# Project IV "Tackling Heterogeneity of Cognitive Trajectory in LBD"

> **NIH NIH U19** · UNIVERSITY OF PENNSYLVANIA · 2020 · $518,460

## Abstract

PROJECT SUMMARY/ABSTRACT
Project IV: Tackling Heterogeneity of Cognitive Trajectory in Lewy Body Disorders
Project IV Leader: Alice Chen-Plotkin; Co-Leaders: Daniel Weintraub, Rizwan Akhtar
While patients with Lewy body disorders (LBD) share the core feature of deposition of misfolded alpha-synuclein
(aSyn) into neuropathological inclusions, they exhibit pronounced heterogeneity in both initial clinical
phenomenology, as well as in trajectory of outcome. Specifically, among human patients with aSyn inclusions in
neurons (or neuronal synucleinopathy), some manifest predominantly with cognitive symptoms and dementia
from disease onset – resulting in a clinical diagnosis of Dementia with Lewy bodies (DLB). Others manifest
predominantly with motor symptoms – resulting in a clinical diagnosis of Parkinson’s Disease (PD). Among PD
patients, some subsequently develop significant cognitive decline and eventual dementia (Parkinson’s Disease
with Dementia, or PDD), while others do not. The reasons for these differences in phenomenology among
synucleinopathy patients are not well understood. Project IV, like Projects I, II, and III, investigates the role of
aSyn in the Alzheimer’s Disease related dementias (ADRD), in the context of living patients who manifest with
DLB vs. PD vs. PDD vs. AD. This project aims to define endophenotypes within the LBD vs. AD spectrum
using objectively-measured biomarker characteristics. We use both unbiased screening approaches and
hypothesis-driven approaches to develop genetic and biochemical biomarkers in three Aims:
Specific Aim 1: Develop biochemical biomarkers of differential PD cognitive progression. Through
unbiased screening of >1000 plasma proteins in >300 PD patients from multiple cohorts, we have derived a
candidate list of 10 plasma proteins whose baseline levels associate with subsequent cognitive decline. We will
validate these markers in >1000 additional PD subjects, developing multi-protein classifier panels for accurate
prediction of cognitive trajectory. We will characterize these proteins in comparator groups of DLB and AD
patients, as well as neurologically normal controls.
Specific Aim 2: Investigate causal influences on cognitive trajectory among LBD patients using
Mendelian randomization. We will use Mendelian randomization (MR) to test the hypotheses that candidate
biochemical biomarkers and AD-related disease processes influence cognitive trajectory in LBD. To do this, we
will use as instrumental variables for MR single nucleotide polymorphisms (SNPs) nominated from (1) their
relationships with protein levels of candidate biochemical biomarkers or (2) their genomewide association with
AD risk. These SNPs may then be developed as genetic biomarkers predicting cognitive trajectory in LBD.
Specific Aim 3: Define the clinical correlates of different strains of aSyn. We will use enzyme-linked
immunosorbent assays (ELISAs) developed with antibodies raised to different conformations of aSyn – “strains”
as de...

## Key facts

- **NIH application ID:** 10020338
- **Project number:** 5U19AG062418-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** ALICE S CHEN-PLOTKIN
- **Activity code:** U19 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $518,460
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020338

## Citation

> US National Institutes of Health, RePORTER application 10020338, Project IV "Tackling Heterogeneity of Cognitive Trajectory in LBD" (5U19AG062418-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020338. Licensed CC0.

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