A roadmap for research in post-stroke fatigue: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

RATIONALE: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. METHODS: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. RESULTS: We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. CONCLUSIONS: By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue.

A roadmap for research in post-stroke fatigue: Consensus-based core recommendations from the third Stroke Recovery and Rehabilitation Roundtable.

RATIONALE: Fatigue affects almost half of all people living with stroke. Stroke survivors rank understanding fatigue and how to reduce it as one of the highest research priorities. METHODS: We convened an interdisciplinary, international group of clinical and pre-clinical researchers and lived experience experts. We identified four priority areas: (1) best measurement tools for research, (2) clinical identification of fatigue and potentially modifiable causes, (3) promising interventions and recommendations for future trials, and (4) possible biological mechanisms of fatigue. Cross-cutting themes were aphasia and the voice of people with lived experience. Working parties were formed and structured consensus building processes were followed. RESULTS: We present 20 recommendations covering outcome measures for research, development, and testing of new interventions and priority areas for future research on the biology of post-stroke fatigue. We developed and recommend the use of the Stroke Fatigue Clinical Assessment Tool. CONCLUSIONS: By synthesizing current knowledge in post-stroke fatigue across clinical and pre-clinical fields, our work provides a roadmap for future research into post-stroke fatigue.

Brain-associated innate leukocytes display diverse inflammatory states following experimental stroke.

Previous studies investigating innate leukocyte recruitment into the brain after cerebral ischemia have shown conflicting results. Using distinct cell surface and intracellular markers, the current study evaluated the contributions of innate immune cells to the poststroke brain following 1-h middle cerebral artery occlusion (tMCAO) or permanent MCAO (pMCAO), and assessed whether these cells ascribed to an inflammatory state. Moreover, we examined whether there is evidence for leukocyte infiltration into the contralateral (CL) hemisphere despite the absence of stroke infarct. We observed the recruitment of peripheral neutrophils, monocytes and macrophages into the hemisphere ipsilateral (IL) to the ischemic brain infarct at 24 and 96 h following both tMCAO and pMCAO. In addition, we found evidence of increased leukocyte recruitment to the CL hemisphere but to a lesser extent than the IL hemisphere after stroke. Robust production of intracellular cytokines in the innate immune cell types examined was most evident at 24 h after pMCAO. Specifically, brain-associated neutrophils, monocytes and macrophages demonstrated stroke-induced production of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1ß, while only monocytes and macrophages exhibit a significant expression of arginase 1 (Arg1) after stroke. At 96 h after stroke, brain-resident microglia demonstrated production of TNF-α and IL-1ß following both tMCAO and pMCAO. At this later timepoint, neutrophils displayed TNF-α production and brain-associated macrophages exhibited elevation of IL-1ß and Arg1 after tMCAO. Further, pMCAO induced significant expression of Arg1 and IL-1ß in monocytes and macrophages at 96 h, respectively. These results revealed that brain-associated innate immune cells display various stroke-induced inflammatory states that are dependent on the experimental stroke setting.

Dynamic roles of neutrophils in post-stroke neuroinflammation.

Clinical trials involving the blockage of peripheral inflammatory leukocyte recruitment into the brain have puzzlingly led to either no significant improvement in stroke outcome, or even worsened outcomes and increased mortality, prompting a re-evaluation of our understanding into the neuroinflammatory processes after stroke. Whilst traditionally understood as simple effectors of the innate immune system, emerging research in vascular disease biology has redefined the neutrophil as a specialized and highly specific cell type with dynamic functional capacity. Indeed, emerging experimental evidence indicates that neutrophils display diverse roles in the acute stages of ischemic stroke with the ability to elicit both pro-inflammatory and anti-inflammatory effects. Currently, there is some uncertainty as to whether neutrophil diversity is beneficial or harmful in stroke as their interactions with the resident cells of the brain, such as microglia and neurons, would potentially elicit heterogeneous outcomes. Current treatments for patients with stroke aim to remove the vascular blockage and to restore blood flow, but there are currently no drug treatments for managing the loss of functional brain tissue nor restoration of microglial and neuronal damage. If these hypothesized wound-healing functions of neutrophils can be validated in a stroke setting, promoting the recruitment of this type of neutrophils into the injured brain tissue may form a promising therapeutic target for the majority of stroke patients currently without treatment. In this review, we will provide an update on recent research that has explored neutrophil heterogeneity in the neuroinflammatory cascade after ischemic stroke.

Imbalance in the force: the dark side of the microbiota on stroke risk and progression.

The composition of the gut microbiota depends on many factors, including our lifestyle, diet, metabolism, antibiotic use and hygiene. The contribution of these factors in shaping the gut microbiota and the subsequent effects on the prevention and development of stroke has been under intense investigation. Furthermore, several reports have uncovered the impact of stroke on intestinal dysfunction and gut dysbiosis, highlighting the delicate interplay between the brain, gut and microbiome following this acute brain injury. Despite our growing appreciation of the gut microbiota in shaping brain health, the immune system, host metabolism and disease progression, its therapeutic capability in stroke is yet to be fully exploited. This review will explore the microbiota-gut-brain axis in stroke, and examine the potential role of the gut microbiota in the onset, progression and recovery phase of stroke.

IL-33 modulates inflammatory brain injury but exacerbates systemic immunosuppression following ischemic stroke.

Stroke triggers a complex inflammatory process in which the balance between pro- and antiinflammatory mediators is critical for the development of the brain infarct. However, systemic changes may also occur in parallel with brain inflammation. Here we demonstrate that administration of recombinant IL-33, a recently described member of the IL-1 superfamily of cytokines, promotes Th2-type effects following focal ischemic stroke, resulting in increased plasma levels of Th2-type cytokines and fewer proinflammatory (3-nitrotyrosine+F4/80+) microglia/macrophages in the brain. These effects of IL-33 were associated with reduced infarct size, fewer activated microglia and infiltrating cytotoxic (natural killer-like) T cells, and more IL-10-expressing regulatory T cells. Despite these neuroprotective effects, mice treated with IL-33 displayed exacerbated post-stroke lung bacterial infection in association with greater functional deficits and mortality at 24 hours. Supplementary antibiotics (gentamicin and ampicillin) mitigated these systemic effects of IL-33 after stroke. Our findings highlight the complex nature of the inflammatory mechanisms differentially activated in the brain and periphery during the acute phase after ischemic stroke. The data indicate that a Th2-promoting agent can provide neuroprotection without adverse systemic effects when given in combination with antibiotics.

Bugging inflammation: role of the gut microbiota.

The advent of vaccination and improved hygiene have eliminated many of the deadly infectious pathogens in developed nations. However, the incidences of inflammatory diseases, such as inflammatory bowel disease, asthma, obesity and diabetes are increasing dramatically. Research in the recent decades revealed that it is indeed the lack of early childhood microbial exposure, increase use of antibiotics, as well as increase consumption of processed foods high in carbohydrates and fats, and lacking fibre, which wreak havoc on the proper development of immunity and predispose the host to elevated inflammatory conditions. Although largely unexplored and under-appreciated until recent years, these factors impact significantly on the composition of the gut microbiota (a collection of microorganisms that live within the host mucosal tissue) and inadvertently play intricate and pivotal roles in modulating an appropriate host immune response. The suggestion that shifts in the composition of host microbiota is a risk factor for inflammatory disease raises an exciting opportunity whereby the microbiota may also present as a potential modifiable component or therapeutic target for inflammatory diseases. This review provides insights into the interactions between the microbiota and the immune system, how these affect disease phenotypes, and explore current and emerging therapies that target the gut microbiota as potential treatment for inflammatory diseases.