In-Soo Joo

Autologous Mesenchymal Stem Cell Therapy Delays the Progression of Neurological Deficits in Patients With Multiple System Atrophy

We evaluated the feasibility and safety of therapy with mesenchymal stem cells (MSCs) through consecutively intra‐arterial and three repeated intravenous injections and compared the long‐term prognosis between MSC‐treated (n=11) and control multiple system atrophy (MSA) patients (n=18). The MSC‐treated patients showed significantly greater improvement on the unified MSA rating scale (UMSARS) than the control patients at all visits throughout the 12‐month study period. Orthostasis in UMSARS I items and cerebellar dysfunction‐related items of UMSARS II items were significantly different in favor of MSC treatment compared to controls. Serial positron emission tomography scan in the MSC‐treated group showed that increased fluorodeoxyglucose uptake from baseline was noted in cerebellum and frontal white matters. No serious adverse effects related to MSC therapy occurred. This study demonstrated that MSC therapy in patients with MSA was safe and delayed the progression of neurological deficits with achievement of functional improvement in the follow‐up period.

The plasma alpha-synuclein levels in patients with Parkinson's disease and multiple system atrophy.

Summary.α-Synuclein, a synaptic protein of unknown function, is a major component of Lewy bodies and may play a role in the pathophysiological process of Parkinson’s disease (PD). In this study, we measured the plasma α-synuclein levels in 105 patients with PD, 38 patients with multiple system atrophy (MSA), and 51 age-matched controls. The α-synuclein level was significantly elevated in patients with PD (79.9 ± 4.0u2009pg/ml, p < 0.001) and in those with MSA (78.1 ± 3.5u2009pg/ml, p = 0.019) compared with the level in controls (76.1 ± 3.9u2009pg/ml). The α-synuclein level was higher in patients with PD than in those with MSA (79.9 ± 4.0 vs 78.1 ± 3.5, p = 0.016). Our study demonstrated that the α-synuclein level in plasma is elevated in patients with PD and MSA.

Ginsenoside Rb1 and Rg1 Improve Spatial Learning and Increase Hippocampal Synaptophysin Level in Mice

We investigated the cognition enhancing effects of ginsenoside Rb1 and Rg1. Mice were trained in a Morris water maze following injection (i.p.) of Rb1 (1 mg/kg) or Rg1 (1 mg/kg) for 4 days. Both Rb1‐ and Rg1‐injected mice showed enhanced spatial learning compared to control animals. The hippocampus, but not the frontal cortex, of treated mice contained higher density of a synaptic marker protein, synaptophysin, compared to control mice. Electrophysiological recordings in hippocampal slices revealed that Rb1 or Rg1 injection did not change the magnitude of paired‐pulse facilitation or long‐term potentiation. Our results suggest that Rb1 and Rg1 enhance spatial learning ability by increasing hippocampal synaptic density without changing plasticity of individual synapses. J. Neurosci. Res. 63:509–515, 2001.

Estrogen blocks neurotoxic effects of β-amyloid (1–42) and induces neurite extension on B103 cells

Clinical studies have shown that estrogen replacement therapy is associated with reduced risk of Alzheimers disease (AD). We tested whether or not estrogen blocks neurotoxic effects of beta-amyloid (1-42) (A beta1-42) on cultured B103 cells. A beta1-42 (1 microM) induced typical necrotic cell death, as revealed by light and electron microscopic examinations. Co-administration of estrogen not only blocked A beta1-42 toxicity to a large degree, but also enhanced neurite extension. Pretreatment with estrogen was even more effective in blocking A beta1-42 toxicity. When added 18 h after the beginning of A beta1-42 treatment, estrogen was still effective in halting the progress of cell death and enhancing neurite extension. The protection against A beta1-42-induced neuronal death by estrogen was unlikely due to a blockade of lipid peroxidation injury, since estrogen completely failed to attenuate ferrous chloride-induced cell death. These results demonstrate that estrogen blocks A beta1-42-induced neurotoxicity and enhances neurite extension on B103 cells, both of which may well be underlying mechanisms of beneficial effects of estrogen in AD.

Vertebral artery dominance contributes to basilar artery curvature and peri-vertebrobasilar junctional infarcts

Objectives: The diameters of the vertebral arteries (VAs) are very often unequal. Therefore, this study investigated if unequal VA flow contributes to the development of basilar artery (BA) curvature and if it is a link to the laterality of pontine or cerebellar infarcts occurring around the vertebrobasilar junction. Methods: Radiological factors were analysed (infarct laterality, VA dominance, BA curvature and their directional relationships) in 91 patients with acute unilateral pontine or posterior inferior cerebellar artery (PICA) territory infarcts. The “dominant” VA side was defined as either that the VA was larger in diameter or the VA was connected with the BA in more of a straight line, if both VAs looked similar in diameter on CT angiography. Multiple regression analysis was performed to predict moderate to severe BA curvature. Results: The dominant VA was more frequent on the left side (p<0.01). Most patients had an opposite directional relationship between the dominant VA and BA curvature (p<0.01). Pontine infarcts were opposite to the side of BA curvature (p<0.01) and PICA infarcts were on the same side as the non-dominant VA side (p<0.01). The difference in VA diameters was the single independent predictor for moderate to severe BA curvature (OR per 1 mm, 2.70; 95% CI 1.22 to 5.98). Conclusions: Unequal VA flow is an important haemodynamic contributor of BA curvature and development of peri-vertebrobasilar junctional infarcts.

Inflammatory markers, rather than conventional risk factors, are different between carotid and MCA atherosclerosis

Background: The apparent differences in risk factors for intra- and extracranial atherosclerosis are unclear and the mechanisms that underlie strokes in patients with intracranial atherosclerosis are not well known. We investigated the conventional vascular risk factors as well as other factors in stroke patients with large artery atherosclerosis. Methods: Using diffusion weighted imaging (DWI) and vascular and cardiologic studies, we selected patients with acute non-cardioembolic cerebral infarcts within the middle cerebral artery (MCA) territory. Patients were divided into two groups: those with atherosclerotic lesions on the carotid sinus (nu200a=u200a112) and those with isolated lesions on the proximal MCA (nu200a=u200a160). Clinical features, risk factors, and DWI patterns were compared between groups. Results: There were no differences in conventional risk factors, but markers for inflammation were significantly higher in patients with carotid atherosclerosis than in those with isolated MCA atherosclerosis (p<0.01 for both). After adjustments for age/sex and the severity of stroke, an inverse correlation was observed between C-reactive protein levels and MCA atherosclerosis (odds ratio 0.57 per 1 mg/dl increase; 95% confidence interval 0.35 to 0.92; pu200a=u200a0.02). Internal borderzone infarcts suggestive of haemodynamic causes were the most frequent DWI pattern in patients with MCA occlusion, whereas territorial infarcts suggesting plaque ruptures were most common in those with carotid occlusion. Conclusions: Our results indicate that inflammatory markers, rather than conventional risk factors, reveal clinical and radiological differences between patients with carotid and MCA atherosclerosis. Plaques associated with MCA atherosclerosis may be more stable than those associated with carotid atherosclerosis.

Cholinergic modulation of synaptic physiology in deep layer entorhinal cortex of the rat.

We have recently shown that cholinergic effects on synaptic transmission and plasticity in the superficial (II/III) layers of the rat medial entorhinal cortex (EC) are similar, but not identical, to those in the hippocampus (Yun et al. [ 2000 ] Neuroscience 97:671–676). Because the superficial and deep layers of the EC preferentially convey afferent and efferent hippocampal projections, respectively, it is of interest to compare cholinergic effects between the two regions. We therefore investigated the physiological effects of cholinergic agents in the layer V of medial EC slices under experimental conditions identical to those in the previous study. Bath application of carbachol (0.5 μM) induced transient depression of field potential responses in all cases tested (30 of 30; 18.5% ± 2.3%) and rarely induced long‐lasting potentiation (only 3 of 30; 20.4% ± 3.2% in successful cases). At 5 μM, carbachol induced transient depression only (20 of 20, 48.9% ± 2.8%), which was blocked by atropine (10 μM). Paired‐pulse facilitation was enhanced during carbachol‐induced depression, suggesting presynaptic action of carbachol. Long‐term potentiation (LTP) could be induced in the presence of 10 μM atropine by theta burst stimulation, but its magnitude was significantly lower (9.1% ± 4.7%, n = 15) compared to LTP in control slices (22.4% ± 3.9%, n = 20). These results, combined with our previous findings, demonstrate remarkably similar cholinergic modulation of synaptic transmission and plasticity across the superficial and deep layers of EC. J. Neurosci. Res. 66:117–121, 2001.

Isolated middle cerebral artery disease: clinical and neuroradiological features depending on the pathogenesis

Background: Isolated atherosclerotic middle cerebral artery (MCA) disease is often difficult to differentiate from cardioembolic disease if intracranial atherosclerosis coexists with cardiac disease. Objectives: To evaluate whether clinical and neuroradiological features of isolated MCA disease differ according to the underlying aetiology. Methods: Isolated MCA disease was defined as a unilateral angiographically occlusive lesion of the MCA on the symptomatic side without lesions of other intracranial or extracranial vessels. Patients with isolated MCA disease were divided into atherosclerotic and potentially cardioembolic, and the clinical, laboratory, and neuroradiological data analysed. Results: Among the 850 consecutive patients with acute ischaemic stroke or transient ischaemic attack, 107 (12.6%) met the criteria for isolated MCA disease (76 with atherosclerotic disease and 31 with a potential source of cardiac embolism). Total anterior circulation infarcts were more common and baseline NIHSS score was higher in potentially embolic occlusions than in atherosclerotic disease (each p<0.001). While cortical infarcts and territorial infarcts were more common in the potential embolism group (pu200a=u200a0.028 and p<0.001, respectively), subcortical border zone infarcts were more common in the atherosclerotic group (p<0.001). Multiple regression analysis showed that border zone infarcts and mild stroke were independently associated with atherosclerotic MCA disease, while territorial and cortical infarcts were associated with potential cardiac embolic disease. Conclusions: Clinical and neuroradiological characteristics can differentiate isolated atherosclerotic MCA disease from MCA disease associated with potential sources of cardiac embolism, and may reflect the differences in underlying pathogenesis.

Amyloid precursor protein processing is separately regulated by protein kinase C and tyrosine kinase in human astrocytes.

Regulation of amyloid precursor protein (APP) processing by protein kinase C (PKC) and phosphotyrosine pathways was investigated in cultured human astrocytes. Phorbol 12, 13-dibutyrate (PDBu), a PKC activator, increased secretion of APPalpha 2-3-fold over control values, and GF109203X, a PKC inhibitor, blocked this effect. Similarly, platelet derived growth factor (PDGF) increased the secreted form of APPalpha (sAPPalpha) level two-fold, and genistein, a tyrosine kinase inhibitor, blocked the stimulatory effect of PDGF. Co-treatment of PDGF and PDBu resulted in a five-fold increase in the sAPPalpha production, and genistein and GF109203X did not block the stimulatory effects of PDBu and PDGF, respectively. These results indicate that both PKC and phosphotyrosine pathways are involved in APP processing in human astrocytes, but they act independently. The two pathways appear to converge to mitogen-activated protein kinase (MAPK) because PD98059, a MAPK inhibitor, blocked the effects of PDBu and PDGF on APPalpha secretion.

Pathogenesis of deep white matter medullary infarcts: a diffusion weighted magnetic resonance imaging study

Background and Purpose: The pathogenesis of deep white matter medullary (WMM) artery infarcts remains controversial. To address this question, we analysed the stroke patterns of WMM infarcts using diffusion weighted magnetic resonance imaging (DWI) to detect embolic signals and investigate stroke subtypes according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classifications. Methods: We identified WMM infarcts on DWI using templates to determine the subcortical vascular territories. We classified WMM infarcts into those with small artery disease (SAD), large artery disease (LAD), cardioembolism (CE), two or more aetiologies, or undetermined aetiology. Clinical course, risk factors, and cortical spotty lesions were compared. Results: Of the 1420 consecutive patients, 103 (7.3%) met the criteria for WMM infarcts. The stroke subtypes were as follows: 65 (63.1%) patients with LAD, 18 (17.5%) with SAD, 12 (11.7%) with CE, four (3.9%) with two or more aetiologies, three (2.1%) with undetermined aetiology, and one (1.0%) with other determined aetiology. LAD (87.7%) or CE (83.3%) was significantly accompanied by cortical embolic signals as compared to SAD (0%, p<0.001). The LAD infarcts were larger and tended to be chain-like in shape. Ischaemic stroke recurrence was more common in strokes with cortical embolic signals than in those without embolic signals (18.9% v 0%, pu200a=u200a0.009). Conclusions: In present study, the most common pathogenesis of WMM infarcts was LAD. Our study indicates that WMM infarcts accompanying cortical embolic signals warrant evaluation of the underlying embolic sources in the large artery or the heart.