Summary: Mutations of the GBA gene, a known risk factor for Parkinson’s disease, appear to also influence the development of cognitive decline, a new study reports.
Source: Brigham and Women’s Hospital.
A gene defect that causes memory troubles could inspire better therapeutic trials for the most common movement disorder.
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.
About this Parkinson’s disease research article
Funding: 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.
Source: Elaine St. Peter – Brigham and Women’s Hospital Image Source: NeuroscienceNews.com image is in the public domain. Original Research: Full open access research for “Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s” by Ganqiang Liu, Brendon Boot, Joseph J. Locascio, Iris E. Jansen, Sophie Winder-Rhodes, Shirley Eberly, Alexis Elbaz, Alexis Brice, Bernard Ravina, Jacobus J. van Hilten, Florence Cormier-Dequaire, Jean-Christophe Corvol, Roger A. Barker, Peter Heutink, Johan Marinus, Caroline H. Williams-Gray, Clemens R. Scherzer and for the International Genetics of Parkinson Disease Progression (IGPP) Consortium in Annals of Neurology. Published online November 18 2016 doi:10.1002/ana.24781
Cite This NeuroscienceNews.com Article
[cbtabs][cbtab title=”MLA”]Brigham and Women’s Hospital “Genetic Connection Between Parkinson’s and Cognitive Decline.” NeuroscienceNews. NeuroscienceNews, 4 December 2016. <https://neurosciencenews.com/parkinsons-cognition-genetics-5675/>.[/cbtab][cbtab title=”APA”]Brigham and Women’s Hospital (2016, December 4). Genetic Connection Between Parkinson’s and Cognitive Decline. NeuroscienceNew. Retrieved December 4, 2016 from https://neurosciencenews.com/parkinsons-cognition-genetics-5675/[/cbtab][cbtab title=”Chicago”]Brigham and Women’s Hospital “Genetic Connection Between Parkinson’s and Cognitive Decline.” https://neurosciencenews.com/parkinsons-cognition-genetics-5675/ (accessed December 4, 2016).[/cbtab][/cbtabs]
Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s
We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher’s disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson’s disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates.
A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models.
Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance.
Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685
“Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s” by Ganqiang Liu, Brendon Boot, Joseph J. Locascio, Iris E. Jansen, Sophie Winder-Rhodes, Shirley Eberly, Alexis Elbaz, Alexis Brice, Bernard Ravina, Jacobus J. van Hilten, Florence Cormier-Dequaire, Jean-Christophe Corvol, Roger A. Barker, Peter Heutink, Johan Marinus, Caroline H. Williams-Gray, Clemens R. Scherzer and for the International Genetics of Parkinson Disease Progression (IGPP) Consortium in Annals of Neurology. Published online November 18 2016 doi:10.1002/ana.24781