Biomedical subjects

S Minoshima

Publications and source records attributed to S Minoshima.

At least 19 recordsLinked to original sources

PubMed2006

Preclinical evidence of Alzheimer changes in progressive mild cognitive impairment: a qualitative and quantitative SPECT study.

OBJECTIVES: Baseline brain single-photon emission computed tomography (SPECT) can predict mild cognitive impairment (MCI) patients at risk for progressive MCI (PMCI). METHODS: Twenty-eight subjects [12 MCI, 6 with probable Alzheimer's Disease (AD), and 10 normal subjects] underwent baseline brain SPECT and were clinically followed for a mean period of 36 months. RESULTS: Of 12 MCI patients, 6 progressed to PMCI and 6 remained stable. Baseline SPECT identified asymmetric perfusion reduction in the parahippocampus (-5%), lateral parietal (-8%), and posterior cingulate (-11%) cortices--reductions consistent with that of mild AD--in five of the six PMCI patients. Significant perfusion reduction was observed particularly in the frontal cortices of probable AD when compared with PMCI (P < 0.05). CONCLUSION: Baseline SPECT can identify brain perfusion abnormalities among patients with MCI for progression to PMCI. This imaging modality may aid in MCI treatment stratification.

Aged↗

PubMed2005

Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium.

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.

Brain↗

PubMed2005

Cerebral glucose metabolism in patients with AD and different APOE genotypes.

OBJECTIVE: To examine the influence of the APOE epsilon4 allele on cerebral glucose metabolism in a large series of patients with Alzheimer disease (AD). METHODS: Eighty-three patients (41 APOE epsilon4 positive and 42 epsilon4 negative) were selected from a pre-existing databank of patients with AD (n > 1,000). The patients were carefully matched for age, age at onset, approximate disease duration, educational level, and overall degree of cognitive impairment. Cerebral [18F]fluorodeoxyglucose PET imaging was performed in all patients by a standardized protocol. Statistical comparison of patient PET data vs a healthy control population was performed as well as an analysis of differences between groups (SPM99; Wellcome Department of Cognitive Imaging, London, UK). RESULTS: A similar pattern of cerebral hypometabolism was detected in the epsilon4-positive and -negative patient groups vs healthy volunteers in regions typically affected by AD (bilateral temporal, parietal, posterior cingulate, and prefrontal cortical areas). The comparison between epsilon4-positive and -negative patients additionally revealed stronger abnormalities in epsilon4 carriers in parietal, temporal, and posterior cingulate cortical regions. CONCLUSIONS: A generally similar pattern of cerebral hypometabolism was detected in APOE epsilon4-positive and -negative patients with Alzheimer disease. However, in direct comparison of the two matched groups, the abnormalities in the epsilon4-positive group were demonstrated to be more pronounced.

Aged↗

PubMed2004

Novel insertional presenilin 1 mutation causing Alzheimer disease with spastic paraparesis.

A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.

Adult↗

PubMed2003

Increased ventral striatal monoaminergic innervation in Tourette syndrome.

BACKGROUND: Excessive striatal dopaminergic innervation is suggested to underlie Tourette syndrome (TS). Prior imaging and postmortem studies yield conflicting data. METHODS: The authors used PET with the type 2 vesicular monoamine transporter ligand [(11)C]dihydrotetrabenazine (DTBZ) to quantify striatal monoaminergic innervation in patients with TS (n = 19) and control subjects (n = 27). Compartmental modeling was used to determine blood to brain ligand transport (K(1)) and tissue to plasma distribution volume (a measure of ligand binding) during continuous infusion of DTBZ. TS data were compared with control data using predefined regions of interest and on a voxel by voxel basis. RESULTS: There were no significant differences in ligand binding or ligand transport between patients with TS and control subjects in the dorsal striatum. With voxel by voxel analysis, there was increased DTBZ binding in the right ventral striatum. CONCLUSIONS: Previously reported differences between patients with TS and control subjects in dorsal striatal dopamine terminal markers may reflect medication-induced regulation of terminal marker expression or be the result of intrinsic differences in striatal dopaminergic synaptic function. Increased right ventral striatal DTBZ binding suggests that abnormal ventral striatal dopaminergic innervation may underlie tics.

Adolescent↗

PubMed2003

Fukutin-related protein gene mutated in the original kindred limb-girdle MD 2I.

The authors mapped an autosomal recessive form of limb-girdle MD on chromosome 19q13.3 (LGMD2I), further narrowed down the candidate region to 1.1 Mb, and identified one new homozygous mutation in the fukutin-related protein (FKRP) gene on patients of the original Tunisian family. Immunohistochemical and immunoblot analysis showed abnormal expression of alpha-dystroglycan and laminin-alpha2 supporting the hypothesis that FKRP has a role in the interaction between the extracellular matrix components.

Amino Acid Substitution↗

PubMed2003

Keeping pain out of mind: the role of the dorsolateral prefrontal cortex in pain modulation.

Frontal lobe activity during pain is generally linked to attentional processing. We addressed the question of whether 'bottom-up' processing and 'top-down' modulation of nociceptive information dissociate anatomically within the frontal lobe by using PET scanning during painful thermal stimulation of normal and capsaicin-treated skin. We showed recently that pain following normally non-painful heat stimuli on chemically irritated skin (heat allodynia) uniquely engages extensive areas of the bilateral dorsolateral prefrontal (DLPFC), ventral/orbitofrontal (VOFC) and perigenual anterior cingulate (ACC) cortices. Here, we applied principal component analysis (PCA) and multiple regression analysis to study the covariance structure of the volumes of interest (VOI) activated specifically during heat allodynia in 14 male healthy subjects and evaluated the relationship of these VOI to ratings of pain intensity and affect. Results yielded a primary principal component (PC) that correlated positively with intensity and unpleasantness and accounted for activity in the medial thalamus, bilateral anterior insula, ventral striatum, perigenual ACC and bilateral VOFC. Activities in the right and left DLPFC loaded on separate PC and correlated negatively with perceived intensity and unpleasantness. The inter-regional correlation of midbrain and medial thalamic activity was significantly reduced during high left DLPFC activity, suggesting that its negative correlation with pain affect may result from dampening of the effective connectivity of the midbrain-medial thalamic pathway. In contrast, right DLPFC activity was associated with a weakened relationship of the anterior insula with both pain intensity and affect. We propose that the DLPFC exerts active control on pain perception by modulating corticosubcortical and corticocortical pathways.

Adult↗

PubMed2001

Molecular cloning of a member of the facilitative glucose transporter gene family GLUT11 (SLC2A11) and identification of transcription variants.

We isolated a member of the facilitative glucose transporter (GLUT) gene family (GLUT11; SLC2A11 as a HGMW-approved symbol) based on the analysis of a human genomic BAC clone KB1125A3 located on band q11.2 of human chromosome 22. The gene GLUT11/SLC2A11 consists of 12 exons spanning over 29 kb in size and is located between two genes, SMARCB1 and MIF. The deduced amino acid sequence indicated the topological features of transmembrane helices and sequence motifs which are common to the GLUT protein family. The cDNA cloning revealed the presence of three types of variation in its transcripts. The first variation is caused by the existence of three distinct first exons (SLC2A11-a, -b, and -c). PCR analysis of multi-tissue-derived cDNA panels indicated the differential expression of these transcript variants. The second variation is caused by skipping over one exon (exon 6). The third variation is caused by the premature transcription termination at a site between exon 8 and exon 9. Both exon skipping and premature termination caused frameshift, resulting in the production of truncated GLUT11/SLC2A11 transcripts. These results suggested that transcription of GLUT11/SCL2A11 gene is controlled in a complex manner.

Amino Acid Motifs↗

PubMed2001

Structure of human holocarboxylase synthetase gene and mutation spectrum of holocarboxylase synthetase deficiency.

Holocarboxylase synthetase (HLCS) is an enzyme that catalyzes the incorporation of biotin into apo-carboxylases, and its deficiency causes biotin-responsive multiple carboxylase deficiency. The reported sequences of cDNA for human HLCS from liver, lymphocyte, and KG-1 myeloid cell lines differ at their 5' regions. To elucidate variations of the human HLCS mRNA and longer 5' cDNA ends, we performed screening of the human liver cDNA library and rapid amplification of the cDNA ends (RACE). Our results suggest the existence of three types of HLCS mRNA that start at different exons. The first type starts at exon 1, and the second type starts at exon 3, and both are found in various human tissues. The third type, corresponding to the cDNA from the KG-1 cell, starts at exon 2 of the HLCS gene. Various splicing patterns from exons 3-6 were also observed. None of the variations of cDNA found created a new initiation codon. Mutation screening from exons 6-14, therefore, was sufficient to detect amino acid changes in HLCS in patients. Our direct sequencing strategy for screening mutations in the HLCS gene revealed mutations in five Japanese patients and seven non-Japanese patients. Our analyses involving 12 Japanese and 13 non-Japanese patients and studies by others indicate that (1) there is no panethnically prevalent mutation; (2) the Arg508Trp, Gly581Ser, and Val550Met mutations are found in both Japanese and non-Japanese populations; (3) the IVS10+5G-->A mutation is predominant and probably a founder mutation in European patients; (4) the 655-656insA, Leu237Pro, and 780delG mutations are unique in Japanese patients; (5) the spectrum of the mutations in the HLCS gene may vary substantially among different ethnic groups.

Base Sequence↗

PubMed2001

The genomic structure and promoter region of the human parkin gene.

Parkin has been identified as a causative gene of the autosomal recessive juvenile parkinsonism (AR-JP). In this study, we determined the genomic structure of the Parkin gene and identified a core promoter region based on the DNA sequence of 1.4 Mb. The 5'-flanking region contained no apparent TATA or CAAT box elements but several putative cis-elements for various transcription factors. The GC- and CpG-rich regions were observed not only in the 5'-flanking sequence but also in the 5'-part of the first intron of Parkin. We identified an exact starting point of Parkin transcription. A core promoter region was determined by transfecting a series of deletion constructs with a dual luciferase reporter system into human neuroblastoma cells. Furthermore, we located a neighboring novel gene in a head-to-head direction with Parkin with only a 198-bp interval.

Base Sequence↗

PubMed2001

Regional cerebral blood flow effects of nicotine in overnight abstinent smokers.

BACKGROUND: Most people agree that dependence to tobacco is mediated by the effects of nicotine on the central nervous system, albeit the neural pathways involved are not clearly delineated. We investigated the effect of nasal nicotine spray on regional cerebral blood flow (rCBF) in a sample of habitual smokers, with H2 15O and positron emission tomography (PET). METHODS: Eighteen volunteer smokers were studied after 12 hours of smoking deprivation. Regional cerebral blood flow measures were obtained with PET and 50 mCi H2 15O in six consecutive scans. Nicotine spray and a placebo spray were administered in a single-blind design, preceded and followed by baseline studies. Images were coregistered and anatomically standardized. Square (9-mm side) regions of interest were placed in 10 preselected brain regions, bilaterally. The effects of the experimental condition and gender were tested with two-way repeated-measures analysis of variance in each of the regions studied. RESULTS: Nicotine reduced rCBF in the left anterior temporal cortex and in the right amygdala. Increases were noted in the right anterior thalamus. CONCLUSIONS: In habitual smokers after overnight abstinence, nicotine induced differing effects on regional blood flow relative to whole brain blood flow. Increases were observed in the thalamus, a region rich in nicotinic receptors, and reductions in limbic and paralimbic (amygdala, anterior temporal cortex) regions.

Adolescent↗

PubMed2001

Molecular mechanisms of human single-minded 2 (SIM2) gene expression: identification of a promoter site in the SIM2 genomic sequence.

We previously postulated that the single-minded 2 (SIM2) gene identified on the human chromosome 21q22.2 is a good candidate gene for the pathogenesis of mental retardation in Down syndrome because its mouse homolog exhibits preferential expression in the mouse diencephalon during early embryogenesis. We analyzed the genomic sequence of the entire SIM2 gene which consists of 11 exons and spans over 50 kb. As a step toward understanding the molecular mechanisms of SIM2 gene expression, we have analyzed the human SIM2 gene expression in nine established human cell lines. Three transcripts of 3.6, 4.4, and 6.0 kb were detected in the glioblastoma cell line, T98G, neuroblastoma cell line, TGW, and transformed embryonic kidney cell line, 293. The RACE analysis using SIM2-expressing human cell line T98G provided evidence for the transcription start site at approximately 1.2 kb upstream of the translation initiation site. The transfection assay using various deletion constructs with reporter gene suggested the presence of a presumptive promoter region. Transient transfection assay in T98G cell line revealed a significant promoter activity located in the 60 bp sequence between nt -1385 and -1325 upstream region of the translation initiation site. This 60 bp sequence contains cis-elements for c-myb, E47 and E2F transcription factors. Moreover, the gel retardation assay using oligo-DNA of various cis-element sequences indicated the presence of protein factor(s) which bind to the cis-element for c-myb. These results suggested that binding of a protein transcription factor(s) such as c-myb or that alike regulates transcription of the SIM2 gene by binding to a small upstream region.

Base Sequence↗

PubMed2001

The KMDB/MutationView: a mutation database for human disease genes.

The KMDB/MutationView is a graphical database of mutations in human disease-causing genes and its current version consists of nine category-based sub-databases including diseases of eye, heart, ear, brain, cancer, syndrome, autoimmunity, muscle and blood. The KMDB/MutationView stores mutation data of 97 genes involved in 87 different disease and is accessible through http://mutview.dmb.med. keio.ac.jp.

Databases, Factual↗

PubMed2001

Alzheimer's disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation.

Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later dinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.

Aged↗

PubMed2001

Isolation and characterization of the UBASH3A gene on 21q22.3 encoding a potential nuclear protein with a novel combination of domains.

In order to identify candidate genes for Down syndrome phenotypes or monogenic disorders that map to human chromosome 21q22.3, we have used genomic sequence and expressed sequence tags mapping to an autosomal recessive deafness (DFNB10) critical region to isolate a novel 2.5-kb cDNA that maps between TFF1 and D21S49. A semi-quantitative reverse transcription/polymerase chain reaction method revealed that UBASH3A gene expression is limited to only a few tissues, with its highest expression in spleen, peripheral blood leukocytes, and bone marrow. The putative 661-amino-acid protein shows considerable homology to a hypothetical protein from Drosophila melanogaster but only domain homologies to other organisms. Both the human and D. melanogaster proteins contain protein-protein interaction domains, viz., SH3 and ubiquitin-associated (UBA) domains, in addition to a novel domain also containing a nuclear localization signal. This is the first protein described containing both UBA and SH3 domains. The gene, thus called UBASH3A, spans 40 kb and is divided into 15 exons. Mutation analysis excluded UBASH3A as being responsible for DFNB10.

Adaptor Proteins, Signal Transducing↗

PubMed2001

Duplication and transposition of the NF1 pseudogene regions on chromosomes 2, 14, and 22.

Numerous NF1 pseudogenes have been identified in the human genome. Those in 2q21, 14q11, and 22q11 form a subset with a similar genomic organization and a high sequence homology. We have studied, by polymerase chain reaction and fluorescence in situ hybridization, the extent of homology of the regions surrounding these NF1 pseudogenes. Our analyses have demonstrated that a fragment of at least 640 kb is homologous between the three regions. Based on previous studies and these new findings, we propose a model for the spreading of the NF1 pseudogene-containing regions. A fragment of approximately 640 kb was first duplicated in chromosome region 2q21 and transposed to 14q11. Subsequently, this fragment was duplicated in 14q11 and transposed to 22q11. A part of the 640-kb fragment in 14q11, with a length of about 430 kb, was further duplicated to a variable extent in 14q11. In addition, we have identified sequences that may facilitate the duplication and transposition of the 640-kb and 430-kb fragments.

Animals↗

PubMed2001

Nucleotide sequence of BamHI family satellite DNA and its unit length polymorphism in bluegill sunfish Lepomis macrochirus.

We have isolated and sequenced a member of tandem repetitive DNA containing BamHI site (BamHI family satellite DNA) from bluegill sunfish Lepomis macrochirus. PCR amplification with specific primers was performed to define the size of unit length repeat of the BamHI family satellite DNA, revealing that there were two distinct size of DNA fragments (0.9 kb and 1.3 kb) in the PCR products. The longer fragment (1.3 kb) consisted of internal sub-duplication of shorter fragment (0.9 kb). We have compared the size of PCR products among four fish populations, and found that both fragments co-existed in one population whereas the longer fragment was dominant in other three populations. The results may reflect ongoing homogenization of satellite DNA type over a short evolutionary time scale.

Animals↗

PubMed2001

Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness.

Approximately 50% of childhood deafness is caused by mutations in specific genes. Autosomal recessive loci account for approximately 80% of nonsyndromic genetic deafness. Here we report the identification of a new transmembrane serine protease (TMPRSS3; also known as ECHOS1) expressed in many tissues, including fetal cochlea, which is mutated in the families used to describe both the DFNB10 and DFNB8 loci. An 8-bp deletion and insertion of 18 monomeric (approximately 68-bp) beta-satellite repeat units, normally present in tandem arrays of up to several hundred kilobases on the short arms of acrocentric chromosomes, causes congenital deafness (DFNB10). A mutation in a splice-acceptor site, resulting in a 4-bp insertion in the mRNA and a frameshift, was detected in childhood onset deafness (DFNB8). This is the first description of beta-satellite insertion into an active gene resulting in a pathogenic state, and the first description of a protease involved in hearing loss.

Adult↗