# Aging and Exercise Effects of Dural Lymphatic Clearance in Healthy Human and Diabetic Brains

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $2,247,456

## Abstract

One in 10 Americans age 65 and older (10%) has Alzheimer’s disease (AD). Among type-2 diabetes mellitus
(DM) patients, nearly 70% develop AD with aging. Numerous studies support the association between DM and
AD. AD is a slowly progressive, irreversible neurodegenerative disease with a long preclinical phase lasting up
to 20 years; the prevalence of AD in DM increases in later years. DM is a known risk factor for vascular disease
and is associated with diffuse sclerosis in microvasculature. The relationship between these two diseases and
the mechanisms that link them together are not fully understood, but slower glymphatic clearance in DM patients
is expected to play a significant role. The concept of glymphatics in the brain was pioneered by Negergaard, who
identified 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 paravascular space. Studies supporting
its importance continue to be expanded upon and validated in ongoing research, primarily in rodents. Sleep and
physical activity have been reported to accelerate glymphatic clearance. During sleep, a nearly 60% increase in
clearance of rat brain wastes has been observed, caused by expansion and contraction of the extracellular space.
Additional studies have shown that glymphatic clearance decreases with increasing age but can be increased
transiently in aged mice by voluntary wheel running exercises. More recently, in humans, use of a gadolinium-
based contrast agent (GBCA) via intrathecal injection allows for observation of glymphatic clearance as a tracer,
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. Physical exercise has been reported to improve
clearance of brain Aβ in rats. Recent small animal studies show GBCA clearance in the interstitial space slowed
by a factor of three in the hippocampus of DM rats. DM rats also showed decline in cognitive function compared
to non-DM rats. Although these studies suggest that reduced glymphatic clearance is important for cognitive
decline in DM rats, interpretation is limited by possible underlying changes between DM and non-DM rats, and
effects of GBCA on CSF clearance. Using a novel, non-invasive, non-contrast MRI techniques we propose to
study dural lymphatic clearance in DM and non-DM human brains, physical activity-induced clearance in
parasagittal dura (PSD) and arachnoid granulations (AGs) fluid at meninges in humans. Our challenges include
identification of PSD and AGs and measurement of subtle changes in dural lymphatic fluid clearance at meninges.
To overcome these challenges, we will develop MR techniques to clarify i) the anatomy of PSD, AG, and superior
sagittal sinus, ii) identify the detailed clearance pathway of dural lymphatic fluid; iii) obtain dural lymphatic fluid
perfusion measures...

## Key facts

- **NIH application ID:** 10420651
- **Project number:** 1RF1AG076692-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Mitsue Miyazaki
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $2,247,456
- **Award type:** 1
- **Project period:** 2022-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10420651

## Citation

> US National Institutes of Health, RePORTER application 10420651, Aging and Exercise Effects of Dural Lymphatic Clearance in Healthy Human and Diabetic Brains (1RF1AG076692-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10420651. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*