Altered neurogenic pathways in experimental rat models of ischemic cerebral stroke: A transcriptome based meta-analysis

Objectives: Promoting neurogenesis mediated recovery is one of the most sought after strategies in recovery after cerebral stroke. In this paper we elucidate how neurogenesis related genes are altered in the early stroke environment, to hint at potential pathways for therapeutic recovery. Materials and Methods: Around 97 microarray datasets derived from stroke affected rat brains were collected from NCBI-GEO. Datasets were normalized and subjected to a meta-analysis in Network Analyst to identify differentially expressed genes. Gene enrichment analyses were carried out using GSEA, and WebGestalt and results were visualized using Cytoscape Enrichment mapping. Results: Nearly 939 differentially expressing genes were identified in the cerebral stroke group. Among them, 30 neurogenesis related genes were identified through enrichment mapping analysis, and 35 genes through Protein-Protein Interaction analysis. Highest upregulated neurogenesis genes were found to be TSPO, GFAP, VIM, and TGFB1. The Highest Downregulated neurogenesis genes were found to be THY1, NR1D1, CDK5, STX1B, and NOG. Conclusions: Through this study, we have identified that during the acute time frame after stroke, the majority of the neurogenesis genes related to neural proliferation and neural differentiation are downregulated, while the majority of the genes related to neuronal migration were upregulated. A single or combined therapeutic approach against the identified dysregulated genes could greatly aid neural restoration and functional recovery during the postischemic stage.

Virtual monoenergetic dual-energy CT reconstructions at 80 keV are optimal non-contrast CT technique for early stroke detection

Background Virtual monoenergetic (VM) dual-energy computed tomography (DE-CT) enables grey-to-white matter contrast-to-noise ratio optimization, potentially increasing ischaemic brain oedema visibility. The aim of this study was to compare the diagnostic accuracy of VM and standard DE-CT reconstructions for early stroke detection. Methods Consecutive patients with non-contrast DE-CT of the brain scanned within 12 h of stroke symptom onset were prospectively included in the study. Patients with other significant brain pathology were excluded. Two radiologists jointly evaluated standard and VM reconstructions (from 40 to 190 keV at increments of 10 keV) for early stroke signs on a four-point Likert scale: (a) stroke definitely present, (b) stroke probably present, (c) probably no stroke, and (d) definitely no stroke. Follow-up imaging and clinical data served as the standard of reference. Diagnostic accuracy was evaluated by receiver operating characteristic analysis. Results Stroke incidence among 184 patients was 76%. In 64 patients follow-up imaging served as the standard of reference: ischemic brain oedema detection was significantly more accurate on VM reconstructions at 80 keV compared with standard DE-CT reconstructions (area under the curve (AUC) = 0.821 vs. AUC = 0.672, p = 0.002). The difference was most prominent within the first 3 h after symptom onset (at 11%, AUC = 0.819 vs. AUC = 0.709, p = 0.17) and in patients with National Institutes of Health Stroke Scale above 16 (at 37.5%, AUC = 1 vs. AUC = 0.625, p = 0.14). Conclusion VM DE-CT reconstructions at 80 keV appear to be the optimal non-contrast CT technique for diagnosing early ischaemic stroke, particularly within the first 3 h after symptom onset and in severely ill patients.

Why Are Stroke Rehabilitation Trial Recruitment Rates in Single Digits?

Background: Recruitment of patients in early subacute rehabilitation trials (<30 days post-stroke) presents unique challenges compared to conventional stroke trials recruiting individuals >6 months post-stroke. Preclinical studies suggest treatments be initiated sooner after stroke, thus requiring stroke rehabilitation trials be conducted within days post-stroke. How do specific inclusion and exclusion criteria affect trial recruitment rates for early stroke rehabilitation trials?Objectives: Provide estimates of trial recruitment based on screening and enrollment data from a phase II early stroke rehabilitation trial.Methods: CPASS, a phase II intervention trial screened ischemic stroke patients in acute care (18-months, N = 395) and inpatient rehabilitation (22-months, N = 673). Patients were stratified by upper extremity (UE) impairment into mild (NIHSS motor arm = 0, 1); moderate (NIHSS = 2, 3); severe (NIHSS = 4) and numbers of patients disqualified due to CPASS exclusion criteria determined. We also examined if a motor-specific evaluation (Action Research Arm Test, ARAT) increases the pool of eligible patients disqualified by the NIHSS motor arm item.Results: CPASS recruitment in acute care (5.3%) and inpatient rehabilitation (5%) was comparable to prior trials. In acute care, a short stay (7–17-days), prior stroke (13.5% in moderately; 13.2% in severely impaired) disqualified the majority. In inpatient rehabilitation, the majority (40.8%) were excluded for “too mild” impairment. The next majority were disqualified for reaching inpatient rehabilitation “too late” to participate in an early stroke trial (15% in moderately; 24% in severely impaired). Mean ARAT in the “too mild” showed significant impairment and potential to benefit from participation in select UE rehabilitation trials.Conclusions: Screening of ischemic stroke patients while they are still in acute care is crucial to successful recruitment for early stroke rehabilitation trials. A significant proportion of eligible patients are lost to “short length of stay” in acute care, and arrive to inpatient rehabilitation “too late” for an early rehabilitation trial. Additional screening of mildly impaired patients using a motor function specific scale will benefit the trial recruitment and generalizability.Trial Registration Number:http://www.clinicaltrials.gov Identifier: NCT02235974.