# Project I: Alpha Synucleinopathy in the Human Brain Connectome

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $634,597

## Abstract

PROJECT I: ABSTRACT
The overall objective of this project is to develop predictive models of alpha-synuclein (aSyn) propagation in the
human brain in Lewy body dementia (LBD) patients to define biologically meaningful subgroups of LBD and
guide the development of prognostic biomarkers to track the propagation of aSyn. There are shared clinical and
biological underpinnings within the spectrum of Parkinson’s disease (PD), PD with dementia (PDD), and
Dementia with Lewy bodies (DLB), collectively referred to as LBD due to the shared pathological substrate of
underlying alpha-synuclein aSyn inclusions in the central nervous system. Our previous histopathological and
autopsy-confirmed biomarker work finds that Alzheimer’s disease (AD) tau co-pathology associates with more
rapid decline and specific features of language and memory dysfunction in LBD. Thus, biological classification
of LBD based on the presence or absence of AD tau co-pathology (i.e. LBD+AD vs LBD-AD) is more clinically
informative than classic LBD phenotypes (i.e. PDD vs DLB) alone. While aSyn pathology propagation within the
nervous system is an important driver of neurodegeneration, there is limited data on specific cellular
vulnerabilities to aSyn in the human brain and how these relate to heterogenous cognitive symptoms of dementia
in LBD. Network science is a powerful approach to study relationships between the complex hierarchical
structure of the human brain and cognitive symptoms, but thus far, has largely been limited to study of in vivo
imaging of relatively small groups of PD or DLB patients without autopsy or biomarker confirmation needed to
account for AD co-pathology and to study cellular aSyn pathologic contributions to network breakdown on the
macroscopic level. Here, we propose two specific aims to uniquely apply network science to our large autopsy
cohort using graph theoretical analyses to analyze gold-standard digital histopathology metrics postmortem and
integrate these cellular models on the microscopic and mesoscopic levels with antemortem autopsy/biomarker-
confirmed in vivo MRI data to comprehensively examine the cellular substrates of neurocognitive degeneration
and cognitive impairment in LBD. This project integrates seamlessly into the overall aims and objectives of this
program project grant by providing critical human clinical and pathological data to guide future imaging
biomarkers sensitive to tracking aSyn and tau propagation and identify neuronal populations selectively
vulnerable to aSyn and tau. Moreover, this project informs the mechanistic work in Projects II-IV, while insights
gained from Projects II-IV enhance the study of human brain tissue and in vivo MRI and clinical data here.

## Key facts

- **NIH application ID:** 10935309
- **Project number:** 1P01AG084497-01A1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** David John Irwin
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $634,597
- **Award type:** 1
- **Project period:** 2024-09-15 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935309

## Citation

> US National Institutes of Health, RePORTER application 10935309, Project I: Alpha Synucleinopathy in the Human Brain Connectome (1P01AG084497-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10935309. Licensed CC0.

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