# Free water imaging in PD

> **NIH NIH R21** · STANFORD UNIVERSITY · 2023 · $501,220

## Abstract

PROJECT SUMMARY/ABSTRACT
Dysfunction in protein clearance mechanisms is thought to underlie many neurodegenerative disorders, and
specifically those with multi-etiology cognitive impairment and dementia. Abnormal protein accumulation of α-
synuclein with aggregates in the form of Lewy bodies (LB) are found in Parkinson’s disease (PD) and β-amyloid
(Aβ) and tau protein accumulations in Alzheimer’s disease (AD). However, multi-etiology dementia with mixed
LB/AD pathology has been observed at autopsy in up to 80% of patients with Lewy Body Dementias, which
includes PD Dementia (PDD) and the closely related Dementia with Lewy Bodies (DLB). For patients who first
present with motor symptoms, Aβ and tau aggregation likely occurs somewhere between motor symptom onset
and dementia. Understanding mechanisms of proteins clearance from brain tissue is critical to developing
interventions prior to dementia onset, but these mechanisms remain controversial. Animal studies show evidence
for several brain waste clearance pathways removing Aβ and tau from extracellular spaces in the brain, and for
sleep playing a key role, during which an expansion of extracellular spaces appears to facilitate protein
clearance. There are limited means of non-invasively evaluating the brain waste clearance system in vivo in
human brains. We propose use of diffusion magnetic resonance imaging (dMRI) of free water (FW) and intra
voxel incoherent motion (IVIM) that will be acquired during simultaneous PET-MR imaging, to identify the
association of brain FW fraction (f) and flow measures with the accumulation of Aβ and tau proteins in patients
across the Lewy Body Disease spectrum (PD/PDD/DLB). This high-risk R21 proposal requests funding for dMRI
FW/IVIM sequence application and analysis of FW f and flow. These data will be integrated with the Aβ and tau
PET, cognitive data, and sleep biomarkers, which are collected through the Stanford Alzheimer’s disease
Research Center (ADRC). Leveraging the deeply phenotyped PD and DLB patient data with pure LB pathology
and with mixed LB/AD pathology, through the Stanford ADRC, we propose two Specific Aims:
 1. Determine associations of FW f and flow (dMRI) with Aβ and tau co-pathology (PET), and cognitive
 function, in PD and DLB
 2. Determine associations of FW fraction and flow with sleep disturbance in PD and DLB.
This proposal addresses a critical gap in understanding the role of FW diffusion within the context of Aβ and tau
protein accumulation, disrupted sleep-wake behavior, and cognitive decline across the Lewy Body Disease
spectrum.

## Key facts

- **NIH application ID:** 10647539
- **Project number:** 1R21NS132101-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Kathleen Lombard Poston
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $501,220
- **Award type:** 1
- **Project period:** 2023-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10647539

## Citation

> US National Institutes of Health, RePORTER application 10647539, Free water imaging in PD (1R21NS132101-01). Retrieved via AI Analytics 2026-08-11 from https://api.ai-analytics.org/grant/nih/10647539. Licensed CC0.

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