SARS-CoV-2 and Precursors of Alzheimer's Disease and Related Dementias: An Ultrahigh Field (7T) MRI Study in a Diverse Multinational Cohort
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SARS-CoV-2 virus displays neurotropism in some infected patients with reports of viral invasion, inflammation, meningoencephalitis, microvascular injury, stroke, delirium and delayed cognitive and psychiatric symptoms. It is unclear if there is any acceleration of neurodegenerative processes and increased risk of Alzheimer’s disease and related dementias (ADRD). Race-, ethnic- minorities and men are known to have a higher risk of dying from COVID and may also have a greater susceptibility to long-term neuropsychiatric sequelae. Ultrahigh field (7T) MRI has increased sensitivity and spatial resolution, compared to 3T MRI and can detect small changes in cortical and white matter structure, integrity and connectivity, inflammation, iron deposition, hippocampal subfields, venular injury and the locus coeruleus. The 7T MRI COVID Consortium is an international collaboration across 5 sites to enroll a diverse, multi-ethnic cohort of 780 persons, aged 55-80. Of these 260 persons will have well-documented SARS-CoV-2 infection (cases) and 260 will be ‘illness’ controls with a clinically similar non-COVID illness (e.g. pneumonia). Cases and controls will include >25% Hispanic and >25% African-Americans. Both groups will be compared to 260 healthy controls with documented normal cognition and no hospitalization in preceding 2 years. Additional data will be drawn from 40 persons with autosomal dominant early-onset AD and 180 population controls, all imaged with the same 7T MRI protocol. All participants will undergo 2 annual 7T MRI scans and 4 detailed exams comprising neurological, cognitive and psychiatric assessments, smell, gait, blood biomarkers of neurodegeneration (p-tau181, NFL, GFAP, amyloid) and systemic inflammation (CRP, IL6, IL10, TNF-alpha, IL1R) and surveillance for incident MCI, ADRD dementia. These exams will occur at the time of each MRI, and at 36, 48 months post-illness. We propose the following specific aims: Aim 1: Detail the range of (Aim 1a) Early (6-12 months) brain pathology in COVID survivors (Aim 1b) assess if early changes improve, persist or worsen at a delayed 7T MRI (12-18 months) and (Aim 1c) Compare findings in COVID survivors to MRI in preclinical EOAD. Aim 2: Compare cross-sectional prevalence of pre-illness ADRD and vascular injury (VCID) and of cognitive, behavioral, mood and functional outcomes across 3 groups. Aim 3: Relate early and delayed 7T MRI measures to subsequent risk of MCI, dementia and cognitive and gait trajectories. Aim 4: Explore if race/ethnic-, sex- differences, blood biomarkers, genetics, or early SARS-CoV-2 ‘treatments’ are effect-modifiers, mediators, or neither, of the associations noted in Aims 1-3. Investigators leading this grant are also members of other larger, less detailed COVID consortia permitting harmonized data analyses. Our study will permit a better biological understanding of mechanisms and modifiers of long-term neurological and psychiatric sequelae of COVID. It could also help illuminate the role of viral infections, inflammation and immune response in ADRD.
