Genetic factors influencing frontostriatal dysfunction and the development of dementia in Parkinson's disease

Abstract

The dual syndrome hypothesis for cognitive impairment in Parkinson's disease (PD) establishes a dichotomy between a frontrostriatal dopamine-mediated syndrome, which leads to executive deficits, and a posterior cortical syndrome, which leads to dementia. Certain genes have been linked to these syndromes although the exact contribution is still controversial. The study’s objective was to investigate the role of APOE, MAPT, COMT, SNCA and GBA genes in the dual syndromes. We genotyped APOE (rs429358 and rs7412), MAPT (rs9468), COMT (rs4680) and SNCA (rs356219) risk polymorphisms and sequenced GBA in a cohort of 298 PD patients. The degree of dopaminergic depletion was investigated with [123I]FP-CIT SPECTs and the presence of dementia was ascertained with a long-term review based on established criteria. The association between genetic and imaging parameters was studied with linear regression, and the relationship with dementia onset with Cox regression. We found that APOE2 allele (Pput = 0.002; Pcau = 0.01), the minor allele 'G' in SNCA polymorphism (Pput = 0.02; Pcau = 0.006) and GBA deleterious variants in (Pput = 0.01; Pcau = 0.001) had a detrimental effect on striatal [123I]FP-CIT uptake in PD. Conversely, Met/Met carriers in COMT polymorphism had increased caudate uptake (Pcau = 0.03). The development of dementia was influenced by APOE4 allele (HR = 1.90; P = 0.03) and GBA deleterious variants (HR = 2.44; P = 0.01). Finally, we observed no role of MAPT locus in any of the syndromes. As a conclusion, APOE2, SNCA, COMT and GBA influence frontostriatal dysfunction whereas APOE4 and GBA influence the development of dementia, suggesting a double-edged role of GBA. The dichotomy of the dual syndromes may be driven by a broad dichotomy in these genetic factors.

In vivo cholinergic basal forebrain atrophy predicts cognitive decline in de novo Parkinson’s disease

“…The extent to which our findings can be reconciled with previous research on genotype–phenotype associations that may underlie the cognitive heterogeneity in early Parkinson’s disease warrants further investigation. Such research has revealed a strong influence of risk alleles in the genes encoding for the apolipoprotein E ( APOE ) and the microtubule-associated protein tau ( MAPT ) on cognitive decline in Parkinson’s disease and the development of dementia ( Williams-Gray et al , 2009 a , b ; Morley et al , 2012 ; Mata et al , 2014 ; Huertas et al , 2017 ). Additionally, functional MRI studies in patients with early Parkinson’s disease show an association between these genotypes and reduced brain activation in medial temporal and parietal regions during memory and visuospatial tasks, respectively, but no association with fronto-striatal function ( Nombela et al , 2014 ; Winder-Rhodes et al , 2015 ).…”

Apolipoprotein E Fragmentation within Lewy Bodies of the Human Parkinson's Disease Brain

“…Human apolipoprotein E (apoE) is a polymorphic gene that includes apoE2, apoE3, and apoE4, which differ by single amino acid substitutions involving cysteine-arginine replacements at positions 112 and 158 [ 4 ]. Although inheritance of APOE4 allele is a well-known risk factor for dementia, whether it poses a similar risk in PD has yielded conflicting results (for examples see [ 5 – 12 ]).…”

Catechol-O-methyltransferase (COMT) genetic variants are associated with cognitive decline in patients with Parkinson's disease

“…However, in this study, we did not discover any association between the genotypes of rs4680 and either cognitive status or cognitive decline to dementia during the follow-up period. Consistently, several cross-sectional studies of European PD patients also failed to identify the association between rs4680 and the risk of dementia [23,25]. A 5-year longitudinal follow-up study of a population-representative cohort of newly diagnosed patients with PD in the United Kingdom (CamPaIGN study) showed that the COMT genotype had no effect on dementia, although it had a significant effect on the performance in the Tower of London test (a frontostriatal task) [12].…”