New Evidence of Healthier Aging: Positive Cohort Effects on Verbal Fluency.

Background and Objectives: Cross-sectional studies have shown improvements in cognition in later-born cohorts. However, it remains unclear whether these cohort effects extend beyond cognitive levels and are also detectable in the rate of age-related cognitive decline. Additionally, evidence is scarce on the presence and consistency of cohort effects throughout different segments of the distribution of cognitive trajectories. Research Design and Methods: This study evaluates the existence and variability of cohort effects across the entire distribution of aging-related trajectories of verbal fluency. With this purpose, we develop sex and education-adjusted longitudinal norms of verbal fluency using data from 9 waves of the English Longitudinal Study of Aging (ELSA) by fitting quantile mixed models. The effect of age was modeled using splines to assess birth cohort effects, after grouping individuals in 5-year groups from 1920 to 1950 according to their age at study entry. To test for possible cohort effects across the 10th, 50th, and 90th quantiles, the coefficients associated with the splines were allowed to vary among cohorts. Results: Our results suggest that, consistently across longitudinal quantiles, decline in verbal fluency across age is less pronounced for later-born individuals (p < .001), supporting the hypothesis of cohort effects. Additionally, we also found that quantiles of verbal fluency at any age are shifted upwards in later-born cohorts compared to those in earlier-born cohorts. Discussion and Implications: These results enhance our understanding of cognitive decline in older adults by demonstrating that cohort effects on cognition are observable both cross-sectionally and longitudinally, affecting the entire range of verbal fluency trajectories.

Improving analysis of cognitive outcomes in cardiovascular trials using different statistical approaches.

BACKGROUND: The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) questionnaires are commonly used to measure global cognition in clinical trials. Because these scales are discrete and bounded with ceiling and floor effects and highly skewed, their analysis as continuous outcomes presents challenges. Normality assumptions of linear regression models are usually violated, which may result in failure to detect associations with variables of interest. METHODS: Alternative approaches to analyzing the results of these cognitive batteries include transformations (standardization, square root, or log transformation) of the scores in the multivariate linear regression (MLR) model, the use of nonlinear beta-binomial regression (which is not dependent on the assumption of normality), or Tobit regression, which adds a latent variable to account for bounded data. We aim to empirically compare the model performance of all proposed approaches using four large randomized controlled trials (ORIGIN, TRANSCEND, COMPASS, and NAVIGATE-ESUS), and using as metrics the Akaike information criterion (AIC). We also compared the treatment effects for the methods that have the same unit of measure (i.e., untransformed MLR, beta-binomial, and Tobit). RESULTS: The beta-binomial consistently demonstrated superior model performance, with the lowest AIC values among nearly all the approaches considered, followed by the MLR with square root and log transformations across all four studies. Notably, in ORIGIN, a substantial AIC reduction was observed when comparing the untransformed MLR to the beta-binomial, whereas other studies had relatively small AIC reductions. The beta-binomial model also resulted in a significant treatment effect in ORIGIN, while the untransformed MLR and Tobit regression showed no significance. The other three studies had similar and insignificant treatment effects among the three approaches. CONCLUSION: When analyzing discrete and bounded outcomes, such as cognitive scores, as continuous variables, a beta-binomial regression model improves model performance, avoids spurious significance, and allows for a direct interpretation of the actual cognitive measure. TRIALS REGISTRATION: ORIGIN (NCT00069784). Registered on October 1, 2003; TRANSCEND (NCT00153101). Registered on September 9, 2005; COMPASS (NCT01776424). Registered on January 24, 2013; NAVIGATE-ESUS (NCT02313909). Registered on December 8, 2014.

Persistent delirium is associated with cerebrospinal fluid markers of neuronal injury.

Delirium is associated with the risk of future long-term cognitive impairment, but the degree to which markers of neuronal injury may be distinct or shared with dementia has yet to be comprehensively described. We investigated CSF biomarkers of dementia, astrocytosis and neuronal damage in a clinical cohort with persistent delirium, comparing them with an outpatient memory clinic sample. Our aim was to determine if different patterns of biomarker changes could implicate specific mechanisms for delirium-related neuronal injury over and above that attributable to comorbid dementia. We recruited 35 participants from the Prince of Wales Hospital, Sydney, Australia. We included inpatients with delirium persisting for at least 5 days (n = 15, 10 with underlying dementia) and participants from outpatient memory clinics (n = 20, 17 with dementia). CSF assays were as follows: amyloid-ß42, amyloid-ß40, phosphorylated tau181, neurofilament light chain and glial fibrillary acidic protein. We used propensity score matching to estimate effect sizes for each standardized CSF biomarker separately for persistent delirium (irrespective of underlying dementia) and dementia (irrespective of superimposed delirium). Compared with individuals without delirium, persistent delirium was associated with elevated glial fibrillary acidic protein (normalized coefficient per transformed standard deviation, ß = 0.85; 95% confidence interval: 0.03-1.68) and neurofilament light chain (ß = 1.1; 95% confidence interval: 0.5-1.6), but not phosphorylated tau181. Compared with individuals without dementia, glial fibrillary acidic protein, neurofilament light chain and phosphorylated tau181 were all increased to expected levels in dementia cases, with the former two biomarkers at levels comparable to those seen in persistent delirium [glial fibrillary acidic protein (ß = 1.54; 95% confidence interval: 1.05-2.0) and neurofilament light chain (ß = 0.65; 95% confidence interval: 0.24-1.1)]. Persistent delirium was linked with changes in CSF biomarkers not necessarily attributable to dementia. These findings support the potential that delirium is associated with direct neuronal injury independent of dementia pathophysiology. Whether this neuronal injury involves astrocyte dysfunction or direct axonal damage are both possibilities. Future work examining acute brain injury in delirium is needed.

Differences in Grey Matter Concentrations and Functional Connectivity between Young Carriers and Non-Carriers of the APOE ε4 Genotype.

Background: The pathophysiology of Alzheimer's disease (AD) may begin developing years or even decades prior to the manifestation of its first symptoms. The APOE ε4 genotype is a prominent genetic risk for AD that has been found to be associated with brain changes across the lifespan since early adulthood. Thus, studying brain changes that may occur in young adults with an APOE ε4 status is highly relevant. Objective: Examine potential differences in grey matter (GM) and functional connectivity (FC) in brains of cognitively healthy young APOE ε4 carriers and non-carriers, denoted here as ε4(+) and ε4(-), respectively. Methods: Three Tesla magnetic resonance imaging (MRI) brain scans were acquired from cognitively healthy young participants aged approximately 20 years (n = 151). Voxel-based morphometry (VBM) analysis was employed to identify potential structural differences in GM between ε4(+) and ε4(-). In a subsequent seed-based connectivity (SBC) analysis, brain regions that structurally differed in the VBM analysis were considered as seeds and correlated with all the remaining voxels across the brains to then measure the differences in FC between groups. Results: The VBM analysis suggested that ε4(+) (n = 28) had greater GM densities relative to ε4(-) (n = 123) in the left hippocampus and the left posterior insula (puncorr < 0.001). However, the effect did not survive the correction for multiple comparisons, suggesting minimal structural differences in this age range. In contrast, the SBC analysis indicated that ε4(+) exhibited significantly decreased FC between the left hippocampus and areas of the left middle temporal gyrus (n = 27) compared to ε4(-) (n = 102). These results remained significant after multiple comparisons (pFDR < 0.05). Lastly, no statistically significant differences in FC between groups were observed for the left insular seed (pFDR > 0.05). Discussion: These results suggest early structural and functional brain changes associated with the APOE ε4 genotype on young adults. Yet, they must be cautiously interpreted and contrasted with both older adults with genetic risk for AD and patients diagnosed with AD.

The association between selenium status and global and attention-specific cognition in very old adults in the Newcastle 85+ Study: cross-sectional and longitudinal analyses.

BACKGROUND: Selenium has potential safeguarding properties against cognitive decline, because of its role in protecting DNA, proteins, and lipids in the brain from oxidative damage. However, acute and chronic overexposure to selenium can be neurotoxic. OBJECTIVE: The aim of this analysis was to explore the association between selenium status [serum selenium and selenoprotein P (SELENOP) concentrations and glutathione peroxidase 3 (GPx3) activity] and cognitive function in 85-y olds living in Northeast England at baseline and ≤5 y of follow-up. METHODS: Global cognitive performance was assessed in 755 participants from the Newcastle 85+ study using the standardized Mini-Mental State Examination and attention-specific cognition was assessed using composite scores derived from the Cognitive Drug Research System. Serum selenium, SELENOP, and GPx3 activity were measured at baseline by total reflection X-ray fluorescence, enzyme-linked immunosorbent assay, and coupled-enzyme reaction, respectively. Regression analyses explored linear and nonlinear associations between continuous values and tertiles of selenium status biomarkers, respectively, and cognitive function at baseline. Generalized linear mixed models explored associations between continuous values and tertiles of selenium status biomarkers, and global cognitive decline over 5 y, and attention-specific cognitive decline over 3 y. RESULTS: Over 3 and 5 y, none of the selenium biomarkers were associated with the rate of cognitive decline. At baseline, in fully adjusted models, higher serum selenium was nonlinearly associated with global cognition (ß = 0.05 ± 0.01, P = 0.387 linear, ß = 0.04 ± 0.01, P = 0.002 nonlinear). SELENOP and GPx3 activity were not associated with any cognitive outcomes. CONCLUSIONS: There were no associations between selenium status and cognitive decline. However, serum selenium, but not SELENOP or GPx3 activity, was positively associated nonlinearly with global cognition at baseline. Furthermore, these associations were not evident during follow-up, potentially because of residual confounding and reverse causation.

Cardiovascular risk of dementia is associated with brain-behaviour changes in cognitively healthy, middle-aged individuals.

Alzheimer's Disease (AD) neuropathology start decades before clinical manifestations, but whether risk factors are associated with early cognitive and brain changes in midlife remains poorly understood. We examined whether AD risk factors were associated with cognition and functional connectivity (FC) between the Locus Coeruleus (LC) and hippocampus - two key brain structures in AD neuropathology - cross-sectionally and longitudinally in cognitively healthy midlife individuals. Neuropsychological assessments and functional Magnetic Resonance Imaging were obtained at baseline (N=210), and two-years follow-up (N=188). Associations of cognition and FC with apolipoprotein ε4 (APOE ε4) genotype, family history of dementia, and the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score were investigated. Cross-sectionally, higher CAIDE scores were associated with worse cognition. Menopausal status interacted with the CAIDE risk on cognition. Furthermore, the CAIDE score significantly moderated the relationship between cognition and LC-Hippocampus FC. Longitudinally, the LC-Hippocampus FC decreased significantly over 2 years. These results suggest that cardiovascular risk of dementia is associated with brain-behaviour changes in cognitively healthy, middle-aged individuals.

Association of optic disc pallor and RNFL thickness with cerebral small vessel disease in the PREVENT-Dementia study.

INTRODUCTION: We tested associations between two retinal measures (optic disc pallor, peripapillary retinal nerve fiber layer [pRNFL] thickness) and four magnetic resonance imaging markers of cerebral small vessel disease (SVD; lacunes, microbleeds, white matter hyperintensities, and enlarged perivascular spaces [ePVSs]). METHODS: We used PallorMetrics to quantify optic disc pallor from fundus photographs, and pRNFL thickness from optical coherence tomography scans. Linear and logistic regression assessed relationships between retinal measures and SVD markers. Participants (N = 108, mean age 51.6) were from the PREVENT Dementia study. RESULTS: Global optic disc pallor was linked to ePVSs in the basal ganglia in both left (ß = 0.12, standard error [SE] = 0.05, P < 0.05) and right eyes (ß = 0.13, SE = 0.05, P < 0.05). Associations were also noted in different disc sectors. No pRNFL associations with SVD markers were found. DISCUSSION: Optic disc pallor correlated with ePVSs in the basal ganglia, suggesting retinal examination may be a useful method to study brain health changes related to SVD. Highlights: Optic disc pallor is linked to enlarged perivascular spaces in basal ganglia.There is no association between peripapillary retinal nerve fiber layer thickness and cerebral small vessel disease markers.Optic disc examination could provide insights into brain health.The sample included 108 midlife adults from the PREVENT Dementia study.

Neuroimaging and Clinical Findings in Healthy Middle-Aged Adults With Mild Traumatic Brain Injury in the PREVENT Dementia Study.

Importance: Traumatic brain injuries (TBI) represent an important, potentially modifiable risk factor for dementia. Despite frequently observed vascular imaging changes in individuals with TBI, the relationships between TBI-associated changes in brain imaging and clinical outcomes have largely been overlooked in community cases of TBI. Objective: To assess whether TBI are associated with and interact with midlife changes in neuroimaging and clinical features in otherwise healthy individuals. Design, Setting, and Participants: This cross-sectional analysis used baseline data from the PREVENT Dementia program collected across 5 sites in the UK and Ireland between 2014 and 2020. Eligible participants were cognitively healthy midlife adults aged between 40 and 59 years. Data were analyzed between January 2023 and April 2024. Exposure: Lifetime TBI history was assessed using the Brain Injury Screening Questionnaire. Main Outcomes and Measures: Cerebral microbleeds and other markers of cerebral small vessel disease (white matter hyperintensities [WMH], lacunes, perivascular spaces) were assessed on 3T magnetic resonance imaging. Clinical measures were cognition, sleep, depression, gait, and cardiovascular disease (CVD) risk, assessed using Computerized Assessment of Information Processing (COGNITO), Pittsburgh Sleep Quality Index, Center for Epidemiologic Studies Depression Scale, clinical interviews, and the Framingham Risk Score, respectively. Results: Of 617 participants (median [IQR] age, 52 [47-56] years; 380 female [61.6%]), 223 (36.1%) had a history of TBI. TBI was associated with higher microbleed count (ß = 0.10; 95% CI, 0.01-0.18; P = .03), with a dose-response association observed with increasing number of TBI events (ß = 0.05; 95% CI, 0.01-0.09; P = .03). Conversely, TBI was not associated with other measures of small vessel disease, including WMH. Furthermore, TBI moderated microbleed associations with vascular risk factors and clinical outcomes, such that associations were present only in the absence of TBI. Importantly, observations held when analyses were restricted to individuals reporting only mild TBI. Conclusions and Relevance: In this cross-sectional study of healthy middle-aged adults, detectable changes in brain imaging and clinical features were associated with remote, even mild, TBI in the general population. The potential contribution of vascular injury to TBI-related neurodegeneration presents promising avenues to identify potential targets, with findings highlighting the need to reduce TBI through early intervention and prevention in both clinical care and policymaking.

Older caregivers' depressive symptomatology over time: evidence from the Survey of Health, Ageing and Retirement in Europe.

The prevalence of informal caregiving is increasing as populations across the world age. Caregiving has been found to be associated with poor mental health outcomes including depressive symptoms. The purpose of this study is to examine the mean trajectory of depressive symptomatology in older caregivers in a large European sample over an eight-year period, the effects of time-varying and time-invariant covariates on this trajectory, and the mean trajectory of depressive symptomatology according to pattern of caregiving. The results suggest that depressive symptoms in the full sample of caregivers follow a nonlinear trajectory characterized by an initial decrease which decelerates over time. Caregiver status and depressive symptoms were significantly associated such that depressive symptoms increased as a function of caregiver status. The trajectory in caregivers who report intermittent or consecutive occasions of caregiving remained stable over time. Significant associations were found between sociodemographic, health and caregiving characteristics and the initial levels and rates of change of these trajectories. While these results point to the resilience of caregivers, they also highlight the factors that are related to caregivers' adaptation over time. This can help in identifying individuals who may require greater supports and, in turn, ensuring that caregivers preserve their well-being.

Texture-based morphometry in relation to apolipoprotein ε4 genotype, ageing and sex in a midlife population.

Brain atrophy and cortical thinning are typically observed in people with Alzheimer's disease (AD) and, to a lesser extent, in those with mild cognitive impairment. In asymptomatic middle-aged apolipoprotein ε4 (ΑPOE4) carriers, who are at higher risk of future AD, study reports are discordant with limited evidence of brain structural differences between carriers and non-carriers of the ε4 allele. Alternative imaging markers with higher sensitivity at the presymptomatic stage, ideally quantified using typically acquired structural MRI scans, would thus be of great benefit for the detection of early disease, disease monitoring and subject stratification. In the present cross-sectional study, we investigated textural properties of T1-weighted 3T MRI scans in relation to APOE4 genotype, age and sex. We pooled together data from the PREVENT-Dementia and ALFA studies focused on midlife healthy populations with dementia risk factors (analysable cohort: 1585 participants; mean age 56.2 ± 7.4 years). Voxel-based and texture (examined features: contrast, entropy, energy, homogeneity) based morphometry was used to identify areas of volumetric and textural differences between APOE4 carriers and non-carriers. Textural maps were generated and were subsequently harmonised using voxel-wise COMBAT. For all analyses, APOE4, sex, age and years of education were used as model predictors. Interactions between APOE4 and age were further examined. There were no group differences in regional brain volume or texture based on APOE4 carriership or when age × APOE4 interactions were examined. Older people tended to have a less homogeneous textural profile in grey and white matter and a more homogeneous profile in the ventricles. A more heterogeneous textural profile was observed for females in areas such as the ventricles, frontal and parietal lobes and for males in the brainstem, cerebellum, precuneus and cingulate. Overall, we have shown the absence of volumetric and textural differences between APOE4 carriers and non-carriers at midlife and have established associations of textural features with ageing and sex.

Demographic factors associated with within-individual variability of lung function for adults with cystic fibrosis: A UK registry study.

BACKGROUND: Lung function is a key outcome used in the evaluation of disease progression in cystic fibrosis. The variability of individual lung function measurements over time (within-individual variability) has been shown to predict subsequent lung function changes. Nevertheless, the association between within-individual lung function variability and demographic and genetic covariates has not been quantified. METHODS: We performed a longitudinal analysis of data from a cohort of 7099 adults with cystic fibrosis (between 18 and 49 years old) from the UK cystic fibrosis registry, containing annual review data between 1996 and 2020. A mixed-effects location-scale model is used to quantify mean FEV1 (forced expiratory volume in 1 s) trajectories and FEV1 within-individual variability as a function of sex, age at annual review, diagnosis after first year of life, homozygous F508 genotype and birth cohort. RESULTS: Mean FEV1 decreased with age and lung function variability showed a near-quadratic trend by age. Males showed higher FEV1 mean and variability than females across the whole age range. Earlier diagnosis and homozygous F508 genotype were also associated with higher FEV1 mean and variability. Individuals who died during follow-up showed on average higher lung function variability than those who survived. CONCLUSIONS: Key variables known to be linked with mean lung function in cystic fibrosis are also associated with an individual's lung function variability. This work opens new avenues to understand the role played by lung function variability in disease progression and its utility in predicting key outcomes such as mortality.

The Flynn effect and cognitive decline among americans aged 65 years and older.

To contribute to our understanding of cohort differences and the Flynn effect in the cognitive decline among older Americans, this study aims to compare rates of cognitive decline between two birth cohorts within a study of older Americans and to examine the importance of medical and demographic confounders. Analyses used data from the National Health and Aging Trends Study (2011-2019), which recruited older Americans in 2011 and again in 2015 who were then followed for 5 years. We employed mixed-effect models to examine the linear and quadratic main and interaction effects of year of birth while adjusting for covariates such as annual round, sex/gender, education, race/ethnicity, heart disease, hypertension, diabetes, test unfamiliarity, and survey design. We analyzed data from 11,167 participants: 7,325 from 2011 to 2015 and 3,842 from 2015 to 2019. The cohort recruited in 2015 was born, on average, 5.33 years later than that recruited in 2011 and had higher functioning than the one recruited in 2011 across all observed cognitive domains that persisted after adjusting for covariates. In multivariable-adjusted analyses, a 1-year increase in year of birth was associated with increased episodic memory (ß = 0.045, SE = 0.001, p < .001), orientation (ß = 0.034, SE = 0.001, p < .001), and executive function (ß = 0.036, SE = 0.001, p < .001). Participants born 1 year later had slower rates of decline in episodic memory (ß = 0.004, SE = 0.000, p < .001), orientation (ß = 0.003, SE = 0.000, p < .001), and executive function (ß = 0.001, SE = 0.000, p = .002). Additionally, sex/gender modified this relationship for episodic memory (-0.007, SE = 0.002, p < .001), orientation (-0.005, SE = 0.002, p = .008), and executive function (-0.008, SE = 0.002, p < .001). These results demonstrate the persistence of the Flynn effect in old age across cognitive domains and identified a deceleration in the rate of cognitive decline across cognitive domains. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Healthy lifestyle and cognitive decline in middle-aged and older adults residing in 14 European countries.

Studies examining lifestyle and cognitive decline often use healthy lifestyle indices, making it difficult to understand implications for interventions. We examined associations of 16 lifestyles with cognitive decline. Data from 32,033 cognitively-healthy adults aged 50-104 years participating in prospective cohort studies of aging from 14 European countries were used to examine associations of lifestyle with memory and fluency decline over 10 years. The reference lifestyle comprised not smoking, no-to-moderate alcohol consumption, weekly moderate-plus-vigorous physical activity, and weekly social contact. We found that memory and fluency decline was generally similar for non-smoking lifestyles. By contrast, memory scores declined up to 0.17 standard deviations (95% confidence interval= 0.08 - 0.27) and fluency scores up to 0.16 standard deviations (0.07 - 0.25) more over 10 years for those reporting smoking lifestyles compared with the reference lifestyle. We thus show that differences in cognitive decline between lifestyles were primarily dependent on smoking status.

Towards a lifelong personalized brain health program: empowering individuals to define, pursue, and monitor meaningful outcomes.

Incorporating person-centered outcomes into clinical trials for neurodegenerative diseases has been challenging due to a deficiency in quantitative measures. Meanwhile, the integration of personally meaningful treatment targets in clinical practice remains qualitative, failing to truly inform evaluations, therapeutic interventions and longitudinal monitoring and support. We discuss the current advances and future directions in capturing individualized brain health outcomes and present an approach to integrate person-centered outcome in a scalable manner. Our approach stems from the evidence-based electronic Person-Specific Outcome Measure (ePSOM) program which prompts an individual to define personally meaningful treatment priorities and report level of confidence in managing items that matter to the individual the most (e.g., "Do I feel confident in my ability to contribute to a conversation?"). Deployed either as a single version (person only) or a dyad version (person and care partner), our proposed tool could be used as an endpoint in clinical trials, offering proof of meaningful intervention benefits and in clinical practice, by establishing an anchor for the therapeutic objectives sought by the individual.

The PREVENT dementia programme: baseline demographic, lifestyle, imaging and cognitive data from a midlife cohort study investigating risk factors for dementia.

PREVENT is a multi-centre prospective cohort study in the UK and Ireland that aims to examine midlife risk factors for dementia and identify and describe the earliest indices of disease development. The PREVENT dementia programme is one of the original epidemiological initiatives targeting midlife as a critical window for intervention in neurodegenerative conditions. This paper provides an overview of the study protocol and presents the first summary results from the initial baseline data to describe the cohort. Participants in the PREVENT cohort provide demographic data, biological samples (blood, saliva, urine and optional cerebrospinal fluid), lifestyle and psychological questionnaires, undergo a comprehensive cognitive test battery and are imaged using multi-modal 3-T MRI scanning, with both structural and functional sequences. The PREVENT cohort governance structure is described, which includes a steering committee, a scientific advisory board and core patient and public involvement groups. A number of sub-studies that supplement the main PREVENT cohort are also described. The PREVENT cohort baseline data include 700 participants recruited between 2014 and 2020 across five sites in the UK and Ireland (Cambridge, Dublin, Edinburgh, London and Oxford). At baseline, participants had a mean age of 51.2 years (range 40-59, SD ± 5.47), with the majority female (n = 433, 61.9%). There was a near equal distribution of participants with and without a parental history of dementia (51.4% versus 48.6%) and a relatively high prevalence of APOEɛ4 carriers (n = 264, 38.0%). Participants were highly educated (16.7 ± 3.44 years of education), were mainly of European Ancestry (n = 672, 95.9%) and were cognitively healthy as measured by the Addenbrookes Cognitive Examination-III (total score 95.6 ± 4.06). Mean white matter hyperintensity volume at recruitment was 2.26 ± 2.77 ml (median = 1.39 ml), with hippocampal volume being 8.15 ± 0.79 ml. There was good representation of known dementia risk factors in the cohort. The PREVENT cohort offers a novel data set to explore midlife risk factors and early signs of neurodegenerative disease. Data are available open access at no cost via the Alzheimer's Disease Data Initiative platform and Dementia Platforms UK platform pending approval of the data access request from the PREVENT steering group committee.

A call for caution when using network methods to study multimorbidity: an illustration using data from the Canadian Longitudinal Study on Aging.

OBJECTIVES: To examine the impact of two key choices when conducting a network analysis (clustering methods and measure of association) on the number and type of multimorbidity clusters. STUDY DESIGN AND SETTING: Using cross-sectional self-reported data on 24 diseases from 30,097 community-living adults aged 45-85 from the Canadian Longitudinal Study on Aging, we conducted network analyses using 5 clustering methods and 11 association measures commonly used in multimorbidity studies. We compared the similarity among clusters using the adjusted Rand index (ARI); an ARI of 0 is equivalent to the diseases being randomly assigned to clusters, and 1 indicates perfect agreement. We compared the network analysis results to disease clusters independently identified by two clinicians. RESULTS: Results differed greatly across combinations of association measures and cluster algorithms. The number of clusters identified ranged from 1 to 24, with a low similarity of conditions within clusters. Compared to clinician-derived clusters, ARIs ranged from -0.02 to 0.24, indicating little similarity. CONCLUSION: These analyses demonstrate the need for a systematic evaluation of the performance of network analysis methods on binary clustered data like diseases. Moreover, in individual older adults, diseases may not cluster predictably, highlighting the need for a personalized approach to their care.

The Mediterranean diet is not associated with neuroimaging or cognition in middle-aged adults: a cross-sectional analysis of the PREVENT dementia programme.

BACKGROUND AND PURPOSE: The Mediterranean diet (MedDiet) has been associated with reduced dementia incidence in several studies. It is important to understand if diet is associated with brain health in midlife, when Alzheimer's disease and related dementias are known to begin. METHODS: This study used data from the PREVENT dementia programme. Three MedDiet scores were created (the Pyramid, Mediterranean Diet Adherence Screener [MEDAS] and MEDAS continuous) from a self-reported food frequency questionnaire. Primary outcomes were hippocampal volume and cube-transformed white matter hyperintensity volume. Secondary outcomes included cornu ammonis 1 and subiculum hippocampal subfield volumes, cortical thickness and measures of cognition. Sex-stratified analyses were run to explore differential associations between diet and brain health by sex. An exploratory path analysis was conducted to study if any associations between diet and brain health were mediated by cardiovascular risk factors for dementia. RESULTS: In all, 504 participants were included in this analysis, with a mean Pyramid score of 8.10 (SD 1.56). There were no significant associations between any MedDiet scoring method and any of the primary or secondary outcomes. There were no differences by sex in any analyses and no significant mediation between the Pyramid score and global cognition by cardiovascular risk factors. CONCLUSIONS: Overall, this study did not find evidence for an association between the MedDiet and either neuroimaging or cognition in a midlife population study. Future work should investigate associations between the MedDiet and Alzheimer's disease and related dementias biomarkers as well as functional neuroimaging in a midlife population.

Investigating the brain's neurochemical profile at midlife in relation to dementia risk factors.

Changes in the brain's physiology in Alzheimer's disease are thought to occur early in the disease's trajectory. In this study our aim was to investigate the brain's neurochemical profile in a midlife cohort in relation to risk factors for future dementia using single voxel proton magnetic resonance spectroscopy. Participants in the multi-site PREVENT-Dementia study (age range 40-59 year old) underwent 3T magnetic resonance spectroscopy with the spectroscopy voxel placed in the posterior cingulate/precuneus region. Using LCModel, we quantified the absolute concentrations of myo-inositol, total N-acetylaspartate, total creatine, choline, glutathione and glutamate-glutamine for 406 participants (mean age 51.1; 65.3% female). Underlying partial volume effects were accounted for by applying a correction for the presence of cerebrospinal fluid in the magnetic resonance spectroscopy voxel. We investigated how metabolite concentrations related to apolipoprotein ɛ4 genotype, dementia family history, a risk score (Cardiovascular Risk Factors, Aging and Incidence of Dementia -CAIDE) for future dementia including non-modifiable and potentially-modifiable factors and dietary patterns (adherence to Mediterranean diet). Dementia family history was associated with decreased total N-acetylaspartate and no differences were found between apolipoprotein ɛ4 carriers and non-carriers. A higher Cardiovascular Risk Factors, Aging, and Incidence of Dementia score related to higher myo-inositol, choline, total creatine and glutamate-glutamine, an effect which was mainly driven by older age and a higher body mass index. Greater adherence to the Mediterranean diet was associated with lower choline, myo-inositol and total creatine; these effects did not survive correction for multiple comparisons. The observed associations suggest that at midlife the brain demonstrates subtle neurochemical changes in relation to both inherited and potentially modifiable risk factors for future dementia.

Visit-to-visit variability in multiple biological measurements and cognitive performance and risk of cardiovascular disease: A cohort study.

Background: Visit-to-visit variability in single biological measurements has been associated with cognitive decline and an elevated risk of cardiovascular diseases (CVD). However, the effect of visit-to-visit variability in multiple biological measures is underexplored. We investigated the effect of visit-to-visit variability in blood pressure (BP), heart rate (HR), weight, fasting plasma glucose, cholesterol, and triglycerides on cognitive performance and CVD. Methods: Data on BP, HR, weight, glucose, cholesterol, and triglycerides from study visits in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were used to estimate the association between visit-to-visit variability, cognitive performance (Mini Mental State Examination (MMSE) score) and CVD (non-fatal stroke, non-fatal myocardial infarction, or cardiovascular death). Visit-to-visit variation for each measurement was estimated by calculating each individuals visit-to-visit standard deviation for that measurement. Participants whose standard deviation was in the highest quarter were classified as having high variation. Participants were grouped into those having 0, 1, 2, 3, or ≥ 4 high variation measurements. Regression and survival models were used to estimate the association between biological measures with MMSE and CVD with adjustment for confounders and mean measurement value. Results: After adjustment for covariates, higher visit-to-visit variability in BP, HR, weight, and FPG were associated with poorer MMSE and a higher risk of CVD. Effect sizes did not vary greatly by measurement. The effects of high visit-to-visit variability were additive; compared to participants who had no measurements with high visit-to-visit variability, those who had high visit-to-visit variability in ≥4 measurements had poorer MMSE scores (-0.63 (95 % CI -0.96 to -0·31). Participants with ≥4 measurements with high visit-to-visit variability compared to participants with none had higher risk of CVD (hazard ratio 2.46 (95 % CI 1.63 to 3.70). Conclusion: Visit-to-visit variability in several measurements were associated with cumulatively poorer cognitive performance and a greater risk of CVD.