Cerebrovascular reactivity dispersion as a new biomarker of recent stroke symptomatology in moyamoya

Background Moyamoya disease (MMD) is a non-atherosclerotic intracranial steno-occlusive condition placing patients at high risk for ischemic stroke. Direct and indirect surgical revascularization can improve blood flow in MMD; however, randomized trials demonstrating efficacy have not been performed and biomarkers of parenchymal hemodynamic impairment are needed to triage patients for interventions and evaluate post-surgical efficacy. We test the hypothesis that hypercapnia-induced maximum cerebrovascular reactivity (CVRMAX) and the more novel indicator cerebrovascular reactivity (CVR) response time (CVRDELAY), both assessed from time-regression analyses of non-invasive hypercapnic imaging, correlate with recent focal ischemic symptoms. Methods Hypercapnic reactivity medical resonance imaging (blood oxygenation level-dependent; echo time=35ms; spatial resolution=3.5×3.5×3.5mm) and catheter angiography assessments of cortical reserve capacity and vascular patency, respectively, in MMD participants (n=73) were performed in sequence. Time regression analyses were applied to quantify CVRMAX and CVRDELAY. Symptomatology information for each hemisphere (n=109) was categorized into symptomatic (ischemic symptoms within six months) or asymptomatic (no history of ischemic symptoms) and logistic regression analysis assessed the association of CVR metrics with ischemic symptoms after controlling for age and sex. Results Symptomatic hemispheres displayed lengthened CVRDELAY (p<0.001), which was more discriminatory between hemispheres than CVRMAX (p=0.037). CVRDELAY (p<0.001), but not CVRMAX (p=0.127), was found to be sensitively related to age in asymptomatic tissue (0.33-unit increase/year); age-dependent normative ranges are presented to enable quantitative assessment of patient-specific impairment. Furthermore, the area under the receiver operating characteristic curves shows that CVRDELAY predicts ischemic symptoms (p<0.001), whereas CVRMAX does not (p=0.056). Conclusion Findings support that CVR metrics are uniquely altered in hemispheres with recent ischemic symptoms, motivating the investigation of CVR as a surrogate of ischemic symptomatology and treatment efficacy. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the National Institute of Neurological Disorders and Stroke (NINDS): 5R01NS078828 and 1R01NS097763. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a prospective study that was approved by the Vanderbilt University Institutional Review Board. All participants provided informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes We will make all of the data for this manuscript available upon request for those who have completed the CITI training. * AUC : area under the curve BOLD : blood oxygen level-dependent CSF : cerebrospinal fluid CVR : cerebrovascular reactivity CVRRAW : uncorrected cerebrovascular reactivity weighted metrics CVRMAX : maximum cerebrovascular reactivity CVRDELAY : cerebrovascular reactivity delay time DWI : diffusion-weighted imaging EtCO2 : end-tidal carbon dioxide FLAIR : FLuid-Attenuated Inversion Recovery FSL : Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library HIPPA : Health Insurance Portability and Accountability Act ICA : intracranial carotid artery IRB : Institutional Review Board MCA : middle cerebral artery MMD : moyamoya disease MMS : moyamoya syndrome MRI : medical resonance imaging PET : positron emission tomography ROC : receiver operating characteristic SaO2 : arterial oxygen saturation SPECT : single position emission computerized tomography STROBE : Strengthening the Reporting of Observational studies in Epidemiology TE : echo time T1W : T1-weighted TR : repetition time