Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome.

The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p =  0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation

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

Herpes simplex encephalitis – diagnostic imaging

The phenomena of neuroinvasiveness, latency and reactivation are characteristics of the Herpes simplex virus (HSV). The Herpes simplex encephalitis (HSE) prevalence rate is 1 up to 3 in a million cases, which is about 10-20% of all viral encephalitis cases. The course of the disease shows the prodromal period and the symptomatic one; the clinical course is usually rapid and may lead to sudden death. As for the symptomatic period, there are usually neurological focal symptoms and seizures as well as fluctuating consciousness leading to coma. The mortality rate in the course of HSE in non-treated individuals reaches up to 70%, it is lowered to 15% with early treatment with Acyclovir. However, most patients present persistent neurological and cognitive disorders. There are usually no changes in the CT scan as far as the early stage of the disease is concerned. Thus, the imaging technique of choice is MR scan, which shows the changes already on the second day after clinical symptoms. On the basis of MR scans, more or less symmetrical hyperintense cortical and subcortical white matter lesions occur on T2-weighted images with gyral and/or leptomeningeal contrast enhancement. MR spectroscopy can be helpful in lesion diagnosis and monitoring, while diffusion-weighted imaging (DWI) can be used to evaluate inflammatory process activity. Differentiation of HSE in imaging should consider limbic encephalitis, gliomatosis cerebri, cerebral ischemia, cerebral edema after seizure episodes, and MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes), among others. HSV identification in cerebrospinal fluid by PCR (polymerase chain reaction) method is a confirmation of the diagnosis

Herpes simplex encephalitis – diagnostic imaging

The phenomena of neuroinvasiveness, latency and reactivation are characteristics of the Herpes simplex virus (HSV). The Herpes simplex encephalitis (HSE) prevalence rate is 1 up to 3 in a million cases, which is about 10-20% of all viral encephalitis cases. The course of the disease shows the prodromal period and the symptomatic one; the clinical course is usually rapid and may lead to sudden death. As for the symptomatic period, there are usually neurological focal symptoms and seizures as well as fluctuating consciousness leading to coma. The mortality rate in the course of HSE in non-treated individuals reaches up to 70%, it is lowered to 15% with early treatment with Acyclovir. However, most patients present persistent neurological and cognitive disorders. There are usually no changes in the CT scan as far as the early stage of the disease is concerned. Thus, the imaging technique of choice is MR scan, which shows the changes already on the second day after clinical symptoms. On the basis of MR scans, more or less symmetrical hyperintense cortical and subcortical white matter lesions occur on T2-weighted images with gyral and/or leptomeningeal contrast enhancement. MR spectroscopy can be helpful in lesion diagnosis and monitoring, while diffusion-weighted imaging (DWI) can be used to evaluate inflammatory process activity. Differentiation of HSE in imaging should consider limbic encephalitis, gliomatosis cerebri, cerebral ischemia, cerebral edema after seizure episodes, and MELAS syndrome (Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like episodes), among others. HSV identification in cerebrospinal fluid by PCR (polymerase chain reaction) method is a confirmation of the diagnosis