Assessment of a polygenic hazard score for the onset of pre-clinical Alzheimer’s disease

Background: With a growing number of loci associated with late-onset (sporadic) Alzheimer’s disease (AD), the polygenic contribution to AD is now well established. The development of polygenic risk score approaches have shown promising results for identifying individuals at higher risk of developing AD, thereby facilitating the development of preventative and therapeutic strategies. A polygenic hazard score (PHS) has been proposed to quantify age-specific genetic risk for AD. In this study, we assessed the predictive power and transferability of this PHS in an independent cohort, to support its clinical utility. Results: Using genotype and imaging data from 780 individuals enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study, we investigated associations between the PHS and several AD-related traits, including 1) cross-sectional Aβ-amyloid (Aβ) deposition, 2) longitudinal brain atrophy, 3) longitudinal cognitive decline, 4) age of onset. Except in the cognitive domain, we obtained results that were consistent with previously published findings. The PHS was associated with increased Aβ burden, faster regional brain atrophy and an earlier age of onset. Conclusion: Overall, the results support the predictive power of a PHS, however, with only marginal improvement compared to apolipoprotein E alone

Fifteen years of the Australian imaging, biomarkers and lifestyle (AIBL) study: Progress and observations from 2,359 older adults spanning the spectrum from cognitive normality to Alzheimer\u27s disease

Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer\u27s disease dementia (AD)) as an \u27Inception cohort\u27 who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an \u27Enrichment cohort\u27 (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims

Les responsabilités civiles et pénales des médecins généralistes libéraux (Etude qualitative de données d expertises médicales réalisées dans la Loire et le Rhône)

La judiciarisation de la médecine générale doit-elle inquiéter le praticien ? Afin de répondre à cette question, nous avons réalisé une étude qualitative portant sur les motifs de mise en cause des médecins généralistes libéraux ainsi que les étapes de procédures et les conclusions judiciaires rendues. Nous avons obtenu de médecins experts et d avocats de la Loire et du Rhône trente-et-un dossiers d expertises médicales. Seules les mises en cause civiles et pénales de médecins généralistes libéraux jugées après 2002 ont été analysées, soit vingt-six dossiers, excluant les procédures administratives, ordinales ou de CCI, et les jugements antérieurs à 2002 ou concernant des praticiens hospitaliers. Dans notre étude, les mises en cause civiles concernent le retard au diagnostic, l erreur diagnostique, le défaut d information et le défaut de suivi médical. Au pénal, le médecin est prévenu du chef d accusation d homicide involontaire par imprudence et d atteinte involontaire à l intégrité physique occasionnant une ITT supérieure à 3 mois. L expert retient la faute dans 50% des cas, la justice suit l avis de l expert dans 93.3% des cas et le jugement en appel confirme 100% des jugements de première instance. Ces procédures sont longues, plus de cinq ans et onéreuses (minimum 3 000 EUR, frais de procédure hors indemnisation). La littérature montre que la mise en cause de médecins généralistes est très rare, notre étude montre que les condamnations qui en découlent sont d autant plus rares. Mais il existe certaines situations à risque justifiant d une vigilance accrue de la part du médecin.ST ETIENNE-BU Médecine (422182102) / SudocSudocFranceF

Comprehensive analysis of epigenetic clocks reveals associations between disproportionate biological ageing and hippocampal volume

The concept of age acceleration, the difference between biological age and chronological age, is of growing interest, particularly with respect to age-related disorders, such as Alzheimer’s Disease (AD). Whilst studies have reported associations with AD risk and related phenotypes, there remains a lack of consensus on these associations. Here we aimed to comprehensively investigate the relationship between five recognised measures of age acceleration, based on DNA methylation patterns (DNAm age), and cross-sectional and longitudinal cognition and AD-related neuroimaging phenotypes (volumetric MRI and Amyloid-β PET) in the Australian Imaging, Biomarkers and Lifestyle (AIBL) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Significant associations were observed between age acceleration using the Hannum epigenetic clock and cross-sectional hippocampal volume in AIBL and replicated in ADNI. In AIBL, several other findings were observed cross-sectionally, including a significant association between hippocampal volume and the Hannum and Phenoage epigenetic clocks. Further, significant associations were also observed between hippocampal volume and the Zhang and Phenoage epigenetic clocks within Amyloid-β positive individuals. However, these were not validated within the ADNI cohort. No associations between age acceleration and other Alzheimer’s disease-related phenotypes, including measures of cognition or brain Amyloid-β burden, were observed, and there was no association with longitudinal change in any phenotype. This study presents a link between age acceleration, as determined using DNA methylation, and hippocampal volume that was statistically significant across two highly characterised cohorts. The results presented in this study contribute to a growing literature that supports the role of epigenetic modifications in ageing and AD-related phenotypes

Trends in Fatal Poisoning Among Drug Users in France From 2011 to 2021

Importance The DRAMES (Décès en Relation avec l’Abus de Médicaments Et de Substances) register is a database of drug-related deaths with the aim of identifying the psychoactive substances associated with and estimating the trends in these deaths. Our novel approach is based on the collection of data on all deaths for which toxicology experts have performed analyses. Objective To describe drug-related deaths in France and report trends over an 11-year period. Design, Setting, and Participants This case series used a national register to assess 4460 drug-related deaths that occurred from 2011 to 2021 in France. Data analyses were performed from January 1, 2012, to December 31, 2022. Main Outcomes and Measures Demographic characteristics; medical and substance abuse history; forensic autopsy findings; and toxicology reports. Results Among the 4460 deceased individuals (mean [SD] age, 37.8 [10.5] years), the mortality rate was highest among men (sex ratio, 4.4:1). Of the deaths involving a single or predominant drug, the legal substitution product, methadone, was the leading cause of death during the entire study period, ahead of heroin—44.7% and 35.9% for methadone vs 15.8% and 21.8% for heroin in 2011 and 2021, respectively. Between 2011 and 2021, most of the drug-related deaths shifted from licit to illicit drugs, and statistically significant variations were found for buprenorphine, cocaine, heroin, methadone, and other licit opioids. Deaths related to polydrug use increased from 23.2% in 2011 to 30.6% in 2021. In this context, opioids remained associated with most deaths, with at least 1 opioid being involved in approximately 9 of 10 cases (85.9%) in 2021. However, the main trend was the dramatic increase in drug combinations with cocaine, from less than one-third of cases in 2011 (30.8%) to more than half in 2021 (57.8%). Conclusions and Relevance This case series assessment of 4460 drug-related deaths found that opioids used alone or in combination were the main contributor to drug-related deaths, despite having a lower prevalence than other drugs. This finding is similar to that of other countries; however, in France licit methadone was the leading cause of opioid-related deaths (ahead of heroin) during the study period. Deaths associated with use of cannabis, new psychoactive substances, and stimulants (including amphetamine-type stimulants and cocaine, especially in combination) have increased and should be closely monitored