Perceived stress and change in cognitive function among adults 65 years and older.

OBJECTIVE: Exposure to acute and chronic stress can affect learning and memory, but most evidence comes from animal studies or clinical observations. Almost no population-based studies have investigated the relation of stress to cognition or changes in cognition over time. We examined whether higher levels of perceived stress were associated with accelerated decline in cognitive function in older blacks and whites from a community-based population sample. METHODS: Participants included 6207 black and white adults (65.7% black, 63.3% women) from the Chicago Health and Aging Project. Two to five in-home assessments were completed over an average of 6.8 years of follow-up and included sociodemographics, health behaviors, psychosocial measures, cognitive function tests, and health history. Perceived stress was measured by a six-item scale, and a composite measure of four tests of cognition was used to determine cognitive function at each assessment. RESULTS: Mixed-effects regression models showed that increasing levels of perceived stress were related to lower initial cognitive scores (B = -0.0379, standard error = 0.0025, p < .001) and a faster rate of cognitive decline (stress × time interaction: B = -0.0015, standard error = 0.0004, p < .001). Results were similar after adjusting for demographic variables, smoking, systolic blood pressure, body mass index, chronic medical conditions, and psychosocial factors and did not vary by race, sex, age, or education. CONCLUSIONS: Increasing levels of stress are independently associated with accelerated declines in cognitive function in black and white adults 65 years and older.

Perceived stress is associated with subclinical cerebrovascular disease in older adults.

OBJECTIVE: To examine the association of perceived stress with magnetic resonance imaging (MRI) markers of subclinical cerebrovascular disease in an elderly cohort. METHODS: Using a cross-sectional study of a community-based cohort in Chicago, 571 adults (57% women; 58.1% African American; 41.9% non-Hispanic white; mean [SD] age: 79.8 [5.9] years) from the Chicago Health and Aging Project, an epidemiologic study of aging, completed questionnaires on perceived stress, medical history, and demographics as part of an in-home assessment and 5 years later underwent a clinical neurologic examination and MRI of the brain. Outcome measures were volumetric MRI assessments of white matter hyperintensity volume (WMHV), total brain volume (TBV), and cerebral infarction. RESULTS: Stress was measured with six items from the Perceived Stress Scale (PSS); item responses, ranging from never (0) to often (3), were summed to create an overall stress score (mean [SD]: 4.9 [3.3]; range: 0-18). Most participants had some evidence of vascular disease on MRI, with 153 participants (26.8%) having infarctions. In separate linear and logistic regression models adjusted for age, sex, education, race, and time between stress assessment and MRI, each one-point increase in PSS score was associated with significantly lower TBV (coefficient = -0.111, SE = 0.049, t[563] = -2.28, p = 0.023) and 7% greater odds of infarction (odds ratio: 1.07; 95% confidence interval: 1.01, 1.13; Wald χ(2)[1] = 4.90; p = 0.027). PSS scores were unrelated to WMHV. Results were unchanged with further adjustment for smoking, body mass index, physical activity, history of heart disease, stroke, diabetes, hypertension, depressive symptoms, and dementia. CONCLUSIONS: Greater perceived stress was significantly and independently associated with cerebral infarction and lower brain volume assessed 5 years later in this elderly cohort.

Accounting for bias due to selective attrition: the example of smoking and cognitive decline.

BACKGROUND: Selective attrition may introduce bias into analyses of the determinants of cognitive decline. This is a concern especially for risk factors, such as smoking, that strongly influence mortality and dropout. Using inverse-probability-of-attrition weights, we examined the influence of selective attrition on the estimated association of current smoking (vs. never smoking) with cognitive decline. METHODS: Chicago Health and Aging Project participants (n = 3713), aged 65-109 years, who were current smokers or never- smokers, underwent cognitive assessments up to 5 times at 3-year interval. We used pooled logistic regression to fit predictive models of attrition due to death or study dropout across the follow-up waves. With these models, we computed inverse-probability-of-attrition weights for each observation. We fit unweighted and weighted, multivariable-adjusted generalized-estimating-equation models, contrasting rates of change in cognitive scores in current versus never-smokers. Estimates are expressed as rates of change in z score per decade. RESULTS: During the 12 years of follow-up, smokers had higher mortality than never-smokers (hazard ratio = 1.93 [95% confidence interval = 1.67 to 2.23]). Higher previous cognitive score was associated with increased likelihood of survival and continued participation. In unweighted analyses, current smokers' cognitive scores declined 0.11 standard units per decade more rapidly than never-smokers' (95% CI = -0.20 to -0.02). Weighting to account for attrition yielded estimates that were 56% to 86% larger, with smokers' estimated 10-year rate of decline up to 0.20 units faster than never-smokers' (95% CI = -0.36 to -0.04). CONCLUSIONS: Estimates of smoking's effects on cognitive decline may be underestimated due to differential attrition. Analyses that weight for the inverse probability of attrition help compensate for this attrition.

Characteristics of MR infarcts associated with dementia and cognitive function in the elderly.

BACKGROUND: Little information exists on the simultaneous effects of magnetic resonance (MR) infarct characteristics, that may increase the likelihood of dementia or lower cognitive function in community populations. METHODS: Participants were 580 community-dwelling individuals from the Chicago Health and Aging Project (CHAP) who underwent detailed clinical evaluation and MR imaging. The association of MR infarct characteristics (region, number, side, and size) with dementia, global cognition and cognition in five separate cognitive domains was examined using logistic and linear regression analyses controlling for age, sex, race, education and time elapsed between clinical evaluation and MRI. RESULTS: A total of 156 persons had MR infarcts: 108 with 1 infarct and 48 with multiple. Poorer cognitive function and, in particular, slower perceptual speed, were associated with infarcts characterized as cortical, multiple, bilateral or large (all p < 0.05). Multiple infarcts in multiple regions were associated with poor performance in all cognitive domains except visuospatial ability (p < 0.05). Race did not modify any of these associations. CONCLUSIONS: In this community sample, cortical and multiple infarcts in multiple regions were associated with dementia; cortical, multiple, large and bilateral infarcts were associated with lower cognition, particularly lower memory function and perceptual speed. These effects were not modified by race.

Bulk IgG glycosylation predicts COVID-19 severity and vaccine antibody response.

Although vaccination efforts have expanded, there are still gaps in our understanding surrounding the immune response to SARS-CoV-2. Measuring IgG Fc glycosylation provides insight into an infected individual's inflammatory state, among other functions. We set out to interrogate bulk IgG glycosylation changes from SARS-CoV-2 infection and vaccination, using plasma from mild or hospitalized COVID-19 patients, and from vaccinated individuals. Inflammatory glycans are elevated in hospitalized COVID-19 patients and increase over time, while mild patients have anti-inflammatory glycans that increase over time, including increased sialic acid correlating with RBD antibody levels. Vaccinated individuals with low RBD antibody levels and low neutralization have the same IgG glycan traits as hospitalized COVID-19 patients. In addition, a small vaccinated cohort reveals a decrease in inflammatory glycans associated with peak IgG concentrations and neutralization. This report characterizes the bulk IgG glycome associated with COVID-19 severity and vaccine responsiveness and can help guide future studies into SARS-CoV-2 protective immunity.

Apolipoprotein E e4 allele is associated with more rapid motor decline in older persons.

We tested the hypothesis that apolipoprotein E allele status predicts the rate of motor decline in the elderly. Eight hundred seventy-six older participants without dementia underwent baseline and annual motor testing for up to 10 years. In a generalized estimating equation controlling for age, sex, and education, motor function declined by about 0.03 U/y. The presence of epsilon4 allele was associated with a 2-fold increase in rate of motor decline epsilon4 allele x time: estimate=-0.027 (SE 0.012, P=0.025)]. The association of epsilon4 allele with motor decline persisted even after controlling for cognitive status, race, body mass index, vascular risk factors, and diseases. Further analyses suggested that the association of epsilon4 with motor decline was for the most part explained by the association between epsilon4 allele and change in muscle strength. These results suggest that the presence of epsilon4 allele is a risk factor for more rapid motor decline in the elderly.

Terminal cognitive decline: accelerated loss of cognition in the last years of life.

OBJECTIVE: To test the hypothesis that rate of cognitive decline accelerates in the last years of life. METHODS: Participants are 853 older persons without dementia at study onset. For up to 8 years, they underwent annual clinical evaluations that included a battery of 19 cognitive tests from which previously established composite measures of global cognition and specific cognitive domains were derived. In analyses, we used linear mixed-effects models that allowed rate of cognitive decline to change at a given point before death to estimate the onset of a terminal decline period and rate of cognitive decline before and after that point. In subsequent analyses, we tested potential modifiers of terminal decline. RESULTS: There were 115 deaths. Those who died did not differ from survivors in their level of global cognitive function at study onset, but beginning a mean of 42 months before death, their rate of global cognitive decline sharply increased. The duration and rapidity of terminal decline in global cognition differed from person to person. Terminal cognitive decline was not modified by age, sex, education, or the presence of mild cognitive impairment, but it was not present in those with vascular disease (e.g., stroke and heart attack) or in those without at least one copy of the apolipoprotein E epsilon4 allele, suggesting that Alzheimer's disease pathology may contribute to the phenomenon. CONCLUSIONS: In old age, cognitive decline markedly accelerates during the last 3 to 4 years of life, consistent with the terminal decline hypothesis.

Motor dysfunction in mild cognitive impairment and the risk of incident Alzheimer disease.

BACKGROUND: Little is known about motor function in mild cognitive impairment (MCI) and its relation to the risk of Alzheimer disease (AD). OBJECTIVE: To examine motor function in persons with MCI and its relation to risk of AD. DESIGN: Longitudinal cohort study. SETTING: More than 40 Catholic religious orders across the United States. PARTICIPANTS: We studied 816 older Catholic clergy members from the Religious Orders Study. At the baseline evaluation, they were classified as having no cognitive impairment (n = 558), MCI (n = 198), or dementia (n = 60). MAIN OUTCOME MEASURES: Motor function was assessed at baseline using performance-based measures of upper and lower extremity function and a modified version of the motor section of the Unified Parkinson's Disease Rating Scale, from which previously established measures of parkinsonian signs were derived. Clinical evaluations for dementia and AD were repeated annually for up to 10 years. All analyses controlled for age, sex, educational level, and possession of at least 1 apolipoprotein E epsilon4 allele. RESULTS: At baseline, individuals with MCI had impaired motor function relative to those without cognitive impairment and superior motor function vs those with dementia. Among those with MCI, baseline levels of lower extremity motor performance, parkinsonian gait, and bradykinesia were inversely related to risk of AD, even after controlling for clinical stroke. Thus, a person with impaired lower limb performance or parkinsonian gait (10th percentile) was 2 to 3 times more likely to develop AD than a person with good lower limb function (90th percentile). CONCLUSIONS: Persons with MCI also have impaired motor function, and the degree of impairment in lower extremity function is related to the risk of AD.

Effect of Demographic Risk Factors on the Change in Cognitive Function in the Presence of Non-Participation and Truncation due to Death.

Missing data due to non-participation and death are two common problems in longitudinal studies of the elderly. The effect of socio-demographic variables on the decline in cognitive function after adjusting for non-participation and truncation due to death has not been well studied. This study is based on 6,105 subjects enrolled in the Chicago Health and Aging Project (CHAP), followed over four cycles of data collection approximately three years apart. Cognitive function was based on a standardized measure of mini-mental state examination. We will study the impact of non-participation and death on the decline in cognitive function with socio-demographic variables as risk factors, using four different modeling approaches: 1) a linear mixed effects model ignoring the missing data, 2) a pattern-mixture model using multiple imputation (MI) stratified by patterns of non-participation and death, 3) MI for non-participation stratified by patterns of non-participation and a pattern-mixture model stratified by the time of death, and 4) MI for non-participation stratified by patterns of non-participation and a pattern-mixture model with a categorical variable for time of death. The baseline association of socio-demographic variables with cognitive function was mostly unchanged among Blacks and Whites. However, the decline in cognitive function over a 10-year period had decreased by approximately 50% (Blacks coefficient changed from -0.544 to -0.285; Whites coefficient changed from -0.682 to -0.339) after accounting for non-participation and death. The effect of age on the change in cognitive function over a 10-year period had reduced by about 30% (Blacks coefficient changed from -0.033 to -0.010; Whites coefficient changed from -0.049 to -0.016). The trajectory of cognitive function for White males had reduced by approximately 45% (changed from 0.12 to 0.055) over a 10-year period. Education was significantly associated with the change in cognitive function among Blacks but not among Whites. Moreover, females showed a significant change in cognitive function among Whites, but not among Blacks. We found significant differences on the change in cognitive function between models that did not adjust for non-participation and death, and models that adjusted for them.

Change in depressive symptoms during the prodromal phase of Alzheimer disease.

CONTEXT: Prospective studies have established an association between depressive symptoms and risk of dementia, but how depressive symptoms change during the evolution of dementia is uncertain. OBJECTIVE: To test the hypothesis that depressive symptoms increase during the prodromal phase of Alzheimer disease (AD). DESIGN: Prospective cohort study. PARTICIPANTS AND SETTING: For up to 13 years, 917 older Catholic nuns, priests, and monks without dementia at study onset completed annual clinical evaluations that included administration of the 10-item Center for Epidemiologic Studies Depression Scale and clinical classification of mild cognitive impairment and AD. MAIN OUTCOME MEASURE: Change in depressive symptoms reported on the Center for Epidemiologic Studies Depression Scale. RESULTS: At baseline, participants reported a mean (SD) of 1.0 (1.5) depressive symptoms. Those who developed AD (n = 190) showed no increase in depressive symptoms before the diagnosis was made, and this finding was not modified by age, sex, education, memory complaints, vascular burden, or personality. There was no systematic change in depressive symptoms after the AD diagnosis, although symptoms tended to decrease in women relative to men and in those with a higher premorbid level of openness and a lower premorbid level of agreeableness. Among those without cognitive impairment at baseline, depressive symptoms did not increase in those who subsequently developed mild cognitive impairment. CONCLUSION: We found no evidence of an increase in depressive symptoms during the prodromal phase of AD.

The apolipoprotein E epsilon4 allele and incident Alzheimer's disease in persons with mild cognitive impairment.

Possession of one or more copies of the apolipoprotein E (APOE) epsilon4 allele is a known risk factor for Alzheimer's disease (AD), but it is uncertain whether the epsilon4 allele is associated with disease incidence among persons with mild cognitive impairment (MCI). We addressed this issue with data from the Religious Orders Study. Participants were 181 older Catholic clergy members who met criteria for MCI based on a uniform structured clinical evaluation; 56 (30.9%) had at least one epsilon4 allele. Clinical evaluations, which included clinical classification of dementia and AD, were repeated annually. During a mean of 5.7 years of observation, 79 persons (43.6%) developed AD. In a proportional hazards model that controlled for age, sex, and education, possession of an epsilon4 allele was associated with a 93% increase in the risk of developing Alzheimer's disease (95% CI; 1.02, 2.63). There was a marginally significant reduction in the effect of epsilon4 in older compared to younger participants (p=.053). The results suggest that possession of an epsilon4 allele does increase risk of AD in persons with MCI.