Cerebrospinal Fluid Α-synuclein Research Articles

Correlation of Plasma EGF with Striatal Dopamine Transporter Availability in Healthy Subjects

We aimed to evaluate the association between plasma epidermal growth factor (EGF) and the availability of dopamine transporter (DAT) measured from 123I-FP-CIT single-photon emission computed tomography in healthy controls in this study. Volume of interest template was applied to measure specific binding ratios (SBRs) of caudate nucleus, putamen, and striatum representing DAT availability as follows; SBR = (target– cerebellum)/cerebellum. Plasma EGF was negatively correlated with the availabilities of both caudate nucleus (r = −0.261, p = 0.019), and putamen (r = −0.341, p = 0.002). After dividing subjects according to Apo E genotyping, DAT availability of caudate nucleus of Apo e4 non-carriers (n = 60) showed the positive correlation with cerebrospinal fluid (CSF) α-synuclein (r = 0.264, p = 0.042). Plasma EGF was negatively correlated with DAT availabilities of Apo e4 non-carriers. Further studies are needed to clarify underlying mechanisms of this phenomenon.

DIFFERENTIAL ROLE OF CSF FATTY ACID BINDING PROTEIN 3, α-SYNUCLEIN AND ALZHEIMER’S DISEASE CORE BIOMARKERS IN LEWY BODY DISORDERS AND ALZHEIMER’S DEMENTIA

Accumulation, in extra- or intracellular deposits, of aggregated and misfolded proteins characterizes Alzheimer disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB). This reflects in an overlapping of clinical presentations, especially between AD and DLB. Here we evaluated the diagnostic performance of a panel of five cerebrospinal fluid (CSF) biomarkers in a cohort of patients diagnosed with AD, DLB, PDD and Parkinson's disease (PD). Here we measured CSF levels of fatty acid binding protein (FABP3), α-synuclein (α-syn) and classical AD biomarkers in a large cohort of patients diagnosed with PD (n= 54), AD (n=48), DLB (n=40), PDD (n=20) and control subjects (n=46). ELISA immunoassays were used to assess CSF levels of fatty acid binding protein (FABP3), α-synuclein (α-syn), amyloid β 1–42 (Aβ1–42), total tau (t-tau) and phosphorylated tau 181 (p-tau). Univariate and multivariate statistical analyses were applied to calculate the diagnostic performance of the five CSF biomarkers, as well as their association with clinical parameters. CSF t-tau, p-tau and α-syn levels were significantly higher in AD than in PDD, DLB, PD patients and controls. CSF FABP3 levels were significantly increased in AD and DLB patients compared to PD and controls (p<0.001). A combination of FABP3 and p-tau reached an optimal accuracy for discriminating AD and DLB (AUC=0.92), while the best performance for distinguishing AD and PDD was obtained using a combination of p-tau, FABP3 and α-syn (AUC = 0.96). CSF FABP3 levels were inversely associated with Mini Mental State Examination scores in the whole cohort (r = -0.42, p < 0.001). No correlation was found between CSF biomarkers and motor scores (UPDRS-III and H&Y). The combination of CSF biomarkers linked to different aspects of neurodegeneration may improve the differential diagnosis of neurodegenerative disorders. In this context FABP3 plays a key role when combined to CSF AD core biomarkers and α-synuclein.

ANALYTICAL PERFORMANCE CHARACTERISTICS OF A PROTOTYPE IMMUNOASSAY FOR QUANTIFICATION OF ALPHA-SYNUCLEIN IN HUMAN CEREBROSPINAL FLUID

α-Synuclein is a pre-synaptic protein whose abnormal aggregation is the main characteristic of a sub-group of neurodegenerative disorders called α-synucleinopathies, including but not limited to Parkinson's disease (PD) and dementia with Lewy bodies (DLB). CFS α-Synuclein levels reflect the presence of Lewy bodies in the brain and have been shown to be decreased in PD and DLB patients as compared to healthy aging controls. Robust assays with good lot-to-lot consistency are required for integration into clinical trials. This study documents the analytical performance characteristics of a novel colorimetric ELISA targeting α-Synuclein in biological fluids, with a focus on cerebrospinal fluid (CSF). α-Synuclein concentrations have been determined using a colorimetric ELISA designed and developed by ADx NeuroSciences using two monoclonal antibodies. The assay was qualified for CSF, but can be modified for application for EDTA-plasma samples. After having performed familiarization runs and some adaptation of the test procedures to the needs of a service provider, the assay was challenged internally for its analytical performance characteristics such as precision, parallelism, spike-recovery, working range, sample stability, and interference using commercially available CSF samples (n=40). α-Synuclein is measured in undiluted CSF and 10–50-fold diluted EDTA-plasma using a 3-hour incubation period for the samples. The new assay format specifically quantifies α-Synuclein in the absence of matrix interference as verified after dilution in α-Synuclein low CSF. Spike/recovery testing revealed good recovery rates (93 % ± 7 %). Our internal precision experiments with CSF resulted in an intra- and inter-assay variability (% CV) below 12 % and 11 %, respectively. The working range is confirmed between 90 pg/mL (Lower Limit of Quantitation) to 6142 pg/mL (Upper Limit of Quantitation). The stability of CSF α-Synuclein was assessed with respect to freeze/thawing and short-term stability at room temperature. No major difference with the reference condition was observed. The newly developed α-Synuclein colorimetric ELISA assay meets all of our internal acceptance criteria for clinical trial sample testing and represents an additional tool for patient enrichment in clinical trials or treatment follow-up.

Validation of electrochemiluminescence assays for highly sensitive and reproducible quantification of α-synuclein in cerebrospinal fluid.

α-Synuclein (aSyn), a putative cerebrospinal fluid biomarker, may support the diagnosis of neurodegenerative diseases. Previous studies led to conflicting results due to different preanalytical and analytical procedures. Standardized assays are required to allow for comparison of results from different laboratories. We performed a side-by-side validation of a commercially available (MSD, MD, USA) and a 'homebrew' assay for quantification of aSyn according to published guidelines. The data showed high sensitivity and reproducibility for both assays. Preanalytical and analytical parameters did not affect the outcome of measurements. We conclude that both assays are very close in performance and suitable for research application of cerebrospinal fluid aSyn.

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.

Cerebrospinal Fluid Biomarkers of Neurodegeneration Are Decreased or Normal in Narcolepsy.

To investigate whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration are altered in narcolepsy in order to evaluate whether the hypocretin deficiency and abnormal sleep-wake pattern in narcolepsy leads to neurodegeneration. Twenty-one patients with central hypersomnia (10 type 1 narcolepsy, 5 type 2 narcolepsy, and 6 idiopathic hypersomnia cases), aged 33 years on average and with a disease duration of 2-29 years, and 12 healthy controls underwent CSF analyses of the levels of β-amyloid, total tau protein (T-tau), phosphorylated tau protein (P-tau181), α-synuclein, neurofilament light chain (NF-L), and chitinase 3-like protein-1 (CHI3L1). Levels of β-amyloid were lower in patients with type 1 narcolepsy (375.4 ± 143.5 pg/mL) and type 2 narcolepsy (455.9 ± 65.0 pg/mL) compared to controls (697.9 ± 167.3 pg/mL, p < .05). Furthermore, in patients with type 1 narcolepsy, levels of T-tau (79.0 ± 27.5 pg/mL) and P-tau181 (19.1 ± 4.3 pg/mL) were lower than in controls (162.2 ± 49.9 pg/mL and 33.8 ± 9.2 pg/mL, p < .05). Levels of α-synuclein, NF-L, and CHI3L1 in CSF from narcolepsy patients were similar to those of healthy individuals. Six CSF biomarkers of neurodegeneration were decreased or normal in narcolepsy indicating that taupathy, synucleinopathy, and immunopathy are not prevalent in narcolepsy patients with a disease duration of 2-29 years. Lower CSF levels of β-amyloid, T-tau protein, and P-tau181 in narcolepsy may indicate that hypocretin deficiency and an abnormal sleep-wake pattern alter the turnover of these proteins in the central nervous system.

Cerebrospinal fluid levels of neurofilament light chain in multiple system atrophy relative to Parkinson's disease: a meta-analysis.

As a biomarker of axonal injury, neurofilament light chain (NFL) in multiple system atrophy (MSA) patients and Parkinson's disease (PD) patients has been investigated by numerous studies. However, cerebrospinal fluid (CSF) NFL changes are conflicting in MSA patients relative to PD patients to date. Therefore, the current study was carried out to find out possible heterogeneity sources. Furthermore, "Neurofilament", "Neurofilament light chain" and "Multiple system atrophy" were employed to search "PubMed", "Springer" and "Medline" databases until August 2016 with standard mean difference (Std.MD) being calculated. In addition, subgroup analysis and meta-regression were performed to assess possible heterogeneity sources. Nine studies were pooled, in which 212 MSA patients and 373 PD patients were involved. Moreover, CSF NFL in MSA patients was higher than that in PD patients [pooled Std.MD=1.56, 95% CI (1.12, 2.00), p<0.00001] with significant heterogeneity (I 2=76%). Besides, population variations, sample size, the difference in CSF phosphorylated tau (p-tau) levels between MSA patients and PD patients, and Hoehn-Yahr staging of PD patients were the main heterogeneity sources. As shown by meta-regression, Hedges'sg of CSF NFL was correlated with CSF Std.MD of α-synuclein between MSA patients and healthy controls (r=-1.34824, p=0.00025). Therefore, CSF NFL increased in MSA patients relative to PD patients. Meta-regression showed that NFL was associated with α-synucleinin CSF of MSA patients relative to healthy controls. Due to the influence of heterogeneity sources, more prospective large sample studies are still needed to assess CSF NFL changes in MSA patients relative to PD patients.

Evaluation of α-synuclein as a novel cerebrospinal fluid biomarker in different forms of prion diseases

IntroductionAccurate diagnosis of prion diseases and discrimination from alternative dementias gain importance in the clinical routine, but partial overlap in cerebrospinal fluid (CSF) biomarkers impedes absolute discrimination in the differential diagnostic context. MethodsWe established the clinical parameters for prion disease diagnosis for the quantification of CSF α-synuclein in patients with sporadic (n = 234) and genetic (n = 56) prion diseases, in cases with cognitive impairment/dementia or neurodegenerative disease (n = 278), and in the neurologic control group (n = 111). ResultsAn optimal cutoff value of 680 pg/mL α-synuclein results in 94% sensitivity and 96% specificity when diagnosing sporadic Creutzfeldt-Jakob disease (CJD). Genetic CJD cases showed increased CSF α-synuclein values. No increased α-synuclein levels were detected in non-CJD cases with rapid progression course. DiscussionDetection of α-synuclein in the CSF of patients with suspected CJD is a valuable diagnostic test reaching almost full discrimination from non-prion disease cases. These data highlight the utility of CSF α-synuclein quantification in front of classical CSF biomarkers in clinical routine.

Progression of Regional Microstructural Degeneration in Parkinson's Disease: A Multicenter Diffusion Tensor Imaging Study.

This study aimed to identify the utility of diffusion tensor imaging (DTI) in measuring the regional distribution of abnormal microstructural progression in patients with Parkinson’s disease who were enrolled in the Parkinson's progression marker initiative (PPMI). One hundred and twenty two de-novo PD patients (age = 60.5±9) and 50 healthy controls (age = 60.6±11) had DTI scans at baseline and 12.6±1 months later. Automated image processing included an intra-subject registration of all time points and an inter-subjects registration to a brain atlas. Annualized rates of DTI variations including fractional anisotropy (FA), radial (rD) and axial (aD) diffusivity were estimated in a total of 118 white matter and subcortical regions of interest. A mixed effects model framework was used to determine the degree to which DTI changes differed in PD relative to changes in healthy subjects. Significant DTI changes were also tested for correlations with changes in clinical measures, dopaminergic imaging and CSF biomarkers in PD patients. Compared to normal aging, PD was associated with higher rates of FA reduction, rD and aD increases predominantly in the substantia nigra, midbrain and thalamus. The highest rates of FA reduction involved the substantia nigra (3.6±1.4%/year from baseline, whereas the highest rates of increased diffusivity involved the thalamus (rD: 8.0±2.9%/year, aD: 4.0±1.5%/year). In PD patients, high DTI changes in the substantia nigra correlated with increasing dopaminergic deficits as well as with declining α-synuclein and total tau protein concentrations in cerebrospinal fluid. Increased DTI rates in the thalamus correlated with progressive decline in global cognition in PD. The results suggest that higher rates of regional microstructural degeneration are potential markers of PD progression.

Aging modifies the effect of GCH1 RS11158026 on DAT uptake and Parkinson's disease clinical severity

Novel single nucleotide polymorphisms within Parkinson's disease (PD) can predict disease risk, but their influence on clinical, cognitive, and neurobiological indices remains unexplored. We investigated differences between functional polymorphisms at RS11158026 coding for guanosine triphosphate cyclohydrolase-1 (GCH1), an essential enzyme for dopamine production in nigrostriatal cells. Among newly diagnosed, untreated PD subjects and age-matched controls from the Parkinson's Progression Markers Initiative, T allele carriers showed higher PD risk (odds ratio = 1.23, p = 0.048), earlier age of onset by 5 years (p = 0.003), and lower striatal dopamine reuptake transporter uptake (p = 0.003). Carriers also had increased cerebrospinal fluid α-synuclein (p = 0.016), worse motor function (p = 0.041), anxiety (p = 0.038), and executive function (p < 0.001). Strikingly, these effects were only in younger T carriers (<50 years), where aging quells the effects of these genetic factors. This suggests GCH1 variants affect early PD risk through altered dopamine uptake, and aging alters how genetic factors contribute to disease development. Future studies should investigate how aging modifies genotypes' contributions on PD risk and sequelae.

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.

Validation of a new assay for α-synuclein detection in cerebrospinal fluid.

Abnormal α-synuclein aggregation and deposition is the pathological hallmark of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), but is also found in Alzheimer disease (AD). Therefore, there is a gaining interest in α-synuclein in cerebrospinal fluid (CSF) as potential biomarker for these neurodegenerative diseases. To broaden the available choices of α-synuclein measurement in CSF, we developed and validated a new assay for detecting total α-synuclein. This novel ELISA uses commercially available antibodies and is based on electrochemiluminescence technology. The assay protocol is straightforward, with short and simple incubation steps, and requires only small amounts of CSF. We validated this assay for precision, parallelism, dilution linearity, specificity, and spike recovery. We further compared it to the newly validated α-synuclein assay from BioLegend by analyzing a set of 50 CSF samples with both assays. The new assay quantifies α-synuclein in CSF with a lower limit of detection of 36.3 pg/mL and shows no cross-reactivity with human β- and γ-synuclein. Results of dilution linearity, parallelism, spike recovery, and precision classify this assay as well suited for α-synuclein detection in human CSF samples. We present a novel assay based on freely available components to quantify total α-synuclein in CSF as an additional method for α-synuclein as a biomarker in neurodegenerative diseases. The assay convinces with its simple and convenient protocol paired with high sensitivity.

White matter hyperintensities, cerebrospinal amyloid-β and dementia in Parkinson's disease

White-matter hyperintensities (WMHs) have been related to small-vessel disease, but also to amyloid-β (Αβ) vascular deposition, particularly in parieto-occipital regions. Low cerebrospinal fluid (CSF) Aβ [1-42] levels (biomarker of parenchymal and/or vascular Aβ deposition) and WMHs have been associated with Parkinson's disease (PD) and related dementia (PDD), separately but not in combination. We studied 50 subjects: 38 PD patients (19 non-demented [PDND]+19 PDD) and 12 healthy-controls. Baseline regional WMHs from FLAIR MRI-sequences were dichotomized into none-to-mild vs. moderate-to-severe by an expert radiologist blind to clinical and CSF data using an adaption of the Age-Related White Matter Changes scale. Baseline CSF α-synuclein, τ and Aβ [1-42] levels were determined with ELISA techniques. Progression to dementia in PDND patients was clinically evaluated at 18months. For analyses purposes patients were considered altogether (PDND+PDD) and separately (PDND vs. PDD). At baseline, moderate-to-severe parieto-occipital WMHs were significantly more frequent in PDD than in PDND (p=0.049) and controls (p=0.029), without significant differences in other regions. In regression models CSF Aβ was significantly associated in the entire PD cohort with moderate-to-severe parieto-occipital WMHs independently of age, vascular risk factors, APOE-4 and dementia. There were no associations with CSF α-synuclein and τ. Progression to dementia at 18months was more frequent in patients with moderate-to-severe parieto-occipital WMHs and low CSF Aβ vs. those with none-to-mild parieto-occipital WMHs and normal CSF Aβ (p=0.007). It remains to be seen whether the relationship between CSF Aβ and WMHs in PD and their association with PD-dementia is a reflection of not only parenchymal, but also vascular Αβ deposition.

Diagnostic utility of CSF α-synuclein species in Parkinson's disease: protocol for a systematic review and meta-analysis

IntroductionThe diagnostic criteria currently used for Parkinson's disease (PD) are mainly based on clinical motor symptoms. For these reasons many biomarkers are under investigation to support the diagnosis at the...

Subgroup differences in 'brain-type' transferrin and α-synuclein in Parkinson's disease and multiple system atrophy.

Two transferrin (Tf) glycan-isoforms were previously found in cerebrospinal fluid (CSF); one appears to be derived from serum (Tf-2) and the other from choroid plexus, a CSF-producing tissue (Tf-1). To analyse metabolic differences associated with the two isoforms, their ratio (Tf-2/Tf-1) was defined as the Tf index. Here we report that Tf indices of patients with tauopathies including Alzheimer's disease (2.29 + 0.64) were similar to those of neurological controls (2.07 + 0.87) (P = 0.147). In contrast, Tf indices with Parkinson's disease (PD, 3.38 ± 1.87) and multiple system atrophy (MSA, 3.15 ± 1.72) were higher than those of the controls (2.07 ± 0.87), the P-values being < 0.001 and 0.024, respectively. Tf indices of PD and MSA did not appear to be normally distributed. Indeed, detrended normal Quantile-Quantile plot analysis revealed the presence of an independent subgroup showing higher Tf indices in PD and MSA. The subgroup of PD showed higher levels of CSF α-synuclein (38.3 ± 17.8 ng/ml) than the rest (25.3 ± 11.3 ng/ml, P = 0.012). These results suggest that PD (and MSA) includes two subgroups, which show different metabolism of CSF transferrin and α-synuclein.

Validation of a commercially available enzyme-linked immunoabsorbent assay for the quantification of human α-Synuclein in cerebrospinal fluid

The quantification of α-Synuclein in cerebrospinal fluid (CSF) as a biomarker has gained tremendous interest in the last years. Several commercially available immunoassays are emerging. We here describe the full validation of one commercially available ELISA assay for the quantification of α-Synuclein in human CSF (Covance alpha-Synuclein ELISA kit). The study was conducted within the BIOMARKAPD project in the European initiative Joint Program for Neurodegenerative Diseases (JPND). We investigated the effect of several pre-analytical and analytical confounders: i.e. (1) need for centrifugation of freshly drawn CSF, (2) sample stability, (3) delay of freezing, (4) volume of storage aliquots, (5) freeze/thaw cycles, (6) thawing conditions, (7) dilution linearity, (8) parallelism, (9) spike recovery, and (10) precision. None of these confounders influenced the levels of α-Synuclein in CSF significantly. We found a very high intra-assay precision. The inter-assay precision was lower than expected due to different performances of kit lots used. Overall the validated immunoassay is useful for the quantification of α-Synuclein in human CSF.

Decreased levels of alpha-synuclein in cerebrospinal fluid of patients with clinically isolated syndrome and multiple sclerosis.

Cerebrospinal fluid (CSF) α-synuclein (ASYN) levels are emerging as a possible biomarker in a number of neurodegenerative conditions; however, there has been little study of such levels in demyelinating conditions with neurodegeneration such as multiple sclerosis (MS). In this study, we aimed to assess CSF ASYN levels in MS spectrum [clinically isolated syndrome (CIS) and MS] patients and compare them to those obtained in control subjects with benign neurological conditions (BNC). We used a recently developed, ultra-sensitive sandwich enzyme-linked immunosorbent assay to measure and compare CSF ASYN levels in three categories of subjects: BNC (n = 38), CIS (n = 36) and MS [Relapsing Remitting (RRMS, n = 22) and Primary Progressive (PPMS, n = 15)]. We also performed secondary analyses, including relationship of CSF ASYN levels to aging, gender, presence of CSF oligoclonal bands (OB) and gadolinium (Gd)-enhancing demyelinating lesions on T1-weighted MRIs. CSF ASYN levels were found to be significantly lower in the CIS (78.2 ± 7.5 pg/mL), RRMS (76.8 ± 5.1 pg/mL), and PPMS (76.3 ± 6.7 pg/mL) groups compared to the BNC (125.7 ± 13.6 pg/mL) group. Secondary analyses did not reveal additional correlations. Our results suggest that in a cohort of CIS and MS patients, CSF ASYN levels are decreased, thus providing another possible link between MS and neurodegeneration. Future studies will need to be performed to confirm and extend these findings, to lead to a fuller understanding of the possible biological link between ASYN and MS. Alpha-synuclein levels in the Cerebrosinal Fluid (CSF) may reflect neurodegenerative processes. Here we measure CSF alpha-synuclein in demyelinating conditions ranging from Clinically Isolated Syndrome to Primary Progressive Multiple Sclerosis (MS). We find a similar magnitude of decreased alpha-synuclein compared to a control group in all such MS spectrum conditions; such a decrease may reflect an underlying early neurodegenerative disease process.

Cerebrospinal fluid α-synuclein and Lewy body-like symptoms in normal controls, mild cognitive impairment, and Alzheimer's disease.

Reduced cerebrospinal fluid (CSF) α-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer's disease (AD) patients, but it is unknown if reduced CSF α-synuclein is associated with Lewy body-like symptomatology in AD. Determine associations between CSF α-synuclein and Lewy body-like symptomatology. We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6-7.8). We tested associations between baseline CSF α-synuclein and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration. Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF α-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF α-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI). The associations of low CSF α-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF α-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification.

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

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.

Cerebrospinal Fluid α-Synuclein In the Differential Diagnosis of Parkinsonian Syndromes

ABSTRACT: Aim: To evaluate the diagnostic value of the level of α-synuclein, DJ-1, and Alzheimer's disease markers in the cerebrospinal fluid (CSF) in patients with parkinsonian syndromes. Materials &amp; methods: We measured α-synuclein, DJ-1 and Alzheimer's disease markers by quantitative immunoassays in 122 CSF samples from patients with Parkinson's disease (PD; n = 38), dementia with Lewy bodies (n = 20), multiple-system atrophy (n = 18), progressive supranuclear palsy (n = 28), corticobasal degeneration (n = 7), unspecified atypical parkinsonian disorders (n = 5) and healthy controls (n = 6). Results: The level of α-synuclein was significantly decreased in CSF from PD patients. For the total tau/α-synuclein ratio, we obtained an area under the curve of 0.80 of the receiver operating characteristics curve for the PD diagnosis. With a cut-off of 1.33, the tau/α-synuclein ratio had 93% diagnostic specificity at 75% sensitivity for PD. Conclusion: CSF α-synuclein measurement may be useful in the differential diagnosis of PD versus other parkinsonian syndromes. CSF α-synuclein is found at low levels in the CSF and requires specifically adjusted assays to be measured.