Project Summary/Abstract: Small-vessel-related vascular contributions to cognitive impairment and dementia (VCID) represent the second leading cause of cognitive dysfunction in older individuals. However, quantitative biomarkers indexing key vascular processes related to VCID that are suitable for use as endpoints in clinical trials are still lacking. The goals of the present application are to 1) participate in the multi-site clinical validation of up to six biomarkers selected by the NINDS through a longitudinal study of diverse all-comers with cognitive complaints and/or early symptomatic signs of cognitive impairment and dementia potentially associated with small vessel disease; 2) lead the multi-site clinical validation of cerebrovascular reactivity (CVR) biomarker in all-comers, if the CVR biomarker is selected to move onto the next-phase study. The present application is a Renewal of UH2/3 NS100588 under RFA-NS-16-020. As one of the funded participating sites of the above-mentioned RFA, hereafter referred to as MarkVCID I study, our team at JHU has made significant contributions to the Consortium: 1) In the UH2 phase, we developed a CVR MRI candidate biomarker and collected data to support its selection by the NINDS to become one of the eleven biomarkers that transited into the UH3 phase; 2) In the UH2 phase, we worked with other sites to standardize MRI, biofluid, clinical, and neuropsychological measures and implemented candidate biomarkers proposed by other sites locally at our site; 3) In the UH3 phase, we participated in the multi-site instrumental and biological validation of biomarkers approved by the NINDS; 4) In the UH3 phase, we led the multi-site instrumental and biological validation of the CVR candidate biomarker. Importantly, our site has the scientific expertise and equipment that are necessary to perform any of the 11 biomarkers currently under consideration; 5) We participated in all Consortium-wide activities such as annual conferences, committee meetings, and calls. In the present application, we propose four Specific Aims. Aim 1 will enroll 220 participants of diverse all-comers that are typical in clinical settings in the United States during the first two years of the project and collect the NINDS-approved biomarker measures. Aim 2 will conduct longitudinal follow-up in a minimum of 200 participants in the latter three years of the project. Aim 3 will provide inputs and participate in the Consortium-wide activities such as serving on committees, discussing protocols, attending and presenting in the annual conferences, participating in multi-site data processing and validation, and sharing data and biospecimens with researchers within and outside the Consortium. In Aim 4 we will lead multi-site clinical validation of cerebrovascular reactivity (CVR) biomarker if CVR is selected to move on to the next phase. Impact: Upon the completion of this project, we will have developed a set of VCID biomarkers that are ready for future clinical trials, including large phase III trials, of VCID.

Project Narrative Small vessel disease can contribute significantly to cognitive impairment and dementia. This project will conduct multi-site clinical validation of 4 image-based and 2 fluid-based biomarkers, so that they are ready for future clinical trials, including large phase III trials, of vascular cognitive impairment and dementia (VCID).