10.5061/DRYAD.G1NQ02R
Espay, Alberto J.
University of Cincinnati
Vizcarra, Joaquin A.
University of Cincinnati
Marsili, Luca
University of Cincinnati
Lang, Anthony E.
University of Toronto
Simon, David K.
Harvard Medical School
Merola, Aristide
University of Cincinnati
Josephs, Keith A.
Mayo Clinic
Fasano, Alfonso
University of Toronto
Morgante, Francesca
St George's, University of London
Savica, Rodolfo
Mayo Clinic
Greenamyre, J. Timothy
University of Pittsburgh
Cambi, Franca
University of Pittsburgh
Yamasaki, Tritia R.
University of Kentucky
Tanner, Caroline M.
University of California San Francisco Medical Center
Gan-Or, Ziv
McGill University
Litvan, Irene
University of California, San Diego
Mata, Ignacio F.
VA Puget Sound Health Care System
Zabetian, Cyrus P.
VA Puget Sound Health Care System
Brundin, Patrik
Center for Neurodegenerative Science, Van Andel Research Institute,
Grand Rapids, MI
Fernandez, Hubert H.
Cleveland Clinic
Standaert, David G.
University of Alabama at Birmingham
Kauffman, Marcelo A.
National Scientific and Technical Research Council
Schwarzschild, Michael A.
Massachusetts General Hospital
Sardi, S. Pablo
Division of Neuroscience, Sanofi-Genzyme, Framingham, MA
Sherer, Todd
Michael J. Fox Foundation
Perry, George
The University of Texas at San Antonio
Leverenz, James B.
Cleveland Clinic
Data from: Revisiting protein aggregation as pathogenic in sporadic
Parkinson’s and Alzheimer’s diseases
Dryad
dataset
2019
disease modifying treatments
Alzheimer’s disease
Clinical trials
Parkinson’s disease
2019-02-12T22:21:35Z
2019-02-12T22:21:35Z
en
https://doi.org/10.1212/wnl.0000000000006926
81352 bytes
1
CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
The gold standard for a definitive diagnosis of Parkinson’s disease (PD)
is the pathologic finding of aggregated alpha-synuclein into Lewy bodies
and for Alzheimer’s disease (AD) aggregated amyloid into plaques and
hyperphosphorylated tau into tangles. Implicit in this
clinico-pathologic-based nosology is the assumption that pathological
protein aggregation at autopsy reflect pathogenesis at disease onset.
While these aggregates may in exceptional cases be on a causal pathway in
humans (e.g., aggregated alpha-synuclein in SNCA gene multiplication or
aggregated -amyloid in APP mutations), their near universality at
postmortem in sporadic PD and AD suggests they may alternatively represent
common outcomes from upstream mechanisms or compensatory responses to
cellular stress in order to delay cell death. These three conceptual
frameworks of protein aggregation (pathogenic, epiphenomenon, protective)
are difficult to resolve because of the inability to probe brain tissue in
real time. Whereas animal models, in which neither PD nor AD occur in
natural states, consistently support a pathogenic role of protein
aggregation, indirect evidence from human studies does not. We hypothesize
that (1) current biomarkers of protein aggregates may be relevant to
common pathology but not to subgroup pathogenesis, and (2)
disease-modifying treatments targeting oligomers or fibrils might be
futile or deleterious because these proteins are epiphenomena or
protective in the human brain under molecular stress. Future
precision-medicine efforts for molecular targeting of neurodegenerative
diseases may require analyses not anchored on current clinico-pathologic
criteria but instead on biological signals generated from large
deeply-phenotyped aging populations or from smaller but well-defined
genetic-molecular cohorts.
Table e-1Search strategyTable e-2Characteristics of Supporting and
Opposing Studies summarized in Table 1eReferences