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.
Highlights
Cognitive impairment is a common and disabling non-motor symptom of Parkinson’s disease (PD)
We found that striatal dopamine transporter (DAT) availability levels in PD were influenced by apolipoprotein E gene (APOE) ε2 allele, catechol-O-methyltransferase gene (COMT) Val158Met, SNCA rs356219 and deleterious variants in GBA, whereas the development of dementia was influenced by the APOE ε4 allele and by deleterious variants in GBA
Our results suggest that APOE2, COMT and SNCA may be related to dopaminergic degeneration, while APOE4 may be related to other, non-dopaminergic degeneration mechanisms, and GBA may be implicated in both
Summary
Cognitive impairment is a common and disabling non-motor symptom of Parkinson’s disease (PD). The rate and pattern of these deficits vary greatly among PD patients, and different biological mechanisms appear to play a role [2] In this regard, the dual syndrome hypothesis was recently proposed, suggesting two facets of cognitive decline in PD: (i) changes in frontostriatal dopaminergic transmission, leading to deficits in planning, working memory, response inhibition and attentional control; and (ii) posterior cortical Lewy body pathology and secondary cholinergic loss, affecting visuospatial, mnemonic and semantic functions and leading to dementia [3]. It is possible to assess the state of the frontostriatal circuitry by imaging the striatal dopamine transporter (DAT) with [123I]FP-CIT SPECT In this scan, dopamine depletion can first be observed in the putamen, which affects the motor loop, whilst dopamine depletion in the caudate usually occurs in later stages, affecting two well-defined frontostriatal loops: the cognitive and the limbic loops [4]. The integrity of this latter pathway is essential to correct cognitive functioning, and a large number of studies have found a correlation between cognitive performance (including executive and working memory tasks) and caudate dopamine levels in PD [5]
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