2 Mutations May Serve as Parkinson Disease Biomarkers

Non-manifesting carriers of the LRRK2 and GBA mutations may exhibit evidence of subtle motor and non-motor signs of Parkinson disease (PD) even before there is a deficit in dopamine transporter (DAT), according to findings from the ongoing Parkinson's Progression Markers Initiative (PPMI).

PPMI is an ongoing observational, longitudinal cohort study of participants with PD, healthy controls, and carriers of the most common PD-related genetic mutations. For this analysis of PPMI data, the researchers aimed to determine whether non-manifesting carriers of the 2 mutations have prodromal features of PD that correlate with reduced DAT binding.

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To perform the analysis, the researchers evaluated the baseline clinical and DAT imaging characteristics of 208 non-manifesting carriers of LRRK2 and 184 non-manifesting carriers of GBA who had been enrolled in the PPMI study between January 1, 2014, and January 1, 2019, from 33 participating sites worldwide.

Of the 286 non-manifesting carriers who had DAT imaging results, 18 LRRK2 carriers (11%) and 4 GBA carriers (3%) had a DAT deficit, which was defined as less than 65% of putamen striatal binding ratio expected for the individual's age.

The DAT imaging characteristics were compared with those of the study’s healthy controls. This comparison showed that non-manifesting carriers of LRRK2 or GBA had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale and on the Scale for Outcomes for PD – autonomic function.

Compared with healthy controls, LRRK2 non-manifesting carriers were significantly more likely to have hyposmia. Moreover, GBA non-manifesting carriers had increased DAT striatal binding ratios in the caudate, putamen, and striatum compared with healthy controls. 

The groups exhibited no difference in daytime sleepiness, anxiety, depression, impulsive–compulsive disorders, blood pressure, urate, and rapid eye movement behavior disorder scores. 

“Our data show evidence of subtle motor and non-motor signs of [PD] in non-manifesting carriers compared with healthy controls that can precede DAT deficit,” the researchers concluded. “Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of [PD].”

—Colleen Murphy

Reference:

Simuni T, Uribe L, Cho HR, et al; PPMI Investigators. Clinical and dopamine transporter imaging characteristics of non-manifest LRRK2 and GBA mutation carriers in the Parkinson's Progression Markers Initiative (PPMI): a cross-sectional study. Lancet Neurol. 2020;19(1):71-80. https://doi.org/10.1016/S1474-4422(19)30319-9.