Objective: To evaluate lateral ventricular (LV) positron emission tomography (PET) signal and choroid plexus (CP) volume as biomarkers of disease progression in Huntington’s disease (HD), and to assess whether markers of epithelial barrier function and cerebrospinal fluid (CSF) clearance mediate associations between disease burden and striatal atrophy.

Background: Reliable objective markers of disease progression in HD are limited. CP volumetrics and LV PET signal have been proposed as in vivo markers of epithelial dysfunction and impaired CSF-mediated solute clearance. However, their relevance to HD severity and striatal degeneration remains elusive.

Method: Fifty-seven people with HD (21 pre-manifest, 18 peri-manifest, 18 manifest) and 34 matched healthy controls (HC) from the iMarkHD study underwent MRI and PET using four tracers: IMA107 (phosphodiesterase 10A enzyme), MDL100907 (serotonin 2A receptor), MePPEP (cannabinoid receptor 1), and MK8278 (histamine 3 receptor). LV signal was quantified using standardised uptake value ratios (SUVR) and CP volumes were segmented using automated deep-learning methods. Group differences were assessed using ANCOVA with Tukey’s HSD post hoc tests. Following subject-specific brain parcellation, mediation analyses tested whether LV SUVR mediated the relationship between genetic disease burden (CAP score) and striatal atrophy.

Results: CP volume was higher in peri-manifest HD compared to HC (p=0.006) and increased progressively with disease severity (p<0.001). LV SUVR showed stage-dependent reduction across all tracers, with the strongest effects observed for MePPEP and MK8278. MK8278 SUVR was reduced in pre-manifest HD and declined across disease stages (p<0.003). MePPEP SUVR was lower in peri-manifest HD compared to HC (p<0.003) and decreased from peri- to manifest stages (p=0.016). Mediation analyses indicated that reduced LV signal partially mediated the association between CAP scores and striatal atrophy, accounting for 30–36% of caudate and 22–23% of putamen volume loss (all indirect effects p<0.021).

Conclusion: Altered LV PET signal and CP enlargement indicate early disruption of CSF-mediated clearance mechanisms in HD, detectable already at pre-manifest stages. These findings support CSF-related imaging measures as potential biomarkers of disease progression and suggest neurofluid and epithelial dysfunction as contributors to HD pathophysiology.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/multi-tracer-positron-emission-tomography-reveals-early-disruption-of-cerebrospinal-fluid-clearance-in-huntingtons-disease/