# Lewy Body Dementia Biomarkers

> **NIH NIH U01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $768,184

## Abstract

Cognitive impairment and dementia are common and disabling problems in patients with neurodegenerations
characterized by intraneuronal α-synuclein (α-Syn) aggregates. These patients are classified clinically as either Parkinson
disease with dementia (PDD) or as dementia with Lewy bodies (DLB). This labeling distinction is based on the order of
presentation of parkinsonism versus dementia – in PDD, the movement disorder occurs first, while in DLB, the cognitive
impairment occurs first or within 1-year of parkinsonism onset. PDD and DLB exhibit virtually identical pathological
findings at autopsy. Abnormalities found include pathological depositions of α-Syn, Aβ-amyloid, and tau proteins, the
latter as intraneuronal paired helical filaments or “neurofibrillary tangles” (NFT). In individual brains, α-Syn alone may
be present in cell bodies (Lewy bodies) or in synaptic terminals (Lewy neurites). In other brains, α-Syn deposits are
present together with Aβ-amyloid plaques. In still other brains, α-Syn, Aβ-amyloid and tau NFT pathologies are all
present, often diagnosed neuropathologically as Alzheimer disease (AD) with PD. The neuropathologic findings do not,
however, correlate substantially with subject clinical classification as PDD versus DLB.
The future development of effective therapy for dementia in α-synucleinopathy will likely require targeting of the
pathologic pathways involved, and this in turn, necessitates ability to determine the type(s) of pathology present in
individual patients and assessment of which pathologies most strongly drive progression of cognitive impairments. To be
effective in disease modification, therapies will require testing and application in patients with only mild symptoms. In
the present proposal, we will determine endophenotypes of mild dementia in patients with α-synucleinopathy, employing
multi-tracer molecular brain imaging with positron emission tomography (PET). We will determine the presence of α-
Syn neuropathology on the basis of [11C]dihydroteterabenazine (DTBZ) PET imaging of nigrostriatal projection integrity.
We will identify the presence of Aβ-amyloid plaque deposition with [11C]Pittsburgh compound-B (PiB) PET imaging, and
the presence of tau NFT pathology with [18F]AV1451 (formerly designated T807) PET imaging. Together, these imaging
results will permit classification of each subject as: “pure” synucleinopathy, or synucleinopathy with Aβ-amyloid, or as
synucleinopathy with both Aβ-amyloid and tau. We will test the hypothesis that the progression of cognitive decline will
be more rapid in the synucleinopathy with both Aβ-amyloid and tau endophenotype, and that the progression of cognitive
impairment in subjects with this endophenotype will correlate with the progression of NFT pathology as determined in
follow-up [18F]AV1451-PET.
The development of reliable trait biomarkers of neurodegenerative pathologies in PDD and DLB will enable progress in
the development and assessment of new therapeutic interv...

## Key facts

- **NIH application ID:** 9838296
- **Project number:** 5U01NS100611-04
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** KIRK A. FREY
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $768,184
- **Award type:** 5
- **Project period:** 2016-09-25 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838296

## Citation

> US National Institutes of Health, RePORTER application 9838296, Lewy Body Dementia Biomarkers (5U01NS100611-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838296. Licensed CC0.

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