Depressive symptoms may either be a risk factor or prodromal to dementia. Investigating this association in midlife may help clarify the role of depression in cognitive aging. We aimed to identify trajectories in depressive symptoms in early to mid-life and related cognitive and brain outcomes in midlife. This study includes 3944 Black and White participants (ages 26-45 years at baseline) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with 20 years of follow-up. Depressive symptoms were assessed using the Center for Epidemiological Studies Depression scale at five time points over 20 years. Growth mixture modeling (GMM) was used to identify depressive symptom trajectories. Participants completed a neuropsychological battery 20 years after baseline, including the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment (MoCA), and category and letter fluency tests. A sub-sample of participants (n = 662) underwent brain magnetic resonance imaging (MRI) to characterize gray matter volumes and white matter hyperintensities (WMHs). We identified four classes of depressive symptom trajectories: a declining class (n = 286, 7.3%) with initially high symptoms and subsequent decline, a class with consistently high symptoms (steady high; n = 264, 6.7%), a class with late increases in symptoms (increasing; n = 277, 7%), and a class with consistently low symptoms (steady low; n = 3117, 79.0%). The steady high and the increasing classes had poorer performance on all cognitive tests, while the declining class had poorer performance on the DSST, verbal fluency, and MoCA. Compared to the steady low symptom class, the steady high class had lower volumes in the entorhinal cortex (β: -180.80, 95% CI: -336.69 to -24.91) and the amygdala (β: -40.97, 95% CI: -74.09 to -7.85), the increasing class had more WMHs (β: 0.55, 95% CI: 0.22 to 0.89), and the declining class was not significantly different in any brain measures. Trajectories in depressive symptoms in young to mid-adulthood show distinct cognitive and brain phenotypes in midlife. Steady high depressive symptoms may represent a group that is at risk for dementia, whereas increasing symptoms in midlife may be associated with white matter damage.

We aimed to evaluate the external performance of prediction models for all-cause dementia or AD in the general population, which can aid selection of high-risk individuals for clinical trials and prevention. We identified 17 out of 36 eligible published prognostic models for external validation in the population-based AGES-Reykjavik Study. Predictive performance was assessed with c statistics and calibration plots. All five models with a c statistic > .75 (.76-.81) contained cognitive testing as a predictor, while all models with lower c statistics (.67-.75) did not. Calibration ranged from good to poor across all models, including systematic risk overestimation or overestimation for particularly the highest risk group. Models that overestimate risk may be acceptable for exclusion purposes, but lack the ability to accurately identify individuals at higher dementia risk. Both updating existing models or developing new models aimed at identifying high-risk individuals, as well as more external validation studies of dementia prediction models are warranted.

Objective

Elevated inflammation is associated with worse late-life cognitive functioning and brain health. Our goal was to examine the relationship between inflammation trajectories and white matter integrity in midlife.

Methods

Participants were 508 adults from the Coronary Artery Risk Development in Young Adults Study (CARDIA; 51% female). Latent class analysis was used to identify inflammation trajectories based on repeated measures of the inflammatory marker C-reactive protein (CRP) over the 18 years before brain magnetic resonance imaging (MRI). Outcomes were brain MRI measures of total and region-specific white matter volume and integrity at a mean age of 50.6 ± 3.4 years. Linear regression was used to examine if inflammation trajectories were associated with brain MRI outcomes, adjusting for potential confounds in all models and for disease and health behaviors in follow-up models.

Results

Lower-stable (38%), moderate-increasing (7%), and consistently-higher (54%), trajectories emerged. Compared to the lower-stable group, the moderate-increasing group showed lower white matter volume (β = -0.18, 95% CI -0.29, -0.06) and worse white matter integrity as indexed by lower fractional anisotropy (FA; β = -0.37, 95% CI -0.70, -0.04) and higher mean diffusivity (β = 0.44, 95% CI 0.11, 0.78) in the whole brain. The consistently-higher group showed lower whole-brain FA (β = -0.20, -0.38, -0.03). In exploratory analyses, the moderate-increasing group showed lower white matter volume, lower FA and higher MD in the frontal, temporal, and parietal lobes compared to the lower-stable group. The consistently-higher group showed lower white matter volume in the parietal lobe and lower FA in the frontal, temporal, and parietal lobes, but similar MD, compared to the lower-stable group. Findings for the moderate-increasing, but not the consistently-higher, group were robust to adjustment for disease and lifestyle factors.

Conclusion

Increasing or high inflammation trajectories from early to mid adulthood are associated with worse brain health, as indexed by lower white matter volume and/or worse white matter integrity.

Objective

Mild parkinsonian signs (MPS) are an underappreciated neurologic condition in older adults; we assessed associations of MPS with measures of dopaminergic (catechol-O-methyltransferase [COMT] genotype, an indicator of synaptic dopamine levels) and vascular (white matter hyperintensities [WMH], an indicator of cerebral small vessel disease) factors.

Methods

In a cohort of older adults (mean age 82.6 years [SD 2.6]; 58.0% female; 38.8% black), we assessed cross-sectional associations of WMH volume and COMT Val158Met (rs4680) genotype (n = 35 Met/Met, n = 180 Val carriers) with MPS by regression models adjusted for demographic and health characteristics. Interactions between WMH and COMT were assessed and analyses were repeated stratified by COMT genotype (Met/Met related to higher synaptic dopamine vs Val carriers related to lower synaptic dopamine).

Results

MPS was present in 42.3% of our sample. WMH (odds ratio [OR] 1.16, confidence interval [CI] 1.05-1.27) but not COMT (Met/Met compared to Val carrier: OR 0.62, CI 0.27-1.42) was related to MPS. There was a significant interaction between WMH and COMT (p = 0.03). Stratified analyses reveled a strong association between WMH and MPS among COMT Val carriers (OR 1.23, CI 1.09-1.38), but not for Met/Met (OR 0.68, CI 0.45-1.02), independent of covariates.

Conclusions

WMH had a direct relation with MPS. In contrast, COMT was not associated with MPS, but it did modify the effect of WMH on MPS. The dopaminergic system may provide compensation for the effects of WMH on MPS. These findings suggest that MPS has a vascular rather than dopaminergic origin in older adults, but both factors are important in MPS manifestation.

The purpose of this study was to investigate whether long-term television viewing patterns, a common sedentary behavior, in early to mid-adulthood is associated with gray matter brain volume in midlife and if this is independent of physical activity. We evaluated 599 participants (51% female, 44% black, mean age 30.3 ± 3.5 at baseline and 50.2 ± 3.5 years at follow-up and MRI) from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study. We assessed television patterns with repeated interviewer-administered questionnaire spanning 20 years. Structural MRI (3T) measures of frontal cortex, entorhinal cortex, hippocampal, and total gray matter volumes were assessed at midlife. Over the 20 years, participants reported viewing an average of 2.5 ± 1.7 h of television per day (range: 0-10 h). After multivariable adjustment, greater television viewing was negatively associated with gray matter volume in the frontal (β = - 0.77; p = 0.01) and entorhinal cortex (β = - 23.83; p = 0.05) as well as total gray matter (β = - 2.09; p = 0.003) but not hippocampus. These results remained unchanged after additional adjustment for physical activity. For each one standard deviation increase in television viewing, the difference in gray matter volume z-score was approximately 0.06 less for each of the three regions (p < 0.05). Among middle-aged adults, greater television viewing in early to mid-adulthood was associated with lower gray matter volume. Sedentariness or other facets of television viewing may be important for brain aging even in middle age.

Background

Whether high blood pressure has a causal effect on cognitive function as early as middle age is unclear. We investigated whether high blood pressure (BP) causally impairs cognitive function at midlife using Mendelian Randomization (MR).

Methods

We applied a two-sample MR approach to investigate the causal relationship between BP and midlife cognitive performance measured by the Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), and Stroop Interference test. We used a total of 109 genetic polymorphisms with established associations with BP as instrumental variables and estimated gene-cognitive function association in 1369 middle-aged adults (Mean age (SD): 50.8 (3.3), 54.0% women) from the CARDIA study.

Results

A 10 mmHg increment in genetically-predicted systolic, diastolic, or pulse pressure was associated with a 4.9 to 7.7-point lower DSST score (P = 0.002, SBP; P = 0.005, DBP and P = 0.008, PP), while a 10 mmHg increment in genetically-predicted SBP was associated with a 0.7 point lower RAVLT and a 2.3 point higher Stroop (P = 0.046 and 0.011, respectively).

Conclusions

This MR analysis shows that high BP, especially SBP, is causally associated with poorer processing speed, verbal memory, and executive function during midlife. These findings emphasize the need for further investigation of the role and mechanisms of BP dysregulation on cognitive health in middle age and perhaps, more broadly, across the lifespan.

We examined associations of an Alzheimers disease (AD) Genetic Risk Score (AD-GRS) and midlife cognitive and neuroimaging outcomes in 1,252 middle-aged participants (311 with brain MRI). A higher AD-GRS based on 25 previously identified loci (excluding apolipoprotein E [APOE]) was associated with worse Montreal Cognitive Assessment (-0.14 standard deviation [SD] [95% confidence interval {CI}: -0.26, -0.02]), older machine learning predicted brain age (2.35 years[95%CI: 0.01, 4.69]), and white matter hyperintensity volume (0.35 SD [95% CI: 0.00, 0.71]), but not with a composite cognitive outcome, total brain, or hippocampal volume. APOE ε4 allele was not associated with any outcomes. AD risk genes beyond APOE may contribute to subclinical differences in cognition and brain health in midlife. ANN NEUROL 2023;93:629-634.

BACKGROUND: Brain-derived neurotrophic factor levels are higher in those who are physically active and lower in people with cognitive dysfunction. This study investigated whether brain-derived neurotrophic factor mediated or modified the association of sedentary time to MRI-estimated brain volumes in midlife. METHODS: Baseline (n = 612) and five-year follow-up (n = 418) data were drawn from the multicenter Coronary Artery Risk Development in Young Adults Brain MRI sub-study, including Black and White participants (aged 50.3 years, 51.6% females, 38.6% Black). Sedentary time (hours per day) was categorized into quartiles with low ≤ 4.3 (reference) and high > 8.4. Outcomes of the study were total brain, white matter, gray matter, hippocampal volumes, and white matter fractional anisotropy at baseline and 5-year percent change from baseline. The study used general linear regression models to examine the mediation and moderation effects of brain-derived neurotrophic factor (natural log transformed) on the associations of sedentary time to brain outcomes. The authors adjusted the regression model for age, sex, race, intracranial volume, education, and vascular factors. RESULTS: Cross-sectionally, baseline participants with the highest sedentary time had a lower total brain (-12.2 cc; 95%CI: -20.7, -3.7), gray matter (-7.8 cc; 95%CI: -14.3, -1.3), and hippocampal volume (-0.2 cc; 95%CI: -0.3, 0.0) compared with populations with the lowest sedentary time. The brain-derived neurotrophic factor levels did not mediate the associations between brain measures and sedentary time. Brain-derived neurotrophic factor was found to moderate associations of sedentary time to total brain and white matter volume such that the brain volume difference between high and low sedentary time decreased as brain-derived neurotrophic factor levels increased. Longitudinally, higher baseline brain-derived neurotrophic factor level was associated with less brain volume decline. The longitudinal associations did not differ by sedentary time, and brain-derived neurotrophic factor did not mediate or moderate the association of sedentary time to brain measure changes. CONCLUSIONS: Higher brain-derived neurotrophic factor levels may buffer the negative effects of sedentary time on the brain.

Objective

In line with cognitive reserve theory, higher occupational cognitive complexity is associated with reduced cognitive decline in older adulthood. How and when occupational cognitive complexity first exerts protective effects during the life span remains unclear. We investigated associations between occupational cognitive complexity during early to midadulthood and brain structure and cognition in midlife.

Method

Participants were 669 adults from the Coronary Artery Risk Development in Young Adults study (aged 18-30 years at baseline, 52% female, 38% Black). We calculated scores reflecting occupational cognitive complexity using Census Occupation Codes (years 10 and 15) and Occupational Information Network (O*NET) data. At year 25, participants had structural brain magnetic resonance imaging, diffusion tensor imaging, and cognitive testing (Rey Auditory Verbal Learning Test, Digit Symbol Substitution Test, Stroop). In adjusted mixed models, we examined associations between occupational cognitive complexity during early to midadulthood and midlife brain structure, specifically gray matter volume and white matter fractional anisotropy, and cognition in midlife (all outcomes converted to z-scores).

Results

Higher occupational cognitive complexity was associated with greater white matter fractional anisotropy (estimate = 0.10, p = .01) but not gray matter volume. Higher occupational cognitive complexity was associated with better Digit Symbol Substitution Test (estimate = 0.13, p < .001) and Stroop (estimate = 0.09, p = .01) performance but not Rey Auditory Verbal Learning Test performance.

Conclusions

Occupational cognitive complexity earlier in adulthood is associated with better white matter integrity, processing speed, and executive function in midlife. These associations may capture how occupational cognitive complexity contributes to cognitive reserve. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Background

Studies have linked midlife and late-life cardiovascular risk factors (CVRFs) to cognitive function, yet little is known about CVRF exposure in early adulthood and subsequent cognitive function. In addition, most studies rely on single assessments of CVRFs, which may not accurately reflect long-term exposure. We sought to determine the association between cumulative exposure to CVRFs from early to middle adulthood and cognitive function at midlife.

Methods and results

In a prospective study of 3381 adults (age, 18-30 years at baseline) with 25 years of follow-up, we assessed cognitive function at year 25 (2010-2011) with the Digit Symbol Substitution Test, Stroop Test, and Rey Auditory Verbal Learning Test analyzed with standardized z scores. The primary predictor was 25-year cumulative exposure estimated by areas under the curve for resting systolic and diastolic blood pressures, fasting blood glucose, and total cholesterol. Higher cumulative systolic and diastolic blood pressures and fasting blood glucose were consistently associated with worse cognition on all 3 tests. These associations were significant primarily for exposures above recommended guidelines; cognitive test z scores were between 0.06 and 0.30 points less, on average, for each 1-SD increase in risk factor area under the curve after adjustment for age, race, sex, and education (P<0.05 for all). Fewer significant associations were observed for cholesterol.

Conclusions

Cumulative exposure to CVRFs from early to middle adulthood, especially above recommended guidelines, was associated with worse cognition in midlife. The meaning of this association and whether it warrants more aggressive treatment of CVRFs earlier in life require further investigation.