Genetic mutations causing neuropathic Gaucher disease (GD) aggravate cognitive dysfunction in Parkinson’s disease (PD), new research shows.
The study “Specifically neuropathic Gaucher’s mutations accelerate cognitive decline in Parkinson’s” was published in the journal Annals of Neurology.
The pace of cognitive worsening in Parkinson’s varies significantly between patients. In order to improve the design of clinical trials and the development of personalized therapies, the study says, clinicians would benefit from information on genes that predict prognosis and modulate disease progression.
Gaucher disease is caused by mutations in the β‐glucocerebrosidase gene (GBA). Different types of Gaucher disease exist, depending on whether it affects the central nervous system (neuropathic Gaucher), or is restricted to peripheral manifestations (non-neuropathic Gaucher).
Although individuals carrying only one mutant copy (heterozygous) of GBA do not develop Gaucher disease, they have been found to be more prone to having Parkinson’s. Furthermore, GBA mutations also may be associated with the rate of progression in Parkinson’s. However, information on whether there is a difference between neuropathic and non-neuropathic Gaucher mutations and their association with Parkinson’s is still unknown.
The scientists hypothesized that homozygous mutations in GBA leading to severe, neuropathic Gaucher disease result in aggressive cognitive deterioration in Parkinson’s. Conversely, mutations associated with non‐neuropathic Gaucher would lead to intermediate progression rates.
The study’s senior author was Clemens R. Scherzer, MD, an associate professor of neurology at Harvard Medical School and co-director of the Harvard NeuroDiscovery Biomarker Program. Scherzer also is an associate neurologist at the Brigham and Women’s Hospital and Massachusetts General Hospital in Boston. The research team included scientists from the Netherlands, Germany, the U.K., and France.
The study included 2,304 Parkinson’s patients from seven groups from North America and Europe. Parkinson’s was evaluated for up to approximately 13 years, with 20,868 in-person study visits. The scientists evaluated the effects of four types of variations in GBA on cognitive decline, addressed by the Mini-Mental State Exam questionnaire.
The results showed that 10.3 percent of patients with Parkinson’s carried a GBA mutation. Patients with neuropathic Gaucher disease mutations (1.4% of patients) and complex GBA alleles (0.7%) had a greater risk for cognitive impairment and an accelerated decline in cognition compared to noncarriers.
Conversely, non‐neuropathic mutation (1.5% of patients) or nonpathogenic risk variants (6.6% of patients) were not different than controls in the rate of cognitive decline.
Overall, the study shows that mutations in the GBA gene that causes neuropathic Gaucher, and complex GBA alleles, accelerate Parkinson’s-associated cognitive decline. The results “have direct implications for improving the design of clinical trials,” the authors wrote.
Genetics-guided, more specific clinical trials in patients with neuropathic GD-PD could “shorten trial duration, shrink sample sizes, and, possibly, cut costs,” they said.
Furthermore, study authors said, these findings could help in conducting studies with more accurate risk-benefit analyses based on individual patients, which may be important in designing prospective interventions and developing new therapies.