P-tau Concentrations Research Articles

A consensus in Korea regarding a protocol to reduce preanalytical sources of variability in the measurement of the cerebrospinal fluid biomarkers of Alzheimer's disease.

Cerebrospinal fluid (CSF) can provide vital informative about pathological processes occurring in the brain. In particular, the CSF concentrations of Aβ42, tTau, and pTau181 are useful for the early diagnosis of Alzheimer's disease (AD). However, many studies have demonstrated that confounding factors related to the preanalytical processing of CSF can seriously influence measurements of these AD biomarkers. It is therefore important to develop a standardized protocol for the acquisition and handling of CSF, particularly with regard to the types of tube used for collection and storage, the proper aliquot volume, blood contamination, and the number of tube transfers and freeze-thaw cycles, because these aspects of the procedure have been shown to affect AD biomarker measurements. A survey of the impact of several individual preanalytical procedures on the measurement of AD biomarkers in CSF was conducted for this review article, and the implications of the differences among them are discussed. Furthermore, following a review of the procedures used in Korean and international biomarker laboratories, a consensus was reached among a cooperative Korean multicenter research group regarding a standardized protocol for the analysis of AD biomarkers in CSF. All efforts were made to be stringent regarding the controversial issues associated with this protocol, thus minimizing the confounding influence of various factors on current investigations using established AD biomarkers and on future studies using novel biomarkers of AD and other neurodegenerative disorders.

Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection.

The character of central nervous system (CNS) HIV infection and its effects on neuronal integrity vary with evolving systemic infection. Using a cross-sectional design and archived samples, we compared concentrations of cerebrospinal fluid (CSF) neuronal biomarkers in 143 samples from 8 HIV-infected subject groups representing a spectrum of untreated systemic HIV progression and viral suppression: primary infection; four groups of chronic HIV infection neuroasymptomatic (NA) subjects defined by blood CD4+ T cells of >350, 200–349, 50–199, and <50 cells/µL; HAD; treatment-induced viral suppression; and ‘elite’ controllers. Samples from 20 HIV-uninfected controls were also examined. The neuronal biomarkers included neurofilament light chain protein (NFL), total and phosphorylated tau (t-tau, p-tau), soluble amyloid precursor proteins alpha and beta (sAPPα, sAPPβ) and amyloid beta (Aβ) fragments 1–42, 1–40 and 1–38. Comparison of the biomarker changes showed a hierarchy of sensitivity in detection and suggested evolving mechanisms with progressive injury. NFL was the most sensitive neuronal biomarker. Its CSF concentration exceeded age-adjusted norms in all HAD patients, 75% of NA CD4<50, 40% of NA CD4 50–199, and 42% of primary infection, indicating common neuronal injury with untreated systemic HIV disease progression as well as transiently during early infection. By contrast, only 75% of HAD subjects had abnormal CSF t-tau levels, and there were no significant differences in t-tau levels among the remaining groups. sAPPα and β were also abnormal (decreased) in HAD, showed less marked change than NFL with CD4 decline in the absence of HAD, and were not decreased in PHI. The CSF Aβ peptides and p-tau concentrations did not differ among the groups, distinguishing the HIV CNS injury profile from Alzheimer's disease. These CSF biomarkers can serve as useful tools in selected research and clinical settings for patient classification, pathogenetic analysis, diagnosis and management.

Association between NME8 Locus Polymorphism and Cognitive Decline, Cerebrospinal Fluid and Neuroimaging Biomarkers in Alzheimer's Disease

Recently, a large meta-analysis of five genome wide association studies (GWAS) identified a novel locus (rs2718058) adjacent to NME8 that played a preventive role in Alzheimer's disease (AD). However, this link between the single nucleotide polymorphism (SNP) rs2718058 and the pathology of AD have not been mentioned yet. Therefore, this study assessed the strength of association between the NME8 rs2718058 genotypes and AD-related measures including the cerebrospinal fluid (CSF) amyloid beta, tau, P-tau concentrations, neuroimaging biomarkers and cognitive performance, in a large cohort from Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We used information of a total of 719 individuals, including 211 normal cognition (NC), 346 mild cognitive impairment (MCI) and 162 AD. Although we didn't observe a positive relationship between rs2718058 and AD, it was significantly associated with several AD related endophenotypes. Among the normal cognitively normal participants, the minor allele G carriers showed significantly associated with higher CDRSB score than A allele carriers (P = 0.021). Occipital gyrus atrophy were significantly associated with NME8 genotype status (P = 0.002), with A allele carriers has more atrophy than the minor allele G carriers in AD patients; lateral ventricle (both right and left) cerebral metabolic rate for glucose (CMRgl) were significantly associated with NME8 genotype (P<0.05), with GA genotype had higher metabolism than GG and AA genotypes in MCI group; the atrophic right hippocampus in 18 months is significantly different between the three group, with GG and AA genotypes had more hippocampus atrophy than GA genotypes in the whole group. Together, our results are consistent with the direction of previous research, suggesting that NME8 rs2718058 appears to play a role in lowering the brain neurodegeneration.

Evaluation of visinin-like protein 1 concentrations in the cerebrospinal fluid of patients with mild cognitive impairment as a dynamic biomarker of Alzheimer's disease.

The correlations between pathology of neurodegenerative diseases, especially Alzheimer's disease (AD), and concentrations of neuronal calcium sensor proteins, such as visinin-like protein 1 (VILIP-1), in cerebrospinal fluid (CSF) have been discussed in the literature but its utility as biomarker of AD in comparison with mild cognitive impairment (MCI) has not been studied yet. Therefore, the aim of our study was to assess the clinical utility of the measurement of CSF concentrations of VILIP-1 in patients with AD, MCI subjects, and non-demented controls. The clinical and neuropsychological diagnoses were supported by CSF biomarkers of neurochemical dementia diagnostics: decreased concentrations of Aβ1-42 and/or Aβ42/40 ratio and increased concentrations of Tau and pTau181 proteins. The study included 33 AD patients, 15 subjects with MCI, and 18 elderly individuals without cognitive deficits. The CSF concentrations of biomarkers tested were determined by using the ELISA method. Concentrations of VILIP-1 in CSF were significantly higher in AD patients compared to the MCI subjects and elderly individuals without cognitive impairment. Increased concentrations of VILIP-1 correlated significantly with reduced Aβ42/40 ratio and higher pTau181 in AD group. Our findings suggest that VILIP-1 may play a role in the AD pathophysiology and is a good candidate for dynamic biomarker of AD, although this issue requires further investigation.

Lyme neuroborreliosis and dementia.

Descriptions of Lyme disease and dementia are rare. To describe patients with dementia and a positive "intrathecal anti-Borrelia antibody index" (AI), specific for neuroborreliosis. Among 1,594 patients seen for dementia, we prospectively identified and studied 20 patients (1.25%) with dementia and a positive AI. Patients underwent a battery of neuropsychological tests brain, MRI, FDG-PET, and cerebrospinal fluid (CSF) analysis. An etiological diagnosis of the dementia was made at the end of the follow-up of 5.0 ± 2.9 years. We found two groups of patients with dementia, the first (n = 7, 0.44%) with certain neuroborreliosis and stability or mild improvement of dementia after treatment by antibiotics and the second (n = 13, 0.81%) with progressive worsening of dementia, despite the antibiotics. In the second group, the final diagnoses were Alzheimer's disease (AD) (n = 4), AD and Lewy body disease (LBD) (n = 3), LBD (n = 1), FTLD (n = 3), hippocampal sclerosis (n = 1), and vascular dementia (n = 1). We did not observe any differences in cognitive test between the two patient groups at baseline. Brain MRI showed more focal atrophy and FDG-PET showed more frontal hypometabolism in the second group. Tau, p-tau, and Aβ42 concentrations in the CSF were normal in the neuroborreliosis group, and coherent with diagnosis in the second. Pure Lyme dementia exists and has a good outcome after antibiotics. It is advisable to do Lyme serology in demented patients, and if serology is positive, to do CSF analysis with AI. Neurodegenerative dementia associated with positive AI also exists, which may have been revealed by the involvement of Borrelia in the CNS.

GENETIC ANALYSIS OF THE STEROIDOGENESIS PATHWAY: ASSOCIATIONS WITH ALZHEIMER'S DISEASE RISK AND RELATED PHENOTYPES

proteins was quantitated using a l abel-free protein quantification method, and these were competed with the concentrations of A b42, pTau181, and tTau. Results: The MMSE score in AD patients was 21.3 6 4.9, and the average CDR scores were 0.86 0.3. All of the CSF samples were sufficient to establish the diagnostic cut-off value of the Ab42/pTau181 and Ab42/ tTau ratios in our laboratory.Fifteen of the 724 protein samples demonstrated a significant correlation with at least one of the AD biomarkers (p < 0.05). Seven of these proteins were previously identified as AD biomarkers, whereas eight were newly found. T he direction of change in the levels of Ab42 was found to be opposite to those of the levels of the Tau proteins in all analytes. Regarding the Ab42 levels, four proteins revealed a significant correlation. Another four proteins demonstrated a significant correlation with both pTau181 and tTau concentrations. We found three proteins to have a significant relationship only with pTau181, whereas two proteins showed a significant correlation only with tTau levels. Interestingly, t here were no analytes that demonstrated a correlation with both Ab42 and Tau proteins simultaneously. The remaining proteins showed a distinct correlation with the combined ratio of Ab42/ pTau181 or Ab42/tTau; however, the relationship with the individual concentrations was statistically negligible. Conclusions: Through our work, we identified new candidate CSF biomarkers of AD. Considering their biological roles, these candidate markers are suggested to be intimately related to AD pathophysiology. Further investigations are needed to identify their values as surrogate biomarkers or therapeutic targets in AD.

Analysis of combined CSF biomarkers in AD diagnosis.

The new proposed diagnostic criteria for early diagnosis of Alzheimer's Disease (AD) underline the value of cerebrospinal fluid (CSF) biomarkers. The first aim of the study was to determine the diagnostic accuracy of CSF biomarker Abeta1-42, T-tau, and P-tau in differentiating AD patients in our cohort by means of "pure" biomarkers and in form of a combined analysis of these biomarkers. The second aim of the study was to determine the diagnostic accuracy of these markers for predicting incipient AD in patients with mild cognitive impairment (MCI). We studied 102 CSF samples: 33 AD [mean age at baseline 71.2 (54-86)], 16 MCI [mean age at baseline 71.3 (57-78)], 24 non AD dementia, including 7 vascular dementia, 4 frontotemporal degeneration, 5 dementia with Lewy Body, and 8 with other dementia [mean age at baseline 72.7 (51-87)] and 32 non-demented neurological patients [mean age at baseline 71.3 (45-87) referred to as control (CO) later in the text]. A double sandwich ELISA (Innotest beta amyloid Abeta1-42, hTau and P-tau181 by Innogenetics, Gent, Belgium) was performed to quantify the concentration of the above biomarkers. The three biomarkers were then combined in the IATI index [(measured Ab1-42)/(240 + 1.18 *measured tau)], and in the ratios Abeta1-42/T-tau, Abeta1-42/P-tau, T-tau/Abeta1-42 and P-tau/Abeta1-42. Abeta1-42, T-tau and P-tau181 concentration showed statistically significant differences between AD and CO (327.2 pg/mL +/- 150.2 pg/mL and 659.4 pg/mL +/- 254.2 pg/mL; 508.2 pg/mL +/- 360.2 pg/mL and 305.3 pg/mL +/- 228.9 pg/mL; 82.2 pg/mL +/- 26.1 pg/mL and 45.3 pg/mL +/- 26.4 pg/mL, respectively, p < 0.05), while the difference between AD and MCI was statistically different only for Abeta1-42 (327.2 pg/mL +/- 150.2 pg/mL and 600.8 +/- 271.9 pg/mL, respectively, p < 0.05). The IATI index was 0.5 +/- 0.3 in AD, 0.9 +/- 0.6 in MCI, 1.37 +/- 0.9 in non AD dementia and 1.26 +/- 0.8 in non-demented neurological patients. With a cut-off fixed at 1 the sensitivity and specificity of the IATI index in discriminating AD from CO was 84% and 52%, respectively. This study confirms the great significance of CSF biomarker measurements in AD diagnosis in clinical routine. It is understood that a clinical diagnostic work-up is necessary in the process. Moreover, a biochemical profile of CSF biomarkers requires further investigations.

Efficacy of the Phosphorylated tau 181 in Differential Diagnosis of the Alzheimer's Disease: A Systematic Review and Meta-Analysis

Background: The purpose of this study was to evaluate the value of phosphorylated tau with epitopes threonine 181(p-tau181) in cerebrospinal fluid (CSF) for the differential diagnosis of Alzheimer's disease typed dementia from other type of dementia. Methods: A systematic literature search was performed to identify studies on p-tau181. Two evaluators independently evaluated the quality of the ten studies using the Scottish Intercollegiate Guidelines Network (SIGN) tool. The literature review covered from October 27, 1946 to October 22, 2013, and eight domestic databases including KoreaMed and international data- bases including Ovid-MEDLINE, EMBASE, and Cochrane Library were used. Tau concentrations were compared to healthy controls and to subjects with Alzheimer's disease (AD) using random effect meta- analysis. Outcome measures were Cohen's delta, sensitivity and specificity. Results: Finally, 8 studies (8 diagnostic evaluation studies) were identified to evaluate CSF p-tau181. The effectiveness of this test was evaluated based on diagnostic accuracy. The diagnostic accuracy for identifying AD by ELISA was high which revealed pooled sensitivity as 0.843 (95% CI 0.818-0.867), pooled specificity as 0.799(95% CI 0.768-0.828) and summary receiver operating characteristic area under the curve 0.9082 ± 0.0236. Con- clusions: CSF p-tau181 concentrations in other type of dementia are intermediate between controls and AD patients. Overlap between both controls and AD patients results in insufficient diagnostic accuracy, and the development of more specific biomarkers for these disorders is needed.

Addition of MHPG to Alzheimer's disease biomarkers improves differentiation of dementia with Lewy bodies from Alzheimer's disease but not other dementias

BackgroundOverlapping clinical features make it difficult to distinguish dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and other dementia types. In this study we aimed to determine whether the combination of cerebrospinal fluid (CSF) biomarkers, amyloid-β42 (Aβ42), total tau protein (t-tau), and phosphorylated tau protein (p-tau), in combination with 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), could be useful in discriminating DLB from vascular dementia (VaD) and frontotemporal dementia (FTD), as we previously demonstrated for differentiation of DLB from AD. MethodsWe retrospectively analyzed concentrations of MHPG, Aβ42, t-tau, and p-tau in CSF in patients with DLB, AD, VaD, and FTD. Using previously developed multivariate logistic regression models we assessed the diagnostic value of these CSF parameters. ResultsThe currently used combination of Aβ42, t-tau, and p-tau yielded a sensitivity of 61.9% and a specificity of 91.7% for the discrimination between DLB and AD, but could not discriminate between DLB and VaD or FTD. The addition of MHPG to Aβ42, t-tau, and p-tau improves the discrimination of DLB from AD, yielding a sensitivity of 65.1% and specificity of 100%, but could not distinguish DLB from other forms of dementia. ConclusionsOur results confirm in a separate patient cohort that addition of MHPG to Aβ42, t-tau, and p-tau improves the discrimination of DLB from AD but not the differentiation of DLB from VaD or FTD.

Association of Cerebrospinal Fluid β-Amyloid 1-42, T-tau, P-tau181, and α-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease

We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and α-synuclein, but not β-amyloid 1-42 (Aβ1-42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (Aβ1-42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau181], and α-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson's Progression Markers Initiative (PPMI) study. Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (Aβ1-42, T-tau, and P-tau181; Innogenetics Inc) or by enzyme-linked immunosorbent assay (α-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. Slightly, but significantly, lower levels of Aβ1-42, T-tau, P-tau181, α-synuclein, and T-tau/Aβ1-42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower Aβ1-42 and P-tau181 levels were associated with PD diagnosis and that decreased CSF T-tau and α-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF Aβ1-42 and P-tau181 concentrations were associated with the postural instability-gait disturbance-dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of α-synuclein with the levels of T-tau and P-tau181. In this first report of CSF biomarkers in PPMI study subjects,we found that measures of CSF Aβ1-42, T-tau, P-tau181, and α-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression

A New Decision Tree Combining Abeta 1-42 and p-Tau Levels in Alzheimer&amp;apos;s Diagnosis

The objective of this work was to improve the clinical diagnosis of Alzheimer's disease (AD) by proposing a simple decision tree based on three major biomarkers of AD found in the cerebrospinal fluid (CSF): amyloid peptide Aβ1- 42, total Tau (t-Tau) and Tau phosphorylated at Thr181 (p-Tau). Two consecutive cohorts comprising 548 patients in total were recruited by the Memory and Neurology Clinics at Lille University Hospital (France). These included 293 patients with AD, 171 patients with other dementias and 84 healthy controls. All patients underwent lumbar puncture for the assessment of CSF concentrations of Aβ1-42, t-Tau and p-Tau. International criteria for dementias were used for diagnosis by investigators blind to CSF test results. To identify the combination of biomarkers that best predicted the 3 diagnoses, we used the CHAID decision tree method with the first cohort. Our analysis yielded a two-step decision tree, with a first stratification step based on the Aβ1-42/p-Tau ratio of the CSF, and a second step based on CSF p-Tau concentrations. The second cohort was then used to determine the power (0.618), sensitivity (82%) and specificity (81%) of this tree in AD diagnosis. These were found to be at least as high as those of other known algorithms based on the three CSF biomarkers, Aβ1-42, t-Tau and p-Tau.For the first time, diagnostic rules for AD based on CSF variables were compared in a single study. Our findings indicate that the measurement of Aβ1-42 and p-Tau levels in the CSF is sufficient to diagnose AD.

Tau phosphorylation is exaggerated in Alzheimer disease with psychosis

The occurrence of psychotic symptoms in Alzheimer's disease subjects (AD+P) represents a subgroup characterized by more severe impairment and more rapid decline in cognition compared to AD without psychosis (AD-P). AD+P aggregates within families with an estimated heritability of 61%, indicating a substantial genetic component. Since the strongest correlate of cognitive impairment in AD is synapse loss across cortical regions, we hypothesize that the genetic architecture of AD+P leads to exaggerated synaptic vulnerability. In dorsolateral prefrontal cortex (DLPFC) we previously found increased disruption of synapse integrity, lower kalirin expression, and greater Aβ42/Aβ40 ratio in AD+P cases. Since hyperphosphorylated tau may be a necessary mediator of Aβ-induced synaptic toxicity, we evaluated DLPFC grey matter phospho-tau (pTau) in a well-matched cohort of 26 AD+P and 19 AD-P cases. We used AT8, an antibody for a triple phosphorylation site epitope (ser199/ser202/thr205) on pTau-associated dystrophic neurites, neuropil threads, and neurofibrillary tangles, and assessed both mean fluorescence intensity, indicative of relative pTau concentration (pTC), and pTau volume fraction (pTVV; fraction of total grey matter volume occupied by pTau) in the DLPFC. Both of our measures were significantly correlated with Braak stage (pTC rs = 0.491, p < 0.001; pTVV rs = 0.758, p < 0.001). In AD+P, we found that pTC was greater (p = 0.006) and that pTVV trended toward an increase (p = 0.082). We then evaluated whether pTC and/or pTVV affected cognitive impairment by examining the most recent scores on the mini-mental status exam (MMSE), as an indication of global cognitive function, and on the digit span backwards test (DSB), as an indicator of cognitive function associated specifically with the DLPFC. Consistent with previous findings, AD+P cases scored lower on the mini-mental status exam (MMSE; p = 0.026), despite similar durations of illness in the two groups. Lower scores on the MMSE were influenced by higher pTC (p = 0.006), and pTVV (p = 0.030); lower scores on the DSB were also influenced by pTC (p = 0.013) and pTVV (p = 0.008). These novel findings indicate that while higher pTC and pTVV are associated with worse cognitive impairment, pTC is specifically higher in AD+P. This suggests that phosphorylation of tau may be exaggerated in AD+P, which along with our previous findings, points to more severe pathological dynamics in AD+P.

Injury markers predict time to dementia in subjects with MCI and amyloid pathology

Alzheimer disease (AD) can now be diagnosed in subjects with mild cognitive impairment (MCI) using biomarkers. However, little is known about the rate of decline in those subjects. In this cohort study, we aimed to assess the conversion rate to dementia and identify prognostic markers in subjects with MCI and evidence of amyloid pathology. We pooled subjects from the VU University Medical Center Alzheimer Center and the Development of Screening Guidelines and Criteria for Predementia Alzheimer's Disease (DESCRIPA) study. We included subjects with MCI, an abnormal level of β-amyloid(1-42) (Aβ(1-42)) in the CSF, and at least one diagnostic follow-up visit. We assessed the effect of APOE genotype, CSF total tau (t-tau) and tau phosphorylated at threonine 181 (p-tau) and hippocampal volume on time to AD-type dementia using Cox proportional hazards models and on decline on the Mini-Mental State Examination (MMSE) using linear mixed models. We included 110 subjects with MCI with abnormal CSF Aβ(1-42) and a mean MMSE score of 26.3 ± 2.8. During a mean follow-up of 2.2 ± 1.0 (range 0.4-5.0) years, 63 subjects (57%) progressed to AD-type dementia. Abnormal CSF t-tau (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.1-4.6, p = 0.03) and CSF p-tau (HR 3.5, 95% CI 1.3-9.2, p = 0.01) concentration and hippocampal atrophy (HR 2.5, 95% CI 1.1-5.6, p = 0.02) predicted time to dementia. For subjects with both abnormal t-tau concentration and hippocampal atrophy, HR was 7.3 (95% CI 1.0-55.9, p = 0.06). Furthermore, abnormal CSF t-tau and p-tau concentrations and hippocampal atrophy predicted decline in MMSE score. In subjects with MCI and evidence of amyloid pathology, the injury markers CSF t-tau and p-tau and hippocampal atrophy can predict further cognitive decline.

Comparison of xMAP and ELISA Assays for Detecting Cerebrospinal Fluid Biomarkers of Alzheimer's Disease

The best-studied biomarkers of Alzheimer's disease (AD) are the pathologically-linked cerebrospinal fluid (CSF) proteins amyloid-β 42 (Aβ(1-42)), total tau (t-tau), and tau phosphorylated on amino acid 181 (p-tau(181)). Many laboratories measure these proteins using enzyme-linked immunosorbent assay (ELISA). Multiplex xMAP Luminex is a semi-automated assay platform with reduced intra-sample variance, which could facilitate its use in CLIA-approved clinical laboratories. CSF concentrations of these three biomarkers reported using xMAP technology differ from those measured by the most commonly used ELISA, confounding attempts to compare results. To develop a model for converting between xMAP and ELISA levels of the three biomarkers, we analyzed CSF samples from 140 subjects (59 AD, 30 controls, 34 with mild cognitive impairment, and 17 with Parkinson's disease, including 1 with dementia). Log-transformation of ELISA and xMAP levels made the variance constant in all three biomarkers and improved the linear regression: t-tau concentrations were highly correlated (r = 0.94); p-tau(181) concentrations by ELISA can be better predicted using both the t-tau and p-tau(181) xMAP values (r = 0.96) as compared to p-tau(181) concentrations alone (r = 0.82); correlation of Aβ(1-42) concentrations was relatively weaker but still high (r = 0.77). Among all six protein/assay combinations, xMAP Aβ(1-42) had the best accuracy for diagnostic classification (88%) between AD and control subjects. In conclusion, our study demonstrates that multiplex xMAP is an appropriate assay platform providing results that can be correlated with research-based ELISA values, facilitating the incorporation of this diagnostic biomarker into routine clinical practice.

P2‐020: Variability in blood‐based beta‐amyloid assays: The need for consensus on preanalytical processing

analysis of peripheral blood plasma biomarkers of Ab40, Ab42, IL-10, TTau, P-Tau181 and IL-6 concentration. Results: One-way ANOVA analysis of Ab40 and IL-10 had statistically significant difference among three groups (P <0.001 and P 1⁄4 0.020). With Ab40 42.70 as the cutoff point, the ability of discriminating between AD and NC was sensitivity 80.0, specificity 69.6. Conclusions: The blood plasma Ab40 had the ability to distinguish between AD and NC. The results of plasma biomarkers in present research cannot distinguish between aMCI and NC.

Cerebrospinal fluid markers for Alzheimer's disease in a cognitively healthy cohort of young and old adults

Low amyloid β42 (Aβ42) and high total tau and phosphorylated tau (p-tau) concentrations in the cerebrospinal fluid (CSF) are biomarkers of Alzheimer's disease (AD), reflecting brain deposition of amyloid plaques and tangles. Age and apolipoprotein E allele E4 are two strong risk factors for AD, but few data are still available on their effect on CSF markers in normal aging. To study the effect of age on CSF Aβ42, total tau, and p-tau levels in a well-characterized group of cognitively normal subjects. CSF Aβ42 levels of 81 subjects (27% female, 53 ± 15.3 years, range: 21-88) were determined with sandwich enzyme-linked immunosorbent assay; of these, total tau and p-tau levels were measured in 61 (75%) and 42 (52%) cases, respectively. A linear regression analysis between age and CSF markers was carried out on the whole sample and separately in apolipoprotein E allele ɛ4 carriers and noncarriers. The median levels of all markers were significantly different between young (<65 years) and old (≥65 years) subjects (Aβ42: P = .03; tau: P = .02; p-tau: P = .002; tau/Aβ42: P = .004; p-tau/Aβ42: P = .03). The association of marker levels with age was confirmed in linear regression models, where a positive relationship with age was observed for total tau (B = 2.3; 95% confidence interval [CI]: 0.89 to 3.7; P = .002), p-tau (B = 0.5; 95% CI: 0.1 to 0.9; P = .02), and tau/Aβ42 ratio (B = 0.006; 95% CI: 0.002 to 0.01; P = .002). No subjects showed abnormal tau, whereas 19% showed abnormal CSF Aβ42 concentrations. In cognitively normal subjects, the concentrations of CSF biomarkers of AD are associated with age. Further longitudinal studies could clarify whether Aβ42 low levels represent a preclinical AD biomarker.

Interest of CSF biomarker analysis in possible cerebral amyloid angiopathy cases defined by the modified Boston criteria

According to the modified Boston criteria, cerebral amyloid angiopathy (CAA) can present with lobar hematoma (LH) or superficial siderosis (SS). Recently, decreased CSF β-amyloid peptide 40 and 42 (Aβ40; Aβ42) and increased total and phosphorylated tau (t-tau; p-tau) concentrations have been described in CAA presenting with LH. Our aim was to analyze CSF biomarkers as a diagnostic tool for CAA according to the modified Boston criteria. We prospectively included patients with possible or probable CAA according to the modified Boston criteria. CSF was analyzed for t-tau, p-tau, Aβ42, and Aβ40. Data were compared with AD patients (n = 42) and controls (n = 14). Thirteen CAA patients were included, nine presenting with LH and four with SS. T-tau and p-tau levels in CAA were higher than controls, but lower than in AD. Differences in t-tau and p-tau levels between CAA versus controls and AD were all significant apart of the CAA p-tau levels comparison with controls. Aβ42 levels in CAA were significantly lower than in controls, and slightly higher than in AD, though non-significantly. Aβ40 levels in CAA were non-significantly lower than in controls, and significantly lower than in AD. Combining the findings of our study and the earlier report, we confirm that patients with suspected CAA have significantly different values for t-tau, Aβ42, Aβ42/t-tau, and Aβ40. Especially Aβ40 levels seem to be of clinical interest to differentiate CAA from AD. CSF biomarkers have to be analyzed in a larger number of CAA patients, and compared to patients with other disorders causing LH or SS.

Total-tau in cerebrospinal fluid of patients with multiple sclerosis decreases in secondary progressive stage of disease and reflects degree of brain atrophy

Introduction. Tau protein is a potential marker of neuronal damage. The aim of the study is to investigate its potential role as a marker of brain atrophy in multiple sclerosis (MS).Materials and methods. Cerebrospinal fluid (CSF) and blood samples were collected from 48 patients with multiple sclerosis. Total-tau (t-tau) and phospho181Thr-tau (p-tau) concentrations were assayed with commercially available INNOTEST® hTAU Ag and INNOTEST® phospho181Thr-tau(181P) and correlated with indices of brain atrophy in magnetic resonance imaging (MRI) and clinical characteristics of the study population.Results. T-tau concentration in CSF was significantly higher in relapsing-remitting (RR) compared to secondary progressive (SP) MS patients (P = 0.01). Brain parenchymal fraction (BPF) was significantly decreased in SP patients (P = 0.002). BPF in the whole study population correlated inversely with Expanded Disability Status Scale (EDSS) (r = –0.51, P = 0.0002) and Multiple Sclerosis Severity Score (MSSS) (r = –0.42, P = 0.002). T-tau in CSF in the whole patient group correlated inversely with EDSS (r = –0.58, P = 0.0006).Conclusions. The results of our study suggest that total-tau concentration in CSF in a MS population decreases in the course of disease and reflects degree of parenchymal brain loss.

COGNITIVE IMPROVEMENT WITH INTRATHECAL ADMINISTRATION OF INFLIXIMAB IN A WOMAN WITH ALZHEIMER'S DISEASE

COGNITIVE IMPROVEMENT WITH INTRATHECAL ADMINISTRATION OF INFLIXIMAB IN A WOMAN WITH ALZHEIMER'S DISEASE

The effect of apolipoprotein E (ApoE) genotype on biomarkers of amyloidogenesis, tau pathology and neurodegeneration in Alzheimer's disease

The presence of the ɛ4 allele in apolipoprotein E (ApoE) represents the most important genetic risk factor for late onset sporadic Alzheimer's disease (AD), together with age and mid-life hypercholesterolemia. ApoE4 is the most important lipid transporter between cells in the CNS and it was found that ApoE4 is involved in Amyloid β (Aβ) formation, fibrilisation, accumulation, in the aggregation and hyperphosphorylation of tau and in the metabolism of brain cholesterol and in neurodegeneration. Low cerebrospinal fluid (CSF) Aβ1-42 is a marker of Aβ plaque load in the brain. High CSF t-tau and p-tau concentrations reflect axonal and neuronal damage and injury, which correlates with a neurofibrillary tangle stage and load, also reflecting the intensity of the disease process. Magnetic resonance imaging (MRI) brain atrophy is a biomarker of neurodegeneration and is the result of loss of neurons, synapses and dendritic arborization. ApoE genotype interacts with the AD biomarkers: ɛ4 carriers were found to present with lower concentrations of Aβ1-42, higher tau and p-tau, higher tau/Aβ ratio and a higher degree of brain atrophy at any disease stage, changing the test performances and the ability to distinguish between the different cognitive condition. The presence of the ɛ4 allele was also found to increase the power to predict further cognitive decline. Even if the presence of ApoE4 is not a deterministic factor for AD, it seems to shift the progression of the disease towards a younger age and faster progression. It is also likely that the ɛ4 allele increases the intensity of the pathological process in several ways. In the study of cognitive impaired patients and in their follow-up, biomarkers should be interpreted in consideration of the ApoE genotype in order to better predict the progression of the disease.