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Biomedical subjects

Ichiro Akiguchi

Publications and source records attributed to Ichiro Akiguchi.

At least 19 recordsLinked to original sources
PubMed2006

Four subgroups of Alzheimer's disease based on patterns of atrophy using VBM and a unique pattern for early onset disease.

To clarify the involvement of the posterior cingulate cortex (PCC) in Alzheimer's disease (AD), we analyzed brain volume loss by voxel-based morphometry. Forty patients with non-familial AD and 20 patients with mild cognitive impairment (MCI) were recruited and compared to 88 elderly volunteers and 40 young volunteers. Local atrophy with aging was observed bilaterally in the perisylvian opercula, anterior cingulate cortex, caudate head, dorsomedial thalamus and parahippocampal cortex. In addition to those, atrophy in AD patients was observed in the amygdala, hippocampus, subcallosal region, posterior-associated cortices and PCC. We classified AD into four subgroups according to the atrophy pattern; atrophy in the amygdala/hippocampal formations (Hipp), in the Hipp and posterior cortices, in the Hipp and PCC and in the PCC and posterior cortices (PCC/-TOPa). As a result, the probability of PCC/-TOPa was 90% for ages <65 years, whereas that of the Hipp was 100% for disease duration >36 months. PCC atrophy was found in 16 of 40 AD patients and eight of 20 MCI patients. There seemed to be two subgroups with atrophy of the PCC, the one with disease progression and the other without. The latter had characteristic features of early onset and no significant atrophy in the amygdala/anterior hippocampus. There are at least four atrophy patterns that raise doubts about a single disease entity or progression in AD. This may reflect a different hierarchical pattern of progression in patients who have atrophy in PCC and posterior cortices when compared to the Braak staging scheme.

Adult↗
PubMed2006

Upregulated expression of 14-3-3 proteins in astrocytes from human cerebrovascular ischemic lesions.

BACKGROUND AND PURPOSE: Several types of chaperone proteins, such as heat shock proteins, have been reported to be associated with brain ischemia. The purpose of this study was to investigate whether an abnormal expression of 14-3-3 proteins, a novel type of molecular chaperones, occurs in human gray and white matter ischemic lesions. METHODS: We prepared formalin-fixed, paraffin-embedded sections from 33 autopsied brains, consisting of 7 normal controls, 4 cases with cerebral thrombosis, 5 cases with cerebral embolism, 8 cases with multiple lacunar infarctions, and 9 cases with Binswanger disease. Deparaffinized sections from all cases were immunostained with anti-14-3-3 antibodies using the avidin-biotin-peroxidase complex method, and some sections were also double-immunostained for 14-3-3 and glial markers. RESULTS: In the normal control brains, 14-3-3 immunoreactivity was mainly localized to the neuronal somata and processes. Strongly 14-3-3-immunopositive astrocytes were distributed in the infarct lesions and were particularly abundant in infarcts at the chronic stage. Intensely 14-3-3-immunolabeled astrocytes were also observed in the ischemic white matter lesions, and in the severely affected white matter lesions from patients with Binswanger disease, dense 14-3-3 immunoreactivity was found in clasmatodendritic astroglia as well as in reactive astrocytes. CONCLUSIONS: Our results suggest that 14-3-3 proteins may be induced mainly in astrocytes from human cerebrovascular ischemic lesions, and that the upregulated expression of 14-3-3 proteins in astrocytes may be involved in the formation of astrogliosis.

14-3-3 Proteins↗
PubMed2006

Nationwide survey of juvenile muscular atrophy of distal upper extremity (Hirayama disease) in Japan.

Juvenile muscular atrophy of the distal upper extremity (JMADUE, Hirayama disease) was first reported in 1959 as 'juvenile muscular atrophy of unilateral upper extremity'. Since then, similar patients in their teens or 20s have been described, under a variety of names, not only in Japan, but also in other Asian countries, as well as Europe and North America. Biomechanical abnormalities associated with JMADUE have recently been reported through various imaging examinations, proposing its disease mechanism. Since JMADUE differs from motor neuron disease, or spinal muscular atrophy, this disease entity should be more widely recognized, and early detection and effective treatments should be considered. We report an epidemiological study in Japan. Two nationwide questionnaire-based surveys, conducted in Japan from 1996 to 1998, identified 333 cases. The numbers of patients per year, distribution of ages at onset, mode of onset, time lapse between onset and quiescence, neurological signs and symptoms, imaging findings, and the effects of conservative treatments were analyzed. The peak age was 15 to 17 years, with a marked male preponderance, usually a slow onset and progression, and quiescence six or fewer years after onset. There was a predominantly unilateral hand and forearm involvement with 'cold paresis'. The imaging findings are described.

Adolescent↗
PubMed2005

Cultured murine dermal fibroblast-like cells from senescence-accelerated mice as in vitro models for higher oxidative stress due to mitochondrial alterations.

The senescence-accelerated mouse is a model for senescence acceleration, a higher oxidative stress status, and age-associated disorders. We studied whether fibroblasts cultured from accelerated senescence-prone SAMP11 mice could be used as in vitro models for oxidative stress in senescence. Dichlorofluorescein and hydroethidine assays demonstrated that cells from SAMP11 mice produced more reactive oxygen species than did cells from accelerated senescence-resistant SAMR1 mice. These differences were not due to the defective induction of antioxidants. Double labeling with hydroethidine and MitoTracker Green revealed that most of the reactive oxygen species were generated within the mitochondria. Nonyl acridine orange and JC-1 assays showed an increase in the mass of the mitochondria, especially those with low membrane potential, in SAMP11 cells. Ultrastructurally, mitochondria with degenerative morphology were increased in SAMP11 cells with longer culture periods. These results suggest that cells from SAMP11 mice are useful models for spontaneous higher oxidative stress in vitro due to dysfunctional mitochondria.

Animals↗
PubMed2004

Upregulation of ceramide and its regulating mechanism in a rat model of chronic cerebral ischemia.

Ceramide is a key mediator of apoptosis, and is involved in the cellular stress response. We examined the alterations in the ceramide levels and their synthetic/degradative pathway in a rat model of chronic cerebral ischemia, in which ischemic white matter (WM) lesions occur in association with oligodendroglial cell apoptosis. Chronic cerebral ischemia was induced by clipping both common carotid arteries in male Wistar rats. After predetermined periods of 1, 3, 7 and 14 days, the animals were subjected to immunohistochemical and biochemical investigations for ceramide in the region containing the frontal cortex and corpus callosum (region 1), and the region containing the internal capsule and globus pallidus (region 2). After 14 days, the myelin was degraded in the corpus callosum, internal capsule and the optic tract in Klüver-Barrera staining. There was a significant increase in the ceramide level and the activity of its synthetic enzyme, acidic sphingomyelinase (SMase), whereas its degrading enzyme, glucosylceramide synthase (GCS), was downregulated in both regions 1 and 2 as compared to the sham-operated rats. Simultaneously, ceramide immunoreactive glia increased in number in the corpus callosum and the internal capsule after 3, 7 and 14 days. Double labeling for ceramide with glial fibrillary acidic protein but not with leukocyte common antigen indicated the astroglial nature of these glia. These findings indicate that chronic cerebral ischemia induces an increased ceramide level in astroglia as a result of downregulation of GCS and an upregulation of ASMase activity.

Animals↗
PubMed2004

14-3-3 proteins in Lewy body-like hyaline inclusions in patients with sporadic amyotrophic lateral sclerosis.

14-3-3 proteins are highly conserved eukaryotic proteins that regulate various types of signal transduction pathways through phosphorylation-dependent protein-protein interactions. 14-3-3 mRNAs have been shown to be up-regulated in the injured rat motor neurons and in the spinal cords of patients with amyotrophic lateral sclerosis (ALS). To investigate the role of 14-3-3 proteins in ALS, we performed immunohistochemical studies on 14-3-3 using autopsied spinal cords from patients with sporadic ALS (sALS) and non-ALS subjects without spinal cord involvement. In the anterior horn of both groups, strong 14-3-3 immunoreactivity was observed in the somata and proximal processes of motor neurons. Many spheroids from all of the sALS cases were also immunopositive for 14-3-3. In addition, Lewy body-like hyaline inclusions (LBHIs), which were present in some sALS cases, were intensely immunostained. Our findings suggest that even in the severely affected anterior horn of patients with sALS, remaining motor neurons may contain abundant 14-3-3 proteins, and that 14-3-3 proteins may be partly associated with the pathogenesis of sALS, in particular with the formation of LBHIs.

14-3-3 Proteins↗
PubMed2004

Enhanced expression of 14-3-3 proteins in reactive astrocytes in Creutzfeldt-Jakob disease brains.

14-3-3 proteins have been reported to be detected specifically in the cerebrospinal fluid (CSF) from patients with Creutzfeldt-Jakob disease (CJD). To elucidate the role of 14-3-3 proteins in patients with CJD, we performed immunohistochemical studies on 14-3-3 proteins in autopsied brains from five patients with sporadic CJD (sCJD), three patients with Alzheimer's disease (AD), and seven normal control subjects. Formalin-fixed, paraffin-embedded sections from all cases were immunostained with several types of specific anti-14-3-3 antibodies. In the normal control brains, 14-3-3 immunoreactivity was localized mainly in the neuronal somata and processes; in contrast, glial cells showed no or faint immunoreactivity. In the brains from the patients with AD, 14-3-3 immunoreactivity was observed in the surviving neurons as well as some neurofibrillary tangles. In the brains from the patients with sCJD, 14-3-3 immunoreactivity was well preserved in the remaining neurons. Furthermore, the glial cells, especially the reactive astrocytes, were intensely immunostained in the brains affected by sCJD. Our findings suggest that 14-3-3 proteins may be up-regulated in the glial cells, particularly in reactive astrocytes, and that the enhanced expression of 14-3-3 proteins in these glial elements may be associated with the pathogenesis of sCJD.

14-3-3 Proteins↗
PubMed2004

Topographical and cytopathological lesion analysis of the white matter in Binswanger's disease brains.

The purpose of the present study was to document the topographical and cytopathological lesions in the white matter (WM) of Binswanger's disease (BD) brains. Subcortical WM lesions in each lobe and fiber bundle lesions related to the medial thalamic and hippocampal structures in clinicopathologically proven BD brains were evaluated by Klüver-Barrera staining using a grading score. Lesions in the frontal subcortical WM of BD brains, brains from non-neurological patients, and brains with cerebral hemorrhage or large cortical infarcts were also examined immunohistochemically using molecular markers for axonal flow damage: amyloid precursor protein (APP); and for demyelinating axonopathy: encephalitogenic peptide (EP). Our results indicated that the WM lesions in BD were significantly more prominent in the frontal periventricular and subcortical regions as compared with other subcortical WM lesions, in the order of the parietal, occipital and temporal lobes. Fiber bundle lesions in the capsular genu, including the anterior thalamic peduncle, were also significantly more prominent in BD brains as compared with the other bundle lesions. Furthermore, the frequency of damaged nerve fibers labeled by the EP antiserum and APP immunoreactive fibers was significantly higher in BD brains as compared with the control brains. The grading scores for the WM damage correlated significantly with those for the APP and EP immunoreactive fibers in all brains, including the control brains. The axonal damage in the frontal WM lesions of the BD brains was clearly revealed in our study using immunohistochemistry for APP and EP.

Adult↗
PubMed2004

Blood-brain barrier is impaired in the hippocampus of young adult spontaneously hypertensive rats.

A causative role of blood-brain barrier (BBB) impairment is suggested in the pathogenesis of vascular dementia with leakage of serum components from small vessels leading to neuronal and glial damage. We examined the BBB function of young adult spontaneously hypertensive rats (SHR) in order to determine earlier changes in the BBB in chronic hypertension. SHR and stroke-prone SHR (SHRSP) were injected with horseradish peroxidase (HRP) as an indicator of BBB function and compared with Wistar Kyoto rats (WKY). The brain tissues were further examined with cationized ferritin, a marker for evaluating glycocalyx. The staining for HRP was distributed around the vessels in the hippocampal fissure of SHR and SHRSP, but not in WKY. With electron microscopy, the extravasated reaction product of HRP appeared in abluminal pits of the endothelial cells of arterioles and within the basal lamina in the hippocampus, but not the cerebral cortex, of SHR and SHRSP. On the contrary, the reaction product of HRP was never seen in the abluminal pits of the endothelial cells or the basal lamina of vessels in WKY. The number of cationized ferritin particles binding to the endothelial cells of capillaries was decreased in the hippocampus of SHR and SHRSP, while the number decreased in the cerebral cortex of SHRSP compared with those in WKY. However, the cationized ferritin binding was preserved in the endothelial cells of the arterioles with an increased vascular permeability. These findings suggest that the chronic hypertensive state induces BBB dysfunction in the hippocampus at an early stage.

Animals↗
PubMed2004

A compensatory mechanism in unilateral akinetic-rigid syndrome: an fMRI study.

The motor mechanisms of a patient with unilateral hand clumsiness in the early stages of akinetic-rigid syndrome were assessed by functional magnetic resonance imaging (fMRI). Movements of the unaffected hand produced activation in the contralateral sensorimotor cortex (SMC) and ipsilateral SMC and superior parietal lobule (SPL). The affected hand activated the bilateral SMCs, supplementary motor areas, and SPLs. We speculated that the bilateral activation indicated recruitment of a pre-existing bilaterally organized large-scale neural network to perform the motor task.

Aged↗
PubMed2003

Ibudilast, a phosphodiesterase inhibitor, protects against white matter damage under chronic cerebral hypoperfusion in the rat.

Cerebrovascular white matter (WM) lesions, which are frequently observed in vascular cognitive impairment and vascular dementia, can be produced in rats by clipping the common carotid arteries bilaterally. Since TNF-alpha is known to cause the degeneration of myelin, we examined whether these lesions can be ameliorated by ibudilast, a cyclic AMP phosphodiesterase (PDE) inhibitor that suppresses tumor necrosis factor (TNF)-alpha production. After the ligation of both common carotid arteries in 29 rats, 21 rats received a daily oral administration of 10, 30 or 60 mg/kg ibudilast and 8 rats received vehicle for 14 days. The pathological changes in the white matter were quantified in terms of white matter lesions and the emergence of activated microglia immunoreactive for major histocompatibility complex (MHC) antigen. In the vehicle-treated animals, white matter lesions and microglial activation occurred in the optic tract, internal capsule and corpus callosum. A low dose (10 mg/kg) of ibudilast failed to suppress the white matter lesions and microglial activation, whereas a dose of either 30 or 60 mg/kg ibudilast ameliorated these lesions (p<0.001). Without an alterations in laboratory blood data, 60 mg/kg ibudilast exhibited percent reduction of the white matter lesions ranging between 50% and 70%, which was more effective than 30 mg/kg ibudilast (p<0.05). The TNF-alpha immunoreactive glia decreased in number in the 60 mg/kg ibudilast-treated group as compared to the vehicle-treated group (p<0.001). These results indicate a dose-dependent protective effect of ibudilast against cerebrovascular white matter lesions and suggest a potential use for ibudilast in the treatment of vascular dementia.

Administration, Oral↗
PubMed2003

Increased 14-3-3 immunoreactivity in glial elements in patients with multiple sclerosis.

14-3-3 proteins have been shown to be increased in the cerebrospinal fluid from patients with several kinds of neurological diseases, including multiple sclerosis (MS). To investigate whether 14-3-3 proteins are closely related to the pathogenesis of MS, we performed immunohistochemical studies for 14-3-3 in autopsied brains from ten patients with MS, five patients with progressive multifocal leukoencephalopathy (PML), and seven normal control subjects. Formalin-fixed, paraffin-embedded sections from all cases were immunostained with a specific anti-14-3-3 antibody, and some sections from the MS cases were double-immunostained with antibodies raised against 14-3-3 and glial markers. In the normal control brains, 14-3-3 immunoreactivity was localized mainly in the neuronal somata and processes, and some glial cells showed only weak immunoreactivity. In the plaque lesions from the MS cases, the astrocytes and oligodendrocytes were intensely immunostained, and strong immunoreactivity was also found in some microglia and macrophages, most of which were located in the perivascular areas. In the PML brains, a similar immunolabeling pattern was observed in the demyelinated lesions, in which the astrocytes and oligodendrocytes exhibited dense 14-3-3 immunoreactivity. Our results suggest that 14-3-3 may be up-regulated in the glial cells, especially in astrocytes and oligodendrocytes, in patients with MS or PML. The exaggerated 14-3-3 accumulation in these glial elements may be associated with the pathogenesis of both demyelinating disorders.

14-3-3 Proteins↗
PubMed2003

The mechanisms of recovery from cerebellar infarction: an fMRI study.

Patients with cerebellar infarction frequently make an excellent functional recovery. However, the mechanisms of functional recovery from cerebellar infarction remain unclear. Thus, functional MRI was used to investigate these mechanisms in six right-handed patients with complete recovery after cerebellar infarction, and nine right-handed normal subjects. The non-infarcted side of the cerebellum and the sensorimotor cortex contralateral to the non-infarcted side of the cerebellum were significantly activated during the infarcted-side hand movement. In the infarcted side of the cerebellum, intact regions were activated. Our results indicate that recovery from cerebellar infarction depends on reorganization in the infarcted side of the cerebellum, and recruitment of the cerebellocortical loop involving the cerebrum ipsilateral to the movement and the cerebellum contralateral to the movement.

Adult↗
PubMed2003

Association of the cytoskeletal GTP-binding protein Sept4/H5 with cytoplasmic inclusions found in Parkinson's disease and other synucleinopathies.

alpha-Synuclein-positive cytoplasmic inclusions are a pathological hallmark of several neurodegenerative disorders including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Here we report that Sept4, a member of the septin protein family, is consistently found in these inclusions, whereas five other septins (Sept2, Sept5, Sept6, Sept7, and Sept8) are not found in these inclusions. Sept4 and alpha-synuclein can also be co-immunoprecipitated from normal human brain lysates. When co-expressed in cultured cells, FLAG-tagged Sept4 and Myc-tagged alpha-synuclein formed detergent-insoluble complex, and upon treatment with a proteasome inhibitor, they formed Lewy body-like cytoplasmic inclusions. The tagged Sept4 and alpha-synuclein synergistically accelerated cell death induced by the proteasome inhibitor, and this effect was further enhanced by expression of another Lewy body-associated protein, synphilin-1, tagged with the V5 epitope. Moreover, co-expression of the three proteins (tagged Sept4, alpha-synuclein, and synphilin-1) was sufficient to induce cell death. These data raise the possibility that Sept4 is involved in the formation of cytoplasmic inclusions as well as induction of cell death in alpha-synuclein-associated neurodegenerative disorders.

Aged↗
PubMed2003

Cerebral vasomotor reactivity to postural change is impaired in patients with cerebrovascular white matter lesions.

Vasomotor reactivity is decreased in terms of cerebral blood flow (CBF) response to hypercapnia in patients with cerebrovascular white matter (WM) lesions. This study evaluated whether vasomotor reactivity is altered during postural change in these patients. We examined 28 consecutive patients with cerebrovascular WM lesions, subgrouped into 19 with Schmidt scale 2 and 9 with scale 3 WM lesions. These patients were compared with 15 age-matched patients with lacunar infarction but without significant WM lesions and 6 controls without cerebrovascular disease. With blood pressure monitoring, brain SPECT scans were done in the supine and upright position using HMPAO as a tracer. The ratio of radioisotope (RI) counts in the frontal and parieto-temporal lobes to those in the cerebellar hemispheres (CBF ratio) was evaluated. In the comparison among the three groups, there were no significant differences in the changes of systemic blood pressure after rising. The baseline CBF ratio in the supine position was also not different among the three groups. After rising, the CBF ratio in each region of interest (ROI) did not change significantly in either lacunar infarction or control groups. By contrast, in patients with WM lesions, the CBF ratio in the frontal lobe decreased after rising (p < 0.0001). In the subgroup analysis, there was a significant increase in blood pressure 1, 2 and 3 min after rising (p < 0.05), with a higher tendency in the scale 3 WM lesion group as compared to the scale 2 WM lesion group. The CBF ratio was decreased in both frontal and parieto-temporal areas in the scale 2 WM lesion group, whereas this was significant only in the frontal areas in the scale 3 WM lesion group. Vasomotor reactivity is impaired in cerebrovascular WM lesions, suggesting a susceptibility to postural changes in these patients.

Aged↗
PubMed2003

Hypertensive brainstem encephalopathy.

A 45-year-old man developed severe arterial hypertension associated with unusual hyperintensity in the brainstem, around the right internal capsule and in the deep white matter around the bilateral anterior horn of the lateral ventricle on T2-weighted and fluid-attenuated inversion-recovery images. The characteristic clinical findings were mild left hepiparesis and altered mental status which corresponded to the lesions of MR imagings. The lesions improved gradually with improvements in hypertension, which suggested that edema could be the principal cause of the unusual hyperintensity on MR images.

Brain Edema↗