Serum neurofilament light chain cut-off definition for clinical diagnosis and prognosis of amyotrophic lateral sclerosis.

BACKGROUND: The neurofilament light chain (NfL) assay is gradually becoming an essential diagnostic tool for the diagnosis of many neurological diseases including amyotrophic lateral sclerosis (ALS). Different methods for the determination of this biomarker in serum have been developed in recent years. METHODS: We measured blood NfL in 429 patients referred to the tertiary ALS center of Montpellier, France using two different ultrasensitive methods (Ella™ and Simoa™) and we compared the clinical performances of these two approaches. We also converted NfL values into age and body mass index-adjusted Z-scores to assess cut-off values of this biomarker in this clinical context. RESULTS: We show comparable diagnostic and prognostic performance of Ella™ and Simoa™ technologies in ALS, with specificities and sensitivities exceeding 80% for both. We propose cut-off values for serum NfL in this clinical context, thus enabling the routine clinical use of this biomarker. CONCLUSION: The use of NfL in routine clinical practice will help predict survival and improve diagnostic accuracy by distinguishing ALS from other neurological diseases and motor neuron disease mimics.

CSF ß-amyloid is not a prognostic marker in multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disorder. Given its variable prognosis, the identification of new prognostic biomarkers is needed. OBJECTIVES: The aims of our study were to assess the prognostic values of CSF ß-amyloid-42 (Aß42) and ß-amyloid-40 (Aß40) levels in MS patients. METHODS: Eighty-nine (55 RRMS, 34 PPMS) patients with a recent diagnosis and 27 controls were included in this single-centre retrospective study. Clinical, MRI and CSF data have been collected and were analysed to evaluate the potential value of CSF Aß42 and Aß40 levels as MS biomarkers. RESULTS: CSF Aß levels as well as Aß42/Aß40 ratio were identical in MS patients and controls. Although CSF Aß42 and Aß40 levels were higher in PPMS than in RRMS and in patients with higher EDSS, a multivariate analysis including age and EDSS demonstrated that only age of patients was associated with CSF amyloid levels. Additionally, 55 RRMS patients were followed for 3 years. We found no association between baseline amyloid levels and 3-year disability. CONCLUSION: Our data do not support an association between CSF amyloid levels and MS status and disease severity. We suggest that CSF amyloid levels are not a prognostic biomarker in recently diagnosed RRMS.

Serum glial fibrillary acidic protein is a predictor of brain metastases in patients with metastatic breast cancer.

In patients with metastatic breast cancer (MBC), brain metastases (BM) are associated with high morbidity and mortality. However, there is no validated serum biomarker that accurately predicts BM occurrence in these patients, and the role of serum biomarkers for prognosis remains unclear. Here, we evaluated the association of neurofilament light chain (NfL), ubiquitin C-terminal hydrolase L1 (UCHL1), glial fibrillary acidic protein (GFAP) and tau serum levels with BM presence and prognosis in patients with MBC. In serum samples from patients with MBC with (n = 100) and without BM (n = 47), we measured the biomarker serum levels using single molecule array (Simoa) technology (Neurology-4-Plex assay). To evaluate their accuracy to identify patients with BM, we determined the receiver operating characteristic curve and the area under the curve (AUC) for each biomarker and calculated their sensitivity and specificity. The median serum levels of NfL, UCHL1, tau and GFAP were significantly higher in patients with BM. The AUC for GFAP (0.82, 95% confidence interval [CI] 0.75-0.88) was significantly higher than those of the other biomarkers considered independently. Using the medians as cutoff values, elevated serum levels of NfL, UCHL1, tau and GFAP were associated with BM in univariate analysis, but only high GFAP levels in multivariate analysis (odd ratio 23.4, 95% CI 6.8-80.5, P < .001). Elevated serum GFAP levels were independently associated with poor outcome. GFAP outperforms NfL, UCHL1 and tau as diagnostic and prognostic factor of BM in patients with MBC. These results must now be validated in an independent cohort of patients.

Tau protein in cerebrospinal fluid: a novel biomarker of the time of death?

BACKGROUND: Tau proteins are recognized biomarkers of neurodegeneration and neuronal damage in the cerebrospinal fluid (CSF). It has also been suggested that these CSF proteins could increase post-mortem due to neuronal death. The aim of this study was to investigate the changes in CSF total and phosphorylated tau (p-tau) levels in the early post-mortem interval (PMI), to determine whether these proteins could be relevant biomarkers of time since death. METHODS: Tau and p-tau levels were measured by ELISA in lumbar and cisternal CSF samples from 82 corpses (46 men, 36 women, mean age: 72.4 ± 15.2 years) with a PMI < 12 h. Forty-eight of them were considered neurologically healthy at the time of death. Rectal and tympanic temperatures were also measured in 37 individuals, and two validated temperature-based methods of PMI estimation were applied (Henssge's nomogram and Baccino's method). RESULTS: CSF tau and p-tau levels were significantly increased, with respective median values of 3315 pg/mL and 68.5 pg/mL in the whole cohort, while lower but still increased levels were observed in neurologically healthy patients. Sub-occipital punctures systematically provided higher tau and p-tau values (p < 0.0001). Despite a great inter-individual variability, the concentrations of both biomarkers were positively correlated with the early PMI, with the highest correlation for cisternal p-tau (r = 0.50, p < 0.0001 in the whole cohort; r = 0.58, p = 0.0003 in the neurologically healthy patients). Higher levels of CSF biomarkers were observed for PMI > 6 h versus PMI ≤ 6 h, the discriminatory power of the biomarkers being higher in the subgroup of neurologically healthy patients. Based on cut-off values obtained by ROC curve analysis, the CSF biomarkers could rectify or adjust the time interval provided by the temperature-based methods in a significant number of cases. A predictive model combining tympanic temperature and cisternal tau values was found to be particularly accurate to assign individuals according to their PMI (≤ or > 6 h), with a Se of 83% and a Sp of 100% (AUC = 0.95). CONCLUSION: Our findings suggest that CSF tau and p-tau proteins could serve as potential biomarkers of time since death, in association with tympanic temperature. The practical applicability of such an integrated approach has to be assessed by further studies.

Cerebrospinal fluid A beta 1-40 peptides increase in Alzheimer's disease and are highly correlated with phospho-tau in control individuals.

BACKGROUND: Amyloid pathology, which is one of the characteristics of Alzheimer's disease (AD), results from altered metabolism of the beta-amyloid (Aß) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aß1-42 is evident in AD, and the CSF ratio Aß42/Aß40 has recently been identified as one of the most reliable diagnostic biomarkers of amyloid pathology. Variations in inter-individual levels of Aß1-40 in the CSF have been observed in the past, but their origins remain unclear. In addition, the variation of Aß40 in the context of AD studied in several studies has yielded conflicting results. METHODS: Here, we analyzed the levels of Aß1-40 using multicenter data obtained on 2466 samples from six different cohorts in which CSF was collected under standardized protocols, centrifugation, and storage conditions. Tau and p-tau (181) concentrations were measured using commercially available in vitro diagnostic immunoassays. Concentrations of CSF Aß1-42 and Aß1-40 were measured by ELISA, xMAP technology, chemiluminescence immunoassay (CLIA), and mass spectrometry. Statistical analyses were calculated for parametric and non-parametric comparisons, linear regression, correlation, and odds ratios. The statistical tests were adjusted for the effects of covariates (age, in particular). RESULTS: Regardless of the analysis method used and the cohorts, a slight but significant age-independent increase in the levels of Aß40 in CSF was observed in AD. We also found a strong positive correlation between the levels of Aß1-40 and p-tau (181) in CSF, particularly in control patients. CONCLUSIONS: These results indicate that an increase in the baseline level of amyloid peptides, which are associated with an increase in p-tau (181), may be a biological characteristic and possibly a risk factor for AD. Further studies will be needed to establish a causal link between increased baseline levels of Aß40 and the development of the disease.

Relevance of Aß42/40 Ratio for Detection of Alzheimer Disease Pathology in Clinical Routine: The PLMR Scale.

Background: Cerebrospinal fluid (CSF) biomarkers (Aß peptides and tau proteins) improved the diagnosis of Alzheimer's disease (AD) in research and clinical settings. We previously described the PLM-scale (Paris-Lille-Montpellier study), which combines Aß42, tau, and phosphorylated ptau(181) biomarkers in an easy to use and clinically relevant way. The purpose of this work is to evaluate an optimized PLMR-scale (PLM ratio scale) that now includes the Aß42/Aß40 ratio to detect AD versus non-AD (NAD) participants in clinical routine of memory centers. Methods: Both scales were compared using 904 participants with cognitive impairment recruited from two independent cohorts (Mtp-1 and Mtp-2). The CSF Aß42/Aß40 ratio was measured systematically in Mtp-1, and only on biologically discordant cases in Mtp-2. Two different ELISA kit providers were also employed. The distribution of AD and NAD patients and the discrepancies of biomarker profiles were computed. Receiver Operating Characteristic curves were used to represent clinical sensitivity and specificity for AD detection. The classification of patients with the net reclassification index (NRI) was also evaluated. Results: Nine hundred and four participants (342 AD and 562 NAD) were studied; 400 in Mtp-1 and 504 in Mtp-2. For AD patients, the mean CSF Aß42 and CSF Aß42/40 ratio was 553 ± 216 pg/mL and 0.069 ± 0.022 pg/mL in Mtp-1 and 702 ± 335 pg/mL and 0.045 ± 0.020 pg/mL in Mtp-2. The distribution of AD and NAD differed between the PLM and the PLMR scales (p < 0.0001). The percentage AD well-classified (class 3) increased with PLMR from 38 to 83% in Mpt-1 and from 33 to 53% in Mpt-2. A sharp reduction of the discordant profiles going from 34 to 16.3% and from 37.5 to 19.8%, for Mtp-1 and Mtp-2 respectively, was also observed. The AUC of the PLMR scale was 0.94 in Mtp-1 and 0.87 in Mtp-2. In both cohorts, the PLMR outperformed CSF Aß42 or Aß42/40 ratio. The diagnostic performance was improved with the PLMR with an NRI equal to 44.3% in Mtp-1 and 28.8% in Mtp-2. Conclusion: The integration of the Aß42/Aß40 ratio in the PLMR scale resulted in an easy-to-use tool which reduced the discrepancies in biologically doubtful cases and increased the confidence in the diagnosis in memory center.