# Impact of white matter hyperintensities on structural connectivity and cognition

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2020 · $446,355

## Abstract

There is increasing recognition that much of vascular cognitive impairment and dementia (VCID)
is attributable to cerebral small vessel disease (SVD), which typically manifests as white matter
hyperintensities (WMH) on T2-weighted fluid attenuated inversion recovery (FLAIR) magnetic
resonance imaging (MRI). WMH are highly prevalent in older adults, including asymptomatic
individuals, and are also linked to clinical progression in mild cognitive impairment (MCI) and
Alzheimer’s disease (AD). Yet, the mechanisms by which WMH cause cognitive deficits remain
incompletely understood. White matter lesions such as lacunar infarcts classically cause
disconnection syndromes by interrupting communication between the brain regions that they
connect. Connectivity effects of WMH in SVD are more challenging to study because they are
more diffuse than lacunar infarcts and often occur in regions of crossing white matter fiber
tracts. We recently implemented a ‘virtual lesion connectome’ approach to characterize the
evolution of widespread partial disconnection caused by WMH using FLAIR-based WML data
from older subjects as regions of avoidance for fiber tracking on high quality diffusion tensor
imaging (DTI) data acquired in healthy subjects. For this project, we will apply the virtual lesion
approach to MRI and cognitive performance data from the Alzheimer’s Disease Neuroimaging
Initiative (ADNI) to test the hypothesis that the spatial distribution and extent of WM tract
disconnection due to WMH is associated with corresponding cognitive performance deficits. We
will also examine the effects of amyloid status on the relationship between structural
connectivity and cognition. The results of this project will provide the computational
infrastructure to calculate robust individual virtual lesion connectomes, advance knowledge on
the mechanisms by which WMH cause cognitive deficits, provide mechanistically-specific
biomarkers for cognitive decline in VCID, and help dissociate the direct effects of WMH on
cognition in patients with mixed pathologies.

## Key facts

- **NIH application ID:** 10106085
- **Project number:** 1R21AG070434-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JOHN A DETRE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $446,355
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10106085

## Citation

> US National Institutes of Health, RePORTER application 10106085, Impact of white matter hyperintensities on structural connectivity and cognition (1R21AG070434-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10106085. Licensed CC0.

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