Abstract
Despite a hypothesis that harboring a leucine-rich repeat kinase 2(LRRK2) G2019S variation and a glucocerebrosidase (GBA) variant would have a combined deleterious association with disease pathogenesis, milder clinical phenotypes have been reported in dual LRRK2 and GBA variations Parkinson disease (PD) than in GBA variation PD alone. To evaluate the association of LRRK2 G2019S and GBA variants with longitudinal cognitive and motor decline in PD. This longitudinal cohort study of continuous measures in LRRK2 PD, GBA PD, LRRK2/GBA PD, and wild-type idiopathic PD used pooled annual visit data ranging from 2004 to 2019 from the Mount Sinai Beth Israel, Parkinson Disease Biomarker Program, Harvard Biomarkers Study, Ashkenazi Jewish-LRRK2-Consortium, Parkinson Progression Marker Initiative, and SPOT-PD studies. Patients who were screened for GBA and LRRK2 variations and completed either a motor or cognitive assessment were included. Data were analyzed from May to July 2020. The associations of LRRK2 G2019S and GBA genotypes on the rate of decline in Montreal Cognitive Assessment (MoCA) and Movement Disorders Society-Unified Parkinson Disease Rating Scale-Part III scores were examined using linear mixed effects models with PD duration as the time scale. Among 1193 individuals with PD (mean [SD] age, 66.6 [9.9] years; 490 [41.2%] women), 128 (10.7%) had GBA PD, 155 (13.0%) had LRRK2 PD, 21 (1.8%) had LRRK2/GBA PD, and 889 (74.5%) had idiopathic PD. Patients with GBA PD had faster decline in MoCA than those with LRRK2/GBA PD (B [SE], -0.31 [0.09] points/y; P < .001), LRRK2 PD (B [SE], -0.33 [0.09] points/y; P < .001), or idiopathic PD (B [SE], -0.23 [0.08] points/y; P = .005). There was a LRRK2 G2019S × GBA interaction in MoCA decline (B [SE], 0.22 [0.11] points/y; P = .04), but not after excluding severe GBA variations (B [SE], 0.12 [0.11] points/y; P = .28). Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004). These findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD. This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction. However, the biological basis of a dominant association or interaction is not clear and is apparently contrary to basic investigations. Study of a larger cohort of individuals with severe GBA variation is warranted.
Highlights
Variants in the leucine-rich repeat kinase 2 (LRRK2; OMIM 609007) and glucocerebrosidase (GBA; OMIM 606463) genes are frequent and worldwide genetic contributors to Parkinson disease (PD) susceptibility.[1,2] LRRK2 variations occur in approximately 2% of PD overall, and up to 40% of PD in certain ethnic groups, individuals of Ashkenazi Jewish or Arabian Berber descent.[1]
Patients with GBA PD had significantly worse motor progression compared with those with idiopathic PD (B [SE], 0.49 [0.22] points/y; P = .03) or LRRK2 PD (B [SE], 0.77 [0.26] points/y; P = .004). These findings suggest that longitudinal cognitive decline in patients with GBA PD was more severe than in those with LRRK2/GBA PD, which more closely resembled LRRK2 PD
This further supports the notion of a dominant association of LRRK2 on GBA in individuals who carry both and raises the possibility of an LRRK2 × GBA interaction
Summary
Variants in the leucine-rich repeat kinase 2 (LRRK2; OMIM 609007) and glucocerebrosidase (GBA; OMIM 606463) genes are frequent and worldwide genetic contributors to Parkinson disease (PD) susceptibility.[1,2] LRRK2 variations occur in approximately 2% of PD overall, and up to 40% of PD in certain ethnic groups, individuals of Ashkenazi Jewish or Arabian Berber descent.[1]. The penetrance of LRRK2 variations ( G2019S), or the chance that a carrier of this variation will manifest PD by late adulthood, has been estimated at 26% to 43% and is lower in individuals with GBA variations, ranging from 9% to 19%.5-8. Additional risk factors are clearly at play.[9,10,11] One potential critical interaction is the association of GBA and LRRK2 variations in carriers of both variations (hereafter, LRRKR2/GBA) The penetrance of LRRK2 variations ( G2019S), or the chance that a carrier of this variation will manifest PD by late adulthood, has been estimated at 26% to 43% and is lower in individuals with GBA variations, ranging from 9% to 19%.5-8 additional risk factors are clearly at play.[9,10,11] One potential critical interaction is the association of GBA and LRRK2 variations in carriers of both variations (hereafter, LRRKR2/GBA)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
