Impaired Cerebrovascular Reactivity in Huntington's Disease.

Suk Tak Chan,Herminia D Rosas,Kenneth K Kwong,Steven M Hersch,Nathaniel D Mercaldo

doi:10.3389/fphys.2021.663898

Abstract

There is increasing evidence that impairments of cerebrovascular function and/or abnormalities of the cerebral vasculature might contribute to early neuronal cell loss in Huntington’s disease (HD). Studies in both healthy individuals as well as in patients with other neurodegenerative disorders have used an exogenous carbon dioxide (CO2) challenge in conjunction with functional magnetic resonance imaging (fMRI) to assess regional cerebrovascular reactivity (CVR). In this study, we explored potential impairments of CVR in HD. Twelve gene expanded HD individuals, including both pre-symptomatic and early symptomatic HD and eleven healthy controls were administered a gas mixture targeting a 4–8 mmHg increase in CO2 relative to the end-tidal partial pressure of CO2 (PETCO2) at rest. A Hilbert Transform analysis was used to compute the cross-correlation between the time series of regional BOLD signal changes (ΔBOLD) and increased PETCO2, and to estimate the response delay of ΔBOLD relative to PETCO2. After correcting for age, we found that the cross-correlation between the time series for regional ΔBOLD and for PETCO2 was weaker in HD subjects than in controls in several subcortical white matter regions, including the corpus callosum, subcortical white matter adjacent to rostral and caudal anterior cingulate, rostral and caudal middle frontal, insular, middle temporal, and posterior cingulate areas. In addition, greater volume of dilated perivascular space (PVS) was observed to overlap, primarily along the periphery, with the areas that showed greater ΔBOLD response delay. Our preliminary findings support that alterations in cerebrovascular function occur in HD and may be an important, not as yet considered, contributor to early neuropathology in HD.

Highlights

Huntington’s Disease (HD) is a devastating fully penetrant autosomal dominant progressive, rare neurological disorder that is characterized by progressive motor dysfunction, emotional disturbances, dementia, and weight loss (Conneally, 1984; Hersch and Rosas, 2008)
It is caused by the abnormal expansion of a CAG repeat length in the gene that codes for an ubiquitously expressed protein, huntingtin (MacDonald et al, 1993), which can be found in neurons as well as all major components of the neurovascular unit including the basal lamina, endothelial cell, pericytes, smooth muscle cells (Lin et al, 2013; Drouin-Ouellet et al, 2015), astrocytes, and Impaired cerebrovascular reactivity (CVR) in Huntington’s Disease oligodendrocytes and microglia (Jansen et al, 2017)
Using a novel automated segmentation algorithm (Chan et al, 2020b), we found that the load of enlarged perivascular spaces (PVS) was greater in patients with HD in a manner that directly correlated with disease severity and caudate atrophy

Summary

Introduction

Huntington’s Disease (HD) is a devastating fully penetrant autosomal dominant progressive, rare neurological disorder that is characterized by progressive motor dysfunction, emotional disturbances, dementia, and weight loss (Conneally, 1984; Hersch and Rosas, 2008). Using a novel automated segmentation algorithm (Chan et al, 2020b), we found that the load of enlarged PVS was greater in patients with HD in a manner that directly correlated with disease severity and caudate atrophy Together, these findings converge to provide support for early impairment of cerebrovascular function, including prior to neuronal cell loss or to early clinical symptoms including weight loss, behavioral changes (Padel et al, 2018) or motor dysfunction (Lin et al, 2013; Drouin-Ouellet et al, 2015) in HD

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Conclusion