Blinded Comparison of Different Alpha-Synuclein Seeding Assays as Cutaneous Biomarkers of Lewy Body Dementias

Abstract
With increasing longevity in our population, dementia is widely recognized as an impending public health crisis.
Lewy body dementia (LBD), encompassing dementia with Lewy bodies (DLB) and Parkinson disease dementia
(PDD), is the second most common cause. LBD is characterized by abnormal aggregation and accumulation of
a protein, α-synuclein (aSyn). PDD and DLB are clinically separated only by the relative timing of the onset of
parkinsonism and dementia. At present, advances in the treatment of these conditions are critically hampered
by the lack of non-invasive, inexpensive biomarkers that can provide accurate diagnostic and prognostic
information. This situation may soon be resolved, as in recent years it has become apparent, through our own
studies and those of others, that biopsies of peripheral tissue sites can detect diagnostically significant aSyn.
Our project will assess aSyn in punch biopsies of the skin. Our preliminary data from new “seeding assay”
methods including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification
(PMCA), from autopsy-confirmed LBD subjects, indicate high sensitivity and specificity for predicting the
presence of aSyn in the skin of affected subjects. Further work is necessary to confirm these results in living
subjects with these conditions, which is the objective of this proposed project. We will biopsy, twice during a
four year period, 90 subjects with aSyn disease, 30 each with PD, PDD and DLB, as well as 30 normal control
subjects. Two independent laboratories will blindly perform separately-developed seeding assays, rigorously
testing the interlaboratory reliability and providing estimates of aSyn density change over time. The seeding
assay results will be compared with those obtained by the current gold-standard biopsy method,
immunohistochemistry (IHC). All subjects will receive cognitive and movement disorder assessments at two
timepoints in this four year project, enabling comparisons of assay measures with cognitive and motor decline
rates. Many of the subjects will be enrolled in the Arizona Study of Aging and Neurodegenerative Disorders
(AZSAND), a longitudinal clinicopathological study with an autopsy rate exceeding 90%. This will allow, in a
substantial subset, eventual neuropathological confirmation of the molecular cause of parkinsonism and
dementia in each subject.

Grant Number: 5R01NS118669-04
NIH Institute/Center: NIH
Principal Investigator: THOMAS BEACH