Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a post-hoc analysis of the Whitehall II cohort study

Background: Type 2 diabetes increases the risk for dementia, but whether it affects cognition before old age is unclear. We investigated whether duration of diabetes in late midlife and poor glycaemic control were associated with accelerated cognitive decline. Methods: 5653 participants from the Whitehall II cohort study (median age 54·4 years [IQR 50·3-60·3] at first cognitive assessment), were classified into four groups: normoglycaemia, prediabetes, newly diagnosed diabetes, and known diabetes. Tests of memory, reasoning, phonemic and semantic fluency, and a global score that combined all cognitive tests, were assessed three times over 10 years (1997-99, 2002-04, and 2007-09). Mean HbA1c was used to assess glycaemic control during follow-up. Analyses were adjusted for sociodemographic characteristics, health-related behaviours, and chronic diseases. Findings: Compared with normoglycaemic participants, those with known diabetes had a 45% faster decline in memory (10 year difference in decline -0·13 SD, 95% CI -0·26 to -0·00; p=0·046), a 29% faster decline in reasoning (-0·10 SD, -0·19 to -0·01; p=0·026), and a 24% faster decline in the global cognitive score (-0·11 SD, -0·21 to -0·02; p=0·014). Participants with prediabetes or newly diagnosed diabetes had similar rates of decline to those with normoglycaemia. Poorer glycaemic control in participants with known diabetes was associated with a significantly faster decline in memory (-0·12 [-0·22 to -0·01]; p=0·034) and a decline in reasoning that approached significance (-0·07 [-0·15 to 0·00]; p=0·052). Interpretation: The risk of accelerated cognitive decline in middle-aged patients with type 2 diabetes is dependent on both disease duration and glycaemic control. Funding: US National Institutes of Health, UK Medical Research Council. © 2013 Elsevier Ltd. All rights reserved

Multicentre, interventional, single-arm study protocol of telemonitored circadian rhythms and patient-reported outcomes for improving mFOLFIRINOX safety in patients with pancreatic cancer (MultiDom, NCT04263948)

Introduction: Circadian clocks regulate cellular proliferation and drug effects. Tolerability and/or efficacy of anticancer therapies have been improved by their administration according to circadian rhythms, while being predicted by circadian robustness. The combination of leucovorin, fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) is a standard treatment for pancreatic ductal adenocarcinoma (PDAC), that generates grades 3–4 adverse events in the majority of patients and an estimated 15%–30% emergency admission rate. The MultiDom study evaluates whether mFOLFIRINOX safety can be improved using a novel circadian-based telemonitoring-telecare platform in patients at home. The detection of early warning signals of clinical toxicities could guide their early management, possibly preventing emergency hospital admissions. Methods and analysis: This multicentre, interventional, prospective, longitudinal, single-arm study hypothesises that the mFOLFIRINOX-related emergency admission rate will be 5% (95% CI 1.7% to 13.7%), among 67 patients with advanced PDAC. Study participation is 7 weeks for each patient, including a reference week before chemotherapy onset and 6 weeks afterwards. Accelerometry and body temperature are measured q1-min using a continuously worn telecommunicating chest surface sensor, daily body weight is self-measured with a telecommunicating balance and 23 electronic patient-reported outcomes (e-PROs) are self-rated using a tablet. Hidden Markov model, spectral analyses and other algorithms automatically compute physical activity, sleep, temperature, body weight change, e-PRO severity and 12 circadian sleep/activity parameters, including the dichotomy index I<O (% activity ‘in-bed’ below median activity ‘out-of-bed’), once to four times daily. Health professionals access visual displays of near-real time parameter dynamics and receive automatic alerts, with trackable digital follow-up. Ethics and dissemination: The study has been approved by the National Agency for Medication and Health Product Safety (ANSM) and Ethics Committee West V (2 July 2019; third amendment, 14 June 2022). The data will be disseminated at conferences and in peer-reviewed journals and will support large-scale randomised evaluation. Trial registration numbers: NCT04263948 and ID RCB-2019-A00566-51

Type 2 diabetes, depressive symptoms and trajectories of cognitive decline in a national sample of community-dwellers: a prospective cohort study

We examined the individual and synergistic effects of type 2 diabetes and elevated depressive symptoms on memory and executive function trajectories over 10 and eight years of follow-up, respectively. Our sample comprised 10,524 community-dwellers aged ≥50 years in 2002±03 from the English Longitudinal Study of Ageing. With respect to memory (word recall), participants with either diabetes or elevated depressive symptoms recalled significantly fewer words compared with those free of these conditions (reference category), but more words compared with those with both conditions. There was a significant acceleration in the rate of memory decline in participants aged ≤50±64 years with both conditions (-0.27, 95% CI, -0.45 to -0.08, per study wave), which was not observed in those with either condition or aged ≥65 years. With respect to executive function (animal naming), participants aged 65 years with diabetes or those with elevated depressive symptoms named significantly fewer animals compared with the reference category, while those with both conditions named fewer animals compared with any other category. The rate of executive function decline was significantly greater in participants with both conditions (-0.54, 95% CI, -0.99 to -0.10; and ±0.71, 95% CI, -1.16 to -0.27, per study wave, for those aged 50±64 and ≥65 years, respectively), but not in participants with either condition. Diabetes and elevated depressive symptoms are inversely associated with memory and executive function, but, individually, do not accelerate cognitive decline. The co-occurrence of diabetes and elevated depressive symptoms significantly accelerates cognitive decline over time, especially among those aged 50±64 years

Determinants of Cognitive Decline in Aging : Role of Type 2 Diabetes and Antidiabetic Medications

Le déclin des performances cognitives au cours du vieillissement représente une problématique majeure dans le contexte actuel de vieillissement de la population. Le processus de vieillissement cognitif est complexe et multifactoriel. Dans la première partie de nos travaux, nous nous sommes intéressés particulièrement au rôle du diabète de type 2 dans le déclin des fonctions cognitives à partir des données longitudinales de la cohorte Whitehall II. Les performances cognitives ont été évaluées à travers une batterie de tests neuropsychologiques chez des individus âgés de 45 à 70 ans lors du premier passage de tests cognitifs. Nous avons ainsi observé que le diabète de type 2 à l'inclusion dans l'étude était associée à de moins bonnes performances cognitives et à un déclin cognitif plus important au cours du suivi, en particulier chez des patients diabétiques de type 2 de longue date. Nous avons observé une relation entre le mauvais équilibre glycémique et le déclin accéléré des fonctions cognitives. Dans la deuxième partie de ce travail de thèse, nous nous sommes intéresses au rôle potentiellement protecteur des médicaments antidiabétiques sur le déclin cognitif dans le cadre d'une méta-analyse des essais contrôles randomisés. Les résultats de la méta-analyse indiquent que le contrôle glycémique strict n'est pas associé à une diminution du risque de déclin cognitif chez les patients diabétiques de type 2. Nos résultats sont en faveur d'une contribution du diabète de type 2 diagnostiqué en milieu de vie au déclin des fonctions cognitives et participent à une meilleure compréhension de ce processus.Cognitive decline represents a major issue given the current context of population aging. The cognitive aging process is complex and multifactorial. In first part of our work, we addressed in particular the contribution of type 2 diabetes to cognitive decline, based on longitudinal data from the Whitehall 2 study. Cognitive function was assessed through a battery of neuropsychological tests in participants aged 45 to 70 years old at the beginning of cognitive testing. We observed that baseline type 2 diabetes was associated with lower cognitive performance at baseline and greater decline over follow-up, particularly in patients with longer duration of type 2 diabetes. We observed a relationship between poor glycemic control and faster cognitive decline. In second part of our work, we were interested in the potentially protective role of antidiabetic medications on cognitive decline in a meta-analysis of randomized controlled trials. The meta-analysis indicated that intensive glycemic control was not associated with slower cognitive decline. Our results support the hypothesis of a contribution of type 2 diabetes to cognitive decline in midlife and contribute to improve our understanding of this process

Déterminants du déclin cognitif au cours du vieillissement : rôle du diabète de type 2 et des médicaments antidiabétiques

Cognitive decline represents a major issue given the current context of population aging. The cognitive aging process is complex and multifactorial. In first part of our work, we addressed in particular the contribution of type 2 diabetes to cognitive decline, based on longitudinal data from the Whitehall 2 study. Cognitive function was assessed through a battery of neuropsychological tests in participants aged 45 to 70 years old at the beginning of cognitive testing. We observed that baseline type 2 diabetes was associated with lower cognitive performance at baseline and greater decline over follow-up, particularly in patients with longer duration of type 2 diabetes. We observed a relationship between poor glycemic control and faster cognitive decline. In second part of our work, we were interested in the potentially protective role of antidiabetic medications on cognitive decline in a meta-analysis of randomized controlled trials. The meta-analysis indicated that intensive glycemic control was not associated with slower cognitive decline. Our results support the hypothesis of a contribution of type 2 diabetes to cognitive decline in midlife and contribute to improve our understanding of this process.Le déclin des performances cognitives au cours du vieillissement représente une problématique majeure dans le contexte actuel de vieillissement de la population. Le processus de vieillissement cognitif est complexe et multifactoriel. Dans la première partie de nos travaux, nous nous sommes intéressés particulièrement au rôle du diabète de type 2 dans le déclin des fonctions cognitives à partir des données longitudinales de la cohorte Whitehall II. Les performances cognitives ont été évaluées à travers une batterie de tests neuropsychologiques chez des individus âgés de 45 à 70 ans lors du premier passage de tests cognitifs. Nous avons ainsi observé que le diabète de type 2 à l'inclusion dans l'étude était associée à de moins bonnes performances cognitives et à un déclin cognitif plus important au cours du suivi, en particulier chez des patients diabétiques de type 2 de longue date. Nous avons observé une relation entre le mauvais équilibre glycémique et le déclin accéléré des fonctions cognitives. Dans la deuxième partie de ce travail de thèse, nous nous sommes intéresses au rôle potentiellement protecteur des médicaments antidiabétiques sur le déclin cognitif dans le cadre d'une méta-analyse des essais contrôles randomisés. Les résultats de la méta-analyse indiquent que le contrôle glycémique strict n'est pas associé à une diminution du risque de déclin cognitif chez les patients diabétiques de type 2. Nos résultats sont en faveur d'une contribution du diabète de type 2 diagnostiqué en milieu de vie au déclin des fonctions cognitives et participent à une meilleure compréhension de ce processus

Cognitive performance declines in older adults with type 1 diabetes: results from 32 years of follow-up in the DCCT and EDIC Study

Background: With improved treatment, individuals with type 1 diabetes are living longer but there is limited information on the effects of type 1 diabetes on cognitive ability as they become older adults. We followed up individuals with type 1 diabetes to identify independent risk factors for cognitive decline as people age. Methods: 1051 participants with type 1 diabetes enrolled in the Diabetes Control and Complications Trial (DCCT) and its follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study. Participants completed cognitive assessments at baseline (median age 27 years) and 2, 5, 18, and 32 years later (median age 59). HbA1c levels, frequency of severe hypoglycaemia, non-glycemic risk factors such as elevated blood pressure, and microvascular and macrovascular complications were assessed repeatedly. We examined the effects of these on measures of memory and psychomotor and mental efficiency. These studies are registered with clinicaltrials.gov, NCT00360815 (DCCT) and NCT00360893 (EDIC). Findings: Over 32 years of follow-up, we found substantive declines in memory and psychomotor and mental efficiency. Between 18 and 32 years of follow-up, the decline in psychomotor and mental efficiency was five times larger than the change from baseline to year 18. Independent of the other risk factors and comorbidities, exposure to higher HbA1c levels, more episodes of severe hypoglycaemia, and elevated systolic blood pressure were associated with greater decrements in psychomotor and mental efficiency that was most notable by year 32 (p\u3c0·0001). The combined effect of the presence of these three risk factors is the equivalent to an additional 9·4 years of age. Interpretation: Cognitive function declines with ageing in type 1 diabetes. The association of glycaemia and blood pressure levels with cognitive decline suggests that better management might preserve cognitive function. Funding: United States National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease