The Length of SNCA Rep1 Microsatellite May Influence Cognitive Evolution in Parkinson’s Disease

Abstract

BackgroundAlpha-synuclein is a constituent of Lewy bodies and mutations of its gene cause familial Parkinson’s disease (PD). A previous study showed that a variant of the alpha-synuclein gene (SNCA), namely the 263 bp allele of Rep1 was associated with faster motor progression in PD. On the contrary, a recent report failed to detect a detrimental effect of Rep1 263 on both motor and cognitive outcomes in PD. Aim of this study was to evaluate the influence of the Rep1 variants on disease progression in PD patients.MethodsWe recruited and genotyped for SNCA Rep1 426 PD patients with age at onset ≥40 years and disease duration ≥4 years. We then analyzed frequency and time of occurrence of wearing-off, dyskinesia, freezing of gait, visual hallucinations, and dementia using a multivariate Cox’s proportional hazards regression model.ResultsSNCA Rep1 263 carriers showed significantly increased risk of both dementia (HR = 3.03) and visual hallucinations (HR = 2.69) compared to 263 non-carriers. Risk of motor complications did not differ in the two groups.ConclusionSNCA Rep1 263 allele is associated with a worse cognitive outcome in PD.

SNCA Rep1 promoter variability influences cognition in Parkinson's disease

“…Although no association of SNCA rs356219 with cognition was found in a previous study in PD, the identification of a haplotype in intron 4 of SNCA and its direct association with PD dementia further strengthened the possibility that alpha‐synuclein–related mechanisms are strongly associated with cognitive deficits in sporadic PD . The relationship between variability in its gene promoter (Rep1) allele length with cognition, however, was suggested when a population‐based study by Corrado and colleagues reported that PD carriers of long Rep1 alleles (263 bp) showed significantly increased risk of both dementia (hazard ratio [HR] = 3.03) and visual hallucinations (HR = 2.69) compared to carriers of shorter alleles (263 noncarriers), but cognitive test scores were not available in this report, in contrast to our study. A second study by Markopoulou and colleagues reported that the longer Rep1 genotypes associated with increased PD risk paradoxically had better motor and cognitive outcomes, but this study had significant methodological limitations, including the use of a telephone interview to determine cognitive status in a retrospective manner, rather than use of standardized cognitive tests …”

TAM Receptor Pathways at the Crossroads of Neuroinflammation and Neurodegeneration

“…Widespread aggregation of the α -synuclein protein into inclusions called Lewy bodies, which can be detected in both the central and peripheral nervous systems, is the pathological hallmark of the disease [142, 143]. It is currently believed that a higher α -synuclein burden is associated to a more severe PD phenotype [144]. TAMs may play a role in PD pathogenesis, influencing microglial activation and phagocytosis and regulating alpha-synuclein deposition.…”

<i>SNCA</i> Rep1 microsatellite length influences non-motor symptoms in early Parkinson&#x2019;s disease

“…Additionally, 263bp carriers have shown a four-fold increased risk of faster motor decline [ 15 ]. The strong biological link is further supported by studies that demonstrated that longer Rep1 allele carriers were more cognitively impaired [ 16 ] and at greater risk for dementia [ 17 ] than carriers of the shorter allele. No study, however, has yet investigated the relationship between Rep1 length and non-motor symptoms in PD.…”