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.

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

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