Tackling gaps in developing life-changing treatments for dementia.

Since the G8 dementia summit in 2013, a number of initiatives have been established with the aim of facilitating the discovery of a disease-modifying treatment for dementia by 2025. This report is a summary of the findings and recommendations of a meeting titled "Tackling gaps in developing life-changing treatments for dementia", hosted by Alzheimer's Research UK in May 2018. The aim of the meeting was to identify, review, and highlight the areas in dementia research that are not currently being addressed by existing initiatives. It reflects the views of leading experts in the field of neurodegeneration research challenged with developing a strategic action plan to address these gaps and make recommendations on how to achieve the G8 dementia summit goals. The plan calls for significant advances in (1) translating newly identified genetic risk factors into a better understanding of the impacted biological processes; (2) enhanced understanding of selective neuronal resilience to inform novel drug targets; (3) facilitating robust and reproducible drug-target validation; (4) appropriate and evidence-based selection of appropriate subjects for proof-of-concept clinical trials; (5) improving approaches to assess drug-target engagement in humans; and (6) innovative approaches in conducting clinical trials if we are able to detect disease 10-15 years earlier than we currently do today.

Nutrition for the ageing brain: Towards evidence for an optimal diet.

As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline.

Characterisation of temporal microglia and astrocyte immune responses in bile duct-ligated rat models of cirrhosis.

BACKGROUND & AIMS: Microglia and astrocyte related pro-inflammatory responses are thought to underpin cerebral sequelae of acute liver failure. Conversely, despite background pro-inflammatory responses in cirrhosis, overt brain swelling and coma associated with acute-on-chronic liver failure, is infrequent unless precipitated (e.g. sepsis). Moreover in other chronic neurodegenerative disorders and sepsis, the brain is protected from recurrent microbial insults by compensatory microglial-associated immune responses. To characterise longitudinal cerebral immune responses in a bile duct-ligated (BDL) rat model of cirrhosis. METHOD: Rats underwent BDL or sham operation before sacrifice at either 1-day, 1, 2 and 4 weeks post-surgery. We analysed consciousness, brain water, biochemistry and immunohistochemistry to assess activation of microglia (ED-1, OX6 and Iba-1), astrocytes (Glial fibrillary acidic protein - GFAP), cellular stress (Heat shock protein - Hsp 25) and pro-inflammatory mediator expression (inducible nitric oxide synthase (iNOS), interleukin-1beta (IL-1ß) and tumour growth factor-beta (TGF-ß)). RESULTS: BDL significantly increased ammonia and bilirubin (P < 0.01 respectively). The classical microglial markers OX6, ED1 and Iba-1 and pro-inflammatory IL-1ß and iNOS were not significantly increased. However, the alternative microglial marker and regulatory cytokine TGF-ß was elevated from day 1 to 4 weeks post-BDL. GFAP expression was significantly increased in corpus callosum in all groups. In BDL rats, Hsp 25 was also increased in the corpus callosum, peaking at 2 weeks. CONCLUSION: BDL triggers early alternative, but not classical, microglial activation. There was a correlation between astrocyte activation and cellular stress. These findings indicate early cerebral immune responses, which may be associated with immune tolerance to further challenge.

Does the vagus nerve inform the brain about preclinical tumours and modulate them?

The inflammatory microenvironment is thought to play a pivotal part in tumorigenesis. But, can the brain be informed about peripheral preclinical cancer cells? Can it modulate tumour development? One of the key routes for information to reach the brain from visceral regions is through the vagus nerve. Yet, patients with ulcers who have had a vagotomy have been shown to die from cancer more frequently than do those who have not had this procedure, and surgical and chemical vagotomy attenuates tumour-induced anorexia and leads to enhanced tumour progression. We therefore postulate that the vagus nerve participates in informing the brain about tumorigenesis by transmiting information to the brain about tumour-associated proinflammatory cytokines. Furthermore, activation of the vagus could slow tumorigenesis by suppression of peripheral proinflammatory cytokines.