Neural and biomarker correlates of the Parkinson's Disease-Cognitive Rating Scale in Huntington's disease.

Background: Cognitive decline is a core feature of Huntington's disease (HD), often preceding motor symptoms and progressing with disease severity. While several neuropsychological tests track cognitive changes, few studies have examined the biological correlates of brief screening tools adapted for HD. Objectives: This study investigates the neuroanatomical and fluid biomarker correlates of performance on the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), aiming to validate it as a clinically and biologically grounded tool for cognitive assessment in HD. Methods: Fifty-two symptomatic gene-expansion carriers (CAG >39) underwent cognitive (PD-CRS), motor (UHDRS), and behavioral (PBA) assessments. Plasma neurofilament light chain (NfL) levels were measured via Simoa as a marker of neurodegeneration. Voxel-based morphometry (VBM) was used to identify gray matter volume (GMV) correlates of PD-CRS scores. Linear regressions evaluated relationships among PD-CRS, GMV, and NfL, including subdomain-level and stage-stratified analyses based on HD-ISS classification. Results: PD-CRS scores were significantly associated with GMV in frontostriatal, paralimbic, parietal, and occipital regions. NfL levels correlated with both cognitive scores and GMV in key regions, supporting their value as biomarkers of neurodegeneration. Subdomain analyses revealed region-specific associations (e.g., visuospatial tasks with posterior cortices, fluency with striatum). Perseveration, motor severity, and education predicted PD-CRS performance (adjusted R2 = 0.799). PD-CRS remained the strongest GMV predictor (adjusted R2 = 0.519), particularly in later disease stages. Conclussions: The PD-CRS reflects biologically meaningful aspects of cognitive dysfunction in HD, with robust associations to structural and molecular disease markers. These findings support its use as a practical and sensitive tool for clinical and research applications.