Objective: To quantify histamine 3 receptor (H3R) expression using positron emission tomography (PET) in people with Huntington’s disease (PwHD) across different stages of disease progression.

Background: H3R are widely distributed through the central nervous system and show particularly high striatal expression. Post-mortem data have previously indicated reduced H3R mRNA levels in the caudate of PwHD and preclinical HD models further suggested that modulation of H3R can reduce striatal cell death and improve cognitive and motor deficits. However, in vivo studies investigating H3R expression in PwHD have not been performed.

Method: As part of the iMarkHD study, a longitudinal multimodal neuroimaging study in PwHD, we analysed H3R expression through [¹¹C]MK8278 PET scanning in a sample of 85 participants, consisting of 30 healthy volunteers, 21 PwHD far from onset of motor symptoms (approximately HD-ISS 0/1), 17 PwHD around time of motor onset (approximately HD-ISS 2), and 17 PwHD after motor onset (approximately HD-ISS 3). T1-weighted magnetic resonance imaging and dynamic [¹¹C]MK8278 PET (90 minutes) were acquired for each participant. The two-tissue compartment model was used to derive volume of distribution (V_T). Focusing on subcortical regions, group differences in H3R V_T were assessed through ANCOVA analysis with age, sex, and regional volume as co-variates.

Results: Groups were well-matched for demographics and experimental PET variables (p≥0.17). Significant group differences in H3R V_T were observed across all subcortical regions, including, but not limited to, the striatum, caudate, and putamen (p≤0.001) with post-hoc comparisons showing already early changes in far from onset PwHD in the striatum and caudate (p≤0.044). Moderate to strong negative associations were observed between H3R VT and CAP (R≤-0.42), and Unified HD Rating Scales scores, in particular chorea scores (R≤-0.60; p<0.001).

Conclusion: This first in vivo study of the histaminergic system in HD revealed significant subcortical H3R alterations, detectable even in PwHD far from motor onset (HD-ISS stages 0/1). The strong associations between H3R availability, disease burden, and clinical severity support a close link with disease progression. These findings highlight H3R as a promising novel biomarker candidate and potential therapeutic target in HD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/early-reduction-in-cerebral-histamine-3-receptor-expression-in-people-with-huntingtons-disease-results-from-the-imarkhd-study/