Validation of a Novel Magnetic Resonance Imaging (MRI) Technology for both Diagnostic Screening and Quantification of Brain Vascular Physiology in Alzheimer's-Disease-Related Dementias

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PROJECT SUMMARY Alzheimer’s disease (AD), a degenerative brain disorder, is responsible for 60-70% of all dementia. Currently no reliable biomarkers exist for precision-medicine-level, single-patient diagnostics for the early detection of Alzheimer’s disease and related dementias (AD/ADRD). Imaginostics proposes to clinically valdiate novel magnetic resonance imaging (MRI)-based proprietary biomarkers for the early detection of vascular pathology that predisposes individuals to develop dementia in patients with mild cognitive impairment (MCI). Further, we will validate biomarkers for measuring vascular abnormality in Vascular Dementia (VaD), which accounts for 10% of all dementia. Quantitative Ultra-short Time-to-Echo Contrast-Enhanced (QUTE-CE) MRI is unique in that it generates a quantitative signal directly representative of physiological information. The overall objective of Phase I proposal: Obtain clinical validation of the QUTE-CE imaging approach for our panel of biomarkers for measuring microvascular structure, function and leakage. This first validation is targeted at two groups: 1) MCI: for evaluating the prospects of detecting abnormality before dementia onset and 2) VaD: for evaluating the prospect of characterizing vascular related cognitive impairment (VCID) in the most pertinent dementia population. Their ability to detect dementia will be compared to age-matched individuals and also compared to state-of-the art neuroimaging biomarker approaches to more fully evaluate the potential of QUTE- CE MRI. Specific Aim 1: Establish the merit and feasibility of QUTE-CE MRI vascular imaging biomarkers for detecting vascular abnormality in vascular dementia. The study will include (n=24; 12M/12F) Vascular Dementia subjects and (n=24; 12M/12F) age-matched control subjects. Specific Aim 2: Establish the merit and feasibility of QUTE-CE MRI vascular imaging biomarkers for detecting vascular abnormality in Mild Cognitive Impairment (MCI). The study will include (n=24; 12M/12F) MCI subjects and (n=24; 12M/12F) age-matched control subjects. Primary Endpoints (Specific Aims 1 and 2): (1) Structure: Cerebral Blood Volume (QC-CBV) & Small Vessel Density (QC-SVD): (Hypothesis 1) We will test our hypotheses that QUTE-CE MRI can detect small and large vessel abnormality. (2) Function: Cerebrovascular reactivity (QC-CVR) & CBV-based Functional MRI (QC-fMRI): (Hypothesis 2) We will test our hypotheses that QUTE-CE MRI will outperform EPI-fMRI for cerebrovascular reactivity at the group level, and that QC-CVR can be mapped in individuals MCI and VaD for precision medicine. (3) Leakage: Blood-Brain Barrier leakage (QC-BBB): (Hypothesis 3) We will test our hypotheses that QUTE- CE MRI will outperform DCE-MRI for detecting BBB leakage at the group level, and that BBB leakage can be mapped in individuals MCI and VaD for precision medicine. Further, we will test our hypothesis (Hypothesis 4) that a multivariate model (CBV, CVR, BBB permeability) of neurovascular unit dysfunction will provide diagnostic maps indicating abnormality and correlate to cognitive decline better than any individual imaging measures due to their complementary nature in assessment vascular related neuropathology. In addition, fluid-attenuated inversion recovery (FLAIR), susceptibility-weighted imaging (SWI) and diffusion- weighted imaging (DWI) scans will be acquired to identify white matter hyperintensities (WMHs), cerebral microbleeds (CMBs) and ischemic lesions to quantify the focal burden of microvascular changes from CBV maps. Quantitative performance milestones will be comparative whole-brain biomarker analytics and the analysis of focal burden as identified in FLAIR, SWI and DWI using CBV for identifying the spatial-extent-of-burden, intra- subject left-right brain comparison, and volume-of-interest comparison to the healthy controls. We will also perform cognitive testing on all patients to evaluate the correlation to vascular pathology - as measured with QUTE-CE MRI vascular biomarkers - to clinical measures. We can measure vascular abnormality and metabolic dysfunction throughout the whole brain, so we should have a gamut of tests that can evaluate all cognitive domains: memory, language, attention, executive function, visuospatial skills.