Abstract: Recently, we have reported that a vasoactive peptide adrenomedullin promotes angio/arteriogenesis and prevents cognitive decline after chronic cerebral hypoperfusion in mice. Adrenomedullin upregulated brain levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor, although the regulation mechanism needs to be determined. In this study, we showed that VEGF neutralization partially suppressed adrenomedullin-induced neovascularization and cognitive restoration in vivo. In-vitro, adrenomedullin promoted capillary tube formation of the cultured endothelium, whereas VEGF neutralization abolished these effects. Adrenomedullin was found to upregulate VEGF and basic fibroblast growth factor through the adrenomedullin receptor and the phosphatidylinositol 3-kinase pathway. These results suggest that adrenomedullin has potential as therapy for dementia through enhancement of functional vascular growth.
Abstract: Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia.
Abstract: Autosomal dominant lateral temporal lobe epilepsy (ADLTE) caused by LGI1 (leucine-rich gene, glioma-inactivated-1) mutations is a rare familial epileptic syndrome characterized by the auditory ictal manifestation and rare nocturnal generalized seizures. We have examined the sequence of the LGI1 gene in four Japanese families with lateral temporal lobe epilepsy having characteristic auditory features, and identified one novel (1421G>A), and one reported (1418C>T) point mutation each in two families. These two mutations were 3 bp apart in the LGI1 gene and caused adjoining amino acid substitutions. The two families presented different clinical phenotypes and seizure control to drug treatment. These findings suggest that LGI1 mutations in Japanese ADLTE families may not be uncommon, and that diverse clinical phenotypes make adequate diagnosis of ADLTE difficult when only based on clinical information.
Abstract: BACKGROUND AND PURPOSE: We have previously described effects of chronic cerebral hypoperfusion in mice with bilateral common carotid artery stenosis (BCAS) using microcoils for 30 days. These mice specifically exhibit working memory deficits attributable to frontal-subcortical circuit damage without apparent gray matter changes, indicating similarities with subcortical ischemic vascular dementia. However, as subcortical ischemic vascular dementia progresses over time, the longer-term effects that characterize the mouse model are not known. METHODS: Comprehensive behavioral test batteries and histological examinations were performed in mice subjected to BCAS for up to 8 months. Laser speckle flowmetry and (18)F-fluorodeoxyglucose positron emission tomography were performed to assess cerebral blood flow and metabolism at several time points. RESULTS: At 2 hours after BCAS, cerebral blood flow in the cerebral cortex temporarily decreased to as much as 60% to 70% of the control value but gradually recovered to >80% at 1 to 3 months. At 5 to 6 months after BCAS, reference and working memory were impaired as demonstrated by the Barnes and radial arm maze tests, respectively. Furthermore, (18)F-fluorodeoxyglucose positron emission tomography demonstrated that hippocampal glucose utilization was impaired at 6 months after BCAS. Consistent with these behavioral and metabolic abnormalities, histological analyses demonstrated hippocampal atrophy with pyknotic and apoptotic cells at 8 months after BCAS. CONCLUSIONS: These results suggest that the longer-term BCAS model replicates advanced stages of subcortical ischemic vascular dementia when hippocampal neuronal loss becomes significant.
Abstract: BACKGROUND AND PURPOSE: The effect of telmisartan, an angiotensin II Type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma-modulating activity, was investigated against spatial working memory disturbances in mice subjected to chronic cerebral hypoperfusion. METHODS: Adult C57BL/6J male mice were subjected to bilateral common carotid artery stenosis using external microcoils. Mice received a daily oral administration of low-dose telmisartan (1 mg/kg per day), high-dose telmisartan (10 mg/kg per day), or vehicle with or without peroxisome proliferator-activated receptor-gamma antagonist GW9662 (1 mg/kg per day) for all treatments for 30 days after bilateral common carotid artery stenosis. Cerebral mRNA expression of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha was measured 30 days after bilateral common carotid artery stenosis, and postmortem brains were analyzed for demyelinating change with Klüver-Barrera staining and immunostained for glial, oxidative stress, and vascular endothelial cell markers. Spatial working memory was assessed by the Y-maze test. RESULTS: Mean systolic blood pressure and cerebral blood flow did not decrease with low-dose telmisartan but significantly decreased with high-dose telmisartan. Low-dose telmisartan significantly attenuated, but high-dose telmisartan provoked, spatial working memory impairment with glial activation, oligodendrocyte loss, and demyelinating change in the white matter. Such positive effects of low-dose telmisartan were partially offset by cotreatment with GW9662. Consistent with this, low-dose telmisartan reduced the degree of oxidative stress of vascular endothelial cells and the mRNA levels of monocyte chemoattractant protein-1 and tumor necrosis factor-alpha compared with vehicle. CONCLUSIONS: Anti-inflammatory and antioxidative effects of telmisartan that were exerted in part by peroxisome proliferator-activated receptor-gamma activation, but not its blood pressure-lowering effect, have protective roles against cognitive impairment and white matter damage after chronic cerebral hypoperfusion.
Abstract: BACKGROUND AND PURPOSE: To investigate the efficacy of bone marrow mononuclear cell (BMMNC) treatment against ischemic white matter (WM) damage in a hypoperfused brain. METHODS: Mice were administered intravenous treatment of vehicle, spleen-derived marrow mononuclear cells (MNCs), or BMMNCs (5×10(6) cells) obtained from enhanced green fluorescent protein transgenic mice 24 hours after bilateral common carotid artery stenosis (BCAS), and then euthanized at either 1 day or 30 days after treatment. RESULTS: Laser speckle perfusion imaging analyses revealed marked recovery of cerebral blood flow (CBF) in the early phase after BMMNC treatment (6 hours after administration), before histological evidence of angiogenesis was assessed by fluorescein-isothiocyanate-dextran perfusion assay. BMMNC treatment induced an increase in vascular endothelial growth factor and Ser1177 phosphorylated endothelial nitric oxide synthase levels in the BCAS-induced mouse brains at 1 day after the treatment. BCAS-induced ischemic WM lesions were significantly improved 30 days after BMMNC treatment despite any evidence of direct structural incorporation of donor BMMNCs into endothelial cells and oligodendrocytes. Instead, enhanced green fluorescent protein-positive donor cells with morphological features of pericytes were observed in the vessel walls. Post-BMMNC administration of an NOS inhibitor abolished early CBF recovery and produced protective effects against ischemic WM damage. CONCLUSIONS: BMMNC treatment provides marked protection against ischemic WM damage, enhancing CBF in the early phase and in subsequent angiogenesis, both of which involve nitric oxide synthase activation. These findings suggest promise for the application of BMMNCs for subcortical ischemic vascular dementia.
Abstract: Cortical microinfarcts are reported in Alzheimer's disease, but not in subcortical vascular dementia; the disease specificity of cortical microinfarcts therefore remains unclear. The distribution of cortical microinfarcts in Alzheimer's disease (n = 8) and subcortical vascular dementia (n = 6) was analyzed. Cortical microinfarcts were frequently detected in Alzheimer's disease, whereas they were rarely observed in subcortical vascular dementia. In Alzheimer's disease, cortical microinfarcts were present predominantly in the occipital lobe, the area of predilection for amyloid angiopathy, and also in the vascular borderzone. Cortical microinfarcts were invariably located very close to amyloid beta-deposited vessels with intercellular adhesion molecule-1 expression. These results indicate that cortical microinfarcts are caused by the pathomechanism related to Alzheimer's disease, most likely to amyloid angiopathy.
Abstract: A 34-year-old man with astrocytoma in the left parietal lobe had symptomatic partial epilepsy, and he presented transient episodes of acalculia, agraphia and finger agnosia. Occasionally he had difficulty in finding appropriate letters when making an e-mail, and difficulty in writing and calculation. Neurological examinations revealed ictal symptoms of Gerstmann's syndrome without right to left disorientation. No other higher cortical dysfunction or neurological deficits were noted. Scalp EEGs showed frequent, regional ictal discharges in the left parietal area lasting for 60-240 seconds. These clinico-electrographical observations strongly support that epileptic seizures produced a loss of cortical higher function manifesting Gerstmann's syndrome.
Abstract: Small-vessel pathology is believed to have a critical role in cerebrovascular white-matter (WM) lesions. However, the cellular aspect of vascular pathology, including the phenotypic modulation of smooth-muscle cells (SMCs) and its role in the small-vessel disease, remains undefined. The involvement or otherwise of the phenotypic modulation of SMCs in cerebral small-vessel pathology has been investigated, and the effect of cilostazol on both the small vessels and the WM lesions has been determined in stroke-prone spontaneously hypertensive rats (SHRSP). Male SHRSP and Wistar Kyoto rats were used. SHRSP were divided into two groups: the cilostazol-treated (20-week treatment) and vehicle-treated groups. Small-vessel pathology was analyzed using both histopathology and immunohistochemistry for smooth-muscle actin and nonmuscle myosin heavy chain (SMemb, a marker for the synthetic phenotype of SMC). The pathological changes in the WM were quantified in terms of the numerical density of activated microglia and the degree of WM lesions. Vascular wall thickening and perivascular fibrosis, determined by the wall area/lumen area ratio and the collagen area/total vessel area ratio, respectively, showed an increase in the vehicle-treated SHRSP, and this increase was significantly attenuated by cilostazol treatment. The percentage of small vessels immunopositive for SMemb was also reduced by cilostazol treatment. In the cilostazol-treated SHRSP, microglial activation and the degree of WM lesions were attenuated compared with the vehicle-treated SHRSP. The results indicated that cilostazol attenuates the phenotypic modulation of SMC associated with cerebral small-vessel pathology and WM lesions without causing changes in the blood pressure.
Abstract: BACKGROUND AND PURPOSE: We recently designed a mouse model of chronic cerebral hypoperfusion, in which the cerebral white matter is damaged without significant gray matter lesions. The behavioral characteristics of these mice were studied using a test battery for neurological and cognitive functions. METHODS: Adult C57Bl/6 male mice were subjected to either sham-operation or bilateral common carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm. At 30 days after BCAS, 70 animals were divided into 3 groups and subjected to behavioral test batteries. The first group underwent comprehensive behavioral test, including the neurological screen, prepulse inhibition, hot plate, open field, light/dark transition, Porsolt forced swim and contextual and cued fear conditioning (BCAS n=13; sham-operated n=11). The second group was for the working memory task of the 8-arm radial maze test (BCAS n=12; sham-operated n=10), and the third for the reference memory task of the 8-arm radial maze test (BCAS n=13; sham-operated n=11). Another batch of animals were examined for histological changes (BCAS n=11; sham-operated n=12). RESULTS: The white matter including the corpus callosum was consistently found to be rarefied without clear ischemic lesions in the hippocampus. No apparent differences were observed in the comprehensive test batteries between the control and BCAS mice. However, in the working memory tasks tested with the 8-arm radial maze, the BCAS mice made significantly more errors than the control mice (P<0.0001). Again, there were no detectable differences in the reference memory tasks between the groups. CONCLUSIONS: At 30 days after BCAS, working memory deficits as well as white matter changes were apparent in the mice. Working memory deficit was attributable to damage of the frontal-subcortical circuits, suggesting the BCAS model is useful to evaluate the substrates of subcortical vascular dementia.
Abstract: We present a patient with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who developed severe bladder and bowel dysfunction (BBD) as evidenced by constipation, voiding difficulty, and urinary urgency. These symptoms appeared 10 years after onset of CIDP. Cystometry showed disturbance of bladder sensation and detrusor areflexia. Magnetic resonance imaging (MRI) showed greatly enlarged nerve roots filling the lumbosacral spinal canal; this appeared to be the likely cause of BBD. A 3-day course of intravenous methylprednisolone (1 g/day), followed by 30 mg/day of oral prednisolone, ameliorated the sensory disturbance and muscle weakness, but not BBD.
Abstract: We report a case of a 70-year-old man who developed Churg-Strauss syndrome (CSS), diagnosed by characteristic histological findings, clinical presentations of mononeuritis multiplex, and multiple small intestinal ulcers with perforations, after discontinuation of corticosteroid therapy. The patient had developed asthma at age of 45, treated with oral prednisolone (10-20 mg daily) from that time. At the age of 70 he developed pneumonia. The condition responded to antibiotics, and the corticosteroid was quickly tapered and discontinued. He was never given leukotriene receptor antagonists during the course of treatment. Approximately two weeks after discontinuation of steroid therapy, he developed severe abdominal pain and mononeuritis multiplex, confirmed by nerve conduction studies. Laboratory evaluation revealed an eosinophil count of 30,450/microliter, and P-antineutrophil cytoplasmic antibody (ANCA) was positive. An abdominal CT scan revealed free air in the abdominal cavity. Laparotomy revealed multiple small intestinal ulcers with perforations. Histologic examination of the intestine showed eosinophilic vasculitis and fibrinoid necrosis. Treatment with systemic corticosteroid (prednisolone 60 mg daily) led to a clinical improvement of neurological and gastroenterological deficits. The prednisolone dose was tapered to 20 mg daily without disease flares. Recently, there have been several reports of CSS that manifested after withdrawal of steroid therapy. CSS can be precipitated in patients with adult-onset, steroid-dependent bronchial asthma after corticosteroid withdrawal.
