Alzheimer Disease: Yamada M

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.

Hirohata M, Ono K, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan. · Curr Pharm Des. · Pubmed #19075706 No free full text.

Abstract: Amyloidosis is a clinical disorder caused by deposition of proteins that abnormally self-assemble into insoluble fibrils and impair organ function. More than 20 unrelated precursor proteins lose their native structure and misfold, leading to the formation of amyloid fibrils. The latter share cross-beta core structure in vivo and in vitro and gain abnormal functions. Local amyloid deposition occurs in the central nervous system in Alzheimer's disease (AD) and cerebral amyloid angiopathy. AD is the most common form of neurodegenerative disorder, with dementia in the elderly as well as dementia with Lewy bodies (DLB). Extracellular deposition of amyloid beta-peptide (Abeta) has been implicated as a critical step in the pathogenesis of AD. Involvement of neuroinflammation and microglial activation has been emphasized in the AD brain. Recent epidemiological studies have shown that long-term therapeutic use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delayed the onset of AD. We review epidemiological studies of anti-AD effects of NSAIDs, experimental studies of anti-amyloidogenic as well as anti-inflammatory effects of NSAIDs, and recent clinical trials for AD with NSAIDs. We refer to the anti-fibrillogenic and fibril-destabilizing activities of NSAIDs for other proteins that can aggregate and form amyloid-like fibrils, including alpha-synuclein in DLB. The anti-amyloidogenic properties of some NSAIDs provide new insights for future therapeutic and preventative opportunities for AD and other amyloidoses, and protein-misfolding disorders.

Hamaguchi T, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13 1 Takara-machi, Kanazawa 920-8641, Japan. · Brain Nerve. · Pubmed #19069161 No free full text.

Abstract: Cerebral amyloid angiopathy (CAA) is cerebrovascular amyloid deposition and is related to stroke and dementia. CAA is classified into 6 types according to the biochemical properties of amyloid proteins, and among 6 types, the sporadic CAA of amyloid beta protein (Abeta) type is most frequently found in elderly people or patients with Alzheimer's disease (AD). In sporadic CAA of the Abeta type, the epsilon4 allele of the apolipoprotein E gene is associated with increased vascular Abeta deposition, while the epsilon2 allele is associated with CAA-related intracerebral hemorrhage. We have also reported that the genetic polymorphisms of presenilin-1, neprilysin, transforming growth factor beta-1, and alpha1-antichymotrypsin are associated with CAA. In the case of hereditary CAA of the Abeta type, mutations in the genes of amyloid precursor protein (APP) and presenilins have been reported. Interestingly, the missense mutations associated with CAA are located in the middle portion of Abeta, while those associated with familial AD (FAD) are near the N- or C- terminals of Abeta. Individuals with FAD with APP duplication have been reported to present with severe CAA. Some of the FAD patients with mutations in the presenilin genes and patients with Down syndrome also show CAA as a complication. Besides sporadic or hereditary CAA of the Abeta type, hereditary CAA with cerebrovascular deposition of cystatin C, transthyretin, gelsolin, prion protein, and ABri/ADan have also been reported in association with mutations in the genes of the precursor proteins. Better understanding of the genetic factors influencing CAA will lead to identification of novel diagnostic markers and the development of preventive for CAA and CAA-related disorders.

Ono K, Naiki H, Yamada M. · Department of Neurology & Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan. · Curr Pharm Des. · Pubmed #17105432 No free full text.

Abstract: Neuritic plaques composed mainly of amyloid beta-protein (Abeta) in the brain are an early and invariant neuropathological feature of Alzheimer's disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of Abeta deposition in the brain. In this article, the recent development of the molecules that inhibit the formation of beta-amyloid fibrils (fAbeta), as well as destabilize preformed fAbeta is reviewed. Recently, various compounds such as curcumin, nicotine and wine-related polyphenols have been reported to inhibit the formation, extension of fAbeta, as well as destabilize preformed fAbeta at pH 7.5 at 37 degrees C in vitro. In cell culture experiments, destabilized fAbeta were suggested to be less toxic than intact fAbeta. In transgenic mice model study, some coumpounds such as curcumin and nicotine have also been reported to reduce plaque burden in vivo. Although the mechanisms by which these compounds inhibit fAbeta formation from Abeta, and destabilize preformed fAbeta are still unclear, they could be key molecules for the development of preventives and therapeutics for AD.

Hamaguchi T, Ono K, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa, 920-8640, Japan. · Cell Mol Life Sci. · Pubmed #16804637 No free full text.

Abstract: Deposition of amyloid beta-protein (Abeta) in the brain is an early and invariant neuropathological feature of Alzheimer's disease (AD). The current search for anti-AD drugs is mainly focused on modification of the process of accumulation of Abeta in the brain. Here, we review four anti-amyloidogenic strategies: (i) reduction of Abeta production, which has mainly been approached with secretase inhibition, (ii) promotion of the Abeta degrading catabolic pathway, including an Abeta degrading enzyme, neprilysin, (iii) immunotherapy for Abeta and (iv) inhibition of Abeta aggregation. We have reported that AD patients have a favorable molecular environment for Abeta aggregation and that various compounds, such as polyphenols, interfere with Abeta aggregation and destabilize preformed Abeta fibrils.

Ono K, Hamaguchi T, Naiki H, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan. · Biochim Biophys Acta. · Pubmed #16644188 No free full text.

Abstract: Alzheimer's disease (AD) is one of the most common dementing disorders and has profound medical and social consequences. The initiating molecular event is unknown, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in this disorder, and many studies using surrogate markers of oxidative damage have provided evidence supporting this hypothesis. Various compounds with antioxidant ability attenuated the oxidative stress induced by amyloid beta-protein (Abeta) in studies done in vitro and in vivo. Moreover, various antioxidants have been reported to inhibit the formation and extension of beta-amyloid fibrils (fAbeta), as well as to destabilize preformed fAbeta in vitro. In cell culture experiments, destabilized fAbeta were suggested to be less toxic than intact fAbeta. In transgenic mice model studies, some antioxidant compounds reduced plaque burden in vivo. In this article, we review the recent advances in the research on the antioxidants that inhibit the formation of fAbeta, as well as destabilize preformed fAbeta. Although the mechanisms by which these compounds inhibit fAbeta formation from Abeta, and destabilize preformed fAbeta are still unclear, they could be key molecules for the development of preventives and therapeutics for AD.

Hamaguchi T, Kitamoto T, Sato T, Mizusawa H, Nakamura Y, Noguchi M, Furukawa Y, Ishida C, Kuji I, Mitani K, Murayama S, Kohriyama T, Katayama S, Yamashita M, Yamamoto T, Udaka F, Kawakami A, Ihara Y, Nishinaka T, Kuroda S, Suzuki N, Shiga Y, Arai H, Maruyama M, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Takara-machi, Kanazawa, Japan. · Neurology. · Pubmed #15728285 No free full text.

Abstract: BACKGROUND: No method for the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease (sCJD) has been established except for pathologic examination. OBJECTIVE: To identify a reliable marker for the clinical diagnosis of MM2-type sCJD. METHODS: CSF, EEG, and neuroimaging studies were performed in eight patients with MM2-type sCJD confirmed by neuropathologic, genetic, and western blot analyses. RESULTS: The eight cases were pathologically classified into the cortical (n = 2), thalamic (n = 5), and combined (corticothalamic) (n = 1) forms. The cortical form was characterized by late-onset, slowly progressive dementia, cortical hyperintensity signals on diffusion-weighted imaging (DWI) of brain, and elevated levels of CSF 14-3-3 protein. The thalamic form showed various neurologic manifestations including dementia, ataxia, and pyramidal and extrapyramidal signs with onset at various ages and relatively long disease duration. Characteristic EEG and MRI abnormalities were almost absent. However, all four patients examined with cerebral blood flow (CBF) study using SPECT showed reduction of the CBF in the thalamus as well as the cerebral cortex. The combined form had features of both the cortical and the thalamic forms, showing cortical hyperintensity signals on DWI and hypometabolism of the thalamus on [18F]2-fluoro-2-deoxy-d-glucose PET. CONCLUSION: For the clinical diagnosis of MM2-type sporadic Creutzfeldt-Jakob disease, cortical hyperintensity signals on diffusion-weighted MRI are useful for the cortical form and thalamic hypoperfusion or hypometabolism on cerebral blood flow SPECT or [18F]2-fluoro-2-deoxy-d-glucose PET for the thalamic form.

Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1, Takara-machi, Kanazawa 920-8640, Japan. · J Neurol Sci. · Pubmed #15537517 No free full text.

Abstract: Cerebral amyloid angiopathy (CAA) is characterized by cerebrovascular amyloid deposition, associated with intracerebral hemorrhage and other cerebrovascular disorders and dementia. Several types of CAA have been identified in association with various amyloid proteins including amyloid beta protein (Abeta), cystatin C, prion protein, ABri/ADan, transthyretin, and gelsolin. Hereditary forms of CAA are associated with mutations in the genes coding these proteins or their precursors. Sporadic CAA of Abeta type is most common in elderly individuals as well as patients with Alzheimer disease (AD). Several gene polymorphisms have been reported to be associated with sporadic CAA or CAA-related hemorrhage, including apolipoprotein E (APOE), presenilin 1 (PS1), and alpha1-antichymotrypsin (ACT). As for the APOE, which has been well studied for CAA as well as AD and Abeta deposition, the epsilon4 allele is found to be associated with CAA, and the epsilon2 with CAA-related hemorrhage. Recently, we investigated whether gene polymorphisms of neprilysin (NEP), an Abeta-degrading enzyme, and the transforming growth factor (TGF)-beta1 (TGF-beta1), a multifunctional cytokine implicated in Abeta deposition, are associated with sporadic CAA. Concerning a GT repeat polymorphism in the enhancer/promoter region of the NEP, the shorter repeat alleles were associated with the CAA severity. The T/C polymorphism at codon 10 in exon 1 of the TGF-beta1 was also associated with the severity of CAA. These data suggest that multiple gene polymorphisms, including molecules related to the Abeta cascade, could be associated with the risk of sporadic CAA.

Nicoll JA, Yamada M, Frackowiak J, Mazur-Kolecka B, Weller RO. · Clinical Neurosciences, University of Southampton, Southampton General Hospital, Mailpoint 813, Southampton, SO 16 6YD, UK. · Neurobiol Aging. · Pubmed #15172734 No free full text.

Abstract: For the purposes of this debate here we argue the case that cerebral amyloid angiopathy (CAA) has a direct role in the pathogenesis of Alzheimer's disease (AD). Firstly, there is a very close relationship between CAA and AD and they share genetic risk factors. Secondly, we propose a specific mechanism which puts age-related cerebrovascular degeneration at a crucial point in the pathogenesis of AD as follows. Amyloid beta-protein (Abeta) is normally eliminated from the brain along with extracellular fluid by bulk flow along the perivascular pathway. Age-related fibrosis of cerebral cortical and meningeal arteries leads to impaired drainage of Abeta along the perivascular pathway and, together with the production of Abeta by smooth muscle cells and perivascular cells, is responsible for accumulation of Abeta as CAA. Reduced elimination leads to increased concentration of soluble Abeta in the extracellular fluid of the brain parenchyma. Increased concentration of soluble Abeta leads to the formation of insoluble Abeta plaques, other features of AD pathology, and dementia.

Yamada M, Yasuhara H. · Department of Psychiatry, Showa University Karasuyama Hospital, 6-11-11 Kitakarasuyama, Setagaya, Tokyo 157-8577, Japan. · Neurotoxicology. · Pubmed #14697896 No free full text.

Abstract: In this article, we review the clinical pharmacology of monoamine oxidase inhibitors (MAOIs). Now, MAOIs are used for the treatment of depressive disorders, anxiety disorders, Parkinson's disease, and Alzheimer's disease. The selective monoamine oxidase-B inhibitor selegiline and the selective and reversible inhibitor of monoamine oxidase-A (RIMA) moclobemide are free from the hypertensive crisis, the so-called "cheese effect." Therefore, selective MAO-B inhibitors and RIMAs hold promise as safer alternatives to classical MAOIs. It is clear that much remains to be investigated with regard to the clinical pharmacology of MAOIs. It seems obvious that a greater understanding of the pharmacodynamics and pharmacokinetics of MAOIs could result in improved treatment of the patients in the future.

Grammas P, Yamada M, Zlokovic B. · Department of Pathology and the Oklahoma Center for Neuroscience, University of Oklahoma Health Science Center, 975 NE 10th Street, Biomedical Research Center, Oklahoma City, OK 73104, USA. · J Alzheimers Dis. · Pubmed #12226540 No free full text.

Abstract: Neuronal cell death is the primary underlying pathogenic lesion in Alzheimer's disease (AD). Despite intense research efforts, the mechanisms that contribute to neuronal cell death have not been clarified. In this debate we address the question, Is AD a vascular or metabolic disorder? Here we defend the hypothesis that the cerebromicrovasculature is a key player in the pathogenesis of AD. Evidence is presented that vascular amyloid beta (Abeta) is more closely associated with tau pathology than the distribution of diffuse or neuritic plaque Abeta. Furthermore, brain endothelial cells are identified as important regulators of the neuronal microenvironment, including Abeta levels. Finally, evidence is presented that brain endothelial cells undergo cellular and biochemical changes in AD and that the release of neurotoxic factors from these dysfunctional cells contributes to the neuronal cell loss characteristic of AD.

Yamada M. · Department of Neurology & Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa 920-8640, Japan. · No To Shinkei. · Pubmed #11761907 No free full text.

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Yamada M. · Department of Neurology, Kanazawa University School of Medicine, Japan. · Neuropathology. · Pubmed #10935432 No free full text.

Abstract: Cerebral amyloid angiopathy (CAA) is characterized by amyloid deposition in cortical and leptomeningeal vessels. Several cerebrovascular amyloid proteins (amyloid beta-protein (Abeta), cystatin C (ACys), prion protein (AScr), transthyretin (ATTR), gelsolin (AGel), and ABri (or A-WD)) have been identified, leading to the classification of several types of CAA. Sporadic CAA of Abeta type is commonly found in elderly individuals and patients with Alzheimer's disease. Cerebral amyloid angiopathy is an important cause of cerebrovascular disorders including lobar cerebral hemorrhage, leukoencephalopathy, and small cortical hemorrhage and infarction. We review the clinicopathological and molecular aspects of CAA and discuss the pathogenesis of CAA with future perspectives.

Yamada M, Kasagi F, Mimori Y, Miyachi T, Ohshita T, Sasaki H. · Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan. · J Neurol Sci. · Pubmed #19327783 No free full text.

Abstract: Radiotherapy has been reported to cause neuropsychological dysfunction. Here we examined whether exposure to atomic bomb radiation affected the incidence of dementia among 2286 atomic bomb survivors and controls - all members of the Adult Health Study cohort. Study subjects were non-demented and aged >or=60 years at baseline examination and had been exposed in 1945 at >or=13 years of age to a relatively low dose (<or=4 Gy), compared with total dose from radiotherapy. Dementia diagnoses were made during biennial health examinations with a two-phase procedure. DSM IV criteria were used for diagnosing dementia, NINCDS-ADRDA for Alzheimer disease, and NINDS-AIREN for vascular disease. To estimate the effect of radiation on the dementia incidence rate, we applied Poisson regression analysis. Incidence per 1000 person-years was 16.3 in the <5 mGy group, 17.0 in the 5-499 mGy group, and 15.2 in the >or=500 mGy group. Alzheimer disease was the predominant type of dementia in each dose category. After adjustment for potential risk factors, radiation exposure did not affect the incidence rate of either all dementia or any of its subtypes. No case of dementia had a history of therapeutic cranial irradiation. Although we found no relationship between radiation exposure and the development of dementia among atomic bomb survivors exposed at >or=13 years old in this longitudinal study, effects on increased risk of early death among atomic bomb survivors will be considered.

Yamada M, Mimori Y, Kasagi F, Miyachi T, Ohshita T, Sasaki H. · Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan. · J Neurol Sci. · Pubmed #19268313 No free full text.

Abstract: BACKGROUND: Although dementia has a great impact on public health, there are few reports on dementia incidence and risk factors for Asian populations. OBJECTIVES: To determine incidence and risk factors of dementia, Alzheimer disease (AD), and vascular dementia (VaD) among Japanese women. METHODS: Between 1992 and 1996, 1637 non-demented women aged > or =60 years were followed for an average of 5.9 years in RERF's Adult Health Study. Dementia diagnoses were made during biennial health examinations using a two-phase procedure. DSM IV criteria were used for diagnosing dementia, NINCDS-ADRDA for AD, and NINDS-AIREN for VaD. Potential risk factors were analyzed using Poisson regression analysis. RESULTS: 161 cases of dementia (109 of AD and 56 of VaD, based on individual criteria) were newly diagnosed. Incidence increased dramatically with age, especially for AD. Probable AD decreased with increasing education level. Probable VaD was significantly associated with hypertension and stroke. Age at menopause did not show any effect on dementia. All dementia and probable AD were significantly associated with grip strength. CONCLUSIONS: AD is predominant in dementia incidence among Japanese women. Modification of stroke risk factors and improvement of physical fitness may help prevent dementia.

Noguchi-Shinohara M, Tokuda T, Yoshita M, Kasai T, Ono K, Nakagawa M, El-Agnaf OM, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. · Brain Res. · Pubmed #19071095 No free full text.

Abstract: Dementia with Lewy bodies (DLB) is characterized by widespread depositions of alpha-synuclein, which are described as Lewy bodies. Recently, it was shown that neuronal cells in culture constitutively release alpha-synuclein into the culture medium and that alpha-synuclein is normally present in human cerebrospinal fluid (CSF). The aim of the present study was to evaluate the diagnostic value of CSF alpha-synuclein levels in discriminating DLB from Alzheimer's disease (AD). Alpha-synuclein was measured in CSF from 16 patients with DLB and 21 patients with AD. Iodine-123 metaiodobenzylguanidine cardiac scintigraphy was also performed to assess Lewy body pathology. CSF alpha-synuclein levels did not differ significantly between DLB and AD patients. However, the duration of illness was associated with lower alpha-synuclein levels (p<0.05) in DLB, while no such association was found in AD. The present data show CSF alpha-synuclein levels are not sensitive diagnostic markers to discriminate DLB from AD. However, the lower alpha-synuclein levels in DLB patients with longer duration suggest a reduction in CSF alpha-synuclein in association with increased severity of alpha-synucleinopathy in the brain.

Chiba T, Yamada M, Sasabe J, Terashita K, Shimoda M, Matsuoka M, Aiso S. · Department of Anatomy, School of Medicine, KEIO University, Tokyo, Japan. · Mol Psychiatry. · Pubmed #18813209 No free full text.

Abstract: Elevation of intracranial soluble amyloid-beta (Abeta) levels has been implicated in the pathogenesis of Alzheimer's disease (AD). Intracellular events in neurons, which lead to memory loss in AD, however, remain elusive. Humanin (HN) is a short neuroprotective peptide abolishing Abeta neurotoxicity. Recently, we found that HN derivatives activate the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis. We here report that an HN derivative named colivelin completely restored cognitive function in an AD model (Tg2576) by activating the JAK2/STAT3 axis. In accordance, immunofluorescence staining using a specific antibody against phospho- (p-) STAT3 revealed that p-STAT3 levels in hippocampal neurons age-dependently decreased in both AD model mice and AD patients. Intracerebroventricular administration of Abeta1-42 downregulated p-STAT3 whereas passive immunization with anti-Abeta antibody conversely restored hippocampal p-STAT3 levels in Tg2576 mice, paralleling the decrease in the brain Abeta burden. Abeta1-42 consistently modulated p-STAT3 levels in primary neurons. Pharmacological inhibition of the JAK2/STAT3 axis not only induced significant loss of spatial working memory by downregulating an acetylcholine-producing enzyme choline acetyltransferase but also desensitized the M(1)-type muscarinic acetylcholine receptor. Thus, we propose a novel theory accounting for memory impairment related to AD: Abeta-dependent inactivation of the JAK2/STAT3 axis causes memory loss through cholinergic dysfunction. Our findings provide not only a novel pathological hallmark in AD but also a novel target in AD therapy.

Nozaki I, Watanabe T, Kawaguchi M, Akatsu H, Tsuneyama K, Yamamoto Y, Ohe K, Yonekura H, Yamada M, Yamamoto H. · Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. · Arch Histol Cytol. · Pubmed #18431028 links to  free full text

Abstract: The receptor for advanced glycation endproducts (RAGE) is a cell-surface multiligand receptor, which interacts with amyloid beta (Abeta), a key protein in Alzheimer's disease (AD). RAGE-Abeta interaction is thought to be associated with pathological progression in AD. A splice variant of RAGE, endogenous secretory RAGE (esRAGE) can act as a decoy receptor for RAGE ligands that would prevent the progression of some pathologic conditions. In this study, the expression of esRAGE in the hippocampal tissues from AD brains compared with control (non-AD) was examined by immunohistochemistry and Western blot analysis. Semiquantitative immunohistochemical analysis of hippocampal tissues using esRAGE-specific antibody revealed significantly decreased immunoreactivities in pyramidal cells in CA1 and CA3 regions of AD compared with non-AD. On the other hand, immunoreactivities of astrocytes for esRAGE significantly increased in those regions. Dentate granule cells and astrocytes showed essentially invariant immunoreactivities between AD and non-AD. Changes in esRAGE immunoreactivity in CA3 neurons and astrocytes were observed from the early pathological stages. Moreover, the esRAGE-immunoreactive bands of AD samples were weaker than those of non-AD samples in Western blot analysis. The results indicate that low expression of esRAGE in the hippocampus would be associated with the development of AD.

Yamada M, Mimori Y, Kasagi F, Miyachi T, Ohshita T, Sudoh S, Ikeda J, Matsui K, Nakamura S, Matsumoto M, Fujiwara S, Sasaki H. · Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan. · Neuroepidemiology. · Pubmed #18382114 No free full text.

Abstract: OBJECTIVE: To determine the age-, sex-, and subtype-specific incidence of dementia and to assess the effect of education level on the incidence in a Japanese population. METHODS: 2,286 dementia-free subjects, aged > or =60 years, were followed for 5.9 years through biennial two-phase examinations. RESULTS: 206 cases of dementia were newly diagnosed based on DSM IV. The incidence per 1,000 person-years was 12.0 for men and 16.6 for women. Based on NINCDS-ADRDA criteria, 80 cases of probable Alzheimer disease (AD) and 50 cases of possible AD were diagnosed. Based on NINDS-AIREN criteria, 36 cases of probable vascular dementia (VaD) and 40 cases of possible VaD were diagnosed. Age and education showed the most statistically significant effects for all dementia. Probable AD showed the most remarkable increase with age and decreased with increasing education level (p = 0.001). Probable VaD showed significant effects of sex (p = 0.033) and sex-age interaction (p = 0.048), but not education (p = 0.26). CONCLUSION: AD was the predominant type of dementia in this recent incidence study conducted in Japan, suggesting a reduction in VaD and an increase in AD. Age, sex, and education effects differed by dementia subtype.

Chen WP, Samuraki M, Yanase D, Shima K, Takeda N, Ono K, Yoshita M, Nishimura S, Yamada M, Matsunari I. · Medical and Pharmacological Research Center Foundation, Wo 32, Inoyama, Hakui, Ishikawa, Japan. · Nucl Med Commun. · Pubmed #18349798 No free full text.

Abstract: OBJECTIVE: To investigate the relationship between the sample size for a normal database (NDB) and diagnostic performance of FDG PET using three-dimensional stereotactic surface projection for the detection of Alzheimer's disease. METHODS: We generated nine NDB sets consisting of 4, 6, 8, 10, 20, 30, 40, 50 and 60 normal subjects. In order to assess the diagnostic performance using these NDBs to distinguish Alzheimer's disease patients from normal subjects, we recruited 52 patients with probable Alzheimer's disease (25 males, 27 females; mean age, 66.8+/-8.1 years) and 50 normal subjects (24 males, 26 females; mean age, 65.7+/-9.4 years). A receiver operating characteristic (ROC) analysis was performed for comparison of diagnostic accuracy among NDB sets. RESULTS: Small NDBs (n< or =10) yielded poor quality of mean and SD images as compared with large NDBs (n> or =20). The ROC curves of the smaller group varied inconsistently, whereas those of the larger group were nearly superimposable. The area under the ROC curve (AUC) of the NDBs with sample size 6 (0.911) or 8 (0.929) was significantly smaller than that of the largest NDB (n=60, 0.956). The AUCs of the larger group did not fall below 0.950, whereas AUCs of the smaller subgroup never exceeded 0.950. CONCLUSIONS: Our data indicate that the sample size for an NDB affects the diagnostic performance of FDG PET using automated statistical approach, and that inclusion of at least 10 subjects is recommended, and 20 seems to be preferable for generating NDBs, although even a small NDB may provide clinically relevant results.

Matsumoto Y, Yanase D, Noguchi-Shinohara M, Ono K, Yoshita M, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan. · Dement Geriatr Cogn Disord. · Pubmed #18097142 No free full text.

Abstract: BACKGROUND/AIM: Intrathecal inflammation has been suggested to play an important role in the pathogenesis of Alzheimer's disease (AD). However, there is little clinical evidence in support of this hypothesis in AD patients. We previously reported that the blood-brain barrier permeability represented by the cerebrospinal fluid/serum albumin ratio correlates with medial temporal lobe atrophy (MTA) in AD.The aim of this study was to elucidate the relationship between intrathecal inflammation and the severity of AD. METHODS: We investigated the correlations between the cerebrospinal fluid/serum IgG index and the indices of AD severity, including Clinical Dementia Rating and Mini-Mental State Examination, and MTA on magnetic resonance imaging in 42 AD patients. Further, the number of apolipoprotein E isoforms and the blood-brain barrier permeability were also examined for the correlation with the IgG index. RESULTS: The IgG index showed a positive correlation with the severity of MTA but not with the other parameters examined. CONCLUSION: Our results suggest that intrathecal inflammation increases in association with the severity of MTA in AD.

Matsunari I, Samuraki M, Chen WP, Yanase D, Takeda N, Ono K, Yoshita M, Matsuda H, Yamada M, Kinuya S. · The Medical and Pharmacological Research Center Foundation, Hakui-city, Ishikawa, Japan. · J Nucl Med. · Pubmed #18006622 links to  free full text

Abstract: The aim of this study was to compare optimized voxel-based morphometry (VBM) and (18)F-FDG PET for discrimination between patients with Alzheimer's disease (AD) and healthy subjects in relation to age. METHODS: The study population consisted of 2 groups; the first group (27 AD patients and 40 control subjects) was used to determine the locations of significant abnormalities for both PET and VBM using statistical parametric mapping, and the second group (34 AD patients and 50 control subjects) was used to compare the diagnostic performance of PET and VBM. In the second group, a z-score map for PET or VBM of each subject was obtained by comparison with the mean and SD of PET or gray-matter MR images of the control subjects. Receiver-operating-characteristic (ROC) curve analysis was then performed to compare the diagnostic performance between PET and VBM. Furthermore, group 2 was divided into the early- and late-onset subgroups, and ROC analysis was performed for each subgroup. RESULTS: In the first group, VBM revealed a significant decrease in gray-matter concentration in the hippocampus complex in AD, whereas PET showed a significant reduction in (18)F-FDG uptake in the posterior cingulate and parietotemporal lobe. The diagnostic performance of PET (0.988 +/- 0.008; mean +/- SE), as measured by the area under the ROC curve, was higher than that of VBM with (0.782 +/- 0.059) or without (0.832 +/- 0.049) modulation. PET yielded a sensitivity, specificity, and overall accuracy of 100%, 92%, and 95%, respectively, whereas for VBM the sensitivity, specificity, and accuracy were 74%, 92%, and 85%. Modulation for the VBM did not improve these values (56%, 94%, and 79%, respectively). When the early- and late-onset subjects were analyzed separately, the superiority of (18)F-FDG PET was significant only in the early-onset subgroup. CONCLUSION: The present study indicates that the detection of metabolic alteration by (18)F-FDG PET yields a better diagnostic performance for the discrimination between AD patients and healthy control subjects than does the morphologic approach by VBM, particularly in the early-onset subjects.

Yamada M, Chiba T, Sasabe J, Terashita K, Aiso S, Matsuoka M. · Department of Anatomy, KEIO University School of Medicine, Tokyo, Japan. · Neuropsychopharmacology. · Pubmed #17928813 links to  free full text

Abstract: Humanin (HN) and its derivatives, such as Colivelin (CLN), suppress neuronal death induced by insults related to Alzheimer's disease (AD) by activating STAT3 in vitro. They also ameliorate functional memory impairment of mice induced by anticholinergic drugs or soluble toxic amyloid-beta (Abeta) in vivo when either is directly administered into the cerebral ventricle or intraperitoneally injected. However, the mechanism underlying the in vivo effect remains uncharacterized. In addition, from the standpoint of clinical application, drug delivery methods that are less invasive and specific to the central nervous system (CNS) should be developed. In this study, we show that intranasally (i.n.) administered CLN can be successfully transferred to CNS via the olfactory bulb. Using several behavioral tests, we have demonstrated that i.n. administered CLN ameliorates memory impairment of AD models in a dose-responsive manner. Attenuation of AD-related memory impairment by HN derivatives such as CLN appears to be correlated with an increase in STAT3 phosphorylation levels in the septohippocampal region, suggesting that anti-AD activities of HN derivatives may be mediated by activation of STAT3 in vivo as they are in vitro. We further demonstrate that CLN treatment inhibits an Abeta induced decrease in the number of choline acetyltransferase (ChAT)-positive neurons in the medial septum. Combined with the finding that HN derivatives upregulate mRNA expression of neuronal ChAT and vesicular acetylcholine transporter (VAChT) in vitro, it is assumed that CLN may ameliorate memory impairment of AD models by supporting cholinergic neurotransmission, which is at least partly mediated by STAT3-mediated transcriptional upregulation of ChAT and VAChT.

Morinaga A, Hirohata M, Ono K, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa 920-8640, Japan. · Biochem Biophys Res Commun. · Pubmed #17559807 No free full text.

Abstract: Inhibition of the assembly of amyloid beta-peptide (Abeta) as well as the destabilization of preformed beta-amyloid fibrils (fAbeta) in the central nervous system could be valuable therapeutics of patients with Alzheimer's disease (AD). Epidemiological studies have indicated that estrogen therapy reduced the risk of developing AD in women. Here, we examined the effects of estrogen (estrone (E1), estradiol (E2), and estriol (E3)) and related sexual steroids (androstenedione (AND) and testosterone (TES)) on the polymerization, extension and destabilization of fAbeta(1-42) and fAbeta(1-40) at pH 7.5 at 37 degrees C in vitro, using fluorescence spectroscopic analysis with thioflavin T and electron microscopic studies. E1, E2, and E3 dose-dependently inhibited the formation, as well as destabilization of fAbetas. The overall anti-amyloidogenic activity of these molecules was in the order of: E3>E2=E1>>AND=TES. Estrogen could be a potential therapeutic agent to prevent or delay AD progression.

Samuraki M, Matsunari I, Chen WP, Yajima K, Yanase D, Fujikawa A, Takeda N, Nishimura S, Matsuda H, Yamada M. · Department of Neurology and Neurobiology of Aging, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan. · Eur J Nucl Med Mol Imaging. · Pubmed #17520250 No free full text.

Abstract: PURPOSE: Although( 18)F-fluorodeoxyglucose (FDG) PET is an established imaging technique to assess brain glucose utilisation, accurate measurement of tracer concentration is confounded by the presence of partial volume effect (PVE) due to the limited spatial resolution of PET, which is particularly true in atrophic brains such as those encountered in patients with Alzheimer's disease (AD). Our aim was to investigate the effects of PVE correction on FDG PET in conjunction with voxel-based morphometry (VBM) in patients with mild AD. METHODS: Thirty-nine AD patients and 73 controls underwent FDG PET and MRI. The PVE-corrected grey matter PET images were obtained using an MRI-based three-compartment method. Additionally, the results of PET were compared with grey matter loss detected by VBM. RESULTS: Before PVE correction, reduced FDG uptake was observed in posterior cingulate gyri (PCG) and parieto-temporal lobes (PTL) in AD patients, which persisted after PVE correction. Notably, PVE correction revealed relatively preserved FDG uptake in hippocampal areas, despite the grey matter loss in medial temporal lobe (MTL) revealed by VBM. CONCLUSION: FDG uptake in PCG and PTL is reduced in AD regardless of whether or not PVE correction is applied, supporting the notion that the reduced FDG uptake in these areas is not the result of atrophy. Furthermore, FDG uptake by grey matter tissue in the MTL, including hippocampal areas, is relatively preserved, suggesting that compensatory mechanisms may play a role in patients with mild AD.