From Genetic Risk Toward Genetic Prognosis
Biosample and Tissue Resource, 2013
The progression and prognosis of Parkinsonís disease (PD) varies considerably between individual patients ó ranging from a manageable, functional decline to an aggressive course. This variation is a major source of noise and inefficiency in clinical drug trials. To overcome this roadblock, markers that predict prognosis are needed ó for improving trial design as well as for a personalized clinical care.
Project Description: † † † † † ††
Variants in a known PD risk gene will be systematically identified through resequencing of the locus in the ~ 400 PD patients with available DNA enrolled and longitudinally followed in the DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) study. Statistical analyses will be performed to determine whether these variants predict disease progression.
Relevance to Diagnosis/Treatment of Parkinsonís Disease: † † † † † † † † † ††
Prognostic markers will enable recruiting trial populations with a more homogeneous disease course thereby increasing power, lowering sample sizes, saving costs and facilitating mechanism-directed therapies.
Anticipated Outcome: † † † † †
Consistent with our preliminary studies, DATATOP participants carrying these gene variants will have a more rapid disease progression.
The effect of gene mutations on cognitive and motor outcomes were evaluated in DATATOP (current award) and additional cohorts (additional MJFF support) comprising 2,304 patients with PD using sequencing (in 1,921) or genotyping (in 383). Patients carrying a mutation had a 63% increased risk of developing dementia over ten years compared to patients free of a mutation. They had a 46% increased risk of rapid motor disease progression.
Much progress has been made in delineating genome variation associated with susceptibility for developing PD, but little is known about the genetic architecture controlling disease progression. With this study we propose to shift the paradigm from genetic risk to genetic prognosis. Progression genes should facilitate patient stratification and recruiting trial populations with a more homogeneous disease course thereby increasing power, lowering costs, and facilitating mechanism-directed therapies.
Head of the Neurogenomics Lab and the Parkinson Personalized Medicine Initiative at Harvard and Brigham and Womenís Hospital
Associate Professor of Neurology at Harvard Medical School
Location: Cambridge, Massachusetts, United States
Instructor in Neurology at Brigham and Womenís Hospital
Neurologist at Harvard Medical School
Location: Boston, Massachusetts, United States