# Synucleinopathies – Novel Targets in Early Diagnosis, Pathophysiology, and Therapeutic Approach

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2022 · $765,405

## Abstract

PROJECT SUMMARY/ABSTRACT
Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) comprise a
group of neurodegenerative diseases that share the pathophysiological mechanism of abnormal aggregation of
alpha-synuclein (αSyn). Promising attempts at disease modification in established synucleinopathies have
failed, raising the important issue that patients who have clinically overt, established disease are too advanced
for disease-modifying therapies to be efficacious. Therefore, strategies have evolved to allow for earlier
disease detection and confirmation which was pursued in our current grant period with focus on pure
autonomic failure (PAF). PAF has more recently been established as one of the synucleinopathies, and is
characterized by isolated autonomic failure without motor or cognitive deficits, representing a pre-motor stage
with high risk of conversion to MSA, PD, or DLB. The main goal of the current grant period was to identify and
validate spinal fluid (CSF) and MRI biomarkers of conversion of PAF to motor synucleinopathies. We have
accomplished that goal by identifying highly predictive mechanism-based CSF and MRI markers in established
synucleinopathies, that when applied to the pre-motor stage can predict conversion and conversion phenotype.
REM sleep behavior disorder (RBD) is a condition with close association with synucleinopathies and frequently
presents as isolated RBD (iRBD) years before motor or cognitive symptoms develop. The relevance and
implications of iRBD as prodromal synucleinopathy has been well recognized, but to date there are no reliable
predictors of conversion, phenotype of conversion, or timing of conversion to an established synucleinopathy.
We have expanded the biomarkers developed to predict PAF phenoconversion to iRBD patients and identified
discrete CSF profiles akin to those seen in PAF and in manifest motor and cognitive synucleinopathies, so that
we are now in a position to test the biomarker potential of these markers at the prodromal stage.
In this renewal, we shall study sleep-study confirmed iRBD patients stratified by baseline CSF biomarker
phenotype (MSA-, PD/DLB, or normal type) along with healthy control subjects with serial clinical evaluations
combined with autonomic, CSF, and MRI biomarker studies. We will enhance the feasibility of reaching
recruitment goals for each biomarker phenotype by enriching recruitment with participants in the North
American Prodromal Synucleinopathy Consortium identified as biomarker phenotype required to reach our
recruitment goals. Secondly, we will continue to follow PAF patients enrolled during the current grant period
who have not yet phenoconverted to solidify the predictive value of developed biomarkers.
The findings from this renewal proposal should result in establishing biomarkers for the pre-motor and
prodromal stages of syncucleinopathies, which may translate to disease-modifying therapy trials standing a
better chance at...

## Key facts

- **NIH application ID:** 10447698
- **Project number:** 5R01NS092625-07
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Wolfgang Singer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $765,405
- **Award type:** 5
- **Project period:** 2015-08-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10447698

## Citation

> US National Institutes of Health, RePORTER application 10447698, Synucleinopathies – Novel Targets in Early Diagnosis, Pathophysiology, and Therapeutic Approach (5R01NS092625-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10447698. Licensed CC0.

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