Empirical antibiotic therapy modalities for Enterobacteriaceae bloodstream infections in older patients and their impact on mortality: a multicentre retrospective study.

PURPOSE: Enterobacteriaceae (EB) bloodstream infections (BSI) are frequent and serious in older patients. Physicians are faced with the dilemma of prescribing early appropriate empirical antibiotics to limit the risk of death, and sparing broad-spectrum antibiotic prescription. The aim of the study was to assess the rate of appropriate empirical antibiotics prescription to treat EB BSI in older patients and its impact on survival. METHODS: This study conducted in 49 centres enrolled retrospectively up to the 10 last consecutive patients aged 75 years and over and treated for EB BSI. Factors related to in-hospital death were investigated using logistic regression. RESULTS: Among the 487 enrolled patients (mean age 86 ± 5.9 years), 70% had at least one risk factor of being infected by third-generation cephalosporins (3GC)-resistant strain; however, only 13.8% of EB strains were resistant to 3GC. An empirical antimicrobial treatment was initiated for 418 patients (85.8%), and for 86% (n = 360/418) of them, it was considered appropriate. In-hospital mortality was 12.7% (n = 62) and was related to the severity of infection (OR 3.17, CI 95% 1.75-5.75), while a urinary portal of entry was protective (OR 0.34, CI 95% 0.19-0.60). Neither the absence of nor inappropriate empirical antibiotics prescription was associated with increased mortality. CONCLUSION: While patients enrolled in this study were at risk of being infected by multidrug-resistant bacteria, yet mainly treated with 3GC, empirical antibiotics prescription was appropriate in most cases and did not influence mortality.

Early rise of glutamate-glutamine levels in mild cognitive impairment: Evidence for emerging excitotoxicity.

BACKGROUND: Use proton magnetic resonance spectroscopy (1H-MRS) non invasive technique to assess the modifications of glutamate-glutamine (Glx) and gammaaminobutyric acid (GABA) brain levels in patients reporting a cognitive complain METHODS: Posterior cingular cortex 1H-MRS spectra of 46 patients (19 male, 27 female) aged 57 to 87 years (mean : 73.32 ± 7.33 years) with a cognitive complaint were examined with a MEGA PRESS sequence at 3T, and compounds Glutamateglutamine (Glx), GABA, Creatine (Cr) and NAA were measured. From this data the metabolite ratios Glx/Cr, GABA/Cr and NAA/Cr were calculated. In addition, all patient performed the Mini Mental State Evaluation (MMSE) and 2 groups were realized with the clinical threshold of 24. RESULTS: 16 patients with MMSE 〈 24 and 30 patients with MMSE 〉 24. Significant increase of Glx/Cr in PCC of patients with MMSE 〈 24 compared to patients with MMSE 〉 24. Moreover, GABA/Cr ratio exhibited a trend for a decrease in PCC between the two groups, while they showed a significant decrease NAA/Cr ratio. CONCLUSION: Our results concerning Glx are in agreement with a physiopathological hypothesis involving a biphasic variation of glutamate levels associated with excitotoxicity, correlated with the clinical evolution of the disease. These observations suggest that MRS assessment of glutamate levels could be helpful for both diagnosis and classification of cognitive impairment in stage.

Procalcitonin to reduce exposure to antibiotics and individualise treatment in hospitalised old patients with pneumonia: a randomised study.

BACKGROUND: Treating pneumonia in old patients remains challenging for clinicians. Moreover, bacterial antimicrobial resistance is a major public health threat. OBJECTIVE: The PROPAGE study evaluated the interest of a strategy using serial measurements of procalcitonin (PCT) to reduce the duration of antibiotic therapy in old patients with pneumonia. METHODS: PROPAGE took place from Dec.-2013 to Jun.-2016 in eight French geriatric units. It was a prospective, comparative, randomised, open-label study involving old patients (≥ 80 years) who had initiated antibiotic treatment for pneumonia in the previous 48 h. PCT was monitored in all patients and two decision-making PCT-based algorithms guided antibiotic therapy in patients from the PCT group. RESULTS: 107 patients were randomised (PCT, n = 50; Control, n = 57). Antibiotic therapy exposure was reduced in the PCT group as compared to the Control group (median duration of antibiotic therapy, 8 vs. 10 days [rank-test, p = 0.001]; antibiotic persistence rates on Days 6 and 8, 54% and 44% vs. 91% and 72%) and no significant difference was found in recovery rate (84% vs. 89.5%; Pearson Chi² test, p = 0.402). CONCLUSION: Although, the superiority of the strategy was not tested using a composite criterion combining antibiotic therapy duration and recovery rate was not tested due to the small sample size, the present study showed that monitoring associated with PCT-guided algorithm could help shorten antibiotic treatment duration in the very old patients without detrimental effects. Measuring PCT levels between Day 4 and Day 6 could be helpful when making the decision regarding antibiotic discontinuation. TRIAL REGISTRATION: NCT02173613. This study was first registered on 25/06/2014.

Plasma amyloid beta predicts conversion to dementia in subjects with mild cognitive impairment: The BALTAZAR study.

INTRODUCTION: Blood-based biomarkers are the next challenge for Alzheimer's disease (AD) diagnosis and prognosis. METHODS: Mild cognitive impairment (MCI) participants (N = 485) of the BALTAZAR study, a large-scale longitudinal multicenter cohort, were followed-up for 3 years. A total of 165 of them converted to dementia (95% AD). Associations of conversion and plasma amyloid beta (Aß)1-42 , Aß1-40 , Aß1-42 /Aß1-40 ratio were analyzed with logistic and Cox models. RESULTS: Converters to dementia had lower level of plasma Aß1-42 (37.1 pg/mL [12.5] vs. 39.2 [11.1] , P value = .03) and lower Aß1-42 /Aß1-40 ratio than non-converters (0.148 [0.125] vs. 0.154 [0.076], P value = .02). MCI participants in the highest quartile of Aß1-42 /Aß1-40 ratio (>0.169) had a significant lower risk of conversion (hazard ratio adjusted for age, sex, education, apolipoprotein E ε4, hippocampus atrophy = 0.52 (95% confidence interval [0.31-0.86], P value = .01). DISCUSSION: In this large cohort of MCI subjects we identified a threshold for plasma Aß1-42 /Aß1-40 ratio that may detect patients with a low risk of conversion to dementia within 3 years.

Characteristics and management of giant cell arteritis in France: a study based on national health insurance claims data.

OBJECTIVE: Few data are available on the epidemiology and management of GCA in real life. We aimed to address this situation by using health insurance claims data for France. METHODS: This retrospective study used the Echantillon Généraliste de Bénéficiaires (EGB) database, a 1% representative sample of the French national health insurance system. The EGB contains anonymous data on long-term disease status, hospitalizations and reimbursement claims for 752 717 people. Data were collected between 2007 and 2015. The index date was defined as the date of the first occurrence of a GCA code. Demographics, comorbidities, diagnostic tests and therapies were analysed. Annual incidence rates were calculated, and incident and overall GCA cases were studied. RESULTS: We identified 241 patients with GCA. The annual incidence was 7-10/100 000 people ⩾50 years old. Among the 117 patients with incident GCA, 74.4% were females, with mean age 77.6 years and mean follow-up 2.2 years. After the index date, 51.3% underwent temporal artery biopsy and 29.1% high-resolution Doppler ultrasonography. Among the whole cohort, 84.3% used only glucocorticoids. The most-prescribed glucocorticoid-sparing agent was methotrexate (12.0%). CONCLUSION: The incidence of GCA in France is 7-10/100 000 people ⩾ 50 years old. Adjunct agents, mainly methotrexate, are given to only a few patients. The use of temporal artery biopsy in only half of the patients might reflect a shift toward the use of imaging techniques to diagnose GCA.

Comprehensive geriatric assessment in older patients with cancer: an external validation of the multidimensional prognostic index in a French prospective cohort study.

BACKGROUND: Older patients with cancer require specific and individualized management. The 3-group Multidimensional Prognostic Index (MPI) based on the Comprehensive Geriatric Assessment (CGA) has shown a predictive interest in terms of mortality. The objective of our study was to assess the prognostic value of MPI for 1-year mortality in an external prospective French cohort of elderly patients with cancer. METHODS: From March 2015 to March 2017 a prospective single-center cohort study enrolled all patients with cancer, aged 75 years and older referred to the geriatric oncology clinic. We used a proportional hazard model for 1-year mortality adjusted for age, sex, tumor sites and metastatic status. C-statistics were used to assess the incremental predictive value of MPI index to these risk factors. RESULTS: overall, 433 patients underwent CGA with MPI (women 42%; mean age 82.8 ± 4.8 years). The most common tumor sites were prostate (23%), skin (17%), colorectum (15%) and breast (12%); 29% of patients had a metastatic disease; 231 patients (53%) belonged to the "MPI-1" group, 172 (40%) to the "MPI-2" group and 30 patients were classified in the "MPI-3" group. One-year mortality rate was 32% (23% in MPI-1, 41% in MPI-2 and 53% in MPI-3, p = 0.024). All domains of MPI except cognition and living status were significantly associated with mortality at one-year, as well as tumor sites and metastatic status. Higher MPI was associated with a higher mortality risk (adjusted HR 1.56 [95%CI 1.70-2.09] and 1.72 [1.33-2.22] for MPI groups 2 and 3 compared to 1; p < 0.0001). CONCLUSIONS: In addition to established risk factors, MPI improves risk prediction of 1-year mortality. This practical prognostic tool may help to optimize management of these vulnerable patients.

Frailty and diabetes status in older patients with cancer: impact on mortality in the ANCRAGE cohort.

BACKGROUND: Frailty, diabetes and cancer are associated with aging, but the relationship between these conditions is not well defined. AIMS: We studied older patients with cancer from the prospective single-center cohort ANCRAGE (ANalyses of CanceR in AGEd) aiming to determine the impact of type 2 diabetes (T2D) and its vascular complications (VC) on frailty and adverse outcomes (mortality, unplanned readmission) during follow-up. METHODS: Analysis of cohort patients ≥ 75 years, included between 2009 and 2017, who underwent a comprehensive geriatric assessment (CGA). Variables of interest were history of T2D and VC, tumor site and metastatic status, CGA including eight domains (social environment, functional status, mobility, nutrition, mood, cognition, polypharmacy and comorbidities) and frailty. RESULTS: Among 1092 patients (47% female, mean age 82 ± 5 years), 219 (20%) had a reported diagnosis of T2D at baseline including 152 (69%) with VC. The most common tumor sites were prostate (15%), breast (15%), skin (12%), and colorectum (11%); 29% of patients had a metastatic disease. Frailty was highly prevalent (84%). During follow-up (median of 15.3 months), 653 (60%) patients died (60% no T2D, 43% T2D without VC, 66% with VC). After adjustment for age, gender and metastatic status, diabetics with VC had a higher risk of all-cause death (aHR1.89, 1.24-2.86, p = 0.004). Death was more frequently due to a non-cancer cause (p < 0.001). No difference in unplanned readmissions was observed in the three groups. Frailty was an independent risk factor for mortality and unplanned readmissions (p < 0.001 both). CONCLUSION: In older cancer patients from the prospective ANCRAGE cohort, all-cause mortality was significantly higher in frail patients and those with complicated T2D, a finding questioning the quality of care management in such vulnerable patients, and stimulating further research in this multidisciplinary field.

Using the Multidimensional Prognostic Index (MPI) to improve cost-effectiveness of interventions in multimorbid frail older persons: results and final recommendations from the MPI_AGE European Project.

MPI_AGE is a European Union co-funded research project aimed to use the Multidimensional Prognostic Index (MPI), a validated Comprehensive Geriatric Assessment (CGA)-based prognostic tool, to develop predictive rules that guide clinical and management decisions in older people in different European countries. A series of international studies performed in different settings have shown that the MPI is useful to predict mortality and risk of hospitalization in community-dwelling older subjects at population level. Furthermore, studies performed in older people who underwent a CGA before admission to a nursing home or receiving homecare services showed that the MPI successfully identified groups of persons who could benefit, in terms of reduced mortality, of specific therapies such as statins in diabetes mellitus and coronary artery disease, anticoagulants in atrial fibrillation and antidementia drugs in cognitive decline. A prospective trial carried out in nine hospitals in Europe and Australia demonstrated that the MPI was able to predict not only in-hospital and long-term mortality, but also institutionalization, re-hospitalization and receiving homecare services during the one-year follow-up after hospital discharge. The project also explored the association between MPI and mortality in hospitalized older patients in need of complex procedures such as transcatheter aortic valve implantation or enteral tube feeding. Evidence from these studies has prompted the MPI_AGE Investigators to formulate recommendations for healthcare providers, policy makers and the general population which may help to improve the cost-effectiveness of appropriate health care interventions for older patients.

Prevalence of cancer and management in elderly nursing home residents. A descriptive study in 45 French nursing homes.

This study aimed to determine cancer prevalence occurring after the age of 75 in 45 French nursing homes (NH), as well as residents' characteristics and parameters associated with cancer-specific management. Descriptive retrospective study including 214 residents (mean age, 89.7 years) with cancer diagnosed after age 75. The studied parameters were sociodemographic, functional, nutritional and cognitive data; comorbidity assessment; date of tumoral diagnosis; cancer type; tumoral stage; treatment plan; multidisciplinary staff decision and oncologic follow-up. Our results showed that cancer prevalence in NH was 8.4 ± 1.1%, diagnosed before admission in 63% of cases. The most common tumoral sites were skin (26%), digestive tract and breast (18% for both); 12% had metastasis. Cognitive impairment was the most common comorbidity (42%), and 44% of the residents were highly dependent. Multivariate analysis showed that therapeutic decisions were associated with age. Older patients had less staging exploration (odd ratios [ORs], 0.90, 95% confidence interval [CI], 0.85-0.97) and underwent less cancer-specific treatment (ORs, 0.92; 95%CI, 0.86-0.99). Oncologic follow-up was more frequent in younger patients (ORs, 0.90; 95%CI, 0.81-0.99) and those with recent diagnosis (ORs, 0.37; 95%CI, 0.23-0.61). This study identified factors associated with substandard neoplastic management in elderly NH residents. It highlights needs for information, education and training in cancer detection to improve cancer consideration and care in NH.

Trans ε-viniferin is an amyloid-ß disaggregating and anti-inflammatory drug in a mouse primary cellular model of Alzheimer's disease.

Alzheimer's disease (AD) is marked by several cellular and molecular damage. Therefore, the therapeutic interest of multi-target molecules is increasingly justified. Polyphenols presenting multiple pharmacological effects would be more efficient. In this study, beneficial effects of trans ε-viniferin, a natural polyphenol were thus evaluated. This study reported that this stilbenoid (1) induced the disaggregation of amyloid ß (Aß) peptide and (2) rescued inflammation in murine primary neuronal cultures. These both effects are higher than those of resveratrol, and so, trans ε-viniferin could be a good therapeutic multi-target candidate.

Study protocol on Alzheimer's disease and related disorders: focus on clinical and imaging predictive markers in co-existing lesions.

BACKGROUND: One of the crucial challenges for the future of therapeutic approaches to Alzheimer's disease (AD) is to target the main pathological processes responsible for disability and dependency. However, a progressive cognitive impairment occurring after the age of 70, the main population affected by dementia, is often related to mixed lesions of neurodegenerative and vascular origins. Whereas young patients are mostly affected by pure lesions, ageing favours the occurrence of co-lesions of AD, cerebrovascular disease (CVD) and Lewy body dementia (LBD). Most of clinical studies report on functional and clinical disabilities in patients with presumed pure pathologies. But, the weight of co-morbid processes involved in the transition from an independent functional status to disability in the elderly with co-lesions still remains to be elucidated. Neuropathological examination often performed at late stages cannot answer this question at mild or moderate stages of cognitive disorders. Brain MRI, Single Photon Emission Computed Tomography (SPECT) with DaTscan®, amyloid Positron Emission Tomography (PET) and CerebroSpinal Fluid (CSF) AD biomarkers routinely help in performing the diagnosis of underlying lesions. The combination of these measures seems to be of incremental value for the diagnosis of mixed profiles of AD, CVD and LBD. The aim is to determine the clinical, neuropsychological, neuroradiological and biological features the most predictive of cognitive, behavioral and functional impairment at 2 years in patients with co-existing lesions. METHODS: A multicentre and prospective cohort study with clinical, neuro-imaging and biological markers assessment will recruit 214 patients over 70 years old with a cognitive disorder of AD, cerebrovascular and Lewy body type or with coexisting lesions of two or three of these pathologies and fulfilling the diagnostic criteria for dementia at a mild to moderate stage. Patients will be followed every 6 months (clinical, neuropsychological and imaging examination and collection of cognitive, behavioural and functional impairment) for 24 months. DISCUSSION: This study aims at identifying the best combination of markers (clinical, neuropsychological, MRI, SPECT-DaTscan®, PET and CSF) to predict disability progression in elderly patients presenting coexisting patterns. TRIAL REGISTRATION: NCT02052947 .

Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers.

INTRODUCTION: Diagnostic relevance of plasma amyloid ß (Aß) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aß42 and Aß40 in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers. METHODS: One thousand forty participants (417 amnestic MCI, 122 nonamnestic MCI, and 501 AD) from the Biomarker of AmyLoïd pepTide and AlZheimer's diseAse Risk multicenter prospective study with cognition, plasma, cerebrospinal fluid (CSF), and magnetic resonance imaging assessments were included. RESULTS: Plasma Aß1-42 and Aß1-40 were lower in AD (36.9 [11.7] and 263 [80] pg/mL) than in amnestic MCI (38.2 [11.9] and 269 [68] pg/mL) than in nonamnestic MCI (39.7 [10.5] and 272 [52] pg/mL), respectively (P = .01 for overall difference between groups for Aß1-42 and P = .04 for Aß1-40). Globally, plasma Aß1-42 correlated with age, Mini-Mental State Examination, and APOE Îµ4 allele. Plasma Aß1-42 correlated with all CSF biomarkers in MCI but only with CSF Aß42 in AD. DISCUSSION: Plasma Aß was associated with cognitive status and CSF biomarkers, suggesting the interest of plasma amyloid biomarkers for diagnosis purpose.

Tolerance of subcutaneously administered antibiotics: a French national prospective study.

Background/ Objective: Although poorly documented, subcutaneous (SC) administration of antibiotics is common practice in France especially in Geriatrics Departments. The aim of this study was to determine the tolerance of such a practice. Design: Prospective observational multicentre study. Methods: Sixty-six physicians accepted to participate from 50 French Infectious Diseases and Geriatrics Departments. From May to September 2014, patients treated at least one day with SC antibiotics could be included. Modalities of subcutaneous administration, occurrence of local and systemic adverse effects (AE) and clinical course were collected until the end of the treatment. Results: Two hundred-nineteen patients (83.0 [19­104] yo) were included. Ceftriaxone (n = 163, 74.4%), and ertapenem (n = 30, 13.7%) were the most often prescribed antibiotics. The SC route was mainly used because of poor venous access (65.3%) and/or palliative care (32.4%). Fifty patients (22.8%) experienced at least one local AE that led to an increased hospital stay for two patients (4.0%) and a discontinuation of the SC infusion in six patients (12.0%). A binary logistic regression for multivariate analysis identified the class of antibiotic (p = 0.002) especially teicoplanin and the use of rigid catheter (p = 0.009) as factors independently associated with AE. In over 80% of cases, SC antibiotics were well tolerated and associated with clinical recovery. Conclusions: SC administration of antibiotics leads to frequent but local and mild AE. Use of non-rigid catheter appears to be protective against AE. As it appears to be a safe alternative to the intravenous route, more studies are needed regarding efficacy and pharmacokinetics.

Aging Stereotypes Must be Taken Into Account for the Diagnosis of Prodromal and Early Alzheimer Disease.

Because of a dramatic increase of older people worldwide, screening for prodromal state of Alzheimer disease (AD) is a major societal challenge. Many individuals diagnosed with prodromal AD, do not convert to AD, some remaining stable and others reversing back to normal. We argue that an important source of this overdiagnosis comes from negative aging stereotypes (eg, the culturally shared beliefs that aging inescapably causes severe cognitive decline and diseases). Many laboratory studies show that such stereotypes impair memory performance in healthy older adults, producing inflated age differences. Research is needed to examine how aging stereotypes implicitly permeate neuropsychological testing and contribute to false positives.

Factors associated with orthostatic hypotension in hospitalized elderly patients.

OBJECTIVE: To assess the factors associated with orthostatic hypotension (OH) in hospitalized elderly patients. DESIGN: Prospective observational single center study. SETTING: A French academic center. PARTICIPANTS: One hundred and thirty-one patients without OH symptoms who underwent OH testing. MEASUREMENTS: The OH test was performed when the patient was able to get out of the bed and was no longer receiving parenteral fluids. The blood pressure was measured after a 10-min rest while the patients were sitting and then standing at 1 and 3 min. Demographic data, co-morbidities, current medications and biological parameters were recorded. RESULTS: The mean patient age was 84.3 ± 7 years. The mean CIRS-G score was 10.6 ± 3.8. The OH test was performed 6.3 ± 3.9 days after admission and was positive in 39 (29.8 %) patients (95 % confidence interval (CI) 22, 38) and positive at 1 min in 87.2 % of the cases. Multivariate analysis showed that OH prevalence correlated with diabetes (odds ratio (OR) = 4.23; 95 % CI 1.10, 16.24; P = 0.03), serum 25-hydroxyvitamin D <20 ng/ml (OR = 3.38; 95 % CI 1.36, 8.42; P = 0.008), use of tranquilizers (anxiolytic and hypnotic) (OR = 2.96; 95 % CI 1.18, 7.4; P = 0.02), CIRS-G score (OR = 1.15; 95 % CI 1.01, 1.31; P = 0.03) and lack of diuretics (OR = 0.20; 95 % CI 0.06, 0.63; P = 0.005). CONCLUSION: In older adults, OH is often misdiagnosed because it is asymptomatic. As practitioners may be reluctant to perform the OH test because of time constraints, targeting a subgroup of patients with a higher risk of OH should be worthwhile to prevent further OH complications.

Burden of herpes zoster: the direct and comorbidity costs of herpes zoster events in hospitalized patients over 50 years in France.

BACKGROUND: The objectives of this study were to describe hospital stays related to HZ and to evaluate the direct and indirect cost of hospitalizations due to HZ among patients aged over 50 years. METHODS: The hospitalizations of people aged over 50 years were selected from the French national hospital 2011 database (PMSI) using ICD-10 diagnosis codes for HZ. Firstly, stays with HZ as principal or related diagnostic were described through the patient characteristics, type of hospitalization and the related costs. Secondly, a retrospective case-control analysis was performed on stays with HZ as comorbidity in 5 main hospitalizations causes (circulatory, respiratory, osteo-articular, digestive systems and diabetes) to assess the impact of HZ as co-morbidity on the length of stay, mortality rate and costs. RESULTS: In the first analysis, 2,571 hospital stays were collected (60 % of women, mean age: 76.3 years and mean LOS: 9.5 days). The total health assurance costs were 10,8 M€. Mean cost per hospital stay was 4,206€. In the second analysis, a significant difference in LOS and costs was shown when HZ was associated as comorbidity in other hospitalization's causes. CONCLUSIONS: HZ directly impacts on the hospital cost. When present as comorbidity for other medical reasons, HZ significantly increases the length of hospital stay with subsequent economic burden for the French Health System.

There is no correlation between peripheral inflammation and cognitive status at diagnosis in Alzheimer's disease.

BACKGROUND: Besides the neurofibrillary tangles and amyloid plaques, an inflammatory process is involved at central and peripheral levels in Alzheimer's disease (AD). We aimed to determine whether peripheral inflammatory parameter levels, in plasma and in peripheral blood mononuclear cells (PBMCs), could be correlated with the cognitive status at the time of AD diagnosis. METHODS: Patients were included at diagnosis with MMSE score between 16 and 25 and were naive of symptomatic treatment for AD. C-reactive protein >10 mg/L and any acute or chronic inflammation were considered as exclusion criteria. Cognitive assessment also included the ADAScog scale. Plasma interleukins (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α and the chemokine ligand 5 (CCL5) were measured using Luminex(®) X-MAP(®) technology. A subgroup of patients also underwent measures of these parameters in extracellular and intracellular compartments of PBMCs (ancillary study). RESULTS: One hundred and nine patients were included; mean age 79.4 ± 6.8 years with 37 patients in the ancillary study. The mean values of IL-1ß, TNF-α, IL-6 and CCL5 values were 1.49, 7.18, 3.09 and 69,615.81 pg/mL, respectively. No correlation between plasma cytokines or chemokine levels and cognitive scores was found. In PBMCs, the levels of cytokines were detectable but did not either show any correlation with cognitive scores. CONCLUSION: Our data indicate that at diagnosis, peripheral levels of cytokines and CCL5 display low values without any correlation with the cognitive status. Further results of our study will show if these circulating markers are related to the progression of AD.

Longitudinal follow-up of autophagy and inflammation in brain of APPswePS1dE9 transgenic mice.

BACKGROUND: In recent years, studies have sought to understand the mechanisms involved in the alteration of autophagic flux in Alzheimer's disease (AD). Alongside the recent description of the impairment of lysosomal acidification, we wanted to study the relationships between inflammation and autophagy, two physiological components deregulated in AD. Therefore, a longitudinal study was performed in APPswePS1dE9 transgenic mice at three, six and twelve months of age. METHODS: Autophagic markers (Beclin-1, p62 and LC3) and the activation of mammalian Target of Rapamycin (mTOR) signaling pathway were quantified by western blot. Cytokine levels (IL-1ß, TNF-α and IL-6) were measured by ELISA. Transmission electron microscopy was performed to detect autophagic vacuoles. Mann-Whitney tests were used to compare wild-type (WT) versus APPswePS1dE9 mice. Longitudinal changes in parameters were analyzed with a Kruskal-Wallis test followed by a post-hoc Dunn's test. Correlation between two parameters was assessed using a Spearman test. RESULTS: Compared to 12-month old WT mice, 12-month old APPswePS1dE9 mice had higher levels of IL-1ß and TNF-α, a greater inhibition of the mTOR signaling pathway and lower levels of Beclin-1 expression both in cortex and hippocampus. Regarding the relationship of the various parameters in 12-month old APPswePS1dE9 mice, Beclin-1 rates were positively correlated with IL-1ß and TNF-α levels. And, on the contrary, TNF-α levels were inversely correlated with the levels of mTOR activation. Altogether, these results suggest that inflammation could induce autophagy in APPswePS1dE9 mice. However, these transgenic mice displayed a large accumulation of autophagic vesicles within dystrophic neurons in cortex and hippocampus, indicating a terminal failure in the autophagic process. CONCLUSIONS: This first demonstration of relationships between inflammation and autophagy in in vivo models of AD should be taken into account in new therapeutic strategies to prevent inflammation and/or stimulate autophagy in advanced neurodegenerative process such as AD.

ARIZONA study: is the risk of post-herpetic neuralgia and its burden increased in the most elderly patients?

BACKGROUND: In a context of change in the demographic profile of the older population, to identify an age threshold for increased risk and burden of herpes zoster (HZ) in 70+ patients. METHODS: Post hoc analysis of the 12-month French nationwide prospective observational ARIZONA cohort study. HZ was assessed by means of the following validated questionnaires: Neuropathic Pain Symptom Inventory (NPSI), Zoster Brief Pain Inventory (ZBPI), Short-Form health survey (SF-12), and Hospital Anxiety and Depression Scale (HADS). RESULTS: 644 general practitioners included 1,358 volunteer patients with acute HZ in the ARIZONA study; 609 patients (45%) were 70+. In 70+ patients, age did not increase rash severity or HZ-related pain intensity at diagnosis, but increased by 64% the frequency of ophthalmic zoster (from 5.5% in 70-74 years age-group to 9.0% in 85+ patients, p = NS). Age was significantly associated with low physical health as assessed by the SF-12 Physical Component Summary (SF-12 PCS) score and bad mood as assessed by the HADS depression score (p < 0.001). Within the year following HZ, post-herpetic neuralgia (PHN) was systematically but not significantly more frequent in 85+ patients than in the 70-74, 75-79, or 80-84 years age-groups (19.0% vs. 13.3%/15.3%/11.6% at month 3; 15.1% vs. 7.3%/11.0%/12.2% at month 6; 15.2% vs. 6.0%/8.0%/6.0% at month12, respectively). SF-12 PCS and HADS depression scores improved from day 0 to month 12 in all patients (p < 0.001). 85+ patients were more impaired than younger patients (p < 0.001), but without clear difference according to PHN. CONCLUSIONS: This study did not show in 70+ patients a clear and significant age threshold at which disease burden increased, although for some domains the impact seemed higher among the oldest patients; the cut-off of 70 years remains thus relevant for clinical and epidemiological studies. However, at individual level, assessment of the burden of HZ and HZ-related pain appears necessary to improve management and prevent functional decline in the most vulnerable 70+ patients.