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Introduction: Blood‐based biomarkers are the next challenge for Alzheimer's disease (AD) diagnosis and prognosis. Methods: Mild cognitive impairment (MCI) participants (N = 485) of the BALTAZAR study, a large‐scale longitudinal multicenter cohort, were followed‐up for 3 years. A total of 165 of them converted to dementia (95% AD). Associations of conversion and plasma amyloid beta (Aβ)1‐42, Aβ1‐40, Aβ1‐42/Aβ1‐40 ratio were analyzed with logistic and Cox models. Results: Converters to dementia had lower level of plasma Aβ1‐42 (37.1 pg/mL [12.5] vs. 39.2 [11.1] , P value =.03) and lower Aβ1‐42/Aβ1‐40 ratio than non‐converters (0.148 [0.125] vs. 0.154 [0.076], P value =.02). MCI participants in the highest quartile of Aβ1‐42/Aβ1‐40 ratio (>0.169) had a significant lower risk of conversion (hazard ratio adjusted for age, sex, education, apolipoprotein E ε4, hippocampus atrophy = 0.52 (95% confidence interval [0.31–0.86], P value =.01). Discussion: In this large cohort of MCI subjects we identified a threshold for plasma Aβ1‐42/Aβ1‐40 ratio that may detect patients with a low risk of conversion to dementia within 3 years. [ABSTRACT FROM AUTHOR]

Background: Alpha-synuclein, abnormally aggregated in Dementia with Lewy Bodies (DLB), could represent a potential biomarker to improve the differentiation between DLB and Alzheimer's disease (AD). Our main objective was to compare Cerebrospinal Fluid (CSF) alpha-synuclein levels between patients with DLB, AD and Neurological Control (NC) individuals. Methods: In a monocentric retrospective study, we assessed CSF alpha-synuclein concentration with a validated ELISA kit (ADx EUROIMMUN) in patients with DLB, AD and NC from a tertiary memory clinic. Between-group comparisons were performed, and Receiver Operating Characteristic analysis was used to identify the best CSF alpha-synuclein threshold. We examined the associations between CSF alpha-synuclein, other core AD CSF biomarkers and brain MRI characteristics. Results: We included 127 participants (mean age: 69.3 ± 8.1, Men: 41.7%). CSF alpha-synuclein levels were significantly lower in DLB than in AD (1.28 ± 0.52 ng/mL vs. 2.26 ± 0.91 ng/mL, respectively, p < 0.001) without differences due to the stage of cognitive impairment. The best alpha-synuclein threshold was characterized by an Area Under the Curve = 0.85, Sensitivity = 82.0% and Specificity = 76.0%. CSF alpha-synuclein was associated with CSF AT(N) biomarkers positivity (p < 0.01) but not with hippocampal atrophy or white matter lesions. Conclusion: CSF Alpha-synuclein evaluation could help to early differentiate patients with DLB and AD in association with existing biomarkers. [ABSTRACT FROM AUTHOR]

In clinical practice, we showed that Ng mean concentrations with both immunoassay significantly differed between AD or MCI due to AD patients and other patients (Figure 2A). Keywords: Alzheimer's disease; biomarker; cerebrospinal fluid; immunoassay; neurogranin EN Alzheimer's disease biomarker cerebrospinal fluid immunoassay neurogranin e13 e17 5 11/26/21 20220101 NES 220101 To the Editor, Synaptic demise is increasingly recognized as a core feature of Alzheimer's disease (AD) [[1]] and synaptic protein levels are reduced in AD brains [[2]]. ROC curves (Figure 2B), used to discriminate AD or MCI due to AD from non-AD patients, demonstrated almost identical areas under curves (AUC) in both tests, with AUCs of 0.84 [95% CI 0.79-0.90]. [Extracted from the article]

Abstract Background Amyloid precursor protein (APP), a key molecule in Alzheimer’s disease (AD), is metabolized in two alternative cleavages, generating either the amyloidogenic peptides involved in AD pathology or the soluble form of APP (sAPPα). The level of amyloidogenic peptides in human cerebrospinal fluid (CSF) is considered to be a biomarker of AD, whereas the level of sAPPα in CSF as a biomarker has not been clearly established. sAPPα has neurotrophic and neuroprotective properties. Stimulating its formation and secretion is a promising therapeutic target in AD research. To this end, very sensitive tests for preclinical and clinical research are required. Methods The tests are based on homogenous time-resolved fluorescence and require no washing steps. Results We describe two new rapid and sensitive tests for quantifying mouse and human sAPPα. These 20 μl-volume tests quantify the levels of: i) endogenous mouse sAPPα in the conditioned medium of mouse neuron primary cultures, as well as in the CSF of wild-type mice, ii) human sAPPα in the CSF of AD mouse models, and iii) human sAPPα in the CSF of AD and non-AD patients. These tests require only 5 μl of conditioned medium from 5 × 104 mouse primary neurons, 1 μl of CSF from wild-type and transgenic mice, and 0.5 μl of human CSF. Conclusions The high sensitivity of the mouse sAPPα test will allow high-throughput investigations of molecules capable of increasing the secretion of endogenous sAPPα in primary neurons, as well as the in vivo validation of molecules of interest through the quantification of sAPPα in the CSF of treated wild-type mice. Active molecules could then be tested in the AD mouse models by quantifying human sAPPα in the CSF through the progression of the disease. Finally, the human sAPPα test could strengthen the biological diagnosis of AD in large clinical investigations. Taken together, these new tests have a wide field of applications in preclinical and clinical studies.

Background: The presynaptic protein neuregulin1 (NRG1) is cleaved by beta-site APP cleaving enzyme 1 (BACE1) in a similar way as amyloid precursor protein (APP) NRG1 can activate post-synaptic receptor tyrosine-protein kinase erbB4 (ErbB4) and was linked to schizophrenia. The NRG1/ErbB4 complex is neuroprotective, can trigger synaptogenesis and plasticity, increases the expression of NMDA and GABA receptors, and can induce neuroinflammation. This complex can reduce memory formation. In Alzheimer's disease (AD) brains, NRG1 accumulates in neuritic plaques. It is difficult to determine if NRG1 has beneficial and/or detrimental effects in AD. BACE1 levels are increased in AD brains and cerebrospinal fluid (CSF) and may lead to enhanced NRG1 secretion, but no study has assessed CSF NRG1 levels in AD and mild cognitive impairment (MCI) patients. Methods: This retrospective study included 162 patients suffering from AD dementia (54), MCI with progression to AD dementia (MCI-AD) (27), non-AD MCI (30), non-AD dementias (30), and neurological controls (27). All patients had neurological examinations, brain MRI, and neuropsychological evaluations. After written informed consent and using enzyme-linked immunosorbent assays (ELISAs), CSF samples were evaluated for Aβ1–42, Aβ1–40, total tau (T-tau), phosphorylated tau on threonine 181 (P-tau), BACE1, growth-associated protein 43 (GAP 43), neurogranin (Ng), and NRG1. Results: Levels of NRG1 were significantly increased in the CSF of AD (+ 36%) and MCI-AD (+ 28%) patients compared to neurological controls and also non-AD MCI and non-AD dementias. In addition, in AD and MCI-AD patients, NRG1 levels positively correlated with Aβ1–42 but not with T-tau, P-tau, and BACE1 levels and negatively correlated with MMSE scores. A longitudinal follow-up study of AD patients revealed a trend (p = 0.08) between CSF NRG1 levels and cognitive decline. In the overall population, NRG1 correlated with MMSE and the synaptic biomarkers GAP 43 and neurogranin. Conclusions: Our results showed that CSF NRG1 levels are increased in AD and MCI-AD as compared to controls and other dementias. CSF NRG1 levels are associated with cognitive evolution, and a major outcome of our findings is that synaptic NRG1 could be involved in the pathophysiology of AD. Modulating brain NRG1 activity may represent a new therapeutic target in AD. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between cerebrospinal fluid (CSF) β-amyloid peptide (Aβ42) and CSF Tau in a large population of patients referred to memory clinics for investigation of cognitive dysfunction. Methods: We analyzed Alzheimer’s disease (AD) biomarkers in CSF taken from 3565 patients referred to 18 French memory clinics. Patients were classified into four profiles according to levels of CSF biomarkers (A: amyloidosis, N: neurodegeneration). The association between CSF Tau and CSF Aβ42 were analyzed using general linear regression models, in the overall population and stratified by biomarkers profiles. We compared linear and quadratic models using Akaike information criterion. We also assessed change in biomarker profiles in a subset of patients who had 2 assessments of biomarkers. Results: CSF Tau was negatively associated with CSF Aβ42 in the overall population, following a non-linear quadratic model. However, the nature of this association was different in the 4 profiles: positive association in A-N- profile, negative association in A-N+ and A+N+ profiles, lack of association in A+N- patients. When considering patients with longitudinal data on profiles, 36% of those initially classified as A-N+ evolved to an A+N+ profile. Conclusions: The nature of the association between CSF Aβ42 and CFS Tau depends on the A/N profiles of patients. These results suggest an increase in CSF Aβ42 early in the disease before its decline while tau pathology progresses, this pattern is particularly observed in non-APOE4 subjects. This phenomenon may explain why some patients with neurodegeneration only markers convert to an AD profile (A+N+) over time. [ABSTRACT FROM AUTHOR]

Background: There are few data concerning the association between season and cognition and its neurobiological correlates in older persons-effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects.Methods and Findings: We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07-0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07-0.66], p = 0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years' difference in age (95% CI 2.1-8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10-1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aβ 42 level (amplitude 0.30 SD [95% CI 0.10-0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21-0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27-0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24-0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20-0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere.Conclusions: Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD. [ABSTRACT FROM AUTHOR]

Background: CSF Alzheimer's disease (AD) biomarkers allow classifying individuals based on their levels of amyloid and neurodegeneration pathologies.Objective: To investigate the distribution of AD biomarker profiles from patients suffering from cognitive disorders.Methods: We analyzed 3001 patients with cognitive disorders and referred by 18 French memory clinics located in and around Paris. Patients were classified as normal, amyloidosis (A+/N-), amyloidosis and neurodegeneration (A+/N+) or suspected non-AD pathophysiology (SNAP), according to their CSF levels of biomarkers. Analysis were performed for the overall population and stratified by gender, age quintiles, and Mini-Mental State Examination (MMSE) score quintiles. Results were compared to previous findings in cohorts of healthy elderly adults.Results: 37% of the sample were classified as A+/N+, 22% were classified A+/N-, and 15% as SNAP. The A+/N+ profile was associated with female gender, advanced age, and lower MMSE score, while the A+/N-profile was observed more frequently in men and the distribution was stable across age and MMSE. The SNAP profile showed no association with gender or age, was less frequent in patients with lower MMSE, and had a lower repartition than the one previously reported in asymptomatic populations.Conclusions: While A+/N+ patients had the clinical characteristics typically observed in AD, A+/N-patients had a different epidemiological pattern (higher frequency in men, no association with advanced age or lower MMSE). The SNAP profile was less frequent than previously reported in the general elderly population, suggesting that this profile is not a frequent cause of memory impairment in this population. [ABSTRACT FROM AUTHOR]

Background: Synaptic degeneration is a central pathogenic event in Alzheimer's disease that occurs early during the course of disease and correlates with cognitive symptoms. The pre-synaptic vesicle protein synaptotagmin-1 appears to be essential for the maintenance of an intact synaptic transmission and cognitive function. Synaptotagmin-1 in cerebrospinal fluid is a candidate Alzheimer biomarker for synaptic dysfunction that also may correlate with cognitive decline. Methods: In this study, a novel mass spectrometry-based assay for measurement of cerebrospinal fluid synaptotagmin-1 was developed, and was evaluated in two independent sample sets of patients and controls. Sample set I included cerebrospinal fluid samples from patients with dementia due to Alzheimer's disease (N = 17, age 52-86 years), patients with mild cognitive impairment due to Alzheimer's disease (N = 5, age 62-88 years), and controls (N = 17, age 41-82 years). Sample set II included cerebrospinal fluid samples from patients with dementia due to Alzheimer's disease (N = 24, age 52-84 years), patients with mild cognitive impairment due to Alzheimer's disease (N = 18, age 58-83 years), and controls (N = 36, age 43-80 years). Results: The reproducibility of the novel method showed coefficients of variation of the measured synaptotagmin-1 peptide 215-223 (VPYSELGGK) and peptide 238-245 (HDIIGEFK) of 14 % or below. In both investigated sample sets, the CSF levels of synaptotagmin-1 were significantly increased in patients with dementia due to Alzheimer's disease (P = 0.0001) and in patients with mild cognitive impairment due to Alzheimer's disease (P < 0.001). In addition, in sample set I the synaptotagmin-1 level was significantly higher in patients with mild cognitive impairment due to Alzheimer's disease compared with patients with dementia due to Alzheimer's disease (P ≤ 0.05). Conclusions: Cerebrospinal fluid synaptotagmin-1 is a promising biomarker to monitor synaptic dysfunction and degeneration in Alzheimer's disease that may be useful for clinical diagnosis, to monitor effect on synaptic integrity by novel drug candidates, and to explore pathophysiology directly in patients with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Background: Affective and psychotic disorders are mental or behavioural patterns resulting in an inability to cope with life's ordinary demands and routines. These conditions can be a prodromal event of Alzheimer's disease (AD). The prevalence of underlying AD lesions in psychiatric diseases is unknown, and it would be helpful to determine them in patients. AD cerebrospinal fluid (CSF) biomarkers (amyloid β, tau and phosphorylated tau) have high diagnostic accuracy, both for AD with dementia and to predict incipient AD (mild cognitive impairment due to AD), and they are sometimes used to discriminate psychiatric diseases from AD. Our objective in the present study was to evaluate the clinical utility of CSF biomarkers in a group of patients with psychiatric disease as the main diagnosis. Methods: In a multicentre prospective study, clinicians filled out an anonymous questionnaire about all of their patients who had undergone CSF biomarker evaluation. Before and after CSF biomarker results were obtained, clinicians provided a diagnosis with their level of confidence and information about the treatment. We included patients with a psychiatric disorder as the initial diagnosis. In a second part of the study conducted retrospectively in a followed subgroup, clinicians detailed the psychiatric history and we classified patients into three categories: (1) psychiatric symptoms associated with AD, (2) dual diagnosis and (3) cognitive decline not linked to a neurodegenerative disorder. Results: Of 957 patients, 69 had an initial diagnosis of a psychiatric disorder. Among these 69 patients, 14 (20.2 %) had a CSF AD profile, 5 (7.2 %) presented with an intermediate CSF profile and 50 (72.4 %) had a non-AD CSF profile. Ultimately, 13 (18.8 %) patients were diagnosed with AD. We show that in the AD group psychiatric symptoms occurred later and the delay between the first psychiatric symptoms and the cognitive decline was shorter. Conclusions: This study revealed that about 20 % of patients with a primary psychiatric disorder diagnosis before undergoing a CSF exploration for cognitive disorder displayed a CSF biomarker AD profile. In memory clinics, it seems important to consider AD as a possible diagnosis before finalizing a diagnosis of a psychiatric disorder. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by the accumulation of Aβ peptides, hyperphosphorylated tau proteins, and neuronal loss in the brain of affected patients. The causes of neurodegeneration in AD are not clear, but apoptosis could be one of the cell death mechanisms. According to the amyloid hypothesis, abnormal aggregation of Aβ leads to altered kinase activities inducing tau phosphorylation and neuronal degeneration. Several studies have shown that pro-apoptotic kinases could be a link between Aβ and tau anomalies. Here, we present recent evidences from AD experimental models and human studies that three pro-apoptotic kinases (double-stranded RNA kinase (PKR), glycogen synthase kinase-3β, and C-Jun terminal kinase (JNK) could be implicated in AD physiopathology. These kinases are detectable in human fluids and the analysis of their levels could be used as potential surrogate markers to evaluate cell death and clinical prognosis. In addition to current biomarkers (Aβ1-42, tau, and phosphorylated tau), these new evaluations could bring about valuable information on potential innovative therapeutic targets to alter the clinical evolution. [ABSTRACT FROM AUTHOR]

Introduction: The cerebrospinal fluid (CSF) biomarkers amyloid-ß (Aß), tau and phosphorylated tau (p-tau181) are now used for the diagnosis of Alzheimer's disease (AD). Aβ40 is the most abundant Aβ peptide isoform in the CSF, and the Aβ 42/40 ratio has been proposed to better reflect brain amyloid production. However, its additional value in the clinical setting remains uncertain. Methods: A total of 367 subjects with cognitive disorders who underwent a lumbar puncture were prospectively included at three French memory centers (Paris-North, Lille and Montpellier; the PLM Study). The frequency of positive, negative and indeterminate CSF profiles were assessed by various methods, and their adequacies with the diagnosis of clinicians were tested using net reclassification improvement (NRI) analyses. Results: On the basis of local optimum cutoffs for Aβ42 and p-tau181, 22% of the explored patients had indeterminate CSF profiles. The systematic use of Aβ 42/40 ratio instead of Aβ42 levels alone decreased the number of indeterminate profiles (17%; P = 0.03), but it failed to improve the classification of subjects (NRI = -2.1%; P = 0.64). In contrast, the use of Aβ 42/40 ratio instead of Aβ42 levels alone in patients with a discrepancy between p-tau181 and Aβ42 led to a reduction by half of the number of indeterminate profiles (10%; P < 0.001) and was further in agreement with clinician diagnosis (NRI = 10.5%; P = 0.003). Conclusions: In patients with a discrepancy between CSF p-tau181 and CSF Aβ42, the assessment of Aβ 42/40 ratio led to a reliable biological conclusion in over 50% of cases that agreed with a clinician's diagnosis. [ABSTRACT FROM AUTHOR]

Introduction The relevance of the cerebrospinal fluid (CSF) biomarkers for the diagnosis of Alzheimer's disease (AD) and related disorders is clearly established. However, the question remains on how to use these data which are often heterogeneous (not all biomarkers being pathological). The objective of this study is to propose to physicians in memory clinics a biological scale of probabilities that the patient with cognitive impairments has an Alzheimer's disease (AD) pathological process. Methods For that purpose, we took advantage of the multicenter data of our Paris-North, Lille, and Montpellier (PLM) study which has emerged through the initial sharing of information from these memory centers. Different models combining the CSF levels of amyloid-β 42, tau and p-tau(181) were tested to generate categories of patients with very low (<10%), low (<25%), high (>75%) and very high predictive values (>90%) for positive AD. A total of 1,273 patients (646 AD and 627 non-AD) from six independent memory clinic cohorts were included. Results A prediction model based on logistic regressions achieved a very good stratification of the population but had the disadvantages of needing mathematical optimization and being difficult to use in daily clinical practice. Remarkably, a simple and intuitive model based on the number (from 0 to 3) of three pathological CSF biomarkers resulted in a very efficient predictive scale for AD in patients seen in memory clinics. The scale's overall predictive value for AD for the different categories were: class 0: 9.6% (95% confidence interval, CI: 6.0-13.2%), class 1: 24.7% (95% CI: 18.0-31.3%), class 2: 77.2% (95% CI: 67.8-86.5%) and class 3: 94.2% (95% CI: 90.7-97.7%). In addition, with this scale, a significantly higher number of patients were correctly classified than with the logistic regression. Its superiority in model performance was validated by the computation of the net reclassification index (NRI). The model was also validated in an independent multicenter dataset of 408 patients (213 AD and 195 non-AD). Conclusions In conclusion, we defined a new scale which could be used to facilitate the interpretation, and routine use of multivariate CSF data, as well as helping the stratification of patients in clinical research trials. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are well validated in clinical research but less in clinical practice. Using a questionnaire, we evaluated the reasons for prescriptions and clinician's expectations concerning CSF biomarkers. The results show that CSF AD biomarkers are mainly required in case of atypical dementia and diagnosis uncertainty that are different from indications in clinical research. In the future, clinicians wish to get new biomarkers that could improve differential diagnosis and could have a good pronostic value. Further studies in routine practice are necessary to precise the role of these biomarkers in the management of patients. [ABSTRACT FROM AUTHOR]

Background: Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimer's disease (AD). Objective: The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD). Methods: CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67). and aMCI-AD (n = 27). Results: p-Tau181 levels were higher in the lvPPA-AD group than in the aMCI-AD group (p < 0.05). Total tau levels were higher in the lvPPA-AD group versus those in the nlAD (p < 0.05) and aMCI-AD (p < 0.001) groups. Conclusions: These results suggest a more pronounced involvement of a taupathy in lvPPA-AD compared to aMCI-AD and a more important neuronal death in lvPPA-AD than in nlAD or aMCI-AD. [ABSTRACT FROM AUTHOR]

Abstract: Background: The assessment of total tau, phosphorylated tau (pTau-181) and amyloid beta (Aβ 1–42) concentrations in the cerebrospinal fluid (CSF) of subjects has been validated for the diagnosis of Alzheimer’s disease (AD). Although these measurements have shown some variability, little is known about their intersite variability in clinical settings. Methods: A total of 880 subjects (AD, n = 515; non-AD, n = 365) from three French memory centers were included. Receiver–operating characteristic analyses were performed to computerized area under curves (AUCs) and optimal thresholds for each biomarker in the three centers. A test–retest study was performed in a group of 32 CSF samples by repeated blind analysis of the three biomarkers using the same immunoassay batches in the three centers. Results: In the three centers, tau (AUC, 0.82–0.88) and pTau-181 (AUC, 0.83–0.89) outperformed Aβ 1–42 (AUC, 0.70 –0.73) to discriminate subjects with AD from those without AD. An intersite variation of mean levels and cutoffs was observed for the three biomarkers. This variation was higher for Aβ 1–42 (range of cutoff, 368–582 pg/mL) than for tau (range of cutoff, 289–353 pg/mL). In a test–retest study, the mean interlaboratory coefficients of variation were 12.2% for Aβ 1–42, 11.3% for tau, and 11.5% for pTau-181. Conclusion: Intercenter variability of CSF biomarkers has been confirmed in a multisite cohort of subjects and can be improved in clinical settings. Efforts on harmonization of procedures should be encouraged to optimize the accuracy of CSF biomarkers in AD. [Copyright &y& Elsevier]

The French Alzheimer's Disease Plan aims, in an unprecedented national effort, to develop research, promote optimal diagnosis, and take better care of patients. In order to evaluate the clinical interest and use of cerebrospinal fluid (CSF) biomarkers, a data-sharing project, the PLM (Paris-North, Lille and Montpellier) study has emerged through collaboration between these memory centers, already involved in this field. The revised Alzheimer's disease (AD) diagnosis criteria include CSF biomarkers, but little is known about their use in routine clinical practice. To evaluate their interest and diagnostic accuracy in routine AD diagnosis, a cohort of 677 patients from Montpellier was first analyzed. The results were then validated through the analysis of a second cohort of 638 patients from Lille and Paris-Nord. Diagnoses of AD and other dementias were established by multidisciplinary expert teams, based on neuropsychological exams and structural brain imaging, blinded from CSF results. CSF amyloid-β, tau, and p-tau concentrations were measured for all patients. Receiver-operating characteristic curves were used to define cut-offs and evaluate the ability of each biomarker to discriminate AD from other diagnoses. We showed that p-tau outperformed other biomarkers for discriminating AD from non-AD patients and presents a clear clinical interest. The other biomarkers also showed relevant variations especially when the differential AD diagnoses were taken into account. Altogether we could demonstrate in both mono-centric and multi-centric cohorts from memory clinics the capacity of CSF biomarkers to discriminate AD from non-AD patients in clinical routine with a high sensitivity and specificity. [ABSTRACT FROM AUTHOR]

The cerebrospinal fluid (CSF) levels of the proapoptotic kinase R (PKR) and its phosphorylated PKR (pPKR) are increased in Alzheimer's disease (AD), but whether CSF PKR concentrations are associated with cognitive decline in AD patients remain unknown. In this study, 41 consecutive patients with AD and 11 patients with amnestic mild cognitive impairment (aMCI) from our Memory Clinic were included. A lumbar puncture was performed during the following month of the clinical diagnosis and Mini-Mental State Examination (MMSE) evaluations were repeated every 6 months during a mean follow-up of 2 years. In AD patients, linear mixed models adjusted for age and sex were used to assess the cross-sectional and longitudinal associations between MMSE scores and baseline CSF levels of Aβ peptide (Aβ 1-42), Tau, phosphorylated Tau (p-Tau 181), PKR and pPKR. The mean (SD) MMSE at baseline was 20.5 (6.1) and MMSE scores declined over the follow-up (- 0.12 point/month, standard error [SE] = 0.03). A lower MMSE at baseline was associated with lower levels of CSF Aβ 1-42 and p-Tau 181/Tau ratio. pPKR level was associated with longitudinal MMSE changes over the follow-up, higher pPKR levels being related with an exacerbated cognitive deterioration. Other CSF biomarkers were not associated with MMSE changes over time. In aMCI patients, mean CSF biomarker levels were not different in patients who converted to AD from those who did not convert.These results suggest that at the time of AD diagnosis, a higher level of CSF pPKR can predict a faster rate of cognitive decline. [ABSTRACT FROM AUTHOR]

Glucose dysmetabolism has been consistently associated with an increased risk of cognitive disorders, and brain insulin resistance could play a role in Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We have investigated the relationship between CSF concentrations of amyloid-β peptide 1-42 (Aβ1-42), total tau, and phosphorylated tau (ptau-181) and plasma and CSF glucose levels in a cohort of 94 newly diagnosed non-diabetics AD patients. We report that CSF Aβ1-42 level was inversely associated with CSF to plasma glucose ratio (Spearman's coefficient = -0.27, p = 0.008). This relationship remained after adjustment for age, gender, body mass index, hypertension, and MMSE score (β [SE] of linear regression = -0.93 [0.37], p = 0.01). In stratified analysis, this relationship was observed only in patients who did not carry the apolipoprotein E4 allele. No significant relationship was found between glucose levels and total tau or phosphorylated tau 181. These results support the idea that a link between glucose dysmetabolism and the amyloid pathway may exist in the pathogenesis of AD. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to analyze differences in biomarker outcomes before and after harmonization of cerebrospinal fluid (CSF) collection tubes in Alzheimer's disease (AD) diagnosis. Methods We analyzed data from French memory centers that switched from different CSF collection tubes to a common one. A total of 1966 patients were included in the study. CSF concentrations of β-amyloid 1–42 (Aβ42), total tau, and phosphorylated tau (p-tau181) were measured in each center using the same commercial enzyme-linked immunoabsorbent assay (ELISA) kits. The diagnostic value of CSF biomarkers according to the type of tube used was then assessed using different cutoffs. Results The predictive value of Aβ42 was highly affected by the type of collection tube used. The optimal cutoff value for p-tau181 appeared not to be affected by the type of collection tube whereas that of total tau was slightly changed. New optimal cutoff values were then computed. Conclusions In a routine clinical environment, the selection of the collection tube and biomarker cutoff value makes a major difference in AD biological diagnosis. The use of a common collection tube among different centers will reduce the risk of misdiagnosis and incorrect patient stratification. [ABSTRACT FROM AUTHOR]

• A novel assay for measurement of SNAP-25 in cerebrospinal fluid is presented. • SNAP-25 is considered a potential biomarker for Alzheimer's disease. • SNAP-25 is a potential biomarker for early Alzheimer's disease. Synaptic degeneration is central in Alzheimer's disease (AD) pathogenesis and biomarkers to monitor this pathophysiology in living patients are warranted. We developed a novel sandwich enzyme-linked immunosorbent assay (ELISA) for the measurement of the pre-synaptic protein SNAP-25 in cerebrospinal fluid (CSF) and evaluated it as a biomarker for AD. CSF samples included a pilot study consisting of AD (N = 26) and controls (N = 26), and two independent clinical cohorts of AD patients and controls. Cohort I included CSF samples from patients with dementia due to AD (N = 17), patients with mild cognitive impairment (MCI) due to AD (N = 5) and controls (N = 17), and cohort II CSF samples from patients with dementia due to AD (N = 24), patients with MCI due to AD (N = 18) and controls (N = 36). CSF levels of SNAP-25 were significantly increased in patients with AD compared with controls (P ≤ 0.00001). In both clinical cohorts, CSF levels of SNAP-25 were significantly increased in patients with MCI due to AD (P < 0.0001). SNAP-25 could differentiate dementia due to AD (N = 41) from controls (N = 52) and MCI due to AD (N = 23) from controls (N = 52) with areas under the curve of 0.967 (P < 0.0001) and 0.948 (P < 0.0001), respectively. CSF SNAP-25 is a promising AD biomarker that differentiates AD patients in different clinical stages of the disease from controls with excellent diagnostic accuracy. Future studies should address the specificity of the CSF SNAP-25 against common differential diagnoses to AD, as well as how the biomarker changes in response to treatment with disease-modifying drug candidates. [ABSTRACT FROM AUTHOR]

Abstract: Increasing age is the most important risk factor for developing Alzheimer's disease (AD). The aim of this study was to investigate the relationships between age and cerebrospinal fluid (CSF) levels of β-amyloid (Aβ 1–42), total Tau and phosphorylated Tau (pTau-181), in AD and non-AD patients explored for cognitive disorders. 966 patients (AD, n=528; non-AD, n=438) were included between January 2008 and December 2010 (mean age, 69.5years; mean MMSE, 20.2) from three French memory centers. Multivariable linear regression models were used to study the relationship between CSF biomarker levels and age in AD and non-AD patients. The capacity of each CSF biomarker in discriminating patients was evaluated using the area under the receiver-operating characteristic (ROC) curves by quartile of distribution of age. In AD patients, older age was associated with higher CSF Aβ 1–42 and lower Tau levels. Conversely, in non-AD patients, age was associated with lower CSF Aβ 1–42, higher Tau, and higher pTau-181 levels. In sex-stratified analysis, these relationships were significant only in women. Using ROC curve analysis, CSF AD biomarkers were more discriminant in younger patients than in older ones. In this clinically-based study, younger patients with AD had exacerbated CSF anomalies compared to older patients with AD. CSF biomarkers were more discriminant in younger patients than in older ones for the diagnosis of AD, especially in women. These results support the idea of an overlap in AD neuropathological lesions in oldest subjects with or without AD. [Copyright &y& Elsevier]

Background: The pathological hallmarks of Alzheimer''s disease (AD) include accumulation of amyloid-β (Aß) peptide forming extracellular senile plaques, neurofibrillary tangles made of hyperphosphorylated tau protein with neuronal loss. Aβ peptide (1–42), total tau (T-tau), and phosphorylated tau at threonine 181 (p181tau) levels in the cerebrospinal fluid (CSF) are now validated biomarkers. The proapoptotic kinase R (PKR), is activated by Aβ accumulates in degenerating neurons in AD brains and controls protein synthesis and indirectly tau phosphorylation. Methods: In a prospective cohort study, the CSF of 91 patients were studied (AD: 45; amnestic mild cognitive impairment: 11; neurological disease control subjects [NDC]: 35). The levels of total PKR (T-PKR), phosphorylated PKR (pPKR), Aß 1–42, T-tau, and p181tau were assessed by immunoblotting or enzyme-linked immunosorbent assay methods. Receivers operating characteristic curves were used to examine the discriminatory power of T-PKR, pPKR, and pPKR/T-PKR ratio between AD and NDC patients. Results: Total PKR and pPKR concentrations were elevated in AD and amnestic mild cognitive impairment subjects. We have determined a pPKR value (optical density units) that could discriminate AD patients from control subjects with a sensitivity of 91.1% and a specificity of 94.3%. Among AD patients, T-PKR and pPKR levels correlate with CSF p181tau levels. Some AD patients with normal CSF Aß, T-tau, or p181tau levels had abnormal T-PKR and pPKR levels. Conclusions: The evaluation of CSF T-PKR and pPKR can discriminate between AD patients and NDC and could help to improve the biochemical diagnosis of AD. [Copyright &y& Elsevier]

Abstract: In Alzheimer''s disease (AD), the cognitive reserve theory predicts that at any level of assessed clinical severity, the underlying brain pathology is more advanced in patients with more cognitive reserve. Recent evidences suggest that cerebrospinal fluid (CSF) biomarkers may reflect the brain pathology in AD. We investigated the relationship between education level and CSF concentrations of β-amyloid, total tau and phosphorylated tau (ptau-181) in a cohort of 70 subjects newly diagnosed with AD. We report that CSF concentration of β-amyloid was inversely associated with years of education, after adjustment for age, sex, and severity of the disease. We further demonstrate in stratified analysis that this relation was mainly present in mild form of the disease (CDR1), and was attenuated in more advanced forms of the disease. These results are consistent with the cognitive reserve theory, and suggest that cognitive reserve may be protective against amyloid related cognitive impairment at the onset of the clinical dementia. [Copyright &y& Elsevier]