# Intrinsic CSF outflow metrics for mild cognitive impairment and Alzheimer's disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $763,810

## Abstract

One in 10 Americans aged 65 and older (10%) has Alzheimer’s disease (AD), with prevalence increasing with
age. AD is a slowly progressive, irreversible neurodegenerative disease with a long preclinical phase. The
pathophysiology of AD is not fully understood but is likely to be multifactorial. One postulated contributor is
impaired glymphatic clearance. The glymphatic system is conceptualized as a system by which soluble proteins
and metabolites are eliminated from the central nervous system via cerebrospinal fluid (CSF) and interstitial fluid
(ISF) exchange in the perivascular space (PVS). In rodent models, sleep and physical activity have been reported
to accelerate glymphatic clearance using invasive methods. During sleep, a nearly 60% increase in clearance of
brain waste was observed in rats, caused by expansion and contraction of the extracellular space. Glymphatic
clearance was transiently increased in aged mice by physical activity, and physical activity has been reported to
improve clearance of brain Aβ in rats. Although animal studies suggest that reduced glymphatic clearance is
important for cognitive function in aging, translation of findings from rodents to humans is limited because rodent
models do not fully capture the human experience. In humans, use of a gadolinium-based contrast agent (GBCA)
via intrathecal injection allows for observation of glymphatic clearance, albeit over a long period. However, this
method is limited by its invasiveness, and by the unknown effect of the GBCA tracer on the in vivo time-course
of glymphatic clearance. Using a novel, noninvasive, non-contrast 3D MRI technique, we have shown intrinsic
glymphatic clearance or CSF outflow metrics decreases with age using a single-tagged method. The intrinsic
CSF metrics decrease drastically over 60 years old. Thus, we will develop an advanced double-tagged method
from both brain hemispheres. Using the double-tagged method, we propose to study healthy older adults, mild
cognitive impairment (MCI), and AD patients on intrinsic CSF outflow metrics by segmenting various regions of
interest (ROI) such as upper, middle, and lower parasagittal dura (PSD), superior sagittal sinus (SSS), and entire
SSS region. Because CSF outflow is influenced by physical activity, we will monitor their activity level using
actigraphy. Our challenges include segmentation of these small ROIs, and measurement of subtle changes in
CSF outflow metrics in each ROI. To overcome these challenges, our aims of the project are i) identify the
detailed CSF outflow egress pathways; ii) obtain quantitative measures at each ROI from both sides of brain
hemispheres; iii) compare quantitative measures of intrinsic CSF outflow in MCI and AD patients to age-, and
sex-matched cognitively healthy adults; iv) investigate any preference of intrinsic CSF outflow metrics from the
right- and left-brain hemispheres; and compare with their physical activity level. We expect that intrinsic CSF
outflow will decrease w...

## Key facts

- **NIH application ID:** 10884098
- **Project number:** 1R01AG087407-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Mitsue Miyazaki
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $763,810
- **Award type:** 1
- **Project period:** 2024-05-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10884098

## Citation

> US National Institutes of Health, RePORTER application 10884098, Intrinsic CSF outflow metrics for mild cognitive impairment and Alzheimer's disease (1R01AG087407-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10884098. Licensed CC0.

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