OBJECTIVE: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants. METHODS: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis. RESULTS: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD. INTERPRETATION: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.

• MeSH
• alfa-synuklein genetika   MeSH
• demence s Lewyho tělísky genetika   MeSH
• dospělí MeSH
• genetická predispozice k nemoci MeSH
• jednonukleotidový polymorfismus MeSH
• lidé středního věku MeSH
• lidé MeSH
• logistické modely MeSH
• odds ratio MeSH
• Parkinsonova nemoc genetika   MeSH
• porucha chování v REM spánku genetika   MeSH
• prodromální symptomy * MeSH
• senioři MeSH
• studie případů a kontrol MeSH
• synukleinopatie genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alfa-synuklein MeSH
• SNCA protein, human MeSH Prohlížeč

Cognitive impairment exists in Parkinson's disease (PD) as a transitional state between cognitively intact and demented PD patients. It seems to be a risk factor for the development of dementia in PD, but the precise criteria and unfavorable cognitive profile of mild cognitive impairment in PD (MCI-PD) have not yet been established. The concept may turn to be different from that in Alzheimer's disease since we search for those already diagnosed PD patients who are at risk of developing dementia. In addition, clinical variables specific for PD also play role. Importantly, MCI possesses a metabolic basis in PD. Various biomarkers particularly including neuropsychological testing and the brain imaging hold promise in identification of MCI-PD patients with unfavorable prognoses. Well-designed longitudinal studies in MCI-PD cohorts are needed to assess the sensitivity and specificity of the PD-MCI designation as far as dementia development is concerned.

• MeSH
• kognitivní dysfunkce komplikace   psychologie   MeSH
• lidé MeSH
• neuropsychologické testy MeSH
• Parkinsonova nemoc komplikace   psychologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH