Phil Hyu Lee

Autologous mesenchymal stem cell transplantation in stroke patients.

Mesenchymal stem cell (MSC) transplantation improves recovery from ischemic stroke in animals. We examined the feasibility, efficacy, and safety of cell therapy using culture‐expanded autologous MSCs in patients with ischemic stroke. We prospectively and randomly allocated 30 patients with cerebral infarcts within the middle cerebral arterial territory and with severe neurological deficits into one of two treatment groups: the MSC group (n = 5) received intravenous infusion of 1 × 108 autologous MSCs, whereas the control group (n = 25) did not receive MSCs. Changes in neurological deficits and improvements in function were compared between the groups for 1 year after symptom onset. Neuroimaging was performed serially in five patients from each group. Outcomes improved in MSC‐treated patients compared with the control patients: the Barthel index (p = 0.011, 0.017, and 0.115 at 3, 6, and 12 months, respectively) and modified Rankin score (p = 0.076, 0.171, and 0.286 at 3, 6, and 12 months, respectively) of the MSC group improved consistently during the follow‐up period. Serial evaluations showed no adverse cell‐related, serological, or imaging‐defined effects. In patients with severe cerebral infarcts, the intravenous infusion of autologous MSCs appears to be a feasible and safe therapy that may improve functional recovery. Ann Neurol 2005;57:874–882

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 ± 4.0 pg/ml, p < 0.001) and in those with MSA (78.1 ± 3.5 pg/ml, p = 0.019) compared with the level in controls (76.1 ± 3.9 pg/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.

Frequency and mechanisms of stroke recurrence after cryptogenic stroke

The purpose of this study was to better understand the frequency and mechanisms of stroke recurrence after the stroke with no determined cause (NC). We prospectively studied consecutive patients with acute cerebral infarcts. We divided the patients into five groups (large artery disease [LAD], cardioembolism [CE], small artery disease [SAD], two or more causes [TMC], and NC) and registered recurrent strokes and prognosis for 1 year. Those in the NC group were compared with other subtypes. A total of 204 patients were included; 56 LAD, 22 CE, 62 SAD, 27 TMC, and 37 NC. During follow‐up, there were 7 deaths and 31 first recurrent strokes. Patients of the NC group showed a significantly higher rate (30%) of recurrent stroke than those of other subtypes (LAD 16%; CE 14%; SAD 2%), and it was associated with the existence of mild stenosis (≤50%) on relevant artery or the stenosis of greater than 50% on nonrelevant artery. Occlusive lesions other than significant stenosis of relevant artery may play an important role in the development of stroke recurrence in patients of the NC group. Therefore, from the therapeutic and prognostic point of view, the detection of such occlusive lesions in patients with cryptogenic stroke may be needed.Ann Neurol 2003

Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action.

Epidemiological studies have reported that smoking is associated with a lower incidence of Parkinsons disease (PD), leading to theories that smoking in general and nicotine in particular might be neuroprotective. Recent studies suggested cholinergic anti‐inflammatory pathway‐regulating microglial activation through α7 nicotinic receptors. In the present study, we used lipopolysaccharide (LPS)‐induced in vitro and in vivo inflammation models to investigate whether nicotine has a protective effect on the dopaminergic system through an anti‐inflammatory mechanism. Nicotine pretreatment considerably decreased microglial activation with significant reduction of tumour necrosis factor (TNF)‐α mRNA expression and TNF‐α release induced by LPS stimulation. In co‐cultures of microglia and mesencephalic neurons, nicotine pretreatment significantly decreased the loss of tyrosine hydroxylase‐immunopositive (TH‐ip) cells, approximately twice more than the LPS‐only treatment. α‐Bungarotoxin, an α7 nicotinic acetylcholine receptor subunit‐selective blocker, considerably blocked the inhibitory effects of nicotine on microglial activation and TH‐ip neuronal loss. Chronic nicotine pretreatment in rats showed that TH‐ip neuronal loss induced by LPS stimulation in the substantia nigra was dramatically decreased, which was clearly accompanied by a reduction in the formation of TNF‐α. The present study demonstrated that nicotine has a neuroprotective effect on dopaminergic neurons via an anti‐inflammatory mechanism mediated by the modulation of microglial activation. Along with various neuroprotective effects of nicotine, the anti‐inflammatory mechanism of nicotine could have a major therapeutic implication in the preventive treatment of PD.

A comparison of cerebral glucose metabolism in Parkinson's disease, Parkinson's disease dementia and dementia with Lewy bodies

Parkinsons disease dementia (PDD) and dementia with Lewy bodies (DLB) share many similar aspects, and making a clinical diagnosis of one disorder over the other relies heavily on an arbitrary criterion, so‐called 1‐year rule. This study was designed to search for any difference of metabolic patterns in these two disorders using F‐18 fluorodeoxyglucose (FDG) positron emission tomography (PET) images.

Internal and Cortical Border-Zone Infarction Clinical and Diffusion-Weighted Imaging Features

Background and Purpose— The pathogenesis of internal border-zone (IBZ) and cortical border-zone (CBZ) infarcts is unclear. Both types of infarct have been combined into a single group in most previous reports, which has produced conflicting results. We hypothesized that different pathogenic mechanisms underlie IBZ and CBZ infarcts. Methods— We reviewed 946 consecutive patients with ischemic stroke within the middle cerebral artery territory. IBZ and CBZ infarcts were selected based on diffusion-weighted imaging templates to identify vascular territories. Baseline patient characteristics, clinical courses, and neuroradiological features were compared between patients with IBZ and CBZ infarcts. Results— We identified 45 IBZ and 75 CBZ infarct patients. Compared with the CBZ infarct patients, IBZ infarct patients had a higher degree of stenosis or occlusion in either the middle cerebral or internal carotid artery (P=0.008) and exhibited a rosary-like pattern of infarction more frequently (P<0.001). In contrast, concomitant small cortical infarcts were observed more frequently in CBZ infarct patients (P<0.001). Clinical deterioration during the first 7 days of admission and poor outcome after 3 months after stroke was more prevalent in IBZ infarct patients than in CBZ infarct patients (P=0.002 and P=0.003, respectively). Conclusions— IBZ infarcts are caused mainly by hemodynamic compromise, whereas embolic pathogenesis appears to contribute greatly to the genesis of CBZ infarcts. Patients with IBZ infarcts showed poor early and late clinical courses. Our findings suggest that different therapeutic approaches may be required to prevent early clinical deterioration in patients with different types of border-zone infarcts.

Correlation between cardiac 123I-MIBG and odor identification in patients with Parkinson's disease and multiple system atrophy

We investigated an association between olfaction and cardiac 123I‐metaiodobenzylguanidine (MIBG) uptake in patients with Parkinsons disease (PD) and multiple system atrophy (MSA). There was a significant positive correlation between cardiac MIBG uptake and the Cross‐Cultural Smell Identification (CCSI) score in patients with PD (r = 0.56; P = 0.003) independent of the disease duration or clinical rating of motor status. However, patients with MSA did not show a significant correlation between cardiac MIBG uptake and the CCSI score. Our findings suggest that the functional losses of the olfactory and cardiac sympathetic systems are closely coupled in PD.

Mesenchymal Stem Cells for Ischemic Stroke: Changes in Effects After Ex Vivo Culturing

Although ex vivo culture expansion is necessary to use autologous mesenchymal stem cells (MSCs) in treating stroke patients, and several researchers have utilized culture-expanded cells in their studies, the effects of culture expansion on neurogenesis and trophic support are unknown. Thus, we evaluated the impact of the passage of MSCs on their effects in a rat stroke model. The IV application of ex vivo-cultured human MSCs, earlier (passage 2) or later passage (passage 6), was performed in a rat stroke model. Behavioral tests, immunohistochemical studies, and quantitative analysis using the CAST-grid system were performed to evaluate the degree of neurogenesis. We also evaluated the levels of trophic factors in both control and MSC-treated rat brain extract. Compared to rats that received later-passage human MSCs, behavioral recovery and neurogenesis as revealed by bromodeoxyuridine staining were more pronounced in rats that received earlier-passage human MSCs (p < 0.01 in both cases). Double staining showed that most of the endogenous neuronal progenitor cells, but few human MSCs, expressed neuronal and glial phenotypes. Tissue levels of trophic factors, including glial cell line-derived neurotrophic factor, nerve growth factor, vascular endothelial growth factor, and hepatocyte growth factor, were higher in earlier-passage MSC-treated brains than in control or later-passage MSC-treated brains (p < 0.01 in all cases). Our results indicate that ischemia-induced neurogenesis was enhanced by the IV administration of human MSCs. The effects were more pronounced with earlier-passage than with later-passage human MSCs, which may be related to the differential capacity in trophic support, depending on their passage.

Circulating beta amyloid protein is elevated in patients with acute ischemic stroke

Summary.Recent clinical and experimental studies suggest that ischemic strokes may play an important role in the pathogenesis of Alzheimer’s disease (AD). Beta amyloid (Aβ), a major component of senile plaque in AD, is known to be derived from ischemic brain or activated platelets. We prospectively enrolled 62 patients with acute ischemic stroke and 27 age-matched controls. The serum Aβ and P-selectin levels were determined using the Sandwich-ELISA. We divided ischemic strokes into subgroups according to the clinical syndrome, pathogenesis, and infarct size, and compared the Aβ level between each subgroup. The Aβ1–40 level was markedly elevated in ischemic stroke patients, as compared to controls (140.2 ± 54.0 vs 88.44 ± 34.96 pg/ml, p<0.001). Cardioembolic and larger artery atherosclerotic infarcts had higher Aβ1–40 level than small vessel disease (p = 0.001). Both infarct size and the initial NIHSS score had significantly positive correlations with the serum level of Aβ1–40 (r = 0.539, p<0.001 and r = 0.425, p = 0.001, respectively). However, the P-selectin level was not significantly correlated with serum Aβ1–40. Our data suggest that elevated circulating Aβ1–40 in ischemic stroke patients may be derived from brain as a consequence of ischemic insults.