Translational Stroke Research

Clinical studies on subarachnoid hemorrhage (SAH) have shown discrepancies between large vessel vasospasm, cerebral perfusion, and clinical outcome. We set out to analyze the contribution of large vessel vasospasm to impaired cerebral perfusion and neurological impairment in a murine model of SAH. SAH was induced in C57BL/6 mice by endovascular filament perforation. Vasospasm was analyzed with microcomputed tomography, cortical perfusion by laser SPECKLE contrast imaging, and functional impairment with a quantitative neuroscore. SAH animals developed large vessel vasospasm, as shown by significantly lower vessel volumes of a 2.5-mm segment of the left middle cerebral artery (MCA) (SAH 5.6 ± 0.6 nL, sham 8.3 ± 0.5 nL, p < 0.01). Induction of SAH significantly reduced cerebral perfusion of the corresponding left MCA territory compared to values before SAH, which only recovered partly (SAH vs. sham, 15 min 35.7 ± 3.1 vs. 101.4 ± 10.2%, p < 0.01; 3 h, 85.0 ± 8.6 vs. 121.9 ± 13.4, p < 0.05; 24 h, 75.3 ± 4.6 vs. 110.6 ± 11.4%, p < 0.01; 72 h, 81.8 ± 4.8 vs. 108.5 ± 14.5%, n.s.). MCA vessel volume did not correlate significantly with MCA perfusion after 72 h (r = 0.34, p = 0.25). Perfusion correlated moderately with neuroscore (24 h: r = − 0.58, p < 0.05; 72 h: r = − 0.44, p = 0.14). There was no significant correlation between vessel volume and neuroscore after 72 h (r = − 0.21, p = 0.50). In the murine SAH model, cerebral hypoperfusion occurs independently of large vessel vasospasm. Neurological outcome is associated with cortical hypoperfusion rather than large vessel vasospasm.

Acute ischemic stroke (AIS) is a major medical challenge in China. Thrombolytic drugs recommended for the treatment of AIS usually have a narrow time window. Human urinary kallidinogenase (HUK) was approved by the China Food and Drug Administration (CFDA) in 2005 for the treatment of mild to moderate AIS, and it is thus widely used in China. However, large-scale clinical study data for a more complete understanding of various aspects of its safety and efficacy characteristics are still unavailable. The ongoing Reevaluate the Efficacy and Safety of Human Urinary Kallidinogenase (RESK) trial is designed to reevaluate the safety and efficacy of HUK in Chinese patients with AIS. RESK is an open-label, single-arm, multicenter phase IV trial. A total of 2186 Chinese patients with AIS will be enrolled. All patients receive HUK by intravenous drip once daily for 21 consecutive days. The study has registered on ClinicalTrials.gov (NCT02562183). On 8 September 2016, 202 patients have been enrolled. Primary outcome includes the frequency and severity of adverse events. Secondary outcomes include functional improvement measured by the National Institutes of Health Stroke Scale, Barthel index, and modified Rankin Scale, and recurrence rate of ischemic stroke. Data from large-scale clinical studies are still unavailable concerning the post-marketing use of HUK. The RESK study is designed to provide a comprehensive reevaluation of the safety and efficacy of HUK in Chinese patients with AIS. Trial registration: The study has registered on ClinicalTrials.gov (NCT02562183).

Telmisartan is expected to reduce not only the level of blood pressure but also neuroinflammation and neurotoxicity via pleiotrophic effects as a metabo-sartan. We examined the effects of telmisartan on Alzheimer’s disease (AD) pathology in spontaneously hypertensive rat stroke resistant (SHR-SR) after transient middle cerebral artery occlusion (tMCAO) by giving either telmisartan at 0 (vehicle), 0.3 mg/kg/day (low dose, with no reduction of blood pressure), or 3 mg/kg/day (high dose, with a significant reduction of blood pressure) p.o. from 3 months (M) of age, and performed immunohistological analysis at 6, 12, and 18 M of age. The numbers of amyloid β (Aβ)-positive neurons in the cerebral cortex and hippocampus and senile plaque (SP) in the ipsilateral cerebral cortex progressively increased with age until 18 M in the SHR-SR after tMCAO. On the other hand, low-dose telmisartan significantly reduced the number of Aβ-positive neuron as well as SP at 6, 12, and 18 M. High-dose telmisartan showed further reductions of the above AD pathology. The present study suggests that telmisartan reduced both intracellular Aβ and extracellular SP accumulations after tMCAO in SHR-SR, with a further improvement by combined BP lowering. Such a strong effect of telmisartan could provide a preventative approach for AD in post-stroke patients with hypertension.

In intracerebral hemorrhage (ICH) with pathology-proven etiology, we performed a systematic review and meta-analysis to elucidate the association between cerebral amyloid angiopathy (CAA) and arteriolosclerosis, and directly compared MRI and pathological changes of markers of cerebral small vessel disease (CSVD). Studies enrolling primary ICH who had received an etiological diagnosis through biopsy or autopsy were searched using Ovid MEDLINE, PubMed, and Web of Science from inception to June 8, 2022. We extracted pathological changes of CSVD for each patient whenever available. Patients were grouped into CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis subgroups. Of 4155 studies identified, 28 studies with 456 ICH patients were included. The frequency of lobar ICH (p<0.001) and total microbleed number (p=0.015) differed among patients with CAA + arteriolosclerosis, strict CAA, and strict arteriolosclerosis. Concerning pathology, severe CAA was associated with arteriolosclerosis (OR 6.067, 95% CI 1.107–33.238, p=0.038), although this association was not statistically significant after adjusting for age and sex. Additionally, the total microbleed number (median 15 vs. 0, p=0.006) was higher in ICH patients with CAA evidence than those without CAA. The pathology of CSVD imaging markers was mostly investigated in CAA-ICH. There was inconsistency concerning CAA severity surrounding microbleeds. Small diffusion-weighted imaging lesions could be matched to acute microinfarct histopathologically. Studies that directly correlated MRI and pathology of lacunes, enlarged perivascular spaces, and atrophy were scarce. Arteriolosclerosis might be associated with severe CAA. The pathological changes of CSVD markers by ICH etiology are needed to be investigated further.

Environmental enrichment (EE) refers to different forms of stimulation, where the environment is designed to improve the levels of sensory, cognitive, and motor stimuli, inducing stroke recovery in animal models. Stroke is a leading cause of mortality and neurological disability among older adults, hence the importance of developing strategies to improve recovery for such patients. This review provides an update on recent findings, compiling information regarding the parameters affected by EE exposure in both preclinical and clinical studies. During stroke recovery, EE exposure has been shown to improve both the cognitive and locomotor aspects, inducing important neuroplastic alterations, increased angiogenesis and neurogenesis, and modified gene expression, among other effects. There is a need for further research in this field, particularly in those aspects where the evidence is inconclusive. Moreover, it is necessary refine and adapt the EE paradigms for application in human patients.

Chronic kidney disease (CKD) is an independent risk factor for the development of cerebrovascular disease, particularly small vessel disease which can manifest in a variety of phenotypes ranging from lacunes to microbleeds. Small vessel disease likely contributes to cognitive dysfunction in the CKD population. Non-traditional risk factors for vascular injury in uremia include loss of calcification inhibitors, hyperphosphatemia, increased blood pressure variability, elastinolysis, platelet dysfunction, and chronic inflammation. In this review, we discuss the putative pathways by which these mechanisms may promote cerebrovascular disease and thus increase risk of future stroke in CKD patients.

An accurate etiological classification is key to optimize secondary prevention after ischemic stroke, but the cause remains undetermined in one third of patients. Several studies pointed out the usefulness of circulating gene expression markers to discriminate cardioembolic (CE) strokes, mainly due to atrial fibrillation (AF), while only exploring them in small cohorts. A systematic review of studies analyzing high-throughput gene expression in blood samples to discriminate CE strokes was performed. Significantly dysregulated genes were considered as candidates, and a selection of them was validated by RT-qPCR in 100 patients with defined CE or atherothrombotic (LAA) stroke etiology. Longitudinal performance was evaluated in 12 patients at three time points. Their usefulness as biomarkers for AF was tested in 120 cryptogenic strokes and 100 individuals at high-risk for stroke. Three published studies plus three unpublished datasets were considered for candidate selection. Sixty-seven genes were found dysregulated in CE strokes. CREM, PELI1, and ZAK were verified to be up-regulated in CE vs LAA (p = 0.010, p = 0.003, p < 0.001, respectively), without changes in their expression within the first 24 h after stroke onset. The combined up-regulation of these three biomarkers increased the probability of suffering from CE stroke by 23-fold. In cryptogenic strokes with subsequent AF detection, PELI1 and CREM showed overexpression (p = 0.017, p = 0.059, respectively), whereas in high-risk asymptomatic populations, all three genes showed potential to detect AF (p = 0.007, p = 0.007, p = 0.015). The proved discriminatory capacity of these gene expression markers to detect cardioembolism even in cryptogenic strokes and asymptomatic high-risk populations might bring up their use as biomarkers.

Traumatic brain injury (TBI) affects all age groups in a population and is an injury generating scientific interest not only as an acute event, but also as a complex brain disease with several underlying neurobehavioral and neuropathological characteristics. We review early and long-term alterations after juvenile and adult TBI with a focus on changes in the neurovascular unit, including neuronal interactions with glia and blood vessels at the blood–brain barrier (BBB). Post-traumatic changes in cerebral blood flow, BBB structures and function, as well as mechanistic pathways associated with brain aging and neurodegeneration are presented from clinical and experimental reports. Based on the literature, increased attention on BBB changes should be integrated in studies characterizing TBI outcome and may provide a meaningful therapeutic target to resolve detrimental post-traumatic dysfunction.

Stroke continues to be a serious and significant health problem in the USA and worldwide. This article will emphasize the need for good laboratory practices, transparent scientific reporting, and the use of translational research models representative of the disease state to develop effective treatments. This will allow for the testing and development of new innovative strategies so that efficacious therapies can be developed to treat ischemic and hemorrhagic stroke. This article recommends guidelines for effective translational research, most importantly, the need for study blinding, study group randomization, power analysis, accurate statistical analysis, and a conflict of interest statement. Additional guidelines to ensure reproducibility of results and confirmation of efficacy in multiple species are discussed.