Abstract
Cognitive impairment and depression are among the most prevalent and most disabling non-motor symptoms in Parkinson's disease (PD). The genetic factors that are associated with these symptoms remain uncertain. This systematic review aims to summarise the prevailing evidence from all genetic association studies investigating the genetic variants associated with cognitive impairment and depressive symptoms in people with PD. A systematic review using five online databases: PubMed, PsycINFO, CINAHL, EMBASE and OpenGrey (PROSPERO protocol: CRD42017067431). We completed the quality assessment using the Q-Genie tool. 2353 articles were screened, and 43 articles were found to be eligible to be included. A meta-analysis of studies investigating LRRK2 rs34637584 confirmed that the minor allele carriers had significantly less cognitive impairment (p = 0.015). Further meta-analyses showed that GBA variants rs76763715 (p < 0.001) and rs421016 (p = 0.001) were significantly associated with more cognitive impairment in people with PD. Minor alleles of GBA variants rs76763715, rs421016, rs387906315 and rs80356773 were associated with more depressive symptoms in PD. Moreover, APOE ε4 allele has been associated with more cognitive impairment in PD. BDNF (rs6265) and CRY1 (rs2287161) variants have been associated with more depressive symptoms in people with PD. PD carriers of GBA variants are at high risk for cognitive decline and depression. Screening for these variants may facilitate early identification and effective management of these non-motor symptoms. The molecular mechanisms underlying favourable cognitive functioning in LRRK2 rs34637584 variant carriers warrant further investigation.
Highlights
Complete List of Authors: D’Souza, Tyrra; Institute of Psychiatry, Psychology and Neuroscience, King's College London, Old age Psychiatry
Initial screening of the databases resulted in 2353 titles. 1647 were found in a joint ev search on PsychINFO and EMBASE, 685 on PubMed, five on CINAHL and 16 on OpenGrey. 43 articles were eligible to be included in this systematic review
We systematically reviewed all studies that investigated the associations between various genetic variants and cognitive impairment and/or depressive
Summary
Serotonin and dopamine are the two important neurotransmitters that are involved in the pathophysiology of depression. Their levels in synaptic clefts are regulated by neurotransmitter transporters, and it is the genetic variations of these transporters that are hypothesised as potential risk factors for depression in PD. Where the serotonin transporter gene (SLC6A4) has been extensively studied as a genetic risk factor for depression in people without PD [19], the dopamine transporter gene (SLC6A3) has been examined as a potential candidate gene for depression in PD [20].
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