Coexistence of expanded CAG repeats in the MJD1a and DRPLA genes.
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Ataxin-3↗
Biomedical subjects
H Tomimoto
Publications and source records attributed to H Tomimoto.
Cyclooxygenase-2 is induced in microglia during chronic cerebral ischemia in humans.
Cyclooxygenase-2 (COX-2) is known to be up-regulated in ischemic rodent brains, but only little information is available for the human brain. Using immunohistochemistry for COX-2, we investigated brains from control subjects and from patients with cerebrovascular diseases. COX-2 was markedly up-regulated in the neurons and endothelial cells in acute cerebral infarction, but was detected sparsely at chronic stages in these cellular compartments. In contrast, COX-2 immunoreactivity in glial cells was localized to the perinuclear region even in control brains. This immunolabeling was more intense and occurred also in the glial cytoplasm in the brains with chronic cerebral ischemia such as Binswanger's disease. Double-labeling immunohistochemistry confirmed that COX-2-immunoreactive glia were mostly microglia. These results indicate that prostanoid synthesis is up-regulated in microglia during chronic cerebral ischemia, and that these cells may be involved in tissue repair or inflammation-mediated cell responses.
Aged↗
Vascular cell components of the medullary arteries in Binswanger's disease brains: a morphometric and immunoelectron microscopic study.
BACKGROUND AND PURPOSE: It has been hypothesized that fibrohyalinosis of the medullary arteries may cause white matter lesions in Binswanger's disease (BD). However, previous reports have been inconsistent on the pathological alterations of the cellular components, which may vary in terms of vessel sizes. We therefore quantitatively examined vasculopathy in the medullary arteries of a defined caliber in BD brains with a quantitative technique. METHODS: A total of 20 brains were examined: 10 from patients with BD and 10 from age-matched nonneurological control patients. The alterations in the vascular cell components were examined with quantitative immunohistochemistry and immunoelectron microscopy for collagen and smooth muscle actin. RESULTS: The nonneurological control patients showed no white matter lesions. In contrast, the patients with BD invariably had marked white matter lesions, as well as fibrohyalinosis of the medullary arteries. The ratio of the area immunolabeled for collagen type I and type IV to the cross-sectional area was 2-fold higher in the BD patients than in the control patients, regardless of the vessel caliber (P<0.005). Although the ratio for smooth muscle actin in the BD brains was increased in arteries of <100 microm (P<0.0001), there was no corresponding increase in the arteries of >100 microm. However, in the ultrastructure of these vessels, the cell bodies immunolabeled for smooth muscle actin were hypertrophic and segregated from each other by proliferated fibrils. The basal lamina appeared multilayered, and the endothelial cells were swollen. Collagen type I and type IV immunoreactive fibrils also proliferated in the pericapillary space of the BD brains. CONCLUSIONS: The proliferation of collagen fibrils in the media and adventitia of the blood vessels in BD brains was not specific to small arteries and arterioles but also occurred in the pericapillary spaces. Pericapillary sclerosis, smooth muscle cell proliferation in the terminal arterioles, and their morphological transformation in the proximal arteries may alter the shear rates and thus cause profound microcirculatory disturbances in BD brains.
Actins↗
Binswanger's disease: an ongoing controversy.
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Brain↗
Effects of an antithrombin drug in patients with subacute exacerbations of Binswanger disease.
The blood coagulation system has been shown to be activated in subacute exacerbations of Binswanger disease (BD). In our previous study, the antithrombin drug argatroban t ameliorated the neurological exacerbations in a BD patient with antiphospholipid antibody syndrome. We have further examined the therapeutic efficacy of argatroban in 3 BD patients with subacute exacerbations, but without any immune-mediated prothrombotic complications. In 1 out of these 4 patients, treatment with sodium ozagrel, an antiplatelet drug was applied, but was ineffective. In all patients, argatroban treatment reduced the levels of the hemostatic markers, with a corresponding improvement in cognitive dysfunction and gait disorders. These results suggest that the antithrombin effect is true also for BD patients not compromised by the immune-mediated prothrombotic condition.
Acute Disease↗
A cyclooxygenase-2 inhibitor attenuates white matter damage in chronic cerebral ischemia.
The effects of nimesulide, a cyclooxygenase-2 inhibitor, were examined during chronic cerebral hypoperfusion. After bilateral ligation of the common carotid arteries in 30 rats, 21 received dosages of 2 or 5 mg/kg nimesulide daily and nine received vehicle daily for 14 days. The serum was then analyzed biochemically, and pathological changes were estimated in the white matter by the emergence of major histocompatibility complex (MHC) antigen-immunoreactive activated microglia and white matter lesions. In the vehicle-treated animals, activated microglia and white matter lesions were observed. Following treatment with either 2 or 5mg/kg nimesulide, the magnitude of these changes was reduced (p < 0.001) without significant side effects. These results indicate a potential use for cyclooxygenase-2 inhibitors in cerebrovascular disease.
Analysis of Variance↗
Effects of antithrombin on Binswanger's disease with antiphospholipid antibody syndrome.
The authors present a family with Binswanger's disease (BD) and antiphospholipid antibody syndrome (APAS). In one patient from this family, lupus anticoagulant and high levels of hemostatic markers were detected. The presence of BD and the clinicobiological improvements observed after antithrombin treatment in this patient are peculiar to this familial case of APAS.
Antiphospholipid Syndrome↗
Coagulation activation in patients with Binswanger disease.
BACKGROUND: A hypercoagulable state is often associated with an acute stroke in cerebrovascular disease (CVD). However, in Binswanger disease (BD), no information is available on the coagulation-fibrinolysis pathway except for the presence of high plasma fibrinogen levels. OBJECTIVE: To determine the association of BD and coagulation-fibrinolysis pathway activation. PATIENTS AND METHODS: We examined the levels of fibrinogen, thrombin-antithrombin complex, prothrombin fragment(1+2), and cross-linked D-dimer in 17 patients with BD, 24 neurologic patients without CVD, and 26 patients with lacunar infarction in either the acute or chronic stage. RESULTS: As compared with the non-CVD and lacunar infarction groups, the patients with BD had significantly elevated levels of thrombin-antithrombin complex (P<.001), prothrombin fragment(1+2) (P<.05), and cross-linked D-dimer (P<.01). There was also a significant increase in fibrinogen levels compared with the non-CVD group (P<.05). In the BD group, 8 patients in stable condition (ie, those without obvious neurologic deficits in the past 3 months) showed normal levels or a mild increase in their fibrinogen, thrombin-antithrombin complex, prothrombin fragment(1+2), or cross-linked D-dimer levels. In contrast, 9 patients with BD with a subacute aggravation of their focal or subcortical cerebral functions (deteriorating group) showed a significant increase in their thrombin-antithrombin complex levels compared with the stable patients (P<.01). Similarly, the fibrinogen, prothrombin fragment(1+2), and cross-linked D-dimer levels were elevated in the deteriorating patients, but this trend did not reach statistical significance. CONCLUSIONS: These results indicate that the coagulation-fibrinolysis pathway is activated in patients with BD with a subacute aggravation. Coagulation activation may result in the formation of microthrombi and microcirculatory disturbances in the brains of these patients, and thus promote further biological and neurologic insults.
Aged↗
Immunoelectron microscopic study of c-Fos, c-Jun and heat shock protein after transient cerebral ischemia in gerbils.
The neuroprotective role of the expression of heat shock protein (HSP) and immediate early gene remains unclear. Using immunoelectron microscopy, we examined the ultrastructural integrity of the neurons with expression of c-Fos, c-Jun and HSP70 in gerbils after transient cerebral ischemia and reperfusion. Induction of c-Fos and c-Jun was observed in the CA3 region resistant to ischemia, while HSP70 was expressed not only in the CA3 but also in the vulnerable CAI region. With immunoelectron microscopy, the expression of c-Fos/c-Jun and HSP70 was observed in the neurons which retained neuronal integrity except for mitochondrial swelling and polyribosomal disaggregation. In contrast, the CAI neurons without immunoreaction for HSP70 showed cytoplasmic vacuoles and parallel stacking of rough endoplasmic reticulum, the features associated with the process of delayed neuronal death. These findings suggested that c-Fos and c-Jun were induced selectively in reversibly damaged neurons, whereas HSP70 was up-regulated even in neurons with irreversible damage, but was more preferentially and intensely expressed in neurons with reversible damage.
Animals↗
Vascular changes in white matter lesions of Alzheimer's disease.
The pathogenesis of white matter lesions observed in Alzheimer's disease (AD) is not completely clear. We tested the hypothesis that white matter lesions are correlated with medullary artery sclerosis rather than with amyloid angiopathy. A total of 57 brains were examined, including 39 derived from patients with AD and 13 from patients with Binswanger's disease (BD) along with 5 from non-neurological patients. Moderate or severe amyloid deposits in the meningocortical segment were observed in 32 out of 39 AD patients (82.1%), and in 2 out of 13 BD patients (15.4%). These deposits were not observed in the white matter segment, except for 2 patients with AD. The BD patients invariably had marked white matter lesions and fibrohyalinosis in the medullary arteries, with a mean sclerotic ratio of 48.1%. In contrast, the AD patients had mild or moderate white matter lesions and a sclerotic ratio of 37.9%, which was significantly greater than the controls. The scores for white matter lesions were correlated with the sclerotic ratio of the medullary arteries, but not with the ages of onset or the scores for amyloid angiopathy. Although amyloid angiopathy is an independent risk of white matter lesions, its role is limited in the pathogenesis of those associated with AD. Wall thickening of the medullary arteries, likely due to fibrohyalinosis, is closely correlated with the white matter lesions in AD, thus indicating a heterogeneity in its etiology.
Aged↗
Increased coagulatory activity in subcortical arteriosclerotic encephalopathy (Binswanger's disease)
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Aged↗
[The role of immunologic reactions in the pathogenesis in Binswanger's disease; a clue to therapeutic approach].
We examined the alterations of glial cells in the brains with Binswanger's disease. In comparison to the brains with lacunar cerebral infarction and those from non-neurological controls, oligodendroglia was decreased in number, and microglia was increased and activated in the white matter lesions in Binswanger's disease. Astroglia occasionally showed a regressive change, termed clasmatodendrosis. In rodents, similar white matter lesions could be induced after chronic cerebral hypoperfusion along with a numerical decrease of oligodendroglia, an increase of astroglia and activation of microglia in the corresponding white matter. These white matter lesions were suppressed by injection of immunosuppressant, cyclosporin A or FK506, with a suppression of microglial activation. These findings indicate that the lesion development in the white matter may be mediated by an immunologic reaction. Unfortunately, these drugs may be inappropriate for a practical use in terms of their side effects. Alternatively, we tried the use of anti-thrombin drug, argatroban. In acute neurological exacerbation of Binswanger's disease, markers for coagulation-fibrinolysis pathway were elevated significantly, and this activation was suppressed along with a recovery of neurological symptoms such as parkinsonism and pseudobulbar palsy. Thrombin contributes to a microcirculatory disturbance and may also enhance an inflammatory response through the action of thrombin receptor.
Animals↗
Dose-dependent, protective effect of FK506 against white matter changes in the rat brain after chronic cerebral ischemia.
Neuroprotective effects of immunosuppressive agents have been shown in cerebral ischemia. To investigate the role of immunosuppressive agents in chronic cerebral ischemia and to design a drug protocol with safe therapeutic windows, we examined the effects of FK506, a potent immunosuppressive agent, on chronic cerebral ischemia. Both common carotid arteries were ligated in 73 male Wistar rats. Fifty-eight of these rats received a chronic injection of FK506 (0.2, 0.5, 1.0 mg/kg) and the remaining 15 received a vehicle solution injection. Microglia/macrophage was investigated with immunohistochemistry for leukocyte common antigen and major histocompatibility complex, and astroglia was examined with glial fibrillary acidic protein as markers. White matter rarefaction and the number of immunopositive glial cells were assessed from 7 to 30 days after the ligation. In the vehicle-treated animals, there was persistent and extensive activation of the microglia/macrophages and astroglia in the white matter, including the optic nerve, optic tract, corpus callosum, internal capsule, anterior commissure and traversing fiber bundles of the caudoputamen. In the FK506-treated rats, the number of activated microglia/macrophages was significantly reduced in a dose-dependent manner (p<0.01) as compared to the vehicle-treated rats. Rarefaction of the white matter was also inhibited by FK506 in a dose-dependent manner (p<0. 01). Thus, a clinically-relevant dosage of FK506 attenuated both glial activation and white matter changes in chronic cerebral ischemia in the rat. These results indicate a potential use for FK506 in cerebrovascular diseases.
Animals↗
Blood-brain barrier dysfunction in Binswanger's disease; an immunohistochemical study.
Binswanger's disease is pathologically characterized by a combination of diffuse cerebrovascular white matter lesions and lacunar infarcts in the basal ganglia and white matter. Although a blood-brain barrier (BBB) dysfunction has been implicated in the pathogenesis of these white matter (WM) lesions, few authors have addressed this problem. In the present study, we describe BBB dysfunction and its regional differences in the brains of Binswanger's disease patients. Twelve brains from Binswanger's disease patients (group III) were examined and compared with those from five patients with non-neurological disease (group I) and five cortical infarct patients without significant WM lesions (group II). Immunohistochemistry was performed for glial fibrillary acidic protein and vimentin as astroglial cell markers, and for immunoglobulins, complements and fibrinogen as extravasated serum protein markers. The grading scores for IgG extravasation were significantly higher in group III as compared to group I, in both the periventricular WM and the subcortical WM (P < 0.01). In group III, the scores in the periventricular WM and subcortical WM were significantly higher than in the subcortical U fibers and cerebral cortex (P < 0.01 for the periventricular WM; P < 0.001 for the subcortical WM), respectively. Clasmatodendritic astroglia, which had swollen cell bodies and large cytoplasmic vacuoles with disintegrated processes, incorporated the serum components IgG, IgM, C3d, Clq and fibrinogen, both in the periventricular WM and subcortical WM in 5 out of 12 (42%) Binswanger's disease brains. These results indicate that WM lesions in Binswanger's disease are accompanied by BBB dysfunction, although it remains uncertain whether BBB dysfunction is secondary to either chronic cerebral ischemia or arterial hypertension.
Aged↗
Identification of septins in neurofibrillary tangles in Alzheimer's disease.
Septins are evolutionarily conserved cytoskeletal GTPases that can form heteropolymer complexes involved in cytokinesis and other cellular processes. We detected expression of the human septin genes Nedd5, H5, Diff6, and hCDC100 in postmortem brain tissues using the reverse transcription-coupled polymerase chain reaction and their products by immunoblot analysis. Four antibodies directed against three septins, Nedd5, H5, and Diff6, consistently labeled neurofibrillary tangles, neuropil threads, and dystrophic neurites in the senile plaques in brains affected by Alzheimer's disease but did not label obvious structures in young control brains. Immunoelectron microscopy revealed that Nedd5 localized to the paired helical filaments. Pre-tangles, the precursory granular deposits that accumulate in the neuronal cytoplasm, also were labeled with the antibodies. These findings suggest that at least the three septins are associated with tau-based paired helical filament core, and may contribute to the formation of neurofibrillary tangle as integral constituents of paired helical filaments.
Adult↗
Encephalitogenic peptide (EP) in human cerebrovascular white matter lesions.
The expression of encephalitogenic peptide (EP), a 68-86 amino acid sequence of guinea pig myelin basic protein (MBP), was investigated in autopsied brains with focal cerebral damage or with diffuse white matter (WM) lesions. EP immunoreactive fibers were distributed in parallel with fibers immunoreactive for amyloid protein precursor (APP), an indicator of WM damages. EP was expressed in the periphery of cerebral infarctions and hematoma in the acute and subacute stages, but was also distributed in diffuse WM lesions due to heterogeneous causes. These data indicate that EP epitopes are exposed specifically in ongoing WM damages, and that the destruction of myelin occurs sporadically in diffuse WM lesions of varying intensity.
Aged↗
Ubiquitin-related cytoskeletal abnormality in frontotemporal dementia: immunohistochemical and immunoelectron microscope studies.
Although reports of dementia lacking the distinctive non-Alzheimer-type histopathology have been increasing, the concept is still far from clear. It has become apparent that this population shows neuropathological heterogeneity, and some recent reports have proposed a classification or criteria for these disease conditions. Of the reported cases, frontotemporal dementia (FTD) of motor neuron disease is unique in that the neurons of the hippocampus and entorhinal cortex have ubiquitin-related abnormalities. Recently, a new ubiquitin-related abnormality, characterized by ubiquitinated inclusions in the neurites, has been found in some FTD cases. Using immunoelectron microscopy with immunogold particles, we have found that in these two disease conditions ubiquitinated inclusions consist of abnormal filaments of 10-15 nm in diameter. Our results support the speculation that there is a close relationship between ubiquitin and abnormal filaments in these two types of FTD, indicating that cytoskeletal-related disorders may underlie certain types of FTD.
Aged↗
Regressive changes of astroglia in white matter lesions in cerebrovascular disease and Alzheimer's disease patients.
The pathogenesis of white matter lesions, which are frequently found in ischemic cerebrovascular disease and Alzheimer's disease, remains unclear. Using light and electron microscopic immunohistochemistry for glial fibrillary acidic protein (GFAP) as a marker, the present study focused on the role of astroglia which show characteristic morphological alterations. Of 29 brains of patients with cerebrovascular disease and Alzheimer's disease, 4 brains showed extensive swelling and vacuolation of white matter astroglia with their processes disintegrated and beaded (termed clasmatodendrosis). No such cells were observed in 6 control patients. Clasmatodendritic astroglia were not intensely eosinophilic using hematoxylin and eosin staining and included large lipophilic granules in their perikarya. These astroglia were immunoreactive for serum proteins such as immunoglobulins, fibrinogen and complement C3, C1q and C3d, as well as for proteins which are known to increase in reactive astroglia, such as vimentin, alpha-B crystallin, apolipoprotein-E and laminin. Double labeling for GFAP and microglial cell markers indicated that these cells were of astroglial lineage. Immunoelectron microscopy for GFAP revealed that clasmatodendritic astroglia had condensed chromatin, lysosomes and large membrane-bound osmiophilic cytoplasmic inclusions, which corresponded to the lipophilic granules observed with light microscopy. These cytochemical features collectively suggest that clasmatodendritic astroglia incorporate edema fluid and phagocytose cellular debris, and eventually degenerate as a result of cerebral edema.
Aged↗