# Decoupling neural and vascular functional pathology in individuals at risk for Alzheimer's disease- U.S.-Japan Brain Research Cooperative Program (BRCP) Administrative Supplement

> **NIH NIH R21** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $42,000

## Abstract

Abstract of the funded parent award.
Three major principles are at the forefront of current understanding about the pathology and potential therapeutic
approach to addressing the massive public health burden of Alzheimer’s disease (AD). First, the clinical
symptoms and functional dependence resulting from this disease are known to occur after potentially decades
of degenerative brain changes linked to amyloid plaque and neurofibrillary tangle cortical pathologies; second,
prevalent comorbid pathologies, particularly cerebrovascular dysfunction, contribute to a hastening of disease
processes and clinical decline; third, any therapeutic intervention targeting either of these pathologic domains
would need to be implemented at the earliest time possible, prior to evidence of cognitive decline given that
dementia is only apparent after substantial irrecoverable neurodegeneration has transpired. Functional magnetic
resonance imaging (fMRI) is used to measure brain activity and previously contributed extensively to the
characterization of AD progression. Individuals at genetic risk of AD show altered fMRI indicators even prior to
expression of cognitive impairment, and thus, fMRI has provided critical insights into pathophysiology of
preclinical AD. The fMRI signal is an indirect correlate of neural activity based on the phenomenon of ‘functional
hyperemia’ in which metabolic activity in the brain is followed by a nutritive increase in cerebral blood flow and
this hemodynamic response can be measured through the blood oxygenation level dependent (BOLD) contrast
mechanism. A critical barrier in the application of fMRI to the study of AD is the intricate entanglement of neural
and vascular physiology at the basis of the BOLD signal resulting in an inability to differentiate between the
effects of neural dysfunction and comorbid vascular pathology. The goal of this NIH R21 research proposal is to
decouple neurophysiological from vasculo-physiological components of the fMRI BOLD signal and to apply this
new technology to the study of brain pathology, associated with the genetic risk of AD, before any evidence of
cognitive and functional decline. To this end, we will implement a cutting-edge scanning and analysis paradigm
in cognitively healthy older participants at different levels of genetic risk of AD by [1] simultaneous recording of
combinations between fMRI, electro-encephalographic, and magnetoencephalographic data, [2] quantifying
transient intrinsic neurophysiological states of brain networks, and [3] using these states to anchor measurement
of the neurally induced hemo-dynamic response. We emphasize that the R21 mechanism is
exploratory/developmental, and in this spirit, we propose to explore optimal parameters to advance this novel
technology. Successful implementation of this approach would provide novel insight into how genetic
vulnerabilities are linked to distinct neural and vascular dysfunctions, which have been suggested to influence
the plaq...

## Key facts

- **NIH application ID:** 10020696
- **Project number:** 3R21AG060328-02S1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** DAVID H SALAT
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $42,000
- **Award type:** 3
- **Project period:** 2020-02-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020696

## Citation

> US National Institutes of Health, RePORTER application 10020696, Decoupling neural and vascular functional pathology in individuals at risk for Alzheimer's disease- U.S.-Japan Brain Research Cooperative Program (BRCP) Administrative Supplement (3R21AG060328-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020696. Licensed CC0.

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