Longitudinal Alterations of Alpha-Synuclein, Amyloid Beta, Total, and Phosphorylated Tau in Cerebrospinal Fluid and Correlations Between Their Changes in Parkinson's Disease

Abstract

Background: Parkinson's disease (PD) is characterized by proteinopathies and these proteinopathies seem to interact synergistically and lead to protein aggregations and changes in protein cerebrospinal fluid (CSF) levels. In this study, we aimed to explore the longitudinal changes of CSF a lpha-synuclein (α-syn), total tau (t-tau), phosphorylated tau (p-tau), and beta-amyloid (Aβ1−42) and their relationships with each other and with baseline clinical entities like REM sleep behavior disorder (RBD), cognitive impairment, motor symptoms, and olfaction dysfunction.Method: One hundred and twelve non-demented PD patients and 110 controls were recruited from Parkinson's Progression Markers Initiative (PPMI).We used a linear mixed model within groups to assess longitudinal protein changes over 6 and 12 months and a random regression coefficient within the linear mixed model to investigate the correlation between proteins and their baseline clinical characteristics.Results: P-tau was lower in PDs only at baseline, but during a year, p-tau increased more rapidly in PDs than controls. Aβ1−42 was not significantly different between groups at any separate timepoint; however, when assessed longitudinally, Aβ1−42 showed significant changes in both groups. Conversely, t-tau and α-syn differed significantly between groups, but their longitudinal changes were not significant in either of the groups. Moreover, all proteins' baseline levels, except p-tau, could determine estimated longitudinal tau changes. Baseline RBDSQ scores but not UPDRS III, MoCA, or UPSIT scores were predictive of longitudinal increase in α-syn levels.Conclusion: Longitudinal changes in levels of CSF proteins are related to each other and could help researchers further understand PD pathology. In addition, RBD seems to be a potential prognostic factor for PD progression. However, in order to reach a consensus, longer follow-up times are required.

Alpha-synuclein antisense oligonucleotides as a disease-modifying therapy for Parkinson’s disease

“…aSyn protein is measurable in human CSF, has been shown in patients to not correlate with clinical progression, and levels are relatively stable over 24 months, thus suggesting aSyn levels in the CSF may potentially be used in clinical trials as a pharmacodynamic marker to support demonstration of efficacy of aSyn modulating therapies (Dolatshahi et al, 2018;Mollenhauer, 2014;Mollenhauer et al, 2017;Parnetti et al, 2016;Zhou et al, 2015). Continued evaluation and improved methods for detecting aSyn in the CSF and other fluids are warranted, such as electrochemiluminescense-based detection ( Kruse and Mollenhauer, 2019).…”

Serum Insulin-Like Growth Factor-1 in Parkinson's Disease; Study of Cerebrospinal Fluid Biomarkers and White Matter Microstructure

“…It is proposed that progressive damage of α-synuclein inclusions to the neural cells by causing neuroinflammation and oxidative imbalance plays the central role in PD pathology ( 1 – 4 ). In addition, the existence of extracellular plaques of amyloid-beta and intracellular aggregation of abnormal tau proteins, the main pathological insults in AD, are as well documented in PD with a great impact on the development of cognitive decline and dementia ( 5 , 6 ). Presentation of motor and non-motor symptoms of PD may be delayed after a long preclinical phase of neuronal loss ( 7 ).…”

CSF Biomarkers for Early Diagnosis of Synucleinopathies: Focus on Idiopathic RBD

“…Core AD CSF biomarkers have been studied in RBD in a lesser degree compared to α-synuclein. The great majority of the available studies do not present significant associations between RBD and CSF levels of AD core biomarkers [46,49].…”

“…They found also that RBDSQ score increased concomitantly with higher CSF o-α-syn levels. Accordingly, Dolatshahi and colleagues [46] recruited 112 non-demented PD patients from the Parkinson Progressive Marker Initiative (PPMI), a 5-year observational, multi-center, and international study encompassing 400 recently diagnosed drug-naïve PD patients. They identified greater increase of CSF αsynuclein levels after 1-year follow-up in patients with RBD compared to those without RBD.…”