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

Abstract

Background: The Parkinson's Progression Markers Initiative (PPMI) is an ongoing observational, longitudinal cohort study of participants with Parkinson's disease, healthy controls, and carriers of the most common Parkinson's disease-related genetic mutations, which aims to define biomarkers of Parkinson's disease diagnosis and progression. All participants are assessed annually with a battery of motor and non-motor scales, 123-I Ioflupane dopamine transporter (DAT) imaging, and biological variables. We aimed to examine whether non-manifesting carriers of LRRK2 and GBA mutations have prodromal features of Parkinson's disease that correlate with reduced DAT binding.

Methods: This cross-sectional analysis is based on assessments done at enrolment in the subset of non-manifesting carriers of LRRK2 and GBA mutations enrolled into the PPMI study from 33 participating sites worldwide. The primary objective was to examine baseline clinical and DAT imaging characteristics in non-manifesting carriers with GBA and LRRK2 mutations compared with healthy controls. DAT deficit was defined as less than 65% of putamen striatal binding ratio expected for the individual's age. We used t tests, χ2 tests, and Fisher's exact tests to compare baseline demographics across groups. An inverse probability weighting method was applied to control for potential confounders such as age and sex. To account for multiple comparisons, we applied a family-wise error rate to each set of analyses. This study is registered with ClinicalTrials.gov, number NCT01141023.

Findings: Between Jan 1, 2014, and Jan 1, 2019, the study enrolled 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. Of the 286 (73%) non-manifesting carriers that had DAT imaging results, 18 (11%) LRRK2 and four (3%) GBA non-manifesting carriers had a DAT deficit. Compared with healthy controls, both LRRK2 and GBA non-manifesting carriers had significantly increased mean scores on the Movement Disorders Society Unified Parkinson's Disease Rating Scale (total score 4·6 [SD 4·4] healthy controls vs 8·4 [7·3] LRRK2 vs 9·5 [9·2] GBA, p<0·0001 for both comparisons) and the Scale for Outcomes for PD - autonomic function (5·8 [3·7] vs 8·1 [5·9] and 8·4 [6·0], p<0·0001 for both comparisons). There was no difference in daytime sleepiness, anxiety, depression, impulsive-compulsive disorders, blood pressure, urate, and rapid eye movement (REM) behaviour disorder scores. Hyposmia was significantly more common only in LRRK2 non-manifesting carriers (69 [36%] of 194 healthy controls vs 114 [55%] of 208 LRRK2 non-manifesting carriers; p=0·0003). Finally, GBA but not LRRK2 non-manifesting carriers showed increased DAT striatal binding ratios compared with healthy controls in the caudate (healthy controls 2·98 [SD 0·63] vs GBA 3·26 [0·63]; p<0·0001), putamen (2·15 [0·56] vs 2·48 [0·52]; p<0·0001), and striatum (2·56 [0·57] vs 2·87 [0·55]; p<0·0001).

Interpretation: Our data show evidence of subtle motor and non-motor signs of Parkinson's disease in non-manifesting carriers compared with healthy controls that can precede DAT deficit. Longitudinal data will be essential to confirm these findings and define the trajectory and predictors for development of Parkinson's disease.

Funding: Michael J Fox Foundation for Parkinson's Research.

Conflict of interest statement

Declaration of interests

CSC reports grants from the Michael J Fox Foundation, during the conduct of the study; grants from the National Institute of Neurological Disorders and Stroke and National Heart, Lung, and Blood Institute; and personal fees from the Michael J Fox Foundation, outside the submitted work. KK reports grants from the Michael J Fox Foundation, during the conduct of the study; grants from the National Institute of Neurological Disorders and Stroke, and the National Center for Advancing Translational Sciences; and personal fees from Clintrex and Hoover Brown, outside the submitted work. KM reports partial ownership of Invicro, personal fees from the Michael J Fox Foundation, Roche, Proclara, GEHC, Deanli, Prevail, Lysosomal Therapeutics, Takeda, Lundback, UCB, Invicro, Inhibikase, and Cerapsir, outside the submitted work. BM reports personal fees from the Michael J Fox Foundation and being a Parkinson’s Progression Markers Initiative study eSC committee member, during the conduct of the study. WP reports personal fees from Abb Vie, Affiris, Allergan, AstraZeneca, BIAL, Biogen, Boston Scientific, Britannia, Intec, Ipsen, Lundbeck, Merz, Neuroderm, Novartis, Orion, Pharma, Roche, Prexton, Teva, Tekeda, UCBm and Zambon. KP reports grants from the Michael J Fox Foundation, during the conduct of the study; grants from AztraZeneca and Sanofi; and personal fees from Allergan and Curasen, outside the submitted work. JS reports partial owndership and consultancy work from iNVICRO; and consultancy work from Biogen, Roche, and Life Molecular Imaging, outside the submitted work. LS reports grants from the Michael J Fox Foundation, during the conduct of the study. CT reports grants from the Michael J Fox Foundation, during the conduct of the study; grants from Parkinson Foundation, Gateway LLC, Roche/Genentech, Parkinson Study Group; grants and personal fees from Biogen Idee, personal fees from Acorda, Adamas Therapeutics, Voyager Therapeutics, Intec Pharma, Grey Matter, 23andme, Neurocrine Biosciences, and CNS ratings, outside the submitted work. AT reports grants from the Michael J Fox Foundation, during the conduct of the study. DW reports salary support for serving on the Steering Committee from the Michael J Fox Foundation, during the conduct of the study.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Figures

Figure:. Striatal binding ratios for patients with Parkinson’s disease, healthy controls, and non-manifesting LRRK12 carriers and GBA carriers

The minimum putamen striatal binding ratio differed significantly between GBA carriers and healthy controls (p<0·0001) but did not differ between LRRK2 carriers and healthy controls (p=0·257). The reference line indicates the cutoff for 65% age expected putamen striatal binding ratios used to define DAT deficit. DAT=dopamine transporter.