# Project III "Cognitive Difficulty in LB and AD Dementias"

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2022 · $954,391

## Abstract

Abstract
The presence of α-synuclein (aSyn) pathology defines Lewy Body Disorders (LBD), including Parkinson's
dementia (PDD) and Dementia with Lewy Bodies (DLB). However, LBD has significant clinical heterogeneity,
and current, purely clinical criteria do not identify the mixed pathology found in LBD. We hypothesize two forms
of human aSyn pathology that are biologically meaningful: “pure” aSyn with minimal AD co-pathology (aSyn-
AD), and aSyn modified by AD co-pathology (aSyn+AD). Moreover, these pathologies are related to pathologic
maturity and distinct strains developed in model systems in Projects I/II: One aSyn strain (Strain A) is
associated with less mature pathology and induces only aSyn, and we expect to find this in both aSyn-AD and
aSyn+AD; a second strain (Strain B) is associated with more mature aSyn pathology and induces both aSyn
and less mature tau pathology, and we expect much more Strain B in aSyn+AD than aSyn-AD. We assess
mixed pathologies further using a 2X2 design and compare LBD with AD, where half of clinical AD have “pure”
AD pathology (AD-aSyn) and half have aSyn co-pathology (AD+aSyn) at autopsy. We expect aSyn strains to
be minimal in AD-aSyn, but we expect Strain A in AD+aSyn. Moreover, we expect mature tau pathology in AD.
Aim 1 examines digital histology of the maturity and strain-related pathology in LBD and AD. We use a
validated, parametric histology (DHist) approach to study the anatomy of aSyn, tau and Aβ pathology, relate
these to antemortem clinical features and assess monoclonal antibodies (mAbs) raised against aSyn strains in
Projects I/II. In aSyn+AD, we expect more mature aSyn and less mature tau pathology in frontal and temporal
regions with executive and language deficits, respectively, and less striatal pathology, related to Strain B mAb;
but aSyn-AD will have less aSyn cortical pathology and less impaired cognition, related to less mature aSyn
and mAb to strain A. AD will show more mature tau in a different anatomic locus since the distribution of tau is
guided in part by aSyn Strain B found in aSyn+AD but not AD-aSyn, and less mature aSyn pathology related to
Strain A in AD+aSyn. Aim 2 studies in vivo MRI and cerebrospinal fluid (CSF) markers of strain-related
disease in LBD and AD. Using validated CSF markers of pathology to define cases, we study cross-sectional
and longitudinal cognition and MRI in living patients with likely LBD (aSyn-AD, aSyn+AD) vs. AD (AD-aSyn,
AD+aSyn). In LBD with CSF consistent with aSyn+AD, we expect progressive MRI atrophy in frontal and
temporal regions greater than in striatum, related to declining executive and language function, respectively.
MRI in LBD with CSF consistent with aSyn-AD has less cortical and cognitive decline. Since tau is guided by
the anatomic locus of aSyn induced by Strain B in aSyn+AD, cognitive deficits and MRI atrophy will differ from
AD. Aim 3 studies atrophy in critical medial temporal lobe (MTL) subfields and amygdala in LBD and
AD. Using D...

## Key facts

- **NIH application ID:** 10452564
- **Project number:** 5U19AG062418-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** MURRAY GROSSMAN
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $954,391
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452564

## Citation

> US National Institutes of Health, RePORTER application 10452564, Project III "Cognitive Difficulty in LB and AD Dementias" (5U19AG062418-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10452564. Licensed CC0.

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