Cerebrospinal Fluid Α-synuclein Levels Research Articles

Cerebrospinal fluid α-synuclein adds the risk of cognitive decline and is associated with tau pathology among non-demented older adults

BackgroundThe role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood.MethodsA total of 331 non-demented individuals were included in the study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition.ResultsHigher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1.ConclusionsThese findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.

Elevated ApoE, ApoJ and lipoprotein-bound α-synuclein levels in cerebrospinal fluid from Parkinson's disease patients – Validation in the BioFIND cohort

BackgroundThe progressive accumulation, aggregation, and spread of α-synuclein (aSN) are common hallmarks of Parkinson's disease (PD) pathology. The genotype of apolipoprotein E (ApoE) influences PD progression. Recently we found that aSN co-localize with apolipoproteins on lipoprotein vesicles. We reported an increased level of ApoE, ApoJ and lipoprotein-bound aSN in CSF from early PD patients compared to matched controls. We also found reduced plasma ApoAI in PD patients. ObjectiveIn this study, we used the same approach on the BioFIND cohort to validate our previous results and extended the studies to examine correlations with ApoE genotype, demographic variables, clinical symptoms and other biochemical findings reported in the BioFIND cohort. MethodsFor the assessment, we used Western-Blot (WB) technique for apolipoproteins measurements in CSF and plasma from PD patients and healthy controls. Further, for measurement of aSN bound to lipoproteins, we combined immunodepletion with the enzyme-linked immunosorbent assay (ELISA). ResultsLevels of ApoE, ApoJ and lipoprotein bound aSN were significantly increased in CSF from PD patients compared to controls. We also observed decreased levels of ApoAI and ApoJ in plasma from PD patients compared to controls. ConclusionsConcluding, the present data validated our previous findings. Altered lipoproteins appear to be important in early PD pathology and may be involved in mechanisms underlying aSN cell-to-cell transfer in the nervous system and be developed in algorithms for early diagnosis of PD.

Does TRODAT-1 SPECT Uptake Correlate with Cerebrospinal Fluid α-Synuclein Levels in Mid-Stage Parkinson’s Disease?

Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons with impaired motor and non-motor symptoms. It has been suggested that motor asymmetry could be caused due to an imbalance in dopamine levels, as visualized by dopamine transporter single emission computed tomography test (DAT-SPECT), which might be related to indirect measures of neurodegeneration, evaluated by the Montreal Cognitive Assessment (MOCA) and α-synuclein levels in the cerebrospinal fluid (CSF). Therefore, this study aimed to understand the correlation between disease laterality, DAT-SPECT, cognition, and α-synuclein levels in PD. A total of 28 patients in the moderate-advanced stage of PD were subjected to neurological evaluation, TRODAT-1-SPECT/CT imaging, MOCA, and quantification of the levels of α-synuclein. We found that α-synuclein in the CSF was correlated with global cognition (positive correlation, r2 = 0.3, p = 0.05) and DAT-SPECT concentration in the putamen (positive correlation, r2 = 0.4, p = 0.005), and striatum (positive correlation, r2 = 0.2, p = 0.03), thus working as a neurodegenerative biomarker. No other correlations were found between DAT-SPECT, CSF α-synuclein, and cognition, thus suggesting that they may be lost with disease progression. Our data highlight the importance of understanding the dysfunction of the dopaminergic system in the basal ganglia and its complex interactions in modulating cognition.

The associations of cerebrospinal fluid biomarkers with cognition, and rapid eye movement sleep behavior disorder in early Parkinson's disease.

In Parkinson's disease (PD), levels of cerebrospinal fluid (CSF) biomarkers and progression of non-motor symptoms are associated, but the specifics are not yet clear. The aim of this study was to investigate the associations of non-motor symptoms with CSF biomarkers in PD. We assessed 487 individuals from the Parkinson's Progression Markers Initiative (PPMI), consisting of 155 healthy controls (HCs) and 332 individuals with PD. Patients with PD were grouped according to non-motor symptoms and compared CSF α-synuclein (α-syn), amyloid-beta 1-42 (Aβ1-42), and total tau (t-tau) levels. Multiple linear regressions were used in baseline analysis and linear mixed-effects models in longitudinal analysis. Analyses of mediating effects between cognition and CSF biomarkers were also performed. At baseline, PD patients with cognitive impairment (PDCI) exhibited significantly lower CSF α-syn (β = -0.1244; P = 0.0469), Aβ (β = -0.1302; P = 0.0447), and t-tau (β = -0.1260; P = 0.0131) levels than PD patients without cognitive impairment (PDCU). Moreover, a faster decline of α-syn (β = -0.2152; P = 0.0374) and Aβ (β = -0.3114; P = 0.0023) and a faster rise of t-tau (β = -0.1534; P = 0.0274) have been found in longitudinal analysis. The Aβ positive group showed an earlier decline in cognitive performance (β = -0.5341; P = 0.0180) compared with the negative Aβ group in both analyses. In addition, we found that PD patients with probable rapid eye movement sleep behavior disorder (pRBD) showed decreased CSF α-syn (β = -0.1343; P = 0.0033) levels. Finally, mediation analysis demonstrated that olfactory function partially mediated the relationship between cognition and CSF biomarkers levels. Our study shows that CSF biomarkers are associated with cognition at baseline and longitudinally. Cognitive impairment is more severe in patients with a heavier Aβ burden. CSF α-syn decreased in PD patients with pRBD. This study suggests that early recognition of the increased risk of non-motor symptoms is important for disease surveillance and may be associated with the pathological progression of CSF markers.

Diagnostic Utility of Cerebrospinal Fluid α-Synuclein in Creutzfeldt-Jakob Disease: A Systematic Review and Meta-Analysis.

Creutzfeldt-Jakob disease (CJD) can be difficult to distinguish clinically from some non-prion neurological diseases. Previous studies have reported markedly increased levels of α-synuclein in cerebrospinal fluid (CSF) of CJD patients, indicating that it is a potential diagnostic biomarker. The aim of this study was to assess the diagnostic power of CSF α-synuclein in discriminating CJD from non-prion disorders. The Ovid MEDLINE, Cochrane, and Embase databases were searched for articles published on or before February 25, 2022, using the search term (prion diseases OR Creutzfeldt-Jakob syndrome) AND (synuclein OR α-synuclein). The difference in CSF α-synuclein levels between CJD and non-prion diseases was calculated using random-effects models (I2 > 50%) or fixed-effects models (I2 < 50%) in terms of standardized mean difference (SMD) and 95% confidence interval (CI). The publication bias was estimated using funnel plots and the Egger's test. Ten studies were included in this study. The concentrations of CSF α-synuclein were significantly higher in CJD patients compared to total non-prion controls (SMD = 1.98, 95% CI 1.60 to 2.36, p < 0.00001), tauopathies (SMD = 1.34, 95% CI 0.99 to 1.68, p < 0.00001), synucleinopathies (SMD = 1.78, 95% CI 1.11 to 2.44, p < 0.00001), or Alzheimer's (SMD = 1.14, 95% CI 0.95 to 1.33, p < 0.00001). CSF α-synuclein could distinguish CJD from non-prion diseases with overall sensitivity of 89% (95% CI 80-95%), specificity of 92% (95% CI 86-95%), and AUC of 0.96 (95% CI: 0.94-0.97). CSF α-synuclein has excellent diagnostic value in discriminating CJD from non-prion neurological diseases. Given the high heterogeneity among the included studies, further studies are needed to confirm its clinical utility.

Cerebrospinal Fluid Biomarkers of Alzheimer's Disease: Current Evidence and Future Perspectives.

Alzheimer’s disease is a progressive, clinically heterogeneous, and particularly complex neurodegenerative disease characterized by a decline in cognition. Over the last two decades, there has been significant growth in the investigation of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease. This review presents current evidence from many clinical neurochemical studies, with findings that attest to the efficacy of existing core CSF biomarkers such as total tau, phosphorylated tau, and amyloid-β (Aβ42), which diagnose Alzheimer’s disease in the early and dementia stages of the disorder. The heterogeneity of the pathophysiology of the late-onset disease warrants the growth of the Alzheimer’s disease CSF biomarker toolbox; more biomarkers showing other aspects of the disease mechanism are needed. This review focuses on new biomarkers that track Alzheimer’s disease pathology, such as those that assess neuronal injury (VILIP-1 and neurofilament light), neuroinflammation (sTREM2, YKL-40, osteopontin, GFAP, progranulin, and MCP-1), synaptic dysfunction (SNAP-25 and GAP-43), vascular dysregulation (hFABP), as well as CSF α-synuclein levels and TDP-43 pathology. Some of these biomarkers are promising candidates as they are specific and predict future rates of cognitive decline. Findings from the combinations of subclasses of new Alzheimer’s disease biomarkers that improve their diagnostic efficacy in detecting associated pathological changes are also presented.

Mini Review: Correlations of Cognitive Domains With Cerebrospinal Fluid α-Synuclein Levels in Patients With Parkinson's Disease.

The level of α-synuclein, a component of Lewy bodies, in cerebrospinal fluid (CSF) in Parkinson's disease (PD) has attracted recent attention. Most meta-analyses conclude that CSF levels of α-synuclein are decreased in PD. Patients with PD present with cognitive impairment, including frontal/executive dysfunction in the early phase and later emergence of visuospatial and mnemonic deficits. To examine whether CSF α-synuclein levels reflect the activities of various cognitive domains, we reviewed reports examining the association of these levels with cognitive performance in each domain in PD. Among 13 cross-sectional studies, five showed that a lower CSF α-synuclein level was associated with worse cognitive function. In four of these five reports, frontal/executive function showed this association, suggesting a link of the pathophysiology with Lewy bodies. In three other reports, a higher CSF α-synuclein level was associated with temporal-parieto-occipital cognitive deterioration such as memory. In the other five reports, the CSF α-synuclein level did not correlate with cognitive performance for any domain. In four longitudinal studies, a higher baseline CSF α-synuclein level was associated with a worse cognitive outcome, including cognitive processing speed, visuospatial function and memory in two, but not with any cognitive outcome in the other two. The different associations may reflect the heterogeneous pathophysiology in PD, including different pathogenic proteins, neurotransmitters. Thus, more studies of the association between cognitive domains and CSF levels of pathogenic proteins are warranted.

Extrastriatal SPECT-DAT uptake correlates with clinical and biological features of de novo Parkinson's disease

Striatal dopamine transporter (DAT) uptake assessment through I123-Ioflupane Single-Pphoton Emission Computed Tomography (SPECT) provides valuable information about the dopaminergic denervation occurring in Parkinson's disease (PD). However, little is known about the clinical or biological relevance of extrastriatal DAT uptake in PD. Here, from the Parkinson's Progression Markers Initiative, we studied 623 participants (431 PD and 192 healthy controls) with available SPECT data. Even though striatal denervation was undoubtedly the imaging hallmark of PD, extrastriatal DAT uptake was also reduced in patients with PD. Topographically, widespread frontal but also temporal and posterior cortical regions showed lower DAT uptake in PD patients with respect to healthy controls. Importantly, a longitudinal voxelwise analysis confirmed an active one-year loss of extrastriatal DAT uptake within the PD group. Extrastriatal DAT uptake also correlated with the severity of motor symptoms, cognitive performance, and cerebrospinal fluid α-synuclein levels. In addition, we found an association between the Catechol-O-methyltransferase val158met genotype and extrastriatal DAT uptake. These results highlight the clinical and biological relevance of extrastriatal SPECT-DAT uptake in PD.

Ambroxol for the Treatment of Patients With Parkinson Disease With and Without Glucocerebrosidase Gene Mutations

Mutations of the glucocerebrosidase gene, GBA1 (OMIM 606463), are the most important risk factor for Parkinson disease (PD). In vitro and in vivo studies have reported that ambroxol increases β-glucocerebrosidase (GCase) enzyme activity and reduces α-synuclein levels. These observations support a potential role for ambroxol therapy in modifying a relevant pathogenetic pathway in PD. To assess safety, tolerability, cerebrospinal fluid (CSF) penetration, and target engagement of ambroxol therapy with GCase in patients with PD with and without GBA1 mutations. An escalating dose of oral ambroxol to 1.26 g per day. This single-center open-label noncontrolled clinical trial was conducted between January 11, 2017, and April 25, 2018, at the Leonard Wolfson Experimental Neuroscience Centre, a dedicated clinical research facility and part of the University College London Queen Square Institute of Neurology in London, United Kingdom. Participants were recruited from established databases at the Royal Free London Hospital and National Hospital for Neurology and Neurosurgery in London. Twenty-four patients with moderate PD were evaluated for eligibility, and 23 entered the study. Of those, 18 patients completed the study; 1 patient was excluded (failed lumbar puncture), and 4 patients withdrew (predominantly lumbar puncture-related complications). All data analyses were performed from November 1 to December 14, 2018. Primary outcomes at 186 days were the detection of ambroxol in the CSF and a change in CSF GCase activity. Of the 18 participants (15 men [83.3%]; mean [SD] age, 60.2 [9.7] years) who completed the study, 17 (8 with GBA1 mutations and 9 without GBA1 mutations) were included in the primary analysis. Between days 0 and 186, a 156-ng/mL increase in the level of ambroxol in CSF (lower 95% confidence limit, 129 ng/mL; P < .001) was observed. The CSF GCase activity decreased by 19% (0.059 nmol/mL per hour; 95% CI, -0.115 to -0.002; P = .04). The ambroxol therapy was well tolerated, with no serious adverse events. An increase of 50 pg/mL (13%) in the CSF α-synuclein concentration (95% CI, 14-87; P = .01) and an increase of 88 ng/mol (35%) in the CSF GCase protein levels (95% CI, 40-137; P = .002) were observed. Mean (SD) scores on part 3 of the Movement Disorders Society Unified Parkinson Disease Rating Scale decreased (ie, improved) by 6.8 (7.1) points (95% CI, -10.4 to -3.1; P = .001). These changes were observed in patients with and without GBA1 mutations. The study results suggest that ambroxol therapy was safe and well tolerated; CSF penetration and target engagement of ambroxol were achieved, and CSF α-synuclein levels were increased. Placebo-controlled clinical trials are needed to examine whether ambroxol therapy is associated with changes in the natural progression of PD. ClinicalTrials.gov identifier: NCT02941822; EudraCT identifier: 2015-002571-24.

Association of the Polygenic Risk Score with the Incidence Risk of Parkinson's Disease and Cerebrospinal Fluid α-Synuclein in a Chinese Cohort.

Parkinson's disease (PD) is attributed to interactions among genes and environmental and lifestyle factors, but the genetic architecture of PD is complex and not completely understood. To evaluate whether the genetic profile modifies PD development and cerebrospinal fluid (CSF) pathological biomarkers, we enrolled 418 PD patients and 426 age- and sex-matched normal controls. Forty-six single nucleotide polymorphisms (SNPs) that were reported to be significantly associated with PD in large-scale genome-wide association studies (GWASs) were genotyped and analysed. The alleles associated with PD were used to build polygenic risk score (PRS) models to represent polygenic risk. The Cox proportional hazards model and receiver operating characteristic (ROC) analyses were used to evaluate the prediction value of the PRS for PD risk and age at onset. The CSF α-synuclein levels were measured in a subgroup of control subjects (n= 262), and its relationship with the PRS was analysed. We found that some SNPs identified from other populations had significant correlations with PD in our Chinese cohort. The PRS we built had prediction value for PD risk and age at onset. The CSF α-synuclein level had no correlation with the PRS in normal subjects.

Cerebrospinal Fluid and Plasma Biomarkers in Neurodegenerative Diseases.

Cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and tau are biomarkers for Alzheimer's disease (AD); however, the effects of other neurodegenerative processes on these biomarkers remain unclear. We measured Aβ40, Aβ42, total tau, phosphorylated-tau, and α-synuclein in CSF and plasma using matched samples from various neurodegenerative diseases to expand our basic knowledge on these biomarkers and their practical applications. A total of 213 CSF and 183 plasma samples were analyzed from cognitively unimpaired subjects, and patients with Alzheimer's disease dementia (ADD), mild cognitive impairment (MCI), non-AD dementias, and other neurological diseases. The CSF/plasma ratios of Aβ40 and Aβ42 were approximately 25:1. Aβ40/42 ratios in CSF and plasma were both 10:1. The CSF total tau/P181tau ratio was 6:1. The CSF/plasma α-synuclein ratio was 1:65. Significantly decreased Aβ42 levels and an increased Aβ40/42 ratio in CSF in ADD/MCI suggested that these relationships were specifically altered in AD. Increased total tau levels in ADD/MCI, encephalopathy, and multiple system atrophy, and increased P181tau in ADD/MCI indicated that these biomarkers corresponded to neurodegeneration and tauopathy, respectively. Although CSF α-synuclein levels were increased in ADD/MCI, there was no merit in measuring α-synuclein in CSF or plasma as a biomarker. The combination of biomarkers by the Aβ40/42 ratio×p181tau reflected specific changes due to the AD pathology in ADD/MCI. Thus, CSF Aβ40, Aβ42, p181tau, and tau were identified as biomarkers for aggregated Aβ associated state (A), aggregated tau associated state (T), and neurodegeneration state (N) pathologies in AD based on the NIA-AA criteria. Overlaps in these biomarkers need to be considered in clinical practice for differential diagnoses of neurodegenerative diseases.

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

Idiopathic REM sleep behavior disorder (iRBD) is one of the most significant prodromal manifestations of synucleinopathies. Different predictive biomarkers for iRBD conversion have been investigated, but scarce data are present in literature about the predictive role of cerebrospinal fluid (CSF) biomarkers. In this review, we focus on CSF biomarkers in patients with both iRBD and RBD associated with synucleinopathies to explore their potential predictive power. Recent studies revealed that CSF α-synuclein levels are higher in Parkinson's disease (PD) patients with RBD compared to those without RBD, even if α-synuclein does not seem to predict conversion of iRBD into PD. In the Parkinson Progression Marker Initiative (PPMI) cohort, early PD patients with RBD show lower CSF Aβ42 levels, which predict faster cognitive decline. CSF prion protein and inflammatory biomarkers have been also investigated in RBD and synucleinopathies with controversial results. A variety of CSF biomarkers are promising candidate for predicting iRBD conversion into synucleinopathies. Further studies are needed in iRBD patients followed for several years in order to observe the phenoconversion in synucleinopathies and to elucidate the possible role of CSF biomarkers as predictive biomarkers of conversion.

A Genome-Wide Association Study of α-Synuclein Levels in Cerebrospinal Fluid.

α-Synuclein is a 140-amino acid protein produced predominantly by neurons in the brain which plays a role in the regulation of neurotransmitter release, synaptic function, and plasticity, thus making it the focus in understanding the etiology of a group of neurodegenerative diseases. We conducted genome-wide association studies (GWAS) of α-synuclein levels in cerebrospinal fluid (CSF) with 209 non-Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort using a linear regression model to identify novel variants associated with α-synuclein concentration. The minor allele (T) of rs7072338 in the long intergenic non-protein coding RNA 1515 (LINC01515) and the minor allele (T) of rs17794023 in clusterin-associated protein 1 (CLUAP1) were associated with higher CSF α-synuclein levels at genome-wide significance (P = 4.167 × 10-9 and 9.56 × 10-9, respectively). In addition, single nucleotide polymorphisms (SNPs) near amyloid beta precursor protein (APP) (rs1394839) (P = 2.31 × 10-7), Rap guanine nucleotide exchange factor 1 (RAPGEF1) (rs10901091) (P = 8.07 × 10-7), and two intergenic loci on chromosome 2 and 14 (rs11687064 P = 2.50 × 10-7and rs7147386 P = 4.05 × 10-7) were identified as suggestive loci associated with CSF α-synuclein levels. We have identified significantly associated SNPs for CSF α-synuclein. These associations have important implications for a better understanding of α-synuclein regulation and allow researchers to further explore the relationships between these SNPs and α-synuclein-related neurodegenerative disorders.

Effect of rs3910105 in the Synuclein Gene on Dopamine Transporter Availability in Healthy Subjects.

PurposeThe present study investigated associations between dopamine transporter (DAT) availability and α-synuclein levels in cerebrospinal fluid, as well as synuclein gene (SNCA) transcripts, and the effect of single nucleotide polymorphism of SNCA on DAT availability in healthy subjects.Materials and MethodsThe study population comprised healthy controls who underwent 123I-FP-CIT single-photon emission computed tomography screening. Five SNCA probes were used to target the boundaries of exon 3 and exon 4 (SNCA-E3E4), transcripts with a long 3′UTR region (SNCA-3UTR-1, SNCA-3UTR-2), transcripts that skip exon 5 (SNCA-E4E6), and the rare short transcript isoforms that comprise exons 1–4 (SNCA-007).ResultsIn total, 123 healthy subjects (male 75, female 48) were included in this study. DAT availability in the caudate nucleus (p=0.0661) and putamen (p=0.0739) tended to differ according to rs3910105 genotype. In post-hoc analysis, DAT availability in the putamen was lower in subjects of TT genotype than those of CC/CT (p=0.0317). DAT availability in the caudate nucleus also showed a trend similar to that in the putamen (p=0.0597). Subjects of CT genotype with rs3910105 showed negative correlations with DAT availability in the putamen with SNCA-E3E4 (p=0.037, rho=−0.277), and SNCA-E4E6 (p=0.042, rho=−0.270), but not those of CC/TT genotypes.ConclusionThis is the first study to investigate the association of rs3910105 in SNCA with DAT availability. rs3910105 had an effect on DAT availability, and the correlation between DAT availability and SNCA transcripts were significant in CT genotypes of rs3910105.

TMEM230 in Parkinson's disease

A study on familial Parkinson disease (PD) described 4 variants in the gene TMEM230 (Chr. 20p13) as the cause of PD. The aim of this study was to test if variants in the TMEM230 gene are associated with PD in 2 independent American European data sets. No variants in the TMEM230 region were found associated with PD, age at onset, or cerebrospinal fluid α-synuclein levels.

Alpha-synuclein measured in cerebrospinal fluid from patients with Alzheimer's disease, mild cognitive impairment, or healthy controls: a two year follow-up study.

Backgroundα-Synuclein has been proposed as a potential biomarker for Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI). However, results from α-synuclein measurements in cerebrospinal fluid (CSF) have been inconclusive, and to our knowledge, longitudinal studies of changes prior to the AD diagnosis have not been investigated.MethodsLevels of α-synuclein at baseline and after one and two years were measured in CSF, by enzyme-linked immunosorbent assay. Twenty-six patients with early AD (AD-AD), 48 patients with aMCI, subdivided as 23 that developed AD during follow-up (MCI-AD), and 25 that did not (MCI-MCI), and 25 healthy control individuals, were included. One-way ANOVA was applied to compare mean α-synuclein baseline values between all four study groups, and a linear mixed model was used to compare mean change over time between the three patient groups. Linear associations between α-synuclein and amyloid-β 1–42 (Aβ42), amyloid-β 1–40 (Aβ40), total tau and phosphorylated tau were also examined.ResultsA large variation in individual α-synuclein CSF levels was observed, particularly in the MCI-AD group. No significant differences were found in mean α-synuclein levels between all the study groups at baseline. When using a linear mixed model, no significant differences were found at follow-up for estimated mean changes between the patient groups. MCI-AD patients with short duration of symptoms prior to inclusion in the study (≤2 years) had considerably higher mean CSF α-synuclein levels compared to patients with a longer symptom duration (802.2 vs. 442.8 pg/mL, p = 0.01). No such difference was seen in the MCI-MCI or AD-AD groups. Significant linear associations (p < 0.0005) between α-synuclein and Aβ40, total tau and phosphorylated tau were found.ConclusionThe observed difference in mean CSF α-synuclein level according to duration of symptoms in the MCI-AD group, may be an indication of changes related to disease progression. However, the lack of significant differences between groups, as well as the large individual variation in CSF levels of α-synuclein in the present study, suggest that α-synuclein is not a useful biomarker for AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0706-0) contains supplementary material, which is available to authorized users.

Total α-synuclein levels in human blood cells, CSF, and saliva determined by a lipid-ELISA.

The validity of α-synuclein (α-Syn) as a biomarker for Parkinson's disease (PD) is still under investigation. Conventional methods for capture and quantitation of α-Syn protein in human samples are primarily based on anti-α-Syn antibodies. Specific and competent antibodies were raised against α-Syn. However, capture by anti-α-Syn antibodies may be limited to specific epitope recognition, attributed to protein structure or post-translational modifications. Hence, antibody-based methods for α-Syn capture raise a concern regarding their efficacy to detect the intracellular, unfolded α-Syn pool. An alternative is α-Syn capture by membrane lipids, i.e.,to utilize the biochemical property of α-Syn to specifically bind membrane lipids and acquire a characteristic structure following binding. We determined α-Syn levels in human samples using immobilized lipids for α-Syn capture. The lipids used for α-Syn capture consist of phosphatidyl inositol (PI), phosphatidyl serine (PS), and phosphatidyl ethanolamine (PE). Addition of mono-sialoganglioside, GM1 ganglioside, to the immobilized lipids significantly improved α-Syn detection. Following capture, the lipid-bound α-Syn was detected using an anti-α-Syn antibody. Total α-Syn levels in whole blood cells(WBC), cerebrospinal fluid (CSF), and saliva were determined by the lipid-ELISA method.

CSF α-synuclein and UCH-L1 levels in Parkinson's disease and atypical parkinsonian disorders

IntroductionThere is an unmet need for biomarkers for Parkinson's disease (PD) and atypical parkinsonian disorders (APD). α-Synuclein, linked to the pathogenesis of PD, is a promising biomarker candidate in need of further investigation. The ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), a pivotal component of the ubiquitin proteasome system which seems to be disturbed in PD, may also be involved in the pathogenesis of this disorder. MethodsWe investigated cerebrospinal fluid (CSF) α-synuclein and UCH-L1 levels from 22 healthy controls, 52 patients with PD, 34 with multiple system atrophy (MSA), 32 with progressive supranuclear palsy, and 12 with corticobasal degeneration. Resultsα-Synuclein levels were significantly decreased in PD and in MSA compared with controls, and in synucleinopathies compared with tauopathies. UCH-L1 levels were significantly decreased in PD, MSA as well as PSP compared with controls, and in PD compared with APD (p < 0.001). Both markers discriminated PD well from controls (p < 0.0001; area under the curve [AUC] = 0.82 and 0.89, respectively). Additionally, CSF α-synuclein separated patients with synucleinopathies from those with tauopathies (p = 0.015; AUC = 0.63), whereas CSF UCH-L1 discriminated between PD and APD (p = 0.0003; AUC = 0.69). Interestingly, α-synuclein and UCH-L1 levels were strongly correlated in PD and synucleinopathies, and weakly in tauopathies. No correlation was found in controls. ConclusionsCSF levels of α-synuclein and UCH-L1 show distinct patterns in parkinsonian syndromes. Their combined determination may be useful in the differential diagnosis of parkinsonian disorders and provide key to understanding their pathoetiology and clinical course. Further large studies are needed to validate our findings.

Effects of Baseline CSF α-Synuclein on Regional Brain Atrophy Rates in Healthy Elders, Mild Cognitive Impairment and Alzheimer’s Disease

BackgroundCerebrospinal fluid (CSF) α-synuclein is reduced in synucleinopathies, including dementia with Lewy bodies, and some studies have found increased CSF α-synuclein in Alzheimer’s disease (AD). No study has explored effects of CSF α-synuclein on brain atrophy. Here we tested if baseline CSF α-synuclein affects brain atrophy rates and if these effects vary across brain regions, and across the cognitive spectrum from healthy elders (NL), to patients with mild cognitive impairment (MCI) and AD.MethodsBaseline CSF α-synuclein measurements and longitudinal structural brain magnetic resonance imaging was performed in 74 NL, 118 MCI patients and 55 AD patients. Effects of baseline CSF α-synuclein on regional atrophy rates were tested in 1) four pre-hoc defined regions possibly associated with Lewy body and/or AD pathology (amygdala, caudate, hippocampus, brainstem), and 2) all available regions of interest. Differences across diagnoses were tested by assessing the interaction of CSF α-synuclein and diagnosis (testing NL versus MCI, and NL versus AD).ResultsThe effects of CSF α-synuclein on longitudinal atrophy rates were not significant after correction for multiple comparisons. There were tendencies for effects in AD in caudate (higher atrophy rates in subjects with higher CSF α-synuclein, P=0.046) and brainstem (higher atrophy rates in subjects with lower CSF α-synuclein, P=0.063). CSF α-synuclein had significantly different effects on atrophy rates in NL and AD in brainstem (P=0.037) and caudate (P=0.006). Discussion: With the possible exception of caudate and brainstem, the overall weak effects of CSF α-synuclein on atrophy rates in NL, MCI and AD argues against CSF α-synuclein as a biomarker related to longitudinal brain atrophy in these diagnostic groups. Any effects of CSF α-synuclein may be attenuated by possible simultaneous occurrence of AD-related neuronal injury and concomitant Lewy body pathology, which may elevate and reduce CSF α-synuclein levels, respectively.

α-Synuclein in Cerebrospinal Fluid of Alzheimer's Disease and Mild Cognitive Impairment

In addition to amyloid-β (Aβ) and tau, α-synuclein, best known for its role in Parkinson's disease (PD), has been suggested to be involved in cognition and pathogenesis of Alzheimer's disease (AD). We investigate the potential of α-synuclein in cerebrospinal fluid (CSF) as a biomarker of cognitive decline in AD, and its prodromal phase, mild cognitive impairment (MCI). Using an established, sensitive Luminex assay, we measured α-synuclein levels in the CSF of a cohort of close to 400 healthy control, MCI, and AD subjects obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and factored in APOE genotype in data analysis. CSF α-synuclein levels were significantly higher in the MCI (p = 0.005) and AD (p < 0.001) groups, compared to controls. However, receiver operating characteristic (ROC) curve analysis suggests that CSF α-synuclein level on its own only offered modest sensitivity (65%) and specificity (74%) as a diagnostic marker of AD, with an area under the curve (AUC) value of 0.719 for AD versus controls. The effect of APOE genotype, if any, was quite subtle. However, there was a significant correlation between α-synuclein and cognition (p = 0.001), with increased α-synuclein levels associated with decreased Mini-Mental State Exam scores. Our results support a role for α-synuclein even in MCI, the early phase of AD, in addition to being a potential contributor in MCI and AD diagnosis or monitoring of disease progression.