Redefining effect size interpretations for psychotherapy RCTs in depression.

INTRODUCTION: Effect sizes are often used to interpret the magnitude of a result and in power calculations when planning research studies. However, as effect size interpretations are context-dependent, Jacob Cohen's suggested guidelines for what represents a small, medium, and large effect are unlikely to be suitable for a diverse range of research populations and interventions. Our objective here is to determine empirically-derived effect size thresholds associated with psychotherapy randomized controlled trials (RCTs) in depression by calculating the effect size distribution. METHODS: We extracted effect sizes from 366 RCTs provided by the systematic review of Cuijpers and colleagues (2020) on psychotherapy for depressive disorders across all age groups. The 50th percentile effect size, as this represents a medium effect size, and the 25th (small) and 75th (large) percentile effect sizes were calculated to determine empirically-derived effect size thresholds. RESULTS: After adjusting for publication bias, 0.27, 0.53, and 0.86 represent small, medium, and large effect sizes, respectively, for psychotherapy treatment for depressive disorders. DISCUSSION: The effect size distribution for psychotherapy treatment of depression indicates that observed effect size thresholds are larger than Cohen's suggested effect size thresholds (0.2, 0.5, and 0.8). These results have implications for the interpretation of study effects and the planning of future studies via power analyses, which often use effect size thresholds.

No association between metformin initiation and incident dementia in older adults newly diagnosed with diabetes.

BACKGROUND: Metformin has been suggested to reduce dementia risk; however, most epidemiologic studies have been limited by immortal time bias or confounding due to disease severity. OBJECTIVES: To investigate the association of metformin initiation with incident dementia using strategies that mitigate these important sources of bias. METHODS: Residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered this retrospective population-based cohort. To consider the indication for metformin monotherapy initiation, people with hemoglobin A1c of 6.5%-8.0% and estimated glomerular filtration rate ≥45 mL/min/1.73 m2 were selected. Using the landmark method to address immortal time bias, exposure was grouped into "metformin monotherapy initiation within 180 days after new diabetes diagnosis" or "no glucose-lowering medications within 180 days." To address disease latency, 1-year lag time was applied to the end of the 180-day landmark period. Incident dementia was defined using a validated algorithm for Alzheimer's disease and related dementias. Adjusted hazard ratios (aHR) and confidence intervals (CIs) were estimated from propensity-score weighted Cox proportional hazard models. RESULTS: Over mean follow-up of 6.77 years from cohort entry, metformin initiation within 180 days after new diabetes diagnosis (N = 12,331; 978 events; 65,762 person-years) showed no association with dementia risk (aHR [95% CI] = 1.05 [0.96-1.15]), compared to delayed or no glucose-lowering medication initiation (N = 22,369; 1768 events; 117,415 person-years). CONCLUSION: Early metformin initiation was not associated with incident dementia in older adults newly diagnosed with diabetes. The utility of metformin to prevent dementia was not supported.

A mixture model for differentiating longitudinal courses of multiple sclerosis.

BACKGROUND: Multiple sclerosis has a broad spectrum of clinical courses. Early identification of patients at greater risk of accumulating disability is essential. OBJECTIVES: Identify groups of patients with similar presentation through a mixture model and predict their trajectories over the years. METHODS: Retrospective study of patients from 1994 to 2019. We performed a latent profile analysis followed by a latent transition analysis based on eight parameters: age, disease duration, EDSS, number of relapses, multi-topographic symptoms, motor impairment, sphincter impairment, and infratentorial lesions. RESULTS: We included 629 patients, regardless of the phenotypical classification. We identified three distinct groups at the beginning and end of the follow-up. The three-classes model disclosed the "No disability regardless disease duration" (NDRDD) class with low EDSS and younger patients, the "Disability within a short disease duration" (DSDD) class with the worse disability besides short illness, and the "Disability within a long disease duration" (DLDD) class that achieved high EDSS over a long disease duration. EDSS, disease duration, and no sphincter impairment had the best entropy to distinguish classes at the initial presentation. Over time, the patients from NDRDD had a 52.1 % probability of changing to DLDD and 7.7 % of changing to DSDD. CONCLUSIONS: We identified three groups of clinical presentations and their evolution over time based on considered prognostic factors. The most likely transition is from NDRDD to DLDD.

Sexual dimorphism in anxiety is programmed in-utero by sex-steroids: Proof of concept using a disease-model and stress responses to COVID pandemic.

Sex differences in the psychological impact of the COVID-19 pandemic have been consistently reported, showing disproportionally high rates of anxiety/distress in women relative to men. The mechanisms underlying this sexual dimorphism remain unclear. The present study queries the potential protective role of early hyperandrogenism on brain development. A natural model of sex-steroids abnormality, classic congenital adrenal hyperplasia (CAH), was used to test this question. CAH is characterized by adrenal androgen overproduction in utero (prenatal) through the neonatal critical developmental period. An online survey collected information on subjective responses to the COVID-19 pandemic. Matched on demographic variables, 60 adults carrying a diagnosis of classic CAH and 240 adults from the general population (non-CAH) were compared on levels of anxiety/distress in the first year of the COVID-19 pandemic (May 2020-April 2021). Structural Equation Modeling was used to test the modulation by CAH status of Sex effects on anxiety/distress. Results revealed lower levels of anxiety/distress in the female CAH group compared to the other 3 groups (male CAH, female non-CAH, and male non-CAH). This finding suggests that pre-neonatal hyperandrogenism might impact the development of neural circuits underlying anxiety processes, in a way that enhances resilience to chronic stress.

Perivascular spaces mediate a relationship between diabetes and other cerebral small vessel disease markers in cerebrovascular and neurodegenerative diseases.

Type 2 diabetes mellitus (T2DM) and hypertension are risk factors for cerebral small vessel disease (SVD); however, few studies have characterised their relationships with MRI-visible perivascular spaces (PVS). MRI was used to quantify deep (d) and periventricular (p) white matter hyperintensities (WMH), lacunes, PVS in the white matter (wmPVS) or basal ganglia (bgPVS), and diffusion metrics in white matter. Patients with T2DM had greater wmPVS volume and there were greater wmPVS volumes in patients with T2DM and hypertension together. Counterfactual moderated mediation models found indirect effects of T2DM on volumes of other SVD and diffusion markers that were mediated by wmPVS: pWMH, dWMH, periventricular lacunes, and deep lacunes, and progression of deep lacunes over 1 year, in patients with hypertension, but not in patients without hypertension. Studying the regulation of cortical perivascular fluid dynamics may reveal mechanisms that mediate the impact of T2DM on cerebral small vessels.

Social jetlag is associated with adverse cardiometabolic latent traits in early adolescence: an observational study.

Introduction: Adolescence is marked by physiological and social changes, such as puberty, increased responsibilities and earlier school start times. This often leads to insufficient sleep on school nights and the need to compensate for lost sleep on weekends, causing a misalignment between biological and social times, which has been termed social jetlag (SJL). SJL triggers stress responses and is associated with several negative health outcomes, including higher cardiometabolic risk in adults. In adolescence, however, SJL has only been consistently related to increases in adiposity but its association with other cardiometabolic indicators are unclear. Method: In a sample of 278 healthy early adolescents (9-15 years of age; 168 girls) we investigated: 1) whether self-reported SJL is associated (using path analyses) with a cardiometabolic status latent factor obtained by testing the best fitting model via confirmatory factor analyses from an initial set of eight indicators [body mass index (BMI), waist/height ratio, triglyceride concentration, diastolic and systolic blood pressure, glycated hemoglobin, total cholesterol/high-density lipoprotein ratio (chol/HDL), and % body fat]; and 2) whether age and/or pubertal status influence the association between SJL and cardiometabolic status. Result: We found that, for girls, higher SJL was associated with more adverse cardiometabolic latent scores (the shared variance of BMI, waist/height ratio, chol/HDL and systolic blood pressure, which had acceptable model fit indices). However, the role of age and pubertal status in this association was unclear for both sexes. Discussion: SJL was associated with adverse cardiometabolic latent traits beyond increases in adiposity in this observational study in early female adolescents. Because disruptions of circadian rhythms are believed to lead to dysregulated energy homeostasis and not vice-versa, our findings highlight the need for sleep interventions in adolescence to help reduce the global burden of cardiometabolic ill health, especially in girls.

Cut-off point, sensitivity and specificity for screening the reading fluency in children. / Pontos de corte, sensibilidade e especificidade para rastreamento da fluência leitora em crianças.

PURPOSE: to establish cut-off point for reading speed and accuracy, to obtain minimum values for comprehending texts, and allow classifying students from 2nd to 5th grade of elementary school according to good or poor reading performance. METHODS: 147 assessment protocols for oral reading and text comprehension of students from 3rd to 5th grade of Elementary School with and without reading difficulties were analyzed. The oral text reading rate and accuracy values were analyzed. ROC curves were constructed, and sensitivity and specificity calculated for each reading fluency parameter, and each school grade. RESULTS: Sensitivity and specificity for measures of rate and accuracy in text reading were calculated for the 3rd, 4th, and 5th grades. Rate and precision under the ROC curve did not differ statistically. The values for the 2nd grade were mathematically estimated. CONCLUSION: The cutoff values expected for students from 2nd to 3rd grade were identified, with recommendations for using the oral text reading rate for reading comprehension screening procedures.

OBJETIVO: estabelecer pontos de corte para valores de velocidade e acurácia de leitura, a fim de obter valores mínimos para compreensão de textos, e permitir classificar alunos de 2º a 5º ano do Ensino Fundamental, de acordo com bom ou pobre desempenho em leitura. MÉTODO: foram analisados ​​147 protocolos de avaliação de leitura oral e compreensão textual de escolares de 3º a 5º ano com e sem dificuldades de leitura. A taxa de leitura oral de texto e os valores de acurácia foram analisados. Curvas ROC foram construídas e a sensibilidade e a especificidade, calculadas para cada parâmetro de fluência de leitura por ano escolar. RESULTADOS: A sensibilidade e a especificidade para medidas de taxa e acurácia na leitura de texto foram calculadas para o 3º, 4º e 5º anos. A taxa e a precisão sob a curva ROC não diferiram estatisticamente. Os valores do 2º ano foram estimados matematicamente. CONCLUSÃO: Foram identificados os valores de corte esperados para escolares do 2º ao 5º ano, com recomendações de utilização da taxa de leitura de texto oral para procedimentos de rastreamento da compreensão leitora.

Evaluating the Feasibility of Emotion Expressions in Avatars Created From Real Person Photos: Pilot Web-Based Survey of Virtual Reality Software.

BACKGROUND: The availability and potential of virtual reality (VR) has led to an increase of its application. VR is suggested to be helpful in training elements of social competence but with an emphasis on interventions being tailored. Recognizing facial expressions is an important social skill and thus a target for training. Using VR in training these skills could have advantages over desktop alternatives. Children with autism, for instance, appear to prefer avatars over real images when assessing facial expressions. Available software provides the opportunity to transform profile pictures into avatars, thereby giving the possibility of tailoring according to an individual's own environment. However, the emotions provided by such software should be validated before application. OBJECTIVE: Our aim was to investigate whether available software is a quick, easy, and viable way of providing emotion expressions in avatars transformed from real images. METHODS: A total of 401 participants from a general population completed a survey on the web containing 27 different images of avatars transformed, using a software, from real images. We calculated the reliability of each image and their level of difficulty using a structural equation modeling approach. We used Bayesian confirmatory factor analysis testing under a multidimensional first-order correlated factor structure where faces showing the same emotions represented a latent variable. RESULTS: Few emotions were correctly perceived and rated as higher than other emotions. The factor loadings indicating the discrimination of the image were around 0.7, which means 49% shared variance with the latent factor that the face is linked with. The standardized thresholds indicating the difficulty level of the images are mostly around average, and the highest correlation is between faces showing happiness and anger. CONCLUSIONS: Only using a software to transform profile pictures to avatars is not sufficient to provide valid emotion expressions. Adjustments are needed to increase faces' discrimination (eg, increasing reliabilities). The faces showed average levels of difficulty, meaning that they are neither very difficult nor very easy to perceive, which fits a general population. Adjustments should be made for specific populations and when applying this technology in clinical practice.

Establishing new cutoffs for Cohen's d: An application using known effect sizes from trials for improving sleep quality on composite mental health.

OBJECTIVE: Cohen's d conventional effect size cutoffs [small (0.2), medium (0.5), and large (0.8)] might not be representative of the reported distribution of effect sizes across the different areas of health. Effect size cutoffs might vary not only depending on the area of research, but also on the type of intervention and population. That is, they are context dependent. Therefore, we present strategies to redefine small, medium, and large effect size based on 25, 50, and 75th percentile, respectively. METHODS: We illustrate these techniques applying them to 72 effect sizes, derived from 65 randomized controlled trials described in a recent meta-analysis (10.1016/j.smrv.2021.101556) of improving sleep quality on composite mental health. Such percentiles are equally distanced from the average effect size as suggested by Jacob Cohen and checked for potential attenuation effects (via weight selection model) and outliers (via OutRules). RESULTS: new cutoffs for effect size distribution of -0.177, -0.329, and -0.557, for small, medium, and large effect size were found, respectively. applying Cohen's effect size thresholds (0.2, 0.5, and 0.8) for trials of improving sleep quality on composite mental health might over-estimate effect sizes compared to the real-world context, especially around medium and large effect sizes.

Association of sulfonylureas with the risk of dementia: A population-based cohort study.

BACKGROUND: Sulfonylureas are oral glucose-lowering medications positioned as a second-line therapy for type 2 diabetes. Evidence relating them to cognitive decline has been mixed. The objective was to determine whether sulfonylurea use was associated with a differential risk of dementia compared with dipeptidyl peptidase-4 (DPP4) inhibitor use. METHODS: Using administrative data from residents in Ontario, Canada, adults aged ≥66 years who were new users of a sulfonylurea or a DPP4 inhibitor from June 14, 2011, to March 31, 2021 entered this population-based retrospective cohort study. Dementia was ascertained using a validated algorithm for Alzheimer's disease and related dementias. Propensity-score weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and confidence intervals (CI) for time to incident dementia. The observation window started at 1 year after cohort entry to mitigate protopathic bias due to delayed diagnosis. The primary analysis used an intention-to-treat exposure definition. A separate propensity-score weighted analysis was conducted to explore within-class differences in dementia risk among sulfonylurea new users selected from the primary cohort. RESULTS: Among 107,806 DPP4 inhibitor new users and 37,030 sulfonylurea new users, sulfonylureas compared with DPP4 inhibitors were associated with a higher risk of dementia (18.4/1000 person-years; aHR [95% CI] = 1.09 [1.04-1.15]) over a mean follow-up of 4.82 years from cohort entry. Glyburide compared to gliclazide exhibited a higher dementia risk (aHR [95% CI] = 1.17 [1.03-1.32]). CONCLUSION: New use of a sulfonylurea especially glyburide was associated with a higher dementia risk compared with new use of a DPP4 inhibitor in older adults with diabetes.

State, trait, and accumulated features of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) in mild Alzheimer's disease.

Background: The Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog) is used to assess decline in memory, language, and praxis in Alzheimer's disease (AD). Methods: A latent state-trait model with autoregressive effects was used to determine how much of the ADAS-Cog item measurement was reliable, and of that, how much of the information was occasion specific (state) versus consistent (trait or accumulated from one visit to the next). Results: Participants with mild AD (n = 341) were assessed four times over 24 months. Praxis items were generally unreliable as were some memory items. Language items were generally the most reliable, and this increased over time. Only two ADAS-Cog items showed reliability >0.70 at all four assessments, word recall (memory) and naming (language). Of the reliable information, language items exhibited greater consistency (63.4% to 88.2%) than occasion specificity, and of the consistent information, language items tended to reflect effects of AD progression that accumulated from one visit to the next (35.5% to 45.3%). In contrast, reliable information from praxis items tended to come from trait information. The reliable information in the memory items reflected more consistent than occasion-specific information, but they varied between items in the relative amounts of trait versus accumulated effects. Conclusions: Although the ADAS-Cog was designed to track cognitive decline, most items were unreliable, and each item captured different amounts of information related to occasion-specific, trait, and accumulated effects of AD over time. These latent properties complicate the interpretation of trends seen in ordinary statistical analyses of trials and other clinical studies with repeated ADAS-Cog item measures. Highlights: Studies have described unfavorable psychometric properties of the Alzheimer's Disease Assessment Scale Cognitive Subscale (ADAS-Cog), bringing into question its ability to track changes in cognition uniformly over time. There remains a need to estimate how much of the ADAS-Cog measurement is reliable, of that how much is occasion specific versus consistent, and of the consistent information, how much represents enduring traits versus autoregressive effects (i.e., effects of Alzheimer's disease [AD] progression carried over from one assessment to the next).A latent state-trait model with autoregressive effects in mild AD found most items to be unreliable, and each item to capture different amounts of occasion-specific, trait, and autoregressive information. Language items, specifically, naming and the memory item word recall, were the most reliable.Psychometric idiosyncrasies of individual items complicate the interpretation of their summed score, biasing ordinary statistical analyses of repeated measures in mild AD. Future studies should consider item trajectories individually.

Moving Forward to a World Beyond 0.2, 0.5, and 0.8 Effects Sizes: New Cutoffs for School-Based Anti-Bullying Interventions.

Effect sizes of school-based intervention are commonly described as small to moderate when using Cohen's conventional effect size cutoffs (small [0.2], medium [0.5], and large [0.8]). However, Jacob Cohen's rule of thumb might vary across different areas of research, nature of the intervention, and population, because effect sizes are context-dependent. Moreover, when planning research studies, minimum detectable effect sizes are used to calculate the sample size. In the present study, we investigate whether conventional effect size cutoffs (small [0.2], medium [0.5], and large [0.8]) represent the reported distribution of effect sizes in school-based anti-bullying intervention. To determine small, medium, and large effect sizes, we calculated the effect size distribution (ESD) using 50th percentile effect size (medium effect) of the distributions of effect sizes provided by a recent meta-analysis on school-based anti-bullying intervention. Also, the 25th and 75th percentile effects, as they are equidistant from the average effect size, were used redefining small and large effects, respectively. Results showed that 0.07, 0.123, and 0.227 represent small, medium, and large effect sizes in anti-bullying interventions. Our results indicate that Cohen's suggested effect size thresholds (0.2, 0.5, and 0.8) overestimate effect sizes when compared to the real-world context of school based anti-bullying interventions. We also propose sample sizes required to reliably detect small, medium, and large percentile effect sizes in anti-bullying interventions.

Bullying as a Risk Factor for Eating Disorder Behaviors Among Students: Secondary Analysis for a Cluster Randomized Controlled Trial.

This study aimed to examine whether being a victim of bullying predicted body dissatisfaction and eating disorder behavior (EDB). In this study, we performed secondary analysis from a cluster randomized controlled trial among 5208 eight grade students from 73 public schools in three Brazilian cities. Data were collected in 2019 through an anonymous self-report questionnaire on bullying, body dissatisfaction, and EDB. We used factor analysis, multivariate linear regression, and multinomial logistic regression to verify whether being a victim of bullying during the baseline results in body dissatisfaction and EDB at the nine months follow-up for the control and intervention groups. Our results showed that being female (OR 1.41, 95% CI 1.22-1.63) is a risk factor for dissatisfaction by overweight. Bullying was not a predictor of body dissatisfaction; however, being a victim of bullying (ß 0.40, 95% CI 0.35-0.46) is a predictor of having more EDB, independent of the exposure to the program. Therefore, bullying deserves attention in the school environment.

Does #Tamojunto alter the dynamic between drug use and school violence among youth? Secondary analysis from a large cluster-randomized trial.

The present study investigated how intervention might alter the relationship between perpetrating violence and later drug use. A cluster-randomized controlled trial design involving 72 schools (38 intervention, 34 control) and 6390 students attending grades 7 and 8 was employed in Brazil. Drug use and violence were assessed at three points. A random-intercept cross-lagged panel model examined the reciprocal association between drug use and school violence domains across the three data collection waves. For both groups, we found that the cross-lagged effect of perpetration on further drug use in adolescents was stronger than the reverse, but the interrelationship was not statistically significant between #Tamojunto and control schools. The carry-over effects of drug use and violence were also not significantly different between groups. There is a lack of evidence showing that #Tamojunto can modify the dynamics between drug use and school violence across the 21-month period. The direction of the causal effect (i.e., the more perpetration behavior, the more subsequent drug use behavior) is present, but weak in both groups. The trial registration protocol at the national Brazilian Register of Clinical Trials (REBEC) is #RBR-4mnv5g.

Adolescent depression beyond DSM definition: a network analysis.

Calls for refining the understanding of depression beyond diagnostic criteria have been growing in recent years. We examined the prevalence and relevance of DSM and non-DSM depressive symptoms in two Brazilian school-based adolescent samples with two commonly used scales, the Patient Health Questionnaire (PHQ-A) and the Mood and Feelings Questionnaire (MFQ). We analyzed cross-sectional data from two similarly recruited samples of adolescents aged 14-16 years, as part of the Identifying Depression Early in Adolescence (IDEA) study in Brazil. We assessed dimensional depressive symptomatology using the PHQ-A in the first sample (n = 7720) and the MFQ in the second sample (n = 1070). We conducted network analyses to study symptom structure and centrality estimates of the two scales. Additionally, we compared centrality of items included (e.g., low mood, anhedonia) and not included in the DSM (e.g., low self-esteem, loneliness) in the MFQ. Sad mood and worthlessness items were the most central items in the network structure of the PHQ-A. In the MFQ sample, self-hatred and loneliness, two non-DSM features, were the most central items and DSM and non-DSM items in this scale formed a highly interconnected network of symptoms. Furthermore, analysis of the MFQ sample revealed DSM items not to be more frequent, severe or interconnected than non-DSM items, but rather part of a larger network of symptoms. A focus on symptoms might advance research on adolescent depression by enhancing our understanding of the disorder.

Vascular burden and cognition: Mediating roles of neurodegeneration and amyloid PET.

It remains unclear to what extent cerebrovascular burden relates to amyloid beta (Aß) deposition, neurodegeneration, and cognitive dysfunction in mixed disease populations with small vessel disease and Alzheimer's disease (AD) pathology. In 120 subjects, we investigated the association of vascular burden (white matter hyperintensity [WMH] volumes) with cognition. Using mediation analyses, we tested the indirect effects of WMH on cognition via Aß deposition (18 F-AV45 positron emission tomography [PET]) and neurodegeneration (cortical thickness or 18 F fluorodeoxyglucose PET) in AD signature regions. We observed that increased total WMH volume was associated with poorer performance in all tested cognitive domains, with the strongest effects observed for semantic fluency. These relationships were mediated mainly via cortical thinning, particularly of the temporal lobe, and to a lesser extent serially mediated via Aß and cortical thinning of AD signature regions. WMH volumes differentially impacted cognition depending on lobar location and Aß status. In summary, our study suggests mainly an amyloid-independent pathway in which vascular burden affects cognitive function via localized neurodegeneration. HIGHLIGHTS: Alzheimer's disease often co-exists with vascular pathology. We studied a unique cohort enriched for high white matter hyperintensities (WMH). High WMH related to cognitive impairment of semantic fluency and executive function. This relationship was mediated via temporo-parietal atrophy rather than metabolism. This relationship was, to lesser extent, serially mediated via amyloid beta and atrophy.

Factors that influence morningness-eveningness and daytime sleepiness: A cross-cultural comparison of Iranian and Brazilian adolescents.

As adolescents get older, they become more evening oriented and, because they are usually expected to wake early to attend school, they often present daytime sleepiness, which is associated with negative outcomes. It is still unclear if this is similar cross-culturally. Here, we studied morningness-eveningness and daytime sleepiness in early adolescence from two different developing nations (Brazil and Iran). A total sample of 697 Iranian and Brazilian early adolescents (9- to 15-year-old; 358 boys) from Tehran, Iran, and São Paulo, Brazil, varying in age and parental schooling (a proxy of socioeconomic status: SES) completed the Morningness-Eveningness Scale for Children (MESC) and the Pediatric Daytime Sleepiness Scale (PDSS) and reported their total sleep time on school nights. They also filled in the Pubertal Developmental Scale to determine their pubertal status. A negligible cross-cultural difference in morningness-eveningness was found, indicating that Brazilians showed a slight circadian-phase delay compared with Iranians throughout all tested ages. There was also seen a very slight increase in phase delay as early adolescents aged, indicative of more eveningness. However, there were no country differences in daytime sleepiness once total sleep time during school nights was controlled for, which was the only factor that affects PDSS scores.

Cardiovascular Risk Factors and Risk of Alzheimer Disease and Mortality: A Latent Class Approach.

Background Cardiovascular risk factors co-occur with one another, and little is known about the extent of their clustering and risk of Alzheimer disease (AD). We identify groups of cardiovascular risk factors in cognitively normal individuals and investigate between-group differences in incident AD and death. Methods and Results Cognitively normal individuals were recruited from the National Alzheimer's Coordinator Center. A latent class analysis was conducted with hypertension, hypercholesterolemia, heart condition, stroke, smoking history, diabetes, and high body mass index. Between-group differences in the incidence of AD, mortality, and mortality-adjusted AD were investigated. This study included 12 412 cognitively normal individuals (average follow-up, 65 months). Three groups were identified: (1) low probabilities of cardiovascular risk factors (reference; N=5398 [43%]), (2) hypertension and hypercholesterolemia (vascular-dominant; N=5721 [46%]), and (3) hypertension, hypercholesterolemia, diabetes, and high body mass index (vascular-metabolic; N=1293 [10%]). Both vascular groups were significantly older, had more men, were slightly less educated, and were slightly more cognitively impaired than the reference group (all P<0.05). However, only the vascular-metabolic group had a significantly younger age of death compared with the reference group (84.3 versus 88.7 years, P<0.001). Only the vascular-dominant group had a greater incidence of AD (odds ratio [OR], 1.30; P<0.001) compared with the reference group. Mortality was greater in the vascular-dominant (OR, 3.26; P<0.001) and vascular-metabolic groups (OR, 1.84; P=0.02). Mortality-adjusted AD was greater in the vascular-dominant (OR, 1.54; P=0.02) and vascular-metabolic groups (OR, 1.46; P=0.04). Conclusions Three distinct cardiovascular risk factor groups were identified in cognitively normal elderly individuals. Only the vascular-dominant group was associated with a greater incidence of AD. Selective mortality may contribute to the attenuated association between the vascular-metabolic group and incident AD.

Dynamic relationships between depressive symptoms and insulin resistance over 20 years of adulthood.

BACKGROUND: Bidirectional longitudinal relationships between depression and diabetes have been observed, but the dominant direction of their temporal relationships remains controversial. METHODS: The random-intercept cross-lagged panel model decomposes observed variables into a latent intercept representing the traits, and occasion-specific latent 'state' variables. This permits correlations to be assessed between the traits, while longitudinal 'cross-lagged' associations and cross-sectional correlations can be assessed between occasion-specific latent variables. We examined dynamic relationships between depressive symptoms and insulin resistance across five visits over 20 years of adulthood in the population-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Possible differences based on population group (Black v. White participants), sex and years of education were tested. Depressive symptoms and insulin resistance were quantified using the Center for Epidemiologic Studies Depression (CES-D) scale and the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. RESULTS: Among 4044 participants (baseline mean age 34.9 ± 3.7 years, 53% women, 51% Black participants), HOMA-IR and CES-D traits were weakly correlated (r = 0.081, p = 0.002). Some occasion-specific correlations, but no cross-lagged associations were observed overall. Longitudinal dynamics of these relationships differed by population groups such that HOMA-IR at age 50 was associated with CES-D score at age 55 (ß = 0.076, p = 0.038) in White participants only. Longitudinal dynamics were consistent between sexes and based on education. CONCLUSIONS: The relationship between depressive symptoms and insulin resistance was best characterized by weak correlations between occasion-specific states and enduring traits, with weak evidence that insulin resistance might be temporally associated with subsequent depressive symptoms among White participants later in adulthood.

Association of Sodium-Glucose Cotransporter 2 Inhibitors With Time to Dementia: A Population-Based Cohort Study.

OBJECTIVE: Type 2 diabetes (T2D) increases dementia risk, but clear evidence to recommend interventions that can mitigate that risk remains lacking. This population-based retrospective cohort study aimed to determine whether new use of sodium-glucose cotransporter 2 (SGLT2) inhibitors compared with dipeptidyl peptidase 4 (DPP-4) inhibitors was associated with lower dementia risk. RESEARCH DESIGN AND METHODS: Ontario residents aged ≥66 years who were new users of an SGLT2 inhibitor or a DPP-4 inhibitor from 1 July 2016 to 31 March 2021 entered the cohort. Incident dementia was identified using a validated algorithm for Alzheimer's disease and related dementias. Propensity score-weighted Cox proportional hazards models were used to obtain adjusted hazard ratios (aHR) and CIs for time to incident dementia. To address reverse causality and disease latency, the observation window started at 1-year lag time from cohort entry. The primary analysis followed intention-to-treat exposure definition, and a secondary as-treated analysis was performed. RESULTS: Among 106,903 individuals, SGLT2 inhibitors compared with DPP-4 inhibitors were associated with lower risk of dementia (14.2/1,000 person-years; aHR 0.80 [95% CI 0.71-0.89]) over a mean follow-up of 2.80 years from cohort entry. When stratified by different SGLT2 inhibitors, dapagliflozin exhibited the lowest risk (aHR 0.67 [95% CI 0.53-0.84]), followed by empagliflozin (aHR 0.78 [95% CI 0.69-0.89]), whereas canagliflozin showed no association (aHR 0.96 [95% CI 0.80-1.16]). The as-treated analysis observed a larger association (aHR 0.66 [95% CI 0.57-0.76]) than the intention-to-treat analysis. CONCLUSIONS: SGLT2 inhibitors showed an association with lower dementia risk in older people with T2D. Randomized controlled trials are warranted.