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Competing Interests: MTH serves on the science advisory board of the Paris Brain Institute, the UK Dementia Research Institute at Imperial College London, Life and Health Sciences Research Institute of the University of Minho School of Medicine, Alector, Cyclerion, IFM Therapeutics, and T3D Therapeutics. He has received speaking honoraria from NovoNordisk, Novartis, Biogen, and Eli Lilly. CI is listed as inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies.

Background: Rasagiline, a monoamine oxidase B inhibitor with neuroprotective potential in Parkinson's disease, has shown a disease-modifying effect in the SOD1-Gly93Ala low-expressing mouse model of amyotrophic lateral sclerosis, both alone and in combination with riluzole. We sought to test whether or not rasagiline 1 mg/day can prolong survival in patients with amyotrophic lateral sclerosis also receiving riluzole., Methods: Patients with possible, probable, or definite amyotrophic lateral sclerosis were enrolled to our randomised, placebo-controlled, parallel-group, double-blind, phase 2 trial from 15 German network for motor neuron diseases (MND-NET) centres (university hospitals or clinics). Eligible patients were aged at least 18 years, had onset of progressive weakness within the 36 months before the study, had disease duration of more than 6 months and less than 3 years, and had a best-sitting slow vital capacity of at least 50%. After a 4-week screening period, eligible patients were randomly assigned (1:1) to receive either rasagiline (1 mg/day) or placebo in addition to riluzole (100 mg/day), after stratification for site of onset (bulbar or spinal) and study centre. Patients and all personnel assessing outcome parameters were masked to treatment allocation. Patients were followed up 2, 6, 12, and 18 months after randomisation. The primary endpoint was survival time, defined as the time to death or time to study cutoff date (ie, the last patient's last visit plus 14 days). Analyses of primary outcome and safety measures were done in all patients who received at least one dose of trial treatment (intention-to-treat population). The trial is registered with ClinicalTrials.gov, number NCT01879241., Findings: Between July 2, 2013, and Nov 11, 2014, 273 patients were screened for eligibility, and 252 patients were randomly assigned to receive rasagiline (n=127) or placebo (n=125). 126 patients taking rasagiline and 125 taking placebo were included in the intention-to-treat analysis. For the primary outcome, the survival probability at the end of the study was 0·43 (95% CI 0·25-0·59) in the rasagiline group (n=126) and 0·53 (0·43-0·62) in the placebo group (n=125). The estimated effect size (hazard ratio) was 0·91 (one-sided 97·5% CI -infinity to 1·34; p=0·31). Rasagiline was well tolerated, and most adverse events were due to amyotrophic lateral sclerosis disease progression rather than treatment; the most frequent of these were dysphagia (32 [25%] taking rasagiline vs 24 [19%] taking placebo) and respiratory failure (25 [20%] vs 31 [25%]). Frequency of adverse events were comparable between both groups., Interpretation: Rasagiline was safe in patients with amyotrophic lateral sclerosis. There was no difference between groups in the primary outcome of survival, although post-hoc analysis suggested that rasagiline might modify disease progression in patients with an initial slope of Amyotrophic Lateral Sclerosis Functional Rating Scale Revised greater than 0·5 points per month at baseline. This should be confirmed in another clinical trial., Funding: Teva Pharmaceutical Industries., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Sepsis is a potentially fatal whole-body inflammatory state caused by severe infection, in which a maladaptive, system-wide inflammatory response follows initial attempts to eliminate pathogens, leading to a dangerous and often fatal increase in the permeability of the blood-brain barrier. These changes in the blood-brain barrier might lead to a major symptom of sepsis, sepsis-associated encephalopathy, which manifests as confusion with a rapid decline in cognitive functions, especially memory, or coma. Once presumed to be entirely reversible, research suggests that sepsis-associated encephalopathy could lead to permanent neurocognitive dysfunction and functional impairments, even after the patient has recovered. Sepsis might act as a major inflammatory hit and potentially increase the brain's susceptibility to neurodegenerative disease, further deterioration of cognitive ability, and risk of developing dementia in later life. Key opportunities for neuroprotective interventions and after-care for people who have survived sepsis might be lost because the long-term neurocognitive and functional consequences of sepsis are not fully characterised., (Copyright © 2014 Elsevier Ltd. All rights reserved.)