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1.
Biochem Biophys Res Commun ; 456(1): 482-8, 2015 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-25482438

RESUMO

The formation of senile plaques composed of ß-amyloid (Aß) in the brain is likely the initial event in Alzheimer's disease (AD). Possession of the APOE ε4 allele, the strong genetic factor for AD, facilitates the Aß deposition from the presymptomatic stage of AD in a gene-dosage-dependent manner. However, the precise mechanism by which apoE isoforms differentially induce the AD pathology is largely unknown. LR11/SorLA is a type I membrane protein that functions as the neuronal lipoprotein endocytic receptor of apoE and the sorting receptor of the amyloid precursor protein (APP) to regulate amyloidogenesis. Recently, LR11/SorLA has been reported to be involved in the lysosomal targeting of extracellular amyloid-ß (Aß) through the binding of Aß to the vacuolar protein sorting 10 (VPS10) protein domain of LR11/SorLA. Here, we attempted to examine the human-apoE-isoform-dependent effect on the cellular uptake of Aß through the formation of a complex between an apoE isoform and LR11/SorLA. Cell culture experiments using Neuro2a cells revealed that the cellular uptake of secreted apoE3 and apoE4 was enhanced by the overexpression of LR11/SorLA. In contrast, the cellular uptake of apoE2 was not affected by the expression of LR11/SorLA. Co-immunoprecipitation assay revealed that apoE-isoform-dependent differences were observed in the formation of an apoE-LR11 complex (apoE4>apoE3>apoE2). ApoE-isoform-dependent differences in cellular uptake of FAM-labeled Aß were further investigated by coculture assay in which donor cells secrete one of the apoE isoforms and recipient cells express FL-LR11. The cellular uptake of extracellular Aß into the recipient cells was most prominently accentuated when cocultured with the donor cells secreting apoE4 in the medium, followed by apoE3 and apoE2. Taken together, our results provide evidence for the mechanism whereby human-apoE-isoform-dependent differences modulate the cellular uptake of Aß mediated by LR11/SorLA.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/metabolismo , Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Alelos , Animais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Clonagem Molecular , Técnicas de Cocultura , DNA Complementar/metabolismo , Células HEK293 , Humanos , Camundongos , Microscopia Confocal , Microscopia de Fluorescência , Oxigênio/metabolismo , Isoformas de Proteínas/metabolismo , Receptores de LDL/metabolismo
2.
J Hum Genet ; 60(5): 281-3, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25694106

RESUMO

Mutations in APP, PSEN1 and PSEN2 as the genetic causes of familial Alzheimer's disease (FAD) have been found in various ethnic populations. A substantial number of FAD pedigrees with mutations have been reported in the Japanese population; however, it remains unclear whether the genetic and clinical features of FAD in the Japanese population differ from those in other populations. To address this issue, we conducted a systematic review and meta-analysis of Japanese FAD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) by literature search. Using this analysis, we identified 39 different PSEN1 mutations in 140 patients, 5 APP mutations in 35 patients and 16 MAPT mutations in 84 patients. There was no PSEN2 mutation among Japanese patients. The age at onset in Japanese FAD patients with PSEN1 mutations was significantly younger than that in patients with APP mutations. Kaplan-Meier analysis revealed that patients with MAPT mutations showed a shorter survival than patients with PSEN1 or APP mutations. Patients with mutations in different genes exhibit characteristic clinical presentations, suggesting that mutations in causative genes may modify the clinical presentations. By collecting and cataloging genetic and clinical information on Japanese FAD and FTDP-17, we developed an original database designated as Japanese Familial Alzheimer's Disease Database, which is accessible at http://alzdb.bri.niigata-u.ac.jp/.


Assuntos
Doença de Alzheimer/genética , Demência Frontotemporal/genética , Idade de Início , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Cromossomos Humanos Par 17/genética , Demência Frontotemporal/patologia , Demência Frontotemporal/psicologia , Predisposição Genética para Doença , Humanos , Mutação
3.
Intern Med ; 2024 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-39293983

RESUMO

Background Acquired amegakaryocytic thrombocytopenia (AAMT) is a rare disorder characterized by thrombocytopenia, marked megakaryocytic hypoplasia, and preserved other-lineage hematopoiesis in the bone marrow. The etiology of AAMT remains poorly understood owing to its rarity. Case description We encountered a diagnostically challenging case involving a 66-year-old man who showed severe thrombocytopenic bleeding with isolated megakaryocytic hypoplasia, elevated serum thrombopoietin levels, glycoprotein IIb/IIIa antibody positivity, and prolonged platelet transfusion refractoriness following mantle cell lymphoma (MCL). Treatment with corticosteroids and intravenous immunoglobulin was ineffective, while a combination of multiagent chemotherapy, including rituximab, was beneficial for both thrombocytopenia and MCL. Ultimately, the patient was diagnosed with AMMT and immune thrombocytopenia (ITP)-like platelet destruction. Discussion This case suggests that AAMT and ITP are non-exclusive and sometimes overlap as components of a broad spectrum of platelet-related autoimmune diseases.

4.
Intern Med ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38960694

RESUMO

Background Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) is predominantly of B cell origin. The concept of clonal evolution from poly- to monoclonal lymphoproliferation has been put forward, but T-cell PTLDs are rare with an unknown etiology. Case Presentation In a unique autopsy case of a 53-year-old man with EBV-associated T-cell PTLD, we observed polymorphic T-cell proliferation across several organs and monomorphic T-cell proliferation in the perforated ileum. Interestingly, both manifestations exhibited identical monoclonal peaks in the T-cell receptor rearrangement polymerase chain reaction (PCR) analyses. Conclusion These findings suggest the existence of clonal evolution in EBV-associated T-cell PTLD, leading to the proposal of the novel concept of polymorphic T-cell PTLD.

5.
J Biol Chem ; 287(42): 35222-35233, 2012 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-22910909

RESUMO

Alzheimer disease (AD) is neuropathologically characterized by the formation of senile plaques from amyloid-ß (Aß) and neurofibrillary tangles composed of phosphorylated Tau. Although there is growing evidence for the pathogenic role of soluble Aß species in AD, the major question of how Aß induces hyperphosphorylation of Tau remains unanswered. To address this question, we here developed a novel cell coculture system to assess the effect of extracellular Aß at physiologically relevant levels naturally secreted from donor cells on the phosphorylation of Tau in recipient cells. Using this assay, we demonstrated that physiologically relevant levels of secreted Aß are sufficient to cause hyperphosphorylation of Tau in recipient N2a cells expressing human Tau and in primary culture neurons. This hyperphosphorylation of Tau is inhibited by blocking Aß production in donor cells. The expression of familial AD-linked PSEN1 mutants and APP ΔE693 mutant that induce the production of oligomeric Aß in donor cells results in a similar hyperphosphorylation of Tau in recipient cells. The mechanism underlying the Aß-induced Tau hyperphosphorylation is mediated by the impaired insulin signal transduction because we demonstrated that the phosphorylation of Akt and GSK3ß upon insulin stimulation is less activated under this condition. Treating cells with the insulin-sensitizing drug rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, attenuates the Aß-dependent hyperphosphorylation of Tau. These findings suggest that the disturbed insulin signaling cascade may be implicated in the pathways through which soluble Aß induces Tau phosphorylation and further support the notion that correcting insulin signal dysregulation in AD may offer a potential therapeutic approach.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Proteínas tau/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Linhagem Celular Tumoral , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Células HEK293 , Humanos , Insulina/genética , Insulina/metabolismo , Camundongos , Neurônios/patologia , PPAR gama/agonistas , PPAR gama/genética , PPAR gama/metabolismo , Fosforilação/genética , Presenilina-1/genética , Presenilina-1/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Rosiglitazona , Deleção de Sequência , Tiazolidinedionas/farmacologia , Proteínas tau/genética
6.
Neurobiol Aging ; 127: 23-32, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37030016

RESUMO

We aimed to assess the utility of AT(N) classification in clinical practice. We measured the cerebrospinal fluid levels of amyloid-ß (Aß) 42, Aß40, phosphorylated tau, total tau, and neurofilament light chain (NfL) in samples from 230 patients with Alzheimer's clinical syndrome (ACS) and 328 patients with non-ACS. The concordance of two A-markers (i.e., Aß42 alone and the Aß42/Aß40 ratio) was not significantly different between the ACS (87.4%) and non-ACS (74.1%) groups. However, the frequency of discordant cases with AAß42-alone+/AAß-ratio- was significantly higher in the non-ACS (23.8%) than in the ACS group (7.4%). The concordance of two N-markers (i.e., total tau and NfL) was 40.4% in the ACS group and 24.4% in the non-ACS group. In the ACS samples, the frequency of biological Alzheimer's disease (i.e., A+T+) in Ntau+ cases was 95% while that in NNfL+ cases was 65%. Reflecting Aß deposition and neurodegeneration more accurately, we recommend the use of AT(N) classification defined by cerebrospinal fluid AAß-ratioTNNfL in clinical practice.


Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Síndrome , Fragmentos de Peptídeos/líquido cefalorraquidiano
7.
Brain Sci ; 13(6)2023 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-37371433

RESUMO

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

8.
Parkinsonism Relat Disord ; 102: 30-35, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35933820

RESUMO

BACKGROUND: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder. The usefulness of biomarkers in diagnosing MSA has been recently reported, but few studies have investigated the correlations among cerebrospinal fluid (CSF) biomarkers or the relationship between CSF biomarkers and the clinical parameters of patients with MSA. Thus, this was the aim of our study. METHODS: We performed cross-sectional study of CSF biomarkers in 50 patients with MSA and 20 control subjects. Ten of the patients with MSA were longitudinally followed for a period of 2 ± 1 years (mean ± standard deviation) as a substudy. We quantified CSF biomarkers including α-synuclein (α-syn), ß-amyloid42 (Aß42), total tau (t-tau) and phosphorylated tau (p-tau), neurofilament light chain (NfL), and neuron-glia2 (NG2), and assessed their relationship with clinical parameters (clinical subtypes, motor symptoms, nonmotor symptoms, and disease progression). RESULTS: The levels of CSF α-syn, Aß42, and p-tau were significantly lower, while those of NfL were higher in the patients with MSA than in the control subjects. Importantly, we found the significant elevation of soluble NG2 in the CSF of patients with MSA. CSF NfL showed the optimal diagnostic performance for MSA with levels at baseline significantly associated with longitudinal motor progression. With the exception of t-tau, there were no differences in the levels of CSF biomarkers between the MSA-parkinsonism and MSA-cerebellar subtypes. CONCLUSIONS: Our results suggest CSF levels of NG2 and NfL as possible diagnostic and prognostic biomarkers in MSA. Further study is necessary to validate these findings.


Assuntos
Atrofia de Múltiplos Sistemas , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Estudos Transversais , Humanos , Filamentos Intermediários , Atrofia de Múltiplos Sistemas/líquido cefalorraquidiano , Atrofia de Múltiplos Sistemas/diagnóstico , Neuroglia , Neurônios , alfa-Sinucleína/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano
9.
Nutrients ; 14(3)2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35276996

RESUMO

Nutritional epidemiology has shown the importance of protein intake for maintaining brain function in the elderly population. Mild cognitive impairment (MCI) may be associated with malnutrition, especially protein intake. We explored blood-based biomarkers linking protein nutritional status with MCI in a multicenter study. In total, 219 individuals with MCI (79.5 ± 5.7 year) from 10 institutions and 220 individuals who were cognitively normal (CN, 76.3 ± 6.6 year) in four different cities in Japan were recruited. They were divided into the training (120 MCI and 120 CN) and validation (99 MCI and 100 CN) groups. A model involving concentrations of PFAAs and albumin to discriminate MCI from CN individuals was constructed by multivariate logistic regression analysis in the training dataset, and the performance was evaluated in the validation dataset. The concentrations of some essential amino acids and albumin were significantly lower in MCI group than CN group. An index incorporating albumin and PFAA discriminated MCI from CN participants with the AUC of 0.705 (95% CI: 0.632-0.778), and the sensitivities at specificities of 90% and 60% were 25.3% and 76.8%, respectively. No significant association with BMI or APOE status was observed. This cross-sectional study suggests that the biomarker changes in MCI group may be associated with protein nutrition.


Assuntos
Disfunção Cognitiva , Estado Nutricional , Idoso , Aminoácidos , Biomarcadores/metabolismo , Disfunção Cognitiva/metabolismo , Estudos Transversais , Humanos
10.
Front Nutr ; 9: 1040476, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36590218

RESUMO

Background: Nutritional epidemiology has shown that inadequate dietary protein intake is associated with poor brain function in the elderly population. The plasma free amino acid (PFAA) profile reflects nutritional status and may have the potential to predict future changes in cognitive function. Here, we report the results of a 2-year interim analysis of a 3-year longitudinal study following mild cognitive impairment (MCI) participants. Method: In a multicenter prospective cohort design, MCI participants were recruited, and fasting plasma samples were collected. Based on clinical assessment of cognitive function up to 2 years after blood collection, MCI participants were divided into two groups: remained with MCI or reverted to cognitively normal ("MCI-stable," N = 87) and converted to Alzheimer's disease (AD) ("AD-convert," N = 68). The baseline PFAA profile was compared between the two groups. Stratified analysis based on apolipoprotein E ε4 (APOE ε4) allele possession was also conducted. Results: Plasma concentrations of all nine essential amino acids (EAAs) were lower in the AD-convert group. Among EAAs, three branched-chain amino acids (BCAAs), valine, leucine and isoleucine, and histidine (His) exhibited significant differences even in the logistic regression model adjusted for potential confounding factors such as age, sex, body mass index (BMI), and APOE ε4 possession (p < 0.05). In the stratified analysis, differences in plasma concentrations of these four EAAs were more pronounced in the APOE ε4-negative group. Conclusion: The PFAA profile, especially decreases in BCAAs and His, is associated with development of AD in MCI participants, and the difference was larger in the APOE ε4-negative population, suggesting that the PFAA profile is an independent risk indicator for AD development. Measuring the PFAA profile may have importance in assessing the risk of AD conversion in the MCI population, possibly reflecting nutritional status. Clinical trial registration: [https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000025322], identifier [UMIN000021965].

11.
Rinsho Shinkeigaku ; 61(8): 563-566, 2021 Aug 30.
Artigo em Japonês | MEDLINE | ID: mdl-34275957

RESUMO

A 50-year-old man with mitral regurgitation presented with right frontal subcortical hemorrhage. Although he had no fever and his white blood cell count was in the normal range, CT angiography demonstrated a micro cerebral aneurysm, and all three blood cultures were positive for Staphylococcus warneri (S. warneri). Thus, we diagnosed him with infective endocarditis. His condition improved successfully by immediate antibiotics and cerebral aneurysm clipping. S. warneri is a member of coagulase-negative staphylococci that are low-virulence and resident flora of the skin. S. warneri rarely causes infective endocarditis on native valves. Infective endocarditis caused by S. warneri manifests insidious course without inflammatory reactions such as fever and leukocytosis, and thus, diagnosis can be delayed. Attention should be paid to a patient who develops subcortical hemorrhage without a history of hypertension or inflammatory reactions as in this case.


Assuntos
Endocardite Bacteriana , Aneurisma Intracraniano , Hemorragia Cerebral/diagnóstico por imagem , Hemorragia Cerebral/etiologia , Endocardite Bacteriana/complicações , Febre/etiologia , Humanos , Inflamação , Leucocitose/etiologia , Masculino , Pessoa de Meia-Idade , Staphylococcus
12.
Front Neurol ; 12: 719159, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34777195

RESUMO

An easily accessible and non-invasive biomarker for the early detection of Alzheimer's disease (AD) is needed. Evidence suggests that metabolic dysfunction underlies the pathophysiology of AD. While urine is a non-invasively collectable biofluid and a good source for metabolomics analysis, it is not yet widely used for this purpose. This small-scale pilot study aimed to examine whether the metabolic profile of urine from AD patients reflects the metabolic dysfunction reported to underlie AD pathology, and to identify metabolites that could distinguish AD patients from cognitively healthy controls. Spot urine of 18 AD patients (AD group) and 18 age- and sex-matched, cognitively normal controls (control group) were analyzed by mass spectrometry (MS). Capillary electrophoresis time-of-flight MS and liquid chromatography-Fourier transform MS were used to cover a larger range of molecules with ionic as well as lipid characteristics. A total of 304 ionic molecules and 81 lipid compounds of 12 lipid classes were identified. Of these, 26 molecules showed significantly different relative concentrations between the AD and control groups (Wilcoxon's rank-sum test). Moreover, orthogonal partial least-squares discriminant analysis revealed significant discrimination between the two groups. Pathway searches using the KEGG database, and pathway enrichment and topology analysis using Metaboanalyst software, suggested alterations in molecules relevant to pathways of glycerolipid and glycerophospholipid metabolism, thermogenesis, and caffeine metabolism in AD patients. Further studies of urinary metabolites will contribute to the early detection of AD and understanding of its pathogenesis.

13.
J Neurol Neurosurg Psychiatry ; 81(6): 608-10, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20522869

RESUMO

BACKGROUND: The clinical diagnosis of dementia with Lewy bodies (DLB) is made on the basis of consensus criteria; however, the sensitivity of the criteria is relatively low. There are no generally accepted biomarkers to distinguish DLB from other dementias. Here the utility of quantification of alpha-synuclein, beta-amyloid42 (Abeta42) and tau in the CSF of patients with DLB, Alzheimer's disease (AD) and other dementias was examined. METHODS: 86 patients were divided into three age and sex matched groups: DLB (n=34), AD (n=31) and other dementias (n=21). Two patients with alpha-synuclein gene (SNCA) duplication were also examined. Abeta and tau were quantified using an ELISA kit. A modified sandwich ELISA was developed which enables the sensitive quantification of CSF alpha-synuclein. RESULTS: Total and phosphorylated tau levels as well as Abeta40/42 and tau/Abeta42 ratios were significantly higher in AD patients than in patients with DLB (p<0.01) and other dementias (p<0.01). CSF alpha-synuclein levels in DLB patients were significantly lower than those in patients with AD (p<0.05) and other dementias (p<0.01). CSF alpha-synuclein level correlated with the Abeta42 level in DLB patients (p=0.01, r=0.43). Two patients with SNCA duplication exhibited relatively low levels of CSF alpha-synuclein. CONCLUSIONS: The study suggests that reduced levels of CSF alpha-synuclein in DLB may reflect the accumulation of alpha-synuclein with Lewy pathology in the brain and that quantification of CSF alpha-synuclein helps in the differentiation of DLB from AD and other dementias in combination with Abeta42 and tau analysis.


Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/genética , Doença por Corpos de Lewy , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fragmentos de Peptídeos/genética , alfa-Sinucleína/líquido cefalorraquidiano , alfa-Sinucleína/genética , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/genética , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Doença por Corpos de Lewy/líquido cefalorraquidiano , Doença por Corpos de Lewy/epidemiologia , Doença por Corpos de Lewy/genética , Masculino , Fenótipo
14.
Dement Geriatr Cogn Disord ; 30(1): 28-32, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-20689279

RESUMO

BACKGROUND: Recent genetic and pathological studies have suggested that a lipoprotein receptor, LR11, is intricately implicated in the pathogenesis of Alzheimer disease (AD). We have recently established a novel sandwich ELISA, which enabled the sensitive quantification of a soluble LR11 (sLR11). By this ELISA, we attempted to determine the difference in the levels of CSF sLR11 in AD patients. METHODS: We examined CSF from 29 AD patients, 20 frontotemporal lobar degeneration patients and 27 age-matched control subjects. The CSF sLR11 level as well as the levels of tau and beta-amyloid42 (Abeta42) were determined by sandwich ELISA. RESULTS: The CSF tau level and tau/Abeta42 ratio were significantly increased (p < 0.01) in the AD patients. The CSF sLR11 level in the AD patients was significantly higher (p < 0.01) than that of the frontotemporal lobar degeneration patients and the controls. The APOE-epsilon4-positive AD patients have higher sLR11 levels than the APOE-epsilon4-negative patients (p < 0.01). CONCLUSIONS: These results suggest that the quantification of CSF sLR11 may serve as a biomarker of AD, although the diagnostic value for individual patients is limited. An elevated CSF sLR11 level in AD patients may be relevant to AD pathogenesis.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Proteínas Relacionadas a Receptor de LDL/líquido cefalorraquidiano , Proteínas de Membrana Transportadoras/líquido cefalorraquidiano , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Biomarcadores , Ensaio de Imunoadsorção Enzimática , Feminino , Degeneração Lobar Frontotemporal/líquido cefalorraquidiano , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas tau/líquido cefalorraquidiano
15.
Int J Lab Hematol ; 42(1): 46-51, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31821738

RESUMO

INTRODUCTION: Detection of lupus anticoagulant (LA), an antiphospholipid (aPL) antibody, in a clotting time test is an important finding for diagnosis of antiphospholipid syndrome (APS). However, confirmation of LA requires several different testing procedures, some of which can be difficult and require time. We report here a simple and highly specific method for detecting LA. MATERIALS AND METHODS: We examined 66 plasma samples obtained from LA-positive (LA) and 75 from LA-negative (non-LA) subjects, which included patients with acquired hemophilia and coagulation disorders, as well as from 43 healthy volunteer samples as normal controls. Activated partial thromboplastin time (APTT) was determined by adding 20 mmol of CaCl2 (Ca-APTT) or 25 mmol of a mixture of Mg and Ca (Mg-APTT). The ratio of Mg-APTT/Ca-APTT was then calculated and used as the Mg/Ca Index. RESULTS: The Mg/Ca Index value for the LA group was significantly lower than that for the non-LA and normal control groups (P < .0001). When the cutoff value of the Mg/Ca Index was less than 1.00, the sensitivity of LA determination using the Mg-APTT assay was 80.3%, while specificity was 100%. CONCLUSION: Our findings indicate that the present Mg-APTT assay is a simple yet highly specific method for LA detection.


Assuntos
Síndrome Antifosfolipídica/sangue , Inibidor de Coagulação do Lúpus/sangue , Magnésio/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome Antifosfolipídica/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Tempo de Tromboplastina Parcial
16.
Dement Geriatr Cogn Dis Extra ; 10(3): 94-104, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33082773

RESUMO

INTRODUCTION: Biomarkers of Alzheimer's disease (AD) that can easily be measured in routine health checkups are desirable. Urine is a source of biomarkers that can be collected easily and noninvasively. We previously reported on the comprehensive profile of the urinary proteome of AD patients and identified proteins estimated to be significantly increased or decreased in AD patients by a label-free quantification method. The present study aimed to validate urinary levels of proteins that significantly differed between AD and control samples from our proteomics study (i.e., apolipoprotein C3 [ApoC3], insulin-like growth factor-binding protein 3 [Igfbp3], and apolipoprotein D [ApoD]). METHODS: Enzyme-linked immunosorbent assays (ELISAs) were performed using urine samples from the same patient and control groups analyzed in the previous proteomics study (18 AD and 18 controls, set 1) and urine samples from an independent group of AD patients and controls (13 AD, 5 mild cognitive impairment [MCI], and 32 controls) from the National Center for Geriatrics and Gerontology Biobank (set 2). RESULTS: In set 1, the crude urinary levels of ApoD, Igfbp3, and creatinine-adjusted ApoD were significantly higher in the AD group relative to the control group (p = 0.003, p = 0.002, and p = 0.019, respectively), consistent with our previous proteomics results. In set 2, however, the crude urinary levels of Igfbp3 were significantly lower in the AD+MCI group than in the control group (p = 0.028), and the levels of ApoD and ApoC3 did not differ significantly compared to the control group. Combined analysis of all samples revealed creatinine-adjusted ApoC3 levels to be significantly higher in the AD+MCI group (p = 0.015) and the AD-only group (p = 0.011) relative to the control group. CONCLUSION: ApoC3 may be a potential biomarker for AD, as validated by ELISA. Further analysis of ApoC3 as a urinary biomarker for AD is warranted.

17.
Dement Geriatr Cogn Dis Extra ; 9(1): 53-65, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31043964

RESUMO

BACKGROUND/AIMS: The identification of predictive biomarkers for Alzheimer's disease (AD) from urine would aid in screening for the disease, but information about biological and pathophysiological changes in the urine of AD patients is limited. This study aimed to explore the comprehensive profile and molecular network relations of urinary proteins in AD patients. METHODS: Urine samples collected from 18 AD patients and 18 age- and sex-matched cognitively normal controls were analyzed by mass spectrometry and semiquantified with the normalized spectral index method. Bioinformatics analyses were performed on proteins which significantly increased by more than 2-fold or decreased by less than 0.5-fold compared to the control (p < 0.05) using DAVID bioinformatics resources and KeyMolnet software. RESULTS: The levels of 109 proteins significantly differed between AD patients and controls. Among these, annotation clusters related to lysosomes, complement activation, and gluconeogenesis were significantly enriched. The molecular relation networks derived from these proteins were mainly associated with pathways of lipoprotein metabolism, heat shock protein 90 signaling, matrix metalloproteinase signaling, and redox regulation by thioredoxin. CONCLUSION: Our findings suggest that changes in the urinary proteome of AD patients reflect systemic changes related to AD pathophysiology.

18.
Mov Disord ; 23(6): 912-5, 2008 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-18383535

RESUMO

A patient with distal myopathy with rimmed vacuoles (DMRV) exhibited Parkinsonism with a severe writing tremor that responded poorly to levodopa. Molecular genetic analysis revealed that the patient had the D176V/V572L compound heterozygous mutation in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene. Histopathological examination of a biopsied muscle specimen yielded findings compatible with those of DMRV, which is characterized by the presence of rimmed vacuoles without inflammatory cell infiltration in muscle fibers. The finding of normal cardiac meta-iodobenzylguanide uptake makes the possibility of incidental Parkinson's disease in this patient unlikely. These observations raise the possibility that atypical Parkinsonism is a rare complication of DMRV associated with GNE mutation.


Assuntos
Miopatias Distais/patologia , Doença de Parkinson/patologia , Vacúolos/patologia , Distonia/patologia , Distonia/fisiopatologia , Eletromiografia , Humanos , Hipocinesia/etiologia , Masculino , Pessoa de Meia-Idade , Vacúolos/ultraestrutura
19.
J Neurol ; 265(10): 2415-2424, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30136118

RESUMO

OBJECTIVE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12-22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants. METHODS: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants. RESULTS: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic. CONCLUSIONS: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.


Assuntos
Mutação da Fase de Leitura , Leucoencefalopatias/genética , Mutação de Sentido Incorreto , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Análise Mutacional de DNA , Éxons , Feminino , Células HEK293 , Haploinsuficiência , Humanos , Leucoencefalopatias/diagnóstico por imagem , Leucoencefalopatias/metabolismo , Leucoencefalopatias/patologia , Masculino , Pessoa de Meia-Idade , Fosforilação , RNA Mensageiro/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Adulto Jovem
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