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Mov Disord. 2017 Mar;32(3):319-324. doi: 10.1002/mds.26913. Epub 2017 Feb 24.

Biomarker-driven phenotyping in Parkinson's disease: A translational missing link in disease-modifying clinical trials.

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Department of Neurology, UC Gardner Neuroscience Institute, Gardner Center for Parkinson's disease and Movement Disorders, University of Cincinnati, Cincinnati, Ohio, USA.
MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA.
Department of Neurology, University of California-San Francisco and the Parkinson's Disease Research Education and Clinical Center, San Francisco Veterans Affairs Medical Center, San Francisco, California, USA.
Center for Neurological Restoration, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Neurology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA.
Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Center for Neurodegenerative Science, Van Andel Research Institute, Grand Rapids, Michigan, USA.
Consultorio y Laboratorio de Neurogenética, Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, and Programa de Medicina de Precision y Genomica Clinica, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Pilar, Argentina.
Sobell department of Motor Neuroscience and Movement Disorders, University College London, Institute of Neurology, London, United Kingdom.
Department of Neuroscience, Biomedicine and Movement Science, University of Verona, Verona, Italy.
Department of Neurology and CHET, University of Rochester Medical Center, Rochester, New York, USA.
Department of Neurology and Rehabilitation Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio, USA.
Department of Medicine, Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts, USA.
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
Morton and Gloria Shulman Movement Disorders Center, Toronto Western Hospital and The Edmond J. Safra Program in PD, Toronto, Ontario, Canada, University of Toronto, Toronto, Ontario, Canada.


Past clinical trials of putative neuroprotective therapies have targeted PD as a single pathogenic disease entity. From an Oslerian clinicopathological perspective, the wide complexity of PD converges into Lewy bodies and justifies a reductionist approach to PD: A single-mechanism therapy can affect most of those sharing the classic pathological hallmark. From a systems-biology perspective, PD is a group of disorders that, while related by sharing the feature of nigral dopamine-neuron degeneration, exhibit unique genetic, biological, and molecular abnormalities, which probably respond differentially to a given therapeutic approach, particularly for strategies aimed at neuroprotection. Under this model, only biomarker-defined, homogenous subtypes of PD are likely to respond optimally to therapies proven to affect the biological processes within each subtype. Therefore, we suggest that precision medicine applied to PD requires a reevaluation of the biomarker-discovery effort. This effort is currently centered on correlating biological measures to clinical features of PD and on identifying factors that predict whether various prodromal states will convert into the classical movement disorder. We suggest, instead, that subtyping of PD requires the reverse view, where abnormal biological signals (i.e., biomarkers), rather than clinical definitions, are used to define disease phenotypes. Successful development of disease-modifying strategies will depend on how relevant the specific biological processes addressed by an intervention are to the pathogenetic mechanisms in the subgroup of targeted patients. This precision-medicine approach will likely yield smaller, but well-defined, subsets of PD amenable to successful neuroprotection.


Parkinson's disease; biomarkers; neuroprotection; systems biology

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