SORA

Advancing, promoting and sharing knowledge of health through excellence in teaching, clinical practice and research into the prevention and treatment of illness

Disease modification and biomarker development in Parkinson disease: Revision or reconstruction?

Espay, AJ; Kalia, LV; Gan-Or, Z; Williams-Gray, CH; Bedard, PL; Rowe, SM; Morgante, F; Fasano, A; Stecher, B; Kauffman, MA; et al. Espay, AJ; Kalia, LV; Gan-Or, Z; Williams-Gray, CH; Bedard, PL; Rowe, SM; Morgante, F; Fasano, A; Stecher, B; Kauffman, MA; Farrer, MJ; Coffey, CS; Schwarzschild, MA; Sherer, T; Postuma, RB; Strafella, AP; Singleton, AB; Barker, RA; Kieburtz, K; Olanow, CW; Lozano, A; Kordower, JH; Cedarbaum, JM; Brundin, P; Standaert, DG; Lang, AE (2020) Disease modification and biomarker development in Parkinson disease: Revision or reconstruction? Neurology, 94 (11). pp. 481-494. ISSN 1526-632X https://doi.org/10.1212/WNL.0000000000009107
SGUL Authors: Morgante, Francesca

[img] PDF Published Version
Restricted to Repository staff only until 26 February 2021.
Available under License ["licenses_description_publisher" not defined].

Download (439kB)

Abstract

A fundamental question in advancing Parkinson disease (PD) research is whether it represents one disorder or many. Does each genetic PD inform a common pathobiology or represent a unique entity? Do the similarities between genetic and idiopathic forms of PD outweigh the differences? If aggregates of α-synuclein in Lewy bodies and Lewy neurites are present in most (α-synucleinopathies), are they also etiopathogenically significant in each (α-synuclein pathogenesis)? Does it matter that postmortem studies in PD have demonstrated that mixed protein-aggregate pathology is the rule and pure α-synucleinopathy the exception? Should we continue to pursue convergent biomarkers that are representative of the diverse whole of PD or subtype-specific, divergent biomarkers, present in some but absent in most? Have clinical trials that failed to demonstrate efficacy of putative disease-modifying interventions been true failures (shortcomings of the hypotheses, which should be rejected) or false failures (shortcomings of the trials; hypotheses should be preserved)? Each of these questions reflects a nosologic struggle between the lumper's clinicopathologic model that embraces heterogeneity of one disease and the splitter's focus on a pathobiology-specific set of diseases. Most important, even if PD is not a single disorder, can advances in biomarkers and disease modification be revised to concentrate on pathologic commonalities in large, clinically defined populations? Or should our efforts be reconstructed to focus on smaller subgroups of patients, distinguished by well-defined molecular characteristics, regardless of their phenotypic classification? Will our clinical trial constructs be revised to target larger and earlier, possibly even prodromal, cohorts? Or should our trials efforts be reconstructed to target smaller but molecularly defined presymptomatic or postsymptomatic cohorts? At the Krembil Knowledge Gaps in Parkinson's Disease Symposium, the tentative answers to these questions were discussed, informed by the failures and successes of the fields of breast cancer and cystic fibrosis.

Item Type: Article
Additional Information: © 2020 American Academy of Neurology
Keywords: 1103 Clinical Sciences, 1109 Neurosciences, 1702 Cognitive Sciences, Neurology & Neurosurgery
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Neurology
ISSN: 1526-632X
Language: eng
Dates:
DateEvent
17 March 2020Published
26 February 2020Published Online
16 January 2020Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
UNSPECIFIEDKrembil Foundationhttp://dx.doi.org/10.13039/501100004089
UNSPECIFIEDRonald Kimel Foundation TrustUNSPECIFIED
UNSPECIFIEDParkinson's FoundationUNSPECIFIED
UNSPECIFIEDInternational Parkinson and Movement Disorder SocietyUNSPECIFIED
UNSPECIFIEDAmerican Parkinson Disease Associationhttp://dx.doi.org/10.13039/100006309
MR/R007446/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
203151/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
PubMed ID: 32102975
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111707
Publisher's version: https://doi.org/10.1212/WNL.0000000000009107

Actions (login required)

Edit Item Edit Item