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.

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.

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.

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.