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Biomedical subjects

R Fukatsu

Publications and source records attributed to R Fukatsu.

At least 37 records · Page 2Linked to original sources

[Chronic neuropathy, a high level of protein in cerebrospinal fluid, and vitamin B1 and folate deficiency in a patient with normal-pressure hydrocephalus].

A 67-year-old woman presented with a 1-year history of gradual weight loss, reduced mental activity, muscle weakness, and urinary dysfunction. Neurological examination revealed mild lethargy, severe muscular atrophy, and diminished deep tendon reflexes in the extremities. The levels of vitamin B1 and folate in blood were low: 1.9 micrograms/dl (normal range 2.0-7.2) and 0.7 ng/ml (normal range 4.0-12.0). respectively. A lumbar puncture was done. The pressure of the cerebrospinal fluid was within normal limits, the level of protein was very high (467 mg/dl), and only a few lymphocytes were seen. A nerve-conduction study showed low amplitudes of action potentials and slow conduction velocities in both the motor and sensory nerves. Myelin irregularity, "onion bulb formation", and axonal atrophy were seen in a specimen obtained by sural nerve biopsy. A T2-weighted magnetic resonance image of the brain showed ventricular dilatation, high-intensity signals around the lateral ventricles, and a flow-void sign of the cerebral aqueduct. Radioisotope cisternography (111In-DTPA) disclosed ventricular reflux and slow clearance of the tracer from the ventricles. These findings indicated the presence of chronic inflammatory demyelinating polyneuropathy, nutritional polyneuropathy, vitamin B1 deficiency, folate deficiency, and normal pressure hydrocephalus. In this patient, the high level of protein in the cerebrospinal fluid may have caused the hydrocephalus.

Aged↗

[Recent advances in Alzheimer's disease research--amyloid precursor protein trafficking, processing, and mutations in Alzheimer's disease linked genes].

Recent advances in Alzheimer's disease (AD) research were briefly reviewed. The AD affected brain is characterized by numerous amyloid plaques, neurofibrillary tangles, and neuronal losses. The amyloid is composed of amyloid beta peptide (A beta), a 40-42 amino acid fragment of large membrane protein, amyloid precursor protein (APP). A beta is cleaved by proteolytic enzyme, beta, and gamma secretase yielding N and C terminus of the A beta. Considerable effort has been directed to identify these enzymes, and to find the intracellular compartments where A beta is generated. Endosome, lysosomal pathway, or related acidic compartment is one of the candidates for A beta generation. Biochemical and immunopathological data implicate that A beta 42 is more important than A beta 40 in the pathogenesis of AD. On the other hand, many missence mutations in APP gene and other gene, S182 (presenilin1), and STM2 (presenilin2) were identified in familial AD. Neuropathology in these FAD appear basically quite similar, and AD is regarded as cerebral A beta amyloidosis. It was established that missense mutations in the genes encoding APP, presenilin1, and presenilin2, all treated APP processing, leading to increased production of A beta 42. AD amyloid is composed of many other proteins than A beta, designated as amyloid associated proteins, It should be a key issue to determine the precise mechanism, by which A beta is generated, and the alteration of APP trafficking resulting in increased A beta 42 generation with these mutant genes.

Alzheimer Disease↗

[The disturbance of reversible operation in space in the early stage of Alzheimer's disease].

Constructional apraxia is one of the neuropsychological findings frequently observed in the early stage of the Alzheimer's disease, which may result from the visuo-spatial disturbances. The visual space consists of a variety of visual information processing, viewer-centered coordinate system, objects-centered coordinate system, integration of both coordinate systems, and verifying visual representation with the knowledge in the memory. The reversible operation in space, or mental rotation appears to play an important role in visuo-spatial functions, which refers to the operation of the visual representation at one orientation in viewer-centered coordinate system to construct the representation in object-centered coordinate system so that one can look like if it were presented at another orientation. To the present, little is known about reversible operation or mental rotation in patients with Alzheimer's disease. In this present paper, we attempted to investigate the ability of reversible operations in space so as to understand the mechanisms underlying constructional apraxia, or visuo-spatial disturbances in the early stage of Alzheimer's disease. The subjects were 12 patients with Alzheimer's disease in early stage (AD group), 12 patients with multi-infarcts dementia as disease control (MID group), 12 age matched persons as healthy control (HC group). In perspective taking tasks, that requires the subjects to imagine the spatial arrangement of the objects at the different view points from the subjects' one, AD group showed more severe deficits than MID group and HC group. Moreover, in a task that the subjects were asked to assume the photo-angle of the photograph taken of the model which was in front of them, AD group was imparied compared to the control groups. These disturbances were closely associated with deficits in Block Design test of WAIS. These results clearly demonstrate that the patients with Alzheimer's disease have disturbance in reversible operation in space and that the disturbance may be responsible for visuo-spatial dysfunctions, not only the constructional apraxia, but also a variety of performance deficits in the early stage of Alzheimer's disease.

Aged↗

Effect of head-centered and body-centered hemispace in unilateral neglect.

The aim of this study was to evaluate the effects of head-centered and body-centered hemispace on a line bisection task in patients with left unilateral neglect. Five patients with left unilateral neglect were given a line bisection task under four different conditions. The results clearly demonstrate that both head-centered and body-centered hemispace had a statistically significant effect on the line bisection task. The results are discussed with respect to a reference frame of space and the validity of dividing unilateral neglect into two components (i.e., spatial neglect and object neglect) is proposed.

Aged↗

Effects of hand-used on unilateral spatial neglect: a case study.

It was originally claimed that left hand use on line bisection tasks reduced the extent of left neglect by Halligan and Marshall. However, in a following study, the same research group failed to reproduce this left hand amelioration effect if the left hand was initially placed on the right side, and they claimed that spatio-motor cueing was more important in reducing unilateral neglect than the hand used. The present study concerns with the validity of these two theoretical views on modification of unilateral neglect, i.e., hemispheric activation and spatio-motor cueing. A patient with left unilateral neglect and a slight left hemiparesis participated in three experiments. Under conventional testing condition, line bisection performed with the right hand showed more severe left neglect than when performed with the left hand. These hand effects were modified by changing a starting position of the patient's hand when bisecting horizontal lines. However, under body-fixed condition, effects in hand-used as well as starting position were again significant. The results suggest that not only spatio-motor cueing but also differential hemispheric activation can exert a profound effect on unilateral neglect.

Aged↗

[Closing-in phenomena observed in patients with Alzheimer's disease--analysis of drawing behavior and eye movements].

'Closing-in' symptom is defined as a tendency to close-in on the model while performing constructive tasks. This unique symptom is one of the constructional apraxia often observed in Alzheimer's disease (AD), which is considered to be involved in visuospatial dysfunctions. However, little is known about the nature of the symptom and pathophysiology underlying the symptom. In this study, we examined drawing behavior, eye movements of AD (n = 19), multi-infarct dementia (n = 8) and age matched healthy subjects (n = 10). 1) In AD, contrary to age matched healthy subjects, the patients drew slowly with apparent difficulty and drawing behavior was disorganized. The copied figures were incomplete and often fragmented. The spatial relationships of the parts were lost each other during copying a Necker's cube. 2) The characteristic eye movements were observed in AD patients with apraxia, and closing-in symptom. These were consisted of gaze apraxia, and disorders of visual attention appeared similar to Bàlint's syndrome. 3) The eye movements of the AD patients with closing-in symptoms were classified into wandering of fixation, locking of fixation, and mixed types. The 'closing-in' symptoms in copied figures were classified into three types, overlap, adherent, and near types. Then, the wandering type was seen both in near and adherent types, whereas the fixation type was only found in the overlap type. 4) SPECTs showed reduced RI activities in the parieto-occipital and in the frontal regions of AD patients with apraxia and closing-in symptoms. Our results suggest that AD patients may have a difficulty to create abstract space from concrete space. This may also imply regression to a primitive undifferentiated stage where gnostic and practic behavior is not differentiated in terms of space appreciation.

Aged↗

[Aging brains and the dementias].

Dementia has been defined generally as an acquired persistent impairment of intellectual function caused by organic brain diseases. The rapidly increasing incidence of dementias has been claimed on the basis of epidemic studies in Japan as well as in Western developed countries. These observations are justified by the facts that most dementias are found in people over the age of 65 years, and that the elderly population is increasing rapidly resulting in both absolute numbers and percentage of the population. In Japan, it is estimated that 1.5 million of demented persons are present. The purpose of this paper is to describe clinical manifestations and morphological alterations of aged and demented individuals, diagnostic process to differential diagnosis to provide knowledgeable approach to management, and adequate care of the demented individuals. In aged brain, there are a variety of morphological changes. Some of these are usually observed in aged brains; atrophy of the brains, loss of neurons, accumulations of lipofuscin. Others observed in pathologically aged brains, or accelerated aging brains are Alzheimer's neurofibrillary tangles, senile plaques, and granulovacuolar degeneration. Psychiatric manifestations associated with aging and dementing diseases are described. It should be realized that clinical manifestations of the demented reflect primarily the topography of the organic lesions in the brain, and functional alterations, and are influenced by psychological and socio-environmental factors.

Aging↗

[Biological characteristics of amyloid precursor protein and Alzheimer's disease].

Recent advances in Alzheimer's disease (AD) research were briefly reviewed. AD is the most common cause of progressive intellectual decline in the aged in the Western world and also in Japan. The AD-affected brain is characterized by numerous amyloid plaques, neurofibrillary tangles, and neuronal losses. The amyloid deposition is considered to be more important because it appears first, and is followed by NFTs. The amyloid is composed of amyloid beta peptide (Abeta), a 40 approximately 42 amino acid fragment of the large membrane protein, amyloid precursor protein (APP). Abeta is cleaved by the proteolytic enzymes, beta, and gamma secretase. Considerable effort has been directed to identify these enzymes, and to find the intracellular compartments where Abeta is generated. The lysosome, or related acidic compartment is one of the candidates. The N and C terminis of the Abeta is known to vary slightly. Biochemical and immunopathological studies implicate that Abeta42 is more important than Abeta40 in the pathogenesis of AD. On the other hand, many missense mutations in APP gene and other genes, e.g. S182, and STM 2 have been identified in familial AD. Neuropathologically, AD is regarded as cerebral Abeta amyloidosis. The AD amyloid is composed of many proteins other than Abeta, designated as amyloid associated proteins. These proteins may play important roles in amyloid formation, since Abeta itself is soluble. Transgenic mice and chloroquine myopathy rat are available as animal models for AD. Elucidation of the roles of these missense mutations, and amyloid associated proteins in the cascade of AD, may provide a breakthrough to therapeutics for AD.

Alzheimer Disease↗

[Relationship between SPECT and pathological alterations in Alzheimer's disease--a study of a case with left-hemisphere dominant lesions].

123I-IMP SPECT (SPECT) has been widely used in clinical neuropsychiatry for establishing the clinical diagnosis, and evaluating the course of the disease. However, little is known about the significance of alterations in SPECT. In this paper, we present comparative study between alterations in SPECT and neuropathological findings in the case of Alzheimer's disease (AD). The patient, a 59-year-old female, began to show memory disturbance and the left hemisphere disturbances, non-fluent aphasia, but right hemisphere disturbances, constructional apraxia, visuo-spatial dysfunctions were not notable at the early stage. The neuroimaging also revealed left-side dominant cerebral atrophy in MRI and left-side dominant hypoactive regions in SPECT (especially in parietal lobe). Memory disturbance and non-fluent aphasia gradually progressed after admission. Then, mirror phenomenon and Bálint's syndrome appeared at the age of 63 years. In the advanced stage, hypoactive regions in SPECT were expanded into temporal and frontal areas. The laterality observed at the early stage became unremarkable. The patient died from heart failure at 64 years. Pathological diagnosis was AD. Eleven ROI (region of interests) were determined on each hemisphere in transverse SPECT image. We calculated ROI% (each ROI count/ROI count at central cerebellum). Neuronal cell count (NCC) and amyloid beta protein deposited areas (BDA) were estimated using 3 serial sections stained with Nissl's method and immunostained for amyloid using monoclonal antibody raised against synthetic A beta, mcAb 90/12. Digitized images based on photographs were analyzed with NIH-image 1.45. NCC decreased in number in frontal, temporal, and parietal lobes. Significant asymmetrical reduction of NCC (lt. < rt.) was observed in orbital, superior temporal and angular gyri (p < 0.01). BDA in superior parietal lobule, superior temporal gyrus and superior, middle, inferior frontal gyri were larger than those in precentral gyrus and visual cortex. Asymmetry of BDA (lt. > rt.) was significant in middle temporal gyrus (p < 0.01). ROI% at the early stage was correlated with corresponding NCC (r = 0.49, p < 0.05) and BDA (r = -0.55, p < 0.01), but at the advanced stage was not significantly correlated with corresponding NCC (r = 0.26) and BDA (r = -0.20). It is evident that SPECT shows good correlation with clinical features and pathological alterations during the course of AD. Our observations imply that the changes in SPECT usually precede the appearance of the clinical symptoms. SPECT is very sensitive in detecting the functional decline in certain regions of the CNS. In the case of AD, the hypoactive regions in SPECT at the early stage may indicate functional decline of the neuronal cells, and at the advanced stage, these may indicate the degree of pathological changes, especially neuronal loss and amyloid beta protein deposition.

Alzheimer Disease↗

Amyloid beta protein in rat soleus muscle in chloroquine-induced myopathy using end-specific antibodies for A beta 40 and A beta 42: immunohistochemical evidence for amyloid beta protein.

Previous immunohistochemical studies from this laboratory demonstrated that monoclonal antibodies raised against various regions of amyloid precursor protein (APP) (i.e., N-terminus, amyloid beta protein (A beta), and C-terminus) strongly labeled vacuoles in chloroquine-induced myopathy-affected muscle in rats. In this study, we used antibodies end specific for the A beta 40 and A beta 42 species, and a monoclonal antibody to A beta 1-9 which reacts with APP and A beta. Most vacuoles clearly reacted with anti-A beta 1-9, while about half reacted with anti-A beta 42, and only a few reacted with anti-A beta 40. These results demonstrate that vacuoles in chloroquine-induced myopathy-affected muscle contain cleaved A beta, and that distribution of the two major A beta species is similar to what is observed in A beta deposition in Alzheimer's disease (AD)-affected brain. This provides further evidence that chloroquine-induced myopathy in rats provides a suitable model to understand APP processing into A beta, and the role of APP in terms of the pathogenesis of AD.

Amyloid beta-Peptides↗

Co-localization of amyloid-associated proteins with amyloid beta in rat soleus muscle in chloroquine-induced myopathy: a possible model for amyloid beta formation in Alzheimer's disease.

Chloroquine, a potent lysosomotropic agent, induces myopathy in experimental animals similar to rimmed vacuole (RV) myopathy in humans. The abnormal accumulation of amyloid beta protein (A beta), which is the invariable pathological alterations in the brains affected by Alzheimer's disease (AD), has been demonstrated in denervated soleus muscle fibers in chloroquine-induced myopathy in rats. In AD affected brains, a variety of additional proteins are associated with the extracellular deposition of A beta, which leads to the intracellular accumulation of neurofibrillary tangles and finally to neuronal death. In this study, we demonstrate that amyloid-associated proteins, alpha 1-antichymotrypsin, apolipoprotein E, SP-40,40 and ubiquitin co-localize with A beta in vacuolated muscle fibers in chloroquine-induced myopathy. There are striking similarities in immunopathology between experimental RV myopathy and AD. Chloroquine-induced myopathy in rats provides a suitable model not only to obtain insight into the basic mechanisms underlying RV formation in muscle, but also to understand amyloid precursor protein processing into A beta, and the role of amyloid-associated proteins in terms of the pathogenesis of AD.

Alzheimer Disease↗

Effect of age on the line bisection test.

The purpose of this study was to investigate the effect of age on the line bisection test. One hundred and eight normal dextrals of various ages performed a line bisection task with each hand. They were divided into three different age groups of 36 individuals. The old age group bisected lines significantly further to the right than did the middle and young age groups. Results on the line bisection test of the middle and the young age group were not different. Our results are discussed with reference to the theory of asymmetrical decline or maturing of the hemispheric functions over age.

Adult↗

[Left unilateral spatial neglect and its relation to testing methods, neurological manifestations and lesion site].

Unilateral spatial neglect (USN) was assessed in 148 right-handed stroke patients with lesions confined to the right cerebral hemisphere. We focused our study on the USN-positive rates according to method of testing, its association with other neurological findings, and the site of the lesion on X-ray CT scans. Left USN was found in 57 of the 148 patients. There were no significant differences in positive rates on each of the 4 tasks adopted in this study. USN was significantly correlated with hemianopia but not with anosognosia for hemianopia. USN was also significantly correlated with degree of both motor and sensory impairments. Pathologically, no USN was found in patients with lesions in the prerolandic area, but the USN-positive rate was high among patients with lesions in the postrolandic lesions. These findings are discussed in comparison with those of several previous studies.

Aged↗

Immunohistochemical evidence for amyloid beta in rat soleus muscle in chloroquine-induced myopathy.

Deposition of amyloid beta (A beta) is one of the pathological hallmarks of brains affected with Alzheimer's disease (AD). The accumulation of A beta have been observed in human myopathies with rimmed vacuoles (RVs) which might involve lysosomal function. Chloroquine, a potent lysosomotropic agent, induces muscle pathology in experimental animals similar to myopathy with RV. In this study, we demonstrate, for the first time, immunohistochemical evidence that A beta and cathepsin D, a lysosomal enzyme, accumulate in vacuolated rat soleus muscle due to chloroquine-induced myopathy. These data indicate that lysosomes are important in the metabolism of amyloid precursor protein to generate A beta. This experimental system seems to be useful not only to study basic mechanisms underlying RV myopathy but also to understand processing of amyloid precursor protein to A beta in AD.

Amyloid beta-Peptides↗

Potentially amyloidogenic fragment of 50 kDa and intracellular processing of amyloid precursor protein in cells cultured under leupeptin.

The principal neuropathological feature of Alzheimer's disease is extracellular deposition of approximately 4-kDa proteinous fragment, designated as beta-amyloid peptides (beta/A4 peptides) derived by proteolytic cleavage from amyloid precursor protein (APP), a large cell-surface receptor-like protein. There has been evidence that APP is proteolytically degraded in the secretory and endosomal/lysosomal pathways. The pathway in which APP is cleaved to generate beta/A4 peptides is still not identified. To clarify the intracellular processing of APP into the generation of beta/A4 peptides, we detected and characterized potentially amyloidogenic or non-amyloidogenic fragments using newly established monoclonal and polyclonal antibodies in the cultured cells with or without leupeptin, potent lysosomal protease inhibitor of lysosome. APP fragments of 50 and 20 kDa containing full-length beta/A4 peptides were identified in the cultured cells. Immunoblot analysis, biochemical study for specific marker enzyme activity of the fractions obtained from subcellular fractionation, sucrose density gradient centrifugation indicated that the 50-kDa APP fragment was produced in the compartment closely related to endosomal/lysosomal system. Our data suggest that the endosomal/lysosomal pathway is involved in the processing and generation of beta/A4 peptides.

Amyloid↗

[Influence of age on long-term memory].

Memory for past public events having occurred between 1950-1989 was examined in Japanese subjects with average education aged forty to seventy-nine years. We compiled a public events test battery consisting of 80 multiple-choice questions regarding events, persons, or places that were prominent in the news during the four decades 1950 to 1989. With increasing age, performances of a public event test declined equivalently each decade. The effect of both age and decade was significant by three-way analysis of variance. The interaction term (age x decade) was not significant, which indicates that performance on questions relating to each decade was affected about equally by age. Performance on this test was clearly age-dependent across the time period sampled. Considering the results obtained in this study, we could conclude that aging influences very old memories as well as recent memories.

Adult↗

[Disorganized eye movements and visuospatial dysfunctions in an early stage of the patients with Alzheimer's disease--the effects of language and visual information processing on constructional performances].

In Alzheimer's disease higher brain function disorders such as geographical disorientation, visual agnosia and constructional disability are frequently observed in addition to the progressive memory loss. Visual information processing was studied through newly developed technology, vision analyzer, since visuospatial functions play an important role in the pathophysiology underlying these neuropsychiatric symptoms and dementia itself. We found characteristic findings as to eye movements of focus indicating visual cognitive disorders. Language or language functions, however, are considered to be essentially involved in visuospatial functions. We examined eye movements of patients suffering from Alzheimer's disease (15 cases), MID (5 cases), Parkinson's disease (5 cases) and 10 control subjects during constructional behavior under various conditions in terms of visual information processing. 1. Alzheimer's disease (n = 15): All patients showed constructional disabilities when copying geometrical figures. 1) Three dimensional drawing was possible following verbal instructions in 7 out of 15 patients. 2) Three dimensional drawing was successful when the model figure to be copied was covered in 4 out of these 7 patients. 3) Three dimensional drawing was possible following verbal instruction in a dark room, although they were not so accurate but better than those when copied in 4 out of 7 patients. 4) The analysis of eye movements revealed that typical eye movements were confirmed during copying geometric figures. The distribution of the gazing points of focus, and the average eye movement velocity distribution were also distinctive. But these disorganized eye movements in description of graphic figures following verbal instruction became more similar to those of healthy controls when compared to those in the copying graphic figures. 2. MID (n = 5), Parkinson disease (n = 5), healthy controls (n = 10): 1) No subject showed constructional disability when copying a graphic figure. They were also capable to describe a graphic figure both in the dark and following verbal instruction. 2) No remarkable change was observed in the distribution of the eye movement, or in the average eye movement velocity on these subjects. 3. These results indicate that in an early stage of the patients with Alzheimer's disease, primary or fundamental disorders seem to lay in the verification process of visual information, which results in the difficulties in categorization process of the visual objects. The categorization process is involved with language function, which was preserved in a certain period at an early stage of the disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Alzheimer Disease↗