Global Cognitive Measures Research Articles

Four Common Late-Life Cognitive Trajectories Patterns Associate with Replicable Underlying Neuropathologies.

Late-life cognitive function is heterogeneous, ranging from no decline to severe dementia. Prior studies of cognitive trajectories have tended to focus on a single measure of global cognition or individual tests scores, rather than considering longitudinal performance on multiple tests simultaneously. The current study aimed to examine cognitive trajectories from two independent datasets to assess whether similar patterns might describe longitudinal cognition in the decade preceding death, as well as what participant characteristics were associated with trajectory membership. Data were drawn from autopsied longitudinally followed participants of two cohorts (total N = 1,346), community-based cohort at the University of Kentucky Alzheimer's Disease Research Center (n = 365) and National Alzheimer's Coordinating Center (n = 981). We used group-based multi-trajectory models (GBMTM) to identify cognitive trajectories over the decade before death using Mini-Mental State Exam, Logical Memory-Immediate, and Animal Naming performance. Multinomial logistic and Random Forest analyses assessed characteristics associated with trajectory groups. GBMTM identified four similar cognitive trajectories in each dataset. In multinomial models, death age, Braak neurofibrillary tangles (NFT) stage, TDP-43, and α-synuclein were associated with declining trajectories. Random Forest results suggested the most important trajectory predictors were Braak NFT stage, cerebral atrophy, death age, and brain weight. Multiple pathologies were most common in trajectories with moderate or accelerated decline. Cognitive trajectories associated strongly with neuropathology, particularly Braak NFT stage. High frequency of multiple pathologies in trajectories with cognitive decline suggests dementia treatment and prevention efforts must consider multiple diseases simultaneously.

154 Cortical thickness and sleep slow wave activity mediates age-related improvements in cognition during late adolescence

Abstract Introduction Adolescence is a period of rapid brain maturation, and studies have independently documented reductions in cortical thickness, reduced sleep slow wave activity (0.5-4Hz), and improved cognition as a child transitions into adulthood. In the present work, we investigate whether these factors interact in late adolescence. Methods 114 adolescents aged 15-19y (52 males) underwent a structural MRI scan, polysomnography (PSG) and a series of cognitive tests assessing fluid intelligence, sustained attention, speed of processing and working memory. As sleep history has been known to affect EEG measures of slow wave activity, actigraphic recordings ensured that participants received 9h of night the week prior to the PSG session. Cognitive scores were combined to obtain a single measure of global cognition. For assessment of cortical thickness, the Freesurfer (v5.3) pipeline was used to obtain measures for all regions of interest from the Desikan-Killiany cortical atlas. Pearson correlations were conducted to independently confirm associations between aging and reductions in cortical thickness, slow wave activity and improved global cognition, controlling for sex. Finally, a serial mediation model (SPSS PROCESS Model 6) was performed to test the mediating role of cortical thickness and slow wave activity between aging and global cognition. Results Reductions in EEG sleep slow wave activity, cortical thickness and improved global cognition was observed with increasing age, likely representing synaptic pruning and a decrease in waking metabolic activity that contributes to increased overall neural efficiency. Regions in the temporal and parietal areas showed the steepest age-related reductions. In addition, the age-related improvement in cognition was found to be mediated by both cortical thinning as well as reduced SWA activity, particularly in the middle temporal cortex. Conclusion The adolescent brain undergoes rapid growth in preparation for adulthood. Cortical restructuring through pruning of neural circuits during this period is associated with reduced slow wave activity, mediating the age-related improvement in cognition. Future work should investigate whether insults to the brain during this critical period alters this trajectory. Support (if any) This work was supported by grants awarded to Michael Chee (NMRC/STaR/015/2013, NRF2016-SOL002-001 and the Far East Organization).

SPON1 Is Associated with Amyloid-β and APOE ε4-Related Cognitive Decline in Cognitively Normal Adults.

.Background:Genetic variation in Spondin-1, specifically rs11023139, has been associated with reduced rates of cognitive decline in individuals with Alzheimer’s disease.Objective:The aim of this study was to assess whether the association was present in cognitively normal older adults.Methods:Longitudinal cognitive decline was investigated using linear mixed modelling in a cohort of 590 cognitively normal older adults enrolled in the Australian Imaging, Biomarkers and Lifestyle Study.Results:No independent effect of Spondin-1 rs11023139 on cognitive decline was observed. However, significant associations were observed for the interaction between Apolipoprotein E (APOE) ɛ4 and rs11023139 in individuals with high amyloid-β burden. APOE ɛ4/rs11023139-A carriers declined significantly faster than APOE ɛ4/rs11023139-G_G carriers in measures of global cognition (p = 0.011) and verbal episodic memory (p = 0.020).Conclusion:These results suggest that carriage of the Spondin-1 rs11023139-A allele significantly contributes to a worsening of cognitive performance in APOE ɛ4 cognitively normal older adults with a high neocortical amyloid-β burden.

TOMM40-APOE haplotypes are associated with cognitive decline in non-demented Blacks.

The goal was to investigate effects of APOE-TOMM40-'523 haplotypes on cognitive decline in non-demented non-Hispanic Blacks (NHB), and determine whether effects differ from non-Hispanic Whites (NHW). The impact of zero to two copies of the '523-Short variant (S; poly-T alleles<20) within apolipoprotein E (APOE) genotype on a composite measure of global cognition and five domains was examined. In NHB with ε3/ε3 (N=294), '523-S/S was associated with faster decline in global cognition (β=-0.048, P=0.017), episodic memory (β=-0.05, P=0.031), and visuospatial ability (β=-0.037, P=0.034) relative to those without '523-S. For NHB ε4+ (N=182), '523-S/S had slower decline in global cognition (β=0.047, P=0.042) and visuospatial ability (β=0.07, P=0.0005) relative to '523-S non-carriers. NHB ε4+ with '523-S also had a slower rate of decline than NHWs ε4+ with '523-S. '523-S/S has a different effect on cognitive decline among NHB dependent on APOE allele. Differences in the effect of ε4-'523-S in NHB may explain prior mixed findings on ε4 and decline in this population.

The Contribution of Cerebral Vascular Neuropathology to Mild Stage of Alzheimer's Dementia Using the NACC Database.

The interaction between cerebral vessel disease (CVD) pathology and Alzheimer's disease (AD) pathology in the development of dementia is controversial. We examined the association of cerebral vascular neuropathology and cerebrovascular risk factors with the mild stage of Alzheimer's dementia and cognitive function. This cross-sectional study included men and women aged 60 years or over who had yearly clinical assessments and had agreed to brain autopsy at the time of death, and who contributed to data stored at the National Alzheimer's Coordinating Center (NACC) in the USA. Cognitively normal and impaired subjects with presumptive aetiology of AD, including mild cognitive impairment (ADMCI) and dementia (Alzheimer's dementia), and with complete neuropathological data, were included in our analyses. We used neuropsychological data proximate to death to create summary measures of global cognition and cognitive domains. Systematic neuropathological assessments documenting the severity of cerebral vascular pathology were included. Logistic and linear regression analyses corrected for age at death, sex and Lewy body pathology were used to examine associations of vessel disease with the severity of Alzheimer's disease dementia, and cognitive function, respectively. No significant relationship was observed between late-life risk factors and Alzheimer's dementia. The severity of arteriosclerosis and presence of global infarcts/lacunes were related to mild Alzheimer's dementia (B=0.423, p<0.001; B=0.366, p=0.026), and the effects were significant after adjusting for neuritic plaques and neurofibrillary tangles (B=0.385, p<0.001; B=0.63, p=0.001). When vascular brain injuries were subdivided into old and acute/subacute types, we found that old microinfarcts and old microbleeds were associated with mild Alzheimer's dementia (B=0.754, p=0.007; B=2.331, p=0.032). The old microinfarcts remained significantly associated with mild Alzheimer's dementia after correcting AD pathologies (B=1.31, p<0.001). In addition, the number of microinfarcts in the cerebral cortex had a significant relation with mild Alzheimer's dementia, whether or not the data were corrected for AD pathologies (B=0.616, p=0.016; B=0.884, p=0.005). Atherosclerosis, arteriosclerosis and white matter rarefaction were found to be significantly associated with faster progression of Alzheimer's dementia (B=0.068, p=0.001; B=0.046, p=0.016, B=0.081, p=0.037), but white matter rarefaction no longer had a significant effect after adjusting for AD pathologies. We also found that the severity of atherosclerosis was related to impairment in processing speed (β=-0.112, p=0.006) and executive function (β=-0.092, p=0.023). Arteriosclerosis was significantly associated with language (β=-0.103, p=0.011) and global cognition (β=-0.098, p=0.016) deficits. Our study found the significant relation of global, old, acute/subacute and regional cerebral vascular pathologies, but not white matter rarefaction, to the onset and severity of Alzheimer's dementia. We also showed that late-life risk factors were found to have no relation with Alzheimer's dementia, and the increased risk of dementia with APOE ε4 is not mediated by CVD. The best interpretation of these findings is that CVD has a potential additive effect with AD pathologies in the development and progression of what is clinically diagnosed as Alzheimer's dementia.

Longitudinal changes on the Independent Living Scale in amnestic mild cognitive impairment

The Independent Living Scales (ILS) is an objective measure of day-to-day functioning, which can be used to aid in diagnosing dementia in older adults with cognitive impairments. However, no studies have examined this measure longitudinally in individuals with mild cognitive impairment (MCI), a prodromal phase of dementia. Three subscales of the ILS (Managing Money, Managing Home and Transportation, Health and Safety) were administered to a sample of 94 individuals with amnestic MCI twice across 15 months. A measure of global cognition (Total Scale score on the Repeatable Battery for the Assessment of Neuropsychological Status [RBANS]) was also administered twice. In this MCI sample, two of the three subscales of the ILS showed a significant decline over time, where the third ILS subscale and the Total Scale score of the RBANS did not change. Regression-based change models showed that baseline ILS scores were most strongly predictive of follow-up ILS scores compared to RBANS scores at baseline and follow-up and demographic variables (age, education, and sex). These results provide additional information on the longitudinal change on the ILS in a sizeable cohort of older individuals with amnestic MCI, which may make this scale more useful in identifying progression to dementia.

Association between physical functioning with cognition among community-dwelling older adults: a cross-sectional study

Objective: Declines in physical and cognitive functioning often co-exist through aging. Gait-related parameters have been related to cognitive function, although it is unclear whether other measures of physical functioning are similarly related to cognition. Here, we analyzed the relationship between physical functioning with cognition in older adults. Methods: In total, 116 participants were included (M age = 69 years, SD = 6; 71% women). We quantified cognitive functioning using the Montreal Cognitive Assessment (MoCA) and executive functioning tasks (Digit Span Forward minus Backward and verbal fluency tests). Physical function measures included gait speed, Short-physical Performance Battery (SPPB), five-times Sit-to-Stand Test, the Timed Up and Go (TUG) test, the Six-minute Walk Test (6MWT), and lower extremity muscle strength. We used multiple linear regression analyses to explore the association between cognitive measures and each measure of physical functioning, adjusting for age, sex, education, and RCT. Results: We observed a positive association between muscle strength and the MoCA (b = 0.84, SE = 0.40, 95%CI 0.05–1.64) after controlling for covariates. Significant associations were also found between the five-times-sit-to-stand test (b = -0.63, SE = 0.26, 95%CI -1.15–-0.12), TUG (b = -1.13, SE = 0.57, 95%CI -2.26–-0.01), 6MWT (b = 0.04, SE = 0.02, 95%CI 0.01–0.07), and lower extremity muscle strength (b = 1.92, SE = 0.93, 95%CI 0.09–3.77) with the FAS verbal fluency test, and between the TUG (b = -0.62, SE = 0.24, 95%CI -1.11–-0.14) with animal naming. Conclusion: In community-dwelling older adults, higher levels of muscle strength, dynamic balance and cardiorespiratory fitness were positively related with global cognition and executive control measures.

Performance-based IADL evaluation of older adults with cognitive impairment within a smart home: A feasibility study.

IntroductionMild cognitive impairment (MCI) is characterized by subtle deficits that functional assessment via informant‐report measures may not detect. Sensors can potentially detect deficits in everyday functioning in MCI. This study aims to establish feasibility and acceptability of using sensors in a smart home for performance‐based assessments of two instrumental activities of daily living (IADLs).MethodsThirty‐five older adults (>65 years) performed two IADL tasks in a smart home laboratory equipped with sensors and a web camera. Participants’ cognitive states were determined using published criteria including measures of global cognition and comprehensive neuropsychological test batteries. Selected subtasks of the IADL assessment were autonomously captured by the sensors. Total time taken for each task and subtask were computed. A point scoring system captured accuracy and number of attempts. Acceptability of the smart home setup was assessed.ResultsParticipants with MCI (n = 21) took longer to complete both tasks than participants with healthy cognition (HC; n = 14), with significant time differences observed only in "Cost calculation." Completion time for IADL tasks and scores correlated in the expected direction with global cognition. Over 95% of the participants found the smart home assessment acceptable and a positive experience.DiscussionWe demonstrated the feasibility and acceptability of the use of unobtrusive commercially available sensors in a smart home for facilitating parts of the objective assessment of IADL in older adults. Future studies need to identify more IADLs that are suitable for semi‐automated or automated assessments through the use of simple, low‐cost sensors.

Painting by Lesions: Functional Networks Affected by White Matter Lesions Are Associated with Poorer Cognition

Cerebrovascular disease (CvD) is the second most common cause of dementia. Its associated pathology, such as white matter lesions (WML), is associated with reduced cognition. Due to the high variability, the relevance of WML location remains unknown. We hypothesised that although the location of WMLs may appear sporadic, they may actually lie within common functional networks. We used novel imaging methods to map the location of WMLs in a clinical sample with the functional connectivity associated with the same location in the human connectome. This identified the functional networks containing the largest WML load (>50%) in older adults with CvD. We then analyzed the association between level of disruption to these networks and measures of global cognition and executive functions. Included in this study were 164 older adults (>55 years old) with CvD. Cognition was assessed using the: 1) Montreal Cognitive Assessment (MoCA); 2) Stroop Colour Word Test; 3) Trail Making Tests; and 4) Digit Symbol Substitution Test. Our results found that the visual network and ventral attention network (VAN) surpassed the 50% overlap threshold with 85% and 66% overlap respectively. Additionally, after controlling for multiple comparisons and age, the level of disruption to the VAN was significantly associated with poorer global cognition, as measured by the MoCA (p=.001). These novel findings identify the functional networks most affected by the presence of WMLs in older adults with CvD and suggest that the disruption to the VAN caused by WML load may underlie the deficits seen in cognition in this population.

Informant-Reported Cognitive Decline is Associated with Objective Cognitive Performance in Parkinson's Disease.

The utility of informant-based measures of cognitive decline to accurately describe objective cognitive performance in Parkinson's disease (PD) without dementia is uncertain. Due to the clinical relevance of this information, the purpose of this study was to examine the relationship between informant-based reports of patient cognitive decline via the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE) and objective cognition in non-demented PD controlling for cognitive status (i.e., mild cognitive impairment; PD-MCI and normal cognition; PD-NC). One-hundred and thirty-nine non-demented PD participants (PD-MCI n = 38; PD-NC n = 101) were administered measures of language, executive function, attention, learning, delayed recall, visuospatial function, mood, and motor function. Each participant identified an informant to complete the IQCODE and a mood questionnaire. Greater levels of informant-based responses of patient cognitive decline on the IQCODE were significantly associated with worse objective performance on measures of global cognition, attention, learning, delayed recall, and executive function in the overall sample, above and beyond covariates and cognitive status. However, the IQCODE was not significantly associated with language or visuospatial function. Results indicate that informant responses, as measured by the IQCODE, may provide adequate information on a wide range of cognitive abilities in non-demented PD, including those with MCI and normal cognition. Findings have important clinical implications for the utility of the IQCODE in the identification of PD patients in need of further evaluation, monitoring, and treatment.

A characterisation of amyloid status and cognition in late‐life depression

AbstractBackgroundThe link between late‐life depression and Alzheimer’s disease (AD) has long been investigated, however it is still unclear whether depression acts as a risk factor, a prodromal feature or a comorbid condition in AD. Clarifying the nature of this link has important implications in the early intervention and diagnosis of AD. The relatively recent introduction of in‐vivo brain biomarkers for AD pathology offers the chance to explore the relationship between depression and pathologically‐confirmed neurodegeneration. Here, we examined the association among objective cognitive functioning, self‐reported cognitive failures and AD pathology in patients with late‐life depression.MethodSixty‐three older adults with no formal diagnosis of cognitive impairment underwent a comprehensive cognitive assessment and Amyloid‐PET Imaging at the Imperial Memory Unit. Participants were classified into two groups, according to the presence (n=33, mean age=71.82 ±4.98) or absence (n=30, mean age=71.30 ±5.80) of late‐life depression. Late‐life depression was confirmed through validated questionnaires (GDS ≥ 6 and/or HDRS ≥ 12) and medical history review. Amyloid‐PET images were qualitatively read as amyloid positive or amyloid negative by two experienced nuclear medicine radiologists (NMRs). Equivocal scans (6%) were read by a third independent NMR. Cognitive data in the two groups were compared using non‐parametric tests.ResultsAmyloid status did not differ significantly between the two groups (p=.367), with 3 (9%) depressed and 5 (17%) non‐depressed participants reported as amyloid‐positive. Despite higher levels of self‐reported cognitive failures (p&lt;.001), the depressed group did not differ from the non‐depressed group in a global measure of cognition (MMSE depressed: 28.09±1.69; non‐depressed: 28.93±4.66) and showed worse performance in 4 (Word List short‐delay recall, Digit Span backward and forward, Coding) of the 17 cognitive measures administered. Follow up data, currently being collected at our Unit, will add information about the long‐term trajectory of cognition in late life depression.ConclusionsIn our sample, depressive symptoms were associated with a limited number of cognitive measures but not with AD pathology. This suggests that depression seems to have a limited role in the early diagnosis of AD. Future studies should examine the role of specific features of depression and of other widespread neuropsychiatric symptoms (e.g., anxiety) in AD.

Relationships between cerebrovascular health and tau PET uptake are associated with global cognition

AbstractBackgroundBrain accumulation of tau and cerebrovascular dysfunction are both important contributors to AD pathogenesis, but associations between vascular health and tau levels, and their effects on clinical outcome, are poorly understood. We investigated these associations in a cross‐sectional study, by performing comparisons between cerebral blood flow (CBF), measured with ASL perfusion MRI, and tau PET uptake, measured with [18F]flortaucipir (FTP). In a subgroup, we assessed relationships between tau uptake and a CSF marker of vascular health known to be associated with impaired cognition, soluble platelet‐derived growth factor beta (sPDGFR‐β).MethodWe conducted discovery and replication analyses using data from USC (n=68) and ADNI (n=136), respectively. Voxelwise analyses assessed relationships between CBF and FTP standardized uptake value ratio (SUVR), the results of which were used to mask the replication analysis. Secondary analyses were performed on the replication dataset with a gray matter mask. Analyses were corrected for age, sex, gray matter volume, and diagnosis (when appropriate), with voxelwise and cluster‐level thresholds of p&lt;0.001 and p&lt;0.05, respectively. General linear models were used to determine if CBF‐FTP relationships differed between diagnostic groups, as well as between high and low performance on the Montreal Cognitive Assessment (MoCA), a measure of global cognition. Mediation models assessed the relationship between tau, sPDGFR‐β, and cognition.ResultIn the discovery cohort, we observed negative CBF‐FTP correlations mainly in lateral and inferior temporal regions, that were largely replicated in the ADNI cohort. Secondary analyses demonstrated that early negative CBF‐FTP correlations increased in spatial extent and strength of correlation with increased disease severity. Stronger negative CBF‐FTP correlations were observed in participants with more advanced diagnoses and in those with poorer global cognitive performance. sPDGFR‐β was a significant mediator of the relationship between inferior temporal tau uptake and MoCA.ConclusionOur results provide evidence that associations between the cerebrovascular system and tau binding may affect cognition across the AD spectrum. Importantly, the sPDGFR‐β analysis suggests that vascular dysfunction may contribute to cognitive impairment via elevations in tau, potentially caused by reduced tau clearance. Future, longitudinal studies are needed to explore the complex temporal relationship between tau deposition and vascular health.

Longitudinal assessment of cognitive decline in the Amish

AbstractBackgroundThe Modified Mini‐Mental State (3MS) is a widely used measure of global cognition. The Old Order Amish are both genetically and environmentally homogeneous, with similar years of formal education across the population. Here, we investigated the longitudinal course of cognitive function as measured by the distribution of 3MS in the Mid‐Western Amish.MethodAfter extensive QC, the 919 subjects with both baseline 3MS and AD status were analyzed. The change from 1st to 2nd measurement was used as the main longitudinal trait of interest. Mean decline differences in 4 baseline age groups (&lt;70, 70‐80, 80‐90, &gt;=90) were assessed. The differences in the average longitudinal decline of 3MS between AD cases and controls was assessed using Kolmogorov‐Smirnov tests and ANCOVA adjusted for age at exam and sibship.ResultThe overall baseline mean 3MS score was 89.52 [42, 100] at the mean age of exam 75.52 [60, 99]. The overall annual rate of decline was ‐0.3 [‐5, 5] from 1st to 2nd measurement (n=242) and ‐0.6 [‐2.1, 1.3] from 2nd to 3rd measurement (n = 23). The annual rate of decline was ‐0.96 [‐4, 1.7] in AD cases (n=18), ‐0.01 [‐5, 5] in AD controls (n=180) and ‐1.08 [‐5, 0.7] in an ‘Unclear’ group (n = 44). The most rapid annual decline of the 3MS was in age 80 to 90 group and the decline rate was significant (p‐value=0.004) compared to the lowest age group (&lt;70) overall and in AD cases. In the Unclear group, the rate of decline was greatest in age 70 to 80. However, in the control group, cognition improved, with a 1.29 [‐1, 5] annual increase in age 80 to 90. The age and sibship adjusted differences in decline were significant (p‐value&lt;2e‐10) between AD cases vs. controls as well as between Unclear vs. controls.ConclusionWe explored the changes of 3MS scores over time and demonstrated different patterns of decline by age and AD status in the Amish. Our study is the first in this homogeneous Amish population, providing a better understanding and insight into the cognitive decline examining the change in 3MS over time.

Using the Framingham Cardiovascular Disease Risk Score to predict cognitive performance in cognitively normal non‐hispanic whites and Mexican American elders

AbstractBackgroundPrevalence of cardiovascular disease risk factors (CVRFs) is higher among Mexican Americans (MAs) that non‐Hispanic Whites (NHWs), placing this population at a higher risk of cognitive decline. The purpose of this study was to examine the relationship between the Framingham Cardiovascular Disease 10‐years risk score (FCVDRS) and cognitive performance among MAs and NHWs. This study extends the limited literature about FCVDRS and cognition among MAs.MethodWe studied 518 cognitively normal participants (92 NHWs and 426 MAs) from an epidemiological study of aging. Gender, age, hypertension treatment status, systolic blood pressure (SBP) level, smoking status, diabetes mellitus diagnosis (DM), HDL, and total cholesterol levels were used to calculate the FCVDRS for each individual. A linear regression was conducted to examine the association of FCVDRS with MMSE, logical memory I and II, Trails B, FAS, and digit span scores. A one‐way ANOVA was used to analyze the relationship of FCVDRS categories (low &lt; 10, moderate 10 – 20, high &gt; 20), and test scores, along with Tukey post hoc tests to elucidate the magnitude of differences between the groups. Education was entered as a covariate in the model.ResultMAs had a higher prevalence of DM, higher SBP, and lower HDL values. Linear regression model was significant only for executive function in MAs , F(1,352) = 7.86, p = 0.005. One ‐way ANOVA showed a significant difference for Trails B, F(2,351) = 5.21, p = 0.006, and MMSE, F(2,414) = 3.00, p = 0.005 among MAs. In both cases, post hoc test indicated that MMSE and Trails B mean scores were lower in the high risk group when compared to the low risk group. No significant trends were seen in the Non‐Hispanic White subset.ConclusionOur data has shown that FCVDRS can be used to predict performance on measures of global cognition and executive function in MAs. Although more work has to be done to further understand the predictive power of FCVDRS, there is promise in using this model to develop early intervention programs targeted to MAs.

Effects of omega‐3 fatty acids on cerebral white matter hyperintensities and medial temporal lobe atrophy in older non‐demented adults: A 3‐year randomized‐controlled phase 2 trial

AbstractBackgroundThe n‐3 PUFA may modulate risk for age‐related cognitive impairment through vascular mechanisms. MRI derived cerebral white matter hyperintensities (WMH) presumptively reflect small vessel disease and their accumulation increases risk for age‐related cognitive decline and dementia. Blood n‐3 PUFA are consistently associated with reduced WMH and stroke. The primary aim here was to evaluate n‐3 PUFA supplementation on WMH accumulation over 3 years in an older population with evidence of WMH and absence of n‐3 PUFA supplementation.MethodsThe study was a double‐blind, placebo‐controlled trial, with participants randomized to a daily dose of fish oil (1650 mg combined eicosapentaenoic acid‐EPA and docosahexaenoic acid‐DHA) or placebo oil (soybean) for a 3‐year intervention. Main inclusion criteria were: non‐demented (MMSE &gt; 24), age &gt; 74 years, WMH volume &gt; 5.0 cc, and plasma n‐3 PUFA (EPA+DHA) &lt; 110 umol/L (or &lt; 5.5 percent of total fatty acids). The primary endpoint was 3‐year change in total WMH volume. Secondary endpoints include changes in regional brain volumes and white matter integrity. Exploratory endpoints include measures of cerebral blood flow, domain‐specific and global cognitive measures with subgroup analyses by APOE4 genotype. A linear mixed‐effects model was used to assess the outcomes.Results102 subjects were enrolled (mean age 81±4.4, MMSE 27.8±1.7; 60% female, 27.5% APOE4 positive) and a total of 78 participants completed the trial. Supplementation had no beneficial effect on rate of WMH progression, which increased by a mean of 1.07 cc per year in the n‐3 PUFA group vs 1.12 cc per year in the placebo group (p = 0.30 for time*trial arm interaction). Three‐year changes in executive cognitive function z‐scores were not different between treatment groups (p = 0.24). No differences in adverse events between groups were observed .ConclusionN‐3 PUFA compared with placebo, failed to slow 3‐year WMH accumulation and executive function decline in older non‐demented adults presenting with evidence of WMH. N‐3 PUFA at the 1.65‐gram dose appears safe in older adults over 3‐years. Additional MRI and cognitive outcomes with detailed safety profiles are planned for presentation.

Evaluating the Real-World Representativeness of Participants with Mild Cognitive Impairment in Canadian Research Protocols: a Comparison of the Characteristics of a Memory Clinic Patients and Research Samples.

BackgroundStudies of mild cognitive impairment (MCI) employ rigorous eligibility criteria, resulting in sampling that may not be representative of the broader clinical population.ObjectiveTo compare the characteristics of MCI patients in a Calgary memory clinic to those of MCI participants in published Canadian studies.MethodsClinic participants included 555 MCI patients from the PROspective Registry of Persons with Memory SyMPToms (PROMPT) registry in Calgary. Research participants included 4,981 individuals with MCI pooled from a systematic literature review of 112 original, English-language peer-reviewed Canadian studies. Both samples were compared on baseline sociodemographic variables, medical and psychiatric comorbidities, and cognitive performance for MCI due to Alzheimer’s disease and Parkinson’s disease.ResultsOverall, clinic patients tended to be younger, more often male, and more educated than research participants. Psychiatric disorders, traumatic brain injury, and sensory impairment were commonplace in PROMPT (up to 83% affected) but > 80% studies in the systematic review excluded these conditions. PROMPT patients also performed worse on global cognition measures than did research participants.ConclusionStringent eligibility criteria in Canadian research studies excluded a considerable subset of MCI patients with comorbid medical or psychiatric conditions. This exclusion may contribute to differences in cognitive performance and outcomes compared to real-world clinical samples.

Evaluating Cognitive Relationships with Resting-State and Task-driven Blood Oxygen Level-Dependent Variability.

Recent functional magnetic resonance imaging studies have reported that moment-to-moment variability in the blood oxygen level-dependent (BOLD) signal is positively associated with task performance and, thus, may reflect a behaviorally sensitive signal. However, it is not clear whether estimates of resting-state and task-driven BOLD variability are differentially related to cognition, as they may be driven by distinct sources of variance in the BOLD signal. Moreover, other studies have suggested that age differences in resting-state BOLD variability may be particularly sensitive to individual differences in cardiovascular, rather than neural, factors. In this study, we tested relationships between measures of behavioral task performance and BOLD variability during both resting-state and task-driven runs of a Stroop and an animacy judgment task in a large, well-characterized sample of cognitively normal middle-aged to older adults. Resting-state BOLD variability was related to composite measures of global cognition and attentional control, but these relationships were eliminated after correction for age or cardiovascular estimates. In contrast, task-driven BOLD variability was related to attentional control measured both inside and outside the scanner, and importantly, these relationships persisted after correction for age and cardiovascular measures. Overall, these results suggest that BOLD variability is a behaviorally sensitive signal. However, resting-state and task-driven estimates of BOLD variability may differ in the degree to which they are sensitive to age-related, cardiovascular, and neural mechanisms.

Metformin Use Is Associated With Slowed Cognitive Decline and Reduced Incident Dementia in Older Adults With Type 2 Diabetes: The Sydney Memory and Ageing Study.

Type 2 diabetes (diabetes) is characterized by accelerated cognitive decline and higher dementia risk. Controversy exists regarding the impact of metformin, which is associated with both increased and decreased dementia rates. The objective of this study was to determine the association of metformin use with incident dementia and cognitive decline over 6 years in participants with diabetes compared with those not receiving metformin and those without diabetes. A prospective observational study was conducted of N = 1,037 community-dwelling older participants without dementia aged 70-90 years at baseline (the Sydney Memory and Ageing Study). Exclusion criteria were dementia, major neurological or psychiatric disease, or progressive malignancy. Neuropsychological testing measured cognitive function every 2 years; a battery of tests measured executive function, memory, attention/speed, language, and visuospatial function individually. These were used to determine the measure of global cognition. Incident dementia was ascertained by a multidisciplinary panel. Total brain, hippocampal, and parahippocampal volumes were measured by MRI at baseline and 2 years (n = 526). Data were analyzed by linear mixed modeling, including the covariates of age, sex, education, BMI, heart disease, hypertension, stroke, smoking, and apolipoprotein Eε4 carriage. Of n = 1,037, 123 had diabetes; 67 received metformin (DM+MF) and were demographically similar to those who did not (DM-noMF) and participants without diabetes (no-DM). DM+MF had significantly slower global cognition and executive function decline compared with DM-noMF. Incident dementia was significantly higher in DM-noMF compared with DM+MF (odds ratio 5.29 [95% CI 1.17-23.88]; P = 0.05). Older people with diabetes receiving metformin have slower cognitive decline and lower dementia risk. Large randomized studies in people with and without diabetes will determine whether these associations can be attributed to metformin.

Late-onset epilepsy and 25-year cognitive change: The Atherosclerosis Risk in Communities (ARIC) study.

To define the association between late-onset epilepsy (LOE) and 25-year change in cognitive performance. The Atherosclerosis Risk in Communities (ARIC) study is a multicenter longitudinal cohort study with participants from four U.S. communities. From linked Medicare claims, we identified cases of LOE, defined as ≥2 seizure-related diagnostic codes starting at age ≥67. The ARIC cohort underwent evaluation with in-person visits at intervals of 3-15years. Cognition was evaluated 4 times over >25years (including before the onset of seizures) using the Delayed Word Recall Test (DWRT), Digit Symbol Substitution Test (DSST), and Word Fluency Test (WFT); a global z-score was also calculated. We compared the longitudinal cognitive changes of participants with and without LOE, adjusting for demographics and LOE risk factors. From 8033 ARIC participants with midlife cognitive testing and Medicare claims data available (4523 [56%] female, 1392 [17%] Black), we identified 585 cases of LOE. The rate of cognitive decline was increased on all measures in the participants who developed LOE compared to those without LOE. On the measure of global cognition, participants with LOE declined by -0.43 z-score points more over 25years than did participants without epilepsy (95% confidence interval [CI] -0.59 to -0.27). Prior to the onset of seizures, cognitive decline was more rapid on the DWRT, DSST, and global z-scores in those who would later develop LOE than it was in non-LOE participants. Results were similar after excluding data from participants with dementia. Global cognition, verbal memory, executive function, and word fluency declined faster over time in persons developing LOE than without LOE. Declines in cognition preceding LOE suggest these are linked; it will be important to investigate causes for midlife cognitive declines associated with LOE.

Factor analysis of the Cognitive Abilities Screening Instrument: Kuakini Honolulu-Asia Aging Study.

The Cognitive Abilities Screening Instrument (CASI) is a screening test of global cognitive function used in research and clinical settings. However, the CASI was developed using face validity and has not been investigated via empirical tests such as factor analyses. Thus, we aimed to develop and test a parsimonious conceptualization of the CASI rooted in cognitive aging literature reflective of crystallized and fluid abilities. Secondary data analysis implementing confirmatory factor analyses where we tested the proposed two-factor solution, an alternate one-factor solution, and conducted a χ2 difference test to determine which model had a significantly better fit. N/A. Data came from 3,491 men from the Kuakini Honolulu-Asia Aging Study. The Cognitive Abilities Screening Instrument. Findings demonstrated that both models fit the data; however, the two-factor model had a significantly better fit than the one-factor model. Criterion validity tests indicated that participant age was negatively associated with both factors and that education was positively associated with both factors. Further tests demonstrated that fluid abilities were significantly and negatively associated with a later-life dementia diagnosis. We encourage investigators to use the two-factor model of the CASI as it could shed light on underlying cognitive processes, which may be more informative than using a global measure of cognition.