Associations between depression and cardiometabolic health: A 27-year longitudinal study.

BACKGROUND: Clarifying the relationship between depression symptoms and cardiometabolic and related health could clarify risk factors and treatment targets. The objective of this study was to assess whether depression symptoms in midlife are associated with the subsequent onset of cardiometabolic health problems. METHODS: The study sample comprised 787 male twin veterans with polygenic risk score data who participated in the Harvard Twin Study of Substance Abuse ('baseline') and the longitudinal Vietnam Era Twin Study of Aging ('follow-up'). Depression symptoms were assessed at baseline [mean age 41.42 years (s.d. = 2.34)] using the Diagnostic Interview Schedule, Version III, Revised. The onset of eight cardiometabolic conditions (atrial fibrillation, diabetes, erectile dysfunction, hypercholesterolemia, hypertension, myocardial infarction, sleep apnea, and stroke) was assessed via self-reported doctor diagnosis at follow-up [mean age 67.59 years (s.d. = 2.41)]. RESULTS: Total depression symptoms were longitudinally associated with incident diabetes (OR 1.29, 95% CI 1.07-1.57), erectile dysfunction (OR 1.32, 95% CI 1.10-1.59), hypercholesterolemia (OR 1.26, 95% CI 1.04-1.53), and sleep apnea (OR 1.40, 95% CI 1.13-1.74) over 27 years after controlling for age, alcohol consumption, smoking, body mass index, C-reactive protein, and polygenic risk for specific health conditions. In sensitivity analyses that excluded somatic depression symptoms, only the association with sleep apnea remained significant (OR 1.32, 95% CI 1.09-1.60). CONCLUSIONS: A history of depression symptoms by early midlife is associated with an elevated risk for subsequent development of several self-reported health conditions. When isolated, non-somatic depression symptoms are associated with incident self-reported sleep apnea. Depression symptom history may be a predictor or marker of cardiometabolic risk over decades.

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.

Interaction between Alcohol Consumption and Apolipoprotein E (ApoE) Genotype with Cognition in Middle-Aged Men.

OBJECTIVE: Heavy alcohol consumption is associated with poorer cognitive function in older adults. Although understudied in middle-aged adults, the relationship between alcohol and cognition may also be influenced by genetics such as the apolipoprotein (ApoE) ε4 allele, a risk factor for Alzheimer's disease. We examined the relationship between alcohol consumption, ApoE genotype, and cognition in middle-aged adults and hypothesized that light and/or moderate drinkers (≤2 drinks per day) would show better cognitive performance than heavy drinkers or non-drinkers. Additionally, we hypothesized that the association between alcohol use and cognitive function would differ by ApoE genotype (ε4+ vs. ε4-). METHOD: Participants were 1266 men from the Vietnam Era Twin Study of Aging (VETSA; M age = 56; range 51-60) who completed a neuropsychological battery assessing seven cognitive abilities: general cognitive ability (GCA), episodic memory, processing speed, executive function, abstract reasoning, verbal fluency, and visuospatial ability. Alcohol consumption was categorized into five groups: never, former, light, moderate, and heavy. RESULTS: In fully adjusted models, there was no significant main effect of alcohol consumption on cognitive functions. However, there was a significant interaction between alcohol consumption and ApoE ε4 status for GCA and episodic memory, such that the relationship of alcohol consumption and cognition was stronger in ε4 carriers. The ε4+ heavy drinking subgroup had the poorest GCA and episodic memory. CONCLUSIONS: Presence of the ε4 allele may increase vulnerability to the deleterious effects of heavy alcohol consumption. Beneficial effects of light or moderate alcohol consumption were not observed.

Independent and Synergistic Associations Between TBI Characteristics and PTSD Symptom Clusters on Cognitive Performance and Postconcussive Symptoms in Iraq and Afghanistan Veterans.

OBJECTIVE: The investigators sought to evaluate the independent and interactive associations between mild traumatic brain injury (mTBI) characteristics and posttraumatic stress disorder (PTSD) symptoms with regard to postconcussive symptoms and cognition among treatment-seeking veterans of the U.S. conflicts in Iraq and Afghanistan. METHODS: Sixty-seven Iraq and Afghanistan veterans who had a history of mTBI and comorbid PTSD were grouped based on injury mechanism (blast versus nonblast) and number of lifetime mTBIs (one to two versus three or more). Independent associations between mTBI characteristics and PTSD symptom clusters were evaluated with regard to cognition and postconcussive symptoms. Follow-up analyses were conducted to determine any interactive associations between TBI characteristics and PTSD symptom clusters. RESULTS: Higher PTSD symptoms, particularly hyperarousal, were associated with poorer executive functioning and higher postconcussive symptoms. No direct relationships were observed between PTSD symptom clusters and memory or processing speed. The relationship between hyperarousal and processing speed was moderated by lifetime mTBIs, such that those with a history of at least three mTBIs demonstrated a negative association between hyperarousal and processing speed. Blast-related mTBI history was associated with reduced processing speed, compared with non-blast-related mTBI. However, an interaction was observed such that among those with blast-related mTBI history, higher re-experiencing symptoms were associated with poorer processing speed, whereas veterans without history of blast-related mTBI did not demonstrate an association between processing speed and re-experiencing symptoms. CONCLUSIONS: Higher hyperarousal and re-experiencing symptoms were associated with reduced processing speed among veterans with repetitive and blast-related mTBI history, respectively. PTSD symptoms, specifically hyperarousal, were associated with poorer executive functioning and higher postconcussive symptoms. Limited associations were found between injury characteristics and cognition chronically following mTBI. However, these results support synergistic effects of specific PTSD symptom clusters and TBI characteristics.

MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction.

INTRODUCTION: The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression. METHODS: Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction. RESULTS: Heritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction. DISCUSSION: Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.

SMART-CPT for veterans with comorbid post-traumatic stress disorder and history of traumatic brain injury: a randomised controlled trial.

OBJECTIVE: To better concurrently address emotional and neuropsychological symptoms common in veterans with comorbid post-traumatic stress disorder (PTSD) and history of traumatic brain injury (TBI), we integrated components of compensatory cognitive training from the Cognitive Symptom Management and Rehabilitation Therapy (CogSMART) programme into cognitive processing therapy (CPT) for PTSD to create a hybrid treatment, SMART-CPT (CogSMART+CPT). This study compared the efficacy of standard CPT with SMART-CPT for treatment of veterans with comorbid PTSD and history of TBI reporting cognitive symptoms. METHODS: One hundred veterans with PTSD, a history of mild to moderate TBI and current cognitive complaints were randomised and received individually delivered CPT or SMART-CPT for 12 weeks. Participants underwent psychological, neurobehavioural and neuropsychological assessments at baseline, on completion of treatment and 3 months after treatment. RESULTS: Both CPT and SMART-CPT resulted in clinically significant reductions in PTSD and postconcussive symptomatology and improvements in quality of life. SMART-CPT resulted in additional improvements in the neuropsychological domains of attention/working memory, verbal learning/memory and novel problem solving. CONCLUSION: SMART-CPT, a mental health intervention for PTSD, combined with compensatory cognitive training strategies, reduces PTSD and neurobehavioural symptoms and also provides added value by improving cognitive functioning.

The Role of Pain Catastrophizing in Cognitive Functioning Among Veterans With a History of Mild Traumatic Brain Injury.

OBJECTIVE: To determine the role of pain catastrophizing (PC) in neuropsychological functioning in veterans with a history of mild traumatic brain injury (TBI). PARTICIPANTS: Thirty-nine Iraq and Afghanistan combat veterans evaluated in the post-acute phase following mild TBI. METHODS: Participants underwent psychiatric and TBI clinical interviews, neuropsychological tests, and self-report assessments of PC, pain intensity, depression, and posttraumatic stress disorder symptoms. Cognitive functioning composite scores of executive functioning, processing speed, and learning and memory were created. Composites were entered as dependent variables into separate linear regressions to examine relations with PC. RESULTS: Greater PC was associated with worse executive functioning and processing speed even when controlling for confounding variables. CONCLUSIONS: One's interpretation of pain, in addition to pain intensity, has implications for cognitive functioning. Future research is encouraged to determine whether adaptive pain coping mechanisms improve cognitive functioning or, alternatively, whether cognitive rehabilitation strategies reduce PC.

Contributions to Executive Dysfunction in Operation Enduring Freedom/Operation Iraqi Freedom Veterans With Posttraumatic Stress Disorder and History of Mild Traumatic Brain Injury.

OBJECTIVE: Posttraumatic stress disorder (PTSD), history of mild traumatic brain injury (mTBI), and executive function (EF) difficulties are prevalent in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans. We evaluated the contributions of injury variables, lower-order cognitive component processes (processing speed/attention), and psychological symptoms to EF. PARTICIPANTS: OEF/OIF Veterans (N = 65) with PTSD and history of mTBI were administered neuropsychological tests of EF and self-report assessments of PTSD and depression. RESULTS: Those impaired on one or more EF measures had higher PTSD and depression symptoms and lower processing speed/attention performance than those with intact performance on all EF measures. Across participants, poorer attention/processing speed performance and higher psychological symptoms were associated with worse performance on specific aspects of EF (eg, inhibition and switching) even after accounting for injury variables. Although direct relationships between EF and injury variables were equivocal, there was an interaction between measures of injury burden and processing speed/attention such that those with greater injury burden exhibited significant and positive relationships between processing speed/attention and inhibition/switching, whereas those with lower injury burden did not. CONCLUSION: Psychological symptoms as well as lower-order component processes of EF (attention and processing speed) contribute significantly to executive dysfunction in OEF/OIF Veterans with PTSD and history of mTBI. However, there may be equivocal relationships between injury variables and EF that warrant further study. Results provide groundwork for more fully understanding cognitive symptoms in OEF/OIF Veterans with PTSD and history of mTBI that can inform psychological and cognitive interventions in this population.

Pilot investigation of a novel white matter imaging technique in Veterans with and without history of mild traumatic brain injury.

OBJECTIVE: The objective of this study is to assess utility of in vivo myelin imaging in combat Veterans with and without history of mild traumatic brain injury (mTBI). We hypothesized that those with history of mTBI would have lower myelin water fraction (MWF), a marker of myelin integrity and content, than those without, and lower MWF would be associated with worse speeded attention/processing speed. RESEARCH DESIGN: Combat Veterans (N = 70) with (n = 42) and without history of mTBI (n = 28) underwent neuroimaging including a novel myelin-sensitive magnetic resonance imaging technique (multicomponent-driven equilibrium single-pulse observation of T1/T2; mcDESPOT) and comprehensive neuropsychological assessment. RESULTS: There were no group differences in MWF using a region-of-interest approach. An exploratory analysis applying limited spatial constraints, however, revealed significantly more 'potholes' (clusters of low MWF) in Veterans with history of mTBI compared to those without. Lower MWF across several ROIs was associated with worse performance on a speeded attention task across groups. CONCLUSION: Veterans in the post-acute period following mTBI showed limited and spatially heterogeneous MWF changes and myelin integrity was significantly related to processing speed. This preliminary evidence for usefulness of mcDESPOT in combat Veterans with history of mTBI warrants future research to determine mcDESPOT's relative utility compared to techniques such as diffusion tensor imaging.

Statistically Derived Subtypes and Associations with Cerebrospinal Fluid and Genetic Biomarkers in Mild Cognitive Impairment: A Latent Profile Analysis.

OBJECTIVES: Research demonstrates heterogeneous neuropsychological profiles among individuals with mild cognitive impairment (MCI). However, few studies have included visuoconstructional ability or used latent mixture modeling to statistically identify MCI subtypes. Therefore, we examined whether unique neuropsychological MCI profiles could be ascertained using latent profile analysis (LPA), and subsequently investigated cerebrospinal fluid (CSF) biomarkers, genotype, and longitudinal clinical outcomes between the empirically derived classes. METHODS: A total of 806 participants diagnosed by means of the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI criteria received a comprehensive neuropsychological battery assessing visuoconstructional ability, language, attention/executive function, and episodic memory. Test scores were adjusted for demographic characteristics using standardized regression coefficients based on "robust" normal control performance (n=260). Calculated Z-scores were subsequently used in the LPA, and CSF-derived biomarkers, genotype, and longitudinal clinical outcome were evaluated between the LPA-derived MCI classes. RESULTS: Statistical fit indices suggested a 3-class model was the optimal LPA solution. The three-class LPA consisted of a mixed impairment MCI class (n=106), an amnestic MCI class (n=455), and an LPA-derived normal class (n=245). Additionally, the amnestic and mixed classes were more likely to be apolipoprotein e4+ and have worse Alzheimer's disease CSF biomarkers than LPA-derived normal subjects. CONCLUSIONS: Our study supports significant heterogeneity in MCI neuropsychological profiles using LPA and extends prior work (Edmonds et al., 2015) by demonstrating a lower rate of progression in the approximately one-third of ADNI MCI individuals who may represent "false-positive" diagnoses. Our results underscore the importance of using sensitive, actuarial methods for diagnosing MCI, as current diagnostic methods may be over-inclusive. (JINS, 2017, 23, 564-576).

Examining Associations Between Smartphone Use and Clinical Severity in Frontotemporal Dementia: Proof-of-Concept Study.

BACKGROUND: Frontotemporal lobar degeneration (FTLD) is a leading cause of dementia in individuals aged <65 years. Several challenges to conducting in-person evaluations in FTLD illustrate an urgent need to develop remote, accessible, and low-burden assessment techniques. Studies of unobtrusive monitoring of at-home computer use in older adults with mild cognitive impairment show that declining function is reflected in reduced computer use; however, associations with smartphone use are unknown. OBJECTIVE: This study aims to characterize daily trajectories in smartphone battery use, a proxy for smartphone use, and examine relationships with clinical indicators of severity in FTLD. METHODS: Participants were 231 adults (mean age 52.5, SD 14.9 years; n=94, 40.7% men; n=223, 96.5% non-Hispanic White) enrolled in the Advancing Research and Treatment of Frontotemporal Lobar Degeneration (ARTFL study) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS study) Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) Mobile App study, including 49 (21.2%) with mild neurobehavioral changes and no functional impairment (ie, prodromal FTLD), 43 (18.6%) with neurobehavioral changes and functional impairment (ie, symptomatic FTLD), and 139 (60.2%) clinically normal adults, of whom 55 (39.6%) harbored heterozygous pathogenic or likely pathogenic variants in an autosomal dominant FTLD gene. Participants completed the Clinical Dementia Rating plus National Alzheimer's Coordinating Center Frontotemporal Lobar Degeneration Behavior and Language Domains (CDR+NACC FTLD) scale, a neuropsychological battery; the Neuropsychiatric Inventory; and brain magnetic resonance imaging. The ALLFTD Mobile App was installed on participants' smartphones for remote, passive, and continuous monitoring of smartphone use. Battery percentage was collected every 15 minutes over an average of 28 (SD 4.2; range 14-30) days. To determine whether temporal patterns of battery percentage varied as a function of disease severity, linear mixed effects models examined linear, quadratic, and cubic effects of the time of day and their interactions with each measure of disease severity on battery percentage. Models covaried for age, sex, smartphone type, and estimated smartphone age. RESULTS: The CDR+NACC FTLD global score interacted with time on battery percentage such that participants with prodromal or symptomatic FTLD demonstrated less change in battery percentage throughout the day (a proxy for less smartphone use) than clinically normal participants (P<.001 in both cases). Additional models showed that worse performance in all cognitive domains assessed (ie, executive functioning, memory, language, and visuospatial skills), more neuropsychiatric symptoms, and smaller brain volumes also associated with less battery use throughout the day (P<.001 in all cases). CONCLUSIONS: These findings support a proof of concept that passively collected data about smartphone use behaviors associate with clinical impairment in FTLD. This work underscores the need for future studies to develop and validate passive digital markers sensitive to longitudinal clinical decline across neurodegenerative diseases, with potential to enhance real-world monitoring of neurobehavioral change.

Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Four year practice effects on the RBANS in a longitudinal study of older adults.

OBJECTIVE: The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is a widely used measure in neuropsychological assessment. Studies of practice effects on the RBANS have typically been assessed over one or two repeated assessments. The aim of the current study is to examine practice effects across four-years after baseline in a longitudinal study of cognitively healthy older adults. METHOD: 453 Participants from the Louisiana Aging Brain Study (LABrainS) completed the RBANS Form A on up to four annual assessments after baseline. Practice effects were calculated using a modified participants-replacement method where scores of returnees are compared to the baseline scores of matched participants with additional adjustment for attrition effects. RESULTS: Practice effects were observed primarily in the immediate memory, delayed memory, and total score indices. These index scores continued to increase with repeated assessments. CONCLUSIONS: These findings extend past work on the RBANS showing the susceptibility of memory measures to practice effects. Given that memory and total score indices of the RBANS have the most robust relationships with pathological cognitive decline, these findings raise concerns about the ability to recruit those at risk for decline from longitudinal studies using the same form of the RBANS for multiple years.

Misinterpreting cognitive change over multiple timepoints: When practice effects meet age-related decline.

OBJECTIVE: Practice effects (PE) on cognitive testing have been shown to delay detection of impairment and impede our ability to assess change. When decline over time is expected, as with older adults or progressive diseases, failure to adequately address PEs may lead to inaccurate conclusions because PEs artificially boost scores while pathology- or age-related decline reduces scores. Unlike most methods, a participant-replacement approach can separate pathology- or age-related decline from PEs; however, this approach has only been used across two timepoints. More than two timepoints make it possible to determine if PEs level out after the first follow-up, but it is analytically challenging because individuals may not be assessed at every timepoint. METHOD: We examined 1,190 older adults who were cognitively unimpaired (n = 809) or had mild cognitive impairment (MCI; n = 381). Participants completed six neuropsychological measures at three timepoints (baseline, 12-month, 24-month). We implemented a participant-replacement method using generalized estimating equations in comparisons of matched returnees and replacements to calculate PEs. RESULTS: Without accounting for PEs, cognitive function appeared to improve or stay the same. However, with the participant-replacement method, we observed significant PEs within both groups at all timepoints. PEs did not uniformly decrease across time; some-specifically on episodic memory measures-continued to increase beyond the first follow-up. CONCLUSION: A replacement method of PE adjustment revealed significant PEs across two follow-ups. As expected in these older adults, accounting for PEs revealed cognitive decline. This, in turn, means earlier detection of cognitive deficits, including progression to MCI, and more accurate characterization of longitudinal change. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Genetic and Environmental Influences on Structural and Diffusion-Based Alzheimer's Disease Neuroimaging Signatures Across Midlife and Early Old Age.

BACKGROUND: Composite scores of magnetic resonance imaging-derived metrics in brain regions associated with Alzheimer's disease (AD), commonly termed AD signatures, have been developed to distinguish early AD-related atrophy from normal age-associated changes. Diffusion-based gray matter signatures may be more sensitive to early AD-related changes compared with thickness/volume-based signatures, demonstrating their potential clinical utility. The timing of early (i.e., midlife) changes in AD signatures from different modalities and whether diffusion- and thickness/volume-based signatures each capture unique AD-related phenotypic or genetic information remains unknown. METHODS: Our validated thickness/volume signature, our novel mean diffusivity (MD) signature, and a magnetic resonance imaging-derived measure of brain age were used in biometrical analyses to examine genetic and environmental influences on the measures as well as phenotypic and genetic relationships between measures over 12 years. Participants were 736 men from 3 waves of the Vietnam Era Twin Study of Aging (VETSA) (baseline/wave 1: mean age [years] = 56.1, SD = 2.6, range = 51.1-60.2). Subsequent waves occurred at approximately 5.7-year intervals. RESULTS: MD and thickness/volume signatures were highly heritable (56%-72%). Baseline MD signatures predicted thickness/volume signatures over a decade later, but baseline thickness/volume signatures showed a significantly weaker relationship with future MD signatures. AD signatures and brain age were correlated, but each measure captured unique phenotypic and genetic variance. CONCLUSIONS: Cortical MD and thickness/volume AD signatures are heritable, and each signature captures unique variance that is also not explained by brain age. Moreover, results are in line with changes in MD emerging before changes in cortical thickness, underscoring the utility of MD as a very early predictor of AD risk.

Higher cortical thickness/volume in Alzheimer's-related regions: protective factor or risk factor?

Some evidence suggests a biphasic pattern of changes in cortical thickness wherein higher, rather than lower, thickness is associated with very early Alzheimer's disease (AD) pathology. We examined whether integrating information from AD brain signatures based on mean diffusivity (MD) can aid in the interpretation of cortical thickness/volume as a risk factor for future AD-related changes. Participants were 572 men in the Vietnam Era Twin Study of Aging who were cognitively unimpaired at baseline (mean age = 56 years; range = 51-60). Individuals with both high thickness/volume signatures and high MD signatures at baseline had lower cortical thickness/volume in AD signature regions and lower episodic memory performance 12 years later compared to those with high thickness/volume and low MD signatures at baseline. Groups did not differ in level of young adult cognitive reserve. Our findings are in line with a biphasic model in which increased cortical thickness may precede future decline and establish the value of examining cortical MD alongside cortical thickness to identify subgroups with differential risk for poorer brain and cognitive outcomes.

Cognitive Reserve and Related Constructs: A Unified Framework Across Cognitive and Brain Dimensions of Aging.

Cognitive reserve and related constructs are valuable for aging-related research, but consistency and clarification of terms is needed as there is still no universally agreed upon nomenclature. We propose a new set of definitions for the concepts of reserve, maintenance, and resilience, and we invoke parallel concepts for each that are applicable to cognition and to brain. Our definitions of reserve and resilience correspond reasonably well to dictionary definitions of these terms. We demonstrate logical/methodological problems that arise from incongruence between commonly used conceptual and operational definitions. In our view, cognitive reserve should be defined conceptually as one's total cognitive resources at a given point in time. IQ and education are examples of common operational definitions (often referred to as proxies) of cognitive reserve. Many researchers define cognitive reserve conceptually as a property that allows for performing better than expected cognitively in the face of aging or pathology. Performing better than expected is demonstrated statistically by interactions in which the moderator is typically IQ or education. The result is an irreconcilable situation in which cognitive reserve is both the moderator and the moderation effect itself. Our proposed nomenclature resolves this logical inconsistency by defining performing better than expected as cognitive resilience. Thus, in our usage, we would test the hypothesis that high cognitive reserve confers greater cognitive resilience. Operational definitions (so-called proxies) should not conflate factors that may influence reserve-such as occupational complexity or engagement in cognitive activities-with cognitive reserve itself. Because resources may be depleted with aging or pathology, one's level of cognitive reserve may change over time and will be dependent on when assessment takes place. Therefore, in addition to cognitive reserve and cognitive resilience, we introduce maintenance of cognitive reserve as a parallel to brain maintenance. If, however, education is the measure of reserve in older adults, it precludes assessing change or maintenance of reserve. Finally, we discuss consideration of resistance as a subcategory of resilience, reverse causation, use of residual scores to assess performing better than expected given some adverse factor, and what constitutes high vs. low cognitive reserve across different studies.

Practice Effects in Mild Cognitive Impairment Increase Reversion Rates and Delay Detection of New Impairments.

Objective: Cognitive practice effects (PEs) can delay detection of progression from cognitively unimpaired to mild cognitive impairment (MCI). They also reduce diagnostic accuracy as suggested by biomarker positivity data. Even among those who decline, PEs can mask steeper declines by inflating cognitive scores. Within MCI samples, PEs may increase reversion rates and thus impede detection of further impairment. Within an MCI sample at baseline, we evaluated how PEs impact prevalence, reversion rates, and dementia progression after 1 year. Methods: We examined 329 baseline Alzheimer's Disease Neuroimaging Initiative MCI participants (mean age = 73.1; SD = 7.4). We identified test-naïve participants who were demographically matched to returnees at their 1-year follow-up. Since the only major difference between groups was that one completed testing once and the other twice, comparison of scores in each group yielded PEs. PEs were subtracted from each test to yield PE-adjusted scores. Biomarkers included cerebrospinal fluid phosphorylated tau and amyloid beta. Cox proportional models predicted time until first dementia diagnosis using PE-unadjusted and PE-adjusted diagnoses. Results: Accounting for PEs increased MCI prevalence at follow-up by 9.2% (272 vs. 249 MCI), and reduced reversion to normal by 28.8% (57 vs. 80 reverters). PEs also increased stability of single-domain MCI by 12.0% (164 vs. 147). Compared to PE-unadjusted diagnoses, use of PE-adjusted follow-up diagnoses led to a twofold increase in hazard ratios for incident dementia. We classified individuals as false reverters if they reverted to cognitively unimpaired status based on PE-unadjusted scores, but remained classified as MCI cases after accounting for PEs. When amyloid and tau positivity were examined together, 72.2% of these false reverters were positive for at least one biomarker. Interpretation: Even when PEs are small, they can meaningfully change whether some individuals with MCI retain the diagnosis at a 1-year follow-up. Accounting for PEs resulted in increased MCI prevalence and altered stability/reversion rates. This improved diagnostic accuracy also increased the dementia-predicting ability of MCI diagnoses.

Cognitive practice effects delay diagnosis of MCI: Implications for clinical trials.

INTRODUCTION: Practice effects (PEs) on cognitive tests obscure decline, thereby delaying detection of mild cognitive impairment (MCI). Importantly, PEs may be present even when there are performance declines, if scores would have been even lower without prior test exposure. We assessed how accounting for PEs using a replacement-participants method impacts incident MCI diagnosis. METHODS: Of 889 baseline cognitively normal (CN) Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, 722 returned 1 year later (mean age = 74.9 ± 6.8 at baseline). The scores of test-naïve demographically matched "replacement" participants who took tests for the first time were compared to returnee scores at follow-up. PEs-calculated as the difference between returnee follow-up scores and replacement participants scores-were subtracted from follow-up scores of returnees. PE-adjusted cognitive scores were then used to determine if individuals were below the impairment threshold for MCI. Cerebrospinal fluid amyloid beta, phosphorylated tau, and total tau were used for criterion validation. In addition, based on screening and recruitment numbers from a clinical trial of amyloid-positive individuals, we estimated the effect of earlier detection of MCI by accounting for cognitive PEs on a hypothetical clinical trial in which the key outcome was progression to MCI. RESULTS: In the ADNI sample, PE-adjusted scores increased MCI incidence by 19% (P < .001), increased proportion of amyloid-positive MCI cases (+12%), and reduced proportion of amyloid-positive CNs (-5%; P's < .04). Additional calculations showed that the earlier detection and increased MCI incidence would also substantially reduce necessary sample size and study duration for a clinical trial of progression to MCI. Cost savings were estimated at ≈$5.41 million. DISCUSSION: Detecting MCI as early as possible is of obvious importance. Accounting for cognitive PEs with the replacement-participants method leads to earlier detection of MCI, improved diagnostic accuracy, and can lead to multi-million-dollar cost reductions for clinical trials.