# Novel volumetric optical microscopy to unravel cerebral microvascular architecture and the role in functional neuroimaging in human Alzheimer's disease

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $798,774

## Abstract

PROJECT SUMMARY
Alzheimer’s disease (AD) is a neurodegenerative disorder that manifests as progressive loss of memory and the
ability in thinking and action. Despite thirty years accumulation of our knowledge on the pathological
mechanisms, over 400 clinical trials of drugs targeting the pathological pathways have largely failed to reduce
cognitive decline. Recent evidences from epidemiological, neuroimaging, and clinical reports have suggested
that vascular contributions are critical in the pathogenesis of AD. A reduction of cerebral blood flow (CBF) has
been recognized in preclinical AD population, many years before the onset of symptoms and the observed
structural atrophy in the brain. In parallel, vascular pathophysiology is associated with a lower threshold of AD
pathology in cognitive decline and dementia. The characteristic of preceding vascular alterations may offer a
new opportunity in early-stage AD diagnosis and therapeutical assessment. However, current in vivo
neuroimaging tools such as magnetic resonance imaging (MRI) and functional MRI (fMRI) exclusively focus on
large vessels, due to their limited resolution and sensitivity, while leaving the microvascular territories largely
unexplored. Our biophysical simulation work and other studies have indicated that capillaries, small arterioles
and venules could contribute more than 50% of fMRI signals and alterations of microvascular architecture lead
to profound functional changes in the human brain. Despite its intriguing insight on neurodegenerative diseases,
those models were either based on oversimplified vascular geometry or anatomical networks derived from
~1mm3 of mouse cerebral cortex, which often failed to predict the complex architecture and hemodynamics in
the human brain. The goal of the study is to establish a multiscale optical imaging technique to unravel the
microvascular architecture network in the human brain from single capillary level to tens of cubic centimeters of
tissue blocks. Pivoting on a serial sectioning optical coherence tomography combined with a two-photon
microscopy, the multiscale imaging technique leverages a high-throughput and thorough study of vasculature
pathophysiology in AD progression. The study will reconstruct volumetric architectural networks in human brain
tissues at different stages of AD, seek for important features to characterize vascular pathological alterations,
and correlate with quantitative neuropathological assessment to understand the converging path of AD pathology
during disease progression. With the foundation of imaging-based microvascular networks in the human brain,
the study will further build a computational model to investigate the cerebral blood flow, oxygenation, and fMRI
signals during AD progression. This computational framework has been validated using the microvascular
anatomy and dynamics from small animal models, and here we extend it for the first time to the human cortex.
Completion of this project will significan...

## Key facts

- **NIH application ID:** 10520935
- **Project number:** 1R01NS128843-01
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Hui Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $798,774
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520935

## Citation

> US National Institutes of Health, RePORTER application 10520935, Novel volumetric optical microscopy to unravel cerebral microvascular architecture and the role in functional neuroimaging in human Alzheimer's disease (1R01NS128843-01). Retrieved via AI Analytics 2026-05-30 from https://api.ai-analytics.org/grant/nih/10520935. Licensed CC0.

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