Genome-wide meta-analysis for Alzheimer's disease cerebrospinal fluid biomarkers.

Amyloid-beta 42 (Aß42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aß42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aß42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.

Impact of the Ageing Population on the Burden of Stroke: The Dijon Stroke Registry.

BACKGROUND: We aimed to evaluate the impact of the ageing population on temporal trends in burden of stroke and to provide projections for the coming years. METHODS: Stroke cases (ischemic strokes, spontaneous intracerebral hemorrhages, or undetermined strokes) were prospectively identified between 1987 and 2015 in Dijon, France, using a population-based registry. Age-standardized incidence rates of first-ever and recurrent stroke were calculated, and their temporal trends were assessed using age- and sex-adjusted annual incidence rate ratios (RR). RESULTS: The population of Dijon increased by 3.8% over time, with an increase by 28% in the number of residents aged ≥75 years. We recorded 5,899 strokes including 5,101 patients with a first-ever event. Incidence of first-ever stroke was stable both in people < 75 and ≥75 years old, but an increase in standardized incidence rates of total strokes was noted due to a rise in the incidence of recurrent stroke (from 4.7/100,000/year in 1987-1994 to 12.3/100,000/year in 2009-2015 in people < 75 years old, RR 1.036; p < 0.001; from 74/100,000/year in 1987-1994 to 200/100,000/year in 2009-2015 in people ≥75 years, RR 1.040; p < 0.001). The absolute number of first-ever strokes increased by 43%, and that of total stroke events rose by 58% over time, with a more pronounced increase in people ≥75 years old (+47 and +65% respectively). The annual number of patients who survived > 90 days after a first-ever stroke increased by 90%. According to demographic projections, the total number of strokes will increase by 55% (+65% patients ≥75 years, and +25% patients < 75 years) by 2,030 in Dijon. CONCLUSIONS: Ageing and growth of the population led to a rise in the absolute number of strokes, especially in the elderly, that is expected to increase dramatically in the coming years. Improved stroke care was accompanied with an increase in stroke survivors that contributed to a rise in recurrent events. Urgent action is needed to meet this epidemiological challenge.

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 ε4 allele.

COVID-19 In-Hospital Mortality and Use of Renin-Angiotensin System Blockers in Geriatrics Patients.

OBJECTIVE: The role of treatment with renin-angiotensin-aldosterone system blockers at the onset of COVID-19 infection is not known in the geriatric population. The aim of this study was to assess the relationship between angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitor (ACEI) use and in-hospital mortality in geriatric patients hospitalized for COVID-19. DESIGN: This observational retrospective study was conducted in a French geriatric department. Patients were included between March 17 and April 18, 2020. SETTING AND PARTICIPANTS: All consecutive 201 patients hospitalized for COVID-19 (confirmed by reverse-transcriptase polymerase chain reaction methods) were included. All nondeceased patients had 30 days of follow-up and no patient was lost to follow-up. METHODS: Demographic, clinical, and biological data and medications were collected. In-hospital mortality of patients treated or not by ACEI/ARB was analyzed using multivariate Cox models. RESULTS: Mean age of the population was 86.3 (8.0) years, 62.7% of patients were institutionalized, 88.6% had dementia, and 53.5% had severe disability (activities of daily living [ADL] score <2). Sixty-three patients were treated with ACEI/ARB and 138 were not. Mean follow-up was 23.4 (10.0) days, 66 (33.8%) patients died after an average of 10.0 days (6.0). Lower mortality rate was observed in patients treated with ACEI/ARB compared with patients not treated with ARB or ACEI (22.2% [14] vs 37.7% [52], hazard ratio [HR] 0.54; 95% confidence interval 0.30-0.97; P = .03). In a multivariate Cox regression model including age, sex, ADL score, Charlson index, renal function, dyspnea, C-reactive protein, and white blood cell count, use of ACEI/ARB was significantly associated with lower in-hospital mortality (HR 0.52 (0.27-0.99), P = .048). CONCLUSION AND IMPLICATIONS: In very old subjects hospitalized in geriatric settings for COVID-19, mortality was significantly lower in subjects treated with ARB or ACEI before the onset of infection. The continuation of ACEI/ARB therapy should be encouraged during periods of coronavirus outbreak in older subjects.

[Hypertension in the elderly]. / Hypertension artérielle du sujet âgé.

After 80 years old, antihypertensive treatment significantly reduces cardiovascular events. In the elderly, blood pressure target depends on patients' frailty. After 80 years, French guidelines propose to aim a SBP<150 mmHg without orthostatic hypotension and without exceeding the prescription of more than three antihypertensive drugs. The target may be more ambitious for robust elderly patients. The new 2018 European guidelines set: a stricter target for robust elderly patient aged 80 years or older (SBP between 130 and 139 mmHg and DBP between 70 and 79 mmHg); this objective is less strict for frail elderly (with several comorbidities, with loss of autonomy, elderly living in nursing home or with orthostatic hypotension). A recent randomized controlled trial shows a significant reduction in mortality and cardiovascular events by achieving a low blood pressure goal in patients over the age of 75 years old. Five major drug classes can be used: thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and beta-blockers. Beta-blockers are less efficient to prevent stroke and are indicated in second line. However, beta-blockers represent first choice of treatment in cases of heart failure, coronary artery disease or atrial fibrillation. Appropriate follow-up and monitoring enable assessment of safety (recording BP while standing, ionogram, creatinine).

[Capnocytophaga canimorsus: atypical septicemic meningitis, approach to microbiological diagnosis and therapeutic impact]. / Capnocytophaga canimorsus : méningite septicémique atypique, démarche du diagnostic microbiologique et impact thérapeutique.

Meningitis and septicaemia due to Capnocytophaga canimorsus are extremely rare and described as emerging zoonoses because of their low incidence and prevalence, but also because of the challenges in bacterial identification, thus, the real number of cases is probably underestimated. We report the case of a 61-year-old man, with a history a chronic alcoholism, who developed, following a recent dog bite, meningitis with normoglycorachia and concomitant sepsis, and had a favorable outcome after intravenous probabilistic antibiotherapy combining ceftazidime and metronidazole. This association aimed to cover the risks represented by Pseudomonas spp and anaerobic bacteria, once the microorganisms commonly associated with meningitis were excluded using molecular biology tools. In addition to the unusual biological results (normoglycorachia and bacterial morphology after Gram staining), we present the biological diagnostic approach (molecular, biochemical and physical tools successively used to lead, by exclusion and confirmation, to this diagnosis), closely linked to the clinical expertise. This is, to our knowledge, the first described case of meningitis with normoglycorachia and septicaemia due to Capnocytophaga canimorsus successfully treated with ceftazidime and confirmed by identification by MALDI-TOF mass spectrometry.

Pulse Wave Velocity Is Associated With Greater Risk of Dementia in Mild Cognitive Impairment Patients.

To investigate the association between pulse wave velocity, intima-media thickness, carotid artery diameter, carotid plaques, and conversion from mild cognitive impairment to dementia. Three hundred and seventy-five elderly ambulatory subjects with mild cognitive impairment were followed yearly to examine potential conversion to dementia. Vascular function was assessed by carotid-femoral pulse wave velocity. Vascular structure was evaluated by intima-media thickness, carotid artery diameter, and carotid plaques using an ultrasonographic assessment of carotid arteries. One hundred and five patients (28%) converted to dementia during a mean follow-up period of 4.5 years. Higher pulse wave velocity was associated with greater risk of conversion to dementia (1-SD increase of pulse wave velocity: hazard ratio, 1.33; 95% CI, 1.04-1.71; P=0.02) independently of age, sex, educational level, systolic blood pressure, cardiovascular diseases, body mass index, calcium channel blockers intake, Mini-Mental State Examination at baseline, and apoE ε4 status. Intima-media thickness, carotid plaques, and carotid artery diameter did not predict conversion to dementia (1-SD increase of intima-media thickness: hazard ratio, 0.93; 95% CI, 0.73-1.18; P=0.55; presence of carotid plaques: hazard ratio, 1.08; 95% CI, 0.62-1.87; P=0.79; 1-SD increase of carotid artery diameter: hazard ratio, 1.08; 95% CI, 0.89-1.31; P=0.44). Pulse wave velocity was associated with conversion to dementia, whereas intima-media thickness, carotid plaques, or carotid artery diameter were not after controlling for age and other confounding factors. Arterial stiffness could identify mild cognitive impairment patients at higher risk of dementia and may be a therapeutic target to delay or prevent the onset of dementia.

Temporal trends in the premorbid use of preventive treatments in patients with acute ischemic cerebrovascular events and a history of vascular disease: The Dijon Stroke Registry (1985-2010).

INTRODUCTION: Although secondary prevention in patients with arterial vascular diseases has improved, a gap between recommendations and clinical practice may exist. OBJECTIVES: We aimed to evaluate temporal trends in the premorbid use of preventive treatments in patients with ischemic cerebrovascular events (ICVE) and prior vascular disease. METHODS: Patients with acute ICVE (ischemic stroke/TIA) were identified through the population-based stroke registry of Dijon, France (1985-2010). Only those with history of arterial vascular disease were included and were classified into four groups: patients with previous coronary artery disease only (CAD), previous peripheral artery disease only (PAD), previous ICVE only, and patients with at least two different past vascular diseases (polyvascular group). We assessed trends in the proportion of patients who were treated with antihypertensive treatments and antithrombotics at the time of their ICVE using multivariable logistic regression models. RESULTS: Among the 5309 patients with acute ICVE, 2128 had a history of vascular disease (mean age 77.3±11.9, 51% men; 25.1% CAD 7.5% PAD, 39.8% ICVE, and 27.5% poylvascular). A total of 45.8% of them were on antithrombotics, 64.1% on antihypertensive treatment, and 34.4% on both. Compared with period 1985-1993, periods 1994-2002 and 2003-2010 were associated with a greater frequency of prior-to-ICVE use of antithrombotics (adjusted OR=5.94; 95% CI: 4.61-7.65, P<0.01, and adjusted OR=6.92; 95% CI: 5.33-8.98, P<0.01, respectively) but not of antihypertensive drugs. Consistent results were found when analyses were stratified according to the type of history of arterial vascular disease. CONCLUSION: Patients with ICVE and previous vascular disease were still undertreated with recommended preventive therapies.

Epidemiology of stroke in Europe and trends for the 21st century.

Despite major improvements in primary prevention and acute treatment over the last decades, stroke is still a devastating disease. At the beginning of the 21st century, the age-standardized incidence of stroke in Europe ranged from 95 to 290/100,000 per year, with one-month case-fatality rates ranging from 13 to 35%. Approximately 1.1 million inhabitants of Europe suffered a stroke each year, and ischemic stroke accounted for approximately 80% of cases. Although global stroke incidence is declining, rates observed in young adults are on the rise, thus suggesting a need for strategies to improve prevention. In addition, because of the ageing population, the absolute number of stroke is expected to dramatically increase in coming years: by 2025, 1.5 million European people will suffer a stroke each year. Beyond vital prognosis, stroke patients are also at increased risk of poor outcome within the first year of the event including re-hospitalisation (33%), recurrent event (7 to 13%), dementia (7 to 23%) mild cognitive disorder (35 to 47%), depression (30 to 50%), and fatigue (35% to 92%), all of them contributing to affect health related quality of life. Given these observations, an urgent development of acute care provision, as well as resources for post-stroke therapeutic strategies, is needed.

A New Prognosis Score to Predict Mortality After Acute Pneumonia in Very Elderly Patients.

OBJECTIVES: Acute pneumonia (AP) induces an excess of mortality among the elderly. We evaluated the value of a new predictive biomarker index compared to usual prognosis scores for predicting in-hospital and 1-year mortalities in elderly inpatients with AP. DESIGN: Retrospective study in 6 clinical departments of a university hospital. SETTING: Burgundy university hospital (France). PARTICIPANTS: All patients aged 75 and over with AP and hospitalized between January 1 and June 30, 2013, in the departments of medicine (5) and intensive care (1) of our university hospital. MEASUREMENTS: A new index, which we named UBMo, was created by multiplying the uremia (U in the formula) by the N-terminal-pro-brain natriuretic peptide (NT-proBNP) plasmatic rate (B), divided by the monocyte count (Mo). RESULTS: Among the 217 patients included, there were 138 community-acquired pneumonia, 56 nursing home-acquired pneumonia, and 23 hospital-acquired pneumonia. In-hospital and 1-year mortality rates were respectively 19.8% and 43.8%. In multivariate analysis, Pneumonia Severity Index (PSI), unlike CURB-65 (confusion, urea >7 mmol/L, respiratory rate ≥30 breaths/min, blood pressure <90 mmHg systolic or ≤60 mmHg diastolic, age ≥65) score, was associated with in-hospital and 1-year mortalities. UBMo index performed better than PSI and CURB-65 scores in predicting both in-hospital and 1-year mortalities. For in-hospital mortality, the areas under the receiver operating characteristic curves (AUCs) were 0.89 (95% CI = 0.84-0.94), 0.72 (95% CI = 0.65-0.80), and 0.63 (95% CI = 0.54-0.72), respectively, for the 3 scores. For 1-year mortality, the AUCs were 0.93 (95% CI = 0.89-0.98), 0.66 (95% CI = 0.59-0.74), and 0.58 (95% CI = 0.50-0.66), respectively, for the 3 scores. The cut point for the UBMo index of 20,000 × 10-9 ng·mmol/L had a sensitivity of 93.1% and 80.9% and a specificity of 76.3% and 95.8%, respectively, for in-hospital and 1-year mortalities. CONCLUSION: If confirmed by prospective studies, the UBMo index appears very efficient in identifying patients at high risk of in-hospital and 1-year mortalities after an AP.