Cognitive Decline In Later Life Research Articles

EXAMINING THE IMPACT OF CARDIOVASCULAR RISK FACTORS ON NEUROPSYCHIATRIC SYMPTOMS IN THE PACT-MD STUDY

Introduction Although cardiovascular risk factors (CVRFs) have been identified as important risk factors for both major depression and cognitive decline in later life, their association with neuropsychiatric symptoms (NPS) has not been fully elucidated. Furthermore, CVRFs, particularly hypertension, hypercholesterolemia, and diabetes, may ultimately lead to physical conditions such as small vessel disease known to disrupt cognition, thereby leading to the onset of NPS. Thus, a better understanding of the association between CVRFs and NPS could improve the development of treatments and preventative measures for NPS. Methods Using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study, a multi-site intervention study targeting older patients with depression and cognitive decline, we analysed the distribution of CVRFs (Framingham risk scores; Hachinski ischemic score; presence of hypertension, hypercholesterolemia, hyperlipidemia, diabetes, and smoking) in patients with and without NPS as determined by a score of 1 and above or 0 on the Neuropsychiatric Inventory-Questionnaire (NPI-Q). Participants fell into one of the following three diagnosis groups: Mild Cognitive Impairment (MCI) with a lifetime history of major depression (MDD); MCI without MDD; and MDD without MCI. Comparisons of distributions of CVRFs between NPI positive and negative groups were conducted using the non-parametric Mann-Whitney U test at a significance level of Results In a combined sample of 140 participants, there were no significant differences in any CVRF between positive and negative total NPI groups. However, some NPI subscale scores, notably agitation/aggression, anxiety, disinhibition, irritability, and night-time behaviour were significantly associated with increased CVRFs (p Conclusions None of the CVRFs were associated with overall total NPI-Q scores, however, these preliminary analyses suggest that some specific CVRFs were associated with certain NPI-Q subdomains. This suggests that CVRFs contribute to specific NPS domains rather than overall NPS burden. This research was funded by This project has been made possible by Brain Canada through the Canada Brain Research Fund, with the financial support of Health Canada and the Chagnon Family.

Education and Cognition in Middle Age and Later Life: The Mediating Role of Physical and Cognitive Activity.

Although educational attainment is related to cognitive function in later life, little is known about the mechanisms involved. This study assessed the independent mediating effects of two behavioral variables, physical and cognitive activity, on the association between educational attainment and cognitive function and change. Data were derived from the three waves of the Midlife in the United States (MIDUS) study. Predictors (educational attainment) were from the 1995 baseline, mediators (physical and cognitive activities) were from the 2004 wave, and outcomes (cognitive function) were from the 2004 and 2013 waves. Conditional process modeling was applied using PROCESS in SPSS. There were both direct and indirect effects of educational attainment on level and change of executive function (EF) and episodic memory (EM). Physical activity and cognitive activity were both significant mediators for cognitive level. For mediators of change, however, cognitive activity was significant for EF and physical activity was significant for EM. Physical and cognitive activity are discussed as possible factors for protecting against cognitive decline in later life. The findings have implications for advancing supportive policies and practices related to maximizing the benefits of education and physical and cognitive activities for cognition in middle age and later life.

Plasma Lipids, Apolipoproteins, and Subsequent Cognitive Decline in Men with Coronary Heart Disease.

Lipid levels are associated with an increased risk of cardiovascular disease. We investigated the association between plasma lipids, apolipoproteins levels, apolipoprotein B/low-density lipoprotein cholesterol (Apo-B/LDL-C), and Apo-B/Apo-A ratios and rate of cognitive decline two decades later in men with coronary heart disease (CHD). A subset of 337 men (mean age at baseline 56.6±6.4 years) who previously participated in the Bezafibrate Infarction Prevention (BIP) trial (1990-1997) underwent cognitive evaluations 15±3 years (T1) and 19.9±1 years after baseline (T2) as part of the BIP Neurocognitive study. Lipid and apolipoprotein fractions were measured at baseline. Cognitive function for memory, executive function, visual spatial, attention domains, and composite score were assessed using the NeuroTrax Computerized Battery at T1 and T2 evaluations. Linear mixed models were used to assess change in cognitive function between the two cognitive evaluations. Controlling for confounders, the decline in composite cognitive score (β= -0.161±0.06; p = 0.013) as well as in memory (β= -0.269±0.10; p = 0.009) and visual spatial function (β= -0.304±0.12; p = 0.010) was greater among patients in the upper (≥105 mg/dL) Apo-B tertile as compared to counterparts with < 105 mg/dL. The decline in the composite cognitive score (β= -0.124±0.06; p = 0.043) was also greater among patients in the estimated LDL-C≥160 mg/dL group compared to counterparts with LDL-C<160 mg/dL. Upper tertile of Apo-B/LDL-C ratio (≥0.75) compared to the lower tertiles was significantly associated with change in memory score (β= -0.210±0.10; p = 0.041). Our findings suggest that the plasma concentrations of Apo-B, LDL-C, and Apo-B/LDL-C ratio are potential predictors of accelerated late-life cognitive decline among men with CHD.

Lifestyle Patterns as a Modifiable Risk Factor for Late-life Cognitive Decline: A Narrative Review Regarding Dementia Prevention.

Dementias due to neurodegenerative disorders and more specifically, Alzheimer's disease (AD) are the most frequent of all diseases within the industrialized world. Besides this alarming fact, it is noted too that almost three-quarter of people with AD reside in low or middle- income nations. In recent years, cognitive and behavioral neuroscientists have focused on a possible correlation between environmental agents and genetic risk factors for these dementias. In this narrative review, a close review of Medical Literature Analysis and Retrieval System was conducted. The authors aimed at analyzing possible interactions between lifestyle patterns and major risk factors responsible for cognitive decline and dementia, considering that the prevention or treatment of midlife modifiable risks may possibly reduce population-wide late-life pathological neurodegeneration. This review focuses on modifiable risk factors for late-life cognitive decline. A growing number of studies have indicated that the impact of genetics and epigenetic factors on dementia risk is dependent on different lifestyle factors, ranging from leisure activities and nutritional habits, through to social interaction and toxic exposure. Despite all evidence regarding modifiable risk factors possibly reducing the risk of developing dementia in later life, many unanswered questions remain regarding the direct influence of these variables in later life. People who regularly and actively participate in different lifelong activities (social, cultural and intellectual) do tend to perform better on formal cognitive tests, experience fewer cognitive complaints, and are less likely to develop neurodegenerative disorders.

Influence of young adult cognitive ability and additional education on later-life cognition

How and when education improves cognitive capacity is an issue of profound societal importance. Education and later-life education-related factors, such as occupational complexity and engagement in cognitive-intellectual activities, are frequently considered indices of cognitive reserve, but whether their effects are truly causal remains unclear. In this study, after accounting for general cognitive ability (GCA) at an average age of 20 y, additional education, occupational complexity, or engagement in cognitive-intellectual activities accounted for little variance in late midlife cognitive functioning in men age 56-66 (n = 1009). Age 20 GCA accounted for 40% of variance in the same measure in late midlife and approximately 10% of variance in each of seven cognitive domains. The other factors each accounted for <1% of the variance in cognitive outcomes. The impact of these other factors likely reflects reverse causation-namely, downstream effects of early adult GCA. Supporting that idea, age 20 GCA, but not education, was associated with late midlife cortical surface area (n = 367). In our view, the most parsimonious explanation of our results, a meta-analysis of the impact of education, and epidemiologic studies of the Flynn effect is that intellectual capacity gains due to education plateau in late adolescence/early adulthood. Longitudinal studies with multiple cognitive assessments before completion of education would be needed to confirm this speculation. If cognitive gains reach an asymptote by early adulthood, then strengthening cognitive reserve and reducing later-life cognitive decline and dementia risk may really begin with improving educational quality and access in childhood and adolescence.

Working Life Psychosocial Conditions in Relation to Late-Life Cognitive Decline: APopulation-Based Cohort Study.

While the importance of working conditions on cognitive function has been tentatively suggested previously, few studies have considered cumulative effects of exposure throughout the working life. We examined the association between job demand-control status and late-life cognitive decline, taking into account exposure durations. In the population-based cohort study, Swedish National Study on Aging and Care-Kungsholmen, 2,873 dementia-free participants aged 60+ were followed up to nine years. Cognitive function was measured using the Mini-Mental State Examination. The entire working life was outlined through interview and occupations were graded with a psychosocial job-exposure matrix. Multivariate linear mixed-effects models were used. Slower cognitive decline was observed among people with high job control (β: 0.10, 95% CI: 0.03, 0.19) and demands (β: 0.15, 95% CI: 0.07, 0.22) in the longest-held job. Compared to active job, faster decline was shown in low strain (β: - 0.17, 95% CI: - 0.26, - 0.08), high strain (β: - 0.13, 95% CI: - 0.24, - 0.03), and passive job (β: - 0.22, 95% CI: - 0.34, - 0.11). Longer duration of active jobs was associated with slower cognitive decline (β: 0.24, 95% CI: 0.16, 0.32), whereas faster decline was associated with longer durations of low strain (β: - 0.12, 95% CI: - 0.19, - 0.05), high strain (β: - 0.13, 95% CI: - 0.21, - 0.04), and passive jobs (β: - 0.12, 95% CI: - 0.20, - 0.04). In conclusion, not only psychologically stressful jobs, but also low-stimulating and passive jobs are associated with faster cognitive decline in later life. Duration of exposure may play a role in the psychosocial working condition-cognitive decline association.

Intellectual engagement and cognitive ability in later life (the “use it or lose it” conjecture): longitudinal, prospective study

ObjectivesTo examine the association between intellectual engagement and cognitive ability in later life, and determine whether the maintenance of intellectual engagement will offset age related cognitive decline.DesignLongitudinal, prospective, observational study.SettingNon-clinical...

SIRT3 deficiency-induced mitochondrial dysfunction and inflammasome formation in the brain

SIRT3, the primary mitochondrial deacetylase, plays a significant role in enhancing the function of mitochondrial proteins. Downregulation of SIRT3 is a key component of metabolic syndrome, a precondition for obesity, diabetes and cardiovascular diseases. In this study, we examined the effects of brain mitochondrial protein hyperacetylation in western diet-fed Sirt3−/− mice, a model for metabolic syndrome. Brain mitochondrial proteins were hyperacetylated, following western diet feeding and Sirt3 deletion. To identity these hyperacetylated proteins, we performed a comprehensive acetylome analysis by label-free tandem mass spectrometry. Gene ontology pathway analysis revealed Sirt3 deletion-mediated downregulation of enzymes in several metabolic pathways, including fatty acid oxidation and tricarboxylic acid cycle. Mitochondrial respiration was impaired at multiple states, along with lower levels of mitochondrial fission proteins Mfn1 and Mfn2. Cleavage of procaspase-1 suggested inflammasome formation. Assembly of inflammasomes with caspase-1 and NLRP3 was detected as shown by proximity ligation assay. Markers of neuroinflammation including microgliosis and elevated brain IL-1β expression were also observed. Importantly, these findings were further exacerbated in Sirt3−/− mice when fed a calorie-rich western diet. The observations of this study suggest that SIRT3 deficiency-induced brain mitochondrial dysfunction and neuroinflammation in metabolic syndrome may play a role in late-life cognitive decline.

Responses to executive demand in young adulthood differ by APOE genotype

Despite evidence of a relationship between Apolipoprotein E (APOE) ε4+ and later-life cognitive decline, the lifespan effects of carrying an ε4+ allele on cognitive ageing are not well understood. Evidence of ε4+ advantages in early-life are inconsistent, but not inconsiderable. We explored the proposal that APOE ε4+ cognitive advantages arise only in response to complex and sensitive tasks targeting specific executive functions. We systematically manipulated executive demand within verbal fluency, decision-making, prospective memory, and sustained attention tasks. Participants aged 18–25 years (21 ε4+, 63 ε33) also completed a measure of subjective effort. Under low executive demand, ε4+ made fewer verbal fluency word repeats compared to ε33 carriers. Under high executive demand, ε4+ showed lower costs associated with performing concurrent tasks, greater switching errors, and more verbal fluency root repetition errors. Overall, ε4+ appeared to be showing working memory updating advantages under conditions of low executive demand, more effective resource allocation under elevated levels of executive demand, and errors indicating different strategy use compared to ε33 carriers, including speed-accuracy trade-offs.

THE ASSOCIATION BETWEEN BDNF POLYMORPHISM AND BIOMARKERS OF STRESS IN MIDDLE AGED AND OLDER ADULTS

Stress exposure over the lifespan is robustly associated with accelerated cognitive decline in late life. Researchers continue to investigate factors that determine individual differences in stress physiology. Brain derived neurotrophic factor is found to associate with cognitive trajectory in late life, and the Met allele of the functional Val66Met BDNF gene has been found to associate with poorer episodic memory and executive functioning in late life. The objective of this study was to evaluate the association between BDNF polymorphism and indices of stress among adults aged 50+. Community dwelling middle aged and older adults provided a blood sample for BDNF genotyping. Participants also sampled their saliva five times a day over three consecutive days for measurement of diurnal cortisol and underwent the Trier Social Stress Test (TSST) for measurement of stress reactivity. Among 120 adults aged 50–67 (83% female, 89% Caucasian), 73 participants were Val/Val carriers and 47 carried one copy of the Met allele (45 Val/Met, 2 Met/Met carriers). Val/Val and Met carriers did not differ on any demographic factors. Repeated measures analyses did not reveal an association between BDNF genotype and diurnal salivary cortisol (p=.63); however, analyses revealed that Met carriers displayed a blunted cortisol response to the TSST compared with Val/Val carriers, F(9, 936)=2.09, p=.03. This is the first study to evaluate the role of BDNF polymorphism in stress physiology among middle-aged and older adults. Future studies are needed to evaluate lifespan interconnections between BDNF, stress physiology and cognitive function.

Cataract surgery and age-related cognitive decline: A 13-year follow-up of the English Longitudinal Study of Ageing.

BackgroundVisual impairment has been associated with lower cognitive ability among older adults, yet little is known about whether improving visual function with cataract surgery would be associated with slower cognitive decline. This study aimed to assess whether trajectories of cognitive decline differed before and after cataract surgery and compare those trajectories between older adults with cataract surgery and without cataract.Methods and findingsData were drawn from the English Longitudinal Study of Ageing (ELSA) Wave 1 (2002/03) until Wave 7 (2014/15). The study population consisted of 2,068 individuals who underwent cataract surgery between Wave 2 and Wave 6 as the treatment group and 3,636 individuals with no cataract as the control group. We included only respondents who took part in a minimum three waves. Propensity score matching method was used to match the individuals in the treatment group with those in the control group. After we put an “artificial” intervention point for the individuals in the control group at the point that the matched person has cataract surgery, spline method was used to identify differences in cognitive trajectories pre- and post-cataract surgery. In the treatment group, we found that cataract surgery was positively associated with episodic memory scores after controlling for the potential covariates (β = 4.23, p<0.001). Episodic memory scores declined with older age, but the decline in episodic memory scores was slower after cataract surgery (β = -0.05, p<0.001) than before cataract surgery (β = -0.1, p<0.001). Although the episodic memory among respondents in the control group before intervention (β = -0.08, p<0.001) declined slower than those in the intervention group (β = -0.1, p<0.001), the declines in episodic memory scores were similar in both groups after the intervention (control: β = -0.05, p<0.001; intervention: β = -0.05, p<0.001).ConclusionsCataract surgery may have a positive impact on trajectories of cognitive decline in later life. Further research is required to identify the mechanism to explain the association between cataract surgery and cognitive ageing, and whether early intervention towards vision correction results in a reduction in dementia risk.

Public knowledge of late-life cognitive decline and dementia in an international sample

One method of mitigating global increases in dementia prevalence involves assessing public knowledge and then educating laypeople. We measured knowledge of late-life pathological cognitive decline in a diverse, international sample using a standardized, validated instrument.Research design and methods: We assessed 3619 international respondents recruited through Amazon's Mechanical Turk with a 44-item dementia knowledge survey and 18 sociodemographic items. Results suggested that the following sociodemographic variables are associated with less overall knowledge: young age, male gender, low educational attainment, born in a developing nation, of ethnic minority status, not married, and less prior dementia experience. Specific knowledge gaps emerged in cerebrovascular disease, delirium versus dementia, treatment of behavioral dementia symptoms, Alzheimer's disease genetics, Parkinson's disease symptoms, and characteristics of chronic traumatic encephalopathy and subjective cognitive decline.Discussion and implications: Findings may facilitate effective multinational dementia education initiatives by providing specific recommendations as to which sociodemographic populations and content knowledge domains will benefit the most from limited resources.

Reading Habits Among Older Adults in Relation to Level and 15-Year Changes in Verbal Fluency and Episodic Recall.

The main objective of this study was to investigate reading habits in older adults in relation to level and 15-year changes in verbal fluency and episodic recall. We examined a sample of 1157 participants (≥55 years at baseline) up to 15 years after the baseline assessment using latent growth curve modeling of cognitive measures with baseline reading frequency (books, weekly magazines) as a predictor of cognitive level (intercept) and rate of change (slope). Subgroup analyses were performed to investigate the role of an early adult g factor in the association between reading habits and cognitive ability in midlife. Frequent reading of books, but not of magazines, was associated with higher levels of verbal fluency and recall but unrelated to rate of longitudinal decline. Subgroup analyses indicated that the g factor in early adulthood predicted reading and cognitive level in midlife and this factor removed the current association between reading habits and level of cognitive ability (both cognitive factors). The results indicate an enduring relationship between book reading and level of cognitive ability across the adult life span and provide little support of the hypothesis that frequent reading protects against late-life cognitive decline. The extent to which book reading promotes cognitive functioning in childhood/youth remains to be demonstrated. Intervention studies may be useful in this regard.

The effect of midlife cardiovascular risk factors on white matter hyperintensity volume and cognition two decades later in normal ageing women

Cerebral White Matter Hyperintensity (WMH) lesions have been identified as markers of cerebrovascular diseases and they are associated with increased risk of cognitive impairment. In this study, we investigated the relationship between midlife cardiovascular risk factors and late life WMH volumes two decades later, and examined their association with cognitive performance. 135 participants from the Women's Healthy Ageing Project had completed midlife cardiovascular risk measurement in 1992 and late life brain MRI scan and cognitive assessment in 2012. In these community-dwelling normal aging women, we found that higher midlife Framingham Cardiovascular Risk Profile (FCRP) score was associated with greater WMH volume two decades later, and was predominantly driven by the impact of HDL cholesterol level, controlling for age, education and APOE ε4 status. Structural equation modelling demonstrated that the relationship between midlife FCRP score and late life executive function was mediated by WMH volume. These findings suggest intervention strategies that target major cardiovascular risk factors at midlife might be effective in reducing the development of WMH lesions and thus late life cognitive decline.

Changes in cognitive function among older adults: A latent profile transition analysis

Cognitive decline in late life is a crucial health problem. It is important to understand the consistency and change of older adults’ cognitive function in late life. Data for older adults (78 years and above) from the Health and Retirement Study (N = 1680) were used to explore meaningful subtypes of cognitive function and transitions patterns between those profiles across times. Age, gender, levels of education and nursing home were incorporated as covariates to explore the association between these variables and cognitive function transition pattern. Three cognitive function subgroups (Normal Cognitive Function, Fluid Intelligence Impairment and Cognitive Impairment) were identified. Individuals in Normal Cognitive Function status had a high probability to convert to the Fluid Intelligence Impairment status whereas the Cognitive Impairment status appeared a predominant tendency for stability. Increasing age played a significant role in fluid intelligence impairment and cognitive impairment process. Female and individuals with nursing home might be at higher risk of subsequent fluid intelligence impairment, while higher education did not protect against fluid intelligence impairment. These findings highlighted the usefulness to adopt a person-centered approach rather than a variable-centered approach, suggesting directions for future research and tailored interventions approaches to older adults with particular characteristics.

Education and Cognitive Aging: Accounting for Selection and Confounding in Linkage of Data From the Danish Registry and Survey of Health, Ageing and Retirement in Europe.

Earlier studies report inconsistent associations between education and cognitive aging. We assessed the association, accounting for selective dropout due to death or dementia, and, in a subsample, accounting for confounding by early-life intelligence. Data from the Danish component of the Survey of Health, Ageing and Retirement in Europe (n = 3,400) were linked to registry data (education records, dementia diagnoses, and mortality) and the Danish Conscription Database (youth intelligence measurements for 854 men). Word recall and verbal fluency were assessed up to 4 times over 10 years (2004-2013) and combined by averaging the z scores. We fitted a joint model linking a time-to-event model for dementia or death to a linear mixed-effects model for cognitive change. Rate of cognitive decline was slower among people with high education compared with low education (β = 0.112, 95% confidence interval (CI): 0.056, 0.170). Adjusting for youth intelligence did not attenuate the association between education and cognitive decline (crude β = 0.136, 95% CI: 0.028, 0.244 vs. adjusted β = 0.145, 95% CI: 0.022, 0.269). The results suggest that higher education may slow cognitive decline in later life. In this sample, results changed little when accounting for selective attrition and confounding by intelligence.

Long-Term Blood Pressure Level and Variability From Midlife to Later Life and Subsequent Cognitive Change: The ARIC Neurocognitive Study.

BackgroundTo understand how blood pressure (BP) from midlife and beyond is related to cognition in older age, a lifespan approach is needed. We assessed the associations of BP levels and variability from midlife on with subsequent cognitive change.Methods and ResultsThe ARIC (Atherosclerosis Risk in Communities) Study participants underwent 4 clinic BP measurements (visit 1, 2, 3, and 4 BPs) between 1987 and 1998, and their mean levels and average real variability (ARV) were assessed as exposures. A global cognitive z score, estimated from the Delayed Word Recall Test, Digit Symbol Substitution Test, and Word Fluency Test scores, was calculated at 1996 to 1998 (visit 4) and 2011 to 2013 (visit 5). Among 11 408 participants (mean age, 54 years; 56% women; 21% black race), mean systolic BP (SBP)/diastolic BP (DBP) level was 123/72 mm Hg, and ARVSBP/ARVDBP was 11/7 mm Hg. With linear mixed models, 1‐SD increases of ARVSBP (standardized regression coefficient [95% confidence interval], −0.03 [−0.04 to −0.01] points) and ARVDBP (standardized regression coefficient [95% confidence interval], −0.02 [−0.03 to −0.002] points; both P<0.05), but not mean SBP or DBP levels, were associated with lower global cognitive z scores at visit 4. In contrast, mean SBP (standardized regression coefficient [95% confidence interval], −0.04 [−0.06 to −0.02] points) or DBP (standardized regression coefficient [95% confidence interval], 0.04 [0.02–0.06] points; both P<0.001) level, but not ARVSBP or ARVDBP, was associated with change in global cognitive z scores from visits 4 to 5.ConclusionsGreater visit‐to‐visit SBP or DBP variability from midlife on is modestly associated with lower cognitive function, whereas higher mean SBP and lower DBP levels from midlife to later life are modestly associated with cognitive decline in later life.

A longitudinal magnetic resonance imaging study of neurodegenerative and small vessel disease, and clinical cognitive trajectories in non demented patients with transient ischemic attack: the PREVENT study

BackgroundLate-life cognitive decline, caused by progressive neuronal loss leading to brain atrophy years before symptoms are detected, is expected to double in Canada over the next two decades. Cognitive impairment in late life is attributed to vascular and lifestyle related risk factors in mid-life in a substantial proportion of cases (50%), thereby providing an opportunity for effective prevention of cognitive decline if incipient disease is detected earlier. Patients presenting with transient ischemic attack (TIA) commonly display some degree of cognitive impairment and are at a 4-fold increased risk of dementia. In the Predementia Neuroimaging of Transient Ischemic Attack (PREVENT) study, we will address what disease processes (i.e., Alzheimer’s vs. vascular disease) lead to neurodegeneration, brain atrophy, and cognitive decline, and whether imaging measurements of brain iron accumulation using quantitative susceptibility mapping predicts subsequent brain atrophy and cognitive decline.MethodsA total of 440 subjects will be recruited for this study with 220 healthy subjects and 220 TIA patients. Early Alzheimer’s pathology will be determined by cerebrospinal fluid samples (including tau, a marker of neuronal injury, and amyloid β1–42) and by MR measurements of iron accumulation, a marker for Alzheimer’s-related neurodegeneration. Small vessel disease will be identified by changes in white matter lesion volume. Predictors of advanced rates of cerebral and hippocampal atrophy at 1 and 3 years will include in vivo Alzheimer’s disease pathology markers, and MRI measurements of brain iron accumulation and small vessel disease. Clinical and cognitive function will be assessed annually post-baseline for a period of 5-years using a clinical questionnaire and a battery of neuropsychological tests, respectively.DiscussionThe PREVENT study expects to demonstrate that TIA patients have increased early progressive rates of cerebral brain atrophy after TIA, before cognitive decline can be clinically detected. By developing and optimizing high-level machine learning models based on clinical data, image-based (quantitative susceptibility mapping, regional brain, and white matter lesion volumes) features, and cerebrospinal fluid biomarkers, PREVENT will provide a timely opportunity to identify individuals at greatest risk of late-life cognitive decline early in the course of disease, supporting future therapeutic strategies for the promotion of healthy aging.

Does selective survival before study enrolment attenuate estimated effects of education on rate of cognitive decline in older adults? A simulation approach for quantifying survival bias in life course epidemiology.

The relationship between education and late-life cognitive decline is controversial. Selective survival between early life, when education is typically completed, and late life, when cognitive ageing studies take place, could attenuate effect estimates. We quantified potential survival bias (collider-stratification bias) in estimation of the effect of education on late-life cognitive decline by simulating hypothetical cohorts of 20-year-olds and applying cumulative mortality from US life tables. For each of four causal scenarios (2000 replications each), we compared the estimated versus causal effect of education on cognitive decline over 9 years, starting at age 60, 75 or 90 in random samples of n = 2000 people who survived to each age. Effects of education on cognitive decline were underestimated when both education and U, another determinant of cognitive decline, influenced mortality (collider-stratification bias). The magnitude of bias was sensitive to the magnitude of the effect of U on cognitive decline and whether there was a multiplicative interaction between education and U on mortality. For example, when there was a multiplicative interaction between education and U on mortality, 95% confidence interval coverage of the causal effect ranged from 83.4% to 50.4% at age 60 and 25.8% to 0.2% at age 90. Selective survival could lead to underestimation of effects of education on late-life cognitive decline. Our simulations map survival bias to testable assumptions about underlying causal structures.

Postmortem brain MRI is related to cognitive decline, independent of cerebral vessel disease in older adults.

The purpose of this study was to determine whether metrics of brain tissue integrity derived from postmortem magnetic resonance imaging (MRI) are associated with late-life cognitive decline, independent of cerebral vessel disease. Using data from 554 older adults, we used voxelwise regression to identify regions where the postmortem MRI transverse relaxation rate constant R2 was associated with the rate of decline in global cognition. We then used linear mixed models to investigate the association between a composite R2 measure and cognitive decline, controlling for neuropathology including 3 indices of vessel disease: atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy. This composite R2 measure was associated with the rate of decline (0.049 unit annually per R2 unit, p < 0.0001) and accounted for 6.1% of its variance, beyond contributions from vessel disease indices and other prominent age-related neuropathologies. Thus, postmortem brain R2 reflects disease processes underlying cognitive decline that are not captured by vessel disease indices or other standard neuropathologic indices and may provide a measure of brain tissue integrity that is complementary to histopathologic evaluation.