Change In Global Cognition Research Articles

Amyloid and SCD jointly predict cognitive decline across Chinese and German cohorts.

Subjective cognitive decline (SCD) in amyloid-positive (Aβ+) individuals was proposed as a clinical indicator of Stage 2 in the Alzheimer's disease (AD) continuum, but this requires further validation across cultures, measures, and recruitment strategies. Eight hundred twenty-one participants from SILCODE and DELCODE cohorts, including normal controls (NC) and individuals with SCD recruited from the community or from memory clinics, underwent neuropsychological assessments over up to 6 years. Amyloid positivity was derived from positron emission tomography or plasma biomarkers. Global cognitive change was analyzed using linear mixed-effects models. In the combined and stratified cohorts, Aβ+ participants with SCD showed steeper cognitive decline or diminished practice effects compared with NC or Aβ- participants with SCD. These findings were confirmed using different operationalizations of SCD and amyloid positivity, and across different SCD recruitment settings. Aβ+ individuals with SCD in German and Chinese populations showed greater global cognitive decline and could be targeted for interventional trials. SCD in amyloid-positive (Aβ+) participants predicts a steeper cognitive decline. This finding does not rely on specific SCD or amyloid operationalization. This finding is not specific to SCD patients recruited from memory clinics. This finding is valid in both German and Chinese populations. Aβ+ older adults with SCD could be a target population for interventional trials.

High baseline perivascular space volume in basal ganglia is associated with attention and executive function decline in Parkinson's disease.

Pathologic perivascular spaces (PVS), the fluid-filled compartments surrounding brain vasculature, may underlie cognitive decline in Parkinson's disease (PD). However, whether this impacts specific cognitive domains has not been investigated. This study examined the relationship of PVS volume at baseline with domain-specific and global cognitive change over 2 years in PD individuals. A total of 39 individuals with PD underwent 3T T1w magnetic resonance imaging to determine PVS volume fraction (PVS volume normalized to total regional volume) within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, and superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of cognitive domains and global cognitive function at baseline and after 2 years. Higher basal ganglia PVS at baseline was associated with greater decline in attention, executive function, and global cognition scores. While previous reports have associated elevated PVS volume in the basal ganglia with decline in global cognition in PD, our findings show such decline may affect the attention and executive function domains.

Cross-sectional and Longitudinal Age-related Disintegration in Functional Connectivity: Reference Ability Neural Network Cohort.

Some theories of aging have linked age-related cognitive decline to a reduction in distinctiveness of neural processing. Observed age-related correlation increases among disparate cognitive tasks have supported the dedifferentiation hypothesis. We previously showed cross-sectional evidence for age-related correlation decreases instead, supporting an alternative disintegration hypothesis. In the current study, we extended our previous research to a longitudinal sample. We tested 135 participants (20-80 years) at two time points-baseline and 5-year follow-up-on a battery of 12 in-scanner tests, each tapping one of four reference abilities. We performed between-tasks correlations within domain (convergent) and between domain (discriminant) at both the behavioral and neural level, calculating a single measure of construct validity (convergent - discriminant). Cross-sectionally, behavioral construct validity was significantly different from chance at each time point, but longitudinal change was not significant. Analysis by median age split revealed that older adults showed higher behavioral validity, driven by higher discriminant validity (lower between-tasks correlations). Participant-level neural validity decreased over time, with convergent validity consistently greater than discriminant validity; this finding was also observed at the cross-sectional level. In addition, a disproportionate decrease in neural validity with age remained significant after controlling for demographic factors. Factors predicting longitudinal changes in global cognition (mean performance across all 12 tasks) included age, change in neural validity, education, and National Adult Reading Test (premorbid intelligence). Change in neural validity partially mediated the effect of age on change in global cognition. Our findings support the theory of age-related disintegration, linking cognitive decline to changes in neural representations over time.

Associations Between Stroke Type, Ischemic Stroke Subtypes, and Post-Stroke Cognitive Trajectories.

It is unclear how post-stroke cognitive trajectories differ by stroke type and ischemic stroke subtype. We studied associations between stroke types (ischemic, hemorrhagic), ischemic stroke subtypes (cardioembolic, large artery atherosclerotic, lacunar/small vessel, cryptogenic/other determined etiology), and post-stroke cognitive decline. This pooled cohort analysis from four US cohort studies (1971-2019) identified 1,143 dementia-free individuals with acute stroke during follow-up: 1,061 (92.8%) ischemic, 82 (7.2%) hemorrhagic, 49.9% female, 30.8% Black. Median age at stroke was 74.1 (IQR, 68.6, 79.3) years. Outcomes were change in global cognition (primary) and changes in executive function and memory (secondary). Outcomes were standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median follow-up for the primary outcome was 6.0 (IQR, 3.2, 9.2) years. Linear mixed-effects models estimated changes in cognition after stroke. On average, the initial post-stroke global cognition score was 50.78 points (95% CI, 49.52, 52.03) in ischemic stroke survivors and did not differ in hemorrhagic stroke survivors (difference, -0.17 points [95% CI, -1.64, 1.30]; P=0.82) after adjusting for demographics and pre-stroke cognition. On average, ischemic stroke survivors showed declines in global cognition, executive function, and memory. Post-stroke declines in global cognition, executive function, and memory did not differ between hemorrhagic and ischemic stroke survivors. 955 ischemic strokes had subtypes: 200 (20.9%) cardioembolic, 77 (8.1%) large artery atherosclerotic, 207 (21.7%) lacunar/small vessel, 471 (49.3%) cryptogenic/other determined etiology. On average, small vessel stroke survivors showed declines in global cognition and memory, but not executive function. Initial post-stroke cognitive scores and cognitive declines did not differ between small vessel survivors and survivors of other ischemic stroke subtypes. Post-stroke vascular risk factor levels did not attenuate associations. Stroke survivors had cognitive decline in multiple domains. Declines did not differ by stroke type or ischemic stroke subtype.

Cognition and Amyloid-β in Older Veterans: Characterization and Longitudinal Outcomes of Data-Derived Phenotypes.

Within older Veterans, multiple factors may contribute to cognitive difficulties. Beyond Alzheimer's disease (AD), psychiatric (e.g., PTSD) and health comorbidities (e.g., TBI) may also impact cognition. This study aimed to derive subgroups based on objective cognition, subjective cognitive decline (SCD), and amyloid burden, and then compare subgroups on clinical characteristics, biomarkers, and longitudinal change in functioning and global cognition. Cluster analysis of neuropsychological measures, SCD, and amyloid PET was conducted on 228 predominately male Vietnam-Era Veterans from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative. Cluster-derived subgroups were compared on baseline characteristics as well as 1-year changes in everyday functioning and global cognition. The cluster analysis identified 3 groups. Group 1 (n = 128) had average-to-above average cognition with low amyloid burden. Group 2 (n = 72) had the lowest memory and language, highest SCD, and average amyloid burden; they also had the most severe PTSD, pain, and worst sleep quality. Group 3 (n = 28) had the lowest attention/executive functioning, slightly low memory and language, elevated amyloid and the worst AD biomarkers, and the fastest rate of everyday functioning and cognitive decline. Psychiatric and health factors likely contributed to Group 2's low memory and language performance. Group 3 was most consistent with biological AD, yet attention/executive function was the lowest score. The complexity of older Veterans' co-morbid conditions may interact with AD pathology to show attention/executive dysfunction (rather than memory) as a prominent early symptom. These results could have important implications for the implementation of AD-modifying drugs in older Veterans.

Relationship of Perivascular Space Markers With Incident Dementia in Cerebral Small Vessel Disease.

Recent studies, using diffusion tensor image analysis along the perivascular space (DTI-ALPS), suggest impaired perivascular space (PVS) function in cerebral small vessel disease, but they were cross-sectional, making inferences on causality difficult. We determined associations between impaired PVS, measured using DTI-ALPS and PVS volume, and cognition and incident dementia. In patients with lacunar stroke and confluent white matter hyperintensities, without dementia at baseline, recruited prospectively in a single center, magnetic resonance imaging was performed annually for 3 years, and cognitive assessments, including global, memory, executive function, and processing speed, were performed annually for 5 years. We determined associations between DTI-ALPS and PVS volume with cerebral small vessel disease imaging markers (white matter hyperintensity volume, lacunes, and microbleeds) at baseline and with changes in imaging markers. We determined whether DTI-ALPS and PVS volume at baseline and change over 3 years predicted incident dementia. Analyses were controlled for conventional diffusion tensor image metrics using 2 markers (median mean diffusivity [MD] and peak width of skeletonized MD) and adjusted for age, sex, and vascular risk factors. A total of 120 patients, mean age 70.0 years and 65.0% male, were included. DTI-ALPS declined over 3 years, while no change in PVS volume was found. Neither DTI-ALPS nor PVS volume was associated with cerebral small vessel disease imaging marker progression. Baseline DTI-ALPS was associated with changes in global cognition (β=0.142, P=0.032), executive function (β=0.287, P=0.027), and long-term memory (β=0.228, P=0.027). Higher DTI-ALPS at baseline predicted a lower risk of dementia (hazard ratio, 0.328 [0.183-0.588]; P<0.001), and this remained significant after including median MD as a covariate (hazard ratio, 0.290 [0.139-0.602]; P<0.001). Change in DTI-ALPS predicted dementia conversion (hazard ratio, 0.630 [0.428-0.964]; P=0.048), but when peak width of skeletonized MD and median MD were entered as covariates, the association was not significant. There was no association between baseline PVS volume, or PVS change over 3 years, and conversion to dementia. DTI-ALPS predicts future dementia risk in patients with lacunar strokes and confluent white matter hyperintensities. However, the weakening of the association between change in DTI-ALPS and incident dementia after controlling for peak width of skeletonized MD and median MD suggests part of the signal may represent conventional diffusion tensor image metrics. PVS volume is not a predictor of future dementia risk.

Physical Activity and Cognitive Decline Among Older Adults

Physical activity is associated with the risk for cognitive decline, but much of the evidence in this domain comes from studies with short follow-ups, which is prone to reverse causation bias. To examine how length of follow-up, baseline age, physical activity amount, and study quality modify the longitudinal associations of physical activity with cognition. Observational studies of adults with a prospective follow-up of at least 1 year, a valid baseline cognitive measure or midlife cohort, and an estimate of the association of baseline physical activity and follow-up cognition were sought from PsycInfo, Scopus, CINAHL, Web of Science, SPORTDiscus, and PubMed, with the final search conducted on November 2, 2022. Two independent researchers screened titles with abstracts and full-text reports. Two reviewers independently assessed study quality and extracted data. Pooled estimates of association were calculated with random-effects meta-analyses. An extensive set of moderators, funnel plots, and scatter plots of physical activity amount were examined. This study is reported following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Pooled estimates of the associations between physical activity and global cognition, as well as specific cognitive domains, were examined. A total of 104 studies with 341 471 participants were assessed. Analysis of binary outcomes included 45 studies with 102 452 individuals, analysis of follow-up global cognition included 14 studies with 41 045 individuals, and analysis of change in global cognition included 25 studies with 67 463 individuals. Physical activity was associated with a decreased incidence of cognitive impairment or decline after correction for funnel plot asymmetry (pooled risk ratio, 0.97; 95% CI, 0.97-0.99), but there was no significant association in follow-ups longer than 10 years. Physical activity was associated with follow-up global cognition (standardized regression coefficient, 0.03; 95% CI, 0.02-0.03) and change in global cognition (standardized regression coefficient, 0.01; 95% CI, 0.01 to 0.02) from trim-and-fill analyses, with no clear dose-response or moderation by follow-up length, baseline age, study quality or adjustment for baseline cognition. The specific cognitive domains associated with physical activity were episodic memory (standardized regression coefficient, 0.03; 95% CI, 0.02-0.04) and verbal fluency (standardized regression coefficient, 0.05; 95% CI, 0.03-0.08). In this meta-analysis of the association of physical activity with cognitive decline, physical activity was associated with better late-life cognition, but the association was weak. However, even a weak association is important from a population health perspective.

A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol

BackgroundCombining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer’s Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence).MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia.MethodsMET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes.The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded.ConclusionMET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field.Trial registrationClinicalTrials.gov (NCT05109169).

The Impact of Spatial Orientation Changes on Driving Behavior in Healthy Aging.

Global cognitive changes in older age affect driving behavior and road safety, but how spatial orientation differences affect driving behaviors is unknown on a population level, despite clear implications for driving policy and evaluation during aging. The present study aimed to establish how spatial navigation changes affect driving behavior and road safety within a large cohort of older adults. Eight hundred and four participants (mean age: 71.05) were recruited for a prospective cohort study. Participants self-reported driving behavior followed by spatial orientation (allocentric and egocentric) testing and a broader online cognitive battery (visuomotor speed, processing speed, executive functioning, spatial working memory, episodic memory, visuospatial functioning). Spatial orientation performance significantly predicted driving difficulty and frequency. Experiencing more driving difficulty was associated with worse allocentric spatial orientation, processing speed, and source memory performance. Similarly, avoiding challenging driving situations was associated with worse spatial orientation and episodic memory. Allocentric spatial orientation was the only cognitive domain consistently affecting driving behavior in under 70 and over 70 age groups, a common age threshold for driving evaluation in older age. We established for the first time that worse spatial orientation performance predicted increased driving difficulty and avoidance of challenging situations within an older adult cohort. Deficits in spatial orientation emerge as a robust indicator of driving performance in older age, which should be considered in future aging driving assessments, as it has clear relevance for road safety within the aging population.

Effect of cocoa extract supplementation on cognitive function: results from the clinic subcohort of the COSMOS trial

BackgroundSome prior randomized clinical trials (RCTs) that tested the effects of cocoa extract (CE), a source of flavanols, on late-life cognition have yielded promising findings. A long-term RCT using in-person neuropsychological tests covering multiple cognitive domains may clarify the cognitive effects of CE. ObjectivesTo test whether daily supplementation with CE, compared with placebo, produces better cognitive change over 2 y. MethodsThe COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a 2 × 2 factorial RCT of CE [500 mg flavanols/d, including 80 mg (–)-epicatechin] and/or a daily multivitamin-mineral supplement for cardiovascular disease and cancer prevention among 21,442 United States adults aged ≥60 y. There were 573 participants in the clinic subcohort of COSMOS (that is, COSMOS-Clinic) who completed all cognitive tests at baseline; of these, 492 completed 2-y follow-up assessments. The primary outcome was global cognition (averaging z-scores across 11 tests). Secondary outcomes were episodic memory and executive function/attention. Repeated measures models were used to compare randomized groups. ResultsParticipants' mean age (standard deviation) was 69.6 (5.3); 49.2% were females. Daily supplementation with CE, compared with placebo, had no significant effect on 2-y change in global cognition {mean difference [95% confidence interval (CI)]: −0.01 (−0.08, 0.05) standard deviation units (SU)}. CE, compared with placebo, had no significant effects on 2-y change in episodic memory [mean difference (95% CI): −0.01 (−0.13, 0.10) SU] or executive function/attention [mean difference (95% CI): 0.003 (−0.07, 0.08) SU]. Subgroup analyses uncorrected for multiple-testing suggested cognitive benefits of CE supplementation, compared with placebo among those with poorer baseline diet quality. ConclusionsAmong 573 older adults who underwent repeat in-person, detailed neuropsychological assessments over 2 y, daily CE supplementation, compared with placebo, showed no overall benefits for global or domain-specific cognitive function. Possible cognitive benefits of CE among those with poorer diet quality warrant further study. Trial registrationThis trial was registered at clinicaltrials.gov with identifier – NCT02422745.

Investigating the effects of aerobic exercise primed anodal transcranial direct current stimulation on γ‐aminobutyric acid concentrations in mild vascular cognitive impairment

AbstractBackgroundMild vascular cognitive impairment (mVCI) is characterized by minor deficits in cognition and memory due to underlying vascular pathology. Anodal transcranial direct current stimulation (atDCS), a non‐invasive neuromodulation technique, has been demonstrated to improve cognition. The effects of atDCS have been suggested to be mediated by γ‐aminobutyric acid (GABA)–a major inhibitory neurotransmitter associated with cerebral perfusion and oxygenation, and cognition and memory. However, previous studies have reported mixed results regarding changes in GABA concentrations following atDCS. Physical activity has been reported to increase cortical GABA levels, and in particular, aerobic exercise (AE) is associated with improved cognition in older adults. Preliminary data from an ongoing trial (EXPRESS‐V) was used to evaluate whether GABA concentration in the motor cortex was altered following AE and/or atDCS and whether this was associated with changes in global cognition in mVCI.MethodIn this double‐blind, randomized clinical trial, participants received one of four interventions for two weeks: AE and atDCS, AE and sham atDCS, exercise education and atDCS, or exercise education and sham atDCS. mVCI was determined based on a modified Gorelick criteria. At baseline and endpoint, GABA concentration in the motor cortex was measured using magnetic resonance spectroscopy and quantified with the Mescher‐Garwood point resolved spectroscopy pulse sequence, and global cognition was assessed using the Montreal Cognitive Assessment. Wilcoxon signed rank test was used to determine changes in GABA concentrations (ΔGABA). Spearman correlation was used to determine the association between ΔGABA and changes in global cognition (ΔMoCA).ResultTen participants have enrolled so far, with nine participants having completed the study (22.2% female, age = 66.4(9.8), years of education = 8.8(3.4), 55.6% White, baseline MoCA score = 22.8(3.1)). To date, ΔGABA was insignificant between baseline and endpoint (Z = 23.0, p = 0.953). However, a positive trend between ΔGABA and ΔMoCA was observed (ρ = 0.650, p = 0.058).ConclusionPreliminary results from nine participants showed a positive trend between ΔGABA and ΔMoCA. Since the trial is ongoing, with the target of recruiting 80 participants by 2024, analyses on unblinded data upon study completion will determine whether AE and atDCS leads to greater ΔGABA, and whether this is accompanied by greater ΔMoCA in mVCI.

Mapping cognitive trajectories in older adults with essential tremor

AbstractBackgroundOlder adults with essential tremor (ET) are at increased risk for Alzheimer’s disease (AD) and related disorders. Examining cognitive trajectories within this population will enable better identification of individuals who evidence accelerated rates of change. Here we examine how variability in baseline cognitive performance affects trajectories of cognitive change within three subgroups of cognitively normal older adults: 1) those whose baseline neuropsychological scores were entirely within normal limits (WNL); 2) those with at least one low score considered to have unlikely clinical significance (UCS); and 3) those with at least one low score considered to have possible clinical significance (PCS).MethodOlder adults with ET completed comprehensive neuropsychological testing and clinical interviews, and 159 received a consensus diagnosis of cognitively normal. Participants were then subdivided into one of three categories defined above: WNL (N = 66, 75.38 ± 8.96 years of age), UCS (N = 54, 76.35 ± 10.25 years), and PCS (N = 37, 80.22 ± 9.00 years). Generalized estimating equations (GEE) were used to compare rates of change in global cognition, memory, executive function, attention, visuospatial, and language z‐scores over time across these groups. Participants were seen for two to four visits (24.98 ± 20.29 months). Models were adjusted for age, gender, and years of education.ResultAll three groups, WNL (β = ‐.005, p = .028), UCS (β = ‐.006, p = .011), and PCS (β = ‐.012, p = .002), evidenced decline in their memory performance over time, with the latter groups declining faster than the WNL group. Relative to the WNL and UCS groups, the PCS group also declined faster over time in overall cognition (β = ‐.010, p = .029) and in language (β = ‐.024, p = .035).ConclusionHeterogeneity in cognitive performance among cognitively normal older adults with ET predicts trajectories of cognitive decline longitudinally. Specifically, rates of decline were slowest in those with entirely normal test scores, and greatest in those whose scores were considered to have possible clinical significance. These preliminary results provide a starting point for further inquiry into the role of nuanced cognitive profiles in predicting rates of decline, impairment, and dementia in ET cases who may initially be labeled as “cognitively normal.”

Relationship between metabolic disease and Alzheimer’s disease

AbstractBackgroundDiabetes is an enormous and growing global public health problem, associated with poor health outcomes including dementia. Mechanisms underlying the relationship of diabetes to dementia are less well understood.MethodsWe leveraged several large, ongoing community‐based cohorts of older women and men with and without diabetes, taking part in longitudinal, clinical‐pathologic studies of aging at the Rush Alzheimer’s Disease Center. Participants undergo annual clinical evaluations including detailed neuropsychological testing, and brain autopsy at time of death. We examined the relation of diabetes and related clinical variables (e.g., medications, body mass index [BMI], hypertension), and blood and brain biomarkers of insulin resistance and other measures (e.g., epigenetics), to brain outcomes. Level and change in global cognition and five cognitive domains were based on neuropsychological tests, and dementia status was classified. Postmortem human brain specimens of deceased persons were systematically evaluated for neuropathology, including neurodegenerative (e.g., Alzheimer’s disease [AD]) and cerebrovascular disease (e.g., infarcts).ResultsDiabetes, present in 15‐20% of our cohorts, is associated a two‐fold increased risk of dementia and relates to cognitive decline (particularly in some cognitive domains more than others), and these observations are found in both Black and White participants. Some diabetes‐related clinical variables (e.g., BMI) are associated with faster cognitive decline, while others such as medications (metformin) are associated with slower cognitive decline. Regarding human postmortem neuropathologic outcomes, diabetes is associated with cerebrovascular pathologies, and small subcortical infarcts in particular. But, while we have not found clear associations of diabetes with neurodegenerative pathologies such as AD, some brain molecular markers in the insulin signaling pathway (AKT1) are associated with AD (including amyloid‐beta and tau tangles) and cognition (memory). Recently, using blood and brain specimens, we show that genome‐wide 5‐hydroxymethylcytosine profiling uncovers epigenetic features and biologic pathways related to nucleotide sugar metabolism linking diabetes to diabetes‐associated AD.ConclusionDiabetes is a potentially‐modifiable risk factor for dementia and cognitive decline. Clinical, neuropathologic, and epigenetic factors are at play in the underlying mechanisms. A better understanding of mechanisms will inform future research and offer opportunities for precision medicine and dementia prevention (supported by NIH: R01NS084965, RF1AG059621, RF1AG074549, R01AG022018, P30AG10161, P30AG072975, R01AG15819, R01AG17917).

Moderation effects of APOE‐ε4 on marine omega‐3 fatty acids and its relation to change in cognitive function among community‐dwelling older adults

AbstractBackgroundIn a recent trial, we observed no effect of omega‐3 fatty acids (omega‐3s) supplementation on cognitive decline. However, brain concentrations and metabolism of lipid molecules in response to omega‐3s may be regulated by apolipoprotein E (APOE)‐ε4 allele status. Further, while APOE‐ε4 is an established risk factor for Alzheimer disease, its association with cognitive decline is uncertain, especially in more diverse samples. The few randomized clinical trials (RCTs) addressing the moderation of effects of omega‐3s on cognitive decline by APOE‐ε4 have yielded inconsistent findings. Thus, we examined moderation by APOE‐ε4 on effects of omega‐3s vs. placebo for global and domain‐specific cognitive change over 2 years in a well‐characterized, diverse sample of older adults.MethodsVITamin D and OmegA‐3 TriaL (VITAL) is a 2×2 factorial RCT of vitamin D3 (2000 IU/day) and/or omega‐3s (1 g/day including 460 mg of eicosapentaenoic acid and 380 mg of docosahexaenoic acid) for cardiovascular disease and cancer prevention. We included 743 VITAL in‐clinic sub‐cohort participants who completed all cognitive tests at baseline and had APOE genotype data. The primary outcome was change in global cognition (averaging z‐scores of 9 tests) over 2 years; episodic memory and executive function/attention were examined separately. We used multiplicative interaction terms in general linear models of response profiles to examine moderation by APOE‐ε4 carrier status on effects of omega‐3s vs. placebo for cognitive change outcomes over 2 years.ResultsThe mean age (standard deviation) of participants was 67.1 (5.3) years; 50.6% were females; 13.5% were from racial and/or ethnic minority backgrounds; and 24.9% were APOE‐ε4 allele carriers. Over 2 years, compared with APOE‐ε4 non‐carriers, APOE‐ε4 carriers had faster declines in global cognition and episodic memory but not in executive function/attention; e.g., the mean difference in change (95% confidence interval) for episodic memory comparing APOE‐ε4 carriers vs. non‐carriers was ‐0.18 (‐0.33 to ‐0.03). There were no significant interactions between APOE‐ε4 carrier status and randomization status (omega‐3s vs. placebo) on change in global, episodic memory, or executive function/attention scores.ConclusionAPOE‐ε4 significantly predicted cognitive decline but did not modify the effect of omega‐3s on global and domain‐specific cognitive change over 2 years.

Contributions of Vascular Burden and Amyloid Abnormality to Cognitive Decline in Memory Clinic Patients.

Alzheimer's disease pathology and vascular burden are highly prevalent and often co-occur in elderly. It remains unclear how both relate to cognitive decline. To investigate whether amyloid abnormality and vascular burden synergistically contribute to cognitive decline in a memory clinic population. We included 227 patients from Maastricht and Aachen memory clinics. Amyloid abnormality (A+) was defined by CSF Aβ42 using data-driven cut-offs. Vascular burden (V+) was defined as having moderate to severe white matter hyperintensities, or any microbleeds, macrohemorrhage or infarcts on MRI. Longitudinal change in global cognition, memory, processing speed, executive functioning, and verbal fluency was analysed across the A-V-, A-V+, A+V-, A+V+ groups by linear mixed models. Additionally, individual MRI measures, vascular risk and vascular disease were used as V definitions. At baseline, the A+V+ group scored worse on global cognition and verbal fluency compared to all other groups, and showed worse memory compared to A-V+ and A-V- groups. Over time (mean 2.7+ - 1.5 years), A+V+ and A+V- groups showed faster global cognition decline than A-V+ and A-V- groups. Only the A+V- group showed decline on memory and verbal fluency. The A-V+ group did not differ from the A-V- group. Individual MRI vascular measures only indicated an independent association of microbleeds with executive functioning decline. Findings were similar using other V definitions. Our study demonstrates that amyloid abnormality predicts cognitive decline independent from vascular burden in a memory clinic population. Vascular burden shows a minor contribution to cognitive decline in these patients. This has important prognostic implications.

Association of Whole Grain Consumption and Cognitive Decline: An Investigation From a Community-Based Biracial Cohort of Older Adults.

To examine the association of whole grain consumption and longitudinal change in global cognition, perceptual speed, and episodic memory by different race/ethnicity. We included 3,326 participants from the Chicago Health and Aging Project who responded to a Food Frequency Questionnaire (FFQ), with 2 or more cognitive assessments. Global cognition was assessed using a composite score of episodic memory, perceptual speed, and the Mini Mental State Examination (MMSE). Diet was assessed by a 144-item FFQ. Linear mixed-effects models were used to estimate the association of intakes of whole grains and cognitive decline. This study involved 3,326 participants (60.1% African American [AA], 63.7% female) with a mean age of 75 years at baseline and a mean follow-up of 6.1 years. Higher consumption of whole grains was associated with a slower rate of global cognitive decline. Among AA participants, those in the highest quintile of whole grain consumption had a slower rate of decline in global cognition (β = 0.024, 95% CI [0.008-0.039], p = 0.004), perceptual speed (β = 0.023, 95% CI [0.007-0.040], p = 0.005), and episodic memory (β = 0.028, 95% CI [0.005-0.050], p = 0.01) compared with those on the lowest quintile. Regarding the amount consumed, in AA participants, those who consumed >3 servings/d vs those who consumed <1 serving/d had a slower rate of decline in global cognition (β = 0.021, 95% CI [0.005-0.036], p = 0.0093). In White participants, with >3 servings/d, we found a suggestive association of whole grains with global cognitive decline when compared with those who consumed <1 serving/d (β = 0.025, 95% CI [-0.003 to 0.053], p = 0.08). Among AA participants, individuals with higher consumption of whole grains and more frequent consumption of whole grain had slower decline in global cognition, perceptual speed, and episodic memory. We did not see a similar trend in White adults.

HEPPI: a randomized controlled trial of the efficacy of a cognitive-emotional intervention for homebound older adults

Objectives This randomized controlled trial aimed to assess the efficacy of the Homebound Elderly People Psychotherapeutic Intervention (HEPPI), a home-delivered cognitive-emotional intervention, among the homebound older population presenting with mild cognitive impairment and depressive or anxiety symptoms. Methods Participants were randomly assigned either to the intervention group or the treatment-as-usual group and completed baseline, post-intervention, and three-month follow-up assessments. Changes in episodic memory and symptoms of depression and anxiety were the primary outcomes. Secondary outcomes included changes in global cognition, attentional control, subjective memory complaints, functional status, and quality of life. Data were analyzed on an intention-to-treat basis employing a linear mixed models approach. ClinicalTrials.gov identifier: NCT05499767. Results Compared with the treatment-as-usual group, the HEPPI group reported significant immediate improvement in cognition, mood, and daily functional performance. Positive effects of HEPPI were maintained over the follow-up phase only in depressive symptomatology, perceived incapacity to perform advanced instrumental activities of daily living, and self-reported emotional ability. A significant impact of the intervention on the subjective memory complaints level was observed only three months after the intervention. Conclusions This study suggests that HEPPI may be a promising home-delivered cognitive-emotional intervention to help homebound older adults improve their mental health.

Neuroimaging biomarkers of glial activation for predicting the annual cognitive function decline in patients with Alzheimer’s disease

BackgroundGlial activation is central to the pathogenesis of Alzheimer’s disease (AD). However, researchers have not demonstrated its relationship to longitudinal cognitive deterioration. We aimed to compare the prognostic effects of baseline positron emission tomography (PET) imaging of glial activation and amyloid/tau pathology on the successive annual cognitive decline in patients with AD. MethodsWe selected 17 patients diagnosed with mild cognitive impairment or AD. We assessed the annual changes in global cognition and memory. Furthermore, we assessed the predictive effects of baseline amyloid and tau pathology indicated by cerebrospinal fluid (CSF) concentrations and PET imaging of glial activation (11C-DPA-713-binding potential in the area of Braak 1–3 [11C-DPA-713-BPND]) on global cognition and memory using a stepwise regression analysis. ResultsThe final multiple regression model of annual changes in global cognition and memory scores included 11C-DPA-713-BPND as the predictor. The CSF Aβ42/40 ratios and p-tau concentrations were removed from the final model. In stepwise Bayesian regression analysis, the Bayes factor-based model comparison suggested that the best model included 11C-DPA-713-BPND as the predictor of decline in global cognition and memory. ConclusionsTranslocator protein–PET imaging of glial activation is a stronger predictor of AD clinical progression than the amount of amyloid/tau pathology measured using CSF concentrations. Glial activation is the primary cause of tau-induced neuronal toxicity and cognitive deterioration, thereby highlighting the potential of blocking maladaptive microglial responses as a therapeutic strategy for AD treatment.

Long-Term PM2.5 Exposure, Lung Function, and Cognitive Function Among Middle-Aged and Older Adults in China.

Long-term exposure to PM2.5 is related to poor lung function and cognitive impairment, but less is known about the pathway involved in this association. We aimed to explore whether the effect of PM2.5 on cognitive function was mediated by lung function. A total of 7 915 adults older than 45 years old were derived from the China Health and Retirement Longitudinal Study (CHARLS) collected in 2011 and 2015. PM2.5 exposure was estimated using a geographically weighted regression model. Lung function was measured by peak expiratory flow (PEF). Cognitive function was evaluated through a structured questionnaire with 4 dimensions: episodic memory, attention, orientation, and visuoconstruction. Under the counterfactual framework, causal mediation analysis was applied to examine direct and indirect associations. An interquartile range (IQR) increase in PM2.5 change was significantly related to an 8.480 (95% confidence interval [CI]: 3.116, 13.845) decrease in PEF change and a 0.301 (95% CI: 0.100, 0.575) decrease in global cognitive score change. The direct and indirect effects of PM2.5 exposure on global cognitive performance were -0.279 (95% CI: -0.551, -0.060) and -0.023 (95% CI: -0.041, -0.010), respectively. The proportion of the indirect effect was 7.48% (p = .010). The same significant association appeared in only 2 dimensions, episodic memory and attention, which were both mediated by PEF. Lung function played a partially mediating role in the association between long-term PM2.5 exposure and cognition. More clean air actions should be undertaken to improve lung function and cognitive function in older adults.

Longitudinal Associations Between Sleep and Cognitive Function in a Cohort of Older Puerto Rican Adults: Sex and Age Interactions.

Evidence on sleep duration or quality and cognitive function in diverse older adults is limited. We examined prospective associations between subjective sleep measures and cognitive function, with modifying effects of sex and age (<65 vs ≥65 years). Data are from the longitudinal Boston Puerto Rican Health Study, Waves 2 (n = 943) and 4 (n = 444), with mean follow-up of 10.5 years (range 7.2-12.8). Subjective measures of sleep duration (short <7, ref. 7, or long ≥8 hours) and insomnia symptoms (sum of difficulty falling asleep, waking up at night, and early morning awakening), were assessed at Wave 2. Linear regression models were used to assess changes in global cognition, executive function, memory, and Mini-Mental State Examination, and tested for modifying roles of sex and age. Significant 3-way interaction (sex × age × cognition) in fully adjusted models showed greater decline in global cognitive function in older men with short (β [95% confidence interval]: -0.67 [-1.24, -0.10]) or long sleep duration (-0.92 [-1.55, -0.30]), compared to women, younger men, and older men with 7 hours of sleep. Insomnia symptoms were associated with a greater decline in memory (-0.54, [-0.85, -0.22]) among older men, compared to women and younger men. Sleep duration showed a U-shaped association with cognitive decline, and insomnia symptoms were associated with memory decline in fully adjusted models. Older men, versus women and younger men, were at relatively greater risk for cognitive decline associated with sleep factors. These findings are important for personalizing sleep interventions to support cognitive health.