Hiroshi Moriwaki

Increase in Circulating CD34-Positive Cells in Patients with Angiographic Evidence of Moyamoya-like Vessels

Increasing evidence points to a role for circulating endothelial progenitor cells, including populations of CD34-positive (CD34+) cells, in maintenance of cerebral blood flow. In this study, we investigated the link between the level of circulating CD34+ cells and neovascularization at ischemic brain. Compared with control subjects, a remarkable increase of circulating CD34+ cells was observed in patients with angiographic moyamoya vessels, although no significant change was observed in patients with major cerebral artery occlusion (or severe stenosis) but without moyamoya vessels. Our results suggest that the increased level of CD34+ cells associated with ischemic stress is correlated with neovascularization at human ischemic brain.

Motor recovery and microstructural change in rubro-spinal tract in subcortical stroke.

The mechanism of motor recovery after stroke may involve reorganization of the surviving networks. However, details of adaptive changes in structural connectivity are not well understood. Here, we show long-term changes in white matter microstructure that relate to motor recovery in stroke patients. We studied ten subcortical ischemic stroke patients who showed motor hemiparesis at the initial clinical examination and an infarcted lesion centered in the posterior limb of internal capsule of the unilateral hemisphere at the initial diffusion-weighted magnetic resonance imaging scan. The participants underwent serial diffusion tensor imaging and motor function assessments at three consecutive time points; within 2 weeks, and at 1 and 3 months after the onset. Fractional anisotropy (FA) was analyzed for regional differences between hemispheres and time points, as well as for correlation with motor recovery using a tract-based spatial statistics analysis. The results showed significantly increased FA in the red nucleus and dorsal pons in the ipsi-lesional side at 3 months, and significantly decreased FA in the ipsi-lesional internal capsule at all time points, and in the cerebral peduncle, corona radiata, and corpus callosum at 3 months. In the correlation analysis, FA values of clusters in the red nucleus, dorsal pons, midbody of corpus callosum, and cingulum were positively correlated with recovery of motor function. Our study suggests that changes in white matter microstructure in alternative descending motor tracts including the rubro-spinal pathway, and interhemispheric callosal connections may play a key role in compensating for motor impairment after subcortical stroke.

Circulating CD34-Positive Cells Have Prognostic Value for Neurologic Function in Patients with past Cerebral Infarction

Increasing evidence points to a role for circulating endothelial progenitors, including populations of CD34-positive (CD34+) cells present in peripheral blood, in vascular homeostasis and neovascularization. In this report, circulating CD34+ cells in individuals with a history of cerebral infarction were correlated with changes in neurologic function over a period of 1 year. Patients with decreased levels of CD34+ cells displayed significant worsening in neurologic function, evaluated by the Barthel Index and Clinical Dementia Rating. These results support the hypothesis that levels of circulating CD34+ cells have prognostic value for neural function, consistent with their potential role in maintaining cerebral circulation.

Dystypia: Isolated Typing Impairment without Aphasia, Apraxia or Visuospatial Impairment

We report a 60-year-old right-handed Japanese man who showed an isolated persistent typing impairment without aphasia, agraphia, apraxia or any other neuropsychological deficit. We coined the term ‘dystypia’ for this peculiar neuropsychological manifestation. The symptom was caused by an infarction in the left frontal lobe involving the foot of the second frontal convolution and the frontal operculum. The patient’s typing impairment was not attributable to a disturbance of the linguistic process, since he had no aphasia or agraphia. The impairment was not attributable to the impairment of the motor execution process either, since he had no apraxia. Thus, his typing impairment was deduced to be based on a disturbance of the intermediate process where the linguistic phonological information is converted into the corresponding performance. We hypothesized that there is a specific process for typing which branches from the motor programming process presented in neurolinguistic models. The foot of the left second frontal convolution and the operculum may play an important role in the manifestation of ‘dystypia’.

Rapid quantitative CBF and CMRO2 measurements from a single PET scan with sequential administration of dual 15O-labeled tracers

Positron emission tomography (PET) with 15O tracers provides essential information in patients with cerebral vascular disorders, such as cerebral blood flow (CBF), oxygen extraction fraction (OEF), and metabolic rate of oxygen (CMRO2). However, most of techniques require an additional C15O scan for compensating cerebral blood volume (CBV). We aimed to establish a technique to calculate all functional images only from a single dynamic PET scan, without losing accuracy or statistical certainties. The technique was an extension of previous dual-tracer autoradiography (DARG) approach, but based on the basis function method (DBFM), thus estimating all functional parametric images from a single session of dynamic scan acquired during the sequential administration of H215O and 15O2. Validity was tested on six monkeys by comparing global OEF by PET with those by arteriovenous blood sampling, and tested feasibility on young healthy subjects. The mean DBFM-derived global OEF was 0.57 ± 0.06 in monkeys, in an agreement with that by the arteriovenous method (0.54 ± 0.06). Image quality was similar and no significant differences were seen from DARG; 3.57% ± 6.44% and 3.84% ± 3.42% for CBF, and −2.79% ± 11.2% and −6.68% ± 10.5% for CMRO2. A simulation study demonstrated similar error propagation between DBFM and DARG. The DBFM method enables accurate assessment of CBF and CMRO2 without additional CBV scan within significantly shortened examination period, in clinical settings.

The importance of thermal changes in the pathophysiology of stroke: post-stroke fever and hypothermia therapy

In order to elucidate the significance of thermal changes in the pathophysiology of stroke, experimental and clinical studies were performed in rats and stroke patients, respectively. In rats, small infarction restricted to the hypothalamus was produced with intraluminal methods occluding hypothalamic artery selectively. The body temperature increased significantly by 0.6–1.1 °C for 72 hours. Changes in body temperature were retrospectively studied in 45 patients with cardio-embolic stroke admitted within 24 hours after stroke. Body temperature was found to increase significantly during the first 4 days of stroke correlating with the size of infarction. Mild hypothermia (32.5–33.5 °C for 3–5 days) was induced within 6 hours after stroke in 13 patients with embolic occlusion of major cerebral artery. The frequency of good functional outcome as defined by Barthel Index (BI) 75 or more at 3 months after stroke (50%) was significantly larger as compared with that in patients with the similar stroke severity who were admitted at 6–24 hours after stroke and underwent no hypothermic or antipyretic therapy (10%). Antipyretic therapy with oral administration of non-steroidal antipyretic drug (loxoprofen 180 mg/day) was induced within 12 hours after stroke and continued for 5 days in 17 patients with embolic occlusion of major cerebral artery. Good functional outcome at 3 months after stroke (41%) was significantly larger as compared with that in patients without hypothermic or antipyretic therapy (12%). The results of the present study suggest that post-stroke fever is developed commonly following large infarction and aggravates clinical outcome. The management of temperature may bring about better clinical outcome and is considered important for the treatment of severe stroke.

Effects of Hyperthermia and Hypothermia on Ischemic Vascular Damages

To clarify effects of hyperthermia and hypothermia on ischemic vascular damages from the clinical aspect, retrospective and prospective studies were undertaken in patients with acute embolic stroke. The retrospective study was performed in 60 embolic stroke patients who were admitted within 24 h after stroke. They were divided into two groups, the normothermic group (<37.0°C; n = 49) and the hyper-thermic group (≥37.0°C; n = 11), based on the average body (axillary) temperature measured during the first 3 days of admission. Vascular damages were estimated with computed tomography (CT) findings, assuming that hemorrhagic changes and severe cerebral edema reflect severe vascular damages. All the hyperthermic patients had severe neurologic deficits on admission, with a score of 15 or higher on the NIH stroke scale; only 22% of the normothermic patients had severe deficits on admission. Hemorrhagic changes and severe cerebral edema developed more commonly in the hyperthermic group than in the normothermic group (P < 0.1 and p < 0.001). The prospective study was performed in 22 patients with acute embolic stroke whose score on the NIH stroke scale on admission was 15 or higher. Eleven patients who were admitted within 5 h after stroke underwent hypothermia therapy with brain temperature 33.0°C for 3-5 days. The other 11 patients received antipyretic therapy with oral administration of a nonsteroidal antiinflammatory drug, which mainitained the body temperature below 36.7°C. In both groups the frequency of hemorrhagic changes was significantly smaller compared with the hyperthermic group (P < 0.05), and the magnitude of cerebral edema was significantly reduced (P < 0.05). Hyperthermia appears to aggravate ischemic vascular damage, whereas hypothermia may prevent it.

Treatment of Hyperacute Embolic Stroke with Major Cerebral Artery Occlusion by Mild Hypothermia

Mild hypothermia was utilized for the treatment of hyperacute embolic stroke with major cerebral artery occlusion. The subjects were 12 stroke patients, 61 ± 13 years of age, who had occlusions of internal carotid artery (ICA), 7; middle cerebral artery (MCA) trunk, 4; or basilar artery (BA), 1. All patients were admitted within 4h after stroke. The initial NIH Stroke Scale classification at admission was 21.8 ± 9.3. Hypothermia was induced within 6h after stroke, and the brain temperature was maintained at 33°C for 3–6 days. Two of seven patients with ICA occlusion, one with recurrent multiple emboU and the other with massive hemorrhagic infarction, died during the acute phase. The remainder had a considerably good functional outcome showing Rankin Scale 2.8 ± 1.5 and Barthel Index 69 ± 35 at 3 months after stroke. Computed tomography (CT) findings in those patients were similar in the following two respects: (1) the development of cerebral edema was unremarkable in both the hypothermic and post-hypothermic periods, and (2) ischemic areas were rarely enhanced by contrast agents. It should also be noted that in two patients with delayed recanalization, ischemic lesions on CT developed gradually and were completed at 3–5 days after stroke. Mild hypothermia may have protective effects on stroke preventing the development of blood-brain barrier (BBB) disruption and cerebral edema, provided the hypothermia is induced in the hyperacute phase. Our CT findings suggest that hypothermia prolongs the time window of stroke therapy.

Determination of EC/IC bypass candidate by quantitative CBF measurement with by O-15 brain PET and I-123 IMP brain SPECT

However, extracranial and intracranial arterial bypass surgery (EC/IC BYPASS) was denied by the randomized study, some patients may be suitable for surgery after selecting areas of misery perfusion. Steady-state O-15 positron emission tomography (PET) showed cerebral blood flow of 31.6±4.1 (ml/100 g/min) with acetazolamide reactivity of 30.6±5.4 (%) in misery perfused areas. The authors examined whether or not patients could be selected for surgery through combining cerebral blood flow (CBF) measurements with vasoreactivity determined by I-123 IMP (IMP; N-isopropyl-p-[I-123]-iodoamphetamine) single-photon emission-computed tomography (SPECT), which has good linearization at high flow ranges. Cerebral blood flow was quantified immediately after PET in 24 patients by counting I-123 IMP in arterial blood 10 min after injection. The CBF in the middle-cerebral arterial territories (MCA) was obtained by selecting regions of interest and comparing the fit between O-15 H2O and I-123 IMP using a nonlinear PS model curve. In 48 MCA areas, the CBF correlation between brain PET and IMP brain SPECT was close according to the equation, PET=12.4+0.46×IMP; r=0.743 (p<0.01). The authors extrapolated a line from the relationships between O-15 and I-123 IMP using the PS model to detect CBF and reactivity. The CBF value of 31.6 (ml/100 g/min) and the vasoreactivity 30.6 (%) obtained by PET for identifying the misery perfusion fell on the values of 29.3 (ml/100 g/min) and 29.3 (%) obtained by IMP measurements, respectively. The five areas met the criteria of CBF<29.3 (ml/100 g/min) and vasoreactivity<29.3 (%) were confirmed as misery perfusion, indicating significantly high oxygen extraction fraction (OEF) (0.513±0.029). n nThe authors decided that a CBF value of <29.3 (ml/100 g/min) and vasoreactivity of <29.3 (%) represented misery perfused areas using I-123 IMP measurements after correlation with the nonlinear PS model. Since an EC/IC bypass might benefit patients with misery perfusion, such areas should be identified by I-123 IMP measurements to ensure that patients receive the most effective treatment strategy.