Cerebrospinal fluid α synuclein concentrations in patients with positive AD biomarkers and extrapyramidal symptoms.

Extrapyramidal symptoms (EP) are not uncommon in Alzheimer's Disease (AD); when present, they negatively influence the course of the disorder. A large proportion of AD patients shows concomitant Lewy bodies' pathology post mortem. Total α Synuclein (αSyn) concentrations are frequently increased in the cerebrospinal fluid (CSF) of AD patients, but are decreased in Parkinson's Disease (PD) and Dementia with Lewy Bodies (DLB). αSyn CSF concentrations in AD patients with EP (EP+) have not been reported so far. αSyn and the four Neurochemical Dementia Diagnostics (NDD) CSF biomarkers, (Aß1-42, Aß42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm, were measured in patients with positive NDD results and presence of extrapyramidal symptoms (NDD + / EP+; n = 26), in patients with positive NDD results and absence of extrapyramidal symptoms (NDD+ / EP-; n = 54), and in subjects with negative NDD results (NDD-; n = 34). Compared to the NDD- controls (379.8 ± 125.2 pg/mL), NDD+ patients showed, on average, highly significantly increased CSF αSyn (519 ± 141.3 pg/mL, p < 0.01), but without differences between NDD+ / EP+ and NDD+ / EP- subgroups (p = 0. 38). Moderate but highly significant association was observed between concentrations of αSyn and Tau (r = 0.47, p < 0.01) and pTau181 (r = 0.65, p < 0.01). Adjusted for diagnoses, age, and sex, subjects with more advanced neurodegeneration on neuroimaging showed significantly lower αSyn concentrations (p < 0.02). In the setting AD versus controls, the area under the receiver operating characteristic (ROC) curve was 0.804 [0.712; 0.896] with the sensitivity and the specificity of 0.863 and 0.618, respectively. αSyn in AD patients does not differentiate between subjects with- and without EP. Its increased average concentration reflects probably neurodegenerative process, and is not specific for any pathophysiologic mechanisms. Further studies are necessary to explain the role of CSF αSyn as a potential biomarker.

Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest.

BACKGROUND: Frontotemporal dementia (FTD) is a pathologically heterogeneous neurodegenerative disorder associated usually with tau or TDP-43 pathology, although some phenotypes such as logopenic variant primary progressive aphasia are more commonly associated with Alzheimer's disease pathology. Currently, there are no biomarkers able to diagnose the underlying pathology during life. In this study, we aimed to investigate the potential of novel tau species within cerebrospinal fluid (CSF) as biomarkers for tau pathology in FTD. METHODS: 86 participants were included: 66 with a clinical diagnosis within the FTD spectrum and 20 healthy controls. Immunoassays targeting tau fragments N-123, N-mid-region, N-224 and X-368, as well as a non-phosphorylated form of tau were measured in CSF, along with total-tau (T-tau) and phospho-tau (P-tau(181)). Patients with FTD were grouped based on their Aß42 level into those likely to have underlying Alzheimer's disease (AD) pathology (n=21) and those with likely frontotemporal lobar degeneration (FTLD) pathology (n=45). The FTLD group was then subgrouped based on their underlying clinical and genetic diagnoses into those with likely tau (n=7) or TDP-43 (n=18) pathology. RESULTS: Significantly higher concentrations of tau N-mid-region, tau N-224 and non-phosphorylated tau were seen in both the AD group and FTLD group compared with controls. However, none of the novel tau species showed a significant difference between the AD and FTLD groups, nor between the TDP-43 and tau pathology groups. In a subanalysis, normalising for total-tau, none of the novel tau species provided a higher sensitivity and specificity to distinguish between tau and TDP-43 pathology than P-tau(181)/T-tau, which itself only had a sensitivity of 61.1% and specificity of 85.7% with a cut-off of <0.109. CONCLUSIONS: Despite investigating multiple novel CSF tau fragments, none show promise as an FTD biomarker and so the quest for in vivo markers of FTLD-tau pathology continues.

Interlaboratory proficiency processing scheme in CSF aliquoting: implementation and assessment based on biomarkers of Alzheimer's disease.

BACKGROUND: In this study, we tested to which extent possible between-center differences in standardized operating procedures (SOPs) for biobanking of cerebrospinal fluid (CSF) samples influence the homogeneity of the resulting aliquots and, consequently, the concentrations of the centrally analyzed selected Alzheimer's disease biomarkers. METHODS: Proficiency processing samples (PPSs), prepared by pooling of four individual CSF samples, were sent to 10 participating centers, which were asked to perform aliquoting of the PPSs into two secondary aliquots (SAs) under their local SOPs. The resulting SAs were shipped to the central laboratory, where the concentrations of amyloid beta (Aß) 1-42, pTau181, and albumin were measured in one run with validated routine analytical methods. Total variability of the concentrations, and its within-center and between-center components, were analyzed with hierarchical regression models. RESULTS: We observed neglectable variability in the concentrations of pTau181 and albumin across the centers and the aliquots. In contrast, the variability of the Aß1-42 concentrations was much larger (overall coefficient of variation 31%), with 28% of the between-laboratory component and 10% of the within-laboratory (i.e., between-aliquot) component. We identified duration of the preparation of the aliquots and the centrifugation force as two potential confounders influencing within-center variability and biomarker concentrations, respectively. CONCLUSIONS: Proficiency processing schemes provide objective evidence for the most critical preanalytical variables. Standardization of these variables may significantly enhance the quality of the collected biospecimens. Studies utilizing retrospective samples collected under different local SOPs need to consider such differences in the statistical evaluations of the data.

CSF nonphosphorylated Tau as a biomarker for the discrimination of AD from CJD.

Creutzfeldt-Jakob disease and Alzheimer's disease are characterized by the presence of elevated total-Tau cerebrospinal fluid concentrations while the presence of hyperphosphorylated Tau forms in the cerebrospinal fluid is rather a hallmark of Alzheimer's disease. Here we aimed to investigate potential contribution of nonphospho-Tau epitopes (non-P-Tau) in the discrimination between both diseases. Non-P-Tau cerebrospinal fluid concentration was highly increased in Creutzfeldt-Jakob disease (n = 57, 3683 ± 3599 pg/mL) compared to Alzheimer's disease (n = 41, 148 ± 219 pg/mL) and neurological controls (n = 56, 62 ± 40 pg/mL), and significantly improved the proportion of correctly classified patients (99%) compared to that achieved by total-Tau (90%), P-Tau (62%) and 14-3-3 (91%).

Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer's disease.

BACKGROUND: A growing body of evidence suggests that the plasma concentration of the neurofilament light chain (NfL) might be considered a plasma biomarker for the screening of neurodegeneration in Alzheimer's disease (AD). METHODS: With a single molecule array method (Simoa, Quanterix), plasma NfL concentrations were measured in 99 subjects with AD at the stage of mild cognitive impairment (MCI-AD; n = 25) or at the stage of early dementia (ADD; n = 33), and in nondemented controls (n = 41); in all patients, the clinical diagnoses were in accordance with the results of the four core cerebrospinal fluid (CSF) biomarkers (amyloid ß (Aß)1-42, Aß42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm. The influence of preanalytical storage procedures on the NfL in plasma was tested on samples exposed to six different conditions. RESULTS: NfL concentrations significantly increased in the samples exposed to more than one freezing/thawing cycle, and in those stored for 5 days at room temperature or at 4 °C. Compared with the control group of nondemented subjects (22.0 ± 12.4 pg/mL), the unadjusted plasma NfL concentration was highly significantly higher in the MCI-AD group (38.1 ± 15.9 pg/mL, p < 0.005) and even further elevated in the ADD group (49.1 ± 28.4 pg/mL; p < 0.001). A significant association between NfL and age (ρ = 0.65, p < 0.001) was observed; after correcting for age, the difference in NfL concentrations between AD and controls remained significant (p = 0.044). At the cutoff value of 25.7 pg/mL, unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82, respectively. Unadjusted correlation between plasma NfL and Mini Mental State Examination (MMSE) across all patients was moderate but significant (r = -0.49, p < 0.001). We observed an overall significant correlation between plasma NfL and the CSF biomarkers, but this correlation was not observed within the diagnostic groups. CONCLUSIONS: This study confirms increased concentrations of plasma NfL in patients with Alzheimer's disease compared with nondemented controls.

A Specific Reduction in Aß1-42 vs. a Universal Loss of Aß Peptides in CSF Differentiates Alzheimer's Disease From Meningitis and Multiple Sclerosis.

A reduced concentration of Aß1-42 in CSF is one of the established biomarkers of Alzheimer's disease. Reduced CSF concentrations of Aß1-42 have also been shown in multiple sclerosis, viral encephalitis and bacterial meningitis. As neuroinflammation is one of the neuropathological hallmarks of Alzheimer's disease, an infectious origin of the disease has been proposed. According to this hypothesis, amyloid pathology is a consequence of a microbial infection and the resulting immune defense. Accordingly, changes in CSF levels of amyloid-ß peptides should be similar in AD and inflammatory brain diseases. Aß1-42 and Aß1-40 levels were measured in cerebrospinal fluid by ELISA and Western blotting in 34 patients with bacterial meningitis (n = 9), multiple sclerosis (n = 5) or Alzheimer's disease (n = 9) and in suitable controls (n = 11). Reduced concentrations of Aß1-42 were detected in patients with bacterial meningitis, multiple sclerosis and Alzheimer's disease. However, due to a concurrent reduction in Aß1-40 in multiple sclerosis and meningitis patients, the ratio of Aß1-42/Aß1-40 was reduced only in the CSF of Alzheimer's disease patients. Urea-SDS-PAGE followed by Western blotting revealed that all Aß peptide variants are reduced in bacterial meningitis, whereas in Alzheimer's disease, only Aß1-42 is reduced. These results have two implications. First, they confirm the discriminatory diagnostic power of the Aß1-42/Aß1-40 ratio. Second, the differential pattern of Aß peptide reductions suggests that the amyloid pathology in meningitis and multiple sclerosis differs from that in AD and does not support the notion of AD as an infection-triggered immunopathology.

Cerebrospinal fluid and blood biomarkers for neurodegenerative dementias: An update of the Consensus of the Task Force on Biological Markers in Psychiatry of the World Federation of Societies of Biological Psychiatry.

In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-ß positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.