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1.
Fortschr Neurol Psychiatr ; 90(7-08): 361-367, 2022 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-35858613

RESUMO

Dementias are expensive diseases: the net annual cost in European healthcare is about € 28.000 per case with a strong stage dependency, of which medical care accounts for about 19%. Diagnostic costs, on the other hand, account for only a small proportion of the total costs. With changes in the guidelines, biomarker tests are becoming increasingly important. At present, the concrete economic impact of biomarker-based diagnosis is largely unknown. To determine the actual costs of diagnostic procedures based on guidelines, we conducted a survey among the members of the German Memory Clinic Network (DNG). From 15 expert centres, the staff engagement time for all procedures was collected. Based on the individual engagement times of the different professions, the total of personnel costs for diagnostics was calculated using current gross personnel costs. The total sum of diagnostic costs (personnel plus procedures) was calculated for three different scenarios e. g. € 633,97 for diagnostics without biomarkers, € 1.214,90 for diagnostics with CSF biomarkers and € 4.740,58 € for diagnostics with FDG- plus Amyloid-PET. In addition, the actual diagnostic costs of the current practice in expert memory clinics were estimated, taking into account personnel costs, costs for the different procedures and the frequency of their use across all patients. This results in total average costs of € 1.394,43 per case as the mean across all centres (personnel costs € 351,72, costs for diagnostic procedures € 1.042,71). The results show that state-of-the-art diagnosis of dementia and pre-dementia states, such as mild cognitive impairment (MCI) requires financial resources, which are currently not fully reimbursed in Germany. The need for a biomarker-based etiological diagnosis of dementia and pre-dementia states will increase, due to availability of disease-modifying treatments. Therefore, the current gap of reimbursement must be filled by new models of compensation.


Assuntos
Disfunção Cognitiva , Demência , Disfunção Cognitiva/diagnóstico , Demência/diagnóstico , Diagnóstico Precoce , Alemanha , Custos de Cuidados de Saúde , Humanos
2.
Mol Psychiatry ; 25(3): 629-639, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-29988083

RESUMO

Common variants of about 20 genes contributing to AD risk have so far been identified through genome-wide association studies (GWAS). However, there is still a large proportion of heritability that might be explained by rare but functionally important variants. One of the so far identified genes with rare AD causing variants is ADAM10. Using whole-genome sequencing we now identified a single rare nonsynonymous variant (SNV) rs142946965 [p.R215I] in ADAM17 co-segregating with an autosomal-dominant pattern of late-onset AD in one family. Subsequent genotyping and analysis of available whole-exome sequencing data of additional case/control samples from Germany, UK, and USA identified five variant carriers among AD patients only. The mutation inhibits pro-protein cleavage and the formation of the active enzyme, thus leading to loss-of-function of ADAM17 alpha-secretase. Further, we identified a strong negative correlation between ADAM17 and APP gene expression in human brain and present in vitro evidence that ADAM17 negatively controls the expression of APP. As a consequence, p.R215I mutation of ADAM17 leads to elevated Aß formation in vitro. Together our data supports a causative association of the identified ADAM17 variant in the pathogenesis of AD.


Assuntos
Proteína ADAM17/genética , Doença de Alzheimer/genética , Proteína ADAM17/metabolismo , Idoso , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Alemanha , Humanos , Mutação com Perda de Função/genética , Masculino , Pessoa de Meia-Idade , Mutação , Sequenciamento do Exoma
3.
Acta Neuropathol ; 136(6): 857-872, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29967939

RESUMO

Cerebrospinal fluid (CSF) levels of amyloid-ß 42 (Aß42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aß42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aß42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (ß = - 0.03, p = 4.25 × 10-8; ß = 0.03, p = 3.97 × 10-8) than males (ß = - 0.02, p = 0.009; ß = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (ß = 0.05, p = 4.57 × 10-10) compared to males (ß = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.


Assuntos
Doença de Alzheimer , Biomarcadores/líquido cefalorraquidiano , Encéfalo/patologia , Claudinas/genética , Proteínas Musculares/genética , Serpinas/genética , Fatores de Transcrição/genética , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Amiloidose/complicações , Amiloidose/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Mutação/genética , Fragmentos de Peptídeos/líquido cefalorraquidiano , Fatores Sexuais , Proteínas tau/líquido cefalorraquidiano
4.
Acta Neuropathol ; 133(5): 839-856, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28247064

RESUMO

More than 20 genetic loci have been associated with risk for Alzheimer's disease (AD), but reported genome-wide significant loci do not account for all the estimated heritability and provide little information about underlying biological mechanisms. Genetic studies using intermediate quantitative traits such as biomarkers, or endophenotypes, benefit from increased statistical power to identify variants that may not pass the stringent multiple test correction in case-control studies. Endophenotypes also contain additional information helpful for identifying variants and genes associated with other aspects of disease, such as rate of progression or onset, and provide context to interpret the results from genome-wide association studies (GWAS). We conducted GWAS of amyloid beta (Aß42), tau, and phosphorylated tau (ptau181) levels in cerebrospinal fluid (CSF) from 3146 participants across nine studies to identify novel variants associated with AD. Five genome-wide significant loci (two novel) were associated with ptau181, including loci that have also been associated with AD risk or brain-related phenotypes. Two novel loci associated with Aß42 near GLIS1 on 1p32.3 (ß = -0.059, P = 2.08 × 10-8) and within SERPINB1 on 6p25 (ß = -0.025, P = 1.72 × 10-8) were also associated with AD risk (GLIS1: OR = 1.105, P = 3.43 × 10-2), disease progression (GLIS1: ß = 0.277, P = 1.92 × 10-2), and age at onset (SERPINB1: ß = 0.043, P = 4.62 × 10-3). Bioinformatics indicate that the intronic SERPINB1 variant (rs316341) affects expression of SERPINB1 in various tissues, including the hippocampus, suggesting that SERPINB1 influences AD through an Aß-associated mechanism. Analyses of known AD risk loci suggest CLU and FERMT2 may influence CSF Aß42 (P = 0.001 and P = 0.009, respectively) and the INPP5D locus may affect ptau181 levels (P = 0.009); larger studies are necessary to verify these results. Together the findings from this study can be used to inform future AD studies.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Proteínas tau/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/líquido cefalorraquidiano , Apolipoproteínas E/genética , Biomarcadores/análise , Progressão da Doença , Endofenótipos/líquido cefalorraquidiano , Loci Gênicos , Genótipo , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Proteínas tau/líquido cefalorraquidiano
5.
Biochem J ; 473(11): 1563-78, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27029347

RESUMO

Amyloid beta (Aß) peptides, in particular Aß42 and Aß40, exert neurotoxic effects and their overproduction leads to amyloid deposits in the brain, thus constituting an important biomolecular target for treatments of Alzheimer's disease (AD). We describe the engineering of cognate Anticalins as a novel type of neutralizing protein reagent based on the human lipocalin scaffold. Phage display selection from a genetic random library comprising variants of the human lipocalin 2 (Lcn2) with mutations targeted at 20 exposed amino acid positions in the four loops that form the natural binding site was performed using both recombinant and synthetic target peptides and resulted in three different Anticalins. Biochemical characterization of the purified proteins produced by periplasmic secretion in Escherichia coli revealed high folding stability in a monomeric state, with Tm values ranging from 53.4°C to 74.5°C, as well as high affinities for Aß40, between 95 pM and 563 pM, as measured by real-time surface plasmon resonance analysis. The central linear VFFAED epitope within the Aß sequence was mapped using a synthetic peptide array on membranes and was shared by all three Anticalins, despite up to 13 mutual amino acid differences in their binding sites. All Anticalins had the ability-with varying extent-to inhibit Aß aggregation in vitro according to the thioflavin-T fluorescence assay and, furthermore, they abolished Aß42-mediated toxicity in neuronal cell culture. Thus, these Anticalins provide not only useful protein reagents to study the molecular pathology of AD but they also show potential as alternative drug candidates compared with antibodies.


Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Lipocalinas/química , Engenharia de Proteínas/métodos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Lipocalinas/farmacologia , Lipocalinas/uso terapêutico , Dados de Sequência Molecular , Biblioteca de Peptídeos , Ligação Proteica , Conformação Proteica
6.
FASEB J ; 28(2): 978-97, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24165480

RESUMO

In Alzheimer's disease (AD), disturbed homeostasis of the proteases competing for amyloid precursor protein processing has been reported: a disintegrin and metalloproteinase 10 (ADAM10), the physiological α-secretase, is decreased in favor of the amyloid-ß-generating enzyme BACE-1. To identify transcription factors that modulate the expression of either protease, we performed a screening approach: 48 transcription factors significantly interfered with ADAM10/BACE-1-promoter activity. One selective inducer of ADAM10 gene expression is the X-box binding protein-1 (XBP-1). This protein regulates the unfolded protein-response pathway. We demonstrate that particularly the spliced XBP-1 variant dose dependently regulates ADAM10 expression, which can be synergistically enhanced by 100 nM insulin. Analysis of 2 different transgenic mouse models (APP/PS1 and 5xFAD) revealed that at early time points in pathology XBP-1 metabolism is induced. This is accompanied by a 2-fold augmented ADAM10 amount as compared with nontransgenic littermates (P=0.011). Along with aging of the mice, the system is counterregulated, and XBP-1 together with ADAM10 expression level decreased to ∼50% as compared with control animals. Analyses of expression levels in human AD brains showed that ADAM10 mRNA correlated with active XBP-1 (r=0.3120), but expression did not reach levels of healthy age-matched controls, suggesting deregulation of XBP-1 signaling. Our results demonstrate that XBP-1 is a driver of ADAM10 gene expression and that disturbance of this pathway might contribute to development or progression of AD.


Assuntos
Proteínas ADAM/metabolismo , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Membrana/metabolismo , Fatores de Transcrição/metabolismo , Resposta a Proteínas não Dobradas/fisiologia , Proteínas ADAM/genética , Proteína ADAM10 , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide/genética , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Ensaio de Imunoadsorção Enzimática , Humanos , Proteínas de Membrana/genética , Camundongos , Regiões Promotoras Genéticas/genética , Fatores de Transcrição de Fator Regulador X , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Fatores de Transcrição/genética , Resposta a Proteínas não Dobradas/genética , Proteína 1 de Ligação a X-Box
7.
Mol Ecol ; 22(10): 2797-809, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23506506

RESUMO

The assessment of genetic architecture and selection history in genes for behavioural traits is fundamental to our understanding of how these traits evolve. The dopamine receptor D4 (DRD4) gene is a prime candidate for explaining genetic variation in novelty seeking behaviour, a commonly assayed personality trait in animals. Previously, we showed that a single nucleotide polymorphism in exon 3 of this gene is associated with exploratory behaviour in at least one of four Western European great tit (Parus major) populations. These heterogeneous association results were explained by potential variable linkage disequilibrium (LD) patterns between this marker and the causal variant or by other genetic or environmental differences among the populations. Different adaptive histories are further hypothesized to have contributed to these population differences. Here, we genotyped 98 polymorphisms of the complete DRD4 gene including the flanking regions for 595 individuals of the four populations. We show that the LD structure, specifically around the original exon 3 SNP is conserved across the four populations and does not explain the heterogeneous association results. Study-wide significant associations with exploratory behaviour were detected in more than one haplotype block around exon 2, 3 and 4 in two of the four tested populations with different allele effect models. This indicates genetic heterogeneity in the association between multiple DRD4 polymorphisms and exploratory behaviour across populations. The association signals were in or close to regions with signatures of positive selection. We therefore hypothesize that variation in exploratory and other dopamine-related behaviour evolves locally by occasional adaptive shifts in the frequency of underlying genetic variants.


Assuntos
Adaptação Biológica/genética , Comportamento Exploratório/fisiologia , Variação Genética , Passeriformes/genética , Receptores de Dopamina D4/genética , Seleção Genética , Animais , Sequência de Bases , Europa (Continente) , Genótipo , Haplótipos/genética , Desequilíbrio de Ligação , Modelos Genéticos , Dados de Sequência Molecular , Passeriformes/fisiologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Especificidade da Espécie
8.
JMIR Ment Health ; 10: e37225, 2023 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-36689265

RESUMO

BACKGROUND: Major depressive episode (MDE) is a common clinical syndrome. It can be found in different pathologies such as major depressive disorder (MDD), bipolar disorder (BD), posttraumatic stress disorder (PTSD), or even occur in the context of psychological trauma. However, only 1 syndrome is described in international classifications (Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [DSM-5]/International Classification of Diseases 11th Revision [ICD-11]), which do not take into account the underlying pathology at the origin of the MDE. Clinical interviews are currently the best source of information to obtain the etiological diagnosis of MDE. Nevertheless, it does not allow an early diagnosis and there are no objective measures of extracted clinical information. To remedy this, the use of digital tools and their correlation with clinical symptomatology could be useful. OBJECTIVE: We aimed to review the current application of digital tools for MDE diagnosis while highlighting shortcomings for further research. In addition, our work was focused on digital devices easy to use during clinical interview and mental health issues where depression is common. METHODS: We conducted a narrative review of the use of digital tools during clinical interviews for MDE by searching papers published in PubMed/MEDLINE, Web of Science, and Google Scholar databases since February 2010. The search was conducted from June to September 2021. Potentially relevant papers were then compared against a checklist for relevance and reviewed independently for inclusion, with focus on 4 allocated topics of (1) automated voice analysis, behavior analysis by (2) video and physiological measures, (3) heart rate variability (HRV), and (4) electrodermal activity (EDA). For this purpose, we were interested in 4 frequently found clinical conditions in which MDE can occur: (1) MDD, (2) BD, (3) PTSD, and (4) psychological trauma. RESULTS: A total of 74 relevant papers on the subject were qualitatively analyzed and the information was synthesized. Thus, a digital phenotype of MDE seems to emerge consisting of modifications in speech features (namely, temporal, prosodic, spectral, source, and formants) and in speech content, modifications in nonverbal behavior (head, hand, body and eyes movement, facial expressivity, and gaze), and a decrease in physiological measurements (HRV and EDA). We not only found similarities but also differences when MDE occurs in MDD, BD, PTSD, or psychological trauma. However, comparative studies were rare in BD or PTSD conditions, which does not allow us to identify clear and distinct digital phenotypes. CONCLUSIONS: Our search identified markers from several modalities that hold promise for helping with a more objective diagnosis of MDE. To validate their potential, further longitudinal and prospective studies are needed.

10.
ScientificWorldJournal ; 2012: 141240, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22547976

RESUMO

Lipids play an important role as risk or protective factors in Alzheimer's disease (AD). Previously it has been shown that plasmalogens, the major brain phospholipids, are altered in AD. However, it remained unclear whether plasmalogens themselves are able to modulate amyloid precursor protein (APP) processing or if the reduced plasmalogen level is a consequence of AD. Here we identify the plasmalogens which are altered in human AD postmortem brains and investigate their impact on APP processing resulting in Aß production. All tested plasmalogen species showed a reduction in γ-secretase activity whereas ß- and α-secretase activity mainly remained unchanged. Plasmalogens directly affected γ-secretase activity, protein and RNA level of the secretases were unaffected, pointing towards a direct influence of plasmalogens on γ-secretase activity. Plasmalogens were also able to decrease γ-secretase activity in human postmortem AD brains emphasizing the impact of plasmalogens in AD. In summary our findings show that decreased plasmalogen levels are not only a consequence of AD but that plasmalogens also decrease APP processing by directly affecting γ-secretase activity, resulting in a vicious cycle: Aß reduces plasmalogen levels and reduced plasmalogen levels directly increase γ-secretase activity leading to an even stronger production of Aß peptides.


Assuntos
Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Plasmalogênios/fisiologia , Processamento de Proteína Pós-Traducional , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/genética , Encéfalo/metabolismo , Linhagem Celular , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA/genética
11.
Front Psychiatry ; 12: 704174, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34504447

RESUMO

Recent fMRI studies on specific animal phobias, particularly spider phobia (arachnophobia), have identified a large variety of specific brain regions involved in normal and disturbed fear processing. Both functional and structural brain abnormalities have been identified among phobic patients. Current research suggests that both conscious and subconscious fear processing play a crucial role in phobic disorders. Cognitive behavioral therapy has been identified as an effective treatment for specific phobias and has been associated with neuroplastic effects which can be evaluated using current neuroimaging techniques. Recent research suggests that new approaches using virtual (VR) or augmented reality (AR) tend to be similarly effective as traditional "in vivo" therapy methods and could expand treatment options for different medical or individual scenarios. This narrative review elaborates on neural structures and particularities of arachnophobia. Current treatment options are discussed and future research questions are highlighted.

12.
Nat Commun ; 12(1): 3517, 2021 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112773

RESUMO

Epigenome-wide association studies of Alzheimer's disease have highlighted neuropathology-associated DNA methylation differences, although existing studies have been limited in sample size and utilized different brain regions. Here, we combine data from six DNA methylomic studies of Alzheimer's disease (N = 1453 unique individuals) to identify differential methylation associated with Braak stage in different brain regions and across cortex. We identify 236 CpGs in the prefrontal cortex, 95 CpGs in the temporal gyrus and ten CpGs in the entorhinal cortex at Bonferroni significance, with none in the cerebellum. Our cross-cortex meta-analysis (N = 1408 donors) identifies 220 CpGs associated with neuropathology, annotated to 121 genes, of which 84 genes have not been previously reported at this significance threshold. We have replicated our findings using two further DNA methylomic datasets consisting of a further >600 unique donors. The meta-analysis summary statistics are available in our online data resource ( www.epigenomicslab.com/ad-meta-analysis/ ).


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Metilação de DNA , Córtex Entorrinal/metabolismo , Epigenoma , Córtex Pré-Frontal/metabolismo , Lobo Temporal/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Estudos de Coortes , Ilhas de CpG , Córtex Entorrinal/patologia , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/patologia , Curva ROC , Lobo Temporal/patologia
13.
Aging Cell ; 19(11): e13264, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33128835

RESUMO

One of the major pathological hallmarks of Alzheimer´s disease (AD) is an accumulation of amyloid-ß (Aß) in brain tissue leading to formation of toxic oligomers and senile plaques. Under physiological conditions, a tightly balanced equilibrium between Aß-production and -degradation is necessary to prevent pathological Aß-accumulation. Here, we investigate the molecular mechanism how insulin-degrading enzyme (IDE), one of the major Aß-degrading enzymes, is regulated and how amyloid precursor protein (APP) processing and Aß-degradation is linked in a regulatory cycle to achieve this balance. In absence of Aß-production caused by APP or Presenilin deficiency, IDE-mediated Aß-degradation was decreased, accompanied by a decreased IDE activity, protein level, and expression. Similar results were obtained in cells only expressing a truncated APP, lacking the APP intracellular domain (AICD) suggesting that AICD promotes IDE expression. In return, APP overexpression mediated an increased IDE expression, comparable results were obtained with cells overexpressing C50, a truncated APP representing AICD. Beside these genetic approaches, also AICD peptide incubation and pharmacological inhibition of the γ-secretase preventing AICD production regulated IDE expression and promoter activity. By utilizing CRISPR/Cas9 APP and Presenilin knockout SH-SY5Y cells results were confirmed in a second cell line in addition to mouse embryonic fibroblasts. In vivo, IDE expression was decreased in mouse brains devoid of APP or AICD, which was in line with a significant correlation of APP expression level and IDE expression in human postmortem AD brains. Our results show a tight link between Aß-production and Aß-degradation forming a regulatory cycle in which AICD promotes Aß-degradation via IDE and IDE itself limits its own production by degrading AICD.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Insulisina/metabolismo , Doença de Alzheimer/patologia , Humanos , Transdução de Sinais
14.
Dement Geriatr Cogn Disord ; 27(5): 474-80, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19439965

RESUMO

BACKGROUND: The cerebrospinal fluid (CSF) proteins beta-amyloid 42 (Abeta42) and Tau are believed to indirectly reflect some core pathological features of Alzheimer's disease (AD). Their topographic origin and their association with synaptic dysfunction are still not well understood. AIM: The present study aimed to explore possible associations between cerebral glucose metabolism and CSF Abeta42 as well as Tau protein levels in AD. METHODS: CSF analyses and (18)F-FDG PET scans were conducted on 32 patients with mild-to-moderate AD. Voxel-based statistical parametric correlations were computed for CSF protein levels and cerebral glucose metabolism. RESULTS: After correction for multiple comparisons, a strong positive association between CSF Abeta42 levels and glucose metabolism was identified for 2 extensive clusters located in the right temporal, prefrontal and anterior cingulate cortices. For CSF Tau protein, no association was observed for any brain region. CONCLUSIONS: These findings point to a significant association between synaptic dysfunction as measured with (18)F-FDG PET and CSF Abeta42 levels, but do not suggest a correlation between synaptic function and CSF Tau levels.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Química Encefálica/fisiologia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/psicologia , Feminino , Fluordesoxiglucose F18 , Glucose/metabolismo , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Neurônios/patologia , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos
15.
Neurol Genet ; 4(2): e224, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29577078

RESUMO

OBJECTIVE: The aim of this study was to identify variants associated with familial late-onset Alzheimer disease (AD) using whole-genome sequencing. METHODS: Several families with an autosomal dominant inheritance pattern of AD were analyzed by whole-genome sequencing. Variants were prioritized for rare, likely pathogenic variants in genes already known to be associated with AD and confirmed by Sanger sequencing using standard protocols. RESULTS: We identified 2 rare ABCA7 variants (rs143718918 and rs538591288) with varying penetrance in 2 independent German AD families, respectively. The single nucleotide variant (SNV) rs143718918 causes a missense mutation, and the deletion rs538591288 causes a frameshift mutation of ABCA7. Both variants have previously been reported in larger cohorts but with incomplete segregation information. ABCA7 is one of more than 20 AD risk loci that have so far been identified by genome-wide association studies, and both common and rare variants of ABCA7 have previously been described in different populations with higher frequencies in AD cases than in controls and varying penetrance. Furthermore, ABCA7 is known to be involved in several AD-relevant pathways. CONCLUSIONS: We conclude that both SNVs might contribute to the development of AD in the examined family members. Together with previous findings, our data confirm ABCA7 as one of the most relevant AD risk genes.

16.
Epigenetics Chromatin ; 11(1): 41, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-30045751

RESUMO

BACKGROUND: Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer's disease (AD). However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues. RESULTS: We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as CLU, SYNJ2 and NCOR2 or in glia RAI1,CXXC5 and INPP5A. Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as MCF2L, ANK1, MAP2, LRRC8B, STK32C and S100B. A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., HOXA3 or glia (ANK1). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes APP and ADAM17. CONCLUSIONS: Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.


Assuntos
Envelhecimento/genética , Doença de Alzheimer/genética , Metilação de DNA , Estudo de Associação Genômica Ampla/métodos , Neuroglia/citologia , Neurônios/citologia , Proteína ADAM17/genética , Precursor de Proteína beta-Amiloide/genética , Autopsia , Separação Celular , Epigênese Genética , Epigenômica , Predisposição Genética para Doença , Humanos , Neuroglia/química , Neurônios/química , Especificidade de Órgãos , Transcriptoma
17.
Am J Psychiatry ; 164(10): 1577-84, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17898350

RESUMO

OBJECTIVE: The microtubule-associated protein tau gene (MAPT) contains two extended haplotypes, H1 and H2, which have been linked with sporadic tauopathies. However, there is little evidence as to how these haplotypes may influence the clinical features of the disease. The aim of this study was to investigate the MAPT haplotypes in relation to risk for, and functional alterations of glucose metabolism in, patients with frontotemporal dementia (FTD). METHOD: The authors investigated MAPT haplotypes in 142 individuals with FTD and 292 comparison subjects. Additionally, in a subset of 41 individuals with FTD and 16 comparison subjects, the authors undertook functional [ (18)F]fluorodeoxyglucose positron emission tomography (PET) imaging. RESULTS: MAPT haplotype distribution did not differ significantly between individuals with FTD and comparison subjects. However, the H2 haplotype was clinically associated with an earlier age at onset of FTD, which presented in a dose-dependent manner. Correspondingly, PET analysis revealed functional differences in glucose utilization patterns between MAPT haplotypes, with H2 carriers having a more pronounced hypometabolism in frontal brain areas than H1 carriers, which could not be accounted for by differences in duration of illness. CONCLUSIONS: While the extended MAPT H1 and H2 haplotypes do not appear to confer risk for disease development, the H2 haplotype appears to modify age at onset and functionally shows a more severe decline of glucose utilization in frontal brain areas.


Assuntos
Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Demência/genética , Glucose/metabolismo , Haplótipos/genética , Proteínas tau/genética , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Demência/metabolismo , Fluordesoxiglucose F18 , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/metabolismo , Frequência do Gene , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Fatores de Risco , Tauopatias/diagnóstico por imagem , Tauopatias/genética , Tauopatias/metabolismo
18.
Neurobiol Aging ; 50: 167.e1-167.e10, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27816213

RESUMO

MicroRNAs (miRNAs) are small noncoding RNA molecules, with essential functions in RNA silencing and post-transcriptional regulation of gene expression. miRNAs appear to regulate the development and function of the nervous system. Alterations of miRNA expression have been associated with Alzheimer's disease (AD). To characterize the AD miRNA signature, we examined genome-wide miRNA and mRNA expression patterns in the temporal cortex of AD and control samples. We validated our miRNA results by semiquantitative real-time polymerase chain reaction (PCR) in independent prefrontal cortex. Furthermore, we separated gray and white matter brain sections to identify the cellular origin of the altered miRNA expression. We observed genome-wide downregulation of hsa-miR-132-3p and hsa-miR-212-3p in AD with a stronger decrease in gray matter AD samples. We further identified 10 differently expressed transcripts achieving genome-wide levels of significance. Significantly deregulated miRNAs and mRNAs were correlated and examined for potential binding sites (in silico). This miRNome-wide study in AD provides supportive evidence and corroborates an important contribution of miR-132/212 and corresponding target mRNAs to the pathogenesis of AD.


Assuntos
Doença de Alzheimer/genética , Expressão Gênica , Estudo de Associação Genômica Ampla , MicroRNAs/genética , Família Multigênica/genética , Idoso , Idoso de 80 Anos ou mais , Sítios de Ligação , Regulação para Baixo , Feminino , Substância Cinzenta/metabolismo , Humanos , Masculino , MicroRNAs/metabolismo
19.
Hum Mutat ; 27(6): 532-7, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16652347

RESUMO

The lysosomal protease cathepsin D (CtsD, EC 3.4.23.5; gene, CTSD) has been associated with Alzheimer disease (AD) due to its cerebral expression being increased early in the course of AD; additionally, a CTSD exon 2 polymorphism (rs17571; NT_009237.17:g.569834T>C) may confer risk to AD. Functionally, it may be implicated in amyloid precursor protein (APP) processing and tau protein degradation. The objective of this study was to determine whether the CTSD exon 2 polymorphism affects cerebrospinal fluid (CSF), concentrations of beta-amyloid (Abeta42) and tau in two independent samples from Germany (n=73) and Sweden (n=66). Patients carrying the CTSD rs17571-T allele had significantly decreased CSF levels of tau (Munich, p=0.003; Swedish, p=0.029; combined sample, p<0.001), whereas no significant effect was observed on Abeta42 concentrations. Likewise, no significant impact was observed on Mini Mental State Examination (MMSE) scores. The data of both independent samples suggest that the CTSD rs17571 polymorphism does not affect APP processing but shows significant effects on tau processing. The result may corroborate the implication of the lysosomal system in the pathogenesis of AD and is of particular importance if CSF tau is used as a diagnostic biomarker.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/genética , Catepsina D/genética , Polimorfismo de Nucleotídeo Único , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Feminino , Genótipo , Humanos , Masculino
20.
Neurosci Lett ; 400(3): 187-90, 2006 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-16650578

RESUMO

Alpha2-macroglobulin (alpha2M) as well as its receptor, the low-density lipoprotein receptor-related (LRP) and the receptor-associated protein (RAP) are involved in the clearance of cerebral A beta. Current evidence suggests that polymorphisms in the genes of alpha2M, LRP and RAP may have functional effects on the proteins. Two independent association samples of 271 AD patients and 280 representative controls were investigated whether the risk for developing AD is altered in carriers of polymorphisms in the alpha2M-gene (Va1000Ile), in the LRP-gene (Ala216Val) and in the RAP-gene (Val311Met). Genotypes were determined by standard PCR and restriction fragment length polymorphism. The results were adjusted for age, gender and apolipoprotein E-epsilon4 (APOE) polymorphism. Inheritance of alpha2M conferred a small increased risk for sporadic AD with an estimated Mantel-Haenszel odds ratio of 1.47. There was no age- or gender-dependent increase in alpha2M Val1000Ile allele frequencies in AD patients compared to controls. There was no significant difference in the allele frequencies among control and AD subjects for the LRP and RAP polymorphisms. We found no evidence of an interaction between the alpha2M and RAP or LRP with regard to conferred risk. Our data suggest that the alpha2M Val1000Ile polymorphism is weakly associated with AD. Although LRP as well as RAP seem to play an essential role in the metabolism of alpha2M and APOE, there is no increase in the genetic risk for AD in patients carrying the investigated polymorphisms.


Assuntos
Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Medição de Risco/métodos , alfa-Macroglobulinas/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Fatores de Risco , Distribuição por Sexo
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