Journals
2025 EN
Han Y. Catherine · Nowinski Cindy J. · Dworak Elizabeth M
+4 more
Abstract Background Executive Function (EF) has multiple components (e.g., attention, inhibitory control, etc.) which can be differentially affected by AD/ADRD. Specific EF deficits can be early indicators of cognitive impairment, providing clues about etiology and likelihood of disease progression. The NIH Mobile Toolbox (MTB) includes adapted, self‐administered measures from the NIH Toolbox® (NIHTB) on a smartphone that are brief, sensitive, and easy‐to‐use for tracking cognitive functioning across the lifespan. The primary scores produced for MTB EF measures (Arrow Matching; Shape‐Color Sorting) are rate‐based scores (# correct/time to complete), which have been shown to be reliable and valid (Novack et al., 2024). In the current study, we expand on these measures by investigating a series of secondary scores (anticipation errors, error rate, and median response time for incorrect and correct responses) towards a more comprehensive EF assessment. Method Participants were administered the MTB in person on study‐provided iOS smartphones and completed the NIHTB measures on study‐provided iPads (Study 1: n = 92, aged M=49.27, SD=17.65). Participants also completed external measures intended to assess convergent validity (e.g., D‐KEFS, WCST) and divergent validity (e.g., PPVT‐5, NIHTB PV). Another group of participants completed the NIHTB in person and MTB remotely using their own Android/iOS smartphone no more than 14 days after the first session (Study 2: n = 1021, aged M=43.97, SD=21.24). Result Across studies, there was a significant relationship between all novel scores in both tasks and age ( ρ = [.27,.60], p s < .05); older individuals made more anticipation and total errors and were slower to make correct and incorrect responses. Most scores showed significant, expected correlations against concurrent measures (absolute value ρ = [.13,.77], p s < .05). Most scores showed non‐significant, low correlations with the proposed divergent measures ( ρ = [‐.01,.09], p s > .05), except for anticipation and total error scores, which showed significant but weaker negative relationships with vocabulary measures. All scores showed strong internal reliability via split‐half correlations (Study 2; SCS median = .94, 25‐75th percentile=[.93,.94]; AM median = .98, 25‐75th percentile=[.97,.98]). Conclusion Expanded scores from the MTB EF measures are valid and may be suitable for clinical and pharmaceutical studies, particularly relating to age related cognitive changes. Additional clinical validation is underway, including populations at risk for or diagnosed with cognitive impairment or AD/ADRD.
Journals
2025 EN
Miller Melanie J. · Saito Naomi · Conti Catherine C.
+13 more
Abstract Background Scalable, efficient methods are needed to enroll older adults, especially those with Mild Cognitive Impairment (MCI), into AD observational studies and clinical trials. We evaluated feasibility of a novel, digital approach to recruit and screen participants for the Alzheimer's Disease Neuroimaging Initiative (ADNI4). Method Digital advertising tailored towards older adults residing near clinical ADNI sites directed potential participants to a recruitment website to enroll in a Digital Cohort (Figure 1). They completed remote, unsupervised, digital surveys (demographics, ADNI exclusion criteria, memory concerns and changes, self‐report cognitive impairment, and the Everyday Cognition Scale (ECog)‐12 item); and the Novoic Storyteller self‐administered speech‐based cognitive test. Digital assessment results were used to prioritize those with possible MCI or dementia (based on self‐report cognitive impairment, ECog, and/or Novoic Storyteller scores), to ADNI sites for screening into in‐clinic ADNI. For those screened at ADNI sites, associations between ECog12 or Storyteller score and cognitive impairment assessed using the Clinical Dementia Rating global score were estimated using logistic regression. Result Since June 2023, 8103 participants enrolled in the Digital Cohort (Table 1). Of those, 26% indicated ADNI4 exclusions (such as metal precluding MRI), 93% completed ECog12,16% had study partners who completed ECog12, and 60% completed Storyteller. For referral to clinical sites, 693 were invited, 313 accepted the invitation and were referred to a site, and 54 were screened at one of 44 ADNI sites (Table 1). In a subset with CDR screening data, more report of subjective cognitive decline on ECog12 and worse performance on Storyteller were associated with greater odds of cognitive impairment (CDR global >0) (Table 2). Conclusion Recruitment and assessment of older adults, including those with possible cognitive impairment, is feasible using tailored digital advertising and remote, unsupervised digital assessment. Remote assessments can be used to enrich for cognitive impairment. This approach can be adapted to facilitate recruitment and longitudinal assessment in other AD studies and trials
Journals
2025 EN
Onyancha Catherine Bikeri · Aliwa Benard O · Shah Jasmit
+7 more
Abstract Background Psychological distress is a recognized risk factor for dementia, influencing systemic and cellular aging processes. Subjective cognitive concerns (SCCs) are emerging as early neuropsychiatric symptoms associated with dementia risk. Understanding the interplay between psychological distress, SCCs, and clinical health markers in African populations is critical for developing culturally appropriate interventions to mitigate cognitive decline and systemic health deterioration. Method Baseline data were analysed from 145 adults (105 healthy controls, 20 newly diagnosed with cancer, and 20 caregivers) aged 35 years and above, participating in the Brain Resilience Kenya study. Psychological distress was measured using the PHQ‐9 and GAD‐7 scales, while SCCs were assessed using a validated self‐report questionnaire. Clinical biomarkers analysed included fasting glucose, C‐reactive protein, lipid profiles, creatinine, liver function, and thyroid function tests. Statistical models evaluated associations between psychological distress, SCCs, and clinical biomarkers, adjusting for age and gender. Result Depressive symptoms were significantly associated with the cholesterol/HDL ratio ( p = 0.004) and non‐HDL cholesterol ( p = 0.05). SCCs were significantly linked to depressive symptoms ( p = 0.03), creatinine levels ( p = 0.05), and AST levels ( p = 0.04). However, associations between clinical markers and SCCs were not significant after controlling for age and gender. These findings suggest that while psychological distress and SCCs are associated with certain clinical markers, the observed relationships may be influenced by demographic factors. Conclusion This study highlights significant associations between psychological distress, SCCs, and clinical biomarkers, underscoring the need to address mental health as part of dementia prevention strategies. The attenuation of associations after adjusting for age and gender suggests that demographic factors may play a key role in these relationships. Future research should explore longitudinal changes in these markers to better understand their contribution to dementia risk and the development of targeted interventions for African populations.
Journals
2025 EN
Levine Taylor F · Mashinchi Genna M · Post Emily
+4 more
Abstract Background Women demonstrate an initial verbal learning and memory advantage at the earliest stages of Alzheimer's disease (AD) but more rapid cognitive decline following diagnosis. The mechanisms underlying these sex differences are not well understood. Inflammation represents one potential contributing factor, as inflammatory responses differ by sex and contribute to accumulation of AD pathology. Work from our group in a predominately non‐Hispanic white (NHW) cohort suggests that women demonstrate longitudinal verbal learning and memory performance robust to low‐to‐moderate levels of inflammatory markers but not high levels of inflammatory burden (Caldwell et al., 2021). Here, we investigated inflammation‐based sex differences in an ethnically diverse AD cohort. Method We obtained data from the Health and Aging Brain Study‐Health Disparities and included 661 self‐reported NHW and 631 Hispanic/Latino (HL) participants who completed baseline and follow‐up testing (18‐24 months post baseline). We examined longitudinal sex differences in impact of inflammation (i.e., plasma tumor necrosis factor alpha (TNF‐α), interleukin 6 (IL‐6), and interleukin 10 (IL‐10)) on verbal learning and memory (Spanish English Verbal Learning Test learning (sum of trials 1‐5) and delayed recall). We hypothesized that cognitively normal (CN; CDR=0) women would show preserved learning and memory in the presence of increased inflammatory markers, but mildly cognitively impaired (MCI; CDR = .5) women would not. Result A significant moderation effect of sex was observed for CN HL individuals, such that women retained verbal learning and memory regardless of TNF‐α levels, whereas CN men showed greater decline in verbal learning and memory with increased TNF‐α ( p = .035 and p = .062, respectively). For MCI HL individuals, sex did not moderate the relationship between verbal learning and memory and TNF‐α. In the NHW cohort, sex did not moderate the relationship between inflammatory markers and verbal learning and memory in the CN and MCI groups. All results remained unchanged when controlling for number of anti‐inflammatory medications prescribed. Conclusion Female‐specific verbal learning and memory advantages varied across ethnic groups in the presence of inflammatory marker TNF‐α. Further work is needed to parse complex patterns of resilience and vulnerability across racial and ethnic groups, and to understand causal factors underlying these patterns.
Journals
2025 EN
Dubbelman Mark A. · Ma Grace · Amariglio Rebecca E.
+6 more
Abstract Background Neuropsychiatric symptoms (NPS) in late‐life (e.g., changes in mood, motivation, sleep, and perception) may precede changes in cognition and indicate an underlying neurodegenerative process in the absence of noticeable cognitive decline. Changes in an older adult's ability to perform instrumental activities of daily living (IADLs; e.g., managing medications/finances, shopping and preparing meals) are often the first observable sign of cognitive impairment and may be affected by NPS. In this study, we examine associations between NPS and daily functioning reported by cognitively unimpaired older adults and their study‐partners, focusing on both overall symptoms and affective symptoms (e.g., depression, anxiety) typically seen in preclinical and prodromal stages. We hypothesize that increased self‐ and study‐partner‐reported NPS will be associated with worse daily functioning. Method The sample included 177 community‐dwelling older adults without cognitive impairment or history of major psychiatric disorders (mean age 70.5±6.1 years; 63% female). All participants completed assessments of NPS (Mild Behavioral Impairment Checklist (MBI‐C), Apathy Evaluation Scale (AES), Geriatric Depression Scale (GDS), Geriatric Anxiety Index (GAI), and Snaith Hamilton Pleasure Scale (SHAPS)) and a measure of daily functioning (Alzheimer's Disease Cooperative Study ADL‐Prevention Instrument (ADCS ADL‐PI)). Study‐partners also completed the MBI‐C, AES, and ADCS ADL‐PI. We examined cross‐sectional relationships between participant and study‐partner‐reported functional and NPS assessments using separate linear regression models adjusted for age, sex, and education (in years). Result Self‐reported MBI‐C, GDS, GAI, and self‐ and study‐partner‐reported AES, were found to have significant relationships with self‐reported ADCS ADL‐PI (Table 1). Additionally, study‐partner‐reported ADCS ADL‐PI scores were associated with the SHAPS, MBI‐C (self‐ and study‐partner‐reported), AES (study‐partner‐reported only), GDS, and GAI, such that worse IADL performance was correlated with greater NPS (Table 2). Conclusion In cognitively unimpaired older adults, greater overall NPS and greater affective symptoms, including depression, anxiety, anhedonia, and apathy, were associated with worse participant and study‐partner‐reported daily functioning performance. This relationship underscores the importance of recognizing and treating NPS for improving daily functioning and quality of life, even prior to the onset of overt cognitive impairment, and considering source of report and methods of IADL measurement when utilizing the latter as clinical trial outcome measures.
Journals
2025 EN
Bosyj Catherine · Romero Kristoffer · Badal Ana
+1 more
Abstract Background Analyzing strategy‐use during neuropsychological testing may provide novel, sensitive measures of cognitive decline in neurodegenerative disease. On word‐list learning tasks, strategies can include semantic clustering (i.e., recalling semantically‐related items consecutively), or temporal contiguity (i.e., recalling items in the order in which they were presented). While reduced temporal contiguity has been shown to predict cognitive decline, it is unknown whether its use differs across subtypes of mild cognitive impairment (MCI) or how it relates to semantic strategies. We examined recall output on a word‐list learning task by comparing temporal contiguity and semantic clustering across patient groups. Method Recall on the Word‐List subtest of the Kaplan‐Baycrest Neurocognitive Assessment was analyzed for 194 patients referred to a memory clinic. Included patients met criteria for amnestic MCI (aMCI; n = 65), non‐amnestic MCI (naMCI; n = 42), or had cognition within normal limits (controls; n = 87). Temporal contiguity scores were calculated as average lag between successively recalled words, adjusting for overall recall and the word's original place in the list. Semantic clustering was calculated as average consecutive recall of categorically related words, controlling for recall performance and chance clustering. Temporal contiguity and semantic clustering were averaged across four learning and one delayed recall trial. Result There were significant group differences in temporal contiguity ( p = 0.02), with naMCI patients less likely to use a temporal contiguity strategy to organize recall relative to control, but not aMCI. Group differences in semantic clustering did not reach significance. Participants using temporal contiguity in recall were less likely to use semantic clustering. In aMCI, use of a temporal contiguity strategy was associated with worse immediate recall, whereas semantic clustering was associated with better immediate and delayed recall. The latter finding also observed in controls. Conclusion aMCI participants used temporal contiguity to organize their recall, but this represented a suboptimal strategy relative to semantic clustering. Individuals with aMCI and relatively intact semantic processing may be able to sustain memory performance by adopting semantic strategies. In naMCI, there was less use of temporal contiguity to organize recall, which may be consistent with reduced frontal memory organization abilities.
Journals
2025 EN
Munro Catherine E · LaCasse Abigail · Fu Jessie Fanglu
+15 more
Abstract Background The digital clock drawing test (DCT) is a computerized measure examining executive functioning, information processing, and visuospatial abilities. DCT scores have been shown to discriminate well between mild cognitive impairment and Alzheimer's disease (AD) dementia and have been associated with preclinical AD pathology (i.e., amyloid, tau). Prior work has shown that amyloid moderates the relationship between depression and performance on a standard cognitive composite score. However, it is unclear whether longitudinal trajectories of depressive symptoms impact DCT scores and whether amyloid levels influence such relationships. We sought to determine whether greater depressive symptoms were associated with a decline in DCT scores and whether baseline amyloid moderated this relationship. Method Participants ( n = 90, mean age=77.5±5.3; 58% female, mean education = 16.4 years) were cognitively normal (CN) and enrolled in the Harvard Aging Brain Study. The DCT (higher score=better performance) and Geriatric Depression Scale (GDS; higher score=greater depressive symptoms) were completed at baseline and annually thereafter (mean years follow‐up=5.7±0.9). Ordinary least squares regression slopes were calculated for GDS data. PiB‐PET (amyloid) was completed within 18 months of baseline assessments and examined using a large cortical aggregate. Separate linear mixed‐effects models assessed whether ‘GDS slope*time’ or ‘GDS slope*PiB DVR*time’ predicted longitudinal DCT scores, using continuous PiB values, and controlling for age, sex, education, and random intercept/slope. Result GDS slope*time was not a significant predictor of longitudinal DCT scores. The 3‐way‐interaction with PiB was significant, such that those with greater PiB burden at baseline and higher GDS slopes showed declining DCT performance over time (beta=‐8.78,95%CI[‐14.66,‐2.90], p = 0.004) (Figure 1). Conclusion In a cohort of CN older adults, individuals with higher baseline cortical amyloid burden and worsening depressive symptoms showed steeper declines on the DCT. These results suggest that individuals with greater/worsening depressive symptoms in the context of elevated cortical amyloid burden may be particularly vulnerable to cognitive decline (even in preclinical stages) on sensitive, easy‐to‐administer measures such as the DCT, similar to prior work examining cognitive testing composite scores. Findings highlight the clinical importance of monitoring emerging mood disturbances in older adults. Future work will examine how these relationships relate to clinical progression.
Journals
2025 EN
Njogu Anne Nyambura · Gitere Anne Njoki · Muyela Levi A.
+10 more
Abstract Background Safety is central to brain health; yet, there are currently no tools to assess perceived safety. Here, we describe preliminary psychometric data from a novel Lifetime Sense of Safety (LSS) scale in healthy Kenyan adults. The LSS evaluates self‐perception of safety across childhood and adulthood settings, cumulatively referred to as “the protectome. Method The 6‐item LSS scale was collaboratively developed in English and Kiswahili. Respondents are asked to retrospectively evaluate perceived safety in childhood at (1) home, (2) school, and (3) neighbourhood, as well as in adulthood at (4) home, (5) work, and (6) neighborhood, using a color bar with a corresponding number range from “0” (lowest) to “10” (highest) sense of safety. The LSS scale was administered to 163 Kenyan adults (97 f; 66 m), ranging in age from 35 to 80 years (m=53; sd=10), with broad educational attainment (primary to doctoral level). We evaluated internal consistency, factor structure, sex effects, and convergent validity between LSS total score and measures of perceived stress (PSS‐4) and resiliency (Connor Davidson Resiliency Scale ‐ CDRS). Result Data were normally distributed and internal consistency was good (α = 0.86). Suitability for factor analysis was established by sampling adequacy (KMO=0.81) and item cross‐correlations (Bartlett's test=455; p < 0.001). Exploratory factor analysis with oblimin rotation revealed two latent factors. Childhood items 1‐3 exhibited high loadings on Factor 1 (0.83‐0.95), while adulthood items 4‐6 displayed high loadings on factor 2 (0.72‐0.91). Results support the LSS scale as a measure of two latent factors (childhood and adulthood safety) accounting for 75% of total variance. There were no sex effects on latent factors. The LLS total score was negatively correlated with PSS total score ( r = ‐0.30; p < 0.001) and positively correlated with CDRS total score ( r = 0.26; p <0.001). Conclusion The LSS scale is a psychometrically sound measure of “perceived safety”, with 2 latent factors reflecting childhood and adulthood safety. Perceived safety is negatively associated with stress and positively correlated with resiliency, which supports use of the LSS scale in investigations of the lifetime “protectome” on late‐life brain health.
Journals
2025 EN
Wang Emily Q · Joshi Jarod A · Bosyj Catherine
+3 more
Abstract Background In older age, the ability to learn and remember new information is influenced by a myriad of factors, including the use of internal memory strategies. It has been proposed that individual differences in cognitive reserve (CR) may be related to older adults’ spontaneous use of these strategies. The current study examined the relative importance and moderating effects of two CR proxies—educational attainment and crystallized intelligence—on older adults’ use of a highly effective memory strategy, semantic clustering—grouping words together based on semantic relationships—during a verbal list‐learning task. Method This study analyzed data from an archival sample of 185 older adults ( n = 83 with normal cognition, n = 102 with mild cognitive impairment [MCI]) referred for neuropsychological assessment at a geriatric hospital in Ontario, Canada. A series of hierarchical regression models and relative weight analyses were conducted to examine the effects of education and crystallized intelligence (WASI Vocabulary scores) on semantic clustering, immediate recall, and delayed recall performance on the Kaplan‐Baycrest Neurocognitive Assessment word lists subtest. A moderation analysis examined whether the relationship between semantic clustering and delayed recall was moderated by CR proxies. Result Gender and English language background predicted semantic clustering. Semantic clustering strategy‐use accounted for additional variance in memory performance beyond the effects of demographic or reserve variables. While CR proxies did not significantly enhance the predictive value of any model, a moderation analysis found that crystallized intelligence was negatively associated with delayed recall performance in patients with MCI. Semantic clustering predicted delayed recall performance, and the effect was not moderated by education or crystallized intelligence. Conclusion In a clinical sample of older adults presenting for neuropsychological assessment, women and native English speakers were more likely to use semantic clustering, independent of CR. The relationship between CR and memory performance is complex in a clinical setting, where patients may be assessed at different stages of disease progression. Semantic clustering appears to bolster memory performance regardless of an individual's existing level of CR, suggesting that teaching older adults with both low and high CR internal memory strategies may help to reduce everyday memory problems.
Journals
2025 EN
Venkatesh Mayuri L. · Tarr Natalia · Coussoule Alexa
+8 more
Abstract Background Understanding the relationship between depression and dementia—two leading causes of morbidity and disability—is crucial. However, clinical research in this domain faces challenges related to recruitment and outreach, stigma, risk disclosure, and diversity. The Mood and Memory in Aging Study (MOMENT) at Mass General Brigham (MGB), a 5‐year multimodal biomarker observational study of late‐life depression and dementia risk, has employed various strategies to enhance recruitment and outreach. We summarize these approaches and discuss future directions for optimizing research in this field. Method Recruitment occurred in two phases: an initial K23‐funded phase, and a second R01‐funded phase that aimed to add 50 participants. Non‐demented older adults with major or persistent depressive disorder and moderate to severe depressive symptoms were recruited. Strategies included digital platforms (participant databases, website sign‐ups), clinician referrals, community outreach via social media, and partnerships with neurology clinical research cores. Participant demographics and engagement metrics from the second recruitment phase were analyzed to assess strategies and effectiveness. Result The second recruitment phase, initially projected to finish December 2024, concluded one month early due to enhanced efforts in 2024. Expanded methods—tables at clinics and community fairs, a clinical research database of older adults interested in aging and dementia research, recruitment websites, Craigslist/newspaper ads, and referrals from MGB clinics and the Massachusetts Alzheimer's Disease Research Center—together boosted weekly call volume by 36% relative to 2023. Effective methods included clinician referrals (39.42%), recruitment websites (25.96%), clinical research databases (16.34%), ads (8.65%), websites (5.77%), tabling (0.96%). 56 participants were enrolled, with a 22.2% screen‐fail rate and a ∼85% retention. Study time commitment, travel, and reluctance to complete neuroimaging were among barriers to recruitment and retention. Conclusion We employed a multi‐faceted strategy integrating clinician referrals, advertisements, and partnership with registries to efficiently meet recruitment milestones. Challenges including limited enrollment of Hispanic/Latino or severely symptomatic individuals, and attitudes towards neuroimaging highlight the need to optimize methods to address health disparities. Future efforts including translation of study documents, expanded database queries, and options for non‐imaging participation will improve outcomes and enhance understanding of depression and AD risk.