Peripheral Tissue Biomarker for Premortem Diagnosis of Lewy Body Dementia

Abstract
The overall goal of our project is to validate a diagnostic tool for dementia with Lewy bodies (DLB), and
Parkinson’s disease dementia (PDD), two common neurodegenerative diseases affecting 1.4 million people in
the U.S. Currently, definitive diagnosis of DLB and PDD often requires the postmortem detection of disease-
associated alpha-synuclein (αSynD) aggregates in the brain. Clinically, DLB and PDD can be easily
misdiagnosed with other dementias and parkinsonisms such as Alzheimer’s disease (AD) and tauopathies. An
unmet medical need is to identify biomarkers for early and differential diagnosis of DLB and PDD in more easily
accessible tissues. We have taken advantage of the emerging technology known as the real-time quaking
induced conversion (RT-QuIC) assay to develop a robust platform for ultrasensitive detection of αSynD in
peripheral tissues. In preliminary studies, we are able to detect prion-like seeding activity of αSynD in the skin of
DLB and PD patients with 100% specificity and sensitivity. In addition, we were remarkably successful in
detecting αSynD seeding activity in multiple peripheral tissues including skin, sigmoid colon, and submandibular
glands in autopsied specimens. We hypothesize that RT-QuIC of peripheral αSynD is a highly sensitive and
robust diagnostic biomarker for premortem diagnoses of DLB and PDD. To test this hypothesis, we propose
to pursue the following four Aims: (1) Establish peripheral αSynD as a biomarker for postmortem diagnosis of
DLB and PDD using RT-QuIC assay; (2) Assess skin αSynD as a biomarker for premortem diagnosis of DLB and
PDD; (3) Determine peripheral αSynD and tau as a biomarker for differentiating DLB and PDD from other
dementias and parkinsonisms such as AD and tauopathies; (4) Explore gut αSynD as a biomarker for premortem
diagnosis of DLB and PDD using colon biopsy. Successful implementation of this proposal will establish RT-
QuIC assay utilization for early diagnosis of DLB and PDD using readily available peripheral specimens.

Grant Number: 5R01NS118760-06
NIH Institute/Center: NIH
Principal Investigator: SHU CHEN