The Dynamic Vasoactive Response of Cerebral White Matter Under Hemodynamic Provocation

The dynamics of white matter cerebrovascular reactivity (CVR) are affected by macrovascular steno-occlusive disease (SOD), but may further vary between normal-appearing white matter (NAWM) and microangiopathic white matter hyperintensities (WMH). Here, we assess the temporal dynamics of the white matter vasoactive response, including interactions between WMH and SOD using a dedicated computational pipeline to isolate transient maximal (CVR_max ) and terminal (CVR_end ) CVR and newly isolated time-to-maximum (CVR_Tmax ) of the pharmacologic response to acetazolamide-augmented dynamic BOLD (ACZ-BOLD) hypothesizing differential temporal responses and hemodynamic phenotypes.

Nineteen adults with angiographically-confirmed unilateral, chronic intracranial SOD underwent a total of 25 twenty-minute ACZ-BOLD examinations. Normal-appearing (NAWM) and microangiopathic (WMH) white matter voxels were manually segmented and classified into four tissue groups based on laterality to SOD, i.e.: NAWM_contra , WMH_contra , NAWM_ipsi , and WMH_ipsi . Median CVR_max and CVR_end were analyzed using linear mixed-effects models. The time-to-maximum of the CVR (CVR_Tmax ) and the terminal-to-maximum CVR ratio (CVR_end /CVR_max ) were additionally constructed and compared.

Among the full cohort, ipsilateral WMH demonstrated the lowest estimated CVR_max . The laterality effect was in the hypothesized direction but did not reach statistical significance (β=-0.211; 95% CI:[-0.445, 0.023]; P=0.08). The tissue-by-laterality interaction also suggested an additional reduction in ipsilateral WMH but did not reach statistically significant differences (β=-0.293; 95% CI:[-0.624, 0.038]; P=0.08). Eight examinations from 8 different subjects exhibited paradoxical reverse-steal profiles, and upon their exclusion differences were amplified including significantly lower CVR_max ipsilateral to SOD (β=-0.579; 95% CI:[-0.794, -0.36]; P<0.001). Reverse-steal examinations demonstrated notably altered dynamics with delayed ipsilateral CVR_Tmax (P=0.004) and higher CVR_end /CVR_max ratios (P=0.03).

The dynamics of the CVR response can reveal differential and previously occult temporal signatures in the pharmacologic response of white matter to ACZ, suggesting potential interactions between macrovascular and microvascular hemodynamic impairment.