Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies.

BACKGROUND: Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer's disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood. METHODS: We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation. RESULTS: We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism. CONCLUSION: Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.

Associations between neurofilament light chain levels, disease activity and brain atrophy in progressive multiple sclerosis.

BACKGROUND: Neurofilament light chain is a promising biomarker of disease activity and treatment response in relapsing-remitting multiple sclerosis (MS). Its role in progressive MS is less clear. AIM: The aim of the study was to assess the relationship between plasma neurofilament light chain (pNfL) and disease activity as defined by the concept NEDA-3 (No Evident Disease Activity), and brain volumetry, in a cohort of patients with the progressive disease form (PMS). METHODS: Levels of pNfL (SIMOA technology) were examined in 52 PMS patients and analysed in relationship to NEDA-3 status and annual brain volume loss (BVL) during the last 12 months. The statistical model was developed using logistic regression analysis, including demographic, clinical and magnetic resonance imaging (MRI) data as independent variables. Dependent variables were NEDA-3 status and BVL. RESULTS: The mean age of the study participants (n=52, 50% females) was 45.85 (SD, 9.82) and the median disability score was 5.0 (IQR: 5.0-5.5). ROC analysis showed that pNfL predicts NEDA-3 (the sensitivity and specificity of the model were 77.8% and 87.6%, respectively, P<0.001) and abnormal BVL (the sensitivity and specificity were 96.6% and 68.2%, respectively, P<0.001). CONCLUSIONS: The results show that pNfL levels are a useful biomarker of disease activity determined by NEDA-3 status, including brain MRI-volumetry, in patients with the progressive form of MS.

Neurofilament Light Chain Levels Are Associated with Disease Activity Determined by No Evident Disease Activity in Multiple Sclerosis Patients.

INTRODUCTION: There is a need for blood biomarkers of disease activity in multiple sclerosis (MS). The aim of the study was to assess the relationship between plasma neurofilament light chain (pNfL) and disease activity as defined by the concept three-domain no evident disease activity (NEDA-3). METHODS: Levels of pNfL (SIMOA) were examined in 159 MS patients and analyzed in relationship to NEDA-3 status (absence of relapse, disability score worsening, and brain magnetic resonance activity) during the last 12 months. The accuracy of the proposed model was evaluated by calculating the area under the receiver operating characteristics (ROC) curve. From the pNfL cutoff, we evaluated the NEDA-NfL status (no relapse, no Expanded Disability Status Scale [EDSS] worsening, and pNfL below the cutoff value). RESULTS: Levels of pNfL were significantly higher in MS patients than in healthy controls (p <  0.001). From a total of 159 patients, 80 (50.3%) achieved NEDA-3 status, while 79 (49.7%) patients showed evident disease activity (EDA) status. pNfL were significantly lower in the NEDA-3 group than in the EDA group (pNfL mean 7.06 pg/mL [standard deviation (SD) 2.37] vs. pNfL mean 13.04 pg/mL [SD 7.07]) (p < 0.001). ROC analysis showed that pNfL predicts NEDA-3 status (sensitivity and specificity were 80.5 and 72.7%, respectively, p < 0.001), and NEDA-NfL predicts NEDA-3 status (sensitivity and specificity were 97.1 and 82.9%, respectively, p < 0.001). CONCLUSION: The results show that pNfL levels are a useful biomarker of disease activity determined by NEDA status in patients with MS and could be an alternative to brain magnetic resonance investigation.

ADAMANT: a placebo-controlled randomized phase 2 study of AADvac1, an active immunotherapy against pathological tau in Alzheimer's disease.

Alzheimer's disease (AD) pathology is partly characterized by accumulation of aberrant forms of tau protein. Here we report the results of ADAMANT, a 24-month double-blinded, parallel-arm, randomized phase 2 multicenter placebo-controlled trial of AADvac1, an active peptide vaccine designed to target pathological tau in AD (EudraCT 2015-000630-30). Eleven doses of AADvac1 were administered to patients with mild AD dementia at 40 µg per dose over the course of the trial. The primary objective was to evaluate the safety and tolerability of long-term AADvac1 treatment. The secondary objectives were to evaluate immunogenicity and efficacy of AADvac1 treatment in slowing cognitive and functional decline. A total of 196 patients were randomized 3:2 between AADvac1 and placebo. AADvac1 was safe and well tolerated (AADvac1 n = 117, placebo n = 79; serious adverse events observed in 17.1% of AADvac1-treated individuals and 24.1% of placebo-treated individuals; adverse events observed in 84.6% of AADvac1-treated individuals and 81.0% of placebo-treated individuals). The vaccine induced high levels of IgG antibodies. No significant effects were found in cognitive and functional tests on the whole study sample (Clinical Dementia Rating-Sum of the Boxes scale adjusted mean point difference -0.360 (95% CI -1.306, 0.589)), custom cognitive battery adjusted mean z-score difference of 0.0008 (95% CI -0.169, 0.172). We also present results from exploratory and post hoc analyses looking at relevant biomarkers and clinical outcomes in specific subgroups. Our results show that AADvac1 is safe and immunogenic, but larger stratified studies are needed to better evaluate its potential clinical efficacy and impact on disease biomarkers.

Evaluation of a novel immunoassay to detect p-tau Thr217 in the CSF to distinguish Alzheimer disease from other dementias.

OBJECTIVE: To investigate whether tau phosphorylated at Thr217 (p-tau T217) assay in CSF can distinguish patients with Alzheimer disease (AD) from patients with other dementias and healthy controls. METHODS: We developed and validated a novel Simoa immunoassay to detect p-tau T217 in CSF. There was a total of 190 participants from 3 cohorts with AD (n = 77) and other neurodegenerative diseases (n = 69) as well as healthy participants (n = 44). RESULTS: The p-tau T217 assay (cutoff 242 pg/mL) identified patients with AD with accuracy of 90%, with 78% positive predictive value (PPV), 97% negative predictive value (NPV), 93% sensitivity, and 88% specificity, compared favorably with p-tau T181 ELISA (52 pg/mL), showing 78% accuracy, 58% PPV, 98% NPV, 71% specificity, and 97% sensitivity. The assay distinguished patients with AD from age-matched healthy controls (cutoff 163 pg/mL, 98% sensitivity, 93% specificity), similarly to p-tau T181 ELISA (cutoff 60 pg/mL, 96% sensitivity, 86% specificity). In patients with AD, we found a strong correlation between p-tau T217 and p-tau T181, total tau and ß-amyloid 40, but not ß-amyloid 42. CONCLUSIONS: This study demonstrates that p-tau T217 displayed better diagnostic accuracy than p-tau T181. The data suggest that the new p-tau T217 assay has potential as an AD diagnostic test in clinical evaluation. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a CSF immunoassay for p-tau T217 distinguishes patients with AD from patients with other dementias and healthy controls.