Autologous bone marrow stromal cell transplantation for central nervous system disorders - recent progress and perspective for clinical application.

There is increasing evidence that the transplanted BMSC significantly promote functional recovery after CNS damage in the animal models of various kinds of CNS disorders, including cerebral infarct, traumatic brain injury and spinal cord injury. However, there are several shortages of information when considering clinical application of BMSC transplantation for patients with CNS disorders. In this review, therefore, we discuss what we should clarify to establish cell transplantation therapy as the scientifically proven entity in clinical situation and describe our recent works for this purpose. The BMSC have the ability to alter their gene expression profile and phenotype in response to the surrounding circumstances and to protect the neurons by producing some neurotrophic factors. They also promote neurite extension and rebuild the neural circuits in the injured CNS. The BMSC can be expanded in vitro using the animal serum-free medium. Pharmacological modulation may accelerate the in vitro proliferation of the BMSC. Using in vivo optical imaging technique, the transplanted BMSC can non-invasively be tracked in the living animals for at least 8 weeks after transplantation. It is urgent issues to develop clinical imaging technique to track the transplanted cells in the CNS and evaluate the therapeutic significance of BMSC transplantation in order to establish it as a definite therapeutic strategy in clinical situation in the future.

Autosomal dominant moyamoya disease maps to chromosome 17q25.3.

BACKGROUND: Moyamoya disease (MMD) is an idiopathic steno-occlusive cerebrovascular disease that represents an important cause of stroke. However, etiology of the disease has remained largely unknown. METHODS: We previously showed that the inheritance pattern of MMD is autosomal dominant with incomplete penetrance. Here, we report the genome-wide parametric linkage analysis for MMD in 15 extended Japanese families. We conducted linkage analyses under two diagnostic classifications: narrow and broad. Affected member-only analysis was applied due to incomplete and age-dependent penetrance of the disease. RESULTS: Under both classifications, significant evidence of linkage was only observed on chromosome 17q25.3, with maximum multipoint logarithm of odds (lod) scores of 6.57 (under the narrow classification) and 8.07 (under the broad classification) at D17S704. Haplotype analysis revealed segregation of a disease haplotype in all families but one, and informative crossovers enabled mapping of the MMD locus to a 3.5-Mb region between D17S1806 and the telomere of 17q, encompassing 94 annotated genes. CONCLUSIONS: Our data suggest that there is a major gene locus for autosomal dominant moyamoya disease on chromosome 17q25.3.

Interstitial spinal-cord oedema in syringomyelia associated with Chiari type 1 malformations.

OBJECT: The pathophysiology of syringomyelia in Chiari type 1 malformations has not been clarified. Oedema-like spinal-cord swelling was recently reported in several pathological conditions, including Chiari type 1 malformations as a pre-syrinx state. However, the role of the pre-syrinx state in the development of syringomyelia is unknown. The purpose of this study is to investigate the parenchymal changes of the spinal cord in syringomyelia associated with Chiari type 1 malformations. METHODS: Pre- and postoperative MRI findings in 14 patients who underwent foramen magnum decompression in our institute were reviewed. The analysis was focused on differences in visualisation of the syrinx between T1- and T2-weighted images and abnormal parenchymal signal changes. There were 6 men and 8 women, aged from 6 to 79 years. No patients showed hydrocephalus. RESULTS: Twelve patients had large and expansive syrinx, whereas 2 patients showed small syrinx confined to the centre of the spinal cord. T2-weighted images displayed significantly larger intramedullary abnormal signal areas. Nine patients showed parenchymal hyperintensity areas around the enlarged central canal or base of the posterior white columns adjacent to the syringomyelic cavity. Such parenchymal hyperintensity areas markedly diminished with reduction of the syrinx after surgery and were considered to be interstitial oedema. CONCLUSIONS: From this study, the interstitial oedema of the spinal cord commonly accompanies syringomyelia with Chiari type 1 malformations. Accumulation of the extracellular fluid due to disturbed absorption mechanisms may play an important role in the pathophysiology of syringomyelia associated with Chiari type 1 malformations.

Evaluation of carotid plaque composition by computed tomographic angiography and black blood magnetic resonance images.

The purpose of this study was to evaluate quantitatively the composition of carotid plaque by computed tomographic (CT) angiography and qualitatively by black blood magnetic resonance images (MRI). Thirty-eight patients with high-grade carotid artery stenosis were included in this study. Ultrasonography, CT angiography and black blood MRI of the cervical carotid artery were performed, and the CT number was measured in Hounsfield units (HU). The average CT number of the 15 unstable plaques (39.5%) was 27.7+/-7.5 HU and that of the 23 stable plaques (60.5%) was 60.4+/-20.8 HU (p=0.0001). In the 23 patients with stable plaque, 21 demonstrated isointensity in T (1)- and T (2)-weighted images in the black blood MRI (p=0.0001). By using CT angiography and MRI, precise images of the pathology of the carotid arterial wall can be obtained. It is possible to evaluate the components of carotid artery plaque with high reliability by quantification of the CT number in CT angiography and performing black blood MRI as well as carotid ultrasonography.

Novel epidemiological features of moyamoya disease.

BACKGROUND: Many clinical features that are specific to moyamoya disease have been reported and cited in textbooks based on previous data. The purpose of this study is to investigate the present epidemiological features of moyamoya disease based on recently obtained regional all-inclusive data. METHODS: The authors performed an all-inclusive survey of moyamoya disease in Hokkaido, one of the major islands in Japan that has a population of 5.63 million. The epidemiological features were analysed based on the data from 267 newly registered patients with moyamoya disease in Hokkaido from 2002 to 2006. These analysed data were adjusted to the whole Japanese population at 2005. RESULTS: The detection rate of the disease per year was 0.94 patients per 100,000 people, and prevalence was 10.5 patients per 100,000 people. The incidence of ischaemia concerned with the disease was 0.53 patients per 100,000 people-years and haemorrhage was 0.2 patients per 100,000 people-years. The ratio of female to male patients was 2.18. The ratio of patients aged 10 years and above to under 10 years of age at onset was 6.18. Two peaks for age of onset were seen: the highest was observed between 45 and 49 years, and the second between 5 and 9 years. Asymptomatic patients comprised 17.8% of the total number of patients. CONCLUSION: The epidemiological features of moyamoya disease determined by this survey varied considerably from previous data. The detection rate and prevalence of the disease were higher than those reported previously. The highest peak of onset age was older than those reported previously. In addition, it was revealed that asymptomatic moyamoya patients are not always rare in Japan.

Evaluation of carotid plaque composition by computed tomography angiography and black blood magnetic resonance image.

SUMMARY: The purpose of this study was to evaluate the composition of a carotid plaque quantitatively by computed tomography (CT) angiography and qualitatively by black blood magnetic resonance imaging (MRI). Thirty-eight patients with high-grade carotid artery stenosis were included in this study. Ultrasonography, CT angiography and black blood MRI of the cervical carotid artery were performed, and the CT number was measured in Hounsfield units (HU). The average CT number of the 15 unstable plaques (39.5%) was 27.7 +/- 7.5 HU and that of the 23 stable plaques (60.5%) was 60.4 +/- 20.8 HU (p < 0.0001). In the 23 patients with stable plaque, 21 demonstrated isointensity in T1 and T2 in the black blood MRI (p < 0.0001). By using CT angiography and MRI, precise images of the pathology of the carotid arterial wall can be obtained. It is possible to evaluate the components of a carotid artery plaque with high reliability by quantification of the CT number in CT angiography and performing black blood MRI as well as in carotid ultrasonography.

Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia.

Intravenous delivery of mesenchymal stem cells (MSCs) prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischaemia models. Placental growth factor (PlGF) is angiogenic to impaired non-neural tissue. To test the hypothesis that PlGF contributes to the therapeutic benefits of MSC delivery in cerebral ischaemia, we compared the efficacy of systemic delivery of human MSCs (hMSCs) and hMSCs transfected with a fibre-mutant F/RGD adenovirus vector with a PlGF gene (PlGF-hMSCs). A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. hMSCs and PlGF-hMSCs were intravenously injected into the rats 3 h after MCAO. Lesion size was assessed at 3 and 6 h, and 1, 3, 4 and 7 days using MR imaging and histology. Functional outcome was assessed using the limb placement test and the treadmill stress test. Both hMSCs and PlGF-hMSCs reduced lesion volume, induced angiogenesis and elicited functional improvement compared with the control sham group, but the effect was greater in the PlGF-hMSC group. Enzyme-linked immunosorbent assay of the infarcted hemisphere revealed an increase in PlGF in both hMSC groups, but a greater increase in the PlGF-hMSC group. These data support the hypothesis that PlGF contributes to neuroprotection and angiogenesis in cerebral ischaemia, and cellular delivery of PlGF to the brain can be achieved by intravenous delivery of hMSCs.

The 5-hydroxytryptamine2A receptor antagonist sarpogrelate hydrochloride inhibits acute platelet aggregation in injured endothelium.

In this study, the effect of sarpogrelate hydrochloride, a 5-hydroxytryptamine2A receptor antagonist, on platelet aggregation at the site of injured carotid artery endothelium was examined. The rat common carotid artery was clamped for 30 min to induce endothelial injury. Sarpogrelate hydrochloride was administered before and after the injury, and the effects were compared with those in rats receiving sham operation only and those receiving clipping injury but no sarpogrelate hydrochloride. The animals were killed 24 h after the procedure. The common carotid artery was examined by scanning electron microscopy and stained immunochemically for factor VIII. Sarpogrelate hydrochloride treatment was associated with reduced aggregation of platelets on electron microscopy and lower expression of factor VIII at the injured intima. Sarpogrelate hydrochloride has an inhibitory effect on platelet aggregation at the intima in the acute stage after injury, suggesting that this drug may be used to prevent early ischaemic complications after surgical or endovascular arterial intervention.

Intravenous infusion of immortalized human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

Intravenous infusion of bone marrow cells has demonstrated therapeutic efficacy in animal models of cerebral ischemia and spinal cord injury. We intravenously delivered human mesenchymal stem cells (SH2+, SH3+, CD34-, and CD45-) immortalized with a human-telomerase gene (hTERT-MSCs) and transfected with eGFP or LacZ into rats 12 h after induction of transient middle cerebral artery occlusion (MCAO), to study their potential therapeutic benefit. hTERT-MSCs were delivered at 12 h after lesion induction. Lesion size was assessed using MR imaging and spectroscopy, and histological methods. Functional outcome was assessed using the Morris water maze and a treadmill test. Intravenous delivery of hTERT-MSCs reduced lesion volume and the magnitude of the reduction and functional improvement was positively correlated with the number of cells injected. The reduction of lesion size could be assessed in vivo with MRI and MRS and was correlated with subsequent histological examination of the brain. This work demonstrates that highly purified hTERT-MSCs reduce cerebral infarction volume and improve functional outcome.

Risk factors of postprocedural hypotension following carotid artery stenting.

SUMMARY: This study is performed to investigate risk factors of hypotension in response to elective carotid stenting. Forty-four lesions of 40 consecutive patients (mean age 70.4 +/- 8.2 years) were retrospectively analyzed. Easy Wall stent was applied in 15 lesions and SMART stent in 29 lesions. We investigated correlations between the occurrence rate of postoperative hypotension below 90 mmHg and persisting over three hours and findings of preoperative angiograms, ultrasonograms and clinical characteristics. Postprocedural hypotension occurred in 19 patients (47.5%) and medical treatment (intravenous administration of catecholamines) was required in eleven patients (27.5%). Although there was no permanent neurological deficits related with postprocedural hypotension, transient neurological deficits were found in three patients. Risk factors of prolonged postprocedural hypotension were statistically analyzed. On angiographic characteristics; 1) distance between the carotid bifurcation and the lesion with maximum stenosis ( 10 mm: p=0.031), 2) type of stenosis (eccentric vs. concentric: p=0.014) On ultrasonographic characteristics; 1) calcifications at the carotid bifurcation (present vs. absent: p < 0.001). Other variables, including age and degree of stenosis, were not associated with postprocedural hypotension after carotid stenting. These angiographic and ultrasonographic variables can be used to identify patients at risk for postprocedural hypotension after carotid stenting. Such identification may help in selection of patients who will benefit from appropriate pharmacological treatment.

I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat.

I.V. delivery of mesenchymal stem cells prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischemia models. Administration of the brain-derived neurotrophic factor to the infarction site has also been demonstrated to be neuroprotective. To test the hypothesis that brain-derived neurotrophic factor contributes to the therapeutic benefits of mesenchymal stem cell delivery, we compared the efficacy of systemic delivery of human mesenchymal stem cells and human mesenchymal stem cells transfected with a fiber-mutant F/RGD adenovirus vector with a brain-derived neurotrophic factor gene (brain-derived neurotrophic factor-human mesenchymal stem cells). A permanent middle cerebral artery occlusion was induced by intraluminal vascular occlusion with a microfilament. Human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells were i.v. injected into the rats 6 h after middle cerebral artery occlusion. Lesion size was assessed at 6 h, 1, 3 and 7 days using MR imaging, and histological methods. Functional outcome was assessed using the treadmill stress test. Both human mesenchymal stem cells and brain-derived neurotrophic factor-human mesenchymal stem cells reduced lesion volume and elicited functional improvement compared with the control sham group, but the effect was greater in the brain-derived neurotrophic factor-human mesenchymal stem cell group. ELISA analysis of the infarcted hemisphere revealed an increase in brain-derived neurotrophic factor in the human mesenchymal stem cell groups, but a greater increase in the brain-derived neurotrophic factor-human mesenchymal stem cell group. These data support the hypothesis that brain-derived neurotrophic factor contributes to neuroprotection in cerebral ischemia and cellular delivery of brain-derived neurotrophic factor can be achieved by i.v. delivery of human mesenchymal stem cells.

[Two cases of "steal VBI" with stenosis of the internal carotid artery].

Although previous reports have suggested "steal VBI" due to occlusive carotid artery diseases, there have been no reports that clearly define "steal VBI" from the viewpoint of cerebral hemodynamics. The authors presented two cases with "steal VBI" due to severe stenosis of the internal carotid artery. Both patients had well-developed collateral circulation through the ipsilateral posterior communicating artery. Although no occlusive lesion was found in the vertebrobasilar system, blood flow studies revealed impaired hemodynamics in the contralateral occipital lobe, which fact correlated with their neurological deficit, visual field disturbance. Carotid stenting markedly corrected the stenotic lesions, leading to neurological improvement. Follow-up blood studies showed normalization of hemodynamics in the contralateral occipital lobe. The findings strongly suggest that carotid surgery or stenting can improve cerebral hemodynamics in the carotid systems, resolving "steal VBI" due to developed collaterals from the posterior to the anterior circulation.

Long-term prognosis of medically treated patients with internal carotid or middle cerebral artery occlusion: can acetazolamide test predict it?

BACKGROUND AND PURPOSE: The importance of hemodynamic parameters for predicting outcome in patients with occlusive carotid disease remains controversial. The present study was aimed at testing the hypothesis that regional cerebrovascular reactivity (rCVR) to acetazolamide can be a reliable predictor of subsequent ischemic stroke in medically treated patients with internal carotid artery or middle cerebral artery occlusion. METHODS: Seventy-seven symptomatic patients were enrolled in this prospective, longitudinal cohort study. All patients met inclusion criteria of cerebral angiography, no or localized cerebral infarction on MRI or CT, and no or minimal neurological deficit. Regional cerebral blood flow (rCBF) and rCVR to acetazolamide were quantitatively determined by (133)Xe SEPCT. All patients were categorized into 4 types on the basis of SPECT studies. RESULTS: During an average follow-up period of 42.7 months, 16 total and 7 ipsilateral ischemic strokes occurred. The annual risks of total and ipsilateral stroke in patients with decreased rCBF and rCVR were 35.6% and 23.7%, respectively, risks that are higher than those in other types of patients. When strokes were categorized into patients with and without decreased rCBF and rCVR, Kaplan-Meier analysis revealed that the risks of total and ipsilateral stroke in patients with decreased rCBF and rCVR were significantly higher than in those without (P<0.0001 and P=0.0001, respectively, log-rank test). Relative risk conferred by decreased rCBF and rCVR was 8.0 (95% CI, 1.9 to 34.4) for ipsilateral stroke and 3.6 (95% CI, 1.4 to 9.3) for total stroke. CONCLUSIONS: Decreased rCBF and rCVR to acetazolamide may identify a subgroup of patients who have a higher risk of subsequent ischemic stroke when treated medically.

Effects of surgical revascularization on peripheral artery aneurysms in moyamoya disease: report of three cases.

OBJECTIVE AND IMPORTANCE: The beneficial effects of surgical revascularization on rebleeding in moyamoya disease remain unclear. This report is intended to clarify the effects of surgical revascularization on peripheral artery aneurysms, which represent one of the causes of intracranial bleeding in moyamoya disease. CLINICAL PRESENTATION: Findings for three female patients who experienced intracranial bleeding are presented. Cerebral angiography revealed that intracranial bleeding resulted from the rupture of peripheral artery aneurysms arising from dilated collateral vessels such as the lenticulostriate artery. INTERVENTION: The patients successfully underwent superficial temporal artery-middle cerebral artery anastomosis combined with encephaloduromyoarteriosynangiosis. Angiography demonstrated obliteration of the peripheral artery aneurysms, together with the disappearance or decrease in caliber of the parent collateral arteries, after surgery. None of the patients experienced rebleeding during the follow-up period (up to 52 mo). CONCLUSION: The results strongly suggest that surgical revascularization potentially improves cerebral circulation and decreases hemodynamic stress on collateral vessels, obliterating peripheral artery aneurysms.

[Diagnosis of cerebral aneurysm using 3-dimensional digital subtraction angiography].

Recent rapid advancement in the technology of magnetic resonance angiography and 3-dimensional computed tomography angiography has opened the door to a less-invasive diagnostic routine for the treatment of cerebral aneurysms. However, from the viewpoint of decision making concerning which treatment to use; conservative therapy; surgical intervention; or endovascular treatment, much more precise information is necessary. Recent progress of rotation digital subtraction angiography has introduced 3-dimensional digital subtraction angiography. In the past year, 28 cases involving 39 aneurysms have been studied using 3-dimensional angiography. This study was carried out, using a rotating C-arm, which rotates 220 degrees in 5.8 seconds. All raw data gathered was transferred to the workstation for image reconstruction. The purpose of this study was to evaluate the clinical potential of 3-dimensional digital subtraction angiography for the diagnosis of the cerebral aneurysms.

Cerebral revascularization for moyamoya disease in children.

Ninety-four patients with moyamoya disease (56 in the pediatric age group and 38 adults) were treated by revascularization surgery in the past 21 years (1979--2000). Combined surgery of the superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis and indirect revascularization of encaphalo-duro-arterio-myo-synangiosis (EDAMS) was performed. Ischemic attacks disappeared in most patients within 1 year (mean) after surgery in pediatric cases. No morbidity or mortality was experienced in the pediatric group. Some children with cerebral infarction before the surgery, however, had mild mental retardation even after the surgery. Early diagnosis and proper prophylactic surgical treatment is indispensable for pediatric patients with moyamoya. MR angiography is an important diagnostic modality for the screening and longitudinal follow-up of moyamoya disease.

Enhanced late components of AEFs associated with the temporal lobe lesions.

We recorded auditory evoked magnetic fields (AEFs) by presenting pure tone bursts once every 4000 ms in 11 patients with a brain lesion in or in the vicinity of the auditory cortex. AEFs on the damaged side revealed several enhanced deflections in late-latency AEFs (slow AEFs), peaking at approximately 320 (DI), 1030 (D2) and 1600 (D3) ms post-stimulus in eight patients. All the dipoles of slow AEFs were concentrated in the superior temporal regions which were not involved by brain lesions. D1, D2 and D3 dipoles were uniformly upward, downward and upward, respectively. The dipole moment varied from 12 to 122 nAm and had no consistent relationship with latency. This is the first report describing slow AEFs in cases with temporal lobe lesions.

Intraoperative measurement of arterial blood flow using a transit time flowmeter: monitoring of hemodynamic changes during cerebrovascular surgery.

BACKGROUND: The purpose of this study was to examine the utility and reliability of arterial flow measurements made with a transit time ultrasonic flowmeter for monitoring blood flow changes during intracranial and carotid surgery. METHOD: A total of 25 patients underwent intra-operative arterial blood flow measurements. The pulsatile flow curve and mean flow values were obtained using 1- to 6-mm transit time probes with a dual channel flowmeter. Four cases underwent aneurysm clipping, 11 cases superficial temporal artery (STA)--middle cerebral artery (MCA) bypass, 2 cases external carotid artery (ECA)--radial artery--MCA bypass for aneurysm trapping, and 8 cases carotid endarterectomy. In aneurysm clipping, blood flow in the branches distal to the aneurysm was measured before and after clipping. Blood flow in the STA was measured before and after STA-MCA anastomosis, and blood flow in the internal carotid artery (ICA) cervical portion was measured during carotid endarterectomy. Blood flow in the MCA and STA was monitored during radial artery grafting. FINDINGS: Blood flow in the STA was elevated after STA-MCA anastomosis. However, post-operative hyperperfusion syndrome was found in some cases whose flow elevation was over 50 ml/min. Also in one case of carotid stenosis, of which blood flow of ICA was elevated to 400 ml/min after carotid endarterectomy, hyperperfusion syndrome was found after surgery. In the cases of MCA aneurysm clipping, decreasing of M2 flow was detected when clipping caused bifurcation stenosis. INTERPRETATION: We found transit time flow measurement useful for management of cerebrovascular surgery: the technique was simple to use and provided stable, reliable results. The method was able to reveal distal branch flow diminution in aneurysm clipping, or residual flow during temporary clipping in aneurysm surgery, and has the potential to predict post-operative complications such as hyperperfusion by signalling over-elevation of donor artery flow in bypass surgery or ICA flow in carotid surgery.

Treatment outcome of single or hypofractionated single-isocentric stereotactic irradiation (STI) using a linear accelerator for intracranial arteriovenous malformation.

BACKGROUND AND PURPOSE: We investigated the use of hypofractionated stereotactic radiotherapy (HFSR) to reduce adverse radiation effects in comparison to single-fraction stereotactic radiosurgery (SRS) for intracranial arteriovenous malformations (AVMs). MATERIALS AND METHODS: This study includes 53 intracranial AVMs treated between 1991-1998. HFSR was selected for 26 AVMs with a maximum diameter > or 2.5 cm or at eloquent area. Twenty-seven patients were treated with SRS (18 AVMs < 2.5 cm at non-eloquent area, nine patients who were unfit for prolonged ring-wearing). The most frequent minimum dose (Dmin) was 20 Gy for SRS and 28 Gy for HFSR in four fractions. The mean follow-up duration was 34.6 months for SRS and 35.4 months for HFSR. RESULTS: As a whole, the 3 and 5-year actuarial obliteration rates were 64 and 92%. Age <20 years old (P=0.02) and a maximum diameter <2 cm were favorable factors (P=0.05). A difference in the distribution of patients was observed in size (> or =2.5 cm or not) (P<0.001) and location (eloquent or not) (P<0.001) between SRS and HFSR due to the treatment selection. However, no significant differences were observed in the actuarial rates of obliteration and transient increased signals with T2-weighted MR images between SRS and HFSR. Radiation necrosis occurred in two patients treated with SRS and in none with HFSR. Intracranial hemorrhage after treatment happened in two treated with SRS and three with HFSR. CONCLUSIONS: HFSR appears to be at least as effective as SRS in achieving complete obliteration of intracranial AVM, although its definitive role remains to be investigated.