CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a \u201cHoly Grail\u201d of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APO\u3b54 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation

Estimating tuberculosis case detection rate in resource-limited countries: a capture-recapture study in Egypt

SETTING: Most countries endemic and highly endemic for tuberculosis (TB) still do not have reliable TB surveillance systems. Indirect estimation of TB incidence is needed to monitor the performance of the National Tuberculosis Programme (NTP) in the context of the World Health Organization implementation and impact targets for TB control. OBJECTIVE: To estimate the case detection rate (CDR) of all TB cases and sputum smear-positive TB cases in Egypt in 2007. METHODS: Record linkage and three-source capture-recapture analysis of data collected through active prospective longitudinal surveillance within the public and private non-NTP sector in four Egyptian governorates selected by stratified cluster random sampling. RESULTS: For all TB cases, the estimated CDR of NTP surveillance and completeness of case ascertainment after record linkage was respectively 55% (95%CI 46-68) and 62% (95%CI 52-77). For sputum smear-positive TB cases, these proportions were respectively 66% (95%CI 55-75) and 72% (95%CI 60-82). CONCLUSION: This pilot study shows that representative sampling, prospective surveillance in the non-NTP sector, record linkage and capture-recapture analysis can improve CDR estimation. For global, standardised and reliable use, this methodology should be further developed. Until then, all resource-limited countries should strengthen their national surveillance systems in the context of the Stop TB strategy