# Impaired cerebral metabolism and blood flow by neuronal and astrocytic dysfunctions in Alzheimer's disease

> **NIH NIH R21** · YALE UNIVERSITY · 2024 · $245,040

## Abstract

ABSTRACT
 Alzheimer’s disease (AD) is a major global health crisis, In USA alone 6 million people are diagnosed with
AD, and without any breakthrough this number will be doubled in the next 3 decades. While new treatments
(e.g. Lecanemab) can extend the self-sustaining life to 5-6 months, effective AD treatment still does not exist,
partially because of the lack of comprehensive understanding of the origin and AD development. Cognitive
dysfunction has been linked to altered brain function and structure. Recent brain imaging studies of AD
patients suggest abnormal brain activity and connectivity, hypometabolism, and loss of cerebral autoregulation,
implying sequelae of dysfunctional events occurring within the neurogliovascular unit. The hypometabolism
hypothesis of AD is that decrease in glucose metabolism causes insulin resistance which consequently alters
amyloid precursor protein processing, causes oxidative stress which lead to mitochondrial dysfunction, and
changes the neuronal and glial signal transduction. Technological barriers have limited the possibility of
disentangling when exactly neuronal and/or astrocytic dysfunctional events occur in relation to
hypometabolism, exhausted cerebral autoregulation, and vascular damage. To unravel the sequelae of
neuronal and astrocytic dysfunctions in relation to cerebral metabolism and cerebrovascular health, we
propose a novel fusion of optical-MRI to study AD longitudinally.
 We will conduct multi-modal optical-MRI experiments in mice during AD pathogenesis, specifically with
innovative advances that allow significantly higher sensitivity of Ca2+ imaging and with a newly developed
multi-wavelength optical system to measure reflectometric hemoglobin signals. Conventional fMRI will track
altered functional connectivity and cerebrovascular reactivity, calibrated fMRI will measure flow-metabolism
uncoupling, and 3D time-of-flight (TOF) angiography will map damaged macrovessels. Using the reflectometric
signals to measure blood volume, and 2D fluorescence imaging to map neuronal (red) and astrocytic (green)
activity, and angiography of microvessels (i.e., <40µm) using our green fluorescently tagged magnetic protein
nanoparticles (f-MPNPs) which also enables high sensitivity macrovessel (i.e., >40µm) mapping by MRI.
 Our specific aims are to behaviorally monitor the development of AD to determine the onset of AD, but in
conjunction with mapping deficits of neuronal/astrocytic dysfunction in relation to hypometabolism and reduced
CBF regulation in AD brain, and microlevel to macrolevel impairments of cerebral vasculature in AD brain in a
series of longitudinal experiments. Measures of functional activity and connectivity, cerebrovascular reactivity,
metabolism, and vascular health in AD brain will reveal insights of when and where these dysfunctions occur
and how distributed they are, information which could guide and track targeted treatments of AD patients. In
summary, this is an extremely significant ...

## Key facts

- **NIH application ID:** 10805861
- **Project number:** 1R21AG085366-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Peter Herman
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $245,040
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10805861

## Citation

> US National Institutes of Health, RePORTER application 10805861, Impaired cerebral metabolism and blood flow by neuronal and astrocytic dysfunctions in Alzheimer's disease (1R21AG085366-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10805861. Licensed CC0.

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