As our population grows older, age-related pathologies are becoming more prevalent. Deterioration of skeletal muscle and the immune system manifests as sarcopenia and immune senescence respectively. ...The disease burden of these pathologies emphasizes the need for a better understanding of the underlying mechanisms. Skeletal muscle has emerged as a potent regulator of immune system function. As such, skeletal muscle might be the central integrator between sarcopenia and immune senescence in an aging biological system. Therapeutic approaches targeting skeletal muscle might be able to restore both muscle and immune system function. In this review, we therefore outline the current - however still fragmentary - knowledge about the potential communication pathways of muscle and immune system, how they are affected by aging of skeletal muscle and discuss possible treatment strategies. The review intends to be hypothesis-generating and should thereby stimulate further research in this important scientific field.
Inflammation triggers secondary brain damage after stroke. The meninges and other CNS border compartments serve as invasion sites for leukocyte influx into the brain thus promoting tissue damage ...after stroke. However, the post-ischemic immune response of border compartments compared to brain parenchyma remains poorly characterized. Here, we deeply characterize tissue-resident leukocytes in meninges and brain parenchyma and discover that leukocytes respond differently to stroke depending on their site of residence. We thereby discover a unique phenotype of myeloid cells exclusive to the brain after stroke. These stroke-associated myeloid cells partially resemble neurodegenerative disease-associated microglia. They are mainly of resident microglial origin, partially conserved in humans and exhibit a lipid-phagocytosing phenotype. Blocking markers specific for these cells partially ameliorates stroke outcome thus providing a potential therapeutic target. The injury-response of myeloid cells in the CNS is thus compartmentalized, adjusted to the type of injury and may represent a therapeutic target.
The CNS is ensheathed by the meninges and cerebrospinal fluid, and recent findings suggest that these CNS-associated border tissues have complex immunological functions. Unlike myeloid lineage cells, ...lymphocytes in border compartments have yet to be thoroughly characterized. Based on single-cell transcriptomics, we here identified a highly location-specific composition and expression profile of tissue-resident leukocytes in CNS parenchyma, pia-enriched subdural meninges, dura mater, choroid plexus and cerebrospinal fluid. The dura layer of the meninges contained a large population of B cells under homeostatic conditions in mice and rats. Murine dura B cells exhibited slow turnover and long-term tissue residency, and they matured in experimental neuroinflammation. The dura also contained B lineage progenitors at the pro-B cell stage typically not found outside of bone marrow, without direct influx from the periphery or the skull bone marrow. This identified the dura as an unexpected site of B cell residence and potentially of development in both homeostasis and neuroinflammation.
Neuroprotection aims to prevent salvageable neurons from dying. Despite showing efficacy in experimental stroke studies, the concept of neuroprotection has failed in clinical trials. Reasons for the ...translational difficulties include a lack of methodological agreement between preclinical and clinical studies and the heterogeneity of stroke in humans compared to homogeneous strokes in animal models. Even when the international recommendations for preclinical stroke research, the Stroke Academic Industry Roundtable (STAIR) criteria, were followed, we have still seen limited success in the clinic, examples being NXY-059 and haematopoietic growth factors which fulfilled nearly all the STAIR criteria. However, there are a number of neuroprotective treatments under investigation in clinical trials such as hypothermia and ebselen. Moreover, promising neuroprotective treatments based on a deeper understanding of the complex pathophysiology of ischemic stroke such as inhibitors of NADPH oxidases and PSD-95 are currently evaluated in preclinical studies. Further concepts to improve translation include the investigation of neuroprotectants in multicenter preclinical Phase III-type studies, improved animal models, and close alignment between clinical trial and preclinical methodologies. Future successful translation will require both new concepts for preclinical testing and innovative approaches based on mechanistic insights into the ischemic cascade.
Primary angiitis of the central nervous system (PACNS) represents a rare inflammatory disease affecting the brain and spinal cord. Stroke, encephalopathy, headache and seizures are major clinical ...manifestations. The diagnosis of PACNS is based on the combination of clinical presentation, imaging findings (magnetic resonance imaging and angiography), brain biopsy, and laboratory and cerebral spinal fluid (CSF) values. PACNS can either be confirmed by magnetic resonance angiography (MRA)/conventional angiography or tissue biopsy showing the presence of typical histopathological patterns. Identification of PACNS mimics is often challenging in clinical practice, but crucial to avoid far-reaching treatment decisions. In view of the severity of the disease, with considerable morbidity and mortality, early recognition and treatment initiation is necessary. Due to the rareness and heterogeneity of the disease, there is a lack of randomized data on treatment strategies. Retrospective studies suggest the combined administration of cyclophosphamide and glucocorticoids as induction therapy. Immunosuppressants such as azathioprine, methotrexate or mycophenolate mofetil are often applied for maintenance therapy. In addition, the beneficial effects of two biological agents (anti-CD20 monoclonal antibody rituximab and tumour necrosis factor-α blocker) have been reported. Nevertheless, diagnosis and treatment is still a clinical challenge, and further insights into the immunopathogenesis of PACNS are required to improve the diagnosis and management of patients. The present review provides a comprehensive overview of diagnostics, differential diagnoses, and therapeutic approaches of adult PACNS.
Purpose
Treatment of post-stroke dysphagia is notoriously difficult with different neurostimulation strategies having been employed with a variable degree of success. Recently, electrical pharyngeal ...stimulation (EPS) has been shown to improve swallowing function and in particular decrease airway aspiration in acute stroke. We performed a randomized controlled trial to assess EPS effectiveness on swallowing function in severely dysphagic tracheotomized patients.
Methods
All consecutive stroke patients successfully weaned from the respirator but with severe dysphagia precluding decannulation were screened for eligibility. Eligible patients were randomized to receive either EPS (
N
= 20) or sham stimulation (
N
= 10) over three consecutive days. Primary endpoint was ability to decannulate the patient. Swallowing function was assessed using fiberoptic endoscopy. Patients having received sham stimulation were offered EPS treatment during unblinded follow-up if required. Investigators were blinded to the patient’s study group allocation.
Results
Both groups were well matched for age, stroke severity, and lesion location. Decannulation after study intervention was possible in 75 % of patients of the treatment group and in 20 % of patients of the sham group (
p
< 0.01). Secondary outcome parameters did not differ. No adverse events occurred.
Conclusion
In this pilot study, EPS enhanced remission of dysphagia as assessed with fiberoptic endoscopic evaluation of swallowing (FEES), thereby enabling decannulation in 75 % of patients.
Neuroprotection seeks to restrict injury to the brain parenchyma following an ischaemic insult by preventing salvageable neurons from dying. The concept of neuroprotection has shown promise in ...experimental studies, but has failed to translate into clinical success. Many reasons exist for this including the heterogeneity of human stroke and the lack of methodological agreement between preclinical and clinical studies. Even with the proposed Stroke Therapy Academic Industry Roundtable criteria for preclinical development of neuroprotective agents for stroke, we have still seen limited success in the clinic, an example being NXY-059, which fulfilled nearly all the Stroke Therapy Academic Industry Roundtable criteria. There are currently a number of ongoing trials for neuroprotective strategies including hypothermia and albumin, but the outcome of these approaches remains to be seen. Combination therapies with thrombolysis also need to be fully investigated, as restoration of oxygen and glucose will always be the best therapy to protect against cell death from stroke. There are also a number of promising neuroprotectants in preclinical development including haematopoietic growth factors, and inhibitors of the nicotinamide adenine dinucleotide phosphate oxidases, a source of free radical production which is a key step in the pathophysiology of acute ischaemic stroke. For these neuroprotectants to succeed, essential quality standards need to be adhered to; however, these must remain realistic as the evidence that standardization of procedures improves translational success remains absent for stroke.
Little is known about the long-term course of arterial stenosis after spontaneous cervical artery dissection (sCAD). We analyzed changes over time and evaluated factors potentially associated with ...these changes and recurring sCAD.
Adult patients with sCAD, admitted to our neurological department between 2004 and 2018, were included. All patients underwent initial and follow-up repetitive neurovascular ultrasound for a mean duration of 15.3 ± 21 months. Clinical and imaging data were registered for each patient.
A total of 259 sCADs were diagnosed in 224 patients. Either internal carotid arteries (
= 133, 59.4%), vertebral arteries (
= 58, 25.9%), or multiple arteries (
= 33, 14.7%) were affected. In 93 out of 183 patients (51%), and in 117 out of 210 arteries under investigation (55.7%), vascular stenosis decreased over time. Occluded arteries recanalized early in 34 (54%) and stayed occluded in 29 patients (46.0%). Of 145 initially hemodynamically relevant stenosis, 77 (53.1%) improved over time. Overall, 12 patients (5.4 %) had a recurring sCAD during follow-up. Pseudoaneurysms were found in 19 patients.
The sonographical course of sCAD is highly dynamic within the first year after disease onset and should be monitored carefully. Decreasing degrees of stenosis and recanalization of occluded arteries occurred in half of all patients. Recurrent sCAD was a rare event in our cohort.
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