NICE, France — Levels of a group of urinary markers correlate with the LRRK2 G2019S gain-of-kinase function gene mutation, a common cause of dominantly inherited Parkinson’s disease (PD), a new study shows.
The markers are isoforms of the lipid bis(monoacylglycerol) phosphate (BMP), and one correlated with cognitive decline among carriers of the LRRK2 mutation but not PD.
“BMP levels are highly correlated with LRRK2 mutation status, which is significantly elevated in LRRK2 carriers compared to noncarriers,” Roy Alcalay, MD, Columbia University, New York City, reported during a guided poster tour at the 2019 International Congress of Parkinson’s Disease and Movement Disorders. The study was funded by the Michael J. Fox Foundation.
“And interestingly, at least for some of the isoforms [of BMP], it’s even further elevated in LRRK2 patients with Parkinson’s compared to LRRK2 patients without Parkinson’s,” he said.
BMPs are lipids localized in the inner membranes of late endosomes and particularly in lysosomes. BMP elevation may be a biomarker of lysosomal dysfunction.
The study used biobanked samples from 80 participants who were part of the LRRK2 Cohort Consortium (LCC), frequency-matched for the study by sex, disease duration, and age of onset. Participants included:
20 PD patients with the LRRK2 G2019S mutation (PD+ LRRK2+)
20 idiopathic PD patients without the mutation (PD+ LRRK2-)
20 mutation carriers not manifesting PD (PD- LRRK2+)
20 healthy individuals without the mutation (PD- LRRK2-)
Fifty-four bioactive lipids, including BMP, were measured in these samples.
A second biobanked cohort, the Columbia University Irving Medical Center (CUIMC) cohort, comprised clinical and genetic data, including motor and cognitive measures, from 116 individuals at a single site. These samples were analyzed for BMP levels. Because BMP data were comparable in both sample sets, the data were combined, and all values were normalized for creatinine levels.
For the four urine BMP analytes assayed, higher levels were found in samples from participants who carried the LRRK2 G2019S mutation, and among those, the highest levels were in samples from participants who were PD-positive. But even for PD-negative samples, BMP levels were higher in samples from participants carrying the mutation.
Table 1. Median Urine BMP Isoform Levels in the Combined Cohort
|Levels (range)||PD+LRRK2+ (n = 45)||PD+LRRK2- (n = 60)||PD-LRRK2+ (n = 36)||PD-LRRK2- (n = 55)||
BMP = bis(monoacylglycerol) phosphate
Researchers tested the association of two disease severity indicators, the Montreal Cognitive Assessment (MoCA) and Unified Parkinson’s Disease Rating Scale-III (UPDRS-III), with BMP isoform levels in linear regression models.
“When you took the LRRK2 patients without Parkinson’s, for at least one of the isoforms, the 22:6, higher levels were associated with…poorer MoCA performance. So it was argued that maybe LRRK2 BMP levels can be correlated with disease severity,” Alcalay said.
When adjusted for age, sex, disease duration, years of education, and LRRK2 status, normalized total di-22:6-BMP and normalized 2,2′ di-22:6-BMP levels were significantly associated with MoCA scores (P = .0461 and P = .0104, respectively).
None of the isoform levels was significantly associated with UPDRS-III scores.
Alcalay cautioned that one cannot use BMP levels “to say if someone is an LRRK2 carrier or not, or if they have Parkinson’s or not,” but if correlated with other biomarkers, BMP could serve as a “target engagement” in drug trials in PD “to see if the drug actually reduces LRRK2 activity in people who participated in LRRK2 studies.”
He suggested that, if given longitudinal samples, BMP levels could possibly be used as a biomarker for disease severity in LRRK2 mutation carriers.
Poster tour co-leader Susan Fox, MB ChB, PhD, of the University Health Network, Toronto, Ontario, Canada, asked Alcalay if the researchers correlated BMP levels only with the G2019S mutation in LRRK2 or if levels also correlated with other LRRK2 mutations.
Alcalay said they only looked at the G2019S mutation in LRRK2 but also looked at mutation carriers of the GBA gene, another risk factor for PD. Because the number of GBA mutation carriers in the study was small, they did not report BMP levels, but he revealed that levels appeared to be decreased in these patients.
In an interview, Alcalay said BMP levels could be useful in a couple of ways. The first way is to target therapy. Second, if a therapy worked in patients with an LRRK2 mutation, one could investigate if it was effective in PD patients without LRRK2 mutations but high BMP levels, the rationale being that the LRRK2 pathway might be activated in different ways and therefore make such patients good candidates for therapies directed at LRRK2.
The second question was whether BMP is just a marker of lysosome dysfunction or if the dysfunction is part of the pathophysiology of PD. Calling it “a great question,” Alcalay said currently there is no answer, adding, “We don’t really explain here, and we don’t really know why BMP is elevated in LRRK2 mutation carriers or why it goes down with LRRK2 inhibitors…but the biology of it, I think there is more to learn.”
He offered that more mechanistic studies, beginning in animal models, should shed light on the answer.
Fox commented to Medscape Medical News that the study was well designed and is from a good research group. Specifically addressing the study, she said, “If you could measure something in the urine…I think that’s good. It’s much easier than doing a lumbar puncture.” However, she questioned whether BMP correlates with disease.
Co-tour leader Michael Schwarzschild, MD, PhD, of Massachusetts General Hospital, Boston, said the study reflects “some of the most exciting developments towards precision medicine, particularly gene-targeted therapies for disease modification and Parkinson’s disease, LRRK2 and GBA being of particular focus.” Biomarkers are some of the tools that will “help us better understand the targets and patient populations, and how to find them and how to follow them.”
Similarly, he said that if BMP levels are a reflection of the pathophysiology of PD and if there is a drug that is designed to compensate for it, then the biomarker could be a simple, accessible measure that will facilitate trials.
“So I thought it was encouraging that you can get a hook at a molecular level. It’s something so accessible, that’s relevant — but why is it relevant? What’s the biology? How reproducible is it? Is it responsive to therapies that target that pathway? [These are] all sort of next-step questions that [Alcalay] seems poised to pursue,” he said.
Looking ahead, Fox said, “If you can expand what’s found in a very well-defined homogeneous population of LRRK2 into the general PD population, that’s where that’s the winner.”
International Congress of Parkinson’s Disease and Movement Disorders 2019. Abstract #553. Presented September 23, 2019.