The effect of robot-assisted versus standard training on motor function following subacute rehabilitation after ischemic stroke - protocol for a randomised controlled trial nested in a prospective cohort (RoboRehab).

BACKGROUND: Body weight unloaded treadmill training has shown limited efficacy in further improving functional capacity after subacute rehabilitation of ischemic stroke patients. Dynamic robot assisted bodyweight unloading is a novel technology that may provide superior training stimuli and continued functional improvements in individuals with residual impairments in the chronic phase after the ischemic insult. The aim of the present study is to investigate the effect of dynamic robot-assisted versus standard training, initiated 6 months post-stroke, on motor function, physical function, fatigue, and quality of life in stroke-affected individuals still suffering from moderate-to-severe disabilities after subacute rehabilitation. METHODS: Stroke-affected individuals with moderate to severe disabilities will be recruited into a prospective cohort with measurements at 3-, 6-, 12- and 18-months post-stroke. A randomised controlled trial (RCT) will be nested in the prospective cohort with measurements pre-intervention (Pre), post-intervention (Post) and at follow-up 6 months following post-intervention testing. The present RCT will be conducted as a multicentre parallel-group superiority of intervention study with assessor-blinding and a stratified block randomisation design. Following pre-intervention testing, participants in the RCT study will be randomised into robot-assisted training (intervention) or standard training (active control). Participants in both groups will train 1:1 with a physiotherapist two times a week for 6 months (groups are matched for time allocated to training). The primary outcome is the between-group difference in change score of Fugl-Meyer Lower Extremity Assessment from pre-post intervention on the intention-to-treat population. A per-protocol analysis will be conducted analysing the differences in change scores of the participants demonstrating acceptable adherence. A priori sample size calculation allowing the detection of the minimally clinically important between-group difference of 6 points in the primary outcome (standard deviation 6 point, α = 5% and ß = 80%) resulted in 34 study participants. Allowing for dropout the study will include 40 participants in total. DISCUSSION: For stroke-affected individuals still suffering from moderate to severe disabilities following subacute standard rehabilitation, training interventions based on dynamic robot-assisted body weight unloading may facilitate an appropriate intensity, volume and task-specificity in training leading to superior functional recovery compared to training without the use of body weight unloading. TRIAL REGISTRATION: ClinicalTrials.gov. NCT06273475. TRIAL STATUS: Recruiting. Trial identifier: NCT06273475. Registry name: ClinicalTrials.gov. Date of registration on ClinicalTrials.gov: 22/02/2024.

Evidence of aberrant anti-epstein-barr virus antibody response, though no viral reactivation, in people with post-stroke fatigue.

BACKGROUND: Fatigue is a common complication of stroke that has a significant impact on quality of life. The biological mechanisms that underly post-stroke fatigue are currently unclear, however, reactivation of latent viruses and their impact on systemic immune function have been increasingly reported in other conditions where fatigue is a predominant symptom. Epstein-Barr virus (EBV) in particular has been associated with fatigue, including in long-COVID and myalgic encephalomyelitis/chronic fatigue syndrome, but has not yet been explored within the context of stroke. AIMS: We performed an exploratory analysis to determine if there is evidence of a relationship between EBV reactivation and post-stroke fatigue. METHODS: In a chronic ischemic stroke cohort (> 5 months post-stroke), we assayed circulating EBV by qPCR and measured the titres of anti-EBV antibodies by ELISA in patients with high fatigue (FACIT-F < 40) and low fatigue (FACIT-F > 41). Statistical analysis between two-groups were performed by t-test when normally distributed according to the Shapiro-Wilk test, by Mann-Whitney test when the data was not normally distributed, and by Fisher's exact test for categorical data. RESULTS: We observed a similar incidence of viral reactivation between people with low versus high levels of post-stroke fatigue (5 of 22 participants (24%) versus 6 of 22 participants (27%)). Although the amount of circulating EBV was similar, we observed an altered circulating anti-EBV antibody profile in participants with high fatigue, with reduced IgM against the Viral Capsid Antigen (2.244 ± 0.926 vs. 3.334 ± 2.68; P = 0.031). Total IgM levels were not different between groups indicating this effect was specific to anti-EBV antibodies (3.23 × 105 ± 4.44 × 104 high fatigue versus 4.60 × 105 ± 9.28 × 104 low fatigue; P = 0.288). CONCLUSIONS: These data indicate that EBV is not more prone to reactivation during chronic stroke recovery in those with post-stroke fatigue. However, the dysregulated antibody response to EBV may be suggestive of viral reactivation at an earlier stage after stroke.

TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-ß42 oligomer-induced bioenergetic changes, suggesting that amyloid-ß42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

Blocking of microglia-astrocyte proinflammatory signaling is beneficial following stroke.

Microglia and astrocytes play an important role in the neuroinflammatory response and contribute to both the destruction of neighboring tissue as well as the resolution of inflammation following stroke. These reactive glial cells are highly heterogeneous at both the transcriptomic and functional level. Depending upon the stimulus, microglia and astrocytes mount a complex, and specific response composed of distinct microglial and astrocyte substates. These substates ultimately drive the landscape of the initiation and recovery from the adverse stimulus. In one state, inflammation- and damage-induced microglia release tumor necrosis factor (TNF), interleukin 1α (IL1α), and complement component 1q (C1q), together "TIC." This cocktail of cytokines drives astrocytes into a neurotoxic reactive astrocyte (nRA) substate. This nRA substate is associated with loss of many physiological astrocyte functions (e.g., synapse formation and maturation, phagocytosis, among others), as well as a gain-of-function release of neurotoxic long-chain fatty acids which kill neighboring cells. Here we report that transgenic removal of TIC led to reduction of gliosis, infarct expansion, and worsened functional deficits in the acute and delayed stages following stroke. Our results suggest that TIC cytokines, and likely nRAs play an important role that may maintain neuroinflammation and inhibit functional motor recovery after ischemic stroke. This is the first report that this paradigm is relevant in stroke and that therapies against nRAs may be a novel means to treat patients. Since nRAs are evolutionarily conserved from rodents to humans and present in multiple neurodegenerative diseases and injuries, further identification of mechanistic role of nRAs will lead to a better understanding of the neuroinflammatory response and the development of new therapies.