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Background: To improve prognostic procedures, we aimed to explore whether diabetes mellitus and Alzheimer's disease (AD) biomarkers are synergistically associated with cognitive decline in persons without dementia. Method: We included 1.737 persons with normal cognition (NC) and 634 with mild cognitive impairment (MCI) from 8 European memory clinic and aging cohorts as part of the PRIME project. We examined cognitive decline in MMSE (raw scores), memory (delayed recall), attention, executive functioning, and language domains (Z‐scores). AD biomarkers included CSF amyloid‐beta42 (data‐driven cut‐offs) or amyloid PET (center‐specific cut‐offs) as measure of amyloid positivity, CSF p‐tau as measure of tau tangle positivity and CSF t‐tau as measure of neurodegeneration (both center‐specific cut‐offs). We performed generalized linear mixed models with random intercepts and slopes, all adjusted for demographics. Result: Mean age was 65.9 (SD=8.9) years, 54% were women, and diabetes was diagnosed in 7% of NC and 12% of MCI. Mean follow‐up time was 1.8 years (range 0.5‐8). In NC, we found decline in memory and attention in persons with both diabetes and t‐tau positivity. This was not shown in persons with only diabetes or only t‐tau positivity (Figure 1). We also found this interaction between diabetes and p‐tau on attention decline (Table 1). When stratifying for amyloid status, we found that this was only significant in amyloid negative individuals (memory t‐tau: p=0.005, attention p‐tau: p=0.033, attention t‐tau: p=0.039). A higher baseline language performance was found in persons with both diabetes and p‐tau or t‐tau positivity (p=0.011; p=0.034) compared to those with only diabetes or tau positivity. We found steeper decline in language in persons with both diabetes and amyloid positivity, compared to other groups (Figure 2). A similar synergism with diabetes was found for p‐tau. No interaction was found for executive functioning. In persons with MCI with both diabetes and t‐tau positivity, we found higher baseline MMSE scores (p=0.041) compared to other groups. Diabetes was not associated with cognitive decline in any domain in MCI. Conclusion: Diabetes may affect non‐AD‐related decline in memory and attention as well as AD‐related decline in language at an early clinical stage. This may help improve prognostic procedures. [ABSTRACT FROM AUTHOR]

Background: Fourty percent of modifying factors explain cognitive decline in elderly, such as a lack of social and physical activities (Livingston 2020). Speech, physical and neuropsychological therapies have shown efficiency, although stopping them can have an impact on quality of life (Leidi, 2020). Therefore, usual models of care need to evolve to build bridges between therapies and community activities. The aim of CareMENS (= Care, MEmory and NeuroScience), a new model, is to provide a continuity in patients' care after the therapies, by assisting them to find a leisure activity in their community in order to stay active and socially involved (Annexe). Setting: Seven Memory clinics in the french speaking part of Switzerland. Main outcome measures: Quality of life (WHOQOL), cognition (MoCA), severity of symptoms (CDR), autonomy in daily life activities (DAD‐6), anxiety and depression (HAD), satisfaction (self‐assessed questionnaire). Method: To meet the needs of patients at risk of dementia and according to their symptomatology, they undergo speech, physical or neuropsychological therapy within a Memory clinic. Then, a care manager organize with the patient a leisure activity in the community to perpetuate the therapies' benefice and to stay socially involved. Paired‐sample t‐tests were conducted between 2 measures: before therapy and after 3 months of leisure activity. Result: Among 150 patients that started a therapy within CareMENS (Neuropsychology: n = 94, speech:n = 26, physical: n = 30), 100 completed their therapy, 61 already integrated a community activity and 31 ended the follow‐up. Results are reported for 25 patients. In a mean follow‐up time of 366 days, autonomy remained stable (p = 0.14), whereas global cognition decreased significantly (p = 0.01). Among anxious people, level of anxiety decreased significantly (p = 0.02). Global QOL was stable in patients (p = 0.15) and caregivers (p = 0.46), while the QOL's dimension of "social participation" improved strongly and significantly in patients (p = 0.0001). Satisfaction to the care manager's interventions and to the therapies were very encouraging (83.5%). Conclusion: CareMENS is a new model of care that give a high satisfaction to patients and caregivers, improves the social dimension of quality of life and integrate patients in the society through community activities, that are enjoyable therefore sustainable. [ABSTRACT FROM AUTHOR]

The study recently published on the clinical effect of lecanemab in early Alzheimer's disease (AD) only includes patients with amnestic presentation. However, a significant portion of AD patients presents a non‐amnestic phenotype of AD, such as primary progressive aphasia (PPA) and could benefit of rather than on lecanemab. Therefore, we conducted a 10‐year retrospective study at the Leenaards Memory Center in Lausanne (Switzerland) to identify how many PPA patients would be eligible for lecanemab. Among 54 patients with PPA, we identified 11 (20%) eligible patients. Furthermore, almost half of the 18 patients with logopenic variant would be eligible for lecanemab treatment. [ABSTRACT FROM AUTHOR]

Objectives: Aging entails deterioration in sensory, physical, and cognitive functions, raising doubt in the driving capacity of older drivers, especially when the deficits are severe, as in dementia. Many older drivers, especially women, adapt their driving habits in order to compensate for these deficits and eventually stop driving. The present prospective study assessed driving cessation in men and women throughout the dementia process, including a 2-year pre-dementia phase.Methods: The study was based on a three-city cohort of subjects who were aged 65 years and older in 2000 and followed for more than 10 years. Active dementia detection was conducted at each follow-up. The probability of driving cessation was assessed in men and women during the 2-year pre-dementia phase and until 5 years after diagnosis.Results: In the 2-year pre-dementia phase, both men and women ceased driving earlier than drivers with no central nervous system pathology (p < 0,001), and women ceased driving earlier than men. A total of 45% of men and 74% of women had already ceased driving at dementia diagnosis. In contrast, the probability of cessation within 3 years after diagnosis was similar between men and women.Conclusion: The study showed that, in this French urban population, few demented drivers, especially women, were still driving after diagnosis. Those who continued to drive 3 years after the diagnosis all had Alzheimer-type dementia. There is certainly a need for physicians to help these drivers to adapt their driving activity to their deficits and to prepare them to stop driving. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Introduction Transition to bathing or dressing disability is a milestone in the evolution of dementia. We examined the transition to disability in these specific activities and considered death to be a competitive event and age and sex to be prognostic factors. Methods From a large cohort of 570 incident dementia cases screened in two prospective population-based cohorts, the Paquid study, and the Three-City study, we estimated the probabilities of remaining nondisabled, becoming disabled in bathing or dressing, or dying after the diagnosis using an illness-death model. Results On average, approximately half of the period (3 years) of living with dementia was free of disability. In women, a higher survival rate was associated with an average of 1 additional year with disability. Discussion The joint prediction of death and disability in dementia by an illness-death model gives original and useful parameters for the prognosis and management of dementia. [ABSTRACT FROM AUTHOR]

Introduction The purpose of this study was to study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD). Methods A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method. Results Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = −1.89%) compared with the placebo group (APC = −3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups. Discussion A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo. [ABSTRACT FROM AUTHOR]

Background We evaluated if plasma β-amyloid (Aβ) levels were associated with mortality risks in a subsample of the French Three-City (3C) prospective cohort study. Methods Analyses were based on 1254 participants randomly selected from the initial 3C cohort stratified by center, sex, and age in the context of a nested case-cohort study to investigate biological variables. Associations between plasma Aβ and mortality were assessed with the Cox regression model with delayed entry including various potential confounding factors and testing possible mediators. Results A relationship between high plasma Aβ 1-40 concentrations and risk of mortality (hazards ratio, 1.15; 95% confidence interval, 1.01–1.31, P = .03) was unveiled independently of age, educational level, vascular risk factors, diet, physical activity, cognitive impairment, or frailty status. It was only modified when we included cystatin C levels. Conclusions Further investigations are needed to determine precisely the pathophysiological roles of plasma Aβ 1-40 and cystatin C and before envisioning any future clinical applications. [ABSTRACT FROM AUTHOR]

Background The contribution of carotid atherosclerosis to incident dementia remains unclear. We examined the association between carotid plaques (CP) and common carotid intima media thickness (CCA-IMT) with incident dementia and its subtypes, and their added value for dementia risk prediction. Methods At baseline, 6025 dementia-free subjects aged 65–86 years underwent bilateral carotid ultrasonography measures of CP and plaque-free CCA-IMT. Subjects were followed-up over 7 years for the detection of dementia. Results After a mean 5.4 years of follow-up, 421 subjects developed dementia including 272 Alzheimer's disease and 83 vascular/mixed dementia (VaD). Only CP were independently related to VaD (HR ≥2 sites with plaques = 1.92; 95% confidence interval or CI = 1.13–3.22) and improved VaD risk prediction (continuous Net Reclassification Index = 30.1%; 95%CI = 8.4–51.7) beyond known dementia risk factors. Accounting for stroke or competing risk by death marginally modified the results. Conclusion In older adults, CP are independent predictors of incident VaD and may improve VaD risk prediction. [ABSTRACT FROM AUTHOR]

In this study, the in vivo allergenicity of bovine beta-lactoglobulin ( BLG) in peptic whey protein hydrolysates generated during microwave and conventional heating treatments was assessed. The allergenicity of the hydrolysates was explored by studying the reaction of the murine jejunum from previously immunised Balb/c mice to treated BLG in an Ussing chamber. Intestinal anaphylactic reactions after stimulation of the gut-associated immune system are a good indicator of potential in vivo allergenicity of whey hydrolysates. Fifty-two per cent of BLG was hydrolysed by pepsin after only 3 min of microwave irradiation at 200 watts (W), yet it remained intact under conventional heating. Far- and near- UV circular dichroism spectra indicated significant changes in BLG secondary and tertiary structures with microwave irradiation at 200 W. Pepsin whey protein hydrolysates obtained with microwave irradiation at 200 W for 3 min did not stimulate secretion of chloride in the Ussing chamber, as shown by the intensity of the short current values recorded (27.86 μA cm−2), compared to the conventional pepsin hydrolysates (68.21 μA cm−2). This demonstrates the low allergenicity of whey protein hydrolysates generated in this manner. These results confirm that microwave treatment combined with peptic hydrolysis could be applied to produce low allergenicity milk peptides. [ABSTRACT FROM AUTHOR]

Abstract: Background: Genetic variation in the estrogen receptor (ESR) may be associated with the incidence of Alzheimer's disease (AD), but this association could be modified by genetic and environmental factors. Methods: The association between five ESR α (ESR1) and β (ESR2) polymorphisms with 7-year dementia incidence was examined among 6959 older men and women from the Three City Study using multivariate-adjusted Cox regression models with delayed entry. Gender, the apolipoprotein E (APOE) ε4 allele, and hormone treatment were considered as potential effect modifiers of this association. Results: Among women, the CC genotype of ESR1 rs2234693 was specifically associated with a small increased risk of AD (adjusted hazard ratio [HR]: 1.54, 95% confidence interval [CI]: 1.03–2.28, P = .03). However, women with this genotype had a substantially increased risk of AD associated with the APOE ε4 allele (adjusted HR: 3.24, 95% CI: 1.81–5.79 for women rs2234693 CC; compared with HR: 1.87, 95% CI: 1.37–2.56 for all women). There was also evidence of a nominally significant interaction between the ESR1 and ESR2 polymorphisms on the risk of all dementias (P = .04). Hormone treatment did not modify these associations, and there were no significant associations in men. Conclusions: Although there was only weak support for a gender-specific association between the common ESR1 rs2234693 polymorphism and AD, this polymorphism may act as an effect modifier, modifying the association between an ESR2 polymorphism and dementia, as well as the risk of AD associated with the APOE ε4 allele. [Copyright &y& Elsevier]

Background Plasma fibrinogen is a strong predictor of ischaemic arterial disease in women. Sex steroid hormones including hormone therapy may play an important role in the development of cardiovascular disease. However, whether endogenous sex steroid hormones influence the plasma fibrinogen concentrations among postmenopausal women remains unclear. Objectives To investigate the association of plasma fibrinogen levels with endogenous sex steroid hormones and sex hormone binding globulin ( SHBG) among postmenopausal women. Methods We used data from the French prospective Three-City cohort study that included 9294 noninstitutionalized men and women over 65 years of age. Total 17β-oestradiol ( E2, pg/ml), total testosterone ( T, ng/ml), SHBG (n m) and fibrinogen (g/l) were measured in stored plasmas in a subcohort of 602 randomly selected postmenopausal women who used neither hormone medication nor anticoagulation therapy. Multivariate linear regression models were used to estimate the regression coefficients assessed in fibrinogen unit by 1 SD increase in log-distribution of sex steroid hormones and SHBG. Results E2 but neither T nor SHBG was positively associated with plasma fibrinogen levels (β = 0·148, P < 0·001). Adjustment for cardiovascular risk factors including diabetes made no substantial change to the results (β = 0·145, P < 0·001). The association of fibrinogen with E2 was stronger among women with body mass index over 25 kg/m2 compared with those with normal weight (β = 0·156, P < 0·001 and β = 0·092, P = 0·02, respectively, P for interaction = 0·04). Conclusion E2 emerges as a positive and independent correlate of plasma fibrinogen among postmenopausal women, especially in subjects who are overweight. These findings suggest a deleterious effect of endogenous oestrogens on cardiovascular risk profile among postmenopausal women. [ABSTRACT FROM AUTHOR]

Objectives To investigate the relationship between frailty and incident vascular dementia ( Va D). Design Seven-year longitudinal study. Setting Three- City Study, a French prospective study designed to evaluate the risk of dementia and cognitive decline attributable to vascular risk factors. Participants Five thousand four hundred eighty community-dwelling persons aged 65 to 95. Measurements An expert committee established a clinical diagnosis of Va D. Frailty was defined as having at least three of the following criteria: weight loss, weakness, exhaustion, slowness, and low physical activity. Participants with prior stroke or prevalent dementia at baseline were excluded from analyses. Multivariate models were used to evaluate the relationship between frailty and incident Va D. Results At baseline, 6.5% of participants were classified as frail. After 7 years of follow-up, 54 persons were diagnosed with Va D, seven of whom where frail. In the proportional hazards models, frailty was marginally associated with greater risk of all types of dementia and was not associated with incident Alzheimer's disease, but frailty status was independently associated with incident Va D. Conclusion Frailty is a major risk factor for incident Va D, so its identification could contribute to better estimates of the risk of Va D in elderly adults. [ABSTRACT FROM AUTHOR]

The article discusses the case of a 67 year old woman hospitalized for ischemic stroke after a computed tomography scan and cerebral magnetic resonance (MRI) indicated right frontoparietal hypodensity. Clopidogrel was given for secondary prevention of stroke but was stopped a year later due to the risk of increased bleeding. Mixed hippocampal and vascular dementia was suspected after cerebral MRI showed frontal lacunar syndrome and hemosiderosis.

Objective The objective of this study was to analyze differences in biomarker outcomes before and after harmonization of cerebrospinal fluid (CSF) collection tubes in Alzheimer's disease (AD) diagnosis. Methods We analyzed data from French memory centers that switched from different CSF collection tubes to a common one. A total of 1966 patients were included in the study. CSF concentrations of β-amyloid 1–42 (Aβ42), total tau, and phosphorylated tau (p-tau181) were measured in each center using the same commercial enzyme-linked immunoabsorbent assay (ELISA) kits. The diagnostic value of CSF biomarkers according to the type of tube used was then assessed using different cutoffs. Results The predictive value of Aβ42 was highly affected by the type of collection tube used. The optimal cutoff value for p-tau181 appeared not to be affected by the type of collection tube whereas that of total tau was slightly changed. New optimal cutoff values were then computed. Conclusions In a routine clinical environment, the selection of the collection tube and biomarker cutoff value makes a major difference in AD biological diagnosis. The use of a common collection tube among different centers will reduce the risk of misdiagnosis and incorrect patient stratification. [ABSTRACT FROM AUTHOR]