Subtle Findings May Predict Parkinson's Disease Risk in LRRK2, GBA Mutation Carriers

By Marilynn Larkin

November 19, 2019

NEW YORK (Reuters Health) - Non-manifesting carriers of LRRK2 and GBA mutations may exhibit subtle symptoms suggesting an increased risk for developing Parkinson's disease (PD), a cross-sectional analysis suggests.

"We are identifying subtle clinical features of Parkinsonism in carriers of the genetic mutations associated with increased risk of PD," Dr. Tanya Simuni of Northwestern University Feinberg School of Medicine in Chicago, told Reuters Health by email.

"Longitudinal data will be essential," she said, "but the ultimate goal is to establish a cohort of people at risk of PD as a target for disease-modifying interventions with the ultimate goal of reducing the risk of PD phenoconversion."

For the analysis, researchers assessed non-manifesting carriers of LRRK2 and GBA mutations enrolled in the ongoing global Parkinson's Progression Markers Initiative study and compared their baseline clinical and DAT imaging characteristics to those of healthy controls.

DAT deficit was defined as less than 65% of the putamen striatal binding ratio expected for the individual's age.

As reported online October 30 in The Lancet Neurology, the study included 208 LRRK2 (93% G2019S) and 184 GBA (96% N370S) non-manifesting carriers. Both groups were similar with respect to mean age, and about 60% were female.

Among the 286 (73%) non-manifesting carriers with DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit.

Compared with controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (4.6 for controls vs. 8.4 for LRRK2 vs. 9.5 for GBA).

Similar increases were found on the Scale for Outcomes for PD - autonomic function: 5.8 versus 8.1 versus 8.4, respectively.

By contrast, no between-groups differences were seen in daytime sleepiness, anxiety, depression, impulsive-compulsive disorders, blood pressure, urate, and rapid eye movement behavior disorder scores.

Of note, hyposmia was significantly more common only in LRRK2 non-manifesting carriers (36% of controls vs. 55% of LRRK2 non-manifesting carriers).

Further, GBA - but not LRRK2 - non-manifesting carriers showed increased DAT striatal binding ratios (controls, 2.98 vs. GBA, 3.26).

Dr. Simuni said, "Clinicians should encourage people who know they carry a PD risk mutation - or who may, based on family history - to get involved in research. We're seeing subtle symptoms in these folks before diagnosis or even significant dopamine loss. Perhaps in the near future we'll be testing therapies to stop Parkinson's before it advances to a 'diagnosable' state."

Dr. Nicolaas Bohnen of the University of Michigan Udall Center and VA Ann Arbor Healthcare System, author of a related editorial, commented in an email to Reuters Health, "Mutations of the LRRK2 and GBA genes are relatively common causes of genetic PD. Imaging and other biomarker assessments in preclinical mutation carriers may offer a window into the pathophysiology of presymptomatic or prodromal PD."

Previous studies have shown loss of presynaptic dopaminergic nerve terminal markers, such as dopamine transporters, in prodromal PD, he noted. In the current study, "novel in vivo imaging observations showing increased striatal dopaminergic binding in non-manifesting GBA mutant carriers raise questions about a possible compensatory mechanism in the prodromal disease stage."

"Compensation may either reflect adaptive or maladaptive neuroplasticity," he noted. "If there is evidence of adaptive plasticity, then further target-engagement research may generate novel therapeutic interventions that could potentially delay or prevent clinical phenoconversion in the non-manifesting mutant carriers."

"An alternative explanation for the apparent striatal hyperdopaminergic binding is that it may be an epiphenomenon of a different, more primary, pathophysiological factor," he added. "Identification of such a factor will be equally important for our understanding of the disease process."

"The cross-sectional imaging and clinical data analysis (in this) study does not allow to tackle these important issues," he said. "We are looking forward to longitudinal clinical and imaging analyses of the PPMI dataset that may shed more light on these questions."


Lancet Neurol 2019.