Normalized cerebrovascular reactivity MRI in small-vessel-disease (SVD) related cognitive impairment

About This Grant

Project Summary/Abstract Small-vessel-disease related vascular contributions to cognitive impairment (VCI) represents a major cause of cognitive dysfunction in older individuals, as up to 80% of patients with Alzheimer’s Disease have vascular pathology. Therefore, there is a real urgency to characterize vascular pathology using biomarkers. Cerebrovascular reactivity (CVR), an index of cerebral vessel’s capacity to dilate in response to vasostimulation such as CO2 inhalation, is a highly promising biomarker in VCI. The PI is a leading expert in CVR mapping and is participating in the MarkVCID study in which CVR is one of the candidate biomarkers for VCI that are undergoing a longitudinal study in 16 sites across the U.S. However, current CVR technique is susceptible to physiological confounding factors, as the BOLD signal that is widely used as a readout of the vascular responses is known to be complex and is confounded by factors such as vessel density (more veins, more BOLD signal), imaging parameters, and hematocrit levels. The central goal of the proposed project is therefore to develop a normalized CVR mapping approach using both hypercapnia and hyperoxia challenges. Based on a rigorous theoretical model, this new technique utilizes the BOLD-reactivity of O2 to normalize the BOLD-reactivity to CO2, which eliminates the dependence of CVR on basal physiological parameters mentioned above. The proposed nCVR will have a direct relationship to cerebral blood flow (CBF), unlike the traditional BOLD-CVR. We will achieve our central goal through three Aims. Aim 1 will focus on the development of the nCVR technique and benchmark its test-retest reproducibility and sensitivity to CVR alterations. We hypothesize that the nCVR technique is superior to the existing BOLD-CVR technique in detecting a CVR reduction. Aim 2 will validate the nCVR technique with massively averaged ASL-CBF-CVR as a gold-standard. We hypothesize that the nCVR and ASL-CBF CVR maps will show highly congruent spatial features, both of which will reveal a homogeneous CVR between tissue and vessel regions, significantly enhancing the utility of CVR as a biomarker in detecting abnormalities. Finally, we will demonstrate the feasibility and diagnostic sensitivity of nCVR in vascular cognitive impairment (VCI) by applying the nCVR technique in three groups of participants, specifically Mild Cognitive Impairment (MCI) patients with high vascular risks, MCI patients with no or low vascular risks, and cognitively normal controls. We will also compare its diagnostic sensitivity to the existing BOLD-CVR method. Impact: Once these specific aims are accomplished, a new clinically practical method of CVR will have been developed, which represents a major technical innovation in CVR mapping and will significantly enhance the sensitivity of CVR as a biomarker for the diagnosis and treatment monitoring of VCI.