Cross-national comparisons of later-life cognitive function using data from the Harmonized Cognitive Assessment Protocol (HCAP): Considerations and recommended best practices.

The Harmonized Cognitive Assessment Protocol (HCAP) is a major innovation that provides, for the first time, harmonized data for cross-national comparisons of later-life cognitive functions that are sensitive to linguistic, cultural, and educational differences across countries. However, cognitive function does not lend itself to direct comparison across diverse populations without careful consideration of the best practices for such comparisons. This perspective discusses theoretical and methodological considerations and offers a set of recommended best practices for conducting cross-national comparisons of risk factor associations using HCAP data. Because existing and planned HCAP studies provide cognition data representing an estimated 75% of the global population ≥65 years of age, these recommended best practices will support high-quality comparative analyses of cognitive aging around the world. The principles described in this perspective are applicable to any researcher aiming to integrate or compare harmonized data on cognitive outcomes and their risk and protective factors across diverse populations.

Harmonization of Later-Life Cognitive Function Across National Contexts: Results from the Harmonized Cognitive Assessment Protocols (HCAPs).

Background: The Harmonized Cognitive Assessment Protocol (HCAP) is an innovative instrument for cross-national comparisons of later-life cognitive function, yet its suitability across diverse populations is unknown. We aimed to harmonize general and domain-specific cognitive scores from HCAPs across six countries, and evaluate precision and criterion validity of the resulting harmonized scores. Methods: We statistically harmonized general and domain-specific cognitive function across the six publicly available HCAP partner studies in the United States, England, India, Mexico, China, and South Africa (N=21,141). We used an item banking approach that leveraged common cognitive test items across studies and tests that were unique to studies, as identified by a multidisciplinary expert panel. We generated harmonized factor scores for general and domain- specific cognitive function using serially estimated graded-response item response theory (IRT) models. We evaluated precision of the factor scores using test information plots and criterion validity using age, gender, and educational attainment. Findings: IRT models of cognitive function in each country fit well. We compared measurement reliability of the harmonized general cognitive function factor across each cohort using test information plots; marginal reliability was high (r> 0·90) for 93% of respondents across six countries. In each country, general cognitive function scores were lower with older ages and higher with greater levels of educational attainment. Interpretation: We statistically harmonized cognitive function measures across six large, population-based studies of cognitive aging in the US, England, India, Mexico, China, and South Africa. Precision of the estimated scores was excellent. This work provides a foundation for international networks of researchers to make stronger inferences and direct comparisons of cross-national associations of risk factors for cognitive outcomes. Funding: National Institute on Aging (R01 AG070953, R01 AG030153, R01 AG051125, U01 AG058499; U24 AG065182; R01AG051158).

Plasma Pro-Enkephalin A and Incident Cognitive Impairment: The Reasons for Geographic and Racial Differences in Stroke Cohort.

Background Cardiovascular disease is a risk factor for cognitive impairment. Evidence links both lower and higher concentration of the circulating opioid pro-enkephalin A (PENK-A) with stroke risk. We studied the association of plasma PENK-A with incident cognitive impairment. Methods and Results REGARDS (Reasons for Geographic and Racial Differences in Stroke) is a prospective cohort study of 30 239 adults enrolled from 2003 to 2007. Baseline PENK-A was measured in a nested case-control study of 462 participants who developed cognitive impairment over 4.7 years, and 556 controls. Logistic regression and spline plots adjusted for confounders estimated odds ratios (ORs) of cognitive impairment by baseline PENK-A. Interaction terms tested for differences in associations by age, sex, and race. Baseline PENK-A was comparable between cases and controls. There were significant differences in the association of PENK-A with cognitive impairment by sex and age (adjusted P=0.003 and 0.06, respectively). In women but not men, spline plots showed that higher and lower PENK-A were associated with decreased odds of cognitive impairment (ORs for 10th and 90th percentiles versus median, 0.65 [95% CI, 0.43-0.96] and 0.64 [95% CI, 0.41-0.99]), with no difference by age. In men ≥65 years of age but not younger men, higher PENK-A was associated with decreased odds for cognitive impairment (OR for fourth versus first quartile 0.47 [95% CI, 0.22-0.99]); this pattern was not confirmed with spline plotting. Conclusions High and low levels of circulating opioid PENK-A were associated with decreased odds of future cognitive impairment in specific subgroups. Additional research is warranted to understand the biology underlying this association and the observed differences by sex.

Brain Aging Among Racially and Ethnically Diverse Middle-Aged and Older Adults.

Importance: Neuroimaging studies have documented racial and ethnic disparities in brain health in old age. It remains unclear whether these disparities are apparent in midlife. Objective: To assess racial and ethnic disparities in magnetic resonance imaging (MRI) markers of cerebrovascular disease and neurodegeneration in midlife and late life. Design, Setting, and Participants: Data from 2 community-based cohort studies, Washington Heights-Inwood Columbia Aging Project (WHICAP) and the Offspring Study of Racial and Ethnic Disparities in Alzheimer Disease (Offspring), were used. Enrollment took place from March 2011 and June 2017, in WHICAP and Offspring, respectively, to January 2021. Of the 822 Offspring and 1254 WHICAP participants approached for MRI scanning, 285 and 176 refused participation in MRI scanning, 36 and 76 were excluded for contraindications/ineligibility, and 4 and 32 were excluded for missing key variables, respectively. Main Outcomes and Measures: Cortical thickness in Alzheimer disease-related regions, white matter hyperintensity (WMH) volume. Results: The final sample included 1467 participants. Offspring participants (497 [33.9%]) had a mean (SD) age of 55 (10.7) years, had a mean (SD) of 13 (3.5) years of education, and included 117 Black individuals (23.5%), 348 Latinx individuals (70%), 32 White individuals (6.4%), and 324 women (65.2%). WHICAP participants (970 [66.1%]) had a mean (SD) age of 75 (6.5) years, had a mean (SD) of 12 (4.7) years of education, and included 338 Black individuals (34.8%), 389 Latinx individuals (40.1%), 243 White individuals (25.1%), and 589 women (65.2%). Racial and ethnic disparities in cerebrovascular disease were observed in both midlife (Black-White: B = 0.357; 95% CI, 0.708-0.007; P = .046) and late life (Black-Latinx: B = 0.149, 95% CI, 0.068-0.231; P < .001; Black-White: B = 0.166; 95% CI, 0.254-0.077; P < .001), while disparities in cortical thickness were evident in late life only (Black-Latinx: B = -0.037; 95% CI, -0.055 to -0.019; P < .001; Black-White: B = -0.064; 95% CI -0.044 to -0.084; P < .001). Overall, Black-White disparities were larger than Latinx-White disparities for cortical thickness and WMH volume. Brain aging, or the association of age with MRI measures, was greater in late life compared with midlife for Latinx (cortical thickness: B = 0.006; 95% CI, 0.004-0.008; P < .001; WMH volume: B = -0.010; 95% CI, -0.018 to -0.001; P = .03) and White (cortical thickness: B = 0.005; 95% CI, 0.002-0.008; P = .001; WMH volume: B = -0.021; 95% CI -0.043 to 0.002; P = .07) participants but not Black participants (cortical thickness: B = 0.001; 95% CI, -0.002 to 0.004; P =.64; WMH volume: B = 0.003; 95% CI, -0.010 to 0.017; P = .61), who evidenced a similarly strong association between age and MRI measures in midlife and late life. Conclusions and Relevance: In this study, racial and ethnic disparities in small vessel cerebrovascular disease were apparent in midlife. In Latinx and White adults, brain aging was more pronounced in late life than midlife, whereas Black adults showed accelerated pattern of brain aging beginning in midlife.

Association of Subjective Cognitive Decline With Progression to Dementia in a Cognitively Unimpaired Multiracial Community Sample.

BACKGROUND AND OBJECTIVES: This prospective study seeks to examine the utility of subjective cognitive decline (SCD) as a marker of future progression to dementia in a community-based cohort of non-Latinx White, non-Latinx Black, and Latinx individuals. Debate surrounds the utility of SCD, the subjective perception of decline in one's cognition before such impairment is evident in traditional neuropsychological assessments, as an early indicator of impending Alzheimer disease. Unfortunately, most studies examining SCD have been conducted in non-Latinx White samples and commonly exclude groups of individuals shown to be most vulnerable to dementia. METHODS: Participants were enrolled into this cohort study from the Washington Heights-Inwood Columbia Aging Project if they were cognitively unimpaired, had baseline measurement of SCD, and self-identified as non-Latinx White, non-Latinx Black, or Latinx. SCD was measured as a continuous sum of 10 items assessing cognitive complaints. Competing risk models tested the main effects of baseline SCD on progression to dementia. Models were adjusted for age, sex/gender, years of education, medical comorbidity burden, enrollment cohort, and baseline memory test performance with death jointly modelled as a function of race/ethnicity. RESULTS: A total of 4,043 (1,063 non-Latinx White, 1,267 non-Latinx Black, and 1,713 Latinx) participants were selected for this study with a mean age of 75 years, 67% women, and with a mean follow-up of 5 years. Higher baseline SCD was associated with increased rates of incident dementia over time in the full sample (hazard ratio [HR] 1.085, CI 1.047-1.125, p < 0.001) and within Latinx (HR 1.084, CI 1.039-1.130, p < 0.001) and non-Latinx Black individuals (HR 1.099, CI 1.012-1.194, p = 0.024). DISCUSSION: Overall results of this study support SCD as a prodromal marker of dementia in a multiracial community sample, and in Latinx and non-Latinx Black individuals in particular. Because models examining the risk of dementia were adjusted for baseline memory test performance, the results support the idea that SCD, a subjective reflection of one's own current cognitive functioning, contributes information above and beyond standard memory testing. Current findings highlight the importance of carefully evaluating any memory concerns raised by older adults during routine visits and underscore the potential utility of screening older adults for SCD.

Effects of Sex, APOE4, and Lifestyle Activities on Cognitive Reserve in Older Adults.

BACKGROUND AND OBJECTIVES: Lifestyle activities, such as physical activity and cognitive stimulation, may mitigate age-associated cognitive decline, delay dementia onset, and increase cognitive reserve. Whether the association between lifestyle activities and cognitive reserve differs by sex and APOE4 status is an understudied yet critical component for informing targeted prevention strategies. The current study examined interactions between sex and physical or cognitive activities on cognitive reserve for speed and memory in older adults. METHODS: Research participants with unimpaired cognition, mild cognitive impairment, or dementia from the Washington Heights-Inwood Columbia Aging Cohort were included in this study. Cognitive reserve scores for speed and memory were calculated by regressing out hippocampal volume, total gray matter volume, and white matter hyperintensity volume from composite cognitive scores for speed and memory, respectively. Self-reported physical activity was assessed using the Godin Leisure Time Exercise Questionnaire, converted to metabolic equivalents (METS). Self-reported cognitive activity (COGACT) was calculated as the sum of 3 yes/no questions. Sex by activity interactions and sex-stratified analyses were conducted using multivariable linear regression models, including a secondary analysis with APOE4 as a moderating factor. RESULTS: Seven hundred fifty-eight participants (mean age = 76.11 ± 6.31 years, 62% women) were included in this study. Higher METS was associated with greater speed reserve in women (ß = 0.04, CI 0.0-08) but not in men (ß = 0.004, CI -0.04 to 0.05). METS was not associated with memory reserve in women or men. More COGACT was associated with greater speed reserve in the cohort (ß = 0.13, CI 0.05-0.21). More COGACT had a trend for greater memory reserve in women (ß = 0.06, CI -0.02 to 0.14) but not in men (ß = -0.04, CI -0.16 to 0.08). Only among women, APOE4 carrier status attenuated relationships between METS and speed reserve (ß = -0.09, CI -0.22 to 0.04) and between COGACT and both speed (ß = -0.26, CI -0.63 to 0.11) and memory reserves (ß = -0.20, CI -0.50.0 to 093). DISCUSSION: The associations of self-reported physical and cognitive activities with cognitive reserve are more pronounced in women, although APOE4 attenuates these associations. Future studies are needed to understand the causal relationship among sex, lifestyle activities, and genetic factors on cognitive reserve in older adults to best understand which lifestyle activities may be most beneficial and for whom.

Integration of GWAS and brain transcriptomic analyses in a multiethnic sample of 35,245 older adults identifies DCDC2 gene as predictor of episodic memory maintenance.

Identifying genes underlying memory function will help characterize cognitively resilient and high-risk declining subpopulations contributing to precision medicine strategies. We estimated episodic memory trajectories in 35,245 ethnically diverse older adults representing eight independent cohorts. We conducted apolipoprotein E (APOE)-stratified genome-wide association study (GWAS) analyses and combined individual cohorts' results via meta-analysis. Three independent transcriptomics datasets were used to further interpret GWAS signals. We identified DCDC2 gene significantly associated with episodic memory (Pmeta = 3.3 x 10-8 ) among non-carriers of APOE ε4 (N = 24,941). Brain transcriptomics revealed an association between episodic memory maintenance and (1) increased dorsolateral prefrontal cortex DCDC2 expression (P = 3.8 x 10-4 ) and (2) lower burden of pathological Alzheimer's disease (AD) hallmarks (paired helical fragment tau P = .003, and amyloid beta load P = .008). Additional transcriptomics results comparing AD and cognitively healthy brain samples showed a downregulation of DCDC2 levels in superior temporal gyrus (P = .007) and inferior frontal gyrus (P = .013). Our work identified DCDC2 gene as a novel predictor of memory maintenance.

A robust brain signature region approach for episodic memory performance in older adults.

The brain signature concept aims to characterize brain regions most strongly associated with an outcome of interest. Brain signatures derive their power from data-driven searches that select features based solely on performance metrics of prediction or classification. This approach has important potential to delineate biologically relevant brain substrates for prediction or classification of future trajectories. Recent work has used exploratory voxel-wise or atlas-based searches, with some using machine learning techniques to define salient features. These have shown undoubted usefulness, but two issues remain. The preponderance of recent work has been aimed at categorical rather than continuous outcomes, and it is rare for non-atlas reliant voxel-based signatures to be reported that would be useful for modelling and hypothesis testing. We describe a cross-validated signature region model for structural brain components associated with baseline and longitudinal episodic memory across cognitively heterogeneous populations including normal, mild impairment and dementia. We used three non-overlapping cohorts of older participants: from the UC Davis Aging and Diversity cohort (n = 255; mean age 75.3 ± 7.1 years; 128 cognitively normal, 97 mild cognitive impairment, 30 demented and seven unclassified); from Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 (n = 379; mean age 75.1 ± 7.2; 82 cognitively normal, 176 mild cognitive impairment, 121 Alzheimer's dementia); and from ADNI2/GO (n = 680; mean age 72.5 ± 7.1; 220 cognitively normal, 381 mild cognitive impairment and 79 Alzheimer's dementia). We used voxel-wise regression analysis, correcting for multiple comparisons, to generate an array of regional masks corresponding to different association strength levels of cortical grey matter with baseline memory and brain atrophy with memory change. Cognitive measures were episodic memory using Spanish and English Neuropsychological Assessment Scales instruments for UC Davis and ADNI-Mem for ADNI 1 and ADNI2/GO. Performance metric was the adjusted R2 coefficient of determination of each model explaining outcomes in two cohorts other than where it was computed. We compared within-cohort performances of signature models against each other and against other recent signature models of episodic memory. Findings were: (i) two independently generated signature region of interest models performed similarly in a third separate cohort; (ii) a signature region of interest generated in one imaging cohort replicated its performance level when explaining cognitive outcomes in each of other, separate cohorts; and (iii) this approach better explained baseline and longitudinal memory than other recent theory-driven and data-driven models. This suggests our approach can generate signatures that may be easily and robustly applied for modelling and hypothesis testing in mixed cognition cohorts.

The Utility of the Repeatable Battery of Neuropsychological Status in Patients with Temporal and Non-temporal Lobe Epilepsy.

OBJECTIVE: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a brief neuropsychological battery that has been validated in the assessment of dementia and other clinical populations. The current study examines the utility of the RBANS in patients with epilepsy. METHODS: Ninety-eight patients with epilepsy completed the RBANS as part of a more comprehensive neuropsychological evaluation. Performance on the RBANS was evaluated for patients with a diagnosis of temporal lobe epilepsy (TLE; n = 51) and other epilepsy patients (non-TLE, n = 47) in comparison to published norms. Multivariate analysis of variance compared group performances on RBANS indices. Rates of impairment were also compared across groups using cutoff scores of ≤1.0 and ≤1.5 standard deviations below the normative mean. Exploratory hierarchical regressions were used to examine the relations between epilepsy severity factors (i.e., age of onset, disease duration, and number of antiepileptic drugs [AEDs]) and RBANS performance. RESULTS: TLE and non-TLE patients performed below the normative sample across all RBANS indices. Those with TLE performed worse than non-TLE patients on the Immediate and Delayed Memory indices and exhibited higher rates of general cognitive impairment. Number of AEDs was the only epilepsy severity factor that significantly predicted RBANS total performance, accounting for 14% of the variance. CONCLUSIONS: These findings suggest that the RBANS has utility in evaluating cognition in patients with epilepsy and can differentiate TLE and non-TLE patients. Additionally, number of AEDs appears to be associated with global cognitive performance in adults with epilepsy.

Education differentially contributes to cognitive reserve across racial/ethnic groups.

INTRODUCTION: We examined whether educational attainment differentially contributes to cognitive reserve (CR) across race/ethnicity. METHODS: A total of 1553 non-Hispanic Whites (Whites), non-Hispanic Blacks (Blacks), and Hispanics in the Washington Heights-Inwood Columbia Aging Project (WHICAP) completed structural magnetic resonance imaging. Mixture growth curve modeling was used to examine whether the effect of brain integrity indicators (hippocampal volume, cortical thickness, and white matter hyperintensity [WMH] volumes) on memory and language trajectories was modified by education across racial/ethnic groups. RESULTS: Higher educational attainment attenuated the negative impact of WMH burden on memory (ß = -0.03; 99% CI: -0.071, -0.002) and language decline (ß = -0.024; 99% CI:- 0.044, -0.004), as well as the impact of cortical thinning on level of language performance for Whites, but not for Blacks or Hispanics. DISCUSSION: Educational attainment does not contribute to CR similarly across racial/ethnic groups.

APOE ε4 and resting-state functional connectivity in racially/ethnically diverse older adults.

INTRODUCTION: Numerous neuroimaging studies demonstrated an association between the apolipoprotein E (APOE) ε4 allele and resting-state functional connectivity (rsFC) of regions within the default mode network (DMN), both in healthy populations and patients with AD. It remains unclear whether the APOE ε4 allele differentially affects the brain's functional network architecture across race/ethnicity. METHODS: We investigated rsFC within DMN subsystems in 170 APOE ε4 carriers compared to 387 APOE ε4 non-carriers across three major racial/ethnic groups, including non-Hispanic Whites (n = 166), non-Hispanic Blacks (n = 185), and Hispanics (n = 206) from the Washington Heights-Inwood Columbia Aging Project. RESULTS: Compared to APOE ε4 non-carriers, APOE ε4 carriers had lower rsFC in temporal DMN, but only in non-Hispanic Whites. Non-Hispanic Black and Hispanic APOE ε4 carriers had slightly higher or similar rsFC compared with non-Hispanic White APOE ε4 non-carriers. DISCUSSION: These findings suggest that APOE ε4 modulates DMN rsFC differently in non-Hispanic Whites compared with non-Hispanic Blacks and Hispanics.

Late-Life Physical and Cognitive Activities Independently Contribute to Brain and Cognitive Resilience.

BACKGROUND: Active lifestyles are related to better cognitive aging outcomes, yet the unique role of different types of activity are unknown. OBJECTIVE: To examine the independent contributions of physical (PA) versus cognitive (CA) leisure activities to brain and cognitive aging. METHODS: Independent samples of non-demented older adults from University of California, San Francisco Hillblom Aging Network (UCSF; n = 344 typically aging) and University of California, Davis Diversity cohort (UCD; n = 485 normal to MCI) completed: 1) self-reported engagement in current PA and CA (UCSF: Physical Activity Scale for the Elderly and Cognitive Activity Scale; UCD: Life Experiences Assessment Form); 2) neuropsychological batteries; and 3) neuroimaging total gray matter volume, white matter hyperintensities, and/or global fractional anisotropy. PA and CA were simultaneously entered into multivariable linear regression models, adjusting for demographic characteristics and functional impairment severity. RESULTS: Brain outcomes: In UCSF, only PA was positively associated with gray matter volume and attenuated the relationship between age and fractional anisotropy. In UCD, only CA was associated with less white matter hyperintensities and attenuated the relationship between age and gray matter volume. Cognitive outcomes: In both cohorts, greater CA, but not PA, related to better cognition, independent of age and brain structure. In UCSF, CA attenuated the relationship between fractional anisotropy and cognition. In UCD, PA attenuated the association between white matter hyperintensities and cognition. CONCLUSIONS: Although their specificity was not easily teased apart, both PA and CA are clearly related to better brain and cognitive resilience markers across cohorts with differing educational, racial, and disease statuses. PA and CA may independently contribute to converging neuroprotective pathways for brain and cognitive aging.

Measurement invariance of neuropsychological measures of cognitive aging across race/ethnicity by sex/gender groups.

OBJECTIVE: The purpose of this study was to evaluate the measurement invariance of a neuropsychological battery across race/ethnicity by sex/gender subgroups over repeated measurements. METHOD: Participants were 6,057 non-Hispanic White (NHW), Black, and Hispanic men and women in the Washington/Hamilton Heights Inwood Columbia Aging Project (WHICAP) who were administered neuropsychological tests of memory, language, and visuospatial abilities at 18 to 24-month intervals for up to 25 years. Invariance analyses were conducted on the three-factor model across sex/gender, racial/ethnic, and sex/gender by racial/ethnic subgroups, as well as across five assessment timepoints. RESULTS: The three-factor model demonstrated full measurement invariance across sex/gender groups and over repeated measurements. However, partial measurement invariance (invariant factor structure and factor loadings but nonequivalent observed score intercepts) for the language domain was exhibited across racial/ethnic and sex/gender by racial/ethnic subgroups. CONCLUSION: Establishing measurement invariance is essential for valid interpretation of group differences in cognitive test performance. Findings from the current study highlight the need for continued examination of sex/gender by racial/ethnic differences in measurement properties of assessment tools, as well as expanded research on sex/gender variability across other understudied racial/ethnic groups. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Aging and HIV/AIDS: neurocognitive implications for older HIV-positive Latina/o adults.

In recent years, HIV/AIDS populations have become older and increasingly more ethnically diverse. Concurrently, the prevalence of HIV-related neurocognitive (NC) impairment remains high. This study examined the effects of age and ethnicity on NC function in HIV-positive adults. The sample (N = 126; 84 Latina/o and 42 Non-Hispanic White) completed a comprehensive NC battery. Global NC and domain average demographically-corrected t-scores were generated. There were no significant differences between Younger (<50 years) Latina/os and non-Hispanic Whites on Global NC function or NC domains (all p's >.10), with generally small effect sizes. Older Latina/os (≥50 years) were significantly more impaired than Older Non-Hispanic Whites on processing speed and learning, with trends in Global NC function and memory. Further, effect sizes fell within the medium to large range (Cohen's d's = .49-1.15). This study suggests that older Latina/os are at potentially greater risk for NC impairment, particularly in processing speed and learning, when compared to similarly-aged non-Hispanic whites.