73 research outputs found
Age and the association between apolipoprotein E genotype and Alzheimer disease: A cerebrospinal fluid biomarker-based case-control study
Background:
The Δ4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of ÎČ-amyloid peptide (A, ÎČ-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD.
Methods and findings:
This caseâcontrol study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44â96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimerâs Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44â94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE Δ4 allele. Compared with non-Δ4 carriers, heterozygous Δ4 carriers had a 4.6 (95% confidence interval 4.1â5.2; p < 0.001) and Δ4/Δ4 homozygotes a 25.4 (20.4â31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one Δ4 allele was greatest in the 65â70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE Δ2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD.
Conclusions:
In this study, we found that AD diagnosis based on biomarkers was associated with APOE Δ4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65â70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE Δ4 at the population level
The discovery space of ELT-ANDES. Stars and stellar populations
The ArmazoNes high Dispersion Echelle Spectrograph (ANDES) is the optical and
near-infrared high-resolution echelle spectrograph envisioned for the European
Extremely Large Telescope (ELT). We present a selection of science cases,
supported by new calculations and simulations, where ANDES could enable major
advances in the fields of stars and stellar populations. We focus on three key
areas, including the physics of stellar atmospheres, structure, and evolution;
stars of the Milky Way, Local Group, and beyond; and the star-planet
connection. The key features of ANDES are its wide wavelength coverage at high
spectral resolution and its access to the large collecting area of the ELT.
These features position ANDES to address the most compelling and potentially
transformative science questions in stellar astrophysics of the decades ahead,
including questions which cannot be anticipated today.Comment: 46 pages, 8 figures; submitted to Experimental Astronomy on behalf of
the ANDES Science Tea
New insights into the genetic etiology of Alzheimer's disease and related dementias
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE Δ4 allele
Plos Med
Background The Δ4 allele of apolipoprotein E (APOE) gene and increasing age are two of the most important known risk factors for developing Alzheimer disease (AD). The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. Accordingly, we examined the global and age-specific association between APOE genotype and AD by using the A/T/N classification, relying on the cerebrospinal fluid (CSF) levels of ÎČ-amyloid peptide (A, ÎČ-amyloid deposition), phosphorylated tau (T, pathologic tau), and total tau (N, neurodegeneration) to identify patients with AD. Methods and findings This caseâcontrol study included 1,593 white AD cases (55.4% women; mean age 72.8 [range = 44â96] years) with abnormal values of CSF biomarkers from nine European memory clinics and the American Alzheimerâs Disease Neuroimaging Initiative (ADNI) study. A total of 11,723 dementia-free controls (47.1% women; mean age 65.6 [range = 44â94] years) were drawn from two longitudinal cohort studies (Whitehall II and Three-City), in which incident cases of dementia over the follow-up were excluded from the control population. Odds ratio (OR) and population attributable fraction (PAF) for AD associated with APOE genotypes were determined, overall and by 5-year age categories. In total, 63.4% of patients with AD and 22.6% of population controls carried at least one APOE Δ4 allele. Compared with non-Δ4 carriers, heterozygous Δ4 carriers had a 4.6 (95% confidence interval 4.1â5.2; p < 0.001) and Δ4/Δ4 homozygotes a 25.4 (20.4â31.2; p < 0.001) higher OR of AD in unadjusted analysis. This association was modified by age (p for interaction < 0.001). The PAF associated with carrying at least one Δ4 allele was greatest in the 65â70 age group (69.7%) and weaker before 55 years (14.2%) and after 85 years (22.6%). The protective effect of APOE Δ2 allele for AD was unaffected by age. Main study limitations are that analyses were based on white individuals and AD cases were drawn from memory centers, which may not be representative of the general population of patients with AD. Conclusions In this study, we found that AD diagnosis based on biomarkers was associated with APOE Δ4 carrier status, with a higher OR than previously reported from studies based on only clinical AD criteria. This association differs according to age, with the strongest effect at 65â70 years. These findings highlight the need for early interventions for dementia prevention to mitigate the effect of APOE Δ4 at the population level
Multiancestry analysis of the HLA locus in Alzheimerâs and Parkinsonâs diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinsonâs disease (PD) and Alzheimerâs disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased AÎČ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues
Maternal and Infant Bone Mineral Density 1 Year After Delivery in a Randomized, Controlled Trial of Maternal Tenofovir Disoproxil Fumarate to Prevent Mother-to-child Transmission of Hepatitis B Virus.
Evaluation de stratĂ©gies visant lâutilisation optimale des services de dĂ©pistage du VIH
Le VIH demeure un problĂšme majeur de santĂ© publique dans le monde. Cela est dĂ» en grande partie Ă la faible proportion de personnes infectĂ©es connaissant leur statut VIH, indiquant que le recours au dĂ©pistage rĂ©gulier du VIH par les personnes Ă risque est insuffisant. Dans le cadre d'un projet de recherche interventionnelle dans le nord de la ThaĂŻlande fournissant des services de dĂ©pistage et de conseil pour le VIH, les hĂ©patites B et C et la syphilis Ă 5 733 usagers entre octobre 2015 et janvier 2019, nous avons Ă©valuĂ© plusieurs stratĂ©gies visant Ă optimiser l'utilisation des services de dĂ©pistage du VIH. Dans un premier essai randomisĂ© contrĂŽlĂ© (ERC), nous avons constatĂ© que le conseil assistĂ© par ordinateur rĂ©duisait considĂ©rablement le temps consacrĂ© au conseil tout en apportant une efficacitĂ© similaire Ă celle du conseil standard en termes de recours Ă un nouveau dĂ©pistage, de changement des connaissances sur le VIH, de changement des comportements sexuels Ă risque et dâacceptabilitĂ©. Dans un second ERC, nous avons constatĂ© que la prise de rendez-vous et l'envoi d'un rappel une semaine Ă lâavance est une intervention simple, facile Ă mettre en Ćuvre et abordable qui a permis dâaugmenter considĂ©rablement le recours Ă un nouveau dĂ©pistage du VIH chez les usagers Ă risque. Dans une Ă©tude rĂ©trospective, nous avons constatĂ© que la dĂ©cision de recommander ou non un nouveau dĂ©pistage du VIH basĂ©e sur lâĂ©valuation du conseiller Ă©tait fortement dĂ©pendante du conseiller et peu en accord avec une dĂ©cision basĂ©e sur des donnĂ©es collectĂ©es (rĂ©ponses des usagers Ă des questionnaires auto-administrĂ©s et rĂ©sultats des tests de syphilis).HIV still remains a major global public health concern. This is due in large part to the low proportion of infected people aware of their HIV status, a clear indicator that uptake of regular HIV testing by at-risk individuals is insufficient. In the setting of an interventions research project in northern Thailand providing testing and counseling services for HIV, hepatitis B and C and syphilis to 5,733 clients between October 2015 and January 2019, we evaluated strategies aimed at optimizing the uptake of HIV testing services. In a first randomized controlled trial (RCT), we found that computer-assisted counseling significantly reduced the time spent on counseling while having similar efficacy as standard counseling in terms of uptake of retesting, change in HIV knowledge, change in sexual risk behaviors, and acceptability. In a second RCT, we found that scheduling an appointment and sending a reminder one week before was a simple, easy-to-implement and affordable intervention that significantly increased the uptake of HIV retesting by at-risk individuals. In a retrospective study, we found that the decision to recommend HIV retesting based on the counselorâs assessment was strongly dependent on the counselor and poorly consistent with that based on data-driven assessment (clientsâ answers to self-administered questionnaires and syphilis test results)
Synthesis and receptor binding analysis of dermorphin hepta-, hexa- and pentapeptide analogues
Identification and FISH mapping of different families of transposons in the Atlantic eel (<em>Anguilla anguilla</em>) genome
International audienc
Feasibility of using dried blood spots for HIV viral load testing among HIV-infected individuals in Thailand using QIAGEN QIAsymphony-artus HIV-1 platform
In settings where plasma preparation and sample centralization are not feasible or inconvenient, dried blood spots (DBS) could be used as an alternative specimen to plasma to assess antiretroviral treatment response among HIV-infected individuals. This study was aimed to (1) validate the recent QIAsymphony-artus assay for DBS HIV viral load (VL) and (2) assess the feasibility of measuring HIV VL on DBS using this assay in Thailand. Ethylenediaminetetraacetic acid-blood samples from 99 HIV-infected individuals were used to prepare paired DBS and plasma. Also, DBS samples were shipped to three distant hospitals in the northern region. After short-term storage, DBS were returned by regular post to the AMS laboratory and were re-tested for HIV VL using the same platform. HIV VL results were compared using Pearson's correlation and Bland-Altman analysis. DBS HIV VL fairly correlated to plasma HIV VL (R = 0.62) with a mean difference of 0.02 log(10)IU/mL (SD = 1.06). A high correlation (R = 0.79) was observed between HIV VL in DBS before and after shipping (mean difference = 0.14 log(10)IU/mL, SD = 0.74), indicating good stability of HIV RNA in DBS. DBS can be used as an alternative specimen for HIV VL monitoring in Thailand. However, measurement of HIV VL with the QIAGEN QIAsymphony-artus assay should be improved, especially the DBS pre-extraction process
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