Alzheimer's disease (AD), a degenerative brain disorder, is responsible for 60-70% of all dementia. Currently noreliable biomarkers exist for precision-medicine-level, single-patient diagnostics for the early detection ofAlzheimer's disease and related dementias (AD/ADRD). Imaginostics proposes to clinically valdiate novelmagnetic resonance imaging (MRI)-based proprietary biomarkers for the early detection of vascular pathologythat predisposes individuals to develop dementia in patients with mild cognitive impairment (MCI). Further, wewill validate biomarkers for measuring vascular abnormality in Vascular Dementia (VaD), which accounts for10% of all dementia. Quantitative Ultra-short Time-to-Echo Contrast-Enhanced (QUTE-CE) MRI is unique in thatit 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 ourpanel of biomarkers for measuring microvascular structure, function and leakage. This first validation is targetedat 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 pertinentdementia population. Their ability to detect dementia will be compared to age-matched individuals and alsocompared 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 fordetecting vascular abnormality in vascular dementia. The study will include (n=24; 12M/12F) VascularDementia 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 fordetecting 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) ofneurovascular unit dysfunction will provide diagnostic maps indicating abnormality and correlate to cognitivedecline better than any individual imaging measures due to their complementary nature in assessment vascularrelated 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), cerebralmicrobleeds (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 offocal 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 alsoperform cognitive testing on all patients to evaluate the correlation to vascular pathology - as measured withQUTE-CE MRI vascular biomarkers - to clinical measures. We can measure vascular abnormality and metabolicdysfunction throughout the whole brain, so we should have a gamut of tests that can evaluate all cognitivedomains: memory, language, attention, executive function, visuospatial skills.
Public Health Relevance Statement: PROJECT NARRATIVE
Currently no reliable biomarkers exist for precision-medicine-level, single-patient diagnostics for early detection
of Alzheimer's disease and related dementias (AD/ADRD). Successful completion of our proposed research will
provide the first clinical validation of breakthrough Quantitative Ultra-short Time-to-Echo Contrast-Enhanced
(QUTE-CE) MRI neurovascular imaging biomarkers for detecting and characterizing the vascular pathologies
that predispose individuals to develop dementia. Our proposed QUTE-CE MRI biomarkers could satisfy the need
for diagnosis and prognosis of AD/ADRD in order provide measurable outcomes for drug development.
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