantly below the normal level on subscales of autonomy as compared to controls. One autonomy subscale was associated with apathy (r = -0.65), but not with other symptoms of Huntington's disease. This study provides evidence for impaired autonomy in individuals with Huntington's disease and an association between autonomy and apathy. The results underline the importance of maintaining patient autonomy and involvement in care throughout the disease.

Lumbar puncture safety and tolerability in premanifest and manifest Huntington’s disease: a multi-analysis cross-sectional study

Lumbar puncture (LP) has become increasingly common for people with Huntington’s disease (HD) both to administer intrathecal investigational medicinal products and to collect cerebrospinal fluid to develop biological markers to track disease stage and progression. We aimed to investigate the safety profile of LP in people with HD, building on a recently published work by increasing the sample size and more specifically, increasing the representation of the premanifest population and healthy controls. We conducted a multi-study cross-sectional analysis including eligible participants from the HDClarity (304 Huntington's disease gene expansion carriers and 91 controls) and HD-YAS studies (54 premanifest and 48 controls), enrolled between February 2016 and September 2019. We investigated the odds of any adverse events, headaches, and back pain independently. Intergroup comparisons and adjusted event odds were derived using hierarchical logistic regressions. A total of 669 LP procedures involving 497 participants were included in this analysis. There were 184 (27.5%) LP procedures associated with one or more adverse events. The two most common adverse events were: post LP headache and back pain. Younger age and female gender were found to be associated with a higher risk of developing adverse events. There was no difference in the rate of adverse events between the disease subgroups after adjusting for covariates such as age and gender. Our results suggest that the LP is safe and tolerable in premanifest and manifest HD subjects, providing useful reassurance about the procedure to the HD community.

Longitudinal evaluation of proton magnetic resonance spectroscopy metabolites as biomarkers in Huntington's disease.

Proton magnetic resonance spectroscopy is a non-invasive method of exploring cerebral metabolism. In Huntington's disease, altered proton magnetic resonance spectroscopy-determined concentrations of several metabolites have been described; however, findings are often discrepant and longitudinal studies are lacking. Proton magnetic resonance spectroscopy metabolites may represent a source of biomarkers, thus their relationship with established markers of disease progression require further exploration to assess prognostic value and elucidate pathways associated with neurodegeneration. In a prospective single-site controlled cohort study with standardized collection of CSF, blood, phenotypic and volumetric imaging data, we used 3 T proton magnetic resonance spectroscopy in conjunction with the linear combination of model spectra method to quantify seven metabolites (total n-acetylaspartate, total creatine, total choline, myo-inositol, GABA, glutamate and glutathione) in the putamen of 59 participants at baseline (15 healthy controls, 15 premanifest and 29 manifest Huntington's disease gene expansion carriers) and 48 participants at 2-year follow-up (12 healthy controls, 13 premanifest and 23 manifest Huntington's disease gene expansion carriers). Intergroup differences in concentration and associations with CSF and plasma biomarkers; including neurofilament light chain and mutant Huntingtin, volumetric imaging markers; namely whole brain, caudate, grey matter and white matter volume, measures of disease progression and cognitive decline, were assessed cross-sectionally using generalized linear models and partial correlation. We report no significant groupwise differences in metabolite concentration at baseline but found total creatine and total n-acetylaspartate to be significantly reduced in manifest compared with premanifest participants at follow-up. Additionally, total creatine and myo-inositol displayed significant associations with reduced caudate volume across both time points in gene expansion carriers. Although relationships were observed between proton magnetic resonance spectroscopy metabolites and biofluid measures, these were not consistent across time points. To further assess prognostic value, we examined whether baseline proton magnetic resonance spectroscopy values, or rate of change, predicted subsequent change in established measures of disease progression. Several associations were found but were inconsistent across known indicators of disease progression. Finally, longitudinal mixed-effects models revealed glutamine + glutamate to display a slow linear decrease over time in gene expansion carriers. Altogether, our findings show some evidence of reduced total n-acetylaspartate and total creatine as the disease progresses and cross-sectional associations between select metabolites, namely total creatine and myo-inositol, and markers of disease progression, potentially highlighting the proposed roles of neuroinflammation and metabolic dysfunction in disease pathogenesis. However, the absence of consistent group differences, inconsistency between baseline and follow-up, and lack of clear longitudinal change suggests that proton magnetic resonance spectroscopy metabolites have limited potential as Huntington's disease biomarkers.

On the association between apathy and deficits of social cognition and executive functions in Huntington's disease.

To investigate if executive and social cognitive dysfunction was associated with apathy in a large cohort of Huntington's disease gene expansion carriers. Eighty premanifest and motor-manifest Huntington's disease gene expansion carriers (Mini-Mental State Examination score ≥ 24 and Montreal Cognitive Assessment score ≥ 19) and thirty-two controls were examined with the Lille Apathy Rating Scale (LARS), a tailored and quantitative measure of apathy, and a comprehensive cognitive battery on executive functions and social cognition (emotion recognition, theory of mind and sarcasm detection), as well as general correlates like demographic variables, and neuropsychiatric and cognitive screening tests. The motor-manifest Huntington's disease gene expansion carriers had significantly different scores on most measures of social cognition and executive functions, compared to premanifest and control participants. Apathy was significantly correlated with most executive test scores, but the Emotion Hexagon was the only social cognitive test score significantly correlated with apathy. We found that the motor score and the depression score were the only significant predictors of the apathy score, when the social cognitive and executive tests with the strongest association with the global LARS score were entered into a multiple stepwise regression model. No cognitive test score could significantly predict apathy. The model explained 21 % of the total variance. Despite being significantly correlated with apathyneuropsychological variables did not have a significant impact on apathy when variables as depression and motor symptoms were taken into account. Apathy should be considered an independent symptom of Huntington's disease that requires specific examination.

Impairments of social cognition significantly predict the progression of functional decline in Huntington’s disease: A 6-year follow-up study

This study sought to investigate if there was a significant difference between the Huntington’s Disease gene expansion carriers who were impaired on the cognitive domains, social cognition and executive functions. Also, it was investigated which of the cognitive domains could predict the decrease in total functional capacity over a 6-year follow-up period. Premanifest and motor-manifest Huntington’s Disease gene expansion carriers (N = 98), were examined with a neurological and neuropsychological examination at Time 1 (year 2012–2013). Regression-based normative data was used to classify impairments on the two cognitive domains. Follow-up participants (N = 80) had their functional capacity reexamined at Time 2 (year 2018–2020), to examine which cognitive domain could predict the decrease in functional capacity over the 6-year follow-up. More than 50% of the participants were impaired on the domain of social cognition. These participants were significantly different from the participants who were impaired on executive functions. The motor function and impairments on social cognition significantly predicted the decline in functional capacity. The Emotion Hexagon test was the only significant social cognitive task, that predicted the decline in functional capacity. Social cognition includes unique and separate functions in Huntington’s Disease, unaffected by executive functions. This study emphasizes the importance of regular assessment of social cognition in Huntington’s Disease and the clinical relevance of impaired social cognitive function.

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.

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.

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.

Gut dysbiosis in Huntington's disease: associations among gut microbiota, cognitive performance and clinical outcomes.

Huntington’s disease is characterized by a triad of motor, cognitive and psychiatric impairments, as well as unintended weight loss. Although much of the research has focused on cognitive, motor and psychiatric symptoms, the extent of peripheral pathology and the relationship between these factors, and the core symptoms of Huntington’s disease, are relatively unknown. Gut microbiota are key modulators of communication between the brain and gut, and alterations in microbiota composition (dysbiosis) can negatively affect cognition, behaviour and affective function, and may be implicated in disease progression. Furthermore, gut dysbiosis was recently reported in Huntington’s disease transgenic mice. Our main objective was to characterize the gut microbiome in people with Huntington’s disease and determine whether the composition of gut microbiota are significantly related to clinical indicators of disease progression. We compared 42 Huntington’s disease gene expansion carriers, including 19 people who were diagnosed with Huntington’s disease (Total Functional Capacity > 6) and 23 in the premanifest stage, with 36 age- and gender-matched healthy controls. Participants were characterized clinically using a battery of cognitive tests and using results from 16S V3 to V4 rRNA sequencing of faecal samples to characterize the gut microbiome. For gut microbiome measures, we found significant differences in the microbial communities (beta diversity) based on unweighted UniFrac distance (P = 0.001), as well as significantly lower alpha diversity (species richness and evenness) between our combined Huntington’s disease gene expansion carrier group and healthy controls (P = 0.001). We also found major shifts in the microbial community structure at Phylum and Family levels, and identified functional pathways and enzymes affected in our Huntington’s disease gene expansion carrier group. Within the Huntington’s disease gene expansion carrier group, we also discovered associations among gut bacteria, cognitive performance and clinical outcomes. Overall, our findings suggest an altered gut microbiome in Huntington’s disease gene expansion carriers. These results highlight the importance of gut biomarkers and raise interesting questions regarding the role of the gut in Huntington’s disease, and whether it may be a potential target for future therapeutic intervention.

Predictive genetic testing in Huntington's disease: should a neurologist be involved?

International guidelines on Huntington’s Disease recommend neurological examination in the predictive testing trajectory. Experiences and personal wishes of persons at risk of Huntington’s Disease regarding this topic have never been evaluated. The objective was to provide an overview of the experiences of Dutch at-risk persons, opting for predictive testing, in consulting a neurologist before and after DNA analysis. Persons who were counseled in four Dutch clinics between 2017 and 2019 were retrospectively or prospectively approached for a questionnaire which listed topics as experiences with consultation and personal wishes. From 71 participants, 44 participants visited a neurologist. 41 participants indicated their visit to a neurologist as positive (93.2%). The majority of participants (n = 59) desired consulting a neurologist. Thirty-two participants indicated consultation shortly after (Desired After Group) and twenty-seven before DNA analysis (Desired Before Group) as personal wish. The Desired Before Group consisted of a significantly higher number of participants who actually consulted a neurologist before predictive testing (n = 26) compared with the number of participants who actually consulted a neurologist after DNA analysis in the Desired After Group (n = 11) (p < 0.001). The Desired After Group (n = 19) had a significantly higher number of Huntington’s disease gene expansion carriers compared with the Desired Before Group (n = 5) (p 0.003). Participants are content with consultation. However, persons without the gene expansion still feel the need to get in touch with a neurologist. Therefore, offering a consultation with a neurologist before DNA analysis might be beneficial for all.

PET Molecular Imaging of Phosphodiesterase 10A: An Early Biomarker of Huntington's Disease Progression.

Changes in phosphodiesterase 10A enzyme levels may be a suitable biomarker of disease progression in Huntington's disease. To evaluate phosphodiesterase 10A PET imaging as a biomarker of HD progression using the radioligand, [18 F]MNI-659. The cross-sectional study (NCT02061722) included 45 Huntington's disease gene-expansion carriers stratified into four disease stages (early and late premanifest and Huntington's disease stages 1 and 2) and 45 age- and sex-matched healthy controls. The primary analysis compared striatal and pallidal phosphodiesterase 10A availability between Huntington's disease gene-expansion carriers and healthy controls as assessed by [18 F]MNI-659 binding. We assessed changes in phosphodiesterase 10A expression using several PET methodologies and compared with previously proposed measures of Huntington's disease progression (PET imaging of D2/3 receptors and anatomical volume loss on MRI). The longitudinal follow-up study (NCT02956148) continued evaluation of phosphodiesterase 10A availability in 35 Huntington's disease gene-expansion carriers at a mean of 18 months from baseline of the cross-sectional study. Primary analyses revealed that phosphodiesterase 10A availability in caudate, putamen, and globus pallidus was significantly lower in Huntington's disease gene-expansion carriers versus healthy controls across all stages. Striatal and pallidal phosphodiesterase 10A availability progressively declined in the premanifest stages and appeared to plateau between stages 1 and 2. The percentage decline of phosphodiesterase 10A availability measured cross-sectionally between Huntington's disease gene-expansion carriers and healthy controls was greater than that demonstrated by D2/3 receptor availability or volumetric changes. Annualized rates of phosphodiesterase 10A change showed a statistically significant decline between the cross-sectional study and follow-up. [18 F]MNI-659 PET imaging is a biologically plausible biomarker of Huntington's disease progression that is more sensitive than the dopamine-receptor and volumetric methods currently used. © 2020 International Parkinson and Movement Disorder Society.

Huntington's Disease Gene Expansion Carriers Are Aware of Their Degree of Apathy.

Huntington's disease is characterized by motor and behavioral symptoms as well as cognitive decline. Apathy is a common behavioral symptom, and its severity is related to disease progression. It has been suggested that Huntington's disease gene expansion carriers (HDGECs) are unaware of the signs and symptoms of the disease, which may account for their own level of awareness of their apathy. Therefore, the authors investigated the level of agreement on the degree of apathy severity between HDGECs and their proxies by using a self-report questionnaire. A total of 109 REGISTRY participants (premotormanifest, N=31; early motormanifest, N=49; and late motormanifest, N=29) and their proxies completed the Apathy Evaluation Scale. The authors used the Wilcoxon signed-rank test to assess whether gene expansion carriers and their proxies agreed on apathy severity. Scores on the Apathy Evaluation Scale significantly increased from the early motormanifest stage to the late motormanifest stage. Premotormanifest carriers scored themselves significantly higher on the Apathy Evaluation Scale than their proxies, whereas no differences were found between all motormanifest carriers and their proxies. Apathy severity increases in the motormanifest stages of Huntington's disease. HDGECs can adequately assess their level of apathy on a self-report questionnaire. These results also suggest that slight changes in the degree of apathy among premotormanifest gene expansion carriers remain unnoticed by their proxies.

Suicidal ideation and suicidal behavior according to the C-SSRS in a European cohort of Huntington's disease gene expansion carriers

BackgroundHuntington's disease (HD) gene expansion carriers are at an increased risk of suicide, but so far, no studies have investigated the full spectrum of suicidality, including suicidal ideation, suicidal behavior and self-injurious behavior. MethodsWe included 1451 HD gene expansion carriers (age 48.4 years (SD 14.0), 54.8% female) of the REGISTRY study of the European Huntington's Disease Network. Lifetime suicidal ideation and suicidal behavior were assessed with the Columbia-Suicidal Severity Rating Scale. Motor symptoms and disease stage were assessed using subscales of the Unified Huntington's Disease Rating Scale, and depressed mood and irritability were assessed by the Problem Behaviors Assessment. ResultsLifetime passive suicidal ideation was reported by 21.2%. Participants in stage II showed the highest prevalence rate of suicidal ideation, while participants in stage IV/V showed the highest prevalence of suicidal behavior. A lifetime suicide attempt was reported by 6.5% of the HD gene expansion carriers. In multivariate regression analyses, both suicidal ideation and suicidal behavior were associated with a depressed mood, and to a lesser extend to irritability. LimitationsResults may have been affected by denial or recall bias and no conclusions can be made about the temporal and causal relationships with depressed mood and irritability because of the cross-sectional analyses. ConclusionsGiven the high prevalence of suicidal ideation and suicidal behavior in all stages of HD, it is important to screen HD gene expansion carriers for suicidal ideation and suicidal behavior on a regular basis in clinical practice.

Selected CSF biomarkers indicate no evidence of early neuroinflammation in Huntington disease.

Objective:To investigate CSF biomarkers of neuroinflammation and neurodegeneration in Huntington disease (HD) gene-expansion carriers compared to controls and to investigate these biomarkers in association with clinical HD rating scales and disease burden score.Methods:We collected CSF from 32 premanifest and 48 manifest HD gene-expansion carriers and 24 gene-expansion negative at-risk controls. We examined biomarkers of neuroinflammation (matrix metalloproteinase 9, C-X-C motif chemokine 13, terminal complement complex, chitinase-3-like-protein 1 [CHI3L1], and osteopontin [OPN]) and neurodegeneration (microtubule-associated protein tau, neurofilament light polypeptide [NFL], and myelin basic protein [MBP]). The study was approved by the Ethics Committee of the Capital Region of Denmark (H2-2011-085) and written informed consent was obtained from each participant before enrollment.Results:NFL was the only biomarker that increased in premanifest stages and no evidence of early involvement of neuroinflammation in HD was found. However, we found that the biomarkers for neurodegeneration, MBP and tau, increased during the disease course in manifest HD gene-expansion carriers and were associated with an increase of the neuroinflammation biomarkers CHI3L1 and OPN. Tau was also increased in all gene-expansion carriers with psychiatric symptoms compared to gene-expansion carriers without psychiatric symptoms.Conclusions:Neuroinflammation, which seems not to be an early event in our cohort, may be secondary to neurodegeneration in late HD. NFL is a possible disease burden correlate in HD, reflecting neuronal loss even before motor symptom onset, and may be useful as a dynamic biomarker in intervention studies.

Ubiquitin: a potential cerebrospinal fluid progression marker in Huntington's disease.

Finding early and dynamic biomarkers in Huntington's disease is a key to understanding the early pathology of Huntington's disease and potentially to tracking disease progression. This would benefit the future evaluation of potential neuroprotective and disease-modifying therapies, as well as aid in identifying an optimal time point for initiating a potential therapeutic intervention. This explorative proteomics study evaluated cerebrospinal fluid from 94 Huntington's disease gene-expansion carriers (39 premanifest and 55 manifest) and 27 Huntington's disease gene-expansion negative individuals using surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry. Differences in peak intensity from SELDI-TOF spectra were evaluated. Levels of 10 peaks were statistically significantly different between manifest gene-expansion carriers and controls. One of them identified as ubiquitin was shown to be dependent on the Unified Huntington Disease Rating Scale Total Functional Capacity, a pseudo-measure of disease severity (P=0.001), and the Symbol Digit Modalities Test (0.04) in manifest and CAG-age product score (P=0.019) in all gene-expansion carriers. Multiple studies have shown that the ubiquitin-proteasome system is involved in Huntington's disease pathogenesis and understanding of this involvement may have therapeutic potential in humans. This is the first study on cerebrospinal fluid to confirm the involvement of the ubiquitin-proteasome system in Huntington's disease. Furthermore it is shown that ubiquitin increases with disease progression and CAG-age product score and therefore may have the potential as a Huntington's disease progression marker, also prior to motor onset.

Assessing impairment of executive function and psychomotor speed in premanifest and manifest Huntington's disease gene-expansion carriers.

Executive functions (EF) and psychomotor speed (PMS) has been widely studied in Huntington's disease (HD). Most studies have focused on finding markers of disease progression by comparing group means at different disease stages. Our aim was to investigate performances on nine measures of EF and PMS in a group of premanifest and manifest HD-gene expansion carriers and to investigate which measures were most sensitive for assessment of individual patients by analyzing frequencies of impaired performances relative to healthy controls. We recruited HD gene-expansion carriers, 48 manifest and 50 premanifest and as controls 39 healthy gene-expansion negative individuals. All participants underwent neurological examination and neuropsychological testing with nine cognitive measures. The frequency of impairment was investigated using cutoff scores. In group comparisons the manifest HD gene-expansion carriers scored significantly worse than controls on all tests and in classification of individual scores the majority of scores were classified as probably impaired (10th percentile) or impaired (5th percentile) with Symbol Digit Modalities Test (SDMT) being the most frequently impaired. Group comparisons of premanifest HD gene-expansion carriers and healthy controls showed significant differences on SDMT and Alternating fluency tests. Nevertheless the frequencies of probably impaired and impaired scores on individual tests were markedly higher for Alternating and Lexical fluency tests than for SDMT. We found distinct group differences in frequency of impairment on measures of EF and PMS in manifest and premanifest HD gene-expansion carriers. Our results indicate to what degree these measures can be expected to be clinically impaired.

G05 Cognitive Impairment And Psychiatric Symptoms In A Danish Cohort Of Huntington's Disease Gene-expansion Carriers

<h3>Background</h3> Involuntary movements, neuropsychiatric symptoms, and cognitive impairment are all part of the symptom triad in Huntington’s disease (HD). Despite the fact that neuropsychiatric symptoms and cognitive decline may be early manifestations of HD, the clinical diagnosis is conventionally based on the presence of involuntary movements and a positive genetic test for the HD CAG repeat expansion. <h3>Aim</h3> To investigate the frequencies of the triad manifestations in a large outpatient clinical cohort of HD gene-expansion carriers. <h3>Methods</h3> In this cross-sectional study, 107 Gene-expansion carriers from a Danish outpatient clinic were recruited. All participants underwent neurological examination, psychiatric evaluation and neuropsychological testing. Participants were categorised according to motor symptoms, neuropsychiatric symptoms, the use of psychotropic medication, and cognitive impairment. <h3>Results</h3> Among the motor manifest HD gene-expansion carriers, 51.8% presented with the full symptom triad, 25.0% were defined as cognitively impaired, 14.3% had neuropsychiatric symptoms and only 8.9% had isolated motor symptoms. Among gene-expansion carriers without motor symptoms, 39.2% had neuropsychiatric symptoms, were cognitively impaired, or had a combination of the two. <h3>Conclusion</h3> This is the first study to report the frequencies of motor symptoms, cognitive impairment, and neuropsychiatric symptoms in HD gene-expansion carriers in a national outpatient HD clinical cohort. We found that almost 40% of the gene-expansion carriers without motor symptoms had either neuropsychiatric symptoms, cognitive impairment or both, emphasising that these patients are not premanifest in psychiatric and cognitive terms, suggesting that the current clinical classification is neither necessarily suitable nor helpful for this patient group.

Assessment of cognitive symptoms in prodromal and early huntington disease.

The Functional Rating Scale Taskforce for pre-Huntington Disease (FuRST-pHD) is a multinational, multidisciplinary initiative with the goal of developing a data-driven, comprehensive, psychometrically sound, rating scale for assessing symptoms and functional ability in prodromal and early Huntington disease (HD) gene expansion carriers. The process involves input from numerous sources to identify relevant symptom domains, including HD individuals, caregivers, and experts from a variety of fields, as well as knowledge gained from the analysis of data from ongoing large-scale studies in HD using existing clinical scales. This is an iterative process in which an ongoing series of field tests in prodromal (prHD) and early HD individuals provides the team with data on which to make decisions regarding which questions should undergo further development or testing and which should be excluded. We report here the development and assessment of the first iteration of interview questions aimed to assess cognitive symptoms in prHD and early HD individuals.