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

BackgroundDespite 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.MethodsForty-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.ResultsOur 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.ConclusionsThe 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. This study investigates individual differences in temporal impulsivity by using a delay discounting task and, its relationship with white matter connectivity. Our findings reveal significant alterations in the microstructure of key tracts of interest, including the right DLPF-Ccn, bilateral uncinate fasciculus and the left accumbo-frontal tract, in individuals with HD. Furthermore, we observed that variability in the structural connectivity in specific tracts is associated with individual differences in temporal impulsivity. imag

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

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. To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. 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. 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. 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

Los síntomas neuropsiquiátricos en la enfermedad de Huntington. Evaluación y análisis de su relacion con variables cognitivas, motoras y funcionales

La Malaltia de Huntington (EH) és una malaltia neurodegenerativa de base genètica que es produeix per una expansió anòmala del triplet CAG que codifica una proteïna anòmala, la huntingtina mutada, responsable d'uns efectes sobre la funció cel·lular que resulten en la seva disfunció i mort cel·lular. S'ha vist que la neuropatología de l'EH evoluciona amb uns patrons temporals concrets el que es tradueix a nivell clínic en l'aparició d'una simptomatologia motora, cognitiva i neuropsiquiátrica característica que evoluciona al llarg de la seva progressió i que afecta la capacitat funcional de l'individu. Encara que diversos estudis han analitzat la prevalença i progressió dels símptomes nuclears de l'EH, la relació al llarg de la malaltia entre els símptomes neuropsiquiátricos (SNP) i les altres dimensions clíniques de la mateixa ha estat menys estudiada, amb resultats dispars a causa de les diferents poblacions estudiades i a la diferent metodologia utilitzada pels investigadors. L'escala d'avaluació dels SNP més àmpliament utilitzada és la Problem Behavior Assessment short (PBA-S). En un primer estudi, es realitza la validació de l'esmentada escala, analitzant les seves característiques psicomètriques sobre una mostra de 117 participants, obtenint-se un conjunt de dades sobre els quals es va dur a terme una anàlisi estadística de: consistència interna, fiabilitat intra i interobservador i validesa concurrent, anàlisi factorial. Els resultats obtinguts suggereixen que la versió en espanyol de l'escala PBA-s és vàlida i fiable per a mesurar els SNP en pacients amb EH. Des del punt de vista clínic, aquest primer estudi va assenyalar una important associació dels SNP amb la funcionalitat, aspecte controvertit en la literatura, la qual cosa va justificar la realització d'un segon estudi amb una mostra més àmplia i una anàlisi de les associacions dels SNP amb variables clíniques i de progressió de la malaltia que llancin pistes sobre la seva fisiopatologia. Es va obtenir una mostra de 639 individus en la fase manifesta de la malaltia que tenien 3 o més avaluacions anuals consecutives completes de les variables motores, cognitives, neuropsiquiátricas i funcionals. Per a aprofundir en el coneixement de les relacions dels SNP es van afegir a més variables relacionades amb el debut clínic i la progressió de la malaltia. Es va dur a terme per a cadascun dels SNP un estudi de models logístics d'efectes mixtos per a avaluar les seves possibles associacions amb les variables cognitives, motores i funcionals. Els resultats assenyalen que els SNP s'associen amb la funcionalitat, indicant que a mesura que la malaltia progressa, els pacients mostren més SNP, especialment apatia i perseveració i de manera menys significativa deliris, al·lucinacions i conductes agressives. L'estudi mostra una notable falta d'associació entre els SNP i les variables cognitives al contrari de l'esperat. Així mateix indiquen la presència de tres perfils diferents en la neuropsiquiatría de l'EH en les seves fases inicials. Un clarament relacionat amb la progressió de la malaltia, que inclou els símptomes apatia i perseveració. Un altre, constituït per la irritabilitat, en relació a variables motores i cognitives i un tercer que tendeix a evolucionar independentment de les altres dimensions de la malaltia (depressió, ansietat, ideació suïcida i agressió).L'absència d'associació entre la majoria dels SNP i les variables cognitives estudiades pot indicar el compromís d'altres vies de connexió a part de les frontosubcorticales en els models explicatius de la neuropsiquiatría de l'EH, així com la influència d'altres variables no incloses en l'anàlisi, com ara les circumstàncies ambientals i l'estil de vida. Així mateix, els diferents perfils trobats evidencien variacions fenotípiques en l'expressió simptomàtica de l'EH que mereixen ser estudiats en el futur.La Enfermedad de Huntington (EH) es una enfermedad neurodegenerativa de base genética que se produce por una expansión anómala del triplete CAG que codifica una proteína anómala, la huntingtina mutada, responsable de unos efectos sobre la función celular que resultan en su disfunción y muerte celular. Se ha visto que la neuropatología de la EH evoluciona con unos patrones temporales concretos lo que se traduce a nivel clínico en la aparición de una sintomatología motora, cognitiva y neuropsiquiátrica característica que evoluciona a lo largo de su progresión y que afecta la capacidad funcional del individuo. Aunque varios estudios han analizado la prevalencia y progresión de los síntomas nucleares de la EH, la relación a lo largo de la enfermedad entre los síntomas neuropsiquiátricos (SNP) y las otras dimensiones clínicas de la misma ha sido menos estudiada, con resultados dispares debido a las diferentes poblaciones estudiadas y a la distinta metodología utilizada por los investigadores. La escala de evaluación de los SNP más ampliamente utilizada es la Problem Behavior Assessment short (PBA-S). En un primer estudio, se realiza la validación de la mencionada escala, analizando sus características psicométricas sobre una muestra de 117 participantes, obteniéndose un conjunto de datos sobre los que se llevó a cabo un análisis estadístico de: consistencia interna, fiabilidad intra e interobservador y validez concurrente, análisis factorial. Los resultados obtenidos sugieren que la versión en español de la escala PBA-s es válida y fiable para medir los SNP en pacientes con EH. Desde el punto de vista clínico, este primer estudio señaló una importante asociación de los SNP con la funcionalidad, aspecto controvertido en la literatura, lo que justificó la realización de un segundo estudio con una muestra más amplia y un análisis de las asociaciones de los SNP con variables clínicas y de progresión de la enfermedad que arrojen pistas sobre su fisiopatología. Se obtuvo una muestra de 639 individuos en la fase manifiesta de la enfermedad que tenían 3 o más evaluaciones anuales consecutivas completas de las variables motoras, cognitivas, neuropsiquiátricas y funcionales. Para profundizar en el conocimiento de las relaciones de los SNP se añadieron además variables relacionadas con el debut clínico y la progresión de la enfermedad. Se llevó a cabo para cada uno de los SNP un estudio de modelos logísticos de efectos mixtos para evaluar sus posibles asociaciones con las variables cognitivas, motoras y funcionales. Los resultados señalan que los SNP se asocian con la funcionalidad, indicando que a medida que la enfermedad progresa, los pacientes muestran más SNP, especialmente apatía y perseveración y de manera menos significativa delirios, alucinaciones y conductas agresivas. El estudio muestra una notable falta de asociación entre los SNP y las variables cognitivas al contrario de lo esperado. Asimismo indican la presencia de tres perfiles distintos en la neuropsiquiatría de la EH en sus fases iniciales. Uno claramente relacionado con la progresión de la enfermedad, que incluye los síntomas apatía y perseveración. Otro, constituido por la irritabilidad, en relación a variables motoras y cognitivas y un tercero que tiende a evolucionar independientemente de las otras dimensiones de la enfermedad (depresión, ansiedad, ideación suicida y agresión).La ausencia de asociación entre la mayoría de los SNP y las variables cognitivas estudiadas puede indicar el compromiso de otras vías de conexión aparte de las frontosubcorticales en los modelos explicativos de la neuropsiquiatría de la EH, así como la influencia de otras variables no incluidas en el análisis, tales como las circunstancias ambientales y el estilo de vida. Asimismo, los distintos perfiles encontrados evidencian variaciones fenotípicas en la expresión sintomática de la EH que merecen ser estudiados en el futuro.Huntington's disease (HD) is a genetically based neurodegenerative disease caused by an abnormal expansion of the CAG triplet encoding an abnormal protein, mutant huntingtin, responsible for effects on cell function that result in cell dysfunction and cell death. The neuropathology of HD has been shown to evolve in specific temporal patterns that translate clinically into the appearance of characteristic motor, cognitive and neuropsychiatric symptomatology that evolves throughout its progression and affects the individual's functional capacity. Although several studies have analyzed the prevalence and progression of the core symptoms of HD, the relationship throughout the disease between neuropsychiatric symptoms (NPS) and the other clinical dimensions of the disease has been less studied, with disparate results due to the different populations studied and the different methodology used by the investigators. The most widely used NPS assessment scale is the Problem Behavior Assessment short (PBA-S). In a first study, the validation of this scale was carried out, analyzing its psychometric characteristics on a sample of 117 participants, obtaining a set of data on which a statistical analysis of: internal consistency, intra- and inter-observer reliability and concurrent validity, factorial analysis was carried out. The results obtained suggest that the Spanish version of the PBA-s scale is valid and reliable for measuring PNS in HD patients. From the clinical point of view, this first study pointed out an important association of NPS with functionality, a controversial aspect in the literature, which justified conducting a second study with a larger sample and an analysis of the associations of NPS with clinical and disease progression variables that shed clues about their pathophysiology. We obtained a sample of 639 individuals in the manifest phase of the disease who had 3 or more consecutive complete annual assessments of motor, cognitive, neuropsychiatric, and functional variables. To deepen the understanding of SNP relationships, variables related to clinical debut and disease progression were also added. A mixed-effects logistic modeling study was performed for each NPS to evaluate their possible associations with cognitive, motor and functional variables. The results indicate that NPS are associated with functionality, indicating that as the disease progresses, patients show more NPS, especially apathy and perseveration and less significantly delusions, hallucinations and aggressive behaviors. The study shows a remarkable lack of association between SNPs and cognitive variables contrary to expectations. They also indicate the presence of three distinct profiles in the neuropsychiatry of early HD. One clearly related to disease progression, which includes symptoms of apathy and perseveration. Another one, constituted by irritability, in relation to motor and cognitive variables and a third that tends to evolve independently of the other dimensions of the disease (depression, anxiety, suicidal ideation and aggression).The absence of association between most of the SNPs and the cognitive variables studied may indicate the involvement of connection pathways other than the frontosubcortical ones in the explanatory models of HD neuropsychiatry, as well as the influence of other variables not included in the analysis, such as environmental circumstances and lifestyle. Likewise, the different profiles found evidence phenotypic variations in the symptomatic expression of HD that deserve future study

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

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. To disentangle underlying white matter microstructural correlates across the apathy spectrum in Huntington's disease. 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. 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. 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

Clinical manifestations of intermediate allele carriers in Huntington disease

Objective: There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry. Methods: We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form-36 [SF-36]). This cohort was subdivided into IA carriers (27-35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores. Results: Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p 0.002). Conclusions: Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling. ClinicalTrials.gov identifier: NCT01590589

Reduced Cancer Incidence in Huntington's Disease: Analysis in the Registry Study

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

Clinical and genetic characteristics of late-onset Huntington's disease

Background: The frequency of late-onset Huntington's disease (&gt;59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Objective: Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Methods: Participants with late- and common-onset (30–50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Results: Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P &lt;.001). Overall motor and cognitive performance (P &lt;.001) were worse, however only disease motor progression was slower (coefficient, −0.58; SE 0.16; P &lt;.001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P &lt;.001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P &lt;.001). Conclusions: Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients