Hajime Takase

Background: Ischemic stroke causes substantial neurological impairment, and although poststroke rehabilitation can support recovery, neurological deficits often limit the feasibility of exercise in clinical settings. Prestroke exercise has emerged as a potential strategy to enhance resilience to ischemic injury, but most preclinical studies have relied on young adult rodents, in which spontaneous recovery can sometimes obscure clinically meaningful functional effects. However, the impact of exercise preconditioning in later stages of adulthood remains insufficiently characterized. Here, we investigated whether a treadmill exercise preconditioning regimen confers neuroprotection and improves recovery‐related responses in late‐adult mice subjected to middle cerebral artery occlusion. Methods: Eight‐month‐old male mice were assigned to sedentary or exercise groups. Following 5 weeks of treadmill running (5 days per week after 1 week of acclimatization), mice underwent 45 minutes of middle cerebral artery occlusion and reperfusion. Behavioral assessments and body‐weight monitoring were performed before and after middle cerebral artery occlusion. Infarct volume and cellular responses were evaluated 14 days after stroke. Results: Fourteen days after stroke, lesion volume was significantly reduced in the exercise group compared with sedentary controls. Exercise preconditioning enhanced neurogenesis, oligodendrogenesis, and CD31‐positive vascular responses while suppressing reactive astrocyte activation. Functional improvements were consistently observed across multiple behavioral assays in late‐adult mice. Conclusions: Preconditioning with treadmill exercise provides neuroprotection against ischemic stroke in late‐adult mice by reducing infarct volume and promoting recovery‐associated cellular responses. These findings demonstrate that the functional benefits of prestroke exercise extend beyond the young adult stage and support the potential value of regular physical activity as a strategy to mitigate ischemic brain injury later in adulthood.

BACKGROUND AND OBJECTIVES: The clinical efficacy of middle meningeal artery embolization (MMAE) in chronic subdural hematoma (CSDH) is increasingly established; yet, recent landmark randomized controlled trials consistently report only a 30% to 50% reduction in recurrence, implying that middle meningeal artery occlusion alone does not fully resolve the pathological microenvironment of the outer hematoma membrane. The mechanistic basis of this incomplete treatment response remains undefined. METHODS: To develop a mechanistic framework for this clinical paradox, we performed a Preferred Reporting Items for Systematic Reviews and Meta-Analyses–compliant systematic review. Of 876 records identified across PubMed, Embase, and ClinicalTrials.gov, 47 underwent full-text review and 18 studies (16 clinical studies and 2 registry records) published through October 2025 were included, integrating clinical outcomes with pathological and molecular insights. A secondary analysis of a publicly available single-cell RNA sequencing data set of normal human dural tissue was performed to map the cellular infrastructure underlying key molecular drivers. RESULTS: CSDH progression is driven by an interconnected triad of inflammatory infiltration, pathological angiogenesis, and vascular hyperpermeability within the outer hematoma membrane. While MMAE suppresses these pathogenic programs by reducing middle meningeal artery–derived arterial supply, we propose that occlusion-induced ischemic stress may paradoxically stabilize hypoxia-inducible factor 1α, triggering compensatory angiogenesis in cases of incomplete devascularization, a mechanism we formally term the “hypoxia paradox”. Secondary single-cell RNA sequencing analysis identified fibroblast-like and endothelial dural populations as the primary cellular platforms for this response, providing a translational cellular basis for the proposed framework. CONCLUSION: The hypoxia paradox represents a testable mechanistic hypothesis, offering a coherent explanation for heterogeneous MMAE outcomes and generates specific, testable predictions regarding post-MMAE molecular signatures in the outer hematoma membrane. Prospective paired tissue sampling integrated with multimodal molecular analyses is essential to validate this model and advance CSDH management toward individualized, mechanism-guided therapy.

The placebo-controlled PENS trial showed that shunting improves gait but not cognition or continence in idiopathic normal-pressure hydrocephalus (iNPH). This selective response highlights an unresolved problem: even among patients who respond to temporary cerebrospinal-fluid (CSF) drainage, we cannot predict which deficits will reverse after shunting. Static structural and perfusion markers, including white-matter hyperintensity load, cerebral small-vessel-disease burden, and baseline cerebral blood flow, do not predict shunt response. In contrast, impaired cerebrovascular reactivity is associated with a favorable response, yet cerebral autoregulation has not been measured before and after CSF diversion. I propose that reversibility in iNPH reflects recoverable hemodynamic reserve, and that this hypothesis can be tested within the existing diagnostic pathway.

Endovascular thrombectomy restores macrovascular patency but fails to achieve tissue-level perfusion in approximately 30% of cases, likely because of the no-reflow phenomenon. Even after optimized hemodynamic management, 40% of patients with angiographically successful recanalization fail to achieve functional independence, revealing a biological ceiling beyond blood pressure optimization. I propose that pericyte contraction via endothelin-1/ET-A receptor signaling, neutrophil CD11b/CD18-dependent capillary plugging, and platelet microthrombus, mechanisms operating orthogonally to systemic hemodynamics, define this ceiling. I review imaging and biomarker strategies for identifying microvascular failure and discuss endothelin receptor antagonism, integrin blockade, and intra-arterial thrombolysis as therapeutic priorities for next-generation of post-thrombectomy trials.

Oligodendrocyte precursor cells (OPCs) have been reported to interact with cerebral microvessels, but the extent and spatiotemporal regulation of this relationship across maturation and hypoperfusion‐induced stress remain incompletely defined. Here, we quantified OPC‐vessel relationships in the mouse corpus callosum using PDGFR‐α/OLIG2/CD31 immunohistochemistry and distance‐based spatial analysis, classifying OPCs within 10 μm of CD31+ vessels as perivascular OPCs. We show that while total OPC density decreases from development to adulthood, the proportion of perivascular OPCs increases in the mature brain. Under cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS), OPC density and the enrichment of perivascular OPCs were increased by Day 7 and remained elevated through Days 14–28. Proliferative OPCs (Ki67‐positive OPCs) were preferentially observed within the vessel‐proximal domain, indicating that the perivascular compartment functions as a stress‐responsive proliferative niche. To identify regulators of this response, we focused on A‐kinase anchoring protein 12 (AKAP12), a scaffolding protein expressed in vascular cells. In middle‐aged Akap12 global knockout mice subjected to BCAS, hypoperfusion‐induced OPC increase was preserved, but perivascular accumulation was reduced. This defect was accompanied by increased IgG leakage without a corresponding reduction in vascular area density, suggesting that AKAP12 supports the integrity of the perivascular microenvironment required for OPC niche remodeling. Together, these findings reveal the perivascular niche as a hypoperfusion‐responsive compartment for OPC activation and suggest that AKAP12‐dependent vascular barrier integrity contributes to the maintenance of this oligovascular niche.

Chronic subdural hematoma (CSDH) is a common neurosurgical disease in the elderly, characterized by inflammation, neovascularization, and increased vascular permeability. Although protease-activated receptor-1 (PAR-1) is known to regulate vascular permeability and is implicated in chronic inflammatory diseases, its role in CSDH remains unclear. In this exploratory study, we investigated PAR-1 expression in the dura mater and outer membrane of patients with CSDH compared with controls. Age- and sex-matched cases (six CSDH, five controls) were selected for analysis. Immunohistochemistry for PAR-1 and zonula occludens-1 (ZO-1), along with mRNA expression analysis, were performed. Histologically, the outer membrane of CSDH exhibited cellular clustering and strong PAR-1 immunoreactivity in vascular structures, whereas the dura mater from both groups showed no significant PAR-1 staining. ZO-1 expression was preserved in the vasculature of the outer membrane in CSDH and the dura mater of both groups. mRNA analysis revealed a trend toward higher PAR-1 and lower ZO-1 expression in CSDH, though not statistically significant. The group effect ( p = 0.24, analysis of covariance [ANCOVA] t -test) represents the adjusted difference in ZO-1 expression between CSDH and control groups after accounting for PAR-1 levels. The main effect of PAR-1 ( p = 0.15, ANCOVA t -test) reflects the overall association between PAR-1 and ZO-1 expression across samples. This study provides the first evidence of PAR-1 expression in the outer membrane of CSDH, suggesting a role in promoting local vascular hyperpermeability. These findings highlight PAR-1 as a possible biomarker and therapeutic target in CSDH. Further studies with larger cohorts and quantitative analyses are warranted to clarify the molecular mechanisms underlying vascular dysfunction in CSDH.

The corpus callosum, a major white matter tract in the brain, undergoes age-related functional changes. To extend our investigation of age-related gene expression dynamics in the mouse corpus callosum, we compared RNA-seq data from 2-week-old and 12-week-old wild-type C57BL/6J mice and identified the differentially expressed genes (e.g., Serpinb1a, Ndrg1, Dnmt3a , etc.) between these ages. Interestingly, we found that genes highly expressed in myelinating oligodendrocytes were upregulated in 12-week-old mice compared to 2-week-old mice, while genes highly expressed in oligodendrocyte precursor cells (OPCs) and newly formed oligodendrocytes were downregulated. Furthermore, by comparing these genes with the datasets from 20-week-old and 96-week-old mice, we identified novel sets of genes with age-dependent variations in the corpus callosum. These gene expression changes potentially affect key biological pathways and may be closely linked to age-related neurological disorders, including dementia and stroke. Therefore, our results provide an additional dataset to explore age-dependent gene expression dynamics of oligodendrocyte lineage cells in the corpus callosum.

Study Design.: Systematic review and meta-analysis. Objective.: Using a network meta-analysis (NMA), this study aimed to compare the risks of C5 palsy after three different procedures of anterior cervical decompression. Summary of Background Data.: C5 palsy is a well-known complication affecting the quality of life after anterior procedures. Due to the limited evidence on the various procedures available, we evaluate the basis for selection to prevent palsy and achieve maximal decompression in cases spanning 3-6 levels. Materials and Methods.: We conducted a comprehensive search for C5 palsy and complications after 3representative procedures, including anterior cervical discectomy and fusion (ACDF), anterior cervical corpectomy and fusion (ACCF), and their combination (hybrid), involving 3 to 6 intervertebral levels. The incidence of C5 palsy was compared using a NMA. Results.: We identified 1655 patients in 11 studies who met inclusion criteria. Sixty-nine patients (4.2%) developed delayed C5 palsies. The incidences among ACDF, ACCF, and hybrid cases were 2.3% (16/684, 95% CI: 1.4% to 3.8%), 6.4% (39/613, 95% CI: 4.7% to 8.6%), and 3.9% (14/358, 95% CI: 2.3% to 6.5%), respectively (P< 0.01). A NMA was performed for 15 pairwise comparisons across the 3 procedure arms: ACDF versushybrid, 7/232 (3.0%) versus11/234 (4.7%); hybrid versusACCF, 14/301 (4.3%) versus18/224 (8.0%); ACCF versusACDF, 38/523 (7.8%) versus16/619 (2.6%). Compared with ACDF, the risk of C5 palsy was significantly higher in ACCF (odds ratio: 2.72, 95% CI: 1.47 to 5.01), whereas ACDF versushybrid did not significantly differ in risk (odds ratio: 1.56, 95% CI: 0.68 to 3.60). Conclusion.: We determined that ACCF was associated with a higher risk of postoperative C5 palsy than ACDF in cases spanning 3 to 6 intervertebral levels. If practicable, ACDF surgery may be an appropriate choice for cases requiring anterior decompression of 3 to 6 levels. Level of Evidence.: Level III.