Disentangling the neurobiological bases of temporal impulsivity in Huntington's disease.

BACKGROUND: Despite its impact on daily life, impulsivity in Huntington's disease (HD) is understudied as a neuropsychiatric symptom. Our aim is to characterize temporal impulsivity in HD and to disentangle the white matter correlate associated with impulsivity. METHODS: Forty-seven HD individuals and 36 healthy controls were scanned and evaluated for temporal impulsivity using a delay-discounting (DD) task and complementary Sensitivity to Punishment and Sensitivity to Reward Questionnaire. Diffusion tensor imaging was employed to characterize the structural connectivity of three limbic tracts: the uncinate fasciculus (UF), the accumbofrontal tract (NAcc-OFC), and the dorsolateral prefrontal cortex connectig the caudate nucleus (DLPFC-cn). Multiple linear regression analyses were applied to analyze the relationship between impulsive behavior and white matter microstructural integrity. RESULTS: Our results revealed altered structural connectivity in the DLPC-cn, the NAcc-OFC and the UF in HD individuals. At the same time, the variability in structural connectivity of these tracts was associated with the individual differences in temporal impulsivity. Specifically, increased structural connectivity in the right NAcc-OFC and reduced connectivity in the left UF were associated with higher temporal impulsivity scores. CONCLUSIONS: The present findings highlight the importance of investigating the spectrum of temporal impulsivity in HD. As, while less prevalent than other psychiatric features, this symptom is still reported to significantly impact the quality of life of patients and caregivers. This study provides evidence that individual differences observed in temporal impulsivity may be explained by variability in limbic frontostriatal tracts, while shedding light on the role of sensitivity to reward in modulating impulsive behavior through the selection of immediate rewards.

Measuring cognitive impairment and monitoring cognitive decline in Huntington's disease: a comparison of assessment instruments.

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.

Longitudinal analysis of neuropsychiatric symptoms in a large cohort of early-moderate manifest Huntington's disease patients.

BACKGROUND: The relationship between neuropsychiatric symptoms (NPS) and other clinical dimensions in Huntington's disease (HD) is controversial. This longitudinal study analyzed the association between NPS and motor, cognitive and functional aspects of the disease along with other variables related to its clinical onset and progression. METHODS: 639 early-moderate HD patients were assessed longitudinally (mean: 4.95 visits/5 years). Generalized linear mixed models were used to explore associations between NPS and the aforementioned aspects. Other variables previously reported as significant in smaller or cross-sectional studies were included in the models. RESULTS: Significant associations found included a negative linear relationship between presence of depressed mood and illness duration (7.2% odds reduction of being depressed per year), a 7.6% increase in the odds of having irritability with increased chorea scores, a negative association (4.3% reduction in odds) between age at onset and aggression (i.e. earlier onset was related to a higher probability of having aggressive behaviors) and a negative association between irritability and the interference component of the Stroop test (3% odds change). Total functional capacity (TFC) was the most frequently associated factor with NPS, with apathy and perseverative behavior having the strongest relations with TFC (22% and 18% increases in odds per unit reduction in TFC respectively). CONCLUSIONS: With the exception of irritability, NPS are not related to motor or cognitive variables in early-moderate HD. Total functional capacity (TFC) is the most frequently associated factor with NPS, with apathy and perseverative behavior having the strongest relations with TFC.

Delineating apathy profiles in Huntington's disease with the short-Lille Apathy Rating Scale.

INTRODUCTION: Apathy, a prevalent feature in neurological disorders including Huntington's disease (HD), is characterized by a reduction in goal-directed behavior across cognitive, auto-activation (i.e., self-activating thoughts/behavior), and emotional domains. Nonetheless, current diagnostic criteria are incapable of distinguishing multidimensional apathy profiles. Meanwhile, the short-Lille Apathy Rating Scale (LARS-s) bears potential as an operative diagnostic tool to disentangle apathy dimensions in clinical practice. The present study thereby examines the psychometric properties and factor structure of the LARS-s to tap into apathy profiles and their underlying neural correlates in HD. METHODS: Forty HD individuals were scanned and evaluated for apathy using the LARS-s, assessed for reliability and validity in HD, and the short-Problem Behavior Assessment (PBA-s). To study the dimensional structure of apathy, principal component analysis (PCA) of the LARS-s was implemented. Resulting factors were associated with gray matter volume through whole-brain voxel-based morphometry. RESULTS: The LARS-s demonstrated satisfactory psychometric properties, sharing convergent validity with PBA-s apathy and discriminant validity against depression. PCA resulted in three factors representative of apathy profiles across cognitive, auto-activation, and emotional domains. Anatomically, global apathy was significantly related with large-scale motor, cognitive, and limbic networks. Exploratory analyses of apathy profiles revealed correspondence between each factor and distinct cortical and subcortical nodes. CONCLUSION: The LARS-s is capable of capturing the multidimensional spectrum of apathy. At the same time, apathy profiles in HD are underpinned by functionally diverse neural networks. Such findings promote the continued study of apathy domains to pinpoint personalized therapeutic targets in neurologic disorders in addition to HD.

Arithmetic Word-Problem Solving as Cognitive Marker of Progression in Pre-Manifest and Manifest Huntington's Disease.

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.

Gray Matter Vulnerabilities Predict Longitudinal Development of Apathy in Huntington's Disease.

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.

Utility of the Parkinson's disease-Cognitive Rating Scale for the screening of global cognitive status in Huntington's disease.

BACKGROUND: Cognitive impairment is an essential feature of Huntington's disease (HD) and dementia is a predictable outcome in all patients. However, validated instruments to assess global cognitive performance in the field of HD are lacking. OBJECTIVES: We aimed to explore the utility of the Parkinson's disease-Cognitive Rating Scale (PD-CRS) for the screening of global cognition in HD. METHODS: A multicenter cohort of 132 HD patients at different disease stages and 33 matched healthy controls were classified as having preserved cognition, mild cognitive impairment (HD-MCI) or dementia (HD-Dem) according to the Clinical Dementia Rating and Functional Independence Score. The PD-CRS and the Mini-Mental State Examination were administered. Receiver operating characteristic curve analysis was used to determine optimal cutoffs to differentiate patients according to their cognitive status. RESULTS: A PD-CRS cutoff score ≤ 81/82 was optimal to detect HD-MCI (sensitivity = 93%; specificity = 80%; area under the curve (AUC) = 0.940), and ≤ 63/64 was optimal to detect HD-Dem (sensitivity = 90%; specificity = 87%; AUC = 0.933). MMSE scores failed to show robust psychometric properties in this context. DISCUSSION: The PD-CRS is a valid and reliable instrument to assess global cognition in HD in routine clinical care and clinical trials.

Language disintegration in spontaneous speech in Huntington's disease: a more fine-grained analysis.

Huntington's disease (HD) is a neurodegenerative disease causing motor symptoms along with cognitive and affective problems. Recent evidence suggests that HD also affects language across core levels of linguistic organization, including at stages of the disease when standardized neuropsychological test profiles are still normal and motor symptoms do not yet reach clinical thresholds ('pre-manifest HD'). The present study aimed to subject spontaneous speech to a more fine-grained linguistic analysis in a sample of 20 identified HD gene-carriers, 10 with pre-manifest and 10 with early manifest HD. We further explored how language performance related to non-linguistic cognitive impairment, using standardized neuropsychological measures. A distinctive pattern of linguistic impairments marked off participants with both pre-manifest and manifest HD from healthy controls and each other. Fluency patterns in premanifest HD were marked by prolongations, filled pauses, and repetitions, which shifted to a pattern marked by empty (unfilled) pauses, re-phrasings, and truncations in manifest HD. Both HD groups also significantly differed from controls and each other in how they grammatically connected clauses and used noun phrases referentially. Functional deficits in language occurred in pre-manifest HD in the absence of any non-linguistic neuropsychological impairment and did largely not correlate with standardized neuropsychological measures in manifest HD. These results further corroborate that language can act as a fine-grained clinical marker in HD, which can track disease progression from the pre-manifest stage, define critical remediation targets, and inform the role of the basal ganglia in language processing.

Deep brain stimulation in treatment resistant schizophrenia: A pilot randomized cross-over clinical trial.

BACKGROUND: Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly. METHODS: Eight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed). FINDINGS: One implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators' knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively). INTERPRETATION: These preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects.

White matter cortico-striatal tracts predict apathy subtypes in Huntington's disease.

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.

Specific patterns of brain alterations underlie distinct clinical profiles in Huntington's disease.

Huntington's disease (HD) is a genetic neurodegenerative disease which involves a triad of motor, cognitive and psychiatric disturbances. However, there is great variability in the prominence of each type of symptom across individuals. The neurobiological basis of such variability remains poorly understood but would be crucial for better tailored treatments. Multivariate multimodal neuroimaging approaches have been successful in disentangling these profiles in other disorders. Thus we applied for the first time such approach to HD. We studied the relationship between HD symptom domains and multimodal measures sensitive to grey and white matter structural alterations. Forty-three HD gene carriers (23 manifest and 20 premanifest individuals) were scanned and underwent behavioural assessments evaluating motor, cognitive and psychiatric domains. We conducted a multimodal analysis integrating different structural neuroimaging modalities measuring grey matter volume, cortical thickness and white matter diffusion indices - fractional anisotropy and radial diffusivity. All neuroimaging measures were entered into a linked independent component analysis in order to obtain multimodal components reflecting common inter-subject variation across imaging modalities. The relationship between multimodal neuroimaging independent components and behavioural measures was analysed using multiple linear regression. We found that cognitive and motor symptoms shared a common neurobiological basis, whereas the psychiatric domain presented a differentiated neural signature. Behavioural measures of different symptom domains correlated with different neuroimaging components, both the brain regions involved and the neuroimaging modalities most prominently associated with each type of symptom showing differences. More severe cognitive and motor signs together were associated with a multimodal component consisting in a pattern of reduced grey matter, cortical thickness and white matter integrity in cognitive and motor related networks. In contrast, depressive symptoms were associated with a component mainly characterised by reduced cortical thickness pattern in limbic and paralimbic regions. In conclusion, using a multivariate multimodal approach we were able to disentangle the neurobiological substrates of two distinct symptom profiles in HD: one characterised by cognitive and motor features dissociated from a psychiatric profile. These results open a new view on a disease classically considered as a uniform entity and initiates a new avenue for further research considering these qualitative individual differences.

An active cognitive lifestyle as a potential neuroprotective factor in Huntington's disease.

A cognitive stimulating lifestyle has been observed to confer cognitive benefits in multiple neurodegenerative diseases. However, the underlying neurobiological basis of this phenomenon remains unclear. Huntington's disease can provide a suitable model to study the effects and neural mechanisms of cognitive engagement in neurodegeneration. In this study, we investigate the effect of lifestyle factors such as education, occupation and engagement in cognitive activities in Huntington's disease gene carriers on cognitive performance and age of onset as well as the underlying neural changes sustaining these effects, measured by magnetic resonance imaging. Specifically, we analyzed both gray matter volume and the strength of connectivity of the executive control resting-state network. High levels of cognitive engagement were significantly associated with more preserved executive functions, a delay in the appearance of symptoms, reduced volume loss of the left precuneus and the bilateral caudate and a modulation of connectivity strength of anterior cingulate cortex and left angular gyrus with the executive control network. These findings suggest that a cognitively stimulating lifestyle may promote brain maintenance by modulating the executive control resting-state network and conferring protection against neurodegeneration, which results in a delayed onset of symptoms and improved performance in executive functions.

Reduced striato-cortical and inhibitory transcallosal connectivity in the motor circuit of Huntington's disease patients.

Huntington's disease (HD) is a neurodegenerative disorder which is primarily associated with striatal degeneration. However, the alterations in connectivity of this structure in HD have been underinvestigated. In this study, we analyzed the functional and structural connectivity of the left putamen, while participants performed a finger-tapping task. Using fMRI and DW-MRI, 30 HD gene expansion carriers (HDGEC) and 29 healthy participants were scanned. Psychophysiological interaction analysis and DTI-based tractography were employed to examine functional and structural connectivity, respectively. Manifest HDGEC exhibited a reduced functional connectivity of the left putamen with the left and the right primary sensorimotor areas (SM1). Based on this result, the inhibitory functional connectivity between the left SM1 and the right SM1 was explored, appearing to be also decreased. In addition, the tract connecting these areas (motor corpus callosum), and the tract connecting the left putamen with the left SM1 appeared disrupted in HDGEC compared to controls. Significant correlations were found between measures of functional and structural connectivity of the motor corpus callosum, showing a coupling of both types of alterations in this tract. The observed reduction of functional and structural connectivity was associated with worse motor scores, which highlights the clinical relevance of these results. Hum Brain Mapp 39:54-71, 2018. © 2017 Wiley Periodicals, Inc.

Experiencia del servicio de hospital de día de neuropsiquiatría del hospital Mare de Déu de la Mercè (2015) / No disponible

Introducción: El hospital de día de Neuropsiquiatría es un dispositivo diurno que atiende a pacientes entre 18 y 65 años, con alteraciones cognitivas y conductuales secundarias a un daño cerebral adquirido, demencias degenerativas de inicio precoz, o a la enfermedad de Huntington. El objetivo del estudio es describir la capacidad resolutiva del citado dispositivo a lo largo del año 2015. Material y métodos: Diseño transversal descriptivo de una muestra de 48 personas, con una media de edad de 50 años, de las cuales 28 (58%) eran mujeres. Como instrumentos de medida se utilizaron tests de despistaje cognitivo, una escala de evaluación de la actividad global, y el porcentaje de reingresos antes de los 30 y 90 días tras el alta. En los pacientes con enfermedad de Huntington se utilizaron además exámenes de evaluación motora y funcional específicos. Resultados: Se objetivó una mejoría de los tests de despistaje cognitivo, de la escala de evaluación de la actividad global, y, en los pacientes con enfermedad de Huntington, de los exámenes de evaluación motora y funcional, salvo en los evaluados con tiempo. El 8,33% de los pacientes abandonaron voluntariamente el programa terapéutico. El porcentaje de reingresos antes de los 30 y 90 días tras el alta fue del 0% y 2,08%, respectivamente. Conclusiones: La intervención del hospital de día de Neuropsiquiatría fue eficaz para mejorar las habilidades cognitivas y funcionales de los pacientes atendidos y el porcentaje de reingresos fue bajo

Introduction: The Neuropsychiatry day hospital attends patients between 18 and 65 years old, suffering cognitive and behavioral symptoms in the context of brain acquired lesions, early - onset degenerative dementias or Huntington's disease. The objective of the study is to describe the solving capacity of the mentioned resource along the year 2015. Material and methods: Transversal design, descriptive, with a sample of 48 persons, with a mean age of 50 years old, of which 28 (58%) were women. The measurement tools used were cognitive screening tests, a global assessment of functioning scale, and the percentage of readmissions before 30 and 90 days after discharge; additionally, specific motor and functional assessments were used to evaluate Huntington's disease patients. Results: It was observed an improvement according to cognitive and functional assessments; Huntington's disease patients also did better on motor and functional specific tests, with the exception of timed scales. The percentage of readmissions before 30 and 90 days after discharge was 0% and 2,08%, respectively. Conclusions: The Neuropsychiatric day hospital intervention was effective in improving the cognitive and functional abilities of cared patients. The percentage of readmissions was low

El Montreal Cognitive Assessment (MOCA) como screening cognitivo en pacientes con trastorno por consumo de alcohol: un estudio Delphi / No disponible

El deterioro cognitivo en personas con trastorno por uso de alcohol puede pasar desapercibido si no se utilizan medidas objetivas para evaluarlo. Se realizó un estudio Delphi modificado para conocer la opinión de un panel de 40 expertos sobre la adecuación del Montreal Cognitive Assessment. La mayoría de los profesionales consultados utilizan el Minimental State Examination y el Test del Reloj, instrumentos que se han mostrado poco sensibles al deterioro cognitivo en esta población. La mayoría de los consultados consideran el MoCA adecuado y suficientemente exhaustivo, siempre y cuando no sustituya a una exploración neuropsicológica completa posterior

Cognitive impairment might go undetected in people with alcohol use disorder if not measured with objective instruments. We conducted a modified Delphi study to gather the opinions of a panel of 40 experts from various disciplines about the suitability of the Montreal Cognitive Assessment (MoCA). The screening instrument most widely used by respondents was the MiniMental State Examination (MMSE), despite the fact that it shows low sensitivity in this population. Most of the respondents considered the MoCA to be suitable and sufficiently exhaustive, provided it does not replace a subsequent and full neuropsychological examination

Spanish Validation of the Problem Behaviors Assessment-Short (PBA-s) for Huntington's Disease.

A prospective, observational multicenter study was carried out assessing neuropsychiatric symptoms in a sample of 117 subjects in order to validate the Spanish version of the Problem Behaviors Assessment-Short (PBA-s). The psychometric properties of this version were analyzed. Inter- and intra-rater reliability were good: the mean weighted Cohen's kappa was 0.90 for severity scores and 0.93 for frequency scores. Four factors accounting for 56% of the total variance were identified after an exploratory factor analysis: apathy, irritability, depression, and perseveration. The PBA-s correlates strongly with the Neuropsychiatric Inventory, demonstrating its accuracy for assessing neuropsychiatric symptoms in patients with Huntington's disease.

Neuropsychiatric symptoms are very common in premanifest and early stage Huntington's Disease.

BACKGROUND: Neuropsychiatric symptoms are common features of Huntington's disease (HD). Whereas most studies have focused on cognitive and neuroimaging markers of disease progression, little is known about the prevalence of neuropsychiatric symptoms in premanifest mutation carriers far-from and close-to disease onset. METHODS: We obtained neurological, cognitive and behavioral data from 230 participants classified as premanifest far-from (preHD-A) and close-to (preHD-B) motor-based disease onset, early-symptomatic (early-HD), and healthy controls. Frequency and severity of neuropsychiatric symptoms were assessed with the short Problem Behaviors Assessment for HD (PBA-s). The odds-ratio (OR) to present symptoms in the clinical range was calculated using the control group as reference. Logistic regression analysis was used to explore relationships between neuropsychiatric symptoms and medication use. RESULTS: Prevalence of depression was similar in all groups. Apathy was already present in 32% of preHD-A increasing to 62% of early-HD patients. The probability of presenting apathetic symptoms was 15-88 times higher in preHD-A and preHD-B respectively than in healthy controls. Irritability and executive dysfunction were present in both preHD-B and early-HD. CONCLUSION: Neuropsychiatric symptoms are highly prevalent in HD, already in the premanifest stage, with increasing prevalence of irritability, apathy and executive dysfunction closer to onset. Compared to controls, HD mutation carriers have the highest probability to develop apathy, with an increasing prevalence along disease stages. Our findings confirm the high prevalence of neuropsychiatric symptoms in HD, already many years before the onset of motor symptoms, with apathy as an early manifestation and core neuropsychiatric feature of the disease.