Alzheimer Disease: Mizuno Y

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Wada K, Motoi Y, Komatsuzaki Y, Takanashi M, Mori H, Urabe T, Mizuno Y. · Department of Neurology, Juntendo University School of Medicine, Tokyo, Japan. · No To Shinkei. · Pubmed #16482927 No free full text.

Abstract: We report an 81-year-old patient with progressive dementia, disinhibition, and gait disturbance. He showed visuospacial disorientation, apathy, and gait disturbance at 76 years of age. When he was 77 years old, he was diagnosed Parkinson's disease and treated with the 1-dopa, the dopamine agonist, the amantadin, and the anti-cholinergic drug. These treatments didn't improve his motor disturbances. His motor disturbances, apathy, and abnormal behavior progressed gradually. He was admitted to the hospital at the age of 77. He was severely demented and akinetic. Sometime, violent behavior and hallucination were seen. The brain MRI showed frontotemporal lobe atrophy and severe leukoaraiosis of the frontal white matter. At 79 years of age, he became mute and bedridden. When he was 80 years old, large infarction occurred in his occipital lobe. He died due to renal failure and respiratory suppression at 81 years of age. His brain was examined pathologically. At the neurological CPC, the chief discussant arrived at the conclusion that his diagnosis was Binswanger's disease. Other possibilities discussed were FTD, CBD, and progressive subcortical gliosis. The post-mortem examination revealed diffuse white matter degeneration due to atherosclerotic change of the small artery, many lacunar infarctions, and severe infarction of the occipital lobe. These findings led the diagnosis of Binswanger's disease and cerebral infarction.

Yokoyama K, Ikebe S, Komatsuzaki Y, Takanashi M, Mori H, Mochizuki H, Mizuno Y. · Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421, Japan. · No To Shinkei. · Pubmed #11889767 No free full text.

Abstract: We report a 68-year-old woman who developed progressive dementia and parkinsonism. She was well until 1990 when she was 58 years of age. She started to show memory loss. Four years later, she developed difficulty in dressing and behavioral problems such as eating rice with her hands, going out of her house without purposes, and difficulty in finding the rest room in her house. She was admitted to the neurology service of Hatsuishi Hospital on January 19, 1996, when she was 64 years of the age. On admission, she was alert but markedly demented. The score of Hansegawa Dementia Scale was 0/30. She was unable to make any coherent conversation. She appeared to have dressing apraxia but did not appear to have aphasia. Cranial nerves were intact. She walked in small steps with stooped posture. She did not have motor weakness but she showed plastic rigidity in all four limbs. No tremor or ataxia was noted. Deep tendon reflexes were within normal limits but the plantar response was extensor bilaterally. She continued to deteriorate after admission. In May of 1998, she started to fall. In June of 1998, she had a generalized convulsion. In January of 1999, she became unable to take foods orally and a gastrostomy was placed. She expired on May 29, 1990. She was discussed in a neurological CPC and the chief discussant arrived at the conclusion that the patient had Alzheimer's disease. The question was whether her parkinsonism was a part of her Alzheimer's disease or she had an additional disease to explain her parkinsonism. Post-mortem examination revealed moderate to marked atrophy of the frontal and the temporal lobes as well as in the limbic areas with dilatation of the lateral ventricles. Marked neuronal loss was noted in the CA 1 to the subiculum region with gliosis. Neurofibrillary tangles were seen in the remaining neurons. Neuropil threads were seen by Gallyas-Braak staining. Similar changes were seen in the parahippocampal gyrus and in the entorhinal cortex. Senile plaques were seen in the insular cortex and in other cortical areas. Cortical type Lewy bodies were seen in the cingulate cortex. The Meynert nucleus showed marked neuronal loss and gliosis. The substantia nigra and the locus coeruleus showed moderate loss of pigmented neurons. Lewy bodies were seen in these regions. The dorsal motor nucleus of the vagal nerve was retained, however, one Lewy body was observed. Pathologic diagnosis was Alzheimer's disease plus Parkinson's disease. It is an interesting question whether or not her parkinsonism was due to nigral lesion or frontal lesions. It is known that parkinsonism may complicate in advanced Alzheimer's disease not necessarily due to nigral lesion. On the other hand, in incidental Lewy body disease, the substantia nigra shows mild Parkinson's disease-like change without clinical parkinsonism. This patient appeared to have been a true complication of Alzheimer's disease and Parkinson's disease.

Kanazawa A, Ikebe S, Komatsuzaki Y, Takanashi M, Mori H, Mochizuki H, Mizuno Y. · Department of Neurology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo, Tokyo 113-8421. · No To Shinkei. · Pubmed #11277107 No free full text.

Abstract: We report an 84-year-old woman with progressive mental deterioration. She was well until January 1994, when she was 80 years of the age. At that time she developed a delusional ideation, in that she stated that she would be killed by her fellow members of the society for elderly, in which she was belonging. At times, she closed the shutter of her house saying that a stranger was wandering outside of her house. In 1995, she could not identify the face of her son's wife. When she went out for shopping, she lost her way to the home. She prowled about in and out of her home. In 1996, she had to be admitted to a nursing home, where quarrelled with other patients and behaved violently. She was admitted to the neurology service of Hatsuishi Hospital on November 20th, 1997. Family history revealed that her mother was said to be demented. On admission, she was alert and behaved in a good manner. She was disoriented to the time and unable to do serial 7. Her memory was very poor. She did not show aphasia or apraxia. Cranial nerves appeared to be intact. She showed no weakness or muscle atrophy. Gait was normal for her age. Plastic rigidity was noted in four limbs more on the right side. No ataxia was noted. Deep tendon reflexes were exaggerated, however, no Babinski sign was noted. Sensory examination was intact. Her hospital course was characterized by the development of progressive gait disturbance, violent behaviour, and prowling around. On November 30th, 1998, she fell down and suffered from a fracture in the neck of her femur. Although replacement of the femur head was performed, she became unable to walk after this episode. Her mental functions deteriorated further. She developed pneumonia and expired on February 2, 1999. She was discussed in a neurological CPC and the chief discussant arrived at a conclusion that the patient probably had diffuse Lewy body disease, because of the combination of dementia and parkinsonism. Other possibilities discussed in the CPC included Pick's disease, frontotemporal dementia and parkinsonism, and Alzheimer's disease. Post-mortem examination revealed moderate atrophy in the frontal and temporal cortices. Microscopic examination showed atrophy and gliosis in the hippocampus. Many diffuse plaque and neuritic plaques were seen in the frontal cortex by methenamine silver staining. Neurofibrillary tangles were also found. The Meynert nucleus was preserved. The putamen and the substantia nigra were also intact. Pathologic diagnosis was consistent with Alzheimer's disease.

Ukai K, Mizuno Y, Ito T, Ozaki K, Tomita K. · Department of Psychogeriatrics, Imaise Branch, Ichinomiya City Hospital. · Seishin Shinkeigaku Zasshi. · Pubmed #19068746 No free full text.

Abstract: The difficulties regarding the diagnosis and treatment of physical complications of senile dementia were considered through focusing on a case of Alzheimer's disease with severe anemia. The first problem encountered is related to medical policies. Recently, there is growing concern about the lack of facilities dealing with physical complications of senile dementia. Few psychiatric hospitals can provide a complete diagnosis and treatment of such complications. In addition, it is economically very difficult to diagnose and treat them in wards for the elderly with senile dementia within the existing medical fee system. It is also very difficult in general hospitals, because most do not have the beds to deal with the behavioral and psychological symptoms of dementia. The second issue regards problems with patients. Many patients with senile dementia do not realize that they are ill. It is difficult to obtain their informed consent, and they often have a sudden change of mind. The third issue concerns problems with the patient's family. It is also difficult to obtain the family's consent because of the death of a spouse and/or children of patients with senile dementia, and/or their weak family ties. The fourth problem involves the recognition of physicians in medical departments who must diagnose and treat physical complications. Their prejudices regarding mental disorders must be brought into the open, and they may well have a similar prejudice regarding dementia. It is a considerable physical and mental load, even for medical doctors without bias in relation to dementia, to frequently obtain informed consent from elderly persons with senile dementia and their non-cooperative families. Despite the various problems mentioned above, if appropriate diagnoses and treatments of physical complications are carried out, it is natural even for the elderly with senile dementia to obtain good prognoses and QOL. Doctors must diagnose and treat physical complications of the elderly with senile dementia, considering their physical and mental conditions, giving due consideration to the treatments possibilities for various diseases, and having careful discussions with patients and their families, while making use of every available method of diagnosis and treatment. Close cooperation with other unbiased medical doctors is extremely important.

Mizuno Y, Ohama E, Hirato J, Nakazato Y, Takahashi H, Takatama M, Takeuchi T, Okamoto K. · Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. · J Neurol Sci. · Pubmed #16616189 No free full text.

Abstract: Nestin, an intermediate filament protein, is mainly expressed in neural progenitor/stem cells in the central nervous system. Recently, we reported that nestin is expressed in Purkinje cells in patients with Creutzfeldt-Jakob disease (CJD). In this study, we examined a total of 19 CJD cerebella to analyze the intensity and pattern of nestin immunoreactivity of Purkinje cells in different pathological stages of degeneration in the cerebellar cortex. The results showed that the Purkinje cells were immunoreactive with nestin regardless of the severity of degenerative cerebellar cortex. Furthermore, we noted several different types of nestin immunoreactivity, indicated by diffuse and fine, coarse, and inclusion-like immunostainings within Purkinje cell bodies as well as dot-like staining outside of the cell bodies. In contrast, on examination of cerebella from non-CJD patients, 6 of 30 cases showed nestin immunoreactivity to a lesser extent. Thus, nestin-positive Purkinje cells are more common in CJD cerebella than in non-CJD cerebella. Although the mechanism of nestin expression in Purkinje cells is not yet understood, we suggest that such nestin-positive Purkinje cells are being reactivated to survive the cell death.

Takeda A, Kawai Y, Hattori Y, Watanabe Y, Mizuno Y, Tabata O, Kawamura Y, Shibayama H, Sobue G. · Department of Neurology, Nagoya University Graduate School of Medicine. · Nippon Ronen Igakkai Zasshi. · Pubmed #15387284 No free full text.

Abstract: We developed a brief scale to evaluate communication ability of the demented elderly. This scale assesses not only abilities related to overall communication such as verbal function, judgment and emotional function, but also non-verbal communication such as eye-contact, nodding and smiling. The scale places little burden on the demented elderly subject and takes only a few minutes to perform, even if the dementia is severe. We evaluated 106 demented elderly residents of nursing homes using this brief communication ability scale, and the following results were obtained. The validity of this scale was confirmed by the high correlation coefficient between this scale and the formal caregiver questionnaire scores concerning communication ability, and the high-correlation coefficient between this scale and intellectual functions (r = -0.904), emotional functions (r = -0.841) and motor functions (r = -0.679) of dementia syndromes rating scale (Gottfries, Bråne, Steen scale; GBS scale), Hasegawa's Dementia Scale-Revised (HDS-R) (r = 0.625) and the Mini-Mental State Examination (MMS) (r = 0.733). The reliability of this scale was confirmed by the high interrater reliability coefficient of 0.828, test-retest reliability coefficient of 0.940 and Cronbach alpha coefficient of 0.938. These results indicate that the new scale is useful in the assessment of communication ability among the demented elderly.

Mizuno Y, Ikeda K, Tsuchiya K, Ishihara R, Shibayama H. · Obu Dementia Care Research and Training Center, Department of Research, Aichi, Japan. · Neuropathology. · Pubmed #14719543 No free full text.

Abstract: The heterogeneity of senile dementia of Alzheimer type (SDAT) has been suggested by some authors clinically and neuropathologically. The heterogeneity of SDAT was investigated based on quantification of NFT combining Braak and Braak's neuropathological staging and the density of NFT in various areas of the cerebral cortex. Brain tissues were examined from 16 autopsy cases with clinically late onset dementia (> age 65) and neuropathologically diagnosed dementia of Alzheimer type (DAT). Gallyas-Braak staining was used for the quantification of NFT. The density of NFT was examined in the precentral gyrus, middle temporal gyrus (T2), parahippocampal gyrus and the amygdaloid nucleus. The 16 cases studied were divided into two groups depending on the number of NFT in the cortex (cut-off score: 5/mm2): the AD-like group (NFT > or = 5/mm2) and the common group (NFT < 5/mm2). The density of NFT in the precentral gyrus (t(3.225) = -9.007, P = 0.002) and T2 (t(3.365) = -3.774, P = 0.027) in the AD-like group was significantly higher than those in the common group. However, no significant difference was observed in the parahippocampal gyrus between the two groups (t(14) = -0.318, NS). Moreover, there were no significant differences between the two groups as regards age at onset and the duration of the illness. The present study revealed the possible existence of two subgroups in SDAT having significantly different NFT densities in various areas of the cerebral cortex without any significant difference in their duration of illness. This classification has no relationship to Braak and Braak's staging, which depends only on the distribution of NFT, irrespective of their density. Arai et al. revealed that the NFT density in AD was significantly higher than in SDAT. We suggest that the neuropathological findings of the AD-like group in SDAT resemble those of presenile AD.

Mizuno Y, Hori S, Kakizuka A, Okamoto K. · Department of Neurology, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. · Neurosci Lett. · Pubmed #12759168 No free full text.

Abstract: Vacuole-creating protein (VCP) is a member of the ATPases associated with diverse cellular activities and is a putative sensor protein for degenerative proteins. Immunohistochemical examinations demonstrated that VCP was observed in ubiquitin-positive intraneuronal inclusions in motor neuron disease with dementia, ballooned neurons in Creutzfeldt-Jakob disease, dystrophic neurites of senile plaque in Alzheimer's disease, and Lewy and Marinesco bodies and Lewy neurites in Parkinson's disease, while granules of granulovacuolar degeneration and neurofibrillary tangles in Alzheimer's disease were not positively stained for VCP. These results indicate that VCP reacts with abnormal or misfolded proteins and plays a role in accelerating the process of degeneration and cell death. The elucidation of an association between VCP and these degenerative proteins will provide an important clue for understanding common mechanisms underlying neurodegenerative diseases.

Ishihara R, Ide-Ektessabi A, Ikeda K, Mizuno Y, Fujisawa S, Takeuchi T, Ohta T. · Department of Psycgiatry, Nagoya University Graduate School of Medicine, Japan. · Neuroreport. · Pubmed #12395131 No free full text.

Abstract: The purpose of this report is to introduce the potential of synchrotron radiation X-ray fluorescence (SRXRF) spectroscopy, by describing the application of this method to mapping and quantification of metallic elements in neurons from brain tissues affected by Alzheimer's disease (AD). In this study, clear images of Fe, Zn and Ca within certain single neurons were obtained. There was a high degree of correlation between Zn and Ca in the groups of cells with lower and relatively higher levels of Ca. These results demonstrate that further investigation with larger numbers of neurons using SRXRF spectroscopy may contribute to advancing the knowledge of the mechanisms of metal-induced cell degeneration in human brain tissues, including those affected by AD.

Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T. · Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. · Nat Genet. · Pubmed #10888878 No free full text.

Abstract: Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.

Motoi Y, Iwamoto H, Itaya M, Kobayashi T, Hasegawa M, Yasuda M, Mizuno Y, Mori H. · No affiliation provided · Acta Neuropathol. · Pubmed #16158330 No free full text.

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