Genetic variants and functional pathways associated with resilience to Alzheimer's disease.

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

Harmonization of delirium severity instruments: a comparison of the DRS-R-98, MDAS, and CAM-S using item response theory.

BACKGROUND: This study aimed to describe the level of agreement of three commonly used delirium instruments: the Delirium Rating Scale-Revised-98 (DRS-R-98), Memorial Delirium Assessment Scale (MDAS), and Confusion Assessment Method-Severity (CAM-S). METHODS: We used data from a prospective clinical research study, in which a team of trained lay interviewers administered each instrument along with supporting interview and cognitive assessments in the same group of patients daily while in the hospital (N = 352). We used item response theory methods to co-calibrate the instruments. RESULTS: The latent traits underlying the three measures, capturing the severity of a delirium assessment, had a high degree of correlation (r's > .82). Unidimensional factor models fit well, facilitating co-calibration of the instruments. Across instruments, the less intense symptoms were generally items reflecting cognitive impairment. Although the intensity of delirium severity for most in the sample was relatively low, many of the item thresholds for the delirium severity scales are high (i.e., in the more severe range of the latent ability distribution). This indicates that even people with severe delirium may have a low probability of endorsing the highest severity categories for many items. Co-calibration enabled us to derive crosswalks to map delirium severity scores among the delirium instruments. CONCLUSION: These delirium instruments measure the same underlying construct of delirium severity. Relative locations of items may inform design of refined measurement instruments. Mapping of overall delirium severity scores across the delirium severity instruments enabled us to derive crosswalks, which allow scores to be translated across instruments, facilitating comparison and combination of delirium studies for integrative analysis.

Children's and Parents' Ability to Tolerate Child Distress: Impact on Cognitive Behavioral Therapy for Pediatric Obsessive Compulsive Disorder.

The present study explored the concept of tolerance for child distress in 46 children (ages 5-8), along with their mothers and fathers, who received family-based CBT for OCD. The study sought to describe baseline tolerance, changes in tolerance with treatment, and the predictive impact of tolerance on symptom improvement. Tolerance was rated by clinicians on a single item and the CY-BOCS was used to measure OCD severity. Descriptive results suggested that all participants had some difficulty tolerating the child's distress at baseline while paired t tests indicated large improvements were made over treatment (d = 1.2-2.0). Fathers' initial tolerance was significantly related to symptom improvement in a multivariate regression as were fathers' and children's changes in distress tolerance over the course of treatment. Overall, results provide support for examining tolerance of child distress including its predictive impact and potential as a supplemental intervention target.

Measurement precision across cognitive domains in the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set.

OBJECTIVE: To demonstrate measurement precision of cognitive domains in the Alzheimer's Disease Neuroimaging Initiative (ADNI) data set. METHOD: Participants with normal cognition (NC), mild cognitive impairment (MCI), and Alzheimer's disease (AD) were included from all ADNI waves. We used data from each person's last study visit to calibrate scores for memory, executive function, language, and visuospatial functioning. We extracted item information functions for each domain and used these to calculate standard errors of measurement. We derived scores for each domain for each diagnostic group and plotted standard errors of measurement for the observed range of scores. RESULTS: Across all waves, there were 961 people with NC, 825 people with MCI, and 694 people with AD at their most recent study visit (data pulled February 25, 2019). Across ADNI's battery there were 34 memory items, 18 executive function items, 20 language items, and seven visuospatial items. Scores for each domain were highest on average for people with NC, intermediate for people with MCI, and lowest for people with AD, with most scores across all groups in the range of -1 to +1. Standard error of measurement in the range from -1 to +1 was highest for memory, intermediate for language and executive functioning, and lowest for visuospatial. CONCLUSION: Modern psychometric approaches provide tools to help understand measurement precision of the scales used in studies. In ADNI, there are important differences in measurement precision across cognitive domains. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

You Say Tomato, I Say Radish: Can Brief Cognitive Assessments in the U.S. Health Retirement Study Be Harmonized With Its International Partner Studies?

OBJECTIVES: To characterize the extent to which brief cognitive assessments administered in the population-representative U.S. Health and Retirement Study (HRS) and its International Partner Studies can be considered to be measuring a single, unidimensional latent cognitive function construct. METHODS: Cognitive function assessments were administered in face-to-face interviews in 12 studies in 26 countries (N = 155,690), including the U.S. HRS and selected International Partner Studies. We used the time point of the first cognitive assessment for each study to minimize differential practice effects across studies and documented cognitive test item coverage across studies. Using confirmatory factor analysis models, we estimated single-factor general cognitive function models and bifactor models representing memory-specific and nonmemory-specific cognitive domains for each study. We evaluated model fits and factor loadings across studies. RESULTS: Despite relatively sparse and inconsistent cognitive item coverage across studies, all studies had some cognitive test items in common with other studies. In all studies, the bifactor models with a memory-specific domain fit better than single-factor general cognitive function models. The data fit the models at reasonable thresholds for single-factor models in 6 of the 12 studies and for the bifactor models in all 12 of the 12 studies. DISCUSSION: The cognitive assessments in the U.S. HRS and its International Partner Studies reflect comparable underlying cognitive constructs. We discuss the assumptions underlying our methods, present alternatives, and future directions for cross-national harmonization of cognitive aging data.

Cognitive function and neuropathological outcomes: a forward-looking approach.

OBJECTIVE: To evaluate the risk of Alzheimer's disease-related neuropathology burden at autopsy given older adults' current cognitive state. METHOD: Participants included 1,303 individuals who enrolled in the Religious Orders Study (ROS) and 1,789 who enrolled in the Rush Memory and Aging Project (MAP). Cognitive status was evaluated via standardized assessments of global cognition and episodic memory. At the time of analyses, about 50% of participants were deceased with the remaining numbers right censored. Using multi-state Cox proportional hazard models, we compared the cognitive status of all subjects alive at a given age and estimated future risk of dying with different AD-related neuropathologies. Endpoints considered were Braak Stages (0-2, 3-4, 5-6), CERAD (0, 1, 2, 3), and TDP-43 (0, 1, 2, 3) level. RESULTS: For all three pathological groupings (Braak, CERAD, TDP-43), we found that a cognitive test score one standard deviation below average put individuals at up to three times the risk for being diagnosed with late stage AD at autopsy according to pathological designations. The effect remained significant after adjusting for sex, APOE-e4 status, smoking status, education level, and vascular health scores. CONCLUSION: Applying multi-state modeling techniques, we were able to identify those at risk of exhibiting specific levels of neuropathology based on current cognitive test performance. This approach presents new and approachable possibilities in clinical settings for diagnosis and treatment development programs.

Evaluating Alzheimer's disease biomarkers as mediators of age-related cognitive decline.

Age-related changes in cognition are partially mediated by the presence of neuropathology and neurodegeneration. This manuscript evaluates the degree to which biomarkers of Alzheimer's disease, (AD) neuropathology and longitudinal changes in brain structure, account for age-related differences in cognition. Data from the AD Neuroimaging Initiative (n = 1012) were analyzed, including individuals with normal cognition and mild cognitive impairment. Parallel process mixed effects regression models characterized longitudinal trajectories of cognitive variables and time-varying changes in brain volumes. Baseline age was associated with both memory and executive function at baseline (p's < 0.001) and change in memory and executive function performances over time (p's < 0.05). After adjusting for clinical diagnosis, baseline, and longitudinal changes in brain volume, and baseline levels of cerebrospinal fluid biomarkers, age effects on change in episodic memory and executive function were fully attenuated, age effects on baseline memory were substantially attenuated, but an association remained between age and baseline executive function. Results support previous studies that show that age effects on cognitive decline are fully mediated by disease and neurodegeneration variables but also show domain-specific age effects on baseline cognition, specifically an age pathway to executive function that is independent of brain and disease pathways.

Deconstructing racial differences: the effects of quality of education and cerebrovascular risk factors.

OBJECTIVES: To evaluate the effects of vascular conditions and education quality on cognition over time in White and African American (AA) older adults. METHOD: We investigated cross-sectional and longitudinal racial differences in executive functioning (EF) and memory composites among Whites (n = 461) and AAs (n = 118) enrolled in a cohort study. We examined whether cerebrovascular risk factors and Shipley Vocabulary scores (a proxy for education quality) accounted for racial differences. RESULTS: On average, AAs had lower quality of education and more cerebrovascular risk factors including hypertension, diabetes, and obesity. AAs had lower mean EF and memory at baseline, but there were no group differences in rates of decline. Cross-sectional racial differences in EF and memory persisted after controlling for vascular disease, but disappeared when controlling for Shipley Vocabulary. DISCUSSION: Quality of education appears to be more important than cerebrovascular risk factors in explaining cross-sectional differences in memory and EF performance between White and AA older adults. Further investigation is needed regarding the relative contribution of education quality and cerebrovascular risk factors to cognitive decline among ethnically/racially diverse older adults.

Neuropsychological profiles of an elderly cohort undergoing elective surgery and the relationship between cognitive performance and delirium.

OBJECTIVES: To examine baseline (preoperative) neuropsychological test performance in a cohort of elderly individuals undergoing elective surgery and the association between specific neuropsychological domains and postoperative delirium. DESIGN: Ongoing prospective cohort study. SETTING: Successful Aging after Elective Surgery Study. PARTICIPANTS: Elderly adults (N=300) scheduled for elective (noncardiac) surgery. MEASUREMENTS: Neuropsychological testing, including standardized assessments of memory, divided and sustained attention, speed of mental processing, verbal fluency, working memory, language, and an overall measure of premorbid cognitive functioning, was performed 2 to 4 weeks before surgery. The relationship between the individual neuropsychological tests and delirium status was examined using linear regression, adjusting for age, sex, and education. RESULTS: Study participants were generally highly educated (mean years of education 15.0±2.9), with minimal or no cognitive impairment (mean Modified Mini-Mental State Examination score 93.2 out of 100). After adjustment, participants who developed postoperative delirium had performed significantly lower preoperatively on measures of speed of mental processing and divided attention (Trail-Making Test Part B, mean difference 17.55, P=.02), category fluency (animal naming, mean difference -1.94, P=.01), sustained visual attention (Visual Search and Attention, mean difference -3.19, P<.001), and working memory with new learning and recall (Hopkins Verbal Learning Test-Revised Total mean difference -0.53 to -0.79, P<.01). CONCLUSION: Individuals who later develop delirium have lower scores on tests evaluating the areas of complex attention, executive functioning, and rapid access to verbal knowledge or semantic networks at baseline. Future studies to better understand how the cognitive profiles identified may predispose individuals to developing delirium may help pave the way to greater understanding of the mechanisms of delirium.

Cognitive and Brain Reserve and the Risk of Postoperative Delirium in Older Patients.

BACKGROUND: Cognitive and brain reserve theories suggest that aspects of neural architecture or cognitive processes modify the impact of neuropathological processes on cognitive outcomes. While frequently studied in the context of dementia, reserve in delirium is relatively understudied. METHODS: We examined the association of three markers of brain reserve (head circumference, MRI-derived brain volume, and leisure time physical activity) and five markers of cognitive reserve (education, vocabulary, cognitive activities, cognitive demand of lifetime occupation, and interpersonal demand of lifetime occupation) and the risk of postoperative delirium in a prospective observational study of 566 older adults free of dementia undergoing scheduled surgery. FINDINGS: Twenty four percent of patients (135/566) developed delirium during the postoperative hospitalization period. Of the reserve markers examined, only the Wechsler Test of Adult Reading (WTAR) was significantly associated with the risk of delirium. A one-half standard deviation better performance on the WTAR was associated with a 38% reduction in delirium risk (P = 0·01); adjusted relative risk of 0·62, 95% confidence interval 0·45-0·85. INTERPRETATION: In this relatively large and well-designed study, most markers of reserve fail to predict delirium risk. The exception to this is the WTAR. Our findings suggest that the reserve markers that are important for delirium may be different from those considered to be important for dementia.

Cognitive and brain reserve and the risk of postoperative delirium in older patients: analysis of data from a prospective observational study.

BACKGROUND: Cognitive and brain reserve theories suggest that aspects of neural architecture or cognitive processes modify the effect of neuropathological processes on cognitive outcomes. Although frequently studied in the context of dementia, reserve in delirium is understudied. METHODS: Using data from a prospective observational study, we examined the association of three markers of brain reserve (head circumference, MRI-derived brain volume, and leisure time physical activity), five markers of cognitive reserve (education, vocabulary, cognitive activities, cognitive demand of lifetime occupation, and interpersonal demand of lifetime occupation), and the risk of postoperative delirium in 566 older adults (age ≥70 years) free of dementia undergoing scheduled surgery. FINDINGS: 135 (24%) of 566 patients developed delirium during the postoperative hospital stay. Of the reserve markers examined, only the Wechsler Test of Adult Reading was associated with the risk of delirium. A 0·5 SD better performance on the Wechsler Test of Adult Reading was associated with a 38% reduction in delirium risk (adjusted risk ratio of 0·62, 95% CI 0·45-0·85; p=0·01). INTERPRETATION: Most markers of reserve failed to predict delirium risk. The exception to this is the Wechsler Test of Adult Reading. Our findings suggest that the reserve markers that are important for delirium might be different from those thought to be important for dementia. FUNDING: National Institute on Aging, National Heart Lung and Blood Institute.

Modeling learning and memory using verbal learning tests: results from ACTIVE.

OBJECTIVE: To investigate the influence of memory training on initial recall and learning. METHOD: The Advanced Cognitive Training for Independent and Vital Elderly study of community-dwelling adults older than age 65 (n = 1,401). We decomposed trial-level recall in the Auditory Verbal Learning Test (AVLT) and Hopkins Verbal Learning Test (HVLT) into initial recall and learning across trials using latent growth models. RESULTS: Trial-level increases in words recalled in the AVLT and HVLT at each follow-up visit followed an approximately logarithmic shape. Over the 5-year study period, memory training was associated with slower decline in Trial 1 AVLT recall (Cohen's d = 0.35, p = .03) and steep pre- and posttraining acceleration in learning (d = 1.56, p < .001). Findings were replicated using the HVLT (decline in initial recall, d = 0.60, p = .01; pre- and posttraining acceleration in learning, d = 3.10, p < .001). Because of the immediate training boost, the memory-trained group had a higher level of recall than the control group through the end of the 5-year study period despite faster decline in learning. DISCUSSION: This study contributes to the understanding of the mechanisms by which training benefits memory and expands current knowledge by reporting long-term changes in initial recall and learning, as measured from growth models and by characterization of the impact of memory training on these components. Results reveal that memory training delays the worsening of memory span and boosts learning.

AD pathology and cerebral infarctions are associated with memory and executive functioning one and five years before death.

We provide rigorous psychometric evidence for distinct patterns of cognitive impairment for Alzheimer's disease (AD) and cerebral infarctions using 440 participants from the Religious Order Study. Latent variable models were used to decompose the effects of AD pathology and cerebral infarctions assessed at autopsy on overall cognition and specific neuropsychological tests at one and five years prior to death. Results support clinical and univariate psychometric analyses that memory impairment is more pronounced in AD, and executive impairment is more pronounced in the presence of cerebral infarctions. These specific effects are subtle relative to the stronger associations of both AD neuropathology and cerebral infarctions with overall levels of cognitive impairment.

Parallel but not equivalent: challenges and solutions for repeated assessment of cognition over time.

OBJECTIVE: Analyses of individual differences in change may be unintentionally biased when versions of a neuropsychological test used at different follow-ups are not of equivalent difficulty. This study's objective was to compare mean, linear, and equipercentile equating methods and demonstrate their utility in longitudinal research. STUDY DESIGN AND SETTING: The Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE, N = 1,401) study is a longitudinal randomized trial of cognitive training. The Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 819) is an observational cohort study. Nonequivalent alternate versions of the Auditory Verbal Learning Test (AVLT) were administered in both studies. RESULTS: Using visual displays, raw and mean-equated AVLT scores in both studies showed obvious nonlinear trajectories in reference groups that should show minimal change and poor equivalence over time (ps ≤ .001), and raw scores demonstrated poor fits in models of within-person change (root mean square errors of approximation, RMSEAs > 0.12). Linear and equipercentile equating produced more similar means in reference groups (ps ≥ .09) and performed better in growth models (RMSEAs < 0.05). CONCLUSION: Equipercentile equating is the preferred equating method because it accommodates tests more difficult than a reference test at different percentiles of performance and performs well in models of within-person trajectory. The method has broad applications in both clinical and research settings to enhance the ability to use nonequivalent test forms.

Disparities in self-reported geriatric depressive symptoms due to sociodemographic differences: an extension of the bi-factor item response theory model for use in differential item functioning.

This study evaluates the measurement noninvariance, or differential item functioning (DIF), in the Center for Epidemiological Studies-Depression (CES-D) items attributable to age, sex, and race/ethnicity among community-dwelling older adults. Participants (N=2773) were from the New Haven site of the Established Populations for Epidemiologic Studies in the Elderly. Statistical analyses included exploratory factor analysis, bi-factor confirmatory factor analysis, and a bi-factor multiple indicator and multiple causes (MIMIC) model to address measurement noninvariance. Blacks, compared with whites, were more likely to endorse items loading on the interpersonal factor, which include "people dislike me" and "people are unfriendly." Women were less likely to endorse the interpersonal items and the "I felt like a failure" item (odds ratio [OR]=0.63, 95% confidence interval [CI]: 0.42, 0.94) than men. But women had a higher proportional odds than men for endorsing the "crying" item (OR=1.86, 95% CI: 1.17, 2.96). Those 75 years and older (relative to those aged 65-74) were less likely to endorse the "I felt like a failure" item (OR=0.65, 95% CI: 0.43, 0.97). However, measurement noninvariance found in both the "crying" and "failure" items were attributable to women and to those aged 75 and older were trivial after controlling for the underlying level of depressive symptomatology. Therefore, the interpersonal items showed measurement noninvariance attributable to sex and race. The bi-factor MIMIC model is useful for examining measurement noninvariance due to sociodemographics in a multidimensional depression instrument.