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NSAIDs Reduce LRRK2 Penetrance in Parkinson's Disease

Article In Brief

Taking ibuprofen or aspirin lowered the risk of penetrance of the mutation in the LRRK2 gene, prompting less risk of developing Parkinson's disease. The study suggests that nonsteroidal anti-inflammatory drugs could be a modifiable determinant of LRRK2 penetrance.

Use of ibuprofen or aspirin reduces the risk of developing Parkinson's disease (PD) in carriers of disease-causing mutations in the LRRK2 gene, according to a July 14 online study in the journal Movement Disorders.

The finding strengthens the longstanding belief that use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of PD, and points toward inflammation as a key determinant in the penetrance of LRRK2 for those carrying mutations or risk variants.

“This study is quite interesting, because it is the first one that has a good chance of demonstrating a potential protective mechanism that might hold up to further scrutiny,” commented Thomas Gasser, MD, PhD, professor of neurology and director of the department of neurodegenerative diseases at the Hertie-Institute for Clinical Brain Research at the University of Tübingen in Germany, who was not involved in the study.

LRRK2 mutations were linked to PD in the early 2000s, and subsequent gene association studies indicated they were the most common mendelian genetic cause of PD, accounting for about 4 percent of familial PD and 1 percent of all PD. Disease-causing mutations are inherited in an autosomal dominant manner, with age-dependent penetrance of about 30 percent by age 80. In addition, there are gene variants that increase risk of PD, mainly found in Asian populations.

“There are a lot of studies that have looked at other genetic contributors to disease in the context of LRRK2 mutations,” said the study's principal investigator Caroline M. Tanner, MD, PhD, FAAN, professor of neurology at the University of California, San Francisco (UCSF). “But there is almost no information on how non-genetic factors might affect penetrance. And because penetrance is relatively low, it seems likely that there are non-genetic factors at work in this population.”

Study Details, Findings

To explore that question, Dr. Tanner, along with lead author Marta San Luciano, MD, also of UCSF, and an international consortium of investigators turned to data collected on PD patients with LRRK2 mutations and risk variants in two large international cohorts—40 sites, comprising enrolled individuals from North America, Europe, Africa, Australia, and Asia. They distinguished gene mutations and risk variants based on consensus from the LRRK2 literature, and defined individuals as either symptomatic (that is, meeting the criteria for a diagnosis of PD) or asymptomatic.

The researchers determined exposure to NSAIDs through the Parkinson's Disease Risk Factor Questionnaire, a standard tool in PD epidemiologic research. Questions included whether the respondent had ever taken an ibuprofen-based drug, aspirin, or another anti-inflammatory medication regularly; they defined “regular use” as taking at least two pills per week for six months or longer before the diagnosis of PD or an equivalent date in those without PD.

The directions included a specific discounting of acetaminophen or opioid medications taken for pain, inflammation, or swelling. Another question asked about the timing and duration of the treatment, and the actual average number of pills taken per week. The reasons for the use of the drugs were not recorded in the questionnaire, and as they are over-the-counter medications, were not necessarily in the individual's medical records either.

The researchers enrolled 259 symptomatic and 318 asymptomatic individuals, including 410 with pathogenic mutations and 176 with risk variants. Symptomatic individuals were on average older, and included a larger proportion of men, than asymptomatic individuals.

“We found that use of NSAIDs was associated with reduced penetrance of LRRK2 in people who had LRRK2 mutations or risk variants,” Dr. Tanner said.

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“This study is quite interesting because it is to my mind the first one that has a good chance of demonstrating a potential protective mechanism that might hold up to further scrutiny.”—DR. THOMAS GASSER

The rates of regular NSAID use were higher among asymptomatic people than in symptomatic cases of PD—31.8 percent versus 10.9 percent, respectively. Asymptomatic individuals reported regular use of ibuprofen (7.3 percent) and aspirin (24.2 percent), while a much smaller percentage of PD patients reported ibuprofen use (2.4 percent) and aspirin (8.2 percent).

The odds ratio for use of any NSAID was 0.34 (95% confidence interval 0.21-0.57); for ibuprofen was 0.19 (0.07-0.50); and for aspirin was 0.51 (0.28-0.91). Risk of PD was reduced in both the gene mutation and risk variant groups. There were not enough data to examine whether there was a dose response.

To rule out reverse causality—that those with incipient PD began taking an NSAID for disease-related pain—the team performed the same analysis but with a five-year and 10-year lag between NSAID treatment and disease onset.

“We saw a similar benefit when NSAID treatment was five years before,” Dr. Tanner said. “The effect was less strong at 10 years, but we also had less information from that far back.”

It is as yet untested whether NSAIDs protect against the effects of other PD-related genes, such as glucocerebrosidase (GBA), which also has reduced penetrance.

“To my knowledge, there is not the same large database of individuals with GBA mutations,” Dr. Tanner said, and the much larger number of known GBA variants would likely complicate the analysis.

“As far as I know there is no clinical trial planned to test prospectively whether NSAID use could delay onset of PD in LRRK2 carriers,” she added. The logistics of such a study would be daunting, requiring many years of follow-up and significant resources, with no potential for blockbuster drug sales from a positive outcome.

Expert Commentary

There has been a longstanding theory that NSAIDs might be protective in PD, but it has been difficult to show because of recall bias, commented Mark Cookson, PhD, senior investigator in the Laboratory of Neurogenetics at the National Institutes of Health. “I think the main message here is that in this genetically homogenous group of patients, there is a very convincing protective effect of NSAID use. The effect is substantial, especially for ibuprofen, and that is quite striking.”

Why might NSAIDs reduce LRRK2's effect? Dr. Cookson said that data suggesting that LRRK2 is active in inflammation “is very convincing.” The inability to regulate its effect because of the mutation might prolong inflammation and increase resultant damage to the central nervous system, an effect that NSAIDs might mitigate.

“This is a very exciting result,” said Dr. Gasser of the University of Tübingen. “I would be interested to see if NSAIDs are modulating the penetrance of GBA, or other risk variants with intermediate penetrance. That would be the crucial study.”

He pointed out that the effect might not be apparent with gene mutations such as alpha-synuclein that have a stronger effect. “It may only be in this intermediate stratum where the effect can be seen.”

In addition, he said, the findings suggest that NSAIDs may potentially be protective in sporadic PD. “The inconsistency of the results in previous epidemiologic studies of sporadic PD may be due to the heterogeneity of the population.”

“This paper is valuable in establishing a prototype of gene-environment interactions in Parkinson's disease, which is also therapeutically relevant,” said Michael Schwarzschild, MD, PhD, professor of neurology at Harvard Medical School and director of the Molecular Neurobiology Laboratory at Massachusetts General Hospital in Boston.

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“The most exciting aspect of the study is that the researchers have identified a modifiable determinant of LRRK2 penetrance.”—DR. MICHAEL SCHWARZSCHILD

Previous literature has “fairly convincingly shown an association” for some NSAIDs in idiopathic PD, “but this is the first study of any genetic form where NSAID use is linked to reduced penetrance. One of the striking features is the robustness of the extent of the link.”

“The most exciting aspect of the study is that the researchers have identified a modifiable determinant of LRRK2 penetrance,” which may help design testable hypotheses for PD disease prevention, Dr. Schwarzschild said.

Other modifiable factors linked to LRRK2 resistance may include caffeine and urate, he added. Nonetheless, he cautioned, “There are risks from regular NSAID use, and I don't think the neurology community can recommend NSAID use even to those who are gene carriers who don't have the disease. Gastrointestinal bleeding can be lethal, and I don't think it is sound medical advice to advise using an NSAID for prevention without further study.”

Disclosures

Dr. Tanner has received grant support from the Michael J. Fox Foundation, Parkinson's Foundation, Department of Defense, BioElectron Technology Corp, Roche/Genentech, Biogen Idec, and the National Institutes of Health. She has received honorarium from and served on the data monitoring committee service for Cadent Therapeutics, Intec Pharma, and Northwestern University. She has consulted for Neurocrine Biosciences, Adamas Therapeutics, Gray Matter Technologies, CNS Ratings, Lundbeck Pharmaceuticals and Acorda Pharmaceuticals. Drs. Gasser, Schwarzschild, and Cookson had no relevant disclosures.

Link Up for More Information

• Luciano MS, Tanner CM, Meng C, et al; for the Michael J. Fox Foundation LRRK2 Consortium. Nonsteroidal anti-inflammatory use and LRRK2 Parkinson's disease penetrance https://onlinelibrary.wiley.com/doi/abs/10.1002/mds.28189. Mov Disord 2020; Epub 2020 Jul 14.