Summations:
1. Available evidence confirms that the LRRK2 variant rs34637584 is associated with less cognitive impairment in people with PD.
2. GBA variants rs76763715 and rs421016 are associated with more severe cognitive impairment in people with PD.
3. The GBA variants rs76763715, rs421016, rs387906315 and rs80356773 have been significantly associated with the onset of depressive symptoms in PD.
Considerations:
1. This systematic review has not included studies that were not published in English. It did not include gene expression and epigenetic studies.
2. Most of the included genetic association studies were small, and they were prone to type II error.
3. There was substantial heterogeneity among the included studies.
Introduction
Parkinson’s disease (PD) is a degenerative neurological disorder that comprises both motor and non-motor manifestations. Various non-motor symptoms emerge throughout the progression of PD, and they may become apparent even before the manifestation of motor symptoms. Such symptoms include insomnia, depression, anxiety and cognitive impairment, including Parkinson’s disease dementia (PDD) (Park & Stacy, Reference Park and Stacy2009). Mild cognitive impairment (MCI) occurs early in the course of PD (Muslimovic et al., Reference Muslimovic, Post, Speelman and Schmand2005), and it affects various cognitive domains including, visuospatial, attentional and executive (Pedersen et al., Reference Pedersen, Larsen, Tysnes and Alves2013). Up to 80% of people with PD will progress from MCI to PDD, after having PD for 15–20 years (Aarsland & Kurz, Reference Aarsland and Kurz2010).
The understanding of cognitive decline in PD is important, because it has direct relations to quality of life, morbidity, nursing home placements and hospital admissions (Vossius et al., Reference Vossius, Larsen, Janvin and Aarsland2011). Therefore, many studies have investigated the associations between genetic variants and cognitive impairment in PD; for example, apolipoprotein E allele (APOE) has been associated with the early onset of PDD and more cognitive decline in PD (Morley et al., Reference Morley, Xie, Hurtig, Stern, Colcher, Horn, Dahodwala, Duda, Weintraub, Chen-Plotkin, Van Deerlin, Falcone and Siderowf2012; Gomperts et al., Reference Gomperts, Locascio, Rentz, Santarlasci, Marquie, Johnson and Growdon2013). However, the results of studies investigating this genetic association have been inconsistent (Kurz et al., Reference Kurz, Dekomien, Nilsen, Larsen, Aarsland and Alves2009; Williams-Gray et al., Reference Williams-Gray, Goris, Saiki, Foltynie, Compston, Sawcer and Barker2009). Other genetic correlates include microtubule-associated protein tau (MAPT) H1 haplotype (Goris et al., Reference Goris, Williams-Gray, Clark, Foltynie, Lewis, Brown, Ban, Spillantini, Compston, Burn, Chinnery, Barker and Sawcer2007) and variants in the glucosidase, beta acid (GBA) gene, which are not only predispositions to PD (Neumann et al., Reference Neumann, Bras, Deas, O’sullivan, Parkkinen, Lachmann, Li, Holton, Guerreiro, Paudel, Segarane, Singleton, Lees, Hardy, Houlden, Revesz and Wood2009) but have also been found to have associations with cognitive impairment in PD (Alcalay et al., Reference Alcalay, Caccappolo, Mejia-Santana, Tang, Rosado, Orbe Reilly, Ruiz, Ross, Verbitsky, Kisselev, Louis, Comella, Colcher, Jennings, Nance, Bressman, Scott, Tanner, Mickel, Andrews, Waters, Fahn, Cote, Frucht, Ford, Rezak, Novak, Friedman, Pfeiffer, Marsh, Hiner, Siderowf, Payami, Molho, Factor, Ottman, Clark and Marder2012). Contrary to this, not all genetic variants, associated with PD, have relations to cognitive impairment in PD. For example, variants of leucine-rich repeat kinase 2 (LRRK2) are the most prevalent known cause of autosomal dominant PD, but a clear association has not been determined between the gene variants and cognition (Alcalay et al., Reference Alcalay, Mejia-Santana, Mirelman, Saunders-Pullman, Raymond, Palmese, Caccappolo, Ozelius, Orr-Urtreger, Clark, Giladi, Bressman and Marder2015; Kalia et al., Reference Kalia, Lang, Hazrati, Fujioka, Wszolek, Dickson, Ross, Van Deerlin, Trojanowski, Hurtig, Alcalay, Marder, Clark, Gaig, Tolosa, Ruiz-Martínez, Marti-Masso, Ferrer, López de Munain, Goldman, Schüle, Langston, Aasly, Giordana, Bonifati, Puschmann, Canesi, Pezzoli, Maues De Paula, Hasegawa, Duyckaerts, Brice, Stoessl and Marras2015; Somme et al., Reference Somme, Molano Salazar, Gonzalez, Tijero, Berganzo, Lezcano, Fernandez Martinez, Zarranz and Gómez-Esteban2015).
Another prevalent non-motor manifestation of PD is depression. The reported prevalence of depression in people with PD has varied from 40% to 90% (Cummings, Reference Cummings1991; Marsh, Reference Marsh2000). Despite there being an abundance of literature regarding the genetics of depression (Anguelova et al., Reference Anguelova, Benkelfat and Turecki2003), research is sparse in regards to the genetic associations of depression in the context of PD. 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 (Wendland et al., Reference Wendland, Martin, Kruse, Lesch and Murphy2006), the dopamine transporter gene (SLC6A3) has been examined as a potential candidate gene for depression in PD (Ohadi et al., Reference Ohadi, Shirazi, Tehranidoosti, Moghimi, Keikhaee, Ehssani, Aghajani and Najmabadi2006). In addition, variants in the parkin gene (PARK2) have also been shown to contribute to a heightened risk of both depression and anxiety in people with PD, especially to those with early onset PD (Arabia et al., Reference Arabia, Grossardt, Geda, Carlin, Bower, Ahlskog, Maraganore and Rocca2007).
There are currently no systematic reviews that comprehensively summarise the relevant literature regarding the effects of genetic variants on non-motor symptoms in PD. This systematic review will be the first to provide a cohesive summary of all genetic association studies that have investigated the genetic factors associated with cognitive impairment and depression in people with PD. This review aims to enhance the understanding of the neurobiology underlying cognitive impairment and depression in people with PD.
Materials and methods
Study design
The protocol of this systematic review has been registered (PROSPERO protocol registration number: CRD42017067431) and is available online (http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42017067431).
Inclusion criteria
All articles studying human participants with a clinical diagnosis of PD, irrespective of their age and gender, were considered. Animal studies and in vitro studies were excluded. Studies that investigated common and rare genetic variations as well as cognitive impairment and/or depressive symptoms as outcome were included. Therefore, genetic association studies that did not include either of these as outcome variables were excluded. All relevant cohort studies, case controls and case series were included. Studies were not excluded because of their controls or the lack of them.
Search strategy
A systematic search was carried out in January 2019 using the following five databases: PubMed (1996–present), PsycINFO (1806–present), CINAHL (1981–present), EMBASE (1974–present) and OpenGrey. The search strategy comprised both ‘Population’ AND ‘Exposure’ AND ‘Outcome’ terms. These terms were searched for in the titles, abstracts and full texts. ‘Parkinson*’ was the population search term. The exposure search terms that were included were: ‘Gene*’, OR ‘LRRK2’, OR ‘GBA’, OR ‘SNCA’. The outcome search terms that were used included were: (‘Cognition’ OR ‘Cognitive’ OR ‘Memory’) OR (‘Depression’ OR ‘Depressive’). Articles that were not published in English were not included.
Study selection
All articles obtained following the search of key terms were screened for their eligibility. The duplicates were removed using Mendeley Desktop 1.17.1 (Mendeley Ltd., London, UK). Articles were initially screened by their titles. The abstracts of remaining articles were then screened for relevance and were evaluated for their eligibility. Articles that did not have cognition or depression as an outcome variable and/or did not include PD service users as participants were deemed ineligible. Full texts of the remaining pertinent articles were then retrieved and assessed. All eligible articles were included in this systematic review.
Quality assessment
The risk of bias and quality assessment of all eligible studies were carried out using the ‘Q-Genie’, a quality assessment tool for genetic association studies (Sohani et al., Reference Sohani, Meyre, De Souza, Joseph, Gandhi, Dennis, Norman and Anand2015). The Q-Genie assesses the following 11 dimensions: (i) the rationale for study, (ii) selection and definition of outcome, (iii) selection and comparability of comparison groups, (iv) technical classification of the genetic variant(s), (v) non-technical classification of the genetic variant(s), (vi) other sources of bias, (vii) sample size and power, (viii) a priori planning of statistical analyses, (ix) statistical methods and control for confounding, (x) tests of assumptions and inferences for the genetic analyses and (xi) appropriate interpretation of the study results. Each dimension is scored on a scale from one (poor) to seven (excellent). For studies with control group, Q-Genie total scores ≤35 indicate poor quality, total scores more than 45 indicate good quality and total scores between 36 and 45 indicate moderate quality. Total scores of ≤35 for studies with control groups and ≤32 for studies without control groups are rated having poor quality. Scores ranging between >35 and ≤45 for studies with control groups and >32 ≤40 without are rated having moderate quality, and those with scores >45 for with control groups and >42 for without are deemed good quality. The reliability and validity of the Q-Genie tool has already been demonstrated (Sohani et al., Reference Sohani, Sarma, Alyass, De Souza, Robiou-Du-Pont, Li, Mayhew, Yazdi, Reddon, Lamri, Stryjecki, Ishola, Lee, Vashi, Anand and Meyre2016).
Data extraction
The data extracted from eligible studies were (i) Participants: The size of the cohort and their average age and standard deviation at the time of the study. Similarly, the corresponding Unified Parkinson’s Disease Rating Scale (UPDRS) (Martinez-Martin et al., Reference Martinez-Martin, Gil-Nagel, Gracia, Gomez, Martinez-Sarries and Bermejo1994) scores for each subgroup were extracted for indicating the severity of PD. (ii) Exposure: Gene names and the investigated single-nucleotide variants were extracted with their ‘rs’ number, if stated. When the included studies have not reported the ‘rs’ numbers, we searched the dbSNP database (https://www.ncbi.nlm.nih.gov/snp) with the reported names of the variants. When our search could not establish an unique dbSNP identifier, we have reported the variant name as it was reported by the original study authors. (iii) Outcome: The outcome was classified as either ‘cognition’ or ‘depression’ to signify what was being measured. The measurement tool or test used to measure either outcome was recorded, for example, ‘Mini-mental State Examination’ (MMSE) (Folstein et al., Reference Folstein, Folstein and Mchugh1975) or ‘Beck Depression Inventory’ (Beck et al., Reference Beck, Steer and Brown1996). We obtained mean differences between groups with statistical significance, as well as effect sizes and confidence intervals, if reported. Duration of follow-up was also obtained, if applicable.
Data synthesis and analyses
The data were firstly classified under the exposure variable (genes), and then classified under the outcome variables (cognition or depression). If three or more studies have investigated the association between a specific genetic variant and cognitive impairment or depression in PD, we combined the reported mean differences or effect sizes using fixed effect meta-analyses. Their degree of heterogeneity was assessed using Cochrane’s Q statistics and Higgin’s I2. We conducted the meta-analyses using the STATA 15.1 software (StataCorp LLC, TX, USA) and its ‘metan’ command.
Results
Included studies
Fig. 1 presents the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) flow chart that exhibits the process of identifying all eligible studies. Initial screening of the databases resulted in 2353 titles. About 1647 were found in a joint search on PsychINFO and EMBASE, 685 on PubMed, 5 on CINAHL and 16 on OpenGrey. About 43 articles were eligible to be included in this systematic review. Among them, 24 measured cognition as an outcome variable, 13 measured depression as an outcome variable and 6 measured both. LRRK2 and GBA were the most commonly investigated genes. Fourteen studies investigated PD service users, who are carriers of one of the GBA variants (rs76763715, rs75548401, rs421016, rs387906315 and rs80356773). Fourteen studies studied PD service users, who are carriers of LRRK2 variants (rs34637584, rs33939927, rs11564148 and rs34778348). Other genes that have been investigated included SNCA (Zheng et al., Reference Zheng, Yang, Zhao, Tian, Huang, Chen and Xu2017), APOE, BDNF (rs6265), SLC6A4, COMT (Val158Met) and MAPT. Only 26 (60.5%) included studies have had sample sizes above 100. We present the quality assessment scores of the included studies in the supplementary information Table 1. Their Q-Genie (Sohani et al., Reference Sohani, Meyre, De Souza, Joseph, Gandhi, Dennis, Norman and Anand2015) total scores ranged from 27 (Estanga et al., Reference Estanga, Rodriguez-Oroz, Ruiz-Martinez, Barandiaran, Gorostidi, Bergareche, Mondragon, Lopez de Munain and Marti-Masso2014) to 55 (Burn et al., Reference Burn, Tiangyou, Allcock, Davison and Chinnery2006) with main areas of concern being the technical and non-technical classification of the genetic exposure variables.
A PRISMA flowchart illustrating the selection process of the 43 articles obtained with reasons for exclusion. PD, Parkinson’s Disease, *Cannot obtain full text of grey literature and author(s) could not be contacted.
Studies investigating the effects of LRRK2 variants on cognition in people with PD
UPDRS, Unified Parkinson’s Disease Rating Scale; HVLT, Hamilton Verbal Learning Test; MMSE, Mini-Mental State Examination; MoCA, Montreal Cognitive Assessment; MDRS, Mattis Dementia Rating Scale; ADAS, The Alzheimer’s Disease Assessment Scale – Cognitive; RAVLT, Rey’s Auditory Verbal Learning Test; JLO, Judgment of Line Orientation Test; FAB, Frontal Assessment Battery; n/s, not specified.
LRRK2
Table 1 summarises the findings of the studies that investigated the effects of LRRK2 variants on cognition in people with PD. Four of these studies have reported that carriers of minor allele of rs34637584 exhibited significantly less cognitive impairment, while comparing with PD non-carriers (Wang et al., Reference Wang, Cai, Gu, Ma, Zheng, Tang, Xu, Zhou, Feng, Wang, Chen and Chan2014; Alcalay et al., Reference Alcalay, Mejia-Santana, Mirelman, Saunders-Pullman, Raymond, Palmese, Caccappolo, Ozelius, Orr-Urtreger, Clark, Giladi, Bressman and Marder2015; Somme et al., Reference Somme, Molano Salazar, Gonzalez, Tijero, Berganzo, Lezcano, Fernandez Martinez, Zarranz and Gómez-Esteban2015; Srivatsal et al., Reference Srivatsal, Cholerton, Leverenz, Wszolek, Uitti, Dickson, Weintraub, Trojanowski, Van Deerlin, Quinn, Chung, Peterson, Factor, Wood-Siverio, Goldman, Stebbins, Bernard, Ritz, Rausch, Espay, Revilla, Devoto, Rosenthal, Dawson, Albert, Mata, Hu, Montine, Johnson, Montine, Edwards, Zhang and Zabetian2015). We conducted a meta-analysis of studies investigating this specific variant using different outcome measures and calculated their standardised mean difference (SMD = 0.21; 95% CI 0.04–0.38) (Fig. 2) (Supplementary Figure 1). The meta-analysis confirmed that people with PD, who carried the minor allele of rs34637584, had significantly less cognitive impairment than non-carriers (z = 2.43; p = 0.015). However, studies investigating the effects of other LRRK2 variants, such as rs33939927, rs11564148 and rs33949390, did not report statistically significant difference on cognition between the carriers and non-carriers (Alcalay et al., Reference Alcalay, Mejia-Santana, Tang, Rakitin, Rosado, Ross, Verbitsky, Kisselev, Louis, Comella, Colcher, Jennings, Nance, Bressman, Scott, Tanner, Mickel, Andrews, Waters, Fahn, Cote, Frucht, Ford, Rezak, Novak, Friedman, Pfeiffer, Marsh, Hiner, Siderowf, Ottman, Clark, Marder and Caccappolo2010; Belarbi et al., Reference Belarbi, Hecham, Lesage, Kediha, Smail, Benhassine, Ysmail-Dahlouk, Lohman, Benhabyles, Hamadouche, Assami, Brice and Tazir2010; Shanker et al., Reference Shanker, Groves, Heiman, Palmese, Saunders-Pullman, Ozelius, Raymond and Bressman2011; Ben Sassi et al., Reference Ben Sassi, Nabli, Hentati, Nahdi, Trabelsi, Ben Ayed, Amouri, Duda, Farrer and Hentati2012; Estanga et al., Reference Estanga, Rodriguez-Oroz, Ruiz-Martinez, Barandiaran, Gorostidi, Bergareche, Mondragon, Lopez de Munain and Marti-Masso2014; Zheng et al., Reference Zheng, Pei, Liu, Zhou, Xian, Fang, Chen and Wu2015; Hong et al., Reference Hong, Kim, Park, Lee, Oh, Chung, Kim, Sung, Lyoo, Lee, Kwon, Kim, Shin, Park, Park, Kim, Lee, Koh, Baik, Kim, Ma, Kim and Kim2017). Most of these studies were cross-sectional. They had relatively small sample sizes, and they have not reported power analyses (Hong et al., Reference Hong, Kim, Park, Lee, Oh, Chung, Kim, Sung, Lyoo, Lee, Kwon, Kim, Shin, Park, Park, Kim, Lee, Koh, Baik, Kim, Ma, Kim and Kim2017). Moreover, three studies have investigated the associations between LRRK2 variants and depressive symptoms in PD. Two of them have reported that depression was significantly more prevalent among the rs34637584 minor allele carriers with PD than the non-carriers (Belarbi et al., Reference Belarbi, Hecham, Lesage, Kediha, Smail, Benhassine, Ysmail-Dahlouk, Lohman, Benhabyles, Hamadouche, Assami, Brice and Tazir2010; Kasten et al., Reference Kasten, Kertelge, Tadic, Bruggemann, Schmidt, Van Der Vegt, Siebner, Buhmann, Lencer, Kumar, Lohmann, Hagenah and Klein2012). However, another study investigating the association between LRRK2 variants and depressive symptoms in PD using the Hospital Anxiety and Depression Scale did not replicate this finding (p = 0.54) (Gaig et al., Reference Gaig, Vilas, Infante, Sierra, Garcia-Gorostiaga, Buongiorno, Schmidt, van der Vegt, Siebner, Buhmann, Lencer, Kumar, Lohmann, Hagenah and Klein2014).
The meta-analysis of five studies investigating the association between LRRK2 variant rs34637584 and cognitive impairment in people with PD.
GBA
Table 2 provides a summary of findings of the studies that investigated the effects of GBA variants on cognition in people with PD. Several studies have reported that minor allele carriers of various GBA variants had significantly worse cognitive function than the non-carriers (Alcalay et al., Reference Alcalay, Caccappolo, Mejia-Santana, Tang, Rosado, Orbe Reilly, Ruiz, Ross, Verbitsky, Kisselev, Louis, Comella, Colcher, Jennings, Nance, Bressman, Scott, Tanner, Mickel, Andrews, Waters, Fahn, Cote, Frucht, Ford, Rezak, Novak, Friedman, Pfeiffer, Marsh, Hiner, Siderowf, Payami, Molho, Factor, Ottman, Clark and Marder2012; Malec-Litwinowicz et al., Reference Malec-Litwinowicz, Rudzinska, Szubiga, Michalski, Tomaszewski and Szczudlik2014; Wang et al., Reference Wang, Cai, Gu, Ma, Zheng, Tang, Xu, Zhou, Feng, Wang, Chen and Chan2014; Zokaei et al., Reference Zokaei, Mcneill, Proukakis, Beavan, Jarman, Korlipara, Hughes, Mehta, Hu, Schapira and Husain2014; Brockmann et al., Reference Brockmann, Srulijes, Pflederer, Hauser, Schulte, Maetzler, Gasser and Berg2015; Davis et al., Reference Davis, Johnson, Leverenz, Weintraub, Trojanowski, Chen-Plotkin, Van Deerlin, Quinn, Chung, Peterson-Hiller, Rosenthal, Dawson, Albert, Goldman, Stebbins, Bernard, Wszolek, Ross, Dickson, Eidelberg, Mattis, Niethammer, Yearout, Hu, Cholerton, Smith, Mata, Montine, Edwards and Zabetian2016; Mata et al., Reference Mata, Leverenz, Weintraub, Trojanowski, Chen-Plotkin, Van Deerlin, Ritz, Rausch, Factor, Wood-Siverio, Quinn, Chung, Peterson-Hiller, Goldman, Stebbins, Bernard, Espay, Revilla, Devoto, Rosenthal, Dawson, Albert, Tsuang, Huston, Yearout, Hu, Cholerton, Montine, Edwards and Zabetian2016, Reference Mata, Johnson, Leverenz, Weintraub, Trojanowski, Van Deerlin, Ritz, Rausch, Factor, Wood-Siverio, Quinn, Chung, Peterson-Hiller, Espay, Revilla, Devoto, Yearout, Hu, Cholerton, Montine, Edwards and Zabetian2017). Alcalay et al. (Reference Alcalay, Caccappolo, Mejia-Santana, Tang, Rosado, Orbe Reilly, Ruiz, Ross, Verbitsky, Kisselev, Louis, Comella, Colcher, Jennings, Nance, Bressman, Scott, Tanner, Mickel, Andrews, Waters, Fahn, Cote, Frucht, Ford, Rezak, Novak, Friedman, Pfeiffer, Marsh, Hiner, Siderowf, Payami, Molho, Factor, Ottman, Clark and Marder2012) found that minor allele carriers of GBA variants rs76763715 and rs36806 obtained significantly less MMSE scores than the non-carriers. Moreover, a longitudinal study (Davis et al., Reference Davis, Johnson, Leverenz, Weintraub, Trojanowski, Chen-Plotkin, Van Deerlin, Quinn, Chung, Peterson-Hiller, Rosenthal, Dawson, Albert, Goldman, Stebbins, Bernard, Wszolek, Ross, Dickson, Eidelberg, Mattis, Niethammer, Yearout, Hu, Cholerton, Smith, Mata, Montine, Edwards and Zabetian2016) investigating the effects of GBA variants, including rs2230288, reported that significantly more carriers developed MCI or PDD, compared to non-carriers (OR = 4.65; 95% CI 1.72–7.58; p = 0.002). Malec-Litwinowicz et al. (Reference Malec-Litwinowicz, Rudzinska, Szubiga, Michalski, Tomaszewski and Szczudlik2014)followed up only five people with PD and GBA variants, and found that minor allele carriers of rs76763715 developed significantly more cognitive impairment than non-carriers over time. GBA variant rs2230288 has been reported to be associated with significantly worse visuospatial abilities (Mata et al., Reference Mata, Johnson, Leverenz, Weintraub, Trojanowski, Van Deerlin, Ritz, Rausch, Factor, Wood-Siverio, Quinn, Chung, Peterson-Hiller, Espay, Revilla, Devoto, Yearout, Hu, Cholerton, Montine, Edwards and Zabetian2017). However, there are studies that have reported that minor allele carriers of GBA variants rs76763715 and rs421016 did not differ significantly from non-carriers on their cognition (Alcalay et al., Reference Alcalay, Mejia-Santana, Tang, Rakitin, Rosado, Ross, Verbitsky, Kisselev, Louis, Comella, Colcher, Jennings, Nance, Bressman, Scott, Tanner, Mickel, Andrews, Waters, Fahn, Cote, Frucht, Ford, Rezak, Novak, Friedman, Pfeiffer, Marsh, Hiner, Siderowf, Ottman, Clark, Marder and Caccappolo2010; Brockmann et al., Reference Brockmann, Srulijes, Hauser, Schulte, Csoti, Gasser and Berg2011). One of them was a longitudinal study including 3 years of follow-up, but it included only 13 people with GBA variants (Brockmann et al., Reference Brockmann, Srulijes, Hauser, Schulte, Csoti, Gasser and Berg2011). We conducted meta-analyses of the studies investigating the effects of GBA rs76763715 (Fig. 3(A)) and rs421016 (Fig. 3(B)) variants on cognition in people with PD (Supplementary Figure 1). Our meta-analyses confirmed that both rs76763715 (z = 3.54; p < 0.001) and rs421016 (z = 3.45; p = 0.001) variants were significantly associated with more cognitive impairment in people with PD.
Studies investigating the effects of GBA variants on cognition in people with PD
UPDRS, Unified Parkinson’s Disease Rating Scale; MMSE, Mini-Mental State Examination; CVLT-II, California Verbal Learning Test-II; BVRT, Benton Visual Retention Test; COWAT, Controlled Oral Word Association Test; WMS-R, Wechsler Memory Scale–Revised; MoCA, Montreal Cognitive Assessment; ADAS, The Alzheimer’s Disease Assessment Scale - Cognitive; VSTM, experimental visual short-term memory task; JLO, Benton Judgment of Line Orientation; HVLT-R, Hamilton Verbal Learning Test-Revised; n/s, not specified.
The meta-analyses of studies investigating the associations between cognitive impairment in people with PD and GBA variants rs76763715 (A) and rs421016 (B).
Table 3 summarises the findings of five studies that investigated the associations between GBA variants and depressive symptoms in people with PD. Four studies that investigated GBA variant rs421016 (Brockmann et al., Reference Brockmann, Srulijes, Hauser, Schulte, Csoti, Gasser and Berg2011; Swan et al., Reference Swan, Ortega, Barrett, Soto-Valencia, Boschung, Deik Acosta Madiedo, Sarva, Cabassa, Johannes, Raymond, Miravite, Severt, Sachdev, Shanker, Bressman and Saunders-Pullman2014; Wang et al., Reference Wang, Cai, Gu, Ma, Zheng, Tang, Xu, Zhou, Feng, Wang, Chen and Chan2014; Dan et al., Reference Dan, Wang, Zhang, Gu, Zhou, Ma and Chan2016) and two studies that investigated GBA variant rs76763715 (Brockmann et al., Reference Brockmann, Srulijes, Hauser, Schulte, Csoti, Gasser and Berg2011; Swan et al., Reference Swan, Ortega, Barrett, Soto-Valencia, Boschung, Deik Acosta Madiedo, Sarva, Cabassa, Johannes, Raymond, Miravite, Severt, Sachdev, Shanker, Bressman and Saunders-Pullman2014) have consistently reported significantly more depressive symptoms in people with PD carrying minor alleles of these variants. GBA variants rs387906315 and rs80356773 have also been associated with significantly higher prevalence of depression among people with PD (Swan et al., Reference Swan, Ortega, Barrett, Soto-Valencia, Boschung, Deik Acosta Madiedo, Sarva, Cabassa, Johannes, Raymond, Miravite, Severt, Sachdev, Shanker, Bressman and Saunders-Pullman2014). However, a small longitudinal study following only 13 people with PD and GBA variants for 3 years has reported that mood symptoms did not differ significantly between the carriers and non-carriers during their follow-up (Brockmann et al., Reference Brockmann, Srulijes, Hauser, Schulte, Csoti, Gasser and Berg2011). This study did not report relevant power analysis, and it did not consider the effects of potential confounders such as age and gender during their analyses (Brockmann et al., Reference Brockmann, Srulijes, Hauser, Schulte, Csoti, Gasser and Berg2011). Another small longitudinal study investigating a heterogeneous PD group with one of several LRRK2 and GBA variants, including rs34637584, rs421016 and rs76763715, has reported them having significantly higher incidence and earlier onset of depressive symptoms than the non-carriers (Da Silva et al., Reference Da Silva, de M Abreu, Cabello Acero, Campos, Pereira, De A Ramos, Nascimento, Voigt, Rosso, Araujo Leite, Vasconcellos, Nicaretta, Della Coletta, da Silva, Gonçalves, Dos Santos, Calassara, Valença, de M Martins, Santos-Rebouças and Pimentel2017) supplementary information Table 2.
Studies investigating the effects of GBA variants on depressive symptoms in people with PD
UPDRS, Unified Parkinson’s Disease Rating Scale; BDI-II, Beck’s Depression Inventory II; CES-D, Center for Epidemiologic Studies-Depression; HDRS, Hamilton Depression Scale; n/s, not specified.
APOE
Most of the studies that investigated the effects of APOE ε4 allele on cognition in people with PD have documented a weak association between the allele and cognitive impairment in PD (Williams-Gray et al., Reference Williams-Gray, Evans, Goris, Foltynie, Ban, Robbins, Brayne, Kolachana, Weinberger, Sawcer and Barker2009). Significantly more rapid cognitive decline, measured by the Hamilton Verbal Learning test (Mata et al., Reference Mata, Leverenz, Weintraub, Trojanowski, Hurtig, Van Deerlin, Ritz, Rausch, Rhodes, Factor, Wood-Siverio, Quinn, Chung, Peterson, Espay, Revilla, Devoto, Hu, Cholerton, Wan, Montine, Edwards and Zabetian2014) and the Mattis Dementia Rating Scale-II (Morley et al., Reference Morley, Xie, Hurtig, Stern, Colcher, Horn, Dahodwala, Duda, Weintraub, Chen-Plotkin, Van Deerlin, Falcone and Siderowf2012), has been reported in people with PD carrying APOE ε4 allele. However, there are negative studies that failed to replicate this association (Troster et al., Reference Troster, Fields, Paolo and Koller2006; Nombela et al., Reference Nombela, Rowe, Winder-Rhodes, Hampshire, Owen, Breen, Duncan, Khoo, Yarnall, Firbank, Chinnery, Robbins, O’Brien, Brooks, Burn and Barker2014). A prior meta-analysis of studies that investigated the genetic association between APOE ε4 allele and cognitive impairment in PD has reported that APOE ε4 allele significantly increases the risk of PDD (OR = 1.74; 95% CI 1.36–2.23; p = 0.0001). However, this meta-analysis has documented significant heterogeneity of relevant studies, and the possibility of publication bias (Williams-Gray et al., Reference Williams-Gray, Evans, Goris, Foltynie, Ban, Robbins, Brayne, Kolachana, Weinberger, Sawcer and Barker2009).
SLC6A4
Three studies have investigated the association between serotonin transporter gene (SLC6A4) 5-HTTLPR variant and depressive symptoms in people with PD. Earliest and the smallest (N = 32) of them reported that people with PD carrying short allele of the 5-HTTLPR variant scored significantly higher on depressive symptoms than corresponding non-carriers (Menza et al., Reference Menza, Palermo, Dipaola, Sage and Ricketts1999). Later, two relatively larger studies have clarified that people with PD carrying this short allele did not differ significantly from non-carriers on their depressive symptoms (Burn et al., Reference Burn, Tiangyou, Allcock, Davison and Chinnery2006; Dissanayaka et al., Reference Dissanayaka, Silburn, O’sullivan and Mellick2009). Moreover, a recent large genetic association study using multiple population-based and case control samples regardless of their PD diagnoses has reported that the association between SLC6A4 5-HTTLPR variant and depressive symptoms was not statistically significant (Border et al., Reference Border, Johnson, Evans, Smolen, Berley, Sullivan and Keller2019).
Other genetic variants associated with cognitive impairment in PD
Supplementary information Table 3 provides an overview of the studies that investigated the associations between cognitive impairment in PD and various genetic variants. A recent study has investigated the associations between 249 336 genetic variants and various cognitive functions in 1105 people with PD, and it has reported false discovery rate adjusted statistically significant associations of 18 genetic variants with the results of one of the cognitive tests. These genetic variants include PARP4 (rs9318600, rs9581094), MDM1 (rs117673673), ALS2CR11 (rs72939119), FAT3 (rs75081660), RYR1 (rs55876273), IFT140 (rs146128830), MTCL1 (rs34877994), MOCS3 (rs7269297), RASAL3 (rs56209154) and ACSBG2 (rs79266675) (Mata et al., Reference Mata, Johnson, Leverenz, Weintraub, Trojanowski, Van Deerlin, Ritz, Rausch, Factor, Wood-Siverio, Quinn, Chung, Peterson-Hiller, Espay, Revilla, Devoto, Yearout, Hu, Cholerton, Montine, Edwards and Zabetian2017). Most of these reported genetic associations have not been replicated so far, so they need to be interpreted with caution. People with PD carrying at least one Met allele of BDNF (rs6265) variant have been found to have significantly more cognitive impairment than non-carriers (Altmann et al., Reference Altmann, Schumacher-Schuh, Rieck, Callegari-Jacques, Rieder and Hutz2016). Moreover, MAPT H1/H1 genotype has been reported to be an independent predictor of PDD (Williams-Gray et al., Reference Williams-Gray, Evans, Goris, Foltynie, Ban, Robbins, Brayne, Kolachana, Weinberger, Sawcer and Barker2009). Low-activity COMT (Val158Met) Met/Met genotype has been associated with cognitive impairment in PD (Williams-Gray et al., Reference Williams-Gray, Hampshire, Barker and Owen2008), but another study failed to verify this association (Nombela et al., Reference Nombela, Rowe, Winder-Rhodes, Hampshire, Owen, Breen, Duncan, Khoo, Yarnall, Firbank, Chinnery, Robbins, O’Brien, Brooks, Burn and Barker2014). Furthermore, a PICALM variant (rs3851179) has been reported to be associated with cognitive impairment in people with PD older than 70 years (Barrett et al., Reference Barrett, Koeppel, Flanigan, Turner and Worrall2016), and this finding needs further replication.
Other genetic variants associated with depression in PD
Supplementary information Table 4 summarises the findings of the studies that investigated the associations between various genetic variants and depressive symptoms in PD. BDNF (rs6265) variant has been associated with depression in people with PD, after accounting for the effects of potential confounders such as gender, disease progression and motor symptoms (p = 0.046) (Cagni et al., Reference Cagni, Campelo, Coimbra, Barbosa, Junior, Neto, Ribeiro, Júnior, Gomes de Andrade and Silva2017). TEF TT genotype (Hua et al., Reference Hua, Liu, Kuo, Zhao, Chen, Zhang, Wang, Guo, Wang, Xiao, Kwan and Wu2012), CRY1 CC genotype (Hua et al., Reference Hua, Liu, Kuo, Zhao, Chen, Zhang, Wang, Guo, Wang, Xiao, Kwan and Wu2012), SLC6A15 (rs1545843) (Zheng et al., Reference Zheng, Yang, Zhao, Tian, Huang, Chen and Xu2017) and TPH2 (rs78162420) (Zheng et al., Reference Zheng, Yang, Zhao, Tian, Huang, Chen and Xu2017) have been associated with depression in people with PD, and these findings have not been replicated so far. Moreover, people with PD carrying SNCA Rep1 (CA)12/12 genotype reportedly has a reduced risk of depression (p = 0.02) (Dan et al., Reference Dan, Wang, Zhang, Gu, Zhou, Ma and Chan2016). Another study has reported a significant association (p = 0.003) between a specific CNR1 genotype and reduced risk of depression in PD (Barrero et al., Reference Barrero, Ampuero, Morales, Vives, De Dios Luna Del Castillo, Hoenicka and García Yébenes2005).
Discussion
For the first time, we systematically reviewed all studies that investigated the associations between various genetic variants and cognitive impairment and/or depressive symptoms in people with PD. The systematic review found that LRRK2 variant rs34637584 has been associated with significantly less cognitive impairment in PD, and we confirmed it by a meta-analysis. More meta-analyses confirmed that GBA variants rs76763715 (p < 0.001) and rs421016 (p = 0.001) were significantly associated with more cognitive impairment in people with PD. Moreover, the systematic review has listed the genetic variants that have been associated with depression in PD, including GBA (rs76763715, rs421016, rs387906315 and rs80356773, BDNF (rs6265) and CRY1 (rs2287161) variants.
The strengths of this systematic review include its broad inclusion criteria, searching multiple databases including grey literature, following PRISMA guidelines and quality assessment using the Q-Genie instrument. Nonetheless, we must acknowledge the limitations of excluding the studies that were not published in English, of not including gene expression and epigenetic studies, and of substantial heterogeneity among the included studies. Most of the included studies were small, and they have not reported sample size estimation or power analysis, so they were prone to type II error. Moreover, there were only five longitudinal studies, and other studies did not evaluate the longitudinal changes in cognition and mood of their participants. Many studies have recruited participants only from specific ethnic groups, such as Ashkenazi Jews, and their findings have limited generalisability. Furthermore, there are concerns over the validity of outcome measures like MMSE, employed by these studies, for assessing cognition and depressive symptoms in people with PD.
LRRK2 variants have the largest body of evidence in this topic. LRRK2 variant rs34637584 may either delay or prevent cognitive decline on its own or because of its interactions with other genetic variants in people with PD (Alcalay et al., Reference Alcalay, Mejia-Santana, Mirelman, Saunders-Pullman, Raymond, Palmese, Caccappolo, Ozelius, Orr-Urtreger, Clark, Giladi, Bressman and Marder2015; Somme et al., Reference Somme, Molano Salazar, Gonzalez, Tijero, Berganzo, Lezcano, Fernandez Martinez, Zarranz and Gómez-Esteban2015; Srivatsal et al., Reference Srivatsal, Cholerton, Leverenz, Wszolek, Uitti, Dickson, Weintraub, Trojanowski, Van Deerlin, Quinn, Chung, Peterson, Factor, Wood-Siverio, Goldman, Stebbins, Bernard, Ritz, Rausch, Espay, Revilla, Devoto, Rosenthal, Dawson, Albert, Mata, Hu, Montine, Johnson, Montine, Edwards, Zhang and Zabetian2015; Zheng et al., Reference Zheng, Yang, Zhao, Tian, Huang, Chen and Xu2017). LRRK2 encodes a kinase, and the minor allele of rs34637584 leads to increased expression and activity of LRRK2 (West et al., Reference West, Moore, Biskup, Bugayenko, Smith, Ross, Dawson and Dawson2005) because of stabilising the kinase activation loop (Gilsbach & Kortholt, Reference Gilsbach and Kortholt2014). Furthermore, the severity of Lewy body pathology correlates with the severity of cognitive impairment in PD (Irwin et al., Reference Irwin, White, Toledo, Xie, Robinson, Van Deerlin, Lee, Leverenz, Montine, Duda, Hurtig and Trojanowski2012), and LRRK2 related PD can be with or without the presence of Lewy bodies (Kalia et al., Reference Kalia, Lang, Hazrati, Fujioka, Wszolek, Dickson, Ross, Van Deerlin, Trojanowski, Hurtig, Alcalay, Marder, Clark, Gaig, Tolosa, Ruiz-Martínez, Marti-Masso, Ferrer, López de Munain, Goldman, Schüle, Langston, Aasly, Giordana, Bonifati, Puschmann, Canesi, Pezzoli, Maues De Paula, Hasegawa, Duyckaerts, Brice, Stoessl and Marras2015). Overexpression of LRRK2 leads to enlarged lysosomes, lower endolysosomal pH, impaired autophagy and diminished lysosomal degradation in vitro (Henry et al., Reference Henry, Aghamohammadzadeh, Samaroo, Chen, Mou, Needle and Hirst2015), and these changes in the morphology and function of lysosomes could be reversed by LRRK2 kinase inhibitors in vitro (Henry et al., Reference Henry, Aghamohammadzadeh, Samaroo, Chen, Mou, Needle and Hirst2015). A neuronal cell culture study using mouse embryos that were homozygous for LRRK2 rs34637584 variant has replicated these findings (Schapansky et al., Reference Schapansky, Khasnavis, Deandrade, Nardozzi, Falkson, Boyd, Sanderson, Bartels, Melrose and LaVoie2018). Despite the progress in the mechanistic understanding of LRRK2 overexpression leading to neurodegeneration in PD, the molecular mechanisms underlying relative preservation of cognitive functioning in people with PD carrying LRRK2 overexpressing variant rs34637584 remain uncertain.
GBA encodes lysosomal acid glucosylceramidase, and homozygous GBA variants cause Gaucher’s disease (GD) that is a lysosomal storage disorder. Minor alleles of GBA variants rs76763715, rs421016, rs387906315 and rs80356773 lead to glucosylceramidase protein misfolding that in turn may lead to either loss or gain of function (Sidransky & Lopez, Reference Sidransky and Lopez2012). Glucosylceramidase deficiency leads to autophagy impairment, lysosomal dysfunction and accumulation of α-synuclein oligomers. These α-synuclein oligomers disrupt misfolded glucosylceramidase and set off a vicious cycle leading to neurodegeneration and cognitive impairment in people with PD carrying GBA variants (Sidransky & Lopez, Reference Sidransky and Lopez2012). Prior studies have reported the associations between these GBA variants and increased presence of cortical Lewy bodies (Clark et al., Reference Clark, Kartsaklis, Wolf Gilbert, Dorado, Ross, Kisselev, Verbitsky, Mejia-Santana, Cote, Andrews, Vonsattel, Fahn, Mayeux, Honig and Marder2009). Our systematic review and meta-analyses have confirmed the associations of these GBA variants with cognitive impairment and depression in people with PD. There is a need for further studies investigating the clinical utility and cost-effectiveness of screening for these GBA variants for early identification of the non-motor symptoms. GBA variant rs421016 is associated with more severe phenotype of PD and GD than rs76763715 variant (Gan-Or et al., Reference Gan-Or, Amshalom, Kilarski, Bar-Shira, Gana-Weisz, Mirelman, Marder, Bressman, Giladi and Orr-Urtreger2015), and LRRK2 rs34637584 leads to more benign PD phenotype than other LRRK2 variants (Li et al., Reference Li, Tan and Yu2014). However, little is known about the differential effects of these variants on cognitive impairment and depression in people with PD (Mata et al., Reference Mata, Leverenz, Weintraub, Trojanowski, Chen-Plotkin, Van Deerlin, Ritz, Rausch, Factor, Wood-Siverio, Quinn, Chung, Peterson-Hiller, Goldman, Stebbins, Bernard, Espay, Revilla, Devoto, Rosenthal, Dawson, Albert, Tsuang, Huston, Yearout, Hu, Cholerton, Montine, Edwards and Zabetian2016). Non-manifesting LRRK2 rs34637584 carriers have been reported to have significantly more cognitive impairment than non-manifesting carriers of GBA variants (Chahine et al., Reference Chahine, Urbe, Caspell-Garcia, Aarsland, Alcalay, Barone, Burn, Espay, Hamilton, Hawkins, Lasch, Leverenz, Litvan, Richard, Siderowf, Coffey, Simuni and Weintraub2018). Hence, further investigation focusing on the effects of individual LRRK2 and GBA variants on the non-motor symptoms of PD is warranted.
Although there is substantial heterogeneity among the studies that investigated the associations between genetic variants and depressive symptoms in PD, it is possible to derive important conclusions. The studies differed widely on their participant characteristics, assessment of depressive symptoms, threshold for diagnosing depression and their analyses addressing potential confounders. Statistically significant associations between depression in PD and BDNF (rs6265), TEF TT genotype (Hua et al., Reference Hua, Liu, Kuo, Zhao, Chen, Zhang, Wang, Guo, Wang, Xiao, Kwan and Wu2012), CRY1 CC genotype (Hua et al., Reference Hua, Liu, Kuo, Zhao, Chen, Zhang, Wang, Guo, Wang, Xiao, Kwan and Wu2012), SLC6A15 variant rs1545843 (Zheng et al., Reference Zheng, Yang, Zhao, Tian, Huang, Chen and Xu2017) and TPH2 variant rs78162420 (Zheng et al., Reference Zheng, Yang, Zhao, Tian, Huang, Chen and Xu2017) have been reported. These reported genetic associations are only tentative, and they need further replication. Further larger studies including structured diagnostic interviews and detailed assessment of confounding psychosocial variables are needed for verifying these reported genetic associations. Unlike the progressive cognitive decline in PD, depressive symptoms in people with PD are often episodic and responsive to treatment with antidepressant medications. However, most of the genetic association studies investigating depression in PD are cross-sectional, and they have not added any information on the longitudinal course of depressive symptoms and their response to antidepressant medications in PD. Further longitudinal studies are needed for addressing this issue. Moreover, an SNCA genotype (Dan et al., Reference Dan, Wang, Zhang, Gu, Zhou, Ma and Chan2016), and a CNR1 genotype (Barrero et al., Reference Barrero, Ampuero, Morales, Vives, De Dios Luna Del Castillo, Hoenicka and García Yébenes2005) have been associated with reduced risk of depression in PD. There is a need for investigating whether these two genetic associations can be replicated. If they can be replicated, investigating underlying molecular mechanisms may facilitate identifying novel therapeutic targets.
Non-motor symptoms of PD have devastating consequences to the service users, their families and societies. Early identification and appropriate multidisciplinary management of non-motor symptoms may improve the quality of life of people with PD (Barone et al., Reference Barone, Erro and Picillo2017). The importance of further systematic research investigating the genetics and molecular biology of non-motor symptoms of PD cannot be overemphasised. Despite the studies highlighting the association between Lewy body pathology and cognitive impairment in PD (Irwin et al., Reference Irwin, White, Toledo, Xie, Robinson, Van Deerlin, Lee, Leverenz, Montine, Duda, Hurtig and Trojanowski2012), there is a conspicuous gap in the available literature for studies investigating the associations between SNCA variants and non-motor symptoms in PD. Moreover, poor replication and inconsistent findings of reported genetic associations can be explained by a small sample of size, lack of study power, and by the differences in outcome measures. Larger multi-centre international collaborations are necessary for conducting future genetic association studies with adequate statistical power. Developing a consensus for standardised assessment of non-motor symptoms in PD will help larger international collaborations and will enhance the generalisability of the study findings. Furthermore, future studies should consider investigating the pharmacogenetic associations between the genetic variants and clinical responses to various medications treating non-motor symptoms of PD.
Supplementary material
To view supplementary material for this article, please visit https://doi.org/10.1017/neu.2019.28
Acknowledgements
This study was funded by an internal grant of King’s College London, London, UK. We thank the authors and participants of all studies that have been included in this systematic review.
Authors’ contributions
APR conceived this study, and both APR and TD designed the review protocol. TD reviewed the literature, identified eligible studies and completed the quality assessment. TD and APR interpreted the findings of the included studies. APR performed necessary statistical analyses. TD wrote the initial draft. Both authors were involved in further revisions of the manuscript, and they have approved the final submitted version of the manuscript.
Financial support
This study was funded by an internal grant of King’s College London, London, UK.
Conflict of interest
Both authors declare that they do not have any competing interests.
