Visuospatial working memory in Huntington’s disease: behavioural and structural brain correlates

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BACKGROUND: Visuospatial working memory (VSWM) deficits are among the earliest cognitive impairments evident in Huntington's disease (HD). They often precede motor symptoms and likely reflect early disruption of cortico-striatal circuits. Both the cognitive components and brain correlates are, however, poorly delineated. OBJECTIVES: This study aims to characterise the progression of VSWM deficits across HD stages and identify their structural brain correlates. METHODS: In this prospective international study, 92 HD mutation carriers (HDmc) (21 premanifest and 71 manifest) and 39 healthy controls underwent cognitive and clinical assessments and structural MRI at baseline; 49 manifest HD and 36 controls completed a 1-year follow-up. VSWM was assessed using the object-location task (OLT), providing continuous measures of location error, object recognition and object-location binding. MRI analyses included caudate, putamen and hippocampal volumes and cortical thickness. RESULTS: We found increased location error and spatial imprecision under high memory load, without binding errors in premanifest HD with an area under the curve of 0.731. Across all HDmc, these location deficits correlated with striatal atrophy and cortical thinning in parietal and middle cingulate regions. Manifest HD individuals exhibited swap errors and hippocampal atrophy. Both location and swap errors worsened over time alongside progressive striatal and hippocampal volume loss. Principal component analysis confirmed a dissociation between spatial location-related deficits (striato-cortically mediated) and binding errors (hippocampally mediated), supporting a hierarchical model of VSWM decline. CONCLUSIONS: HD-related VSWM impairment follows a staged, anatomically dissociable trajectory. The OLT offers sensitive, mechanistic markers of cognitive decline with potential utility for early detection and clinical trial stratification.

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