HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer's disease.

Many studies highlight the potential link between the chronic degenerative Alzheimer's disease and the infection by the herpes simplex virus type-1 (HSV-1). However, the molecular mechanisms making possible this HSV-1-dependent process remain to be understood. Using neuronal cells expressing the wild type form of amyloid precursor protein (APP) infected by HSV-1, we characterized a representative cellular model of the early stage of the sporadic form of the disease and unraveled a molecular mechanism sustaining this HSV-1- Alzheimer's disease interplay. Here, we show that HSV-1 induces caspase-dependent production of the 42 amino-acid long amyloid peptide (Aß42) oligomers followed by their accumulation in neuronal cells. Aß42 oligomers and activated caspase 3 (casp3A) concentrate into intracytoplasmic structures observed in Alzheimer's disease neuronal cells called aggresomes. This casp3A accumulation in aggresomes during HSV-1 infection limits the execution of apoptosis until its term, similarly to an abortosis-like event occurring in Alzheimer's disease neuronal cells patients. Indeed, this particular HSV-1 driven cellular context, representative of early stages of the disease, sustains a failed apoptosis mechanism that could explain the chronic amplification of Aß42 production characteristic of Alzheimer's disease patients. Finally, we show that combination of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), with caspase inhibitor reduced drastically HSV-1-induced Aß42 oligomers production. This provided mechanistic insights supporting the conclusion of clinical trials showing that NSAIDs reduced Alzheimer's disease incidence in early stage of the disease. Therefore, from our study we propose that caspase-dependent production of Aß42 oligomers together with the abortosis-like event represents a vicious circle in early Alzheimer's disease stages leading to a chronic amplification of Aß42 oligomers that contributes to the establishment of degenerative disorder like Alzheimer's disease in patients infected by HSV-1. Interestingly this process could be targeted by an association of NSAID with caspase inhibitors.

Infectious Agents as Potential Drivers of α-Synucleinopathies.

α-synucleinopathies, encompassing Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are devastating neurodegenerative diseases for which available therapeutic options are scarce, mostly because of our limited understanding of their pathophysiology. Although these pathologies are attributed to an intracellular accumulation of the α-synuclein protein in the nervous system with subsequent neuronal loss, the trigger(s) of this accumulation is/are not clearly identified. Among the existing hypotheses, interest in the hypothesis advocating the involvement of infectious agents in the onset of these diseases is renewed. In this article, we aimed to review the ongoing relevant factors favoring and opposing this hypothesis, focusing on (1) the potential antimicrobial role of α-synuclein, (2) potential entry points of pathogens in regard to early symptoms of diverse α-synucleinopathies, (3) pre-existing literature reviews assessing potential associations between infectious agents and Parkinson's disease, (4) original studies assessing these associations for dementia with Lewy bodies and multiple system atrophy (identified through a systematic literature review), and finally (5) potential susceptibility factors modulating the effects of infectious agents on the nervous system. © 2022 International Parkinson and Movement Disorder Society.

Antiherpetic drugs: a potential way to prevent Alzheimer's disease?

BACKGROUND: Considering the growing body of evidence suggesting a potential implication of herpesviruses in the development of dementia, several authors have questioned a protective effect of antiherpetic drugs (AHDs) which may represent a new means of prevention, well tolerated and easily accessible. Subsequently, several epidemiological studies have shown a reduction in the risk of dementia in subjects treated with AHDs, but the biological plausibility of this association and the impact of potential methodological biases need to be discussed in more depth. METHODS: Using a French medico-administrative database, we assessed the association between the intake of systemic AHDs and the incidence of (i) dementia, (ii) Alzheimer's disease (AD), and (iii) vascular dementia in 68,291 subjects over 65 who were followed between 2009 and 2017. Regarding potential methodological biases, Cox models were adjusted for numerous potential confounding factors (including proxies of sociodemographic status, comorbidities, and use of healthcare) and sensitivity analyses were performed in an attempt to limit the risk of indication and reverse causality biases. RESULTS: 9.7% of subjects (n=6642) had at least one intake of systemic AHD, and 8883 incident cases of dementia were identified. Intake of at least one systemic AHD during follow-up was significantly associated with a decreased risk of AD (aHR 0.85 95% confidence interval [0.75-0.96], p=0.009) and, to a lesser extent with respect to p values, to both dementia from any cause and vascular dementia. The association with AD remained significant in sensitivity analyses. The number of subjects with a regular intake was low and prevented us from studying its association with dementia. CONCLUSIONS: Taking at least one systemic AHD during follow-up was significantly associated with a 15% reduced risk of developing AD, even after taking into account several potential methodological biases. Nevertheless, the low frequency of subjects with a regular intake questions the biological plausibility of this association and highlights the limits of epidemiological data to evaluate a potential protective effect of a regular treatment by systemic AHDs on the incidence of dementia.

Herpes simplex virus, early neuroimaging markers and incidence of Alzheimer's disease.

While previous studies suggest the implication of herpes simplex virus (HSV) in the onset of Alzheimer's disease (AD), no study has investigated its association with early neuroimaging markers of AD. In the Three-City and the AMI cohorts, the associations between HSV infection and (i) hippocampal volume (n = 349), (ii) white matter alterations in the parahippocampal cingulum and fornix using diffusion tensor imaging (n = 260), and (iii) incidence of AD (n = 1599) were assessed according to APOE4 status. Regardless of APOE4 status, infected subjects presented (i) significantly more microstructural alterations of the parahippocampal cingulum and fornix, (ii) lower hippocampal volumes only when their anti-HSV IgG level was in the highest tercile-reflecting possibly more frequent reactivations of the virus (p = 0.03 for subjects with a high anti-HSV IgG level while there was no association for all infected subjects, p = 0.19), and (iii) had no increased risk of developing AD. Nevertheless, among APOE4 carriers, infected subjects presented lower hippocampal volumes, although not significant (p = 0.09), and a two or three times higher risk of developing AD (adjusted Hazard ratio (aHR) = 2.72 [1.07-6.91] p = 0.04 for infected subjects and aHR = 3.87 [1.45-10.28] p = 0.007 for infected subjects with an anti-HSV IgG level in the highest tercile) while no association was found among APOE4 noncarriers. Our findings support an association between HSV infection and AD and a potential interaction between HSV status and APOE4. This reinforces the need to further investigate the infectious hypothesis of AD, especially the associated susceptibility factors and the possibility of preventive treatments.

Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer's disease.

INTRODUCTION: Numerous results suggest the implication of infectious agents in the onset of Alzheimer's disease (AD). METHODS: In the Bordeaux-3C prospective cohort, we assessed the impact of herpes simplex virus type 1 (HSV-1) infection on the incidence of AD according to apolipoprotein E (APOE) status, a genetic susceptibility factor. Cox models were performed to estimate the 10-year risk of AD associated with anti-HSV antibodies in 1037 participants according to APOE4 status. RESULTS: Among APOE4 carriers, subjects for whom the frequency of HSV-1 reactivation is supposed to be high, that is, immunoglobulin M (IgM) positive or elevated levels of IgG, had an increased risk of AD with adjusted hazard ratios (HRs) of 3.68 (1.08-12.55) and 3.28 (1.19-9.03), respectively. No significant association was found in APOE4-negative subjects. DISCUSSION: These results, in accordance with a solid pathophysiological rationale, suggest a role for HSV-1 in AD development among subjects with a genetic susceptibility factor, the APOE4 allele.

Differential rates of cesarean delivery by maternal geographical origin: a cohort study in France.

BACKGROUND: In many Western countries, higher rates of cesarean have been described among migrant women compared to natives of receiving countries. We aimed to estimate this difference comparing women originating from France and Sub-Saharan Africa (SSA), identify the clinical situations explaining most of this difference and assess whether maternal origin was independently associated with cesarean risk. METHODS: The PreCARE prospective multicenter cohort study was conducted in 2010-2012 in the north Paris area. Our sample was restricted to 1500 women originating from Sub-Saharan Africa and 2206 from France. Profiles of cesarean section by maternal origin were described by the Robson classification. Independent associations between maternal origin and 1) cesarean before labor versus trial of labor, then 2) intrapartum cesarean versus vaginal delivery were assessed by logistic regression models to adjust for other maternal and pregnancy characteristics. RESULTS: Rates of cesarean for women originating from France and SSA were 17 and 31%. The Robson 5A category "unique uterine scar, single cephalic ≥37 weeks" was the main contributor to this difference. Within this category, SSA origin was associated with cesarean before labor after adjustment for medical risk factors (adjusted odds ratio [aOR] = 2.30 [1.12-4.71]) but no more significant when adjusting on social deprivation (aOR = 1.45 [0.63-3.31]). SSA origin was associated with cesarean during labor after adjustment for both medical and social factors (aOR = 2.95 [1.35-6.44]). CONCLUSIONS: The wide difference in cesarean rates between SSA and French native women is mainly explained by the Robson 5A category. Within this group, medical factors alone do not explain the increased risk of cesarean in SSA women.

Ceftriaxone and Cefotaxime Have Similar Effects on the Intestinal Microbiota in Human Volunteers Treated by Standard-Dose Regimens.

Ceftriaxone has a higher biliary elimination than cefotaxime (40% versus 10%), which may result in a more pronounced impact on the intestinal microbiota. We performed a monocenter, randomized open-label clinical trial in 22 healthy volunteers treated by intravenous ceftriaxone (1 g/24 h) or cefotaxime (1 g/8 h) for 3 days. We collected fecal samples for phenotypic analyses, 16S rRNA gene profiling, and measurement of the antibiotic concentration and compared the groups for the evolution of microbial counts and indices of bacterial diversity over time. Plasma samples were drawn at day 3 for pharmacokinetic analysis. The emergence of 3rd-generation-cephalosporin-resistant Gram-negative enteric bacilli (Enterobacterales), Enterococcus spp., or noncommensal microorganisms was not significantly different between the groups. Both antibiotics reduced the counts of total Gram-negative enteric bacilli and decreased the bacterial diversity, but the differences between the groups were not significant. All but one volunteer from each group exhibited undetectable levels of antibiotic in feces. Plasma pharmacokinetic endpoints were not correlated to alteration of the bacterial diversity of the gut. Both antibiotics markedly impacted the intestinal microbiota, but no significant differences were detected when standard clinical doses were administered for 3 days. This might be related to the similar daily amounts of antibiotics excreted through the bile using a clinical regimen. (This study has been registered at ClinicalTrials.gov under identifier NCT02659033.).

Efficacy of cloxacillin versus cefazolin for methicillin-susceptible Staphylococcus aureus bacteraemia (CloCeBa): study protocol for a randomised, controlled, non-inferiority trial.

INTRODUCTION: Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a common and severe disease responsible for approximately 65 000 deaths every year in Europe. Intravenous antistaphylococcal penicillins (ASP) such as cloxacillin are the current recommended antibiotics. However, increasing reports of toxicity and recurrent stock-outs of ASP prompted healthcare providers to seek for alternative antibiotic treatment. Based on retrospective studies, cefazolin, a first-generation cephalosporin, is recommended in patients at risk of severe ASP-associated toxicity.We hypothesised that cefazolin has a non-inferior efficacy in comparison to cloxacillin, with a better safety profile for the treatment of MSSA bacteraemia. METHODS AND ANALYSIS: The CloCeBa trial is an open-label, randomised, controlled, non-inferiority trial conducted in academic centres throughout France. Eligible patients are adults with MSSA bacteraemia without intravascular device or suspicion of central nervous system infection. Patients will be randomised (1:1) to receive either cloxacillin or cefazolin by the intravenous route, for the first 14 days of therapy. The evaluation criteria is a composite criteria of negative blood cultures at day 5, survival, absence of relapse and clinical success at day 90 after randomisation. Secondary evaluation criteria include both efficacy and safety assessments. Three ancillary studies are planned to describe the epidemiology of ß-lactamase encoding genes, the ecological impact and pharmacokinetic/pharmacodynamic parameters of cefazolin and cloxacillin. Including 300 patients will provide 80% power to demonstrate the non-inferiority of cefazolin over cloxacillin, assuming 85% success rate with cloxacillin and taking into account loss-to-follow-up, with a 0.12 non-inferiority margin and a one-sided type I error of 0.025. ETHICS AND DISSEMINATION: This protocol received authorisation from the ethics committee Sud-Est I on 13 November 2017 (2017-87-PP)and French National Agency for Medicines and Health Products (170661A-43). Results will be disseminated to the scientific community through congresses and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03248063 and 2017-003967-36.