# Vascular contribution to white matter lesions and motor dysfunction in AD and ADRD

> **NIH NIH RF1** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2022 · $1,983,762

## Abstract

Most Alzheimer’s Disease (AD) patients experience severe motor impairment at the later stage of disease and
10 - 40% of AD patients exhibit signs of motor dysfunction at even earlier stages of AD. Furthermore, changes
in motor function often precede other symptoms of AD as well as correlate with increased severity and
mortality. Despite the frequent occurrence of motor dysfunction in AD patients, little is known about the
mechanisms by which this behavior is altered. In several other neurological diseases, such as stroke and
vascular parkinsonism (VP), cerebrovascular lesions underlie motor dysfunction during the progression of
these diseases, especially in the basal ganglia. In addition, white matter lesions (WMLs), which are primarily
considered a small vessel disease and characterized as focal abnormal myelination, are highly correlated with
motor deficits in VP. Moreover, WMLs are strongly associated with the clinical risk of AD and may accelerate
the clinical manifestation of the disease. Familial Danish Dementia (FDD) is another AD-like familial
neurodegenerative disease associated with motor dysfunction, WML, and vascular impairment. However, it is
unclear which pathogenic mechanisms produce vascular impairment, WML, motor dysfunction in AD and FDD.
Since several clinical studies suggest a strong connection between vascular deficits in basal ganglia and motor
dysfunction in several neurological diseases, we investigated these pathologic correlations in AD mouse
model. We found a significant increase in fibrin deposits, demyelination, and axonal degeneration as well as a
decrease in blood vessel density in the striatum of the aged AD mice which exhibited motor deficits.
Furthermore, we found the depletion or destabilization of fibrin in AD mice improved their motor performance.
Based on these findings, we hypothesize that fibrin deposits and vascular degeneration lead to Blood Brain
Barrier (BBB) damage, aggravate inflammation and demyelination, as well as cause axonal degeneration,
finally leading to motor dysfunction in AD and FDD.
In this proposal we will analyze postmortem brain tissues of AD patients who clinically exhibited motor deficits
in the early disease state and investigate the pathogenic mechanism of motor dysfunction in rodent models of
AD and FDD using biochemical, histological, and genetic methods (expertise by MPI Ahn). We will also
investigate how striatal fibrin deposits cause demyelination and motor dysfunction in AD by induction of
resistant fibrin clots or depleting the coagulation factor FXIII. Furthermore, we will employ advanced Magnetic
Resonance Imaging (MRI) techniques in a mouse model of AD, FXIII deficient AD mice and a knock-in rat
model of FDD (expertise by MPI Dyke). Our techniques will interrogate the permeability of the BBB and assess
cerebral blood flow, and WMLs seen in white matter hyperintensities as well as demyelination. Our long-term
objective is to translate our findings in this proposal for the d...

## Key facts

- **NIH application ID:** 10501969
- **Project number:** 1RF1AG078245-01
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Hyung Jin Ahn
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,983,762
- **Award type:** 1
- **Project period:** 2022-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10501969

## Citation

> US National Institutes of Health, RePORTER application 10501969, Vascular contribution to white matter lesions and motor dysfunction in AD and ADRD (1RF1AG078245-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10501969. Licensed CC0.

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