Plasma amyloid ß levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants.

INTRODUCTION: There is increasing interest in plasma amyloid beta (Aß) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aß levels may elucidate important biological processes that determine plasma Aß measures. METHODS: We included 12,369 non-demented participants from eight population-based studies. Imputed genetic data and measured plasma Aß1-40, Aß1-42 levels and Aß1-42/Aß1-40 ratio were used to perform genome-wide association studies, and gene-based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aß deposition and AD risk. RESULTS: Single-variant analysis identified associations with apolipoprotein E (APOE) for Aß1-42 and Aß1-42/Aß1-40 ratio, and BACE1 for Aß1-40. Gene-based analysis of Aß1-40 additionally identified associations for APP, PSEN2, CCK, and ZNF397. There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aß deposition. DISCUSSION: Identification of variants near/in known major Aß-processing genes strengthens the relevance of plasma-Aß levels as an endophenotype of AD.

Exposure to metal fumes and circulating miRNAs in Algerian welders.

PURPOSE: A cross-sectional study was conducted in a group of Algerian welders to study the relationship between the exposure to metal particles from welding fumes and the concentration of three circulating miRNAs, miR-21, miR-146a and miR-155, as markers of renal function injury. METHODS: Characteristics of the subjects and the curriculum laboris were determined by questionnaires. We measured the concentrations of metals in blood and urine samples using ICP-MS. The three circulating miRNAs studied were measured by quantitative PCR. Associations between miRNAs and internal exposure markers were assessed by simple and multiple regression analyses. RESULTS: miR-21 was significantly lower among welders (p = 0.017), compared with controls, adjusted for age, body mass index, smoking status and seniority. Significant adjusted associations were observed between miR-21 or miR-155 and urinary chromium (p = 0.005 or p = 0.041, respectively), miR-146a and urinary nickel (p = 0.019). The results of the multivariate analysis showed that duration of employment was the main factor responsible for the variation of miRNAs among welders. CONCLUSION: In conclusion, a recent exposure to certain metals, mainly chromium and nickel, appears to be associated to a decrease in plasma expression of miR-21, miR-146a and miR-155. Further larger studies would help to determine the mechanisms of action of metal particles on miRNA expression.

The relationship between CSF biomarkers and cerebral metabolism in early-onset Alzheimer's disease.

PURPOSE: One can reasonably suppose that cerebrospinal spinal fluid (CSF) biomarkers can identify distinct subgroups of Alzheimer's disease (AD) patients. In order to better understand differences in CSF biomarker patterns, we used FDG PET to assess cerebral metabolism in CSF-based subgroups of AD patients. METHODS: Eighty-five patients fulfilling the criteria for probable early-onset AD (EOAD) underwent lumbar puncture, brain 18F-FDG PET and MRI. A cluster analysis was performed, with the CSF biomarkers for AD as variables. Vertex-wise, partial-volume-corrected metabolic maps were computed for the patients and compared between the clusters of patients. Linear correlations between each CSF biomarker and the metabolic maps were assessed. RESULTS: Three clusters emerged. The "Aß42" cluster contained 32 patients with low levels of Aß42, while tau and p-tau remained within the normal range. The "Aß42 + tau" cluster contained 41 patients with low levels of Aß42 and high levels of tau and p-tau. Lastly, the "tau" cluster contained 12 patients with very high levels of tau and p-tau and low-normal levels of Aß42. There were no inter-cluster differences in age, sex ratio, educational level, APOE genotype, disease duration or disease severity. The "Aß42 + tau" and "tau" clusters displayed more marked frontal hypometabolism than the "Aß42" cluster did, and frontal metabolism was significantly negatively correlated with the CSF tau level. The "Aß42" and "Aß42 + tau" clusters displayed more marked hypometabolism in the left occipitotemporal region than the "tau" cluster did, and metabolism in this region was significantly and positively correlated with the CSF Aß42 level. CONCLUSION: The CSF biomarkers can be used to identify metabolically distinct subgroups of patients with EOAD. Future research should seek to establish whether these biochemical differences have clinical consequences.

Cerebrospinal fluid Alzheimer biomarkers can be useful for discriminating dementia with Lewy bodies from Alzheimer's disease at the prodromal stage.

BACKGROUND: Differential diagnosis between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) is not straightforward, especially in the early stages of disease. We compared AD biomarkers (phospho-Tau181, total-Tau, Aß42 and Aß40) in cerebrospinal fluid (CSF) of patients with DLB and AD, focusing especially on the prodromal stage. METHODS: A total of 1221 CSF were collected in different memory centres (ePLM network) in France and analysed retrospectively. Samples were obtained from patients with prodromal DLB (pro-DLB; n=57), DLB dementia (DLB-d; n=154), prodromal AD (pro-AD; n=132) and AD dementia (n=783), and control subjects (CS; n=95). These centres use the same diagnostic procedure and criteria to evaluate the patients. RESULTS: In patients with pro-DLB, CSF Aß42 levels appeared much less disrupted than in patients at the demented stage (DLB-d) (P<0.05 CS>pro-DLB; P<0.001 CS>DLB-d). On average, Aß40 levels in patients with DLB (pro-DLB and DLB-d) were much below those in patients with pro-AD (P<0.001 DLB groups

Inferior Parietal Cortex Hypoperfusion is the Most Specific Imaging Marker for AD Patients With Positive CSF Biomarker Assays in a Memory Clinic in France.

The diagnostic accuracy of hexamethylpropyleneamine oxime (HMPAo) single-photon emission computed tomography (SPECT) in Alzheimer disease (AD) remains undetermined in a "real-life" clinical population. The objective was to determine the HMPAo SPECT hypoperfusion pattern in cognitively impaired patients with positive CSF AD biomarker and to evaluate its diagnostic accuracy. This study included 120 patients referred to a university memory clinic assessed using HMPAo SPECT, MRI, and CSF biomarkers. Three biomarker signatures suggestive of AD were analyzed (1, Aß1-42; 2, Aß1-42+t-tau and/or p-tau; 3, Aß1-42/p-tau). The clinical diagnoses were possible AD (n=29) or other causes of cognitive impairment (n=91). All CSF AD signatures were significantly (1, P=0.004; 2, P=0.017; 3, P=0.024) associated with the difference between inferior parietal perfusion and lateral dorsal frontal cortex perfusion. The hypoperfusion pattern discriminated between patients with positive CSF AD biomarkers and those with other cognitive impairments with a sensitivity of 67% to 71% and a specificity of 63% to 65% and a greatest negative predictive value (NPV) of 90%. Inferior parietal cortex hypoperfusion was the most sensitive and specific feature in AD patients diagnosed using clinical and CSF biomarker criteria. This hypoperfusion pattern was associated with an NPV of 90% and therefore discriminated sharply between AD and other cognitive disorders.

Plasma ß-amyloid 40 levels are positively associated with mortality risks in the elderly.

BACKGROUND: We evaluated if plasma ß-amyloid (Aß) levels were associated with mortality risks in a subsample of the French Three-City (3C) prospective cohort study. METHODS: Analyses were based on 1254 participants randomly selected from the initial 3C cohort stratified by center, sex, and age in the context of a nested case-cohort study to investigate biological variables. Associations between plasma Aß and mortality were assessed with the Cox regression model with delayed entry including various potential confounding factors and testing possible mediators. RESULTS: A relationship between high plasma Aß1-40 concentrations and risk of mortality (hazards ratio, 1.15; 95% confidence interval, 1.01-1.31, P = .03) was unveiled independently of age, educational level, vascular risk factors, diet, physical activity, cognitive impairment, or frailty status. It was only modified when we included cystatin C levels. CONCLUSIONS: Further investigations are needed to determine precisely the pathophysiological roles of plasma Aß1-40 and cystatin C and before envisioning any future clinical applications.

Impact of harmonization of collection tubes on Alzheimer's disease diagnosis.

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 ß-amyloid 1-42 (Aß42), 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 Aß42 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.

Exacerbated CSF abnormalities in younger patients with Alzheimer's disease.

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 ß-amyloid (Aß 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 Aß 1-42 and lower Tau levels. Conversely, in non-AD patients, age was associated with lower CSF Aß 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.

Memantine for axial signs in Parkinson's disease: a randomised, double-blind, placebo-controlled pilot study.

BACKGROUND: Given that memantine is thought to decrease N-methyl-D-aspartic-acid-related (NMDA) glutamatergic hyperactivity and improve locomotion in rats, we sought to assess the drug's impact on axial symptoms in advanced Parkinson's disease (PD). METHODS: We performed a 90-day, randomised, double-blind, study with two parallel arms: 20 mg/day memantine versus placebo (ClinicalTrials.gov:NCT01108029). The main inclusion criterion was the presence of a severe gait disorder and an abnormal, forward-leaning stance. The following parameters were analysed under standardised conditions before and after acute administration of L-dopa: gait (stride length as primary criterion), the United-Parkinson's-Disease-Rating-Scale (UPDRS) motor score and its axial subscore, the hypertonia and strength of the axial extensors and flexors (isokinetic dynamometer), the Dyskinesia Rating Scale score (DRS) and its axial subscore. RESULTS: Twenty-five patients were included. The memantine and placebo group did not differ significantly in terms of stride length. However, in the memantine group, we observed significantly better results (vs placebo) for the overall UPDRS score (F(1,21)=4.9; p=0.039(-1)) and its axial subscore (F(1,21)=7.2; p=0.014(-1.1)), axial hypertonia, the axial and overall DRS and axial strength. CONCLUSIONS: Memantine treatment was associated with lower axial motor symptom and dyskinesia scores but did not improve gait. These benefits must be confirmed in a broader population of patients.

Intersite variability of CSF Alzheimer's disease biomarkers in clinical setting.

BACKGROUND: The assessment of total tau, phosphorylated tau (pTau-181) and amyloid beta (Aß 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 Aß 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 Aß 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 Aß 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.

A Pragmatic, Data-Driven Method to Determine Cutoffs for CSF Biomarkers of Alzheimer Disease Based on Validation Against PET Imaging.

BACKGROUND AND OBJECTIVES: To elaborate a new algorithm to establish a standardized method to define cutoffs for CSF biomarkers of Alzheimer disease (AD) by validating the algorithm against CSF classification derived from PET imaging. METHODS: Low and high levels of CSF phosphorylated tau were first identified to establish optimal cutoffs for CSF ß-amyloid (Aß) peptide biomarkers. These Aß cutoffs were then used to determine cutoffs for CSF tau and phosphorylated tau markers. We compared this algorithm to a reference method, based on tau and amyloid PET imaging status (ADNI study), and then applied the algorithm to 10 large clinical cohorts of patients. RESULTS: A total of 6,922 patients with CSF biomarker data were included (mean [SD] age: 70.6 [8.5] years, 51.0% women). In the ADNI study population (n = 497), the agreement between classification based on our algorithm and the one based on amyloid/tau PET imaging was high, with Cohen's kappa coefficient between 0.87 and 0.99. Applying the algorithm to 10 large cohorts of patients (n = 6,425), the proportion of persons with AD ranged from 25.9% to 43.5%. DISCUSSION: The proposed novel, pragmatic method to determine CSF biomarker cutoffs for AD does not require assessment of other biomarkers or assumptions concerning the clinical diagnosis of patients. Use of this standardized algorithm is likely to reduce heterogeneity in AD classification.

The Effect of Lactobacillus fermentum ME-3 Treatment on Glycation and Diabetes Complications.

SCOPE: Type 2 diabetes (T2D) induces organ damage associated with glycation, among other metabolic pathways. While therapeutic strategies have been tested to reduce the formation and impact of glycation products, results remain equivocal. Anti-diabetic therapies using probiotics have been proposed, but their effect upon glycation has not been reported. Here, the effects of the bacterial strain Lactobacillus fermentum ME-3 on glycation and T2D-related complications in a mouse model of T2D are investigated. METHODS & RESULTS: Wild-type LepRdb/+ and diabetic LepRdb/db littermates receive a daily gavage of either water or the probiotic ME-3 strain (1010 CFU). Glycation markers, fructoselysine-derived furosine (FL-furosine) and carboxymethyllysine (CML), are quantified in four major organs and plasma using stable-isotope dilution LC-MS/MS. After 12 weeks of ME-3 treatment, diabetic mice gain less weight and exhibit an apparently improved glucose tolerance. The ME-3 treatment reduces median renal levels of FL-furosine in both genotypes by 12-15%, and renal and pulmonary free-CML in diabetic mice by 30% and 18%, respectively. Attenuated hepatic steatosis and an improved plasma lipid profile are also observed with treatment in both genotypes, while the gut microbiota profile is unchanged. CONCLUSION: L. fermentum ME-3 has therapeutic potential for reducing the formation/accumulation of some glycation products in kidneys and attenuating some common diabetes-related complications.

Frontotemporal dementia is the leading cause of "true" A-/T+ profiles defined with Aß42/40 ratio.

INTRODUCTION: Patients with positive tauopathy but negative Aß42 (A-T+) in the cerebrospinal fluid (CSF) represent a diagnostic challenge. The Aß42/40 ratio supersedes Aß42 and reintegrates "false" A-T+ patients into the Alzheimer's disease spectrum. However, the biomarker and clinical characteristics of "true" and "false" A-T+ patients remain elusive. METHODS: Among the 509 T+N+ patients extracted from the databases of three memory clinics, we analyzed T+N+ patients with normal Aß42 and compared "false" A-T+ with abnormal Aß42/40 ratio and "true" A-T+ patients with normal Aß42/40 ratio, before CSF analysis and at follow-up. RESULTS: 24.9% of T+N+ patients had normal Aß42 levels. Among them, 42.7% were "true" A-T+. "True" A-T+ had lower CSF tauP181 than "false" A-T+ patients. 48.0% of "true" A-T+ patients were diagnosed with frontotemporal lobar degeneration before CSF analysis and 64.0% at follow-up, as compared with 6% in the "false" A-T+ group (P < .0001). DISCUSSION: Frontotemporal lobar degeneration is probably the main cause of "true" A-T+ profiles.

What is the clinical impact of cerebrospinal fluid biomarkers on final diagnosis and management in patients with mild cognitive impairment in clinical practice? Results from a nation-wide prospective survey in France.

OBJECTIVES: New diagnostic criteria for Alzheimer's disease (AD) include cerebrospinal fluid (CSF) biomarkers that allow diagnosis at the stage of mild cognitive impairment (MCI). However, the impact of CSF biomarkers in MCI populations in clinical practice has been poorly evaluated. The objective of this study is to assess the use and impact in clinical practice of AD CSF biomarkers in French memory clinics. DESIGN: We performed a nation-wide, prospective survey between March 2012 and September 2014. Data over the same period was extracted from the French National Database (Banque Nationale Alzheimer, BNA) and compared with the results of the survey. SETTING: 29 secondary and tertiary memory clinics in France. PARTICIPANTS: Clinicians prescribing lumbar puncture (LP) in order to measure AD CSF biomarkers. Clinicians completed a two-part questionnaire for each of their patients undergoing LP. PRIMARY AND SECONDARY OUTCOME MEASURES: Assessment of diagnosis, level of confidence before and after CSF biomarkers and impact on management in patients who underwent LP for CSF AD biomarkers in clinical routine. RESULTS: 977 questionnaires were completed, of which 61 were excluded because of unknown initial/final diagnosis or non-contributory CSF results. Of 916 patients reported, 153 (16.7%) had MCI as the initial diagnosis, of which 51 (33.3%) displayed an AD profile. CSF biomarkers resulted in a change in diagnosis in 44 patients (28.8%). Confidence level significantly increased after LP (8.3±1.4vs 6.73±1.18, p<0.0001), and CSF results modified management in 71/156 patients (46.4%), including 36 (23.5%) enrolled in clinical trials. Comparison of change in diagnosis with the BNA population revealed no difference (32.24%, p=0.4). CONCLUSION: This nation-wide survey, reflecting clinical practice in French memory clinics, describes the impact of CSF AD biomarkers in patients with MCI in clinical practice.

Response to pneumococcal vaccination in multiple myeloma.

BACKGROUND: Streptococcus pneumoniae infection causes morbidity and mortality in multiple myeloma patients. Pneumococcal vaccination is commonly given to immunocompromised myeloma patients; however response data are sparse. Here, we present longitudinal response data to pneumococcal vaccination in multiple myeloma patients. METHOD: Twenty-eight multiple myeloma patients were included, 25 of whom were newly diagnosed. All the patients received two vaccines Prevnar13® and Pneumo23®. Serotype-specific IgG was measured by ELISA for all 23 vaccine serotypes at baseline, and then sequentially at different time points postvaccination until treatment ended. Response to vaccination is available for 20 patients. The primary endpoint was the incidence rate of patients who obtained an isotype response serum concentration after vaccination. Secondary endpoints included detailed isotype increase, time to first increase, further assessment of a decreased anti-pneumococcal serum concentrations following treatment including autologous stem cell transplantation (ASCT), rate of infection with a special attention to pneumococcal infection. RESULTS: The median age was 66 years and the male to female ratio was 0.6. Anti-pneumococcal capsular polysaccharide (anti-PCP23) IgG, IgG2, IgA, and IgM responses were detected within 1 week postvaccination. Response to at least one subtype of antibody was obtained in 85% (n = 17) of patients, for at least two subtypes in 65% (n = 13), for at least three subtypes in 55% (n = 11), and 2 patients responded to all four subtypes. The median increase in the concentration of anti-PCP23 isotypes was threefold following vaccination, with the highest increase observed when Pneumo23® was given more than 30 days after Prevnar13®. The anti-pneumococcal geometric mean concentration decreased significantly for all subtypes over time independently of treatment approaches. CONCLUSION: Myeloma has the ability to demonstrate a response to pneumococcal vaccine, independently of preexisting hypogammaglobulinemia and possibly of treatment-induced immunodepression. We also observed a drop in the serum response overtime and following autologous transplantation. Further studies in larger sample are needed to understand the benefit of vaccination strategies in these patients.

Relevance of Follow-Up in Patients with Core Clinical Criteria for Alzheimer Disease and Normal CSF Biomarkers.

BACKGROUND: Few patients with a normal cerebrospinal fluid (CSF) biomarker profile fulfill the clinical criteria for Alzheimer disease (AD). OBJECTIVE: The aim of this study was to test the hypothesis of misdiagnoses for these patients. METHOD: Patients from the e-PLM centers fulfilling the core clinical criteria for probable AD dementia or mild cognitive impairment due to AD (AD-MCI), with normal CSF Aß1-42, T-tau and P-tau biomarkers and clinical follow-up, were included. Clinical and imaging data were reviewed by an independent board, from baseline (visit with clinical evaluation and CSF analysis) to the end of the follow-up, for a final diagnosis. RESULTS: In the e-PLM cohort of 1098 AD patients with CSF analysis, 37 (3.3%) patients (20 with AD dementia core clinical criteria and 17 with AD-MCI core clinical criteria) had normal CSF biomarker profile and a clinical follow-up. All patients presented with episodic memory impairment and 27 (73%) had medial temporal lobe atrophy on MRI-scan. After a median follow-up of 36 months (range 7-74), the final diagnosis was AD MCI or dementia for 9 (24%) patients, and unlikely due to AD for 28 (76%) patients. A misdiagnosis was corrected in 18 (49%) patients (mood disorders, non-AD degenerative dementia, vascular cognitive impairment, alcohol cognitive disorders, temporal epilepsy and hippocampal sclerosis), and 10 (27%) patients had cognitive disorders of undetermined etiology. CONCLUSION: AD diagnosis (MCI or dementia) with normal CSF biomarkers is a rare condition. A clinical follow- up is particularly recommended to consider an alternative diagnosis.

Heavy + light chain analysis to assign myeloma response is analogous to the IMWG response criteria.

Automated serum heavy + light chain (HLC) immunoassays can measure the intact immunoglobulins of each light chain type separately. We though to compare HLC assays with electrophoretic techniques in determining International Myeloma Working Group (IMWG) response criteria. 114 myeloma patients from 2 trials were included. HLC measurements were made utilizing archived sera and response assessments compared with those based on electrophoretic analysis at the time of the trials. Assessments at ∼90 days and maximal response were compared as was the power of the 2 techniques for predicting later responses, overall survival, and progression. The kappa statistic indicated good agreement between the 2 methods for determining IMWG response criteria, although HLC measurements might give better predictions of subsequent responses and frequently gave an earlier indication of change. HLC measurements could represent an alternative to electrophoretic techniques in determining IMWG response. Validation with a greater range of patient responses is needed for confirmation.