E014 Hypertrophy of the cerebral parasagittal dural space, an emerging neurofluid egress conduit, relates to disease severity in Huntington disease

<h3>Background/Aims</h3> Aberrant cerebrospinal fluid (CSF) flow and egress persist in many patients with Huntington’s disease (HD), and quantitation of these phenomena could inform mechanisms of disease progression and potentially assist with triaging patients for intrathecally-administered therapies. This work reports on the relevance of a recently-identified parasagittal dural (PSD) CSF egress pathway, using magnetic resonance imaging, to symptomatology across the spectrum of HD severity. <h3>Methods</h3> PSD was quantified using a recently-validated T2-weighted MRI and associated deep-learning segmentation in genetic-expanded (GE; n=57) and age-matched gene non-expanded (GNE; n=54) carriers. GE carriers were stratified by disease stage per HD-ISS criteria. CAP score and UHDRS total motor scores (TMS) were used to characterize disease burden and clinical symptom severity, respectively. Linear regression models and Spearman correlation were applied to assess GNE and GE-stage group-wise differences with PSD, and PSD relationship with disease burden, symptomatology, and relevant co-variates (significance criterion: p&lt;0.05). <h3>Results</h3> A significant increase of PSD volume in GE versus GNE carriers, in early (HD-ISS stages=0–1; p=0.046) and later (HD-ISS stages=2–3; p=0.019) stage was observed. PSD hypertrophy relates directly to CAP score (p=0.002) and TMS (p=0.001). These relationships were confirmed with linear regression models after controlling for age, sex, and intracranial volume. <h3>Conclusions</h3> PSD, a structure with emerging relevance to neurofluid egress and proteinopathy, directly relates to HD disease stage, burden, and clinical severity. Disease modification treatment trials, especially antisense oligomer trials, may interpret immune processes and treatment efficacy across the spectrum of diverse neurofluid kinetics within conventional and more novel PSD channels.