General Cognitive Function Research Articles

Sequence of episodic memory-related behavioral and brain-imaging abnormalities in type 2 diabetes.

Episodic memory decline is a common complication of type 2 diabetes (T2D). To comprehensively explore the neural mechanisms underlying it, we aimed to explore the sequence that episodic memory-related behavioral and brain-imaging biomarkers appear abnormal in the progression of T2D. We enrolled 62 healthy controls and 110 patients with T2D. The California Verbal Learning Test, Montreal cognitive assessment, and Stroop color word test was used to assess the episodic memory, general cognitive function, and executive function. Principal component analysis was applied to extract behavioral biomarkers. Imaging biomarkers included structural and functional MRI features of the entorhinal cortex-hippocampus and hippocampus-anterior cingulate cortex pathways. We used a novel discriminative event-based model to determine the sequence that memory-related biomarkers appear abnormal and estimate the stage of memory decline. T2D patients exhibited poorer memory, general cognitive function, and executive function compared to healthy controls after controlling age, sex, and education level. In the progression of T2D, functional interaction between brain regions showed abnormalities first, followed by memory tests, the cerebral spontaneous neural activity, and finally the gray matter volume. Besides, abnormalities appeared earlier in the entorhinal cortex than in the anterior cingulate cortex. Later stage of memory decline was distributed in older patients with T2D and was associated with higher systolic blood pressure, postprandial blood glucose, and low-density lipoprotein. In T2D, behavioral and brain imaging biomarkers of episodic memory appear abnormal in a specific sequence, and the stage of memory decline was closely associated with old age and vascular risk factors. NCT02420470, ClinicalTrials.gov ( https://www. gov/ ).

Dairy intake and cognitive function in older adults in three cohorts: a mendelian randomization study.

Meta-analyses of observational studies on the effect of dairy on cognitive function have yielded inconclusive results, potentially due to unmeasured confounding. To avoid the no-unmeasured confounding assumption, we used lactase persistence genetic variant as an instrumental variable, for which the CC genotype is associated with lower lactase production and, consequently, lower dairy consumption. We used it to assess the effect of long-term consumption of total and non-fermented dairy on cognitive function. We included 43,836 individuals over 55 years old with genotyping, dietary data, and cognitive function measurements from three population-based studies: CoLaus|PsyCoLaus (Switzerland), the Rotterdam Study (the Netherlands) and the Canadian Longitudinal Study on Aging (CLSA - Canada). We performed a one-sample Mendelian randomization using two-stage least-squares regression. First, we estimated total and non-fermented dairy consumption by T-allele frequency. Second, we used the estimated dairy consumption in linear regression models on general cognition, assessed by the Mini-Mental State Examination (MMSE) and the Mental Alternation Test, executive function, verbal fluency, verbal learning, and memory. Per T-allele, total dairy intake and non-fermented was 24.8 and 15.3g/day higher in PsyCoLaus, 57.9 and 49.8g/day in the Rotterdam Study, and 0.31 and 0.29 times/day in CLSA, respectively. We found no association between the genetically predicted difference and the MMSE in PsyCoLaus and the Rotterdam Study. However, lactase persistent individuals scored 3.4 (95% CI2.1- 4.7) and 3.5 (95% CI 2.3-4.7) points more in the Mental Alternation Test for total and fermented dairy, respectively, in CLSA. Similarly, lactase persistent participants in CLSA had higher verbal fluency, verbal learning and executive function, but no differences were found in the other cohorts. Such inconsistencies might stem from different FFQs across cohorts and consumption ranges. Nonetheless, the generally small magnitude of effect sizes may suggest that there is no real effect between total or non-fermented dairy intake and cognitive function. The evidence for a causal effect of dairy consumption on general cognitive function is weak, consistent with previous results from classic analysis from observational studies. Interventions targeting dairy are unlikely to have a relevant effect on cognitive function.

Association Between Relative Hypothermia and Cognitive Function in Older Adults: A Cross-Sectional Study.

This study aimed to investigate the association between relative hypothermia measured by a wearable device and cognitive function, and to clarify whether relative hypothermia is a useful indicator for preventing poor cognitive function. Cross-sectional study. The study included 103 community-dwelling older adults aged 60 to 90years. This study measured body temperature with a wrist-worn device equipped with an accelerometer. Subjects were instructed to wear the Silmee 24hours a day for 1 week, and body temperature data were sampled every minute. Relative hypothermia was calculated as the percentage of time during the daytime active phase in which body temperature was below the 24-hour mean body temperature. Cognitive function was evaluated regarding memory, attention, executive function, processing speed, and general cognitive function. We calculated atrophy within regions of interest such as the parahippocampal gyrus, hippocampus, and amygdala, which show atrophy in the early stages of Alzheimer's disease. Multiple regression analysis was performed, taking into account variables such as age, sex, body mass index, and severity of volume of interest (VOI) atrophy. Relative hypothermia was significantly associated with memory function. Multiple regression analysis considering variables such as age and severity of VOI atrophy also showed that relative hypothermia was independently associated with the decline in memory function. Relative hypothermia was independently associated with the decline in memory function. Our findings suggest that relative hypothermia assessed by a wearable device may be a useful indicator for early prevention of poor cognitive function.

Preserved brain youthfulness: longitudinal evidence of slower brain aging in superagers.

Superagers, older adults with exceptional cognitive abilities, show preserved brain structure compared to typical older adults. We investigated whether superagers have biologically younger brains based on their structural integrity. A cohort of 153 older adults (aged 61-93) was recruited, with 63 classified as superagers based on superior episodic memory and 90 as typical older adults, of whom 64 were followed up after two years. A deep learning model for brain age prediction, trained on 899 diverse-aged adults (aged 31-100), was adapted to the older adult cohort via transfer learning. Brain age gap (BAG), a metric based on brain structural patterns, defined as the difference between predicted and chronological age, and its annual rate of change were calculated to assess brain aging status and speed, respectively, and compared among subgroups. Lower BAGs correlated with more favorable cognitive status in memory and general cognitive function. Superagers exhibited a lower BAG than typical older adults at both baseline and follow-up. Individuals who maintained or attained superager status at follow-up showed a slower annual rate of change in BAG compared to those who remained or became typical older adults. Superaging brains manifested maintained neurobiological youthfulness in terms of a more youthful brain aging status and a reduced speed of brain aging. These findings suggest that cognitive resilience, and potentially broader functional resilience, exhibited by superagers during the aging process may be attributable to their younger brains.

Explainable machine learning models for identifying mild cognitive impairment in older patients with chronic pain

BackgroundMild cognitive impairment (MCI) is prevalent in older adults with chronic pain, making early detection crucial for dementia prevention and healthy aging. This study aimed to determine MCI risk factors in older patients with chronic pain and to develop 9 machine learning models to identify MCI risk.MethodsA total of 612 older patients with chronic pain were recruited between October 2023 and July 2024. Data collected included patients’ general information, cognitive function, pain level, depression, and sleep quality. The dataset was randomly divided into training set and testing set, and processed by Min-Max Normalization and SMOTETomek comprehensive sampling. SVM-RFE and LASSO regression were used for variable selection. We then developed machine learning models and interpreted them by SHAP.ResultsAge, education level, number of pain sites, pain duration, pain level, depression and sleep quality were risk factors of MCI in older patients with chronic pain. The Extreme Gradient Boosting (XGBoost) model performed best (AUC 0.925), with pain level, age, and depression as the most important variables.ConclusionsWe successfully developed 9 machine learning models to identify MCI risk. These models provide a tool for nurses to detect MCI risk early. We recommend that nurses integrate machine learning techniques into clinical nursing practice for managing MCI. However, these findings require validation with longitudinal data to confirm predictive validity for MCI progression.

Characterization of cognitive functioning in complex PTSD compared to non-complex PTSD.

Previous research has indicated cognitive impairments in patients with post-traumatic stress disorder (PTSD), specifically in attention, memory, and executive functioning. However, there is limited knowledge about the cognitive profile of individuals with complex PTSD (cPTSD), a new diagnosis in ICD-11. Moreover, predictors of cognitive impairment remain unclear. The present study aims to enhance understanding of cognitive functioning and its predictors in cPTSD compared with non-complex PTSD (ncPTSD). N = 64 participants (n = 34 cPTSD, n = 30 ncPTSD) completed psychometric questionnaires and the neuropsychological test set Cognitive Basic Assessment (COGBAT) assessing a general cognitive index, attention, visual memory, and executive functioning. First, the test results of both groups were compared to the COGBAT norm sample. Secondly, group differences in cognitive domains were analyzed using student t-tests with independent samples (cPTSD vs. ncPTSD). Thirdly, bivariate and multivariate regressions examined influencing factors of cognitive impairment. Both groups showed cognitive impairments in comparison to the COGBAT norm group. Significant differences between cPTSD and ncPTSD were found in visual memory (p = .003) and selective attention (p = .004). In multivariate regression, type of PTSD and age were found to significantly impact visual memory, while type of PTSD, age, and psychotropic medication showed significant effects on selective attention. Given higher symptom severity and cognitive deficits in cPTSD, more intensive and diverse interventions should be considered in comprehensive treatment plans, for instance, cognitive training.

Virtual Reality Interventions for Older Adults With Mild Cognitive Impairment: Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Alzheimer disease is incurable, but it is possible to intervene and slow down the progression of dementia during periods of mild cognitive impairment (MCI) through virtual reality (VR) technology. This study aimed to analyze the effects of VR interventions on older adults with MCI. The examined outcomes include cognitive abilities, mood, quality of life, and physical fitness, including general cognitive function, memory performance, attention and information processing speed, executive function, language proficiency, visuospatial abilities, depression, daily mobility of individuals, muscle performance, and gait and balance. A total of 4 web-based databases (Web of Science, PubMed, Embase, and Ovid) were searched up to December 30, 2023, for randomized controlled trials assessing the self-reported outcomes of VR-based technology on cognition, mood, quality of life, and physical fitness in older adults (aged ≥55 years) with MCI. Two reviewers independently screened the search results and reference lists of the identified papers and related reviews. Data on the intervention components and delivery and behavioral change techniques used were extracted. A meta-analysis, risk-of-bias sensitivity analysis, and subgroup analysis were performed where appropriate to explore potential moderators. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach was used to assess the quality of evidence. This review analyzed 18 studies involving 722 older adults with MCI. VR was delivered through different immersion levels with VR cognitive training, VR physical training, or VR cognitive-motor dual-task training. VR interventions showed significant improvements in memory (standardized mean difference [SMD] 0.2, 95% CI 0.02-0.38), attention and information processing speed (SMD 0.25, 95% CI 0.06-0.45), and executive function (SMD 0.22, 95% CI 0.02-0.42). VR without therapist involvement improved memory as well as attention and information processing speed. VR cognitive training also resulted in significant improvements in attention and information processing speed in older adults with MCI (SMD 0.31, 95% CI 0.05-0.58). In addition, immersive VR had a significant impact on improving attention and information processing speed (SMD 0.25; 95% CI 0.01-0.50) and executive function (SMD 0.25; 95% CI 0.00-0.50). However, the effects of the intervention were very small in terms of general cognitive function, language proficiency, visuospatial abilities, depression, daily living ability, muscle performance, and gait and balance. Quality of evidence varied, with moderate ratings for certain cognitive functions and low ratings for others, based on the GRADE approach. VR interventions can improve memory, attention and information processing speed, and executive function in older adults with MCI. The quality of evidence is moderate to low, and further research is needed to confirm these findings and explore additional health-related outcomes.

Effects of interactive boxing-cycling on dual-task walking and prefrontal cortex activation in older adults with cognitive frailty: A randomized controlled trial.

Older adults with cognitive frailty often have impaired dual-task walking and prefrontal cortex (PFC) activation. Combining cycling with interactive boxing offers an innovative and interesting dual-task training to challenge both physical and cognitive skills. This study investigated the effects of interactive boxing-cycling on this population. Thirty-nine participants were assigned to the interactive boxing-cycling group (n = 20) or the stationary cycling group (n = 19) for 36 sessions over 12 weeks. The outcomes included dual-task walking performance, PFC activation, cognitive function, and frailty scores. Results showed the interactive boxing-cycling group had greater improvements in dual-task walking speed and cost and beneficially reduced oxygenated hemoglobin levels compared to the stationary group. Furthermore, both groups improved in frailty and cognition, but the interactive boxing-cycling group had better effects on general and specific cognitive function. Interactive boxing-cycling is an efficient intervention to enhance dual-task walking and PFC activation in older adults with cognitive frailty.

Multisensory Stimulation in Rehabilitation of Dementia: A Systematic Review.

Background/Objectives: Dementia leads to cognitive decline, affecting memory, reasoning, and daily activities, often requiring full-time care. Multisensory stimulation (MSS), combined with cognitive tasks, can slow this decline, improving mood, communication, and overall quality of life. This systematic review aims to explore methods that utilize MSS in the rehabilitation of patients with dementia. Its clinical value is rooted in its ability to offer a deep comprehension of how MSS can be successfully incorporated into rehabilitation treatments. Methods: Studies were identified from an online search of PubMed, EBSCOhost, Cochrane Library, Web of Science, Embase, and Scopus databases with a search time frame from 2014 to 2024. This review has been registered on Open OSF (n) 3KUQX. Results: Pilot studies investigating MSS interventions, encompassing Cognitive Stimulation Therapy (CST), Sonas therapy, and combined physical-cognitive exercise programs, have yielded mixed findings in individuals with dementia. CST has demonstrated significant improvements in general cognitive function, particularly in language skills, offering a promising approach for cognitive enhancement. Sonas therapy, while showing positive trends in some studies, does not consistently achieve statistically significant outcomes across all cognitive domains. Conversely, combined exercise programs have shown efficacy in improving dual-task performance, suggesting benefits for motor-cognitive integration. MSS delivered within specialized environments like Snoezelen rooms consistently produces positive effects on mood, reducing agitation and promoting relaxation. Conclusions: This review emphasizes how MSS can enhance cognitive, emotional, and behavioral results for individuals with dementia. It is essential for future research to standardize protocols, incorporate advanced technologies such as virtual reality, and rectify diversity gaps. Collaboration between different fields will improve the effectiveness and usefulness of MSS in caring for individuals with dementia.

EDUCATIONAL ATTAINMENT AND LATER-LIFE COGNITIVE FUNCTION IN HIGH- AND MIDDLE-INCOME COUNTRIES

Abstract The rising number of dementia cases worldwide, especially in low- and middle-income countries (LMICs), underscores the need to identify social policies that promote cognitive health of older adults in LMICs and reduce global dementia burden. Many studies have found that educational attainment is associated with better cognitive function. However, these findings are mostly from Western high-income countries where the social and historical contexts of education differ from LMICs. In this research, we aim to evaluate the importance of educational attainment for later-life cognitive function in various social and geographic settings. Using data from the US Health and Retirement Study (HRS) and its sister studies in England, Mexico, China, and India and each study’s respective Harmonized Cognitive Assessment Protocol (HCAP) (n = 14,978, 2016–2019), we compared later-life global cognitive function across countries, examined educational differences in cognitive function within each country, and evaluated the potential impact of improving educational attainment in LMICs on reducing differences in later-life cognitive function between LMICs and high-income countries. In Mexico, China, and India, the general cognitive function score was approximately one standard deviation of HRS-HCAP scores lower compared to the US and England, paralleling patterns of educational attainment across countries. Higher educational attainment was consistently associated with better cognitive function across countries. Differences in educational attainment explained ~50%–90% of observed differences in cognitive function across countries. Our results underscore the importance of education to promote cognitive health. Continual improvement of educational attainment in LMICs may yield significant payoffs in later-life cognitive health.

Cognitive functioning in children and adolescents with cerebral palsy: protocol for the Danish CPCog-Youth study

BackgroundMany children and adolescents with cerebral palsy (CP) experience cognitive difficulties, impacting their academic, social, and emotional well-being. A Danish study from 2023 revealed that merely 40% of individuals with CP complete their elementary school education, and previous neuropsychological studies have found that most children and adolescents with CP experience cognitive difficulties. Yet, cognitive functioning is often assumed rather than assessed, and CP follow-up programs focus predominantly on physical functioning. Recognizing this gap, we aim to investigate cognitive functioning in children and adolescents with CP in mainstream schools in Denmark, using standardized neuropsychological tests. Our objective is to provide valuable insights to guide clinical practice on cognitive assessment and intervention, ultimately fostering a more effective support system for individuals with CP.MethodsThe study employs a cross-sectional design, involving 100 children and adolescents with CP aged 11–15 years attending mainstream schools in Denmark. Cognitive assessment includes the core battery from a proposed Nordic test protocol for children and adolescents with CP – the CPCog – encompassing general cognitive functioning (intelligence), executive functions, and visuo-motor skills. Supplementary tests cover verbal and nonverbal short-term memory, attention, fatigue, and mental health. The assessment protocol will also be evaluated by parents of participating children and adolescents with CP. The project is conducted collaboratively by the neuropsychological teams at three assessment sites, in conjunction with the Center for Cerebral Palsy, Rigshospitalet, Aarhus University Hospital, and Aalborg University Hospital. The study benefits from an external advisory board comprising leading international CP experts.DiscussionCognitive difficulties in children and adolescents with CP are often overlooked. Few cognitive studies exist, with some providing only estimated cognitive functioning. The CPCog-Youth study will help advance our understanding of the cognitive challenges experienced by children and adolescents attending mainstream schools. The findings will contribute to the development of targeted cognitive assessment and intervention programs for individuals with CP, addressing this commonly neglected aspect of care. By also seeking feedback from participating families and the involved neuropsychologists, we aim to investigate whether the proposed cognitive assessment is feasible and beneficial in real-world settings.Trial registrationThe study was registered on ClinicalTrials.gov on June 27, 2023 (ID: NCT05921422).

Brain maps of general cognitive function and spatial correlations with neurobiological cortical profiles.

In this paper, we attempt to answer two questions: 1) which regions of the human brain, in terms of morphometry, are most strongly related to individual differences in domain-general cognitive functioning (g)? and 2) what are the underlying neurobiological properties of those regions? We meta-analyse vertex-wise g-cortical morphometry (volume, surface area, thickness, curvature and sulcal depth) associations using data from 3 cohorts: the UK Biobank (UKB), Generation Scotland (GenScot), and the Lothian Birth Cohort 1936 (LBC1936), with the meta-analytic N = 38,379 (age range = 44 to 84 years old). These g-morphometry associations vary in magnitude and direction across the cortex (|β| range = -0.12 to 0.17 across morphometry measures) and show good cross-cohort agreement (mean spatial correlation r = 0.57, SD = 0.18). Then, to address (2), we bring together existing - and derive new - cortical maps of 33 neurobiological characteristics from multiple modalities (including neurotransmitter receptor densities, gene expression, functional connectivity, metabolism, and cytoarchitectural similarity). We discover that these 33 profiles spatially covary along four major dimensions of cortical organisation (accounting for 65.9% of the variance) and denote aspects of neurobiological scaffolding that underpin the spatial patterning of MRI-cognitive associations we observe (significant |r| range = 0.21 to 0.56). Alongside the cortical maps from these analyses, which we make openly accessible, we provide a compendium of cortex-wide and within-region spatial correlations among general and specific facets of brain cortical organisation and higher order cognitive functioning, which we hope will serve as a framework for analysing other aspects of behaviour-brain MRI associations.

Joint Contribution of NfL and PSMD for Improved Risk Stratification of VCID

AbstractBackgroundAdvancing therapeutic and prevention strategies for vascular contributions to cognitive impairment and dementia (VCID) warrants identifying novel biomarkers. However, due to the high heterogeneity underlying dementia pathology, a single marker may not fully risk‐stratify for VCID. A blood‐based biomarker of neuroaxonal injury, neurofilament light chain (NfL), and a neuroimaging‐based biomarker of white matter microstructural damage on diffusion weighted imaging, peak width of skeletonized mean diffusivity (PSMD), have been related to worse general cognition and proposed as robust biomarkers for cerebral small vessel disease (cSVD). We investigated the joint contribution of NfL and PSMD for improved specificity/sensitivity to identify persons at risk for VCID.MethodDementia‐free participants from the Framingham Offspring Study with cognitive, neuroimaging, and NfL data were included (N=969). NfL was measured in plasma, and PSMD was derived from MRI diffusion weighted imaging. Executive function and general cognitive function were assessed from a neuropsychological battery. NfL and PSMD were dichotomized by the top quartile and combined to indicate a high cSVD burden. The high NfL‐PSMD risk category was related to cognitive function using linear regression adjusting for age, age‐squared, sex, education, renal function (eGFR), and total intracranial volume. Additional analyses incorporating amyloid PET uptake in 64 participants were performed to discern Alzheimer’s disease pathology from VCID.ResultHigher NfL‐PSMD was significantly associated with worse executive (Beta±SE, ‐0.06±0.02, p=0.002) and general cognitive function (‐0.15±0.07, p=0.02). Additionally, amyloid PET over‐predicted NfL levels in those with PSMD below the median (observed<predicted, Mean(SD), ‐0.06(0.31)) and under‐predicted NfL in those with PSMD above the median (observed>predicted, 0.06 (0.33)). Although results were not significant (p=0.15) due to the limited sample, they suggest that amyloid pathology does not explain cSVD burden measured with NfL and PSMD.ConclusionOur findings suggest combining NfL and PSMD can better risk‐stratify those with VCID and poorer cognitive function. This NfL‐PSMD multi‐biomarker has potential to discriminate vascular dysfunction from Alzheimer’s pathology, improving identification of persons better suited for VCID clinical trials. Utilizing a multi‐biomarker approach may improve accuracy for risk stratification of persons bearing covert cerebral vascular injury. Further studies are underway to confirm these findings in larger, diverse samples.

Depressive and negative symptoms in the early and established stages of schizophrenia: integrating structural brain alterations, cognitive performance, and plasma interleukin-6 levels

BackgroundDepressive and negative symptoms are related to poor functional outcomes in schizophrenia. Cognitive deficits, reduced brain cortical thickness (CT) and volumes as well as inflammation may contribute to depressive and negative symptoms, but pharmacological treatment and disease progression may confound the associations. MethodsWe evaluated whether higher plasma IL-6 levels would be associated with more severe negative or depressive symptoms in schizophrenia and explored illness stage utilizing Early (BeneMin; n=201, males=72.8%) and Established schizophrenia (iRELATE; n=94, males=67.3%) cohorts. Using Structural Equation Modeling (SEM) in a subsample (iRELATE; n=42; males=69.0%; BeneMin; n=102; males=76.5%) with data on structural brain metrics (CT and volume), general cognitive performance, and plasma IL-6 levels, we assessed the interrelationships between these variables on depressive and negative symptom severity in Early and Established schizophrenia samples combined and Early schizophrenia only. All analyses were adjusted for sex, age, and chlorpromazine equivalent dose. ResultsHigher plasma IL-6 levels were related to more severe depressive symptoms in Early (p<0.05) and negative symptoms in Established schizophrenia (p<0.05). SEM findings in Early and Established schizophrenia samples combined, and Early schizophrenia only showed that the interrelationship between higher plasma IL-6 levels, structural brain metrics, and general cognitive performance did not predict the severity of depressive and negative symptoms (p>0.05). Higher plasma IL-6 levels and lower general cognitive performance were associated with reduced brain metrics (p<0.05). ConclusionOur results indicate that higher plasma IL-6 levels may be differently associated with the severity of depressive and negative symptoms dependent on the illness stage. Future work identifying elevated levels of inflammation in larger samples may allow stratification and personalized intervention by subgroups who are at risk of poor outcomes.

Ethnic Differences in the Association Between Cognitive Performance and Informant-rated Cognitive Decline.

It is unknown whether cognitive test scores are equivalently associated with informant-rated cognitive decline across culturally and linguistically diverse older adults. We examined the association between cognitive domain scores on the Harmonized Cognitive Assessment Protocol (HCAP) and informant-rated cognitive decline in a harmonized population-based sample of older adults. We combined data from the HCAP sub-study of the Health and Retirement Study (HRS; 2016) and the Brain Attack Surveillance in Corpus Christi-Cognitive (BASIC-C; 2018-2020) study. We included Hispanic/Latino-a-e-x (H/L; n = 566) and non-H/L white (NHW; n = 2,145) older adults. Both studies included the HCAP cognitive assessment with domain scores for memory, attention/executive function (EF), language, visuospatial, orientation, and general cognitive performance (GCP). Informants rated cognitive decline with the Informant Questionnaire of Cognitive Decline in the Elderly (IQCODE). Cognitive domain scores were more strongly associated with IQCODE scores for NHW than H/L participants for four of six domains (GCP, EF, visuospatial, and orientation) after adjusting for demographics (age, sex/gender, education) and study membership. Informants generally rated greater cognitive decline in NHW than H/L respondents for a given cognitive domain score, and the magnitude of this difference was greater for lower cognitive test scores. We found generally weaker associations between cognitive performance and informant-rated cognitive decline in H/L compared to NHW older adults. These findings suggest cognitive measurement differences across culturally and linguistically diverse older adult populations, which may result in underestimation of cognitive impairment in H/L populations.

Instrumental and biological validation of PSMD as a VCID biomarker

AbstractBackgroundPeak‐width of skeletonized mean diffusivity (PSMD) is an emerging biomarker of cerebral small vessel disease (cSVD)‐related vascular contributions to cognitive impairment and dementia (VCID). Higher PSMD values reflect greater white matter microstructural damage, and prior research has related PSMD to sporadic and monogenic forms of cSVD and worse cognitive function. Therefore, we proposed PSMD as a risk stratification biomarker for VCID. This study aimed to perform a rigorous instrumental and biological validation for PSMD in the MarkVCID‐1 consortium.MethodMethods to derive PSMD were packaged in a kit containing a protocol, scripts, and instructions. The instrumental validation included a pre‐specified plan to assess inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility among MarkVCID‐1 participants aged 53‐78 years across the spectrum of cSVD. We used intra‐class correlations for absolute agreement (ICCAA) and consistency (ICCC) to evaluate results, with ICC&gt;0.07 as the pre‐specified goal.The biological validation was performed on 7,289 participants of diverse ages and racial/ethnic backgrounds from MarkVCID‐1 and population‐based cohorts from CHARGE, RUSH, and UCD‐ADRC. All sites derived a composite measure of general cognitive function using neuropsychological tests assessing distinct cognitive domains. Finally, we used linear regression models to assess the association between log‐PSMD and general cognition adjusting for age, age2, sex, and education.ResultOur instrumental validation results (Figure 1) showed excellent reliability between raters from seven sites (overall ICCAA=0.945, P&lt;0.001), agreement between test and retest measurements obtained within two weeks (ICCAA=0.986, P&lt;0.001), and reproducibility across Philips Achieva, Siemens Prisma, and Siemens Trio scanners (ICCC= 0.954, P&lt;0.001).In the biological validation, higher PSMD values were associated with lower general cognitive function in MarkVCID‐1 (Beta=‐0.82, P&lt;0.001), and these findings were replicated across the CHARGE, RUSH, and UCD‐ADRC cohorts (Table 1).ConclusionOur rigorous instrumental validation study showed excellent inter‐rater reliability, test‐retest repeatability, and inter‐scanner reproducibility for the PSMD kit. We further observed strong associations between higher PSMD values and poorer cognitive function across diverse samples in the biological validation. Taken together, our findings support using PSMD as a robust risk stratification biomarker in multi‐site clinical trials of VCID. Additional longitudinal validation studies for PSMD are underway in MarkVCID‐2.

Plasma neurofilament light as a biomarker for vascular contributions to cognitive impairment and dementia

AbstractBackgroundThe MarkVCID consortium was established to address the paucity of biomarkers for vascular contributions to cognitive impairment and dementia (VCID), a leading cause of dementia. Plasma neurofilament light (NfL), a neuroaxonal injury marker elevated in several neurological and neurodegenerative diseases, was selected as one of the first biomarkers to be examined. We performed comprehensive instrumental and clinical validation of the Quanterix Simoa NfL assay using the first MarkVCID cohort.MethodPlasma NfL was measured using HD‐X and HD‐1 Simoa instruments. Samples from the MarkVCID consortium were used to evaluate intra‐ and inter‐plate reliability, test‐retest repeatability, and inter‐site reproducibility. We used linear regression models to assess the association of NfL in MarkVCID with general cognitive function (GCF) as the primary outcome (n=331). In secondary analyses we assessed NfL associations with white matter hyperintensities (WMH). Models were adjusted for potential confounders, including eGFR as renal function influences NfL clearance. We replicated our findings using cohorts from the CHARGE consortium (CARDIA, ARIC, FHS, AGES; n=4,772), the UKY ADRC (n=350), and the UCD ADRC (n=196).ResultWe found the Quanterix Simoa platform to be reliable with low coefficients of variation (average CV&lt;12%), high inter‐site reproducibility (overall ICC = 0.93) and high repeatability in test‐retest samples drawn within 30 days (ICC=0.968). There was strong consistency across Quanterix instruments (HD‐X and HD‐1; R2≥0.98) and kits (N4PA and single molecule NfL; ICC≥0.81). We observed consistent significant associations between higher NfL concentrations and worse GCF in MarkVCID (β=‐0.23; [95% CI ‐0.41; ‐0.01), CHARGE cohorts (meta‐analysis β=‐0.11; [95% CI ‐0.17; ‐0.06]), the UKY ADRC (β=‐0.16; [95% CI ‐0.27; ‐0.05]) and the UCD ADRC (UCD: β=‐0.28; [95% CI ‐0.48; ‐0.08). Secondary analyses revealed significant associations between elevated NfL concentrations and higher WMH burden in MarkVCID (when controlled for eGFR), CHARGE, and the UCD ADRC.ConclusionWe have found that NfL can be reliably measured using the Quanterix platform, making this marker ideal for multi‐site clinical trials. We observed consistent associations for plasma NfL concentrations with cognition and WMH in MarkVCID and across independent samples, providing evidence that it can be a useful biomarker for stratification in VCID trials.

Direct comparisons of the associations between the tau PET tracers [18F]Flortaucipir and [18F]MK6240 with tests of general cognitive performance ‐ The HEAD study

AbstractBackgroundTau PET tracers are employed to measure the accumulation of tau in vivo in the brain. Each tau tracer possesses unique characteristics, including binding affinity, sensitivity, and specificity to tau aggregates. This study leverages the HEAD study dataset, which is currently performing baseline tau PET tracers and conducting multiple clinical and cognitive assessments. The objective of this study is to elucidate the relationship between tau PET tracers [18F]Flortaucipir and [18F]MK6240 and commonly used tests of general cognitive performance.MethodsWe assessed 170 individuals (107 cognitively unimpaired, and 63 cognitively impaired) with available PET [18F]Flortaucipir [18F]MK6240 and cognitive assessments (MoCA, MMSE, and CDR‐SB). We calculated tau PET SUVR for [18F]Flortaucipir and [18F]MK6240 using the inferior cerebellar grey matter as a reference. Pearson correlations were performed between SUVR values for each Braak region and MoCA, MMSE, and CDR‐SB. In addition, linear regression models accounting for age, sex, years of education, HEAD site, and diagnosis were used to estimate the relationships. The Akaike Information Criterion (AIC) was utilized to evaluate the models, with smaller AIC values signifying better performance.ResultsPerson correlation coefficients (r), which were calculated without considering any covariates, demonstrated higher numerical values between [18F]MK6240 and the scores of MoCA, MMSE, and CDR‐SB across the Braak regions (Figure 1). Similarly, when we performed linear regressions that accounted for relevant covariates, we found that the [18F]MK6240 SUVR in Braak 1 and Braak 4 regions exhibited a stronger association with cognitive tests than in other Braak regions or any region with [18F]Flortaucipir SUVR (Figure 2).ConclusionsBoth [18F]Flortaucipir and [18F]MK6240 SUVR demonstrated a robust association with tests of general cognitive performance commonly used in AD research and clinical practice. Generally, Braak regions 1 and 4 exhibited a stronger association with general cognitive performance using all tests, whereas Braak regions 5‐6 showed the weakest association.

Indian‐enriched genetic variants are associated with cognitive function

AbstractBackgroundThe prevalence of dementia in India is approximately 7.4% among those aged 60 years and older, yet little is known about genetic risk factors for dementia in this population. Examining genetic variants at higher frequency in India than other ancestries (i.e., Indian enriched variants) presents an opportunity to detect genetic effects which might be unique to the Indian population and/or underpowered for detection in other ancestral groups. We examined associations between Indian‐enriched variants and cognitive outcomes in 2680 older adults from the Longitudinal Aging Study in India ‐ Diagnostic Assessment of Dementia (LASI‐DAD) to identify potentially novel variants that may influence cognitive aging and dementia.MethodUsing whole‐genome sequence (WGS) data, we identified 4.8M Indian‐enriched variants, including 4.2M rare variants (0.2%&lt;MAFLASI‐DAD &lt; 5%, and MAFLASI‐DAD/MAFEA&gt;5; and 600K common variants (MAFLASI‐DAD≥5%, and MAFLASI‐DAD /MAFEA&gt;3). We conducted single‐variant association tests for all Indian‐enriched variants with the Hindi Mental State Exam (HMSE) score, a general cognitive function score, and five cognitive domain scores. Given the potential for heterogeneity between sexes, we also added variant‐by‐sex interaction terms to test the joint effects of variants and variant‐by‐sex interactions. In all analyses, we controlled for age, sex, state, education, literacy, rural/urban status, the first 10 genetic principal components, and genetic relatedness.ResultAt 5% false discovery rate, 11 variants were associated with one or more cognitive outcomes, including rs118075114, an intronic variant of CA12 that is in a known risk locus for Alzheimer’s disease in European ancestry. Joint models identified an additional 17 variants with a sex‐specific association with HMSE score (11 in females and 6 in males). Although the identified variants are rarely reported in the literature, partly because they are almost absent in European populations and elsewhere, several of the loci have been associated with neuropsychiatric traits and dementia risk factors such as diabetes, blood pressure, and coronary artery disease.ConclusionThese results demonstrate the potential of LASI‐DAD WGS to identify Indian‐enriched variants that are associated with cognition at older ages. Future studies are warranted to replicate and understand the functional relevance of the identified variants.

Validation of diffusivity along the perivascular space as a biomarker for vascular cognitive impairment and dementia

AbstractBackgroundTo validate the index of diffusivity along the perivascular space (ALPS index) as a biomarker for vascular cognitive impairment and dementia (VCID).MethodThe participants and MRI data used in this study were acquired as part of the MarkVCID consortium, which consisted of seven sites. A total of 578 participants (72.5±7.2 years old, 232 Male) who received baseline and follow‐up cognitive evaluations (Montreal Cognitive Assessment (MoCA), Principal Component Analysis derived General Cognitive Function (GCF_PCA), and composite score of Executive Function (EFC)) and MRI examinations were included in this study. The diffusion tensor imaging (DTI) data were processed by using an in‐house automatic processing pipeline with FMRIB Software Library 6.0.6. The mean free water (mFW) and peak width of skeletonized mean diffusivity (PSMD) were computed in the white matter (WM). The ALPS index was defined as the average of bilateral ALPS indices which were calculated by the ratio of mean of x‐axis diffusivity in the projection fibers (Dxxproj) and x‐axis diffusivity in the association fibers (Dxxassoc) to the mean of y‐axis diffusivity in the projection fibers (Dyyproj) and z‐axis diffusivity in the association fibers (Dzzassoc). The WM hyperintensity volumes (WMHV) were calculated on FLAIR images and normalized by intracranial volume (ICV). Univariate correlation (Pearson or Spearman) was used to examine the associations between imaging markers (ALPS index, mFW, PSMD, and WMHV). Linear regression models were used to evaluate the associations of baseline ALPS index with baseline and longitudinal changes of cognitive outcomes, regressing out three types of covariates: 1) age, sex, and education, 2) added vascular risk factors (VRFs), including diabetes, hypertension and smoking, 3) further added mFW, PSMD and WMHV. SAS 9.4 software was used for all statistical analyses, and P&lt;0.05 was regarded as statistical significance.ResultThe baseline ALPS index was significantly correlated with existing biomarkers of cerebral small vessel disease (cSVD)‐related VCID, i.e., mFW and WMHV (P&lt;0.01) (Figure 1), and baseline cognitive performances, i.e., MoCA total score, GCF_PCA score, and EFC score (P&lt;0.05) after adjusting for the demographics, VRFs, and existing biomarkers (Figure 2).Conclusionthe ALPS index is an independent contributor to the cognitive decline in cSVD.