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Cited by 102Parkinson's Disease Mechanisms and TreatmentsNeuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatments

Alpha-synuclein oligomers and neurofilament light chain predict phenoconversion of pure autonomic failure

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Singer, Wolfgang, Schmeichel, Ann M., Shahnawaz, Mohammad, Schmelzer, James D., Sletten, David M., Gehrking, Tonette L., Gehrking, Jade A., Olson, Anita D. +4 more·2021·Annals of Neurology
DOI 10.1002/ana.26089PMC PMC8168720
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Abstract

OBJECTIVE: To explore the role of alpha-synuclein (αSyn) oligomers and neurofilament light chain (NfL) in cerebrospinal fluid (CSF) of patients with pure autonomic failure (PAF) as markers of future phenoconversion to multiple system atrophy (MSA). METHODS: Well-characterized patients with PAF (n = 32) were enrolled between June 2016 and February 2019 at Mayo Clinic Rochester and followed prospectively with annual visits to determine future phenoconversion to MSA, Parkinson's disease (PD), or dementia with Lewy bodies (DLB). ELISA was utilized to measure NfL and protein misfolding cyclic amplification (PMCA) to detect αSyn oligomers in CSF collected at baseline. RESULTS: Patients were followed for a median of 3.9 years. Five patients converted to MSA, 2 to PD, and 2 to DLB. NfL at baseline was elevated only in patients who later developed MSA, perfectly separating those from future PD and DLB converters as well as non-converters. ASyn-PMCA was positive in all but two cases (94%). The PMCA reaction was markedly different in five samples with maximum fluorescence and reaction kinetics previously described in MSA patients; all of these patients later developed MSA. INTERPRETATION: αSyn-PMCA is almost invariably positive in the CSF of patients with PAF establishing this condition as α-synucleinopathy. Both NfL and the magnitude and reaction kinetics of αSyn PMCA faithfully predict which PAF patients will eventually phenoconvert to MSA. This finding has important implications not only for prognostication, but also for future trials of disease modifying therapies, allowing for differentiation of MSA from Lewy body synucleinopathies before motor symptoms develop. ANN NEUROL 2021;89:1212-1220.

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  • Neuropathologic overlap between pure autonomic failure and Lewy body disorders and multiple system atrophy has been described, supporting close longitudinal clinical surveillance.

    “Neuropathologic overlap with Lewy body disorders and multiple system atrophy has been described, supporting close longitudinal clinical surveillance (Hague et al., 1997; Singer et al., 2021).”

    From Autonomic nervous system and gastrointestinal manifestations with an emphasis on gastric dysfunction (2026) · cites this paper as Singer et al., 2021

    The Discussion (page unavailable) describes Lewy body pathology in autopsy reports of patients with pure autonomic failure and calls for continued surveillance. The Results, under “Follow-up and Phenoconversion” (page unavailable), report conversion to multiple system atrophy, confirmed at autopsy in two patients, but do not establish neuropathologic overlap between pure autonomic failure and multiple system atrophy. (LLM, conf=0.84)

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Authors
Singer, W., Schmeichel, A. M., Shahnawaz, M., Schmelzer, J. D., Sletten, D. M., Gehrking, T. L., Gehrking, J. A., Olson, A. D., Suarez, M. D., Misra, P. P., Soto, C., & Low, P. A.
Affiliations
  • Mayo Clinic (US)
  • The University of Texas Health Science Center at Houston (US)
Corresponding author
Singer, Wolfgang
ORCID
Venue
Annals of Neurology
Publisher
Wiley
Published
2021-04-30
Volume
89
Issue
6
Pages
1212-1220
ISSN
  • 0364-5134 (ISSN-L)
  • 1531-8249
DOI
10.1002/ana.26089
PMC
PMC8168720
OpenAlex
W3153322458
Cited by
102
References
1
Citations by year
2026: 12 · 2025: 18 · 2024: 22 · 2023: 22 · 2022: 18 · 2021: 9
FWCI
8.49
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Annals of Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Mayo Clinic
  • Michael J. Fox Foundation for Parkinson's Research
  • National Institutes of Health (K23NS075141, R01AG055053, R01AG061069, R01NS092625, UL1TR000135)
  • U.S. Food and Drug Administration (R01FD004789)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
pure autonomic failure, phenoconversion, multiple system atrophy, alpha-synuclein oligomers, neurofilament light chain, cerebrospinal fluid biomarkers, protein misfolding cyclic amplification, synucleinopathies, Parkinson's disease, dementia with Lewy bodies, disease-modifying therapy
MeSH terms
Aged, Female, Humans, Longitudinal Studies, Male, Middle Aged, Parkinson Disease, Prospective Studies, Biomarkers, Neurofilament Proteins, Disease Progression, Multiple System Atrophy, Lewy Body Disease, alpha-Synuclein, Pure Autonomic Failure

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