Movement of cerebrospinal fluid tracer into brain parenchyma and outflow to nasal mucosa is reduced at 24 h but not 2 weeks post-stroke in mice

Background Recent data indicates that cerebrospinal fluid (CSF) dynamics are disturbed after stroke. Our lab has previously shown that intracranial pressure rises dramatically 24 h after experimental stroke and that this reduces blood flow to ischaemic tissue. CSF outflow resistance is increased at this time point. We hypothesised that reduced transit of CSF through brain parenchyma and reduced outflow of CSF via the cribriform plate at 24 h after stroke may contribute to the previously identified post-stroke intracranial pressure elevation. Methods Using a photothrombotic permanent occlusion model of stroke in C57BL/6 adult male mice, we examined the movement of an intracisternally infused 0.5% Texas Red dextran throughout the brain and measured tracer efflux into the nasal mucosa via the cribriform plate at 24 h or two weeks after stroke. Brain tissue and nasal mucosa were collected ex vivo and imaged using fluorescent microscopy to determine the change in CSF tracer intensity in these tissues. Results At 24 h after stroke, we found that CSF tracer load was significantly reduced in brain tissue from stroke animals in both the ipsilateral and contralateral hemispheres when compared to sham. CSF tracer load was also reduced in the lateral region of the ipsilateral hemisphere when compared to the contralateral hemisphere in stroke brains. In addition, we identified an 81% reduction in CSF tracer load in the nasal mucosa in stroke animals compared to sham. These alterations to the movement of CSF-borne tracer were not present at two weeks after stroke. Conclusions Our data indicates that influx of CSF into the brain tissue and efflux via the cribriform plate are reduced 24 h after stroke. This may contribute to reported increases in intracranial pressure at 24 h after stroke and thus worsen stroke outcomes.K. E. Warren, K. G. Coupland, R. J. Hood, L. Kang, F. R. Walker, and N. J. Sprat

Mechanisms of Post-Stroke Fatigue: A Follow-Up From the Third Stroke Recovery and Rehabilitation Roundtable

Background Post-stroke fatigue (PSF) is a significant and highly prevalent symptom, whose mechanisms are poorly understood. The third Stroke Recovery and Rehabilitation Roundtable paper on PSF focussed primarily on defining and measuring PSF while mechanisms were briefly discussed. This companion paper to the main paper is aimed at elaborating possible mechanisms of PSF. Methods This paper reviews the available evidence that potentially explains the pathophysiology of PSF and draws parallels from fatigue literature in other conditions. We start by proposing a case for phenotyping PSF based on structural, functional, and behavioral characteristics of PSF. This is followed by discussion of a potentially significant role of early inflammation in the development of fatigue, specifically the impact of low-grade inflammation and its long-term systemic effects resulting in PSF. Of the many neurotransmitter systems in the brain, the dopaminergic systems have the most evidence for a role in PSF, along with a role in sensorimotor processing. Sensorimotor neural network dynamics are compromised as highlighted by evidence from both neurostimulation and neuromodulation studies. The double-edged sword effect of exercise on PSF provides further insight into how PSF might emerge and the importance of carefully titrating interventional paradigms. Conclusion The paper concludes by synthesizing the presented evidence into a unifying model of fatigue which distinguishes between factors that pre-dispose, precipitate, and perpetuate PSF. This framework will help guide new research into the biological mechanisms of PSF which is a necessary prerequisite for developing treatments to mitigate the debilitating effects of post-stroke fatigue

Active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial small vessel disease; no preventive or curative therapy is available. CADASIL is caused by mutations in the NOTCH3 gene, resulting in a mutated NOTCH3 receptor, with aggregation of the NOTCH3 extracellular domain (ECD) around vascular smooth muscle cells. In this study, we have developed a novel active immunization therapy specifically targeting CADASIL-like aggregated NOTCH3 ECD. Immunizing CADASIL TgN3R182C(150) mice with aggregates composed of CADASIL-R133C mutated and wild-type EGF(1-5) repeats for a total of 4 months resulted in a marked reduction (38-48%) in NOTCH3 deposition around brain capillaries, increased microglia activation and lowered serum levels of NOTCH3 ECD. Active immunization did not impact body weight, general behavior, the number and integrity of vascular smooth muscle cells in the retina, neuronal survival, or inflammation or the renal system, suggesting that the therapy is tolerable. This is the first therapeutic study reporting a successful reduction of NOTCH3 accumulation in a CADASIL mouse model supporting further development towards clinical application for the benefit of CADASIL patients

Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma (vol 32, pg 204, 2017)

Ophthalmic researc

Measurement of the Z 0 line shape parameters and the electroweak couplings of charged leptons

Contains fulltext : 125119.pdf (preprint version ) (Open Access