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Biomedical subjects

Kenji Kosaka

Publications and source records attributed to Kenji Kosaka.

At least 19 recordsLinked to original sources
PubMed2006

The DYRK1A gene, encoded in chromosome 21 Down syndrome critical region, bridges between beta-amyloid production and tau phosphorylation in Alzheimer disease.

We scanned throughout chromosome 21 to assess genetic associations with late-onset Alzheimer disease (AD) using 374 Japanese patients and 375 population-based controls, because trisomy 21 is known to be associated with early deposition of beta-amyloid (Abeta) in the brain. Among 417 markers spanning 33 Mb, 22 markers showed associations with either the allele or the genotype frequency (P < 0.05). Logistic regression analysis with age, sex and apolipoprotein E (APOE)-epsilon4 dose supported genetic risk of 17 markers, of which eight markers were linked to the SAMSN1, PRSS7, NCAM2, RUNX1, DYRK1A and KCNJ6 genes. In logistic regression, the DYRK1A (dual-specificity tyrosine-regulated kinase 1A) gene, located in the Down syndrome critical region, showed the highest significance [OR = 2.99 (95% CI: 1.72-5.19), P = 0.001], whereas the RUNX1 gene showed a high odds ratio [OR = 23.3 (95% CI: 2.76-196.5), P = 0.038]. DYRK1A mRNA level in the hippocampus was significantly elevated in patients with AD when compared with pathological controls (P < 0.01). DYRK1A mRNA level was upregulated along with an increase in the Abeta-level in the brain of transgenic mice, overproducing Abeta at 9 months of age. In neuroblastoma cells, Abeta induced an increase in the DYRK1A transcript, which also led to tau phosphorylation at Thr212 under the overexpression of tau. Therefore, the upregulation of DYRK1A transcription results from Abeta loading, further leading to tau phosphorylation. Our result indicates that DYRK1A could be a key molecule bridging between beta-amyloid production and tau phosphorylation in AD.

Aged↗
PubMed2006

Variations in the BDNF gene in autopsy-confirmed Alzheimer's disease and dementia with Lewy bodies in Japan.

BACKGROUND/AIM: Brain-derived neurotrophic factor (BDNF) is associated with the hippocampus and the nigrostriatal dopaminergic function. Data showing that its level was reduced in Alzheimer's disease (AD) and Parkinson's disease (PD) suggested that the BDNF function must play an important role in the pathogenetics of these diseases. Indeed, variation in the BDNF gene may confer susceptibility to AD and PD development. Recently, a functional BDNF Val66Met polymorphism has been found to be associated with episodic memory and hippocampal function, with intracellular trafficking, and with activity-dependent secretion of BDNF. To date, there have been several conflicting reports on the correlation between AD or PD and Val66Met or C270T polymorphism in the BDNF promoter region, although no data on this relationship have been published with respect to dementia with Lewy bodies (DLB). In the present study, we investigated a possible association between such BDNF polymorphisms and susceptibility to AD or DLB. METHODS: BDNF genotyping was carried out by the polymerase chain reaction-restriction fragment length polymorphism method in autopsy-confirmed human samples. RESULTS AND CONCLUSION: On comparing patients and controls, the distribution of BDNF genotypes and alleles did not differ significantly. Our findings suggest that it is unlikely that these BDNF polymorphisms play a major role in the pathogenesis of AD and DLB in the Japanese population.

Aged↗
PubMed2006

Immunohistochemical investigation of neurofibrillary tangles and their tau isoforms in brains of limbic neurofibrillary tangle dementia.

Limbic neurofibrillary tangle dementia (LNTD) is a subset of senile dementia characterized by numerous neurofibrillary tangles (NFT) in the hippocampal area, although there is an absence or scarcity of amyloid deposits (AM) throughout the brain. In the present study, we immunohistochemically investigated regional numbers and tau isoforms of NFT in the hippocampal area of nine LNTD patients with anti-three-repeat (3R) tau-specific and anti-four-repeat (4R) tau-specific antibodies, differentiating NFT into three developmental stages of pretangles (PT), NFT and ghost tangles (GT). Consequently, most PT were 4R tau-positive, most GT were 3R tau-positive, and NFT were 3R tau-, 4R tau- or double-positive, suggesting that composition of tau isoforms may shift from a 4R tau-predominant pattern to a 3R tau-predominant pattern during the development of NFT. In addition, a large number of NFT showing different developmental stages and different rates of 3R tau- and 4R tau-positive neurons according to the region were found in the hippocampal area, suggesting that regions undergoing earlier NFT formation may show higher ratio of 3R tau-positive neurons to 4R tau-positive neurons, and that NFT formation may begin in the entorhinal and transentorhinal cortices, subsequently progress to the subiculum and CA1, and further to the CA2, amygdala and CA3-4, although progression to the neocortex is limited. Furthermore, 4R tau-positive astrocytes and grains were found in several patients, suggesting that LNTD is a form of tauopathy.

Aged, 80 and over↗
PubMed2006

A novel membrane protein, encoded by the gene covering KIAA0233, is transcriptionally induced in senile plaque-associated astrocytes.

Beta-amyloid (Abeta) deposition and senile plaque-associated astrocytes are common neuropathological features of Alzheimer's disease (AD). Although the molecular mechanisms by which Abeta contributes to the progression of neuropathologic changes have not been entirely established, there is little doubt that the association of Abeta with astrocytes, the predominant cell type in brain, significantly influences exacerbation of the disease. In an effort to identify astrocyte-derived molecules that may be intimately associated with progression of AD, we identified a novel Abeta-induced rat gene, designated Mib, whose human counterpart covers KIAA0233. Mib-transfected C6 cells express Mib protein in the endoplasmic reticulum and endplasmic reticulum-Golgi-intermediate compartment. To evaluate roles of Mib in AD, we investigated its expression in the AD brain. In non-AD brains, Mib mRNA has been detected in neurons but not in quiescent astrocytes. On the contrary, in AD brains, Mib mRNA is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. From these observations, Mib appears to be a novel Abeta-responsive gene that may play a role in astrocyte inflammatory activation around senile plaques in the AD brain.

Alzheimer Disease↗
PubMed2006

Ethnicity-dependent genetic association of ABCA2 with sporadic Alzheimer's disease.

A recent study demonstrated a significant genetic association between the ATP-binding cassette transporter A2 (ABCA2) and the risk for Alzheimer's disease (AD) in a large Caucasian sample. The rare T allele of the synonymous exonic single nucleotide polymorphism (SNP) rs908832 was overrepresented in early-onset AD patients as compared to cognitively healthy controls. Here we confirm the association of rs908832 with AD in a Western European population (n = 291, P = 0.008). In a second sample from Southern Europe, rs908832 was not associated with AD. Interestingly, rs908832 was not polymorphic in a Japanese sample. Furthermore, rs908832 was not associated with either serum cholesterol levels or with the risk for coronary artery disease, but seemed to be related to cholesterol levels in the cerebrospinal fluid. These data suggest that ABCA2 may exert population-dependent effects on the genetic risk for sporadic AD and support a role of ABC lipid transporters in the pathogenesis of this disease.

ATP-Binding Cassette Transporters↗
PubMed2006

Investigation of Lewy pathology in the visual pathway of brains of dementia with Lewy bodies.

We examined 19 autopsied cases of dementia with Lewy bodies (DLB) using pathological and alpha-synuclein-immunohistochemical methods, and investigated Lewy pathology in the primary visual pathway (lateral geniculate body and Brodmann's area 17), secondary visual pathway (pulvinar, Brodmann's areas 18 and 19, and inferior temporal cortex), amygdala and substantia nigra, to clarify the relationship between visual misidentification and Lewy pathology in the visual pathway. Consequently, the secondary visual pathway revealed significantly severer Lewy pathology than the primary visual pathway, suggesting that the degeneration of the secondary visual pathway induces dysfunction in the recognition of objects shape and color. In addition, the amygdala revealed significantly severer Lewy pathology and neuronal loss than the primary and secondary visual pathways, suggesting that the degeneration of the amygdala, which receives the afferent connections from the substantia nigra, fails to modulate the visual processing according to cognition and emotion. These findings suggest that Lewy pathologies in the secondary visual pathway and amygdala may cause the dysfunction of the visuo-amygdaloid pathway and participate in visual misidentification in DLB patients. In addition, we compared Lewy pathology between cases with and without visual hallucinations, and showed no significant differences between the two groups.

Aged↗
PubMed2006

Depletion of cholinergic neurons in the nucleus of the medial septum and the vertical limb of the diagonal band in dementia with Lewy bodies.

The cholinergic basal forebrain is divided into four subregions (Ch1-4), and cholinergic neuronal loss in the nucleus basalis of Meynert (Ch4) has been correlated with cognitive impairments in both Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). However, the Ch1-2 regions, which provide the major cholinergic innervation to the hippocampus, have not been investigated in DLB. The purpose of this study was to reveal the cholinergic neuronal changes in the medial septum (Ch1) and the nucleus of the vertical limb of the diagonal band (Ch2) of DLB brains. Using choline acetyltransferase (ChAT) immunohistochemistry, we showed that the number of ChAT-immunoreactive neurons in DLB brains was significantly lower than the numbers in AD and non-demented (control) brains. No significant difference in the number of ChAT-immunoreactive neurons was found between the AD and control brains. Moreover, the size of the ChAT-immunoreactive neurons was significantly smaller in the AD and DLB brains than in the control brains. These results show that cholinergic neurons of the Ch1-2 regions are more severely affected in DLB than in AD. Our DLB cases did not fulfill the neuropathologic criteria for definite AD. Furthermore, some Lewy bodies were observed in the Ch1-2 regions. Thus, cholinergic neuronal loss in the Ch1-2 regions might be specific to the pathology of DLB. Taking the distribution of cholinergic fibers in the hippocampus into consideration, this study suggests a possibility that hippocampal cholinergic projection is involved in Lewy-related neurites in the CA2-3 regions, the origin of which remains unclear.

Aged↗
PubMed2006

Vascular complications in dementia with Lewy bodies: a postmortem study.

The effects of cerebrovascular lesions on DLB are not yet fully understood, whereas the development of Alzheimer's disease (AD) is known to be associated with cerebrovascular lesions. In this study, we investigated the frequency of concomitant cerebrovascular pathologies in autopsy-proven DLB cases (n = 25) in comparison with AD cases (n= 63). We also investigated the correlation between cerebrovascular pathologies and the clinical features of DLB cases. On gross inspection, five cases of DLB and seven cases of AD were complicated by cerebral hemorrhages and the difference was significant; most of the lesions in DLB were subdural hemorrhages, possibly related to trauma. Nine cases of DLB and 25 cases of AD had grossly identified infarctions, but no significant difference was observed. Three cases of DLB and four cases of AD had concomitant hemorrhages, while 10 cases of DLB and 43 cases of AD had infarcts on microscopic inspection. There was a significant difference in the frequency of microscopic infarcts between DLB and AD, whereas no significant difference was noted in the frequency of microscopic hemorrhages. In DLB cases without vascular complications, memory disturbance was common as the initial symptom, while parkinsonism was more common in those with vascular complications. However, no significant difference was observed between DLB cases with and without vascular complications with respect to the frequency of individual clinical symptoms over the whole clinical course. These findings suggest that grossly identified hemorrhages are more common in DLB because of trauma, while microinfarcts are less common in DLB than AD, although the reason remains unclear. Such vascular complications might affect the clinical manifestations, in particular, the initial symptom, of DLB.

Aged↗
PubMed2006

Efficacy and safety of donepezil in patients with dementia with Lewy bodies: preliminary findings from an open-label study.

The objectives of the present study were first to determine the feasibility of conducting a randomized clinical trial of 5 mg/day donepezil in patients with mild to moderate dementia with Lewy bodies (DLB) and second, to obtain preliminary data of possible intervention effects. Twelve patients with probable DLB were evaluated at weeks 4, 8, and 12 using modified Neuropsychiatric Inventory (NPI) with an extra domain to additionally evaluate fluctuation in cognitive functions (NPI-11); the Japanese version of Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-J cog); and the Unified Parkinson's Disease Rating Scale (UPDRS). The NPI-11 scores were significantly improved at weeks 8 and 12 compared with baseline. Despite a significant improvement in ADAS-J-cog at week 4, no more improvement was noted thereafter. Deterioration was not noted in UPDRS scores. Donepezil is expected to be therapeutically useful and safe in treating DLB patients, indicating marked improvements in behavioral and psychological symptoms of dementia (BPSD) rather than in cognitive deficit, without deteriorating parkinsonism.

Aged↗
PubMed2005

A novel alternative splice variant of nicastrin and its implication in Alzheimer disease.

Nicastrin interacts with gamma-secretase complex components predominantly via the N-terminal third of the transmembrane domain. The authentic transmembrane domain is critically required for the interaction with gamma-secretase complex components and for formation of an active gamma-secretase complex. In this study, we have identified a novel alternatively spliced transcript of nicastrin in human brain tissue. This transcript (NCSTN-DeltaE16) lacks exon 16 of nicastrin mRNA, which leads to deletion of 71 amino acids just upstream of its transmembrane domain. Its expression pattern was analyzed in the hippocampus of patients with pathologically diagnosed Alzheimer disease (cases) and non-Alzheimer dementia (controls). In patients with the APOE-epsilon4 allele, the frequency of Alzheimer disease appeared to be increased in the NCSTN-DeltaE16-positive group, but the association was not statistically significant. In conclusion, the expression of NCSTN-DeltaE16 transcript may confer some additional risk for developing Alzheimer disease beyond the risk due to ApoE-epsilon4 allele. Further investigation in larger scale population would be necessary to address its potential implication in Alzheimer disease.

Age of Onset↗
PubMed2005

Lib, transcriptionally induced in senile plaque-associated astrocytes, promotes glial migration through extracellular matrix.

In an effort to identify astrocyte-derived molecules that may be intimately associated with progression of Alzheimer's disease (AD), Lib, a type I transmembrane protein belonging to leucine-rich repeat superfamily, has been identified as a distinctly inducible gene, responsive to beta-amyloid as well as pro-inflammatory cytokines in astrocytes. To evaluate the roles of Lib in AD, we investigated Lib expression in AD brain. In non-AD brain, Lib mRNA has been detected in neurons but not in quiescent astrocytes. On the contrary, in AD brain, Lib mRNA is expressed in activated astrocytes associated with senile plaques, but not expressed in neurons around lesions. Lib-expressing glioma cells displayed promotion of migration ability through reconstituted extracellular matrix and recombinant Lib protein bound to constituents of extracellular matrix. These observations suggest that Lib may contribute to regulation of cell-matrix adhesion interactions with respect to astrocyte recruitment around senile plaques in AD brain.

Aged↗
PubMed2005

Lymphocyte-specific protein tyrosine kinase is a novel risk gene for Alzheimer disease.

Lymphocyte-specific protein tyrosine kinase (LCK) is a lymphoid-specific, Src family protein tyrosine kinase that is known to play a pivotal role in T-cell activation and interact with the T-cell coreceptors, CD4 and CD8. It has been shown to be significantly down-regulated in Alzheimer disease (AD) hippocampus compared with non-demented controls. Furthermore, it is located in a previously identified genetic linkage region (1p34-36) associated with AD. Therefore, we consider it to be a candidate gene for AD. We examined the relationship between AD and the LCK and apolipoprotein E (APOE) genes in 376 AD (including 323 late-onset AD (LOAD) cases and 53 early-onset AD (EOAD) cases) and 378 non-demented controls using a single nucleotide polymorphism (SNP). The polymorphism in intron 1 (+6424 A/G) was significantly associated with AD risk. The odds ratio (OR) for total AD associated with the GG genotype was 1.41 (95% CI=1.06-1.87) and that for LOAD was 1.37 (95%CI=1.02-1.85), while that for APOE-epsilon4 was 5.06 (95% CI=3.60-7.12). In the APOE-epsilon4 non-carrier subgroup, the GG genotype also showed significant association (OR=1.66; 95% CI=1.16-2.38). These results indicate that the LCK is a novel risk gene for AD regardless of the APOE genotype.

Age of Onset↗
PubMed2005

The nigro-striatal and nigro-amygdaloid pathways undergo different degeneration processes in brains of dementia with Lewy bodies.

We immunohistochemically investigated the degeneration processes of the nigro-striatal and nigro-amygdaloid pathways and the relationship between the loss of dopaminergic neurons and Lewy bodies (LB) formation in the substantia nigra using 15 autopsied cases of dementia with Lewy bodies (DLB). The number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and TH-positive axonal terminals in the putamen decreased with a specific pattern. The substantia nigra possessed alpha-synuclein-positive LB-bearing neurons that were almost evenly distributed, while the putamen exhibited diffuse or granular alpha-synuclein-immunostaining. Most of the granular stains were positive for anti-phosphorylated alpha-synuclein antibody, whereas the diffuse stains were negative. These findings suggest that the axonal terminals in the putamen undergo abnormal alpha-synuclein accumulation, but may not always originate from LB-bearing neurons in the substantia nigra. The central amygdaloid nucleus contained anti-alpha-synuclein- and -phosphorylated alpha-synuclein-positive dystrophic axonal terminals, the degree of which was greater for cases with granular staining in the putamen, and which was proportional to the number of alpha-synuclein-positive neurons in the substantia nigra. Thus, the axonal terminals in the central amygdaloid nucleus may have originated from LB-bearing neurons in the substantia nigra. The results of the present study indicate that the nigro-striatal and nigro-amygdaloid pathways undergo different degeneration processes in DLB, and suggest that the degeneration of the nigro-amygdaloid pathway more strongly reflects LB formation in dopaminergic neurons of the substantia nigra than that of the nigro-striatal pathway. In addition, they indicate that there is no direct relationship between the loss of dopaminergic neurons and LB formation in the substantia nigra.

Aged↗
PubMed2005

Identification of hippocampus-related candidate genes for Alzheimer's disease.

Alzheimer's disease (AD) is a complex multifactorial disease in which many genetic and environmental factors are involved. We performed an association study using 376 AD patients and 376 control subjects. We studied 35 single nucleotide polymorphisms in 35 genes that were significantly downregulated or upregulated only in the AD hippocampus compared with control and found that 9 single nucleotide polymorphisms were associated with AD. Our data indicated that single nucleotide polymorphisms could highly reflect differences in gene expression. Furthermore, an intronic polymorphism (+9943T/C) in POU2F1 was most significantly associated with AD (p = 0.0007). Our results suggest that POU2F1 is a candidate gene for AD.

Aged↗
PubMed2005

Non-uniformity in the regional pattern of Lewy pathology in brains of dementia with Lewy bodies.

We examined the regional pattern of Lewy pathology in brains of dementia with Lewy bodies (DLB) to clarify whether Lewy pathology uniformly progresses or not. Thirty-five autopsied DLB cases were examined using alpha-synuclein-immunohistochemistry, and the regional degree of Lewy pathology in the brainstem, diencephalon and cerebral cortex was quantitatively evaluated. Consequently, we found that the regional pattern of Lewy pathology differed according to the pathological subtype, and was divided into three types: type 1 showed a brainstem-predominant pattern, type 2 was almost equal for the brainstem and cerebral cortex, and type 3 showed a cerebral cortex-predominant pattern. The limbic type/pure and common forms were mainly composed of type 1, whereas the neocortical type/common and Alzheimer's disease (AD) forms were mainly composed of type 3. These findings suggest the possibility that Lewy pathology of the limbic type/pure and common forms mainly progresses from the brainstem to the cerebrum, whereas that of the neocortical type/common and AD forms mainly progresses from the cerebrum to the brainstem. Cases with type 1 Lewy pathology mainly developed parkinsonism, whereas those with type 3 Lewy pathology mainly developed dementia. This corresponded to most of the limbic type/ pure and common forms which developed parkinsonism, whereas most of the neocortical type/common and AD forms developed dementia. Type 1 cases may thus be clinically diagnosed as having Parkinson's disease (PD) with dementia. These findings suggest that PD has clinico-pathological continuity with DLB, and that the regional pattern of Lewy pathology is not uniform.

Aged↗
PubMed2005

Clinical features of argyrophilic grain disease: a retrospective survey of cases with neuropsychiatric symptoms.

OBJECTIVE: Although argyrophilic grain disease (AGD) appears common in post-mortem series, its clinical features are not widely known. The aim of this study was to explore such clinical features in neuropathologically-confirmed AGD cases. METHODS: After completing a neuropathological assessment of 386 patients, 33 cases (8.5%) were diagnosed as having AGD; 10 were diagnosed as "pure" cases. These subjects had been admitted to geriatric wards of mental hospitals because of behavioral or neuropsychiatric symptoms requiring medical management. Assessment of the clinical features of the pure cases was based on the evaluations in medical records. RESULTS: The average age at onset was 82.2 years. Amnesia was the most common initial symptom; irritability and agitation were also common as initial symptoms. During the course of the illness, irritability was the most frequently observed, followed by delusions (mostly delusions of persecution), dysphoria, and then agitation, and apathy. In contrast to the severity of amnesia, other cognitive functions were relatively spared, and the sensorimotor symptoms were not remarkable. CONCLUSIONS: AGD is a late-onset dementing disorder clinically characterized by amnesia, with other cognitive functions relatively spared, and prominent neuropsychiatric features. These features may correlate with the high level of AGD seen in limbic structures. Future studies are needed to elucidate whether these features are common to all AGD patients or to a clinical subtype with neuropsychiatric symptoms.

Aged↗
PubMed2005

[Dementia with Lewy bodies].

"Dementia with Lewy bodies (DLB)" was proposed at the first international workshop in 1995. It has received much attention since we had proposed "Lewy body disease" in 1980 and "diffuse Lewy body disease" in 1984. In the CDLB guidelines, which were reported in 1996, the clinical and pathological diagnostic criteria for DLB were shown for the first time. At present, DLB as well as Alzheimer's disease (AD) and vascular dementia (VD) are known as the three major dementing illnesses. The second international workshop was held in 1998, and the third in 2003. One of the authors, K. Kosaka, presented a paper on DLB at each international workshop, based on series of our papers which we had reported since 1976. The revised CDLB guidelines will be reported soon. In addition, the fourth international workshop on DLB will be held by Kosaka in Yokohama in 2007. In this article, we review the history, the clinical, therapeutic, neuropathological, neurochemical and molecular biological issues, based on our previous papers and other important reports on DLB.

Acetylcholine↗