CO2 cerebrovascular reactivity measured with phase‐contrast MRI: A potential biomarker of cognition and physical function in older adults

Background Vascular cognitive decline is a prominent cause of late‐life cognitive impairment. Compared to Alzheimer’s disease(AD), there is a paucity of biomarkers for its diagnosis, stratification, and treatment monitoring. Cerebrovascular‐Reactivity(CVR) MRI measures small‐vessel dilation to vasoactive‐stimuli(e.g. CO2), and has been shown to be associated with cognitive impairment. However, previous CVR studies were based on Blood‐Oxygenation‐Level‐Dependent (BOLD) MRI signal, which reflects a complex interplay of many physiological parameters and thus presents interpretation challenges. We measured CVR using quantitative CBF‐imaging in older participants, and tested for associations with diagnosis (Healthy Control [HC] vs. mild‐cognitive‐impairment [MCI] vs. dementia) cognitive and physical function, amyloid and tau burden, and vascular risk. Methods A cross‐sectional study enrolled 67 participants aged 69±6.5 years (22 HC, 37 MCI, 8 dementia). MoCA (Montreal‐Cognitive‐Assessment) and composite cognition (a z‐score average of 4‐domains: verbal‐memory, executive‐function, language, processing‐speed) assessed overall cognition. Gait(sec,4‐meter‐walk) and chair‐stands (sec,5‐chair‐stands) assessed physical‐function. Clinical Dementia Rating(CDR) 7 indexed disease‐severity. Phase‐contrast flow MRI(3T) was performed while participants breathed room‐air for 1‐minute, followed by ‘CO2‐enriched‐air’(5%CO2, 21%O2, 74%N2) for 2‐minutes. Blood‐flux at Superior‐Sagittal‐Sinus(SSS)(Figure‐1) was quantified for both states. Breathing rate and End‐tidal(Et)‐CO2 were recorded via capnography. CBF‐based CVR was then obtained by: CBF‐CVR = [HypercapniaSSSflux(ml/min)‐RoomairSSSflux(ml/min)]/RoomairSSSflux(ml/min) HypercapniaEtCo2(mmHg)‐RoomairEtCo2(mmHg) FLAIR‐MRI‐images were assigned Fazekas‐scores by a neuroradiologist. AD‐Biomarkers Aβ40, Aβ42, tau, and p‐tau181(pg/ml), were measured in cerebrospinal fluid (CSF) and vascular‐biomarkers HbA1c (mg/dL), homocysteine (umol/l), HDL(mg/dL), and LDL (mg/dL) in blood. Vascular‐Risk‐Score (VRS) is a composite score based on the presence of hypertension, hypercholesterolemia, diabetes, smoking or obesity (body mass index>30 kg/m2). Results Table‐1 summarizes participant‐demographics. CBF‐CVR (%/mmHg) differentiated diagnostic‐categories, and was lower in impaired vs. HC (p=0.027, Figure‐2a). Higher CBF‐CVR predicted better cognitive‐performance [MoCA(p=0.000089) (Figure‐2b), composite‐cognition (p=0.007) and language (p=0.000064)], physical function [faster gait(p=0.001), chair‐stands(p=0.021)], and disease‐severity [global‐CDR (p=0.003), CDR‐sum‐of‐boxes (p=0.001)(Table‐2). These relationships remained after adjusting for AD‐biomarkers. CBF‐CVR remained associated with cognition and physical‐function except chair‐stands, after adjusting for vascular‐markers: WMH‐Fazekas‐score, VRS, and whole‐brain‐CBF(Table‐2). CBF‐CVR was associated with HbA1c(p=0.007) and history of Diabetes (p=0.043), but not other blood biomarkers or VRS. Conclusion We show that a 3‐minute CBF‐based CVR MRI can differentiate diagnostic‐categories, and predict cognitive and physical function, independent of AD pathology.