RESUMEN
[This corrects the article DOI: 10.2196/37225.].
RESUMEN
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.
RESUMEN
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.
Asunto(s)
Disfunción Cognitiva , Demencia , Disfunción Cognitiva/diagnóstico , Demencia/diagnóstico , Diagnóstico Precoz , Alemania , Costos de la Atención en Salud , HumanosRESUMEN
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.
RESUMEN
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/ ).
Asunto(s)
Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Metilación de ADN , Corteza Entorrinal/metabolismo , Epigenoma , Corteza Prefrontal/metabolismo , Lóbulo Temporal/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Estudios de Cohortes , Islas de CpG , Corteza Entorrinal/patología , Epigénesis Genética , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Corteza Prefrontal/patología , Curva ROC , Lóbulo Temporal/patologíaRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Insulisina/metabolismo , Enfermedad de Alzheimer/patología , Humanos , Transducción de SeñalRESUMEN
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.
Asunto(s)
Proteína ADAM17/genética , Enfermedad de Alzheimer/genética , Proteína ADAM17/metabolismo , Anciano , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Alemania , Humanos , Mutación con Pérdida de Función/genética , Masculino , Persona de Mediana Edad , Mutación , Secuenciación del ExomaRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer , Biomarcadores/líquido cefalorraquídeo , Encéfalo/patología , Claudinas/genética , Proteínas Musculares/genética , Serpinas/genética , Factores de Transcripción/genética , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Amiloidosis/complicaciones , Amiloidosis/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Encéfalo/fisiopatología , Femenino , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Masculino , Mutación/genética , Fragmentos de Péptidos/líquido cefalorraquídeo , Factores Sexuales , Proteínas tau/líquido cefalorraquídeoRESUMEN
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.
Asunto(s)
Envejecimiento/genética , Enfermedad de Alzheimer/genética , Metilación de ADN , Estudio de Asociación del Genoma Completo/métodos , Neuroglía/citología , Neuronas/citología , Proteína ADAM17/genética , Precursor de Proteína beta-Amiloide/genética , Autopsia , Separación Celular , Epigénesis Genética , Epigenómica , Predisposición Genética a la Enfermedad , Humanos , Neuroglía/química , Neuronas/química , Especificidad de Órganos , TranscriptomaRESUMEN
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.
Asunto(s)
Acetamidas/efectos adversos , Antidepresivos/efectos adversos , Trastorno Bipolar/etiología , Trastorno Depresivo/tratamiento farmacológico , Acetamidas/uso terapéutico , Adulto , Antidepresivos/uso terapéutico , Trastorno Bipolar/diagnóstico , Trastorno Bipolar/terapia , Femenino , Humanos , RecurrenciaRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Proteínas tau/genética , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/líquido cefalorraquídeo , Apolipoproteínas E/genética , Biomarcadores/análisis , Progresión de la Enfermedad , Endofenotipos/líquido cefalorraquídeo , Sitios Genéticos , Genotipo , Humanos , Persona de Mediana Edad , Factores de Riesgo , Proteínas tau/líquido cefalorraquídeoRESUMEN
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.
Asunto(s)
Enfermedad de Alzheimer/genética , Expresión Génica , Estudio de Asociación del Genoma Completo , MicroARNs/genética , Familia de Multigenes/genética , Anciano , Anciano de 80 o más Años , Sitios de Unión , Regulación hacia Abajo , Femenino , Sustancia Gris/metabolismo , Humanos , Masculino , MicroARNs/metabolismoRESUMEN
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.
Asunto(s)
Péptidos beta-Amiloides/antagonistas & inhibidores , Lipocalinas/química , Ingeniería de Proteínas/métodos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Humanos , Lipocalinas/farmacología , Lipocalinas/uso terapéutico , Datos de Secuencia Molecular , Biblioteca de Péptidos , Unión Proteica , Conformación ProteicaRESUMEN
BACKGROUND AND AIMS: Vitamin D deficiency and depression frequently occur in patients with chronic liver diseases (CLD). Depression has recently been inversely associated with vitamin D in a meta-analysis, and vitamin D receptor is expressed in brain. This pilot study investigates whether vitamin D replacement ameliorates depressive symptoms in CLD patients and consists of a cross-sectional and an interventional analysis. METHODS: Overall, 111 patients with CLD were included in the cross-sectional analysis. The Beck Depression Inventory II (BDI-II) was used to assess depression. Chemiluminescence immunoassay and LC-MS/MS quantified serum 25-hydroxyvitamin D levels. For the interventional analysis, 77 patients with inadequate vitamin D concentrations received 20,000 IU vitamin D per week for six months. The final follow-up was carried out six months post supplementation. RESULTS: In the cross-sectional analysis, 81% of patients (median age 55 years, 47% women) had inadequate baseline vitamin D levels (<30 ng/ml), and 31% presented with depressive symptoms (BDI-II score ≥14). Depression severity correlated inversely with vitamin D level in depressed patients (ß = -0.483, P = 0.004). Depression scores improved significantly from baseline in depressed patients after three and six months (P = 0.003 and P = 0.004, respectively) of supplementation, with vitamin D levels increasing to normal (P < 0.0001). Subgroup analyses revealed this anti-depressant effect of vitamin D to occur predominantly in women. The final follow-up showed increases in median BDI-II scores in the setting of decreased vitamin D levels. CONCLUSIONS: Vitamin D levels correlated with BDI-II scores, and vitamin D replacement significantly improved depressive symptoms in women with CLD. Adjuvant vitamin D may be considered in these patients. REGISTRATION NO: DRKS00007782 German Clinical Trials Registry (DRKS).
Asunto(s)
Depresión/tratamiento farmacológico , Suplementos Dietéticos , Hepatopatías/tratamiento farmacológico , Deficiencia de Vitamina D/tratamiento farmacológico , Vitamina D/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Índice de Masa Corporal , Enfermedad Crónica , Estudios Transversales , Depresión/sangre , Femenino , Estudios de Seguimiento , Humanos , Estilo de Vida , Hepatopatías/sangre , Masculino , Persona de Mediana Edad , Proyectos Piloto , Estudios Prospectivos , Espectrometría de Masas en Tándem , Vitamina D/sangre , Adulto JovenRESUMEN
Accumulation and aggregation of amyloid-ß (Aß) are considered etiologic processes in Alzheimer's disease (AD). However, the roles of other AßPP cleavage products in disease pathology remain elusive. Here, we measured levels of the major secreted AßPP processing products sAßPPα, sAßPPß, and Aß species in postmortem collected ventricular CSF of 196 AD patients and 74 controls. In AD we identified Aß42 to decrease continuously with progressing Braak stages, whereas Aß40 was upregulated in early stages of the disease (Braak stage 4) and down-regulated with progressing pathology. Interestingly, both sAßPPα and sAßPPß were upregulated in AD as compared to controls (sAßPPα, pâ=â0.02; sAßPPß, pâ=â0.01). Moreover, we observed a strong positive correlation of both alternative AßPP processing products, sAßPPα and sAßPPß (r²=â0.781; pâ< â0.0001). Together, our results argue for generally enhanced AßPP processing in AD patients and emphasize the necessity of analyzing the roles of all AßPP processing products in AD pathology.
Asunto(s)
Enfermedad de Alzheimer/líquido cefalorraquídeo , Precursor de Proteína beta-Amiloide/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
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 â¼50% 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.
Asunto(s)
Proteínas ADAM/metabolismo , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de la Membrana/metabolismo , Factores de Transcripción/metabolismo , Respuesta de Proteína Desplegada/fisiología , Proteínas ADAM/genética , Proteína ADAM10 , Enfermedad de Alzheimer/genética , Secretasas de la Proteína Precursora del Amiloide/genética , Animales , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Ensayo de Inmunoadsorción Enzimática , Humanos , Proteínas de la Membrana/genética , Ratones , Regiones Promotoras Genéticas/genética , Factores de Transcripción del Factor Regulador X , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/genética , Transducción de Señal/fisiología , Factores de Transcripción/genética , Respuesta de Proteína Desplegada/genética , Proteína 1 de Unión a la X-BoxRESUMEN
PURPOSE: The aim of this study was to investigate prospectively whether MRI plaque imaging can identify patients with asymptomatic carotid artery stenosis who have an increased risk for future cerebral events. MRI plaque imaging allows categorization of carotid stenosis into different lesion types (I-VIII). Within these lesion types, lesion types IV-V and VI are regarded as rupture-prone plaques, whereas the other lesion types represent stable ones. METHODS: Eighty-three consecutive patients (45 male (54.2%); age 54-88 years (mean 73.2 years)) presenting with an asymptomatic carotid stenosis of 50-99% according to ECST-criteria were recruited. Patients were imaged with a 1.5-T scanner. T1-, T2-, time-of-flight-, and proton-density weighted studies were performed. The carotid plaques were classified as lesion type I-VIII. Clinical endpoints were ischemic stroke, TIA or amaurosis fugax. Survival analysis and log rank test were used to ascertain statistical significance. RESULTS: Six out of 83 patients (7.2%) were excluded: 4 patients had insufficient MR image quality; 1 patient was lost-to-follow-up; 1 patient died shortly after the baseline MRI plaque imaging. The following results were obtained by analyzing the remaining 77 patients. The mean time of follow-up was 41.1 months. During follow-up, nâ=â9 (11.7%) ipsilateral ischemic cerebrovascular events occurred. Only patients presenting with the high-risk lesion types IV-V and VI developed an ipsilateral cerebrovascular event versus none of the patients presenting with the stable lesion types III, VII, and VIII (nâ=â9 (11.7%) vs. nâ=â0 (0%) during follow-up). Event-free survival was higher among patients with the MRI-defined stable lesion types (III, VII, and VIII) than in patients with the high-risk lesion types (IV-V and VI) (log rank test P<0.0001). CONCLUSIONS: MRI plaque imaging has the potential to identify patients with asymptomatic carotid stenosis who are particularly at risk of developing future cerebral ischemia. MRI could improve selection criteria for invasive therapy in the future.
Asunto(s)
Estenosis Carotídea/diagnóstico , Imagen por Resonancia Magnética/métodos , Placa Aterosclerótica/diagnóstico , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Low birth weight is associated with an increased adult metabolic disease risk. It is widely discussed that poor intra-uterine conditions could induce long-lasting epigenetic modifications, leading to systemic changes in regulation of metabolic genes. To address this, we acquire genome-wide DNA methylation profiles from saliva DNA in a unique cohort of 17 monozygotic monochorionic female twins very discordant for birth weight. We examine if adverse prenatal growth conditions experienced by the smaller co-twins lead to long-lasting DNA methylation changes. RESULTS: Overall, co-twins show very similar genome-wide DNA methylation profiles. Since observed differences are almost exclusively caused by variable cellular composition, an original marker-based adjustment strategy was developed to eliminate such variation at affected CpGs. Among adjusted and unchanged CpGs 3,153 are differentially methylated between the heavy and light co-twins at nominal significance, of which 45 show sensible absolute mean ß-value differences. Deep bisulfite sequencing of eight such loci reveals that differences remain in the range of technical variation, arguing against a reproducible biological effect. Analysis of methylation in repetitive elements using methylation-dependent primer extension assays also indicates no significant intra-pair differences. CONCLUSIONS: Severe intra-uterine growth differences observed within these monozygotic twins are not associated with long-lasting DNA methylation differences in cells composing saliva, detectable with up-to-date technologies. Additionally, our results indicate that uneven cell type composition can lead to spurious results and should be addressed in epigenomic studies.
Asunto(s)
Peso al Nacer , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Gemelos Monocigóticos/genética , Adulto , Metilación de ADN , Femenino , Genoma Humano , Humanos , Persona de Mediana Edad , Datos de Secuencia Molecular , Saliva/citología , Análisis de Secuencia de ADN , Adulto JovenRESUMEN
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.