Project Summary/Abstract Vascular cognitive impairment (VCI) is the second leading cause of dementia after Alzheimer?s disease (AD). However, while AD biomarkers are relatively well developed, biomarkers for VCI pathology in the brain are more limited. Cerebrovascular reactivity (CVR), an index of cerebral vessel?s capacity to dilate in response to stimulation, is a promising marker of the brain?s vascular function. Our overarching hypothesis is that CVR is a plausible biomarker for the diagnosis of VCI, for which no other biomarkers are currently available. Despite some promises, CVR is not commonly measured in clinical practice, primarily due to logistical difficulties in applying a vascular ?challenge? during imaging. In current clinical settings, CVR measurement requires a vascular challenge during imaging, involving either the injection of pharmacological agent (e.g. acetazolamide) or inhalation of CO2 gas. However, these strategies are not ideal in terms of both patient burden and costs, due to the complexity of the procedure, requirement of special equipment, and possible side-effect of physiological maneuver to induce vascular challenge. Therefore, development of a CVR technique that does not need an explicit vascular challenge will broaden the clinical utility of CVR in the diagnosis of VCI and vascular dementia. The central goal of this project is to develop a gas-free CVR MRI technique that can provide comparable sensitivity to CO2-inhalation CVR yet maintains a high comfort level to the subjects. This new technique is largely based on resting-state scan and exploits spontaneous fluctuations in the subject?s breathing pattern, but also introduces intermittent modulations of their breathing rhythm to enhance fluctuations in their end-tidal CO2 (EtCO2). This project is divided into three logical steps. First, we will develop the gas-free CVR technique in healthy subjects, separately for BOLD and CBF MRI acquisitions (in Aim 1). Second, since previous work on gas-based CVR has suggested that there exist fairly large variations in CVR in both within and across subjects settings, we will identify physiological mechanism(s) of normal variations in gas-free CVR and then account/control for them in order to reduce variations (in Aim 2). Finally, we will apply the gas-free CVR technique in patients with mild cognitive impairment with and without vascular risk factors, in order to examine the utility of gas-free CVR as a potential biomarker in the diagnosis of vascular cognitive impairment and dementia (in Aim 3). Impact: Once these specific aims are accomplished, clinically practical methods of CVR will have been developed that will have important applications for understanding the neurobiology of vascular disease and for the development of biomarkers (in conjunction with other biomarkers) for the diagnosis and treatment monitoring of vascular cognitive impairment and dementia.