European Huntington's Disease Network

Huntington's disease (HD) is traditionally considered as a triad of movement, cognitive, and emotional disorders.1-4 According to current clinical practice, “manifest HD” is diagnosed primarily according to motor criteria, that is, when a clinician has 99% confidence of “an otherwise unexplained extrapyramidal movement disorder” in someone with a family history of HD. It is desirable to incorporate other features of the triad into a new classification system for clinical care and research. Large observational studies, including TRACK-HD, PREDICT-HD, COHORT-HD, and PHAROS, have greatly expanded our understanding of HD natural history. Subtle motor, cognitive, and emotional changes begin years before motor-manifest HD, and brain changes likely begin even earlier, motivating the consideration of consistent definitions across a wide range including prior to the appearance of manifest HD.5-14 In a previous publication, 3 of us (C.R., B.L., and R.R.) suggested modifying current diagnostic criteria to more broadly incorporate clinical features of HD.15 That article provided background about the natural history of HD, the current diagnostic criteria, and our proposed new diagnostic categories. The Movement Disorder Society commissioned a task force to consider the issues in research and clinical definitions of HD and to develop a lexicon. Christopher Ross was selected as chair with cochairs Francisco Cardoso and Ralf Reilmann. The charge was to “select and convene a committee of HD experts, with involvement of patient and family representatives, to discuss diagnostic categories for Huntington's disease” based on the recent studies of natural history and biomarkers for HD and to “produce a set of recommendations for diagnostic classifications of HD.” The task force met in person on February 4 and 5, 2017, followed by several teleconferences. The task force proposed 3 categories, presymptomatic HD, prodromal HD, and manifest HD, with presymptomatic and prodromal together comprising the premanifest HD period (Fig. 1, Table 1). The criteria for these classifications were developed using an informal consensus approach and include both cognitive and motor components. (2) Prodromal HD (either A or B) A) Dx conf 2 B) Dx conf 3 (A) + Minor or major neurocognitive changes (B) With normal (unchanged) cognition (3) Manifest HD (either A or B) A) Dx conf 3 B) Dx conf 4 (A) + Minor or major neurocognitive changes (B) With normal (unchanged) cognition We propose adding nonmotor signs, particularly cognitive signs, to current motor diagnostic criteria15 (see Table 1). HD is a clinical diagnosis made on the basis of family history, personal history, neurological and psychiatric examinations, and genetic and any other appropriate testing. Extrapyramidal movement disorder is diagnosed based on the neurological examination, and the severity can be quantified using the Unified HD Rating Scale (UHDRS) motor examination,16 which yields a “total motor score” ranging from 0 to 124. Motor abnormalities in individuals tested positive for the Cytosine, Adenine, Guanine (CAG) expansion that causes HD or individuals with a family history of HD are rated on a 0 to 4 “diagnostic confidence” scale. When defining manifest HD, normal is rated 0, nonspecific abnormalities are rated 1, possible HD (“50% probability” of onset) is scored 2, probable onset (“90% confidence”) is rated 3, and definite (“99% probability”) onset is rated 4. Although the diagnostic confidence scale has the disadvantage of implying a “pseudo-precision” via the somewhat arbitrary probability thresholds, it has a long history of use by HD clinicians and researchers. HD is a clinical diagnosis, and so a Total Motor Score (TMS) threshold for diagnosis is not suggested or implied. In the PREDICT-HD study, which followed 225 premanifest cases through motor diagnosis, the mean TMS score at diagnosis was around 15, with a range from about 8 to 35. For individuals not followed longitudinally but seen for the first time, a higher motor score may be appropriate to make a diagnosis of definite HD. In contrast, cognitive disorder is more difficult to diagnose because cognitive abilities vary considerably in the general population. It is optimal to confirm cognitive changes with longitudinal detailed neuropsychological testing, although this is not always feasible or affordable and should not be required. Information from family members or coworkers can provide crucial data about whether there appears to be cognitive impairment with change over time. The task force proposes that cognitive disorder in manifest HD should be diagnosed according to the criteria of the Diagnostic and Statistical Manual, Fifth Edition (DSM)17 for either major neurocognitive disorder or minor neurocognitive disorder. A summary of how major neurocognitive disorder is defined in the DSM is as follows: first, evidence is provided of significant cognitive decline from a previous level of performance in 1 or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual–motor, or social cognition). This is based on concern of the individual, a knowledgeable informant, or the clinician that there has been a significant decline in cognitive function and a substantial impairment in cognitive function, preferably documented by standardized neuropsychological testing or, in its absence, another quantified clinical assessment. Second, the cognitive deficits interfere with the independence in everyday activities (ie, at a minimum, requiring assistance with complex instrumental activities of daily living such as paying bills or managing medications). An important aspect of the DSM criteria is that the cognitive difficulties represent a decline from a previous level of functioning. The tests listed in the National Institute of Neurological Disorders and Stroke Common Data Elements for Huntington's disease, cognitive domain (https://www.commondataelements.ninds.nih.gov/HD.aspx#tab=Data_Standards) provide a useful resource, with the Montreal Neuro Cognitive Assessment (MoCA) perhaps the simplest and most widely used screening test. The Symbol Digit Modalities Test, which is part of the UHDRS cognitive battery, is another well-validated test for HD. Several executive function tests are listed, with the Trail-Making Test perhaps the simplest to use for screening (an abbreviated trail-making test is part of the MoCA). A summary of how mild neurocognitive disorder is defined is as follows: first, evidence is provided of modest cognitive decline from a previous level of performance in 1 or more cognitive domains (complex attention, executive function, learning and memory, language, perceptual–motor, or social cognition), based on concern of the individual, a knowledgeable informant, or the clinician. Second, there is a modest impairment in cognitive performance. In this case, the cognitive impairments do not interfere with independence in everyday activities, but greater effort, compensatory strategies, or accommodation may be required. It is important to exclude cognitive disorder secondary to depression, which can appear clinically similar to the cognitive disorder of HD, both sometimes described as having "subcortical" features. Depression and its associated cognitive disorder are not infrequent in all individuals and can appear many years before the onset of other features of HD and subsequently resolve,2, 14 and depression and other mood disorders are treatable, so the task force agreed that depression by itself should not be used to diagnose HD. Other emotional disorders (irritability, apathy, and personality change) are more variable in their presentation, can occur at any time during the course of HD, and are common in individuals who do not have a CAG repeat expansion, thus making emotional changes challenging for establishing a diagnosis of HD.18, 19 One important complication for the diagnosis of HD is that individuals with HD often have reduced or absent awareness of their impairments, or anosognosia. It is vital that clinicians engage with family members or other informants who often can provide critical longitudinal information, beginning with the initial presentation and continuing throughout the course of HD. Manifest HD causes functional disability. This might be relatively subtle in the earlier phases, for example, greater expenditure of time or effort on adequate work performance, but there is then progressive decline in social and occupational function, and finally difficulty with basic activities of daily living. The division of HD into 5 clinical “stages” based only on functional capacity scores, and not on any biological criteria, appeared arbitrary to the committee, and 3 broad clinical periods such as “early,” “moderate,” and “severe” were favored. We propose that the combination of a motor diagnostic confidence of 3 (notionally “90%”), plus minor neurocognitive disorder, be sufficient for a diagnosis of manifest HD. Some individuals may already have major neurocognitive disorder when seen for diagnosis. Manifest HD could still be diagnosed by motor criteria alone, which would still require a diagnostic confidence of 4. We propose a new diagnostic category of “prodromal HD.” Motor and cognitive changes appear subtly and progress slowly over years during this period until they are prominent enough for a diagnosis of manifest HD. Cognitive changes during the prodromal period often consist of "executive dysfunction," with difficulty recalling and sequencing multiple tasks.20-23 This corresponds to the DSM category of “Minor Neurocognitive Disorder.” We propose that a motor diagnostic confidence of 2 plus clear (although possibly subtle) cognitive changes, that is, “minor neurocognitive disorder,” be sufficient for a diagnosis of prodromal HD. TMS scores for individuals followed longitudinally might typically be in the range of 5 to 15, although as for manifest HD, a motor score threshold is not suggested and not implied, and higher scores may be appropriate for patients being seen for the first time. Prodromal HD may have relatively minor impact on functional capacity, but treatment of motor (eg, tetrabenazine and related compounds or dopamine receptor blockers), cognitive (behavioral strategies), or emotional features (eg antidepressants, other pharmacological treatments for irritability or behavioral interventions) may be warranted. Counseling regarding family and social issues and strategies for coping with the developing illness is also important.24 The potential benefit of earlier access to treatment (both symptomatic and disease modifying—see later) is a key motivator for defining this category. We believe that it is important to establish a category for individuals who have the CAG expansion but as yet have no signs or symptoms related to HD, that is, prior to prodromal HD. These individuals would have no significant motor signs on exam (diagnostic confidence 0 or 1, nonspecific findings) and no cognitive changes. Individuals in this group may be candidates for future disease-modifying treatment to delay or prevent the onset. The term premanifest is defined as the period prior to manifest HD, that is, inclusive of both the presymptomatic period and the prodromal period. There was an agreement that similar categories would be applicable in the absence of genetically confirmed HD. The following terms are suggested: at risk for HD, but nonmanifest (ie, no signs or symptoms); clinically prodromal HD, and clinically manifest HD.15 The diagnostician would likely need more definitive clinical evidence, especially longitudinal data, in those at risk but without genetic testing when compared with individuals with confirmed CAG repeat expansion. There are numerous HD-like syndromes that need to be considered in the differential diagnosis, especially in those without a clear family history.3, 25, 26 Thus, the criteria described in Table 1 are to be reserved for individuals with a positive genetic test for the HD CAG repeat expansion. Task force members generally agreed that the diagnostic categories should currently refer to the clinical status of the patient rather than to genetic or diagnostic testing or biomarker determination. HD is a clinical diagnosis. A combination of CAG repeat length and age, usefully summarized as the CAG age product or CAP score,27, 28 roughly predicts onset in groups of patients and serves as a useful longitudinal index of exposure to the effects of the CAG repeat expansion. However, CAG length by itself only explains about 50% in the variance of onset age. Genetic modifiers provide additional information.29 Quantitative motor examination (eg, Q-Motor instrumentation30) is useful in research, but it has not been evaluated within the diagnostic setting. Many years of study have consistently shown that progressive changes in structural magnetic resonance imaging (and likely functional magnetic resonance imaging and magnetic resonance spectroscopy) begin well before manifest HD,5, 7, 9, 31-33 and perhaps even before the period of prodromal HD. Blood and cerebrospinal fluid biomarkers, especially mutant Huntingtin (Htt) and neurofilament light-chain levels,34, 35 are becoming increasingly relevant. Imaging and other tests should be used to rule out other conditions (especially in older individuals) and to determine whether other conditions may be contributing to the clinical presentation. However, biomarkers, although very useful for studying groups of patients and likely for clinical trials, at present are currently insufficiently precise and well validated for the diagnosis of individual patients. It is increasingly clear that cognitive dysfunction is important in causing functional disability and that prominent cognitive impairment can occur with relatively less noticeable motor changes. It is less clear whether substantial cognitive impairment occurs frequently in the absence of any detectable change on motor exam.23, 36, 37 The use of a multidimensional diagnosis including the cognitive, motor, behavioral, and functional aspects of the UHDRS (question 80) resulted in a slightly earlier diagnosis of HD than when based on motor exam alone (question 17),38 although the difference may have reflected functional as well as cognitive changes. Furthermore, the subgroup described as “predominantly cognitively impaired” in that study actually had higher motor scores than the other subgroups. Longitudinal neuropsychological testing (although time consuming and expensive) can be useful for cognitive assessment, contributing to the diagnosis of both manifest HD and prodromal HD. Individuals with early cognitive and behavioral changes may have greater anosognosia, and thus may not present in a timely fashion for motor examination. Even in the same family and with the same repeat expansion size, HD does not have an identical-appearing onset and progression. Thus we retain motor criteria for the diagnosis of HD, but highlight the importance of cognition. There was general agreement about the importance of emotional alterations in HD. Personality changes, especially apathy and irritability, are increasingly appreciated as important contributors to functional disability. The TRACK-HD study7 has shown that apathy can begin quite early in what we would now term the prodromal phase, consistent with clinical experience. However, great caution should be taken before considering emotional changes exclusively for diagnosis of HD: emotional changes are quite common in individuals without the CAG expansion and may be even more common in individuals at risk for HD because of the disruptive effects of illness on family life.2 Furthermore, depression may be mistaken for apathy, and a readily treatable diagnosis should be prioritized. Nonetheless, emotional changes in someone at risk or with a known CAG expansion should trigger close follow-up of both motor and cognitive features and additional testing as appropriate. The committee discussed whether the diagnostic categories would apply equally well to all individuals with HD. Juvenile-onset patients often have more bradykinesia, dystonia, and rigidity, and less (sometimes essential no) chorea, than adult-onset cases, whereas late-onset patients often have chorea-predominant HD,39, 40 but both variants are well described by the current criteria. Cognitive onset has been proposed to be the most relevant for HD subtypes such as juvenile-onset HD.39 We believe that ultimately the same categories should be used in both clinical and research settings to facilitate the transition from clinical trials to clinical practice. The set of classification criteria proposed are the result of an informal consensus process. The criteria are the result of holistic considerations of a selective group of publications and expert opinion. For these criteria to be refined both in clinical practice and research, it is desirable to validate this classification for accuracy, representativity, and usability in future studies. The currently proposed criteria are primarily designed for research because they use the research-based examination, the UHDRS; however, as clinical trials of disease-modifying therapy are advancing rapidly and early intervention may be most beneficial, we believe that clinical application should come soon, and that it is especially timely to include the prodromal HD diagnosis. We urge diagnostic and clinical practices to continue to be based on research and evidence-based criteria. The composition of the task force was designed to be international, and we hope that our ideas will have wide international application, but we also are aware of the importance of regional and cultural issues. In some countries, such as the United States, the diagnosis and treatment of HD is often restricted by insurance rules to neurologists. The task force recommends that any physician with relevant training and experience should be considered qualified to diagnose and treat HD, including psychiatrists, especially given the increasing awareness of the importance of the cognitive and emotional aspects of the disease. We also highlight that sensitive clinical judgment is of course paramount in discussing diagnostic and prognostic issues with patients and families. Basic and clinical research in HD is moving rapidly, with clinical trials in progress (eg, clinicaltrials.gov, NCT02519036) or in planning stages for several strategies for huntingtin lowering. These disease-modifying strategies have the potential to be applied in the prodromal or presymptomatic periods, making the availability of these diagnostic categories especially relevant for clinical practice.41, 42 In addition, biomarker research is advancing rapidly.28, 34, 35 The proposed categories are based on clinical examination and have the limitation of the use of the diagnostic confidence scale with its disadvantage of implying a “pseudo-precision” via the “probability” thresholds. For many reasons, therefore, we propose a frequent reexamination of these diagnostic categories and a reassessment in 2 to 3 years, especially in relation to biomarkers. We also urge further research on the topics discussed previously. Some topics for further study include the nature of early cognitive and emotional changes and their correlation with imaging and other biomarkers and the question of which signs and symptoms are most important in causing functional disability. The combination of datasets from the large observational studies will facilitate these studies, for instance, the identification of early cognitive changes.43 An important question for the timing of treatment is the point at which neuronal cell death or irreversible neuronal changes begin, as should begin before that the access to brain of some of the large currently study, understanding of the regional (and possible within the of at in the natural history will be especially of these could use the CAP score more to and clinical and changes and in clinical It would be especially to of the changes in functional In with the international nature of the task it would also be useful to the of regional in the impact of definitions and clinical most important will be research to the of or other disease-modifying given during the premanifest period to delay or even prevent the onset of manifest HD. We and should be to the chair We the and Movement Disorder Society for and for We Huntington's Society of and for We also the for of our initial Statistical and of the first and The confirm there were no or patients patient or the of an were not relevant for this We confirm that we have the on issues in and that this work is consistent with those relevant or of given the nature of the of or other treatments for to the February 4 and 5, 2017, from the Movement Disorder for were by the Movement Disorder with and the following for to by for on disease for as the of and Neurological Society for as at the Neurological Society is the for the study by the HD and is the for the study, through the and by is a for the the study is National of for 5 The other that there are no additional to

Patient registries are an essential tool to increase current knowledge regarding rare diseases. Understanding these data is a vital step to improve patient treatments and to create the most adequate tools for personalized medicine. However, the growing number of disease-specific patient registries brings also new technical challenges. Usually, these systems are developed as closed data silos, with independent formats and models, lacking comprehensive mechanisms to enable data sharing. To tackle these challenges, we developed a Semantic Web based solution that allows connecting distributed and heterogeneous registries, enabling the federation of knowledge between multiple independent environments. This semantic layer creates a holistic view over a set of anonymised registries, supporting semantic data representation, integrated access, and querying. The implemented system gave us the opportunity to answer challenging questions across disperse rare disease patient registries. The interconnection between those registries using Semantic Web technologies benefits our final solution in a way that we can query single or multiple instances according to our needs. The outcome is a unique semantic layer, connecting miscellaneous registries and delivering a lightweight holistic perspective over the wealth of knowledge stemming from linked rare disease patient registries.

OBJECTIVE: To evaluate the efficacy and safety of bupropion in the treatment of apathy in Huntington's disease (HD). METHODS: In this phase 2b multicentre, double-blind, placebo-controlled crossover trial, individuals with HD and clinical signs of apathy according to the Structured Clinical Interview for Apathy-Dementia (SCIA-D), but not depression (n = 40) were randomized to receive either bupropion 150/300mg or placebo daily for 10 weeks. The primary outcome parameter was a significant change of the Apathy Evaluation Scale (AES) score after ten weeks of treatment as judged by an informant (AES-I) living in close proximity with the study participant. The secondary outcome parameters included changes of 1. AES scores determined by the patient (AES-S) or the clinical investigator (AES-C), 2. psychiatric symptoms (NPI, HADS-SIS, UHDRS-Behavior), 3. cognitive performance (SDMT, Stroop, VFT, MMSE), 4. motor symptoms (UHDRS-Motor), 5. activities of daily function (TFC, UHDRS-Function), and 6. caregiver distress (NPI-D). In addition, we investigated the effect of bupropion on brain structure as well as brain responses and functional connectivity during reward processing in a gambling task using magnetic resonance imaging (MRI). RESULTS: At baseline, there were no significant treatment group differences in the clinical primary and secondary outcome parameters. At endpoint, there was no statistically significant difference between treatment groups for all clinical primary and secondary outcome variables. Study participation, irrespective of the intervention, lessened symptoms of apathy according to the informant and the clinical investigator. CONCLUSION: Bupropion does not alleviate apathy in HD. However, study participation/placebo effects were observed, which document the need for carefully controlled trials when investigating therapeutic interventions for the neuropsychiatric symptoms of HD. TRIAL REGISTRATION: ClinicalTrials.gov 01914965.

BACKGROUND: Apathy is the neuropsychiatric syndrome that correlates most highly with Huntington's disease progression, and, like early patterns of neurodegeneration, is associated with lesions to cortico-striatal connections. However, due to its multidimensional nature and elusive etiology, treatment options are limited. OBJECTIVES: To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. METHODS: Forty-six Huntington's disease individuals (premanifest (N = 22) and manifest (N = 24)) and 35 healthy controls were scanned at 3-tesla and underwent apathy evaluation using the short-Problem Behavior Assessment and short-Lille Apathy Rating Scale, with the latter being characterized into three apathy domains, namely emotional, cognitive, and auto-activation deficit. Diffusion tensor imaging was used to study whether individual differences in specific cortico-striatal tracts predicted global apathy and its subdomains. RESULTS: We elucidate that apathy profiles may develop along differential timelines, with the auto-activation deficit domain manifesting prior to motor onset. Furthermore, diffusion tensor imaging revealed that inter-individual variability in the disruption of discrete cortico-striatal tracts might explain the heterogeneous severity of apathy profiles. Specifically, higher levels of auto-activation deficit symptoms significantly correlated with increased mean diffusivity in the right uncinate fasciculus. Conversely, those with severe cognitive apathy demonstrated increased mean diffusivity in the right frontostriatal tract and left dorsolateral prefrontal cortex to caudate nucleus tract. CONCLUSIONS: The current study provides evidence that white matter correlates associated with emotional, cognitive, and auto-activation subtypes may elucidate the heterogeneous nature of apathy in Huntington's disease, as such opening a door for individualized pharmacological management of apathy as a multidimensional syndrome in other neurodegenerative disorders.

Abstract Background Changes in phosphodiesterase 10A enzyme levels may be a suitable biomarker of disease progression in Huntington's disease. Objectives To evaluate phosphodiesterase 10A PET imaging as a biomarker of HD progression using the radioligand, [ 18 F]MNI‐659. Methods 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 D 2/3 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. Results 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 D 2/3 receptor availability or volumetric changes. Annualized rates of phosphodiesterase 10A change showed a statistically significant decline between the cross‐sectional study and follow‐up. Conclusions [ 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

BACKGROUND: People with Huntington's disease (HD) have been observed to have lower rates of cancers. OBJECTIVE: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. METHODS: Data were obtained from the European Huntington's disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. RESULTS: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22-0.30). Individual cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). CONCLUSIONS: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis.

BACKGROUND AND PURPOSE: Huntington disease is a devastating genetic neurodegenerative disorder for which no effective treatment is yet available. Although progressive striatal atrophy is its pathologic hallmark, concomitant cortical deterioration is assumed to occur, but it is poorly characterized. Our objective was to study the loss of cortical integrity and its association with clinical indicators throughout the course of the disease. MATERIALS AND METHODS: Using a cohort of 39 patients with Huntington disease and 25 controls with available MR imaging (T1WI and DTI), we compared cortical atrophy and intracortical diffusivity across disease stages. Intracortical diffusivity is a DTI-derived metric that has recently been suggested to detect incipient neuronal death because water can diffuse more freely in cortical regions with reduced neural density. RESULTS: < .05, corrected for multiple comparisons). Most important, in the absence of pronounced atrophy, widespread increased diffusivity was already present in individuals with premanifest Huntington disease, correlating, in turn, with clinical and disease-specific progression markers. CONCLUSIONS: Intracortical diffusivity may be more sensitive than cortical thinning for tracking early neurodegeneration in Huntington disease. Moreover, our findings provide further evidence of an early cortical compromise in Huntington disease, which contributes to our understanding of its clinical phenotype and could have important therapeutic implications.

BACKGROUND: Apathy, a common neuropsychiatric disturbance in Huntington's disease (HD), is subserved by a complex neurobiological network. However, no study has yet employed a whole-brain approach to examine underlying regional vulnerabilities that may precipitate apathy changes over time. OBJECTIVES: To identify whole-brain gray matter volume (GMV) vulnerabilities that may predict longitudinal apathy development in HD. METHODS: Forty-five HD individuals (31 female) were scanned and evaluated for apathy and other neuropsychiatric features using the short-Problem Behavior Assessment for a maximum total of six longitudinal visits (including baseline). In order to identify regions where changes in GMV may describe changes in apathy, we performed longitudinal voxel-based morphometry (VBM) on those 33 participants with a magnetic resonance imaging (MRI) scan on their second visit at 18 ± 6 months follow-up (78 MRI datasets). We next employed a generalized linear mixed-effects model (N = 45) to elucidate whether initial and specific GMV may predict apathy development over time. RESULTS: Utilizing longitudinal VBM, we revealed a relationship between increases in apathy and specific GMV atrophy in the right middle cingulate cortex (MCC). Furthermore, vulnerability in the right MCC volume at baseline successfully predicted the severity and progression of apathy over time. CONCLUSIONS: This study highlights that individual differences in apathy in HD may be explained by variability in atrophy and initial vulnerabilities in the right MCC, a region implicated in action-initiation. These findings thus serve to facilitate the prediction of an apathetic profile, permitting targeted, time-sensitive interventions in neurodegenerative disease with potential implications in otherwise healthy populations. © 2021 International Parkinson and Movement Disorder Society.

INTRODUCTION: Huntington's Disease (HD) is a neurodegenerative disorder of which the main symptoms are motor, cognitive and behavioural problems sometimes including sexual dysfunction. AIM: To review the current knowledge on sexual dysfunction in HD. METHODS: Databases of Pubmed and Scopus were searched. Only original studies performed after 1994 were included (from 1994 a genetic test = proven diagnosis). RESULTS: 162 publications were found, but only nine met our established criteria. The majority of patients with HD suffer from sexual disorders. The most common are: hypoactive sexual disorder (53-83% of patients), hyperactive sexual disorder (6-30%), erectile (48-74%) and ejaculatory dysfunctions (30-65%), lubrication problems (53-83%), and orgasmic dysfunction (35-78%). DISCUSSION: Results may be biased for several reasons e.g.: social taboos regarding sex lives, medications that affect sexual function, impaired self-awareness of patients, small study samples, a lack of standardised questionnaires, and a focus only on the presence of sexual problems without describing them. CONCLUSIONS: Sexual disorders in HD are common. This is a problem that is probably underestimated, both by patients/caregivers and physicians, who should focus more on these symptoms in order to improve patient quality of life.

BACKGROUND: Empathy is a multidimensional construct and a key component of social cognition. In Huntington's disease (HD), little is known regarding the phenomenology and the neural correlates of cognitive and affective empathy, and regarding how empathic deficits interact with other behavioral and cognitive manifestations. OBJECTIVE: To explore the cognitive and affective empathy disturbances and related behavioral and neural correlates in HD. METHODS: Clinical and sociodemographic data were obtained from 36 healthy controls (HC) and 54 gene-mutation carriers (17 premanifest and 37 early-manifest HD). The Test of Cognitive and Affective Empathy (TECA) was used to characterize cognitive (CE) and affective empathy (AE), and to explore their associations with grey matter volume (GMV) and cortical thickness (Cth). RESULTS: Compared to HC, premanifest participants performed significantly worse in perspective taking (CE) and empathic distress (AE). In symptomatic participants, scores were significantly lower in almost all the TECA subscales. Several empathy subscales were associated with the severity of apathy, irritability, and cognitive deficits. CE was associated with GMV in thalamic, temporal, and occipital regions, and with Cth in parietal and temporal areas. AE was associated with GMV in the basal ganglia, limbic, occipital, and medial orbitofrontal regions, and with Cth in parieto-occipital areas. CONCLUSION: Cognitive and affective empathy deficits are detectable early, are more severe in symptomatic participants, and involve the disruption of several fronto-temporal, parieto-occipital, basal ganglia, and limbic regions. These deficits are associated with disease severity and contribute to several behavioral symptoms, facilitating the presentation of maladaptive patterns of social interaction.

OBJECTIVE: The clinical phenotype of Huntington's disease (HD) can be very heterogeneous between patients, even when they share equivalent CAG repeat length, age, or disease burden. This heterogeneity is especially evident in terms of the cognitive profile and related brain changes. To shed light on the mechanisms participating in this heterogeneity, the present study delves into the association between Tau pathology and more severe cognitive phenotypes and brain damage in HD. METHODS: We used a comprehensive neuropsychological examination to characterize the cognitive phenotype of a sample of 30 participants with early-to-middle HD for which we also obtained 3 T structural magnetic resonance image (MRI) and cerebrospinal fluid (CSF). We quantified CSF levels of neurofilament light chain (NfL), total Tau (tTau), and phosphorylated Tau-231 (pTau-231). Thanks to the cognitive characterization carried out, we subsequently explored the relationship between different levels of biomarkers, the cognitive phenotype, and brain integrity. RESULTS: The results confirmed that more severe forms of cognitive deterioration in HD extend beyond executive dysfunction and affect processes with clear posterior-cortical dependence. This phenotype was in turn associated with higher CSF levels of tTau and pTau-231 and to a more pronounced pattern of posterior-cortical atrophy in specific brain regions closely linked to the cognitive processes affected by Tau. INTERPRETATION: Our findings reinforce the association between Tau pathology, cognition, and neurodegeneration in HD, emphasizing the need to explore the role of Tau in the cognitive heterogeneity of the disease.

BACKGROUND: 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. OBJECTIVE: To investigate the safety and feasibility of research lumbar punctures (LP) in HD. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

BACKGROUND: Progressive cognitive decline is an inevitable feature of Huntington's disease (HD) but specific criteria and instruments are still insufficiently developed to reliably classify patients into categories of cognitive severity and to monitor the progression of cognitive impairment. METHODS: We collected data from a cohort of 180 positive gene-carriers: 33 with premanifest HD and 147 with manifest HD. Using a specifically developed gold-standard for cognitive status we classified participants into those with normal cognition, those with mild cognitive impairment, and those with dementia. We administered the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), the MMSE and the UHDRS cogscore at baseline, and at 6-month and 12-month follow-up visits. Cutoff scores discriminating between the three cognitive categories were calculated for each instrument. For each cognitive group and instrument we addressed cognitive progression, sensitivity to change, and the minimally clinical important difference corresponding to conversion from one category to another. RESULTS: The PD-CRS cutoff scores for MCI and dementia showed excellent sensitivity and specificity ratios that were not achieved with the other instruments. Throughout follow-up, in all cognitive groups, PD-CRS captured the rate of conversion from one cognitive category to another and also the different patterns in terms of cognitive trajectories. CONCLUSION: The PD-CRS is a valid and reliable instrument to capture MCI and dementia syndromes in HD. It captures the different trajectories of cognitive progression as a function of cognitive status and shows sensitivity to change in MCI and dementia.

BACKGROUND: Patients with Huntington's disease (HD) exhibit a variable predominance of cognitive, behavioral and motor symptoms. A specific instrument focusing on the impact of cognitive impairment in HD over functional capacity is lacking. OBJECTIVE: To address the need for a brief and specifically developed HD questionnaire able to capture functional aspects suspected to be sensitive to cognitive impairment. METHODS: We developed and validated the "Huntington's Disease-Cognitive Functional Rating Scale" (HD-CFRS) in 78 symptomatic carriers of the Huntington's disease mutation. We also administered the HD-CFRS to a knowledgeable informant to measure the level of agreement. To explore the association between HD-CFRS scores and participants' cognitive status, we administered objective measures of cognition. Participants were classified as cognitively preserved (HD-NC), as having mild cognitive impairment (HD-MCI), or as having dementia (HD-Dem). RESULTS: The HD-CFRS showed concurrent validity and internal consistency in the three groups. HD carriers and informants in the HD-NC group obtained similar HD-CFRS scores. However, in patients with mild cognitive impairment and dementia, informers reported greater functional impairment than HD participants. The HD-CFRS total score showed strong correlations with measures assessing cognition. CONCLUSIONS: These findings support the utility of the HD-CFRS as a brief and reliable instrument to measure functional defects associated with cognitive impairment in HD. We believe this questionnaire could be a useful tool both for clinical practice and research.

Dilemmas arise concerning how to design studies aimed at preventing or slowing Huntington’s disease (HD) in mutation-positive presymptomatic individuals. HD is an autosomal dominant neurodegenerative disease. Each child of an HD gene expansion carrier (HDGEC) has a 50% chance of inheriting the mutation but the clinical symptoms typically only appear in middle age. In the absence of clinical symptoms or having obtained predictive genetic testing, such a person is considered at risk of HD. While genotyping for the HD mutation approaches 100% accuracy, the decision to undergo predictive genetic testing for a debilitating and stigmatized, ultimately fatal disease is highly personal. Predictive testing rates in HD are &lt;20% in Europe and only 5–7% in the US. We now know that the underlying neurodegeneration starts at least a decade before clinically overt symptoms appear, with the implication that it may be too late to modify the disease once signs and symptoms are apparent. Several potential HD therapeutics are now reaching clinical development, raising ethical questions of whether clinical trials should include at risk individuals who choose not to undergo testing. Within this context, there is an important distinction in the way that the genetic status of an individual is identified. Whereas ‘predictive testing’ is a personalized feedback process initiated by a person who wants to know if he or she carries the HD gene expansion, ‘research genotyping’ is only done for the purposes of a study; results are not disclosed and are usually only made accessible in the form of aggregate, anonymized databases. We examine here three possible trial designs for interventions in premanifest HD using the four basic ethical principles (autonomy, beneficence, non-maleficence and justice).

BACKGROUND: Emerging research implicates tau protein dysregulation in the pathophysiology of Huntington's disease. OBJECTIVE: This study investigated skin tau quantification as a potential biomarker for Huntington's disease and its correlation with disease burden outcomes. METHODS: In this cross-sectional study, we measured skin tau levels using enzyme-linked immunosorbent assay in 23 Huntington's disease mutations carriers and eight control subjects, examining group discrimination, correlations with genetic markers, clinical assessments, and neuroimaging data. Brain atrophy was quantified by both volumetric measurements from brain segmentation and a voxel-based morphometry approach. RESULTS: Our findings showed elevated skin tau levels in manifest Huntington's disease compared with premanifest and healthy controls. These levels correlated with CAG repeat length, CAG-Age-Product score, composite Unified Huntington's Disease Rating Scale Total Motor Score, cognitive assessments, and disease-related cortical and subcortical volumes, all independent of age and gender. Using skin tau levels in cluster analysis along with genetic and clinical measures led to improved subject stratification, providing enhanced distinction and validity of clusters. CONCLUSIONS: This study not only confirms the feasibility of skin tau quantification in Huntington's disease but also establishes its potential as a biomarker for enhancing group classification and assessing disease severity across the Huntington's disease spectrum, opening new directions in biomarker research. © 2024 International Parkinson and Movement Disorder Society.

OBJECTIVE: Huntington's disease (HD) speech/language disorders have typically been attributed to motor and executive impairment due to striatal dysfunction. In-depth study of linguistic skills and the role of extrastriatal structures in HD is scarce. This study aimed to explore the profile of language compromise in HD and identify the structural neuroimaging correlates. METHODS: Language and structural correlates were assessed using the Mini Linguistic State Examination (MLSE) in 81 participants (20 HD-ISS 0-1, 40 HD-ISS 2-3 and 21 controls). Clinical and global cognition measures were also obtained. Imaging data included computed gray matter volume (GMV) and cortical thickness (CTh) values extracted from a general linear model with the MLSE. Correlation analyses were performed with the language components of the MLSE. Multivariate regression analyses were used to explore the predictive ability of the language components on GMV and CTh loss. RESULTS: HD individuals showed impaired MLSE performance (84.5 ± 12.8), particularly in syntax, motor speech, and to a lesser extent, semantics and phonology. Significant associations were found between linguistic performance and the structural integrity of nodes within the temporo-parietal, fronto-parietal, and fronto-striatal lexical-semantic and syntactic networks. Correlation analyses linked motor speech and syntax with predominantly left fronto-striatal GMV and CTh clusters, while semantics had a bilateral fronto-parietal topography. Multivariate regression analyses showed language domains as independent contributing factors of GMV and CTh loss in classical language-related regions. INTERPRETATION: Language impairment is an integral part of the HD cognitive phenotype, with severity associated with structural disintegration in extensive cortico-subcortical territories involved in language production and processing.

<h3>Background</h3> Degeneration of striatal medium-spiny neurons is a pathological feature of Huntington´s disease (HD). D2 receptor imaging with positron emission tomography (PET) is a marker of neuronal integrity in HD. Phosphodiesterase 10A (PDE10A) enzyme is highly enriched in the striatal medium-spiny neurons and is a target of interest for drug development in HD. <h3>Aims</h3> The aim of this study was to quantify the PDE10A enzyme and D2 receptor availability in HD gene expansion carriers (HDGECs) with PET. <h3>Methods</h3> Five stage 1 HDGECs (4M/1F, 54 ± 9y), 10 pre-manifest HDGECs (6M/4F, 42 ± 8y; disease burden score ≥275) and 15 age- and gender-matched controls (10M/5F, 46 ± 11y) were studied. PET measurements with [¹¹C]raclopride (D2 receptors) and [¹⁸F]MNI-659 (PDE10A) were performed using the high-resolution research tomograph. 3T magnetic resonance imaging was performed for striatal volume measures and region-of-interest delineation using FreeSurfer. PET outcome measures were the binding potential (BPND) estimated with simplified reference tissue model for [¹¹C]raclopride and calculated with Logan graphical analysis (VT/VND-1=BPND) for [¹⁸F]MNI-659. Data were expressed as percent of the age-related control values. <h3>Results</h3> Striatal volumes, D2 receptor and PDE10A availability were 62 ± 5%, 62 ± 12%, and 21 ± 33% of control values (p &lt; 0.05) in stage 1 HDGECs, and 80 ± 18%, 72 ± 12% and 53 ± 22% of control values (p &lt; 0.05, except for n.accumbens´ volume) in pre-manifest HDGECs. <h3>Conclusion</h3> [¹⁸F]MNI-659 BPND showed larger between-subject variability than [¹¹C]raclopride BPND. Differences of PET outcome measures between HDGECs and controls were larger than differences of striatal volumes. PDE10A enzyme (direct and indirect pathway) availability was more affected than D2 receptor (indirect pathway) availability. [¹⁸F]MNI-659 PET might serve as suitable molecular imaging marker of PDE10A for therapeutical trials in HD.

BACKGROUND: Arithmetic word-problem solving depends on the interaction of several cognitive processes that may be affected early in the disease in gene-mutation carriers for Huntington's disease (HD). OBJECTIVE: Our goal was to examine the pattern of performance of arithmetic tasks in premanifest and manifest HD, and to examine correlations between arithmetic task performance and other neuropsychological tasks. METHODS: We collected data from a multicenter cohort of 165 HD gene-mutation carriers. The sample consisted of 31 premanifest participants: 16 far-from (>12 years estimated time to diagnosis; preHD-A) and 15 close-to (≤12 years estimated time to diagnosis; preHD-B), 134 symptomatic patients (early-mild HD), and 37 healthy controls (HC). We compared performance between groups and explored the associations between arithmetic word-problem solving and neuropsychological and clinical variables. RESULTS: Total arithmetic word-problem solving scores were lower in preHD-B patients than in preHD-A (p < 0.05) patients and HC (p < 0.01). Early-mild HD patients had lower scores than preHD patients (p < 0.001) and HC (p < 0.001). Compared to HC, preHD and early-mild HD participants made more errors as trial complexity increased. Moreover, arithmetic word-problem solving scores were significantly associated with measures of global cognition (p < 0.001), frontal-executive functions (p < 0.001), attention (p < 0.001) visual working memory (p < 0.001), mental rotation (p < 0.001), and confrontation naming (p < 0.05). CONCLUSION: Arithmetic word-problem solving is affected early in the course of HD and is related to deficient processes in frontal-executive and mentalizing-related processes.

To identify vulnerability in gray matter volume (GMV) at the whole-brain level that may predict longitudinal apathy development in Huntington’s disease (HD).