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

• Autores: Espay, Alberto J.; Schwarzschild, Michael A.; Tanner, Caroline M.; Fernandez, Hubert H.; Simon, David K.; Leverenz, James B.; Merola, Aristide; Chen Plotkin, Alice; Brundin, Patrik; Kauffman, Marcelo Andres; Erro, Roberto; Kieburtz, Karl; Woo, Daniel; Macklin, Eric A.; Standaert, David G.; Lang, Anthony E.
• Año de publicación: 2017
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: Biomarkers; Neuroprotection; Parkinson'S Disease; Systems Biology; Parkinson'S Disease
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

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.
Fil: Espay, Alberto J.. University of Cincinnati; Estados Unidos
Fil: Schwarzschild, Michael A.. Massachusetts General Hospital; Estados Unidos
Fil: Tanner, Caroline M.. University of California; Estados Unidos
Fil: Fernandez, Hubert H.. Cleveland Clinic; Estados Unidos
Fil: Simon, David K.. Harvard Medical School; Estados Unidos
Fil: Leverenz, James B.. Cleveland Clinic; Estados Unidos
Fil: Merola, Aristide. University of Cincinnati; Estados Unidos
Fil: Chen Plotkin, Alice. University of Pennsylvania; Estados Unidos
Fil: Brundin, Patrik. Van Andel Research Institute. Center for Neurodegenerative Science; Estados Unidos
Fil: Kauffman, Marcelo Andres. Universidad Austral; Argentina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Agudos "Ramos Mejía"; Argentina
Fil: Erro, Roberto. Universita di Verona; Italia. University College London; Reino Unido
Fil: Kieburtz, Karl. University of Rochester Medical Center; Estados Unidos
Fil: Woo, Daniel. University of Cincinnati; Estados Unidos
Fil: Macklin, Eric A.. Massachusetts General Hospital; Estados Unidos
Fil: Standaert, David G.. University of Alabama at Birmingahm; Estados Unidos
Fil: Lang, Anthony E.. University of Toronto; Canadá