CSF levels of oligomeric alpha-synuclein and beta-amyloid as biomarkers for neurodegenerative disease

Sierks, Michael R.; Chatterjee, Gaurav; McGraw, Claire; Kasturirangan, Srinath; Schulz, Philip; Prasad, Shalini

doi:10.1039/c1ib00018g

Cited by 76 publications

(47 citation statements)

References 69 publications

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“…Confirming several studies showing relatively low CSF AS concentrations in both PD and DLB [731,[773][774][775], more recent ones reported significantly lower AS levels in PD [776,777] as well as in PD, DLB and MSA than in AD [777][778][779]. While CSF levels of AS oligomers were significantly increased in PD patients against controls [298,416,780], AD and progressive supranuclear palsy (PSP) [781], others were unanble to detect oligomeric AS in CSF [776]. Recent work detected alterations in AS phosphorylation (Ser129) in the CSF of PD patients [782].…”

Section: α-Synuclein As a Biomarker For Synucleinopathiessupporting

confidence: 60%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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Section: α-Synuclein As a Biomarker For Synucleinopathiessupporting

confidence: 60%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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“…A combination of α-synuclein with other documented biomarkers may improve the discrimination between PD patients and controls. This has been reported with the combination of α-synuclein and α-synuclein oligomers levels in CSF [31][32][33]. Additional detailed studies of the levels of post-translational modified forms of α-synuclein (phosphorylated, glycosylated, nitrated, ubiquitinated or truncated forms) in biological fluids should also be explored as potential biomarkers for PD.…”

Section: Discussionmentioning

confidence: 90%

Cerebrospinal fluid alpha-synuclein as a biomarker for Parkinson's disease diagnosis: a systematic review and meta-analysis

Gao

Tang

Nie

et al. 2014

International Journal of Neuroscience

159

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To date, there are no definitive biomarkers for Parkinson's disease (PD) diagnosis. The detection of cerebrospinal fluid (CSF) alpha (α)-synuclein in PD patients has yielded promising but inconclusive results. To determine the performance of CSF α-synuclein as a diagnostic biomarker of PD and whether CSF α-synuclein can discriminate PD from other neurodegenerative diseases, a systematic search of all relevant studies investigating reproducible CSF α-synuclein quantification methods was conducted in electronic databases. A total of 17 studies that included 3311 patients were included in this systemic review and meta-analysis. The mean CSF α-synuclein concentration was significantly lower in PD patients compared to normal/neurological controls [weighted mean difference (WMD) -0.31; 95% CI, -0.45, -0.16; p < 0.0001] and patients with Alzheimer's disease (AD) [WMD -0.15; 95% CI, -0.26, -0.04; p < 0.0001]. There was no significant difference between PD patients and dementia with Lewy bodies (DLB) patients [WMD -0.03; 95% CI, -0.16, 0.09; p = 0.58] or patients with multiple system atrophy (MSA) [WMD 0.05; 95% CI, -0.04, 0.13; p = 0.25]. Sensitivity and specificity of CSF α-synuclein in the diagnosis of PD was 0.88 (95% CI, 0.84-0.91) and 0.40 (95% CI, 0.35-0.45), respectively. The positive and negative likelihood ratios of CSF α-synuclein in the diagnosis of PD were 1.41 (95% CI, 1.24-1.60), and 0.29 (95% CI, 0.15-0.56), respectively. The corresponding summary receiver operating characteristic (SROC) curve showed an area under the curve (AUC) of 0.73. The concentration of CSF α-synuclein may be a biomarker for the diagnosis of PD. The use of α-synuclein alone however is not sufficient as a single biomarker and it must therefore be used in conjunction with other documented and reliable biomarkers.

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“…In one study, this ratio demonstrated 89.3% sensitivity and 90.6% specificity for the diagnosis of PD (Tokuda et al, 2010). Two additional studies have supported the application of a oligomer:total SNCA ratio ; Sierks et al, 2011). The relationship between SNCA levels and the stage of disease and/or its evolution over time is unknown.…”

Section: Alpha Synucleinmentioning

confidence: 99%