CSF alpha-Synuclein Does Not Discriminate Dementia with Lewy Bodies from Alzheimer's Disease
ABSTRACT In this study, we assessed whether cerebrospinal fluid (CSF) levels of the biomarker α-synuclein have a diagnostic value in differential diagnosis of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). We also analyzed associations between CSF biomarkers and cognitive performance in DLB and in AD. We included 35 DLB patients, 63 AD patients, 18 patients with Parkinson's disease (PD), and 34 patients with subjective complaints (SC). Neuropsychological performance was measured by means of the Mini-Mental Status Examination (MMSE), Visual Association Test (VAT), VAT object-naming, Trail Making Test, and category fluency. In CSF, levels of α-synuclein, amyloid-β 1-42 (Aβ1-42), total tau (tau), and tau phosphorylated at threonine 181 (ptau-181) were measured. CSF α-synuclein levels did not differentiate between diagnostic groups (p=0.16). Higher ptau-181 and higher tau levels differentiated AD from DLB patients (p< 0.05). In DLB patients, lower Aβ1-42 and higher total tau levels were found than in SC and PD patients (p< 0.05). In DLB patients, linear regression analyses of CSF biomarkers showed that lower α-synuclein was related to lower MMSE-scores (β (SE) = 6(2) and p< 0.05) and fluency (β (SE) = 4(2), p< 0.05). Ultimately, CSF α-synuclein was not a useful diagnostic biomarker to differentiate DLB and/or PD (α-synucleinopathies) from AD or SC. In DLB patients maybe lower CSF α-synuclein levels are related to worse cognitive performance.
- SourceAvailable from: Suvankar Pal
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- "Only two studies reported efforts to blind assay results   and clinical data  while none of the studies attempted to blind the reference standard using an external clinical reviewer. Mean and standard deviation of concentrations of alpha-synuclein between patient subgroups were sometimes not reported as well. "
ABSTRACT: Dementia with Lewy Bodies (DLB) can be difficult to distinguish clinically from other dementias. To investigate the diagnostic utility of CSF alpha-synuclein in differentiating between DLB and other dementias. Electronic databases were systematically searched for studies investigating reproducible alpha synuclein quantification methods. Random effects model was used to calculate weighted mean difference (WMD) and 95% confidence intervals between DLB and other groups. A total of 13 studies, comprising 2728 patients were included. Mean CSF alpha-synuclein concentration was significantly lower in DLB patients compared to those with Alzheimers disease (AD) [WMD -0.24; 95% CI, -0.45, -0.03; p = 0.02]. No significant difference was found between patients with DLB compared to Parkinsons disease [WMD 0.05; 95% CI, -0.17, 0.28; p = 0.65] or other neurodegenerative conditions. CSF alpha synuclein may be of diagnostic use in differentiating between DLB and AD. We propose several recommendations to guide better design of future studies.Parkinsonism & Related Disorders 07/2013; 19(10). DOI:10.1016/j.parkreldis.2013.06.008 · 4.13 Impact Factor
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- "However, in a later study (Tokuda et al., 2010) no such clear differences were seen. Elsewhere, Mollenhauer et al. (2008, 2011) have similarly reported a lowering of total α-syn levels between PD patients and controls, though this finding has not been replicated by others (Ohrfelt et al., 2009; Spies et al., 2009; Reesink et al., 2010; Aerts et al., in press). In the present study, using a similar immunoassay protocol to Tokuda et al. (2006, 2010), we also found no significant differences in total α-syn levels between PD patients and controls, or between DLB patients and controls. "
ABSTRACT: Differentiating clinically between Parkinson's disease (PD) and the atypical parkinsonian syndromes of Progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) and multiple system atrophy (MSA) is challenging but crucial for patient management and recruitment into clinical trials. Because PD (and the related disorder Dementia with Lewy bodies (DLB)) and MSA are characterised by the deposition of aggregated forms of α-synuclein protein (α-syn) in the brain, whereas CBS and PSP are tauopathies, we have developed immunoassays to detect levels of total and oligomeric forms of α-syn, and phosphorylated and phosphorylated oligomeric forms of α-syn, within body fluids, in an attempt to find a biomarker that will differentiate between these disorders. Levels of these 4 different forms of α-syn were measured in post mortem samples of ventricular cerebrospinal fluid (CSF) obtained from 76 patients with PD, DLB, PSP or MSA, and in 20 healthy controls. Mean CSF levels of total and oligomeric α-syn, and phosphorylated α-syn, did not vary significantly between the diagnostic groups, whereas mean CSF levels of phosphorylated oligomeric α-syn did differ significantly (p<0.001) amongst the different diagnostic groups. Although all 4 measures of α-syn were higher in patients with MSA compared to all other diagnostic groups, these were only significantly raised (p<0.001) in MSA compared to all other diagnostic groups, for phosphorylated oligomeric forms of α-syn. This suggests that this particular assay may have utility in differentiating MSA from control subject and patients with other α-synucleinopathies. However, it does not appear to be of help in distinguishing patients with PD and DLB from those with PSP or from control subjects. Western blots show that the principal form of α-syn within CSF is phosphorylated, and the finding that the phosphorylated oligomeric α-syn immunoassay appears to be the most informative of the 4 assays would be consistent with this observation.Neurobiology of Disease 08/2011; 45(1):188-95. DOI:10.1016/j.nbd.2011.08.003 · 5.20 Impact Factor
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ABSTRACT: 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.06/2012; 3(2). DOI:10.2478/s13380-012-0013-1