Functional and Structural Evidence of Neurofluid Circuit Aberrations in Huntington Disease

OBJECTIVE: Disrupted neurofluid regulation may contribute to neurodegeneration in Huntington disease (HD). Because neurofluid pathways influence waste clearance, inflammation, and the distribution of central nervous system (CNS)-delivered therapeutics, understanding their dysfunction is increasingly important as targeted treatments emerge. We aimed to evaluate structural and physiological changes in two key neurofluid components, the choroid plexus (ChP), which produces cerebrospinal fluid (CSF), and the parasagittal dural (PSD) space, a major CSF outflow pathway, across the HD spectrum and in relation to CSF flow dynamics. METHODS: -weighted and FLAIR MRI. CSF flow at the cerebral aqueduct was measured with phase contrast MRI, and ChP perfusion was quantified using pseudo-continuous arterial spin labeling MRI. Linear regression models assessed the relationships between PSD and ChP volume, CSF flow kinetics, ChP hemodynamics, disease severity, disease exposure, and disease presentation, adjusting for age, sex, and intracranial volume. RESULTS: 80 HD participants and 65 age-matched healthy controls were included. HD showed significantly larger ChP and PSD volumes (p < 0.01) and reduced ChP perfusion (p < 0.01). Greater CAG repeat expansion correlated with larger PSD and ChP volume and lower ChP perfusion (p < 0.01). These alterations were associated with worse motor impairment (p < 0.01). INTERPRETATION: HD is associated with structural and functional alterations in neurofluid pathways. These findings suggest relevance for disease mechanisms and for optimizing CSF-based therapeutic delivery, highlighting the need for further mechanistic studies.