The aim of this study was to reveal the relationship between misfolded α-Syn aggregate concentration in cerebrospinal fluid (CSF) and cognitive decline risk in PD.
In conclusion, our data suggest that plasma pS129-α-synuclein levels correlate with motor severity and progression, but not cognitive decline, in patients with PD.
The presence of RBD was a predictor for motor progression only in patients with PD who had both low α-synuclein levels and low [<sup>123</sup>I]FP-CIT uptake in the striatum (HR = 2.091, 95% CI = 1.116-3.918; <i>p</i> = 0.021) and a predictor for cognitive decline only in patients with PD who had both low Aβ<sub>42</sub> and low α-synuclein levels (HR = 2.810, 95% CI = 1.462-5.400; <i>p</i> = 0.002).
CSF total α-synuclein levels did not distinguish PD patients from controls, displayed no substantial changes during a period of up to 4 years, and did not predict subsequent motor or cognitive decline.
The results demonstrated that baseline and longitudinal increases in total α-synuclein predicted progression of cognitive decline in hyposmic individuals with dopamine transporter (DAT) binding reduction.
Hence, alpha-synucleinp.A53V homozygous mutation leads to a distinct phenotype of progressive parkinsonism and cognitive decline, commonly observed in patients with SNCA missense mutation or multiplications.
This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline.
Moreover, we found decreased active CaN and reduced levels of phosphorylated CREB in autopsy brain tissue from patients affected by dementia with Lewy bodies, which is characterized by deposition of αSyn aggregates and progressive cognitive decline.
Thus, the cognitive decline observed in aged αSYN transgenic mice might be due to impairment of neurotransmission and synaptic plasticity in the limbic system by distinct αSYN species.
Despite increasing evidence suggesting synergistic reactions between alpha-synuclein (alphaSyn), tau and Abeta-peptides, the major protein markers of both AD and Lewy body diseases, and of both vascular pathology and AD, the molecular background and pathophysiological impact of these pathologies on the progression of neurodegeneration and development of cognitive decline in PD await further elucidation.
By contrast with SNCA triplication families, the clinical phenotype of SNCA duplication closely resembles idiopathic Parkinson's disease, which has a late age-of-onset, progresses slowly, and in which neither cognitive decline nor dementia are prominent.