Background: Delayed arrival at hospital is one of the major obstacles in enhancing the rate of thrombolysis therapy in patients with acute ischemic stroke. Our study aimed to investigate factors associated with prehospital delay after acute ischemic stroke in Korea. Methods: A prospective, multicenter study was conducted at 14 tertiary hospitals in Korea from March 2009 to July 2009. We interviewed 500 consecutive patients with acute ischemic stroke who arrived within 48 hours. Univariate and multivariate analyses were performed to evaluate factors influencing prehospital delay. Results: Among the 500 patients (median 67 years, 62% men), the median time interval from symptom onset to arrival was 474 minutes (interquartile range, 170-1313). Early arrival within 3 hours of symptom onset was significantly associated with the following factors: high National Institutes of Health Stroke Scale (NIHSS) score, previous stroke, atrial fibrillation, use of ambulance, knowledge about thrombolysis and awareness of the patient/bystander that the initial symptom was a stroke. Multivariable logistic regression analysis indicated that awareness of the patient/bystander that the initial symptom was a stroke (OR 4.438, 95% CI 2.669-7.381), knowledge about thrombolysis (OR 2.002, 95% CI 1.104-3.633) and use of ambulance (OR 1.961, 95% CI 1.176-3.270) were significantly associated with early arrival. Conclusions: In Korea, stroke awareness not only on the part of patients, but also of bystanders, had a great impact on early arrival at hospital. To increase the rate of thrombolysis therapy and the incidence of favorable outcomes, extensive general public education including how to recognize stroke symptoms would be important.

Background and Purpose—: Chronic cerebral hypoperfusion can lead to ischemic white matter injury resulting in vascular dementia. To characterize white matter injury in vascular dementia, we investigated disintegration of diverse white matter components using a rat model of chronic cerebral hypoperfusion. Methods—: Chronic cerebral hypoperfusion was modeled in Wistar rats by permanent occlusion of the bilateral common carotid arteries. We performed cognitive behavioral tests, including the water maze task, odor discrimination task, and novel object test; histological investigation of neuroinflammation, oligodendrocytes, myelin basic protein, and nodal or paranodal proteins at the nodes of Ranvier; and serial diffusion tensor imaging. Cilostazol was administered to protect against white matter injury. Results—: Diverse cognitive impairments were induced by chronic cerebral hypoperfusion. Disintegration of white matter was characterized by neuroinflammation, loss of oligodendrocytes, attenuation of myelin density, structural derangement at the nodes of Ranvier, and disintegration of white matter tracts. Cilostazol protected against cognitive impairments and white matter disintegration. Conclusions—: White matter injury induced by chronic cerebral hypoperfusion can be characterized by disintegration of diverse white matter components. Cilostazol might be a therapeutic strategy against white matter disintegration in patients with vascular dementia.

Increased level of blood viscosity, which is one of the major factors that determine blood rheology, has been reported as a risk factor or predictor for cerebrovascular events. We investigated how blood viscosity is associated with acute stroke and chronic radiological manifestations of cerebral small vessel disease, and how blood viscosity changes after stroke. We prospectively enrolled consecutive patients with acute ischemic stroke. Whole blood viscosities at a low or high shear rate were measured using a scanning capillary tube viscometer, and were referred to as diastolic blood viscosity (DBV) and systolic blood viscosity (SBV), respectively. Correlations between blood viscosity and acute stroke etiology or chronic radiological manifestations of cerebral small vessel disease were investigated. The temporal profiles of blood viscosity at the onset of stroke and follow-up at 1 and 5 weeks were investigated. Of the 127 patients admitted with acute ischemic stroke, 63 patients were included in the final analyses. DBV at the onset of stroke was significantly higher in small artery occlusion (SAO) stroke than in other stroke subtypes (p = 0.037). DBV showed a significant positive correlation with the number of chronic lacunes (r = 0.274, p = 0.030). The temporal profiles of DBV in SAO stroke showed a transient decrease due to the hydration therapy after 1 week and recurrent elevation at 5 week follow-up (p = 0.009). Our study suggests that elevated DBV may play a role in the development of acute and chronic manifestations of cerebral small vessel disease. The recurring elevation of DBV in SAO stroke indicates that sufficient hydration and additional therapeutic interventions targeting blood viscosity may be needed in patients with SAO stroke.

Post-stroke dementia (PSD) is one of the major consequences after stroke. Chronic cerebral hypoperfusion (CCH) can induce vascular cognitive impairment and potentiate amyloid pathology. We investigated how CCH contributes to the development of PSD after stroke in the context of neuroinflammation and amyloid pathology. We designed a unique animal model for PSD. We performed middle cerebral artery occlusion (MCAO) surgery in rats mimicking acute territorial infarct, which was followed by bilateral common carotid artery occlusion (BCCAo) surgery mimicking CCH. We performed behavioral tests including neurologic function test and water maze task and histological investigations including neuroinflammation, neuronal cell death, amyloid pathology, and aquaporin 4 (AQP4) distribution. Spatial memory was synergistically impaired when BCCAo was superimposed on MCAO. Neuroinflammation with astroglial or microglial activation and amyloid pathology were enhanced in the ipsilateral cortex, thalamus, and hippocampus when BCCAo was superimposed on MCAO. Glymphatic pathway-related AQP4 distribution changed from perivascular to parenchymal pattern. Our experimental results suggest that CCH may contribute to the development of PSD by interfering with amyloid clearance through the glymphatic pathway and concomitant neuroinflammation. Therapeutic strategy to clear brain metabolic waste through the glymphatic pathway may be a promising approach to prevent PSD after stroke.

Post-stroke dementia (PSD) is a major neurodegenerative consequence of stroke. Tauopathy has been reported in diverse neurodegenerative diseases. We investigated the cognitive impairment and pathomechanism associated with tauopathy in a rat model of PSD by modeling acute ischemic stroke and underlying chronic cerebral hypoperfusion (CCH). We performed middle cerebral artery occlusion (MCAO) surgery in rats to mimic acute ischemic stroke, followed by bilateral common carotid artery occlusion (BCCAo) surgery to mimic CCH. We performed behavioral tests and focused on the characterization of tauopathy through histology. Parenchymal infiltration of cerebrospinal fluid (CSF) tracers after intracisternal injection was examined to evaluate glymphatic function. In an animal model of PSD, cognitive impairment was aggravated when BCCAo was combined with MCAO. Tauopathy, manifested by tau hyperphosphorylation, was prominent in the peri-infarct area when CCH was combined. Synergistic accentuation of tauopathy was evident in the white matter. Microtubules in the neuronal axon and myelin sheath showed partial colocalization with the hyperphosphorylated tau, whereas oligodendrocytes showed near-complete colocalization. Parenchymal infiltration of CSF tracers was attenuated in the PSD model. Our experimental results suggest a hypothesis that CCH may aggravate cognitive impairment and tau hyperphosphorylation in a rat model of PSD by interfering with tau clearance through the glymphatic system. Therapeutic strategies to improve the clearance of brain metabolic wastes, including tau, may be a promising approach to prevent PSD after stroke.

To develop new rehabilitation therapies for chronic stroke, this study examined the effectiveness of task-specific training (TST) and TST combined with DNA methyltransferase inhibitor in chronic stroke recovery. Eight weeks after photothrombotic stroke, 5-Aza-2′-deoxycytidine (5-Aza-dC) infusion was done on the contralesional cortex for four weeks, with and without TST. Functional recovery was assessed using the staircase test, the cylinder test, and the modified neurological severity score (mNSS). Axonal plasticity and expression of brain-derived neurotrophic factor (BDNF) were determined in the contralateral motor cortex. TST and TST combined with 5-Aza-dC significantly improved the skilled reaching ability in the staircase test and ameliorated mNSS scores and cylinder test performance. TST and TST with 5-Aza-dC significantly increased the crossing fibers from the contralesional red nucleus, reticular formation in medullar oblongata, and dorsolateral spinal cord. Mature BDNF was significantly upregulated by TST and TST combined with 5-Azd-dC. Functional recovery after chronic stroke may involve axonal plasticity and increased mature BDNF by modulating DNA methylation in the contralesional cortex. Our results suggest that combined therapy to enhance axonal plasticity based on TST and 5-Aza-dC constitutes a promising approach for promoting the recovery of function in the chronic stage of stroke.