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Parkinson's disease and cognitive decline: A genetic connection revealed

November 30, 2016

Boston, MA-- Although the hallmark symptoms of Parkinson's disease (PD) - such as involuntary shaking, slowness of movement and muscle rigidity - are related to movement, recent evidence has suggested that memory impairment plays an outsized role in diminished quality of life and the burden placed on caregivers. A new study led by investigators in the Ann Romney Center for Neurological Diseases at Brigham and Women's Hospital finds that mutations in the gene for glucocerebrosidase (GBA), known to be a risk factor for PD, also have a powerful influence on the development of cognitive decline. The study is available online and published in the November edition of Annals of Neurology, the journal of the American Neurological Association.

"I believe this is the dawn of personalized medicine for Parkinson's disease," said corresponding author Clemens Scherzer, MD, associate professor of Neurology, who leads the Neurogenomics Lab and Parkinson Personalized Medicine Initiative of Brigham and Women's Hospital and Harvard Medical School. "This is one of the largest longitudinal assessments of patients with Parkinson's disease, and we believe that its insights will help to fix what is currently broken with clinical trials for patients. We see more precise clinical trials that will help match the right therapist with the right patient as the next logical step."

Two defective copies of the GBA gene are known to cause Gaucher's disease, a childhood disorder that causes death by age two or severe neurologic complications. One defective copy of the gene was once thought to be of little consequence, but has recently emerged as a common risk factor for Parkinson's disease.

The new report examined 2,304 patients from the US, Canada and Europe, finding that 10 percent carried one (or more) defects in copies of the GBA gene. Patients carrying one defective GBA gene copy had an increased risk of memory troubles. This effect was most troublesome for patients carrying a GBA copy with the most severe type of defect -- known as a neuropathic GBA mutation -- whose risk of developing cognitive decline over time was increased by 217 percent. Approximately half of the carriers of a neuropathic GBA mutation developed global cognitive impairment within ten years of being diagnosed with Parkinson's. Among the PD patients without a mutation, only about 20 percent developed this decline in cognitive function.

Therapies for Gaucher disease have been available since 1994. Scherzer and colleagues hope that their findings will open the door for a completely new type of clinical trials in Parkinson's -- GBA-directed trials designed to proactively prevent memory troubles in patients with movement-related symptoms. They estimate that such innovative, nimble trials would need 25-fold fewer patients then conventional trials, with reduced costs and a better chance of success.

More than 15 previous clinical trials for medications designed to slow or halt Parkinson's have been inconclusive or failed, perhaps in part, Scherzer notes, due to cumbersome and inefficient trial designs. Scherzer and his colleagues hope that their findings will breathe new life into better trial design and interest from pharmaceutical companies to tackle Parkinson's.

"We have now launched a Consortium with The Michael J. Fox Foundation and industry to put together a tool kit for GBA-directed, molecularly targeted trials in PD," said Scherzer. "This tool kit will be an open resource for all scientists and pharma, and will comprise gene tests, biomarkers, and clinical parameters needed for successful proof-of-concept trials in PD. Smaller, more efficient trials remove a big entry barrier for pharma companies. This is good news for drug development and patients."

The new work represents seven international, longitudinal studies, and a collaboration among Scherzer and colleagues from the International Genetics of Parkinson Disease Progression (IGPP) Consortium.
-end-
This study was supported by The Michael J. Fox Foundation; the National Institutes of Health; Harvard NeuroDiscovery Center; U.S. Department of Defense; M.E.M.O. Hoffman Foundation; Parkinson's Disease Foundation; Wellcome Trust; MRC; Parkinson's UK; Cure-PD; Patrick Berthoud Trust; Van Geest Foundation; NIHR; Assistance Publique Hôpitaux de Paris; French clinical research hospital program-PHRC; "Investissements d'Avenir"; Prinses Beatrix Fonds; Stichting Alkemade-Keuls; and Stichting ParkinsonFonds.

Paper cited: Liu G et al. "Neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's" Annals of Neurology DOI: 10.1002/ana.2478

Brigham and Women's Hospital (BWH) is a 793-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners HealthCare. BWH has more than 4.2 million annual patient visits and nearly 46,000 inpatient stays, is the largest birthing center in Massachusetts and employs nearly 16,000 people. The Brigham's medical preeminence dates back to 1832, and today that rich history in clinical care is coupled with its national leadership in patient care, quality improvement and patient safety initiatives, and its dedication to research, innovation, community engagement and educating and training the next generation of health care professionals. Through investigation and discovery conducted at its Brigham Research Institute (BRI), BWH is an international leader in basic, clinical and translational research on human diseases, more than 3,000 researchers, including physician-investigators and renowned biomedical scientists and faculty supported by nearly $666 million in funding. For the last 25 years, BWH ranked second in research funding from the National Institutes of Health (NIH) among independent hospitals. BWH is also home to major landmark epidemiologic population studies, including the Nurses' and Physicians' Health Studies and the Women's Health Initiative as well as the TIMI Study Group, one of the premier cardiovascular clinical trials groups. For more information, resources and to follow us on social media, please visit BWH's online newsroom.

Brigham and Women's Hospital

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