Impaired Cerebrovascular Reactivity in Huntington's Disease

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 (P _ET CO₂) 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 P _ET CO₂, and to estimate the response delay of ΔBOLD relative to P _ET CO₂. After correcting for age, we found that the cross-correlation between the time series for regional ΔBOLD and for P _ET CO₂ 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.

Keywords: Huntington’s disease; cerebrovascular reactivity; exogenous CO2 challenge; functional magnetic resonance imaging; perivascular space; presymptomatic.

FIGURE 1

Paradigm of hypercapnic challenge using externally administered CO₂.

FIGURE 2

Cross-correlation of ΔBOLD with P_ETCO₂. (A) Brain maps of cross-correlation of ΔBOLD with P_ETCO₂ for individual HD subjects. The strength of cross-correlation increases from light color to dark color. Brain regions without color indicate that the ΔBOLD in these areas are not correlated with the changes in P_ETCO₂. Multiple comparisons are corrected using clustering at an overall p < 0.05. (B) Group comparison of Fisher-transformed cross-correlation values between HD subjects and controls after adjusting for age. Cold colors represent the weaker cross-correlation found in HD subjects than in controls. Multiple comparisons were corrected at false discovery rate p_fdr < 0.05.