# Tracing Spread of Pathology Within The HD Brain via Automated Neuroimaging

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $599,917

## Abstract

TRACING SPREAD OF PATHOLOGY WITHIN THE HD BRAIN VIA AUTOMATED NEUROIMAGING
 Huntington's disease (HD) is a progressive fatal neurodegenerative disorder caused by an expanding CAG
repeat in the Huntingtin gene coding for an expanding polyglutamine stretch in the Huntingtin protein.
Neurodegeneration in HD is in large part caused by toxic effects of the abnormal Htt protein, and there is
increasing evidence that mutant Htt can spread, like prions, and like abnormal proteins in other
neurodegenerative diseases, from one neuron to another. Elucidating the sequence and pattern of atrophy in
the HD brain is of special current importance, with “gene silencing” or “RNA-lowering” trials, using antisense
oligonucleotides, or shRNA, or related reagents, in active development. The key to success of these trials will
be to know where and when to intervene, since these reagents do not penetrate the blood-brain-barrier, and
must be injected into the CNS. Our studies will elucidate the temporal and spatial patterns of the spread of HD
neurodegeneration, to elucidate the pathogenesis of HD and to help guide interventional trials. In Specific Aim
1, we will conduct cross sectional and longitudinal analyses of the spatial and temporal pattern of volumetric
change and shape change in subregions of HD compared to control brains, using longitudinal T1 and DTI
scans from HD cases and controls from the PREDICT-HD study and the TRACK-HD study. Scans will
undergo automated processing through MRICloud, segmented into about 400 subregions. We hypothesize
that atrophy will begin in the striatum and spread sequentially to adjacent white matter and then to cortical gray
matter. Alternatively degeneration may be multifocal. In Specific Aim 2 we will determine clinical correlations of
the brain atrophy from Aim 1. In Specific Aim 3 we will use tract-tracing methods to study the spread of
pathology in the HD brain. We hypothesize that the spread of atrophy in the HD brain follows patterns of
axonal connectivity. Alternatively, it is possible that pathology begins and spreads in a multifocal fashion.
Taken together these studies will delineate the longitudinal spread of pathology within the HD brain, and its
clinical consequences. This information will elucidate the pathogenesis of HD and will be critical for designing
the timing and localization of planned interventional trials.

## Key facts

- **NIH application ID:** 9924675
- **Project number:** 5R01NS102670-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** MICHAEL I MILLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $599,917
- **Award type:** 5
- **Project period:** 2018-06-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9924675

## Citation

> US National Institutes of Health, RePORTER application 9924675, Tracing Spread of Pathology Within The HD Brain via Automated Neuroimaging (5R01NS102670-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9924675. Licensed CC0.

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