bluuebunny/crossref_metadata_2025 huggingface dataset:
Objective memory impairment in individuals with memory complaints: baselinedata from the Brazilian Longitudinal Study of Aging (ELSI‐Brazil)
Authors: Pinho Pedro JDMR , Bertola Laiss , Teixeir Lucas Martins , Barbosa Matheus Ghossain , Lima‐Costa Maria Fernanda , Ferri Cleusa P
Published: January 2025

Background

Subjective Memory Complaints (SMC) are common with aging and might be associated with objective memory impairment (MI) and with higher risk to develop dementia. This association is understudied in socially and ethnically diverse populations, such as Brazilians.

Method

This study uses the baseline data from the ELSI‐Brazil, a representative sample of 9402 Brazilians over 50 years. We used the question “Currently, how do you rate your memory?” to classify the participants as without SMC (excellent/very good/good) and with SMC (fair/bad). Memory impairment (MI) was defined through a z‐score extracted from a regression based‐norms approach (based on their age, education, and gender/sex) derived from a healthy subset of individuals from the ELSI‐Brazil study. The memory score is based on a combination of immediate and delayed response from the episodic memory test (10‐word list). Other data about sociodemographic factors (sex, age, education, income), depressive symptoms, self‐rated health, number of chronic illnesses, and activities of daily living: basic (BADL), instrumental (IADL) and advanced (AADL) were measured. We used logistic regression with robust variance to estimate the association between the above variables and MI.

Result

From the original sample, 7831 participants had no missing data for all variables, with 3402 (41.9%) individuals with SMC and included in this study. People with SMC had a mean age of 62.6 years (SD = 9.3), a mean education of 4.7 years (SD = 3.9), and 24.8% had MI (table 1). Logistic regression shows that, in individuals with SMC, higher education, greater impairment in IADLs and AADLs, and a higher number of depressive symptoms were associated with MI. However, higher household income per capita were associated with less MI (table 2).

Conclusion

While SMC affects 42% of the original sample, objective MI affects only a quarter of these individuals, showing that most of them have complaints but not objective memory deficits. Memory impairment in individuals with memory complain is associated with higher education, lower income, depressive symptoms, and disability in instrumental and advanced activities of daily living.
Relationships between Circulating Monocyte and Brain Transcriptional Profiles in Nonhuman Primates Consuming Mediterranean versus Western Like Diets
Authors: Register Thomas C. , Frye Brett M. , Negrey Jacob D. , Johnson Corbin S.C. , Snyder‐Mackler Noah , Craft Suzanne , Montine Thomas J. , Shively Carol A.
Published: January 2025

Background

Mediterranean diets may reduce Alzheimer’s disease (AD) risk and preserve cognitive function relative to Western diets by protecting against inflammation. In a long term controlled randomized trial of Mediterranean vs. Western diet consumption in cynomolgus macaques (Macaca fascicularis), difficult to conduct in humans, we found significant anti‐inflammatory effects of Mediterranean diet on circulating monocyte and brain temporal cortex transcriptional profiles. Here we examine relationships between monocyte and temporal cortex gene expression profiles.

Methods

38 middle‐aged (mean = 12 years of age) female macaques were fed Western or Mediterranean diets for 2.5 years in a randomized nonhuman primate trial. RNAseq was used to assess transcriptional profiles in CD14+ monocytes after 15 months of diet consumption while temporal cortex was obtained after 2.5 years.

Results

Cortex expression of cyclin dependent kinase 14 (CDK14), a proinflammatory regulator, was lower in the Mediterranean group. Six other cortex transcripts [i.e., “lunatic fringe” (LFNG), mannose receptor C type 2 (MRC2), solute carrier family 3 member 2 (SLCA32), butyrophilin subfamily 2 member A1 (BTN2A1), katanin regulatory subunit B1 (KATNB1), and transmembrane protein 268 (TMEM268)] higher in the Mediterranean group were associated with anti‐inflammatory/neuroprotective pathways. Monocyte patterns of gene expression predicted expression of these targets in the brain, with consistent anti‐inflammatory effects of the Mediterranean Diet relative to the Western Diet (Figure 1). Monocyte transcripts associated with inflammation, including proinflammatory components of the constitutive transcriptional response to adversity (CTRA, Cole et al. 2015), NFKB1, NFKB2, and IL6, were positively associated with temporal cortex transcript level of the pro‐inflammatory gene CDK14 (all p’s≤0.0?). In general, these proinflammatory monocyte transcript levels were negatively correlated with temporal cortex anti‐inflammatory transcripts LFNG, SLC3A2, and MRC2 (8 of 12 correlations p<0.05; 11 of 12 correlations p<0.10), consistent with an overall anti‐inflammatory effect of the Mediterranean diet.

Conclusion

Circulating monocyte gene expression profiles correlated with temporal cortex transcript levels consistent with anti‐inflammatory effects of the Mediterranean Diet relative to the Western Diet, suggesting that peripheral inflammation may promote neuroinflammation. Interventions including diet to target inflammation may have a role in prevention or treatment of systemic as well as neuro‐inflammation and neuropathology.
Remote App‐Based Cognitive Assessment in Aging and Pre‐Clinical Alzheimer’s Disease in a Diverse Sample of Older Adults
Authors: Mechanic‐Hamilton Dawn , Humphreys Valerie , Prusky Alex , Halberstadter Kimberly , Wolk David A.
Published: January 2025

Background

Mobile, valid and engaging cognitive assessments are essential for detecting and tracking change in research participants and patients at risk for Alzheimer’s Disease and Related Dementias (ADRDs). This pilot study aims to determine the feasibility and generalizability of an at‐home, app‐based cognitive assessment, the mobile cognitive app performance platform (mCAPP), to detect cognitive changes associated with aging and preclinical AD.

Method

mCAPP includes three gamified tasks (Figure 1): (1) a “concentration” memory task that includes learning and matching hidden card pairs with increasing memory load, pattern separation features (lure vs. non‐lure), and spatial memory (2) a stroop‐like task (“brick drop”) with speeded word and color identification and response inhibition components and (3) a digit‐symbol coding‐like task (“space imposters”) with increasing pairs. Participants used mCAPP at home for two weeks and completed the NACC UDS3 and additional paper and pencil tests. Participants included ninety‐three adults (72% female; age = 72.5±5.5, education = 16.4±2.6; 49.5% White, 49.5% Black/African American, 1% Multiracial) without cognitive impairment enrolled in the Penn ADRC cohort. A subgroup also completed longitudinal mCAPP testing and amyloid PET imaging.

Result

Participants played 11±4 sessions over two weeks, with 61% playing more than the assigned sessions. Most participants (97%) used a smartphone. Usability rating was 6.3±0.8 (1‐7 scale). Most participants rated the difficulty of the tasks as “just right” for Concentration (93%), Brick Drop (84%), and Space Imposters (87%) after playing the games for the first time. 70% reported preferring mobile device cognitive assessment to standard in‐person cognitive batteries. All tasks showed lower performance with increasing cognitive load (p’s<.05). mCAPP measures correlated with paper and pencil tests from analogous domains on paper and pencil measures (p’s<.01). Participants with a positive amyloid PET scan showed a trend toward slower and less accurate performance on some mCAPP measures.

Conclusion

This pilot study shows mCAPP usability for at‐home use in a diverse cohort of older adults. Performance across measures indicate initial reliability and validity of mCAPP. Future work will include the evaluation of mCAPP performance relationships with biomarkers and longitudinal data analysis. Remote, accessible, and reliable cognitive assessment has the potential to reduce barriers to research participation and clinical care.
Remote Cognitive Assessment for Preoperative Evaluation in Older Adults: Feasibility and Associations with Subjective Cognitive Concerns
Authors: Wise Amy B. , Dhanam Sreya , Zhou Sara , Sinha Anika , Hernandez Kaylee , Pawar Niti , Boxer Adam L. , Chang Odmara L Barreto , Staffaroni Adam M.
Published: January 2025

Background

Postoperative complications of major surgical interventions include delirium. Delirium is a risk factor for dementia, and in some cases, may signal underlying neuropathological processes. Cognitive tests that accurately predict post‐operative outcomes could identify patients with cognitive vulnerabilities who may benefit from preoperative counseling and postoperative interventions. Unfortunately, in‐person presurgical cognitive evaluations are often not available, but digital technologies may improve access. In this pilot study, we evaluate the feasibility of utilizing a smartphone app to conduct preoperative remote cognitive assessment in patients undergoing spine surgery. We also evaluate the relationship of app‐based assessments with subjective cognitive concerns.

Method

We enrolled 30 older adults (≥ 65 years old) who were scheduled for elective spinal surgery anticipated to last at least three hours. On the ALLFTD Mobile App, participants completed a battery of cognitive tests, a measure of subjective cognitive concerns (12‐item self‐reported everyday cognition scale, Ecog‐12), and a user experience survey. A subset (N = 12) had a study partner complete the 41‐item Ecog, reporting on observed changes in cognitive function over a 10‐year period prior to the surgery. Linear regressions adjusted for age evaluated the associations between subjective cognitive concerns and the objective app‐based outcomes (Flanker task and a composite of several measures).

Result

Average age of participants was 71.2 years (SD = 4.4); 46.1% were women and 75% identified as White. Most (96%) participants indicated that the time required to complete the app assessments was acceptable, 77% indicated that the app instructions were clear, and all participants indicated that the text on the app was large enough to read comfortably. Participants’ subjective cognitive concerns (ECog‐12) were significantly associated with a composite of app tasks (β = ‐0.48, p = 0.01). The executive functioning domain of the study partner Ecog was significantly associated with patient performance on an app‐based executive functioning task (β = 0.75, p = 0.007).

Conclusion

These findings support the feasibility of remote preoperative assessments in older adults using smartphones. The study also provides preliminary support that these measures can objectively quantify self‐ and partner‐reported cognitive concerns. Future work will explore associations with postoperative outcomes.
Generating a novel and reliable human iPSC‐derived midbrain organoid model of sporadic progressive supranuclear palsy
Authors: Selecky Grace A. , Whitney Kristen R. , Krassner Margaret M. , Cervera Alessandra , De Sanctis Claudia , Almazan Victoria Flores , Delica Sean Thomas , Kim SoongHo , Farrell Kurt W. , Christie Thomas D. , Iida Megan A , Sarrafha Lily , Parfitt Gustavo , Walker Ruth H. , Nirenberg Melissa J , Riboldi Giulietta M. , Frucht Steven J. , Ahfeldt Tim , Temple Sally , Crary John F.
Published: January 2025

Background

The accumulation of abnormal tau protein in neurons and glia in the human brain is the defining feature of neurodegenerative diseases known as tauopathies. Progressive supranuclear palsy (PSP), the most common primary tauopathy, is typified by selective vulnerability of dopaminergic neurons and glia in the midbrain leading to an atypical parkinsonian movement disorder. To investigate candidate disease mechanisms underlying PSP, there is a critical need for model systems that more accurately recapitulate the cellular and molecular environment in the human brain. Human induced pluripotent stem cell (hiPSC)‐derived organoid models have emerged as a powerful tool to address this gap.

Method

Skin biopsies were collected from living clinically diagnosed PSP patients or during autopsy. Fibroblasts were cultured and reprogrammed into hiPSCs using Sendai virus. HiPSCs were maintained with StemCultures FGF2 Discs to improve pluripotency and FACS was performed to confirm pluripotency marker expression. To generate midbrain organoids, hiPSCs were seeded into suspension spinner flasks, patterned using pharmacological directed differentiation, and grown for four months. Reliable patterning was confirmed with qRT‐PCR, immunohistochemistry and immunoblot using a panel of cell‐type specific markers. Astrocytes were extracted from mature organoids, cultured, and screened for astrocyte‐specific markers.

Result

Fibroblasts have been banked from twenty‐two PSP patients and seven reprogrammed into hiPSCs. Sporadic case status was determined by Sanger sequencing confirming the absence of a MAPT mutation. We found that hiPSCs grown with controlled‐release FGF2 discs were 90‐100% positive for pluripotency markers and negative for off‐target genes. During patterning, organoids displayed morphological and cytoarchitectural patterns consistent with developing neuroectoderm and midbrain. Midbrain neural progenitor and dopaminergic markers such as FOXA2, LMX1A, and TH were positive in a time‐dependent manner, with mature dopaminergic neurons expressing NURR1 and GIRK2 detected by day 30. GFAP‐positive astrocytes appeared around day 100. Astrocytes extracted from mature organoids were positive for multiple astrocyte markers.

Conclusion

Sporadic PSP patient hiPSCs reliably differentiate into midbrain dopaminergic organoids and astrocytes, resulting in a sporadic tauopathy model containing key cell types affected in PSP. This cell collection is a valuable resource to investigate candidate mechanisms underlying tauopathy and could provide insight into cell‐type specific disease drivers.
Assessing Cognitive Impairment in Quechua and Aymara Patients: A Critical Examination of the Rowland Universal Dementia Assessment Scale’s Discriminative Capacity
Authors: Malaga Marco , Bustamante‐Paytan Diego , Ruiz‐Yaringaño Arturo Jhonny , Custodio Belen , Soto‐Añari Marcio F. , Ore‐Gomez Maria Fernanda , Quiroz Juan Carlos Duran , Cusicanqui María Isabel , Montesinos Rosa , Custodio Nilton , Tosto Giuseppe
Published: January 2025

Background

The global aging population raises concerns about increased neurodegenerative diseases, particularly in low‐ and middle‐income countries like Latin America and the Caribbean. However, the situation among the indigenous inhabitants remains unknown due to various barriers, including cultural diversity, lack of studies, low awareness, language barriers, and limited healthcare access. Brief cognitive tests like the Rowland Universal Dementia Assessment Scale (RUDAS) show promise in overcoming these challenges.

Method

A secondary analysis was conducted on a substantial patient cohort derived from the GAPP study (NIA grant #alz093273AG069118), categorizing participants based on whether their native language was Spanish or Quechua/Aymara. Descriptive analysis of variables was performed, with the Wilcoxon test applied to compare total RUDAS scores among distinct patient groups, including controls, individuals with Mild Cognitive Impairment (MCI), and those with dementia. Comparisons were specifically made between Spanish speakers and native language speakers. Additionally, the ROC (Receiver Operating Characteristic) curve was employed to evaluate the discriminative capacity of RUDAS in distinguishing between controls and dementia, as well as between controls/MCI and dementia cases within native and Spanish‐speaking populations.

Result

A total of 405 controls, 126 individuals with Mild Cognitive Impairment (MCI), and 133 participants with dementia were included in the analysis. Among them, 91 patients were native language speakers, with a median age of 74 (range 54 ‐ 92). The majority were female (69.2%), and 65.9% were Aymara speakers. Native participants reported an average education level of 3.1 years (SD 4.4). The RUDAS mean score was lower in the native speaker group compared to Spanish‐speaking participants (21 vs. 23). Additionally, the analysis revealed significantly lower scores in controls within the native speaker group (Fig. 1). Diagnostic performance for native speakers was poor when comparing control/MCI (Fig. 2) vs. dementia and control vs. dementia (Fig. 3).

Conclusion

The use of the RUDAS in native language speakers and its ability to distinguish between Mild Cognitive Impairment (MCI) and dementia raise some concerns. To improve assessments for various communities in Latin America and the Caribbean, there is a need for culturally adapted brief cognitive tests.
Reducing the effects of aging on cognition with therapeutic intervention of an oral multi‐nutrient combination (REACTION): A pilot study – Report of primary feasibility outcomes and quality of unblinding
Authors: Camargo Christian J , McInerney Katalina F , Merritt Stacy S , Modjeski Marisa , Rundek Tatjana
Published: January 2025

Background

Age‐related cognitive decline (ARCD) refers to the cognitive changes that occur in individuals because of aging. Research suggests that the underlying mechanism behind ARCD is a loss of synaptic plasticity and altered dendritic spine morphology. Similarly, the cognitive changes in Alzheimer’s Disease (AD) are also thought to arise from impaired synaptic plasticity and dendritic spine loss. A specific combination of precursors and cofactors for phospholipid biosynthesis has shown beneficial effects on memory, cognition, and brain atrophy in prodromal AD. To test the feasibility of this multi‐nutrient combination intervention in ARCD, the REACTION pilot study was developed.

Method

REACTION is a 6‐month single‐center randomized, double‐blind, placebo‐controlled parallel group virtual pilot clinical trial. The study factors in local COVID‐19 restrictions and trial visits are done virtually using secure online video communication. Eligible subjects are English or Spanish speaking people aged 55−89 years from all ethnic groups with ARCD and screened and randomized to the oral multi‐nutrient combination (Souvenaid) or placebo on a 1:1 basis. The main outcome is feasibility (recruitment rate, recruitment time, adherence rate and retention rate). Exploratory outcomes include memory (e.g., Ray Verbal Learning Task), performance on other cognitive tasks (e.g., Oral Trail Making Test), and quality of life (e.g., Amsterdam IADL Questionnaire) outcome measures.

Result

In JPAD (Camargo et al., JPAD. 2023;10:821‐7), we published our final pre‐specified criteria for feasibility. We report that we met pre‐specified criteria for “feasible” for recruitment rate, recruitment time, and study retention. We are unable to draw conclusive data on adherence to intervention due to staff shortages for data acquisition. After unblinding, for the placebo‐controlled portion of the study, we report that our randomization was successful, e.g., with matched age (69.8 years ± 9.12 [STD] and 68.5 years ± 8.67 [STD], p = N.S.), years of education (17.3 ± 2.38 [STD] and 16.69 ± 2.36 [STD], p = N.S.) for placebo and active groups, respectively. This will enable exploratory analysis of efficacy outcomes of cognitive and behavioral data.

Conclusion

This study shows that conducting a fully virtual study with a nutritional intervention to test its effect on ARCD progression is feasible in persons with ARCD.
Synergism between Lewy body and Alzheimer’s disease pathology differs by sex
Authors: Alexander Madeline Wood , Barnes Lisa L. , Schneider Julie A. , Casaletto Kaitlin B. , Rabin Jennifer S
Published: January 2025

Background

Parkinson’s disease and dementia with Lewy bodies are more common in men, while Alzheimer’s disease (AD) is more common in women. Lewy body disease (LBD) and AD pathologies are highly comorbid and may be mechanistically linked. It remains unclear whether LBD and AD co‐pathology manifest differently across sexes. Here, we investigated sex differences in associations of LBD with β‐amyloid and tau. We also tested whether age at menopause modifies the relationship between LBD and AD pathology in women.

Method

We used data from autopsied participants in the Religious Orders Study, Memory and Aging Project, and Minority Aging Research Study cohorts. Immunohistochemistry was used to quantify LBD stage, β‐amyloid, and tau. To capture cortical LBD pathology, LBD stage was dichotomized as neocortical‐type/limbic‐type vs. nigral‐predominant/none. Linear regressions tested interactive effects of 1) sex and LBD on AD pathology in the entire sample and 2) age at menopause and LBD on AD pathology among female participants who reported natural menopause, adjusting for age at death and APOE4.

Results

We included N = 1,798 participants (mean (SD) age at death = 89.5 (6.74) years, N (%) female = 1,225 (68.1)). Between sexes, men exhibited more LBD pathology after adjusting for β‐amyloid and tau (β = 0.31, p = .02), while women showed a greater burden of both β‐amyloid (β = ‐0.10, p = .002) and tau (β = ‐0.08, p = .01) after adjusting for LBD. There was an interaction between sex and LBD on tau but not β‐amyloid, such that women with LBD had more tau than men with LBD after adjusting for β‐amyloid (male sex*β‐amyloid: β = 0.03, p = .7; male sex*tau: β = ‐0.16, p = .03; Figure 1). In women with natural menopause, age at menopause modified the association of LBD with tau, such that women with earlier menopause had greater tau burden in the presence of LBD (β = ‐0.03, p = .003; Figure 2). Post hoc analyses showed that the interactions between 1) sex and LBD on tau and 2) age at menopause and LBD on tau were driven mainly by neocortical‐type LBD and not limbic‐type LBD.

Conclusion

LBD pathology might have a more pronounced impact on tau vulnerability in women than men. Female hormonal processes may further modify the relationship between LBD pathology and tau.
Cognitive trajectory patterns in oldest‐old individuals for identifying SuperAgers: The Life After 90 Study
Authors: Biswas Roshni , Jiang Luohua , Kawas Claudia H. , Gilsanz Paola , Whitmer Rachel A. , Corrada María M. M.
Published: January 2025

Background

Oldest‐old individuals exhibit heterogeneous cognitive function ranging from superior cognitive performance to dementia. Most SuperAger definitions rely on cross‐sectional memory scores. Here, we extend the definition by identifying distinct subgroups based on longitudinal trajectories for memory. We also evaluated longitudinal trajectories for executive function.

Method

The 774 study participants were from the LifeAfter90 study (LA90), a multi‐ethnic cohort of individuals aged 90 or older. Verbal episodic memory (VEM) and executive function (EF) were assessed approximately every 6 months using the Spanish and English Neuropsychological Assessment Scale from at least two visits (mean = 4; range: 2‐7). Using group‐based trajectory modelling, we identified unique trajectories separately for VEM and EF, accounting for baseline age, sex, education, and race/ethnicity.

Result

62% of participants were women, the overall mean baseline age was 92.4 (±2.3), and 26% had ≤high school education (Table 1). We identified four distinct trajectories for VEM (Figure 1). Group 4‐High stable performers: with the highest baseline performance, largest practice effects, and no decline; Group 3‐Stable performers: with a lower baseline than group 4, moderate practice effects, and slight decline; Group 2‐Slow decliners: with lower baseline than groups 4 and 3, slight practice effects, and a slow declining trajectory; and Group 1‐Accelerated decliners: with the lowest baseline performance, no practice effects, and rapid decline. Thus, we identified one subgroup with no decline in longitudinal performance and with practice effects that could be classified as SuperAgers. For EF, we also identified four groups (Figure 2). Baseline EF scores varied for Groups 4, 2, and 1 (Group 4 being the highest) and followed relatively stable trajectories. Group 3, which had the second highest baseline score, had a slowly declining trajectory. For EF, stable trajectories were not limited to the top baseline performing groups. The two domains had distinct patterns with limited overlap in group memberships.

Conclusion

Using longitudinal patterns, we identified SuperAgers based on superior memory performance and no decline. In future research, we will further explore the use of longitudinal performance trajectories and the use of multiple cognitive domains in the definition of SuperAgers. We will also identify defining characteristics of each subgroup.
Exploring the differential impact of sociodemographic and extrinsic factors on mobility‐based digital phenotypes versus standard cognitive tests among older adults
Authors: Hackett Katherine , Xu Shiyun , McKniff Moira , Barnett Ian , Giovannetti Tania
Published: January 2025

Background

Passively‐obtained smartphone digital phenotypes may yield objective estimates of everyday cognition in older adults compared to traditional cognitive/self‐report measures typically confounded by sociodemographics. However, it is currently unknown what covariates are relevant when interpreting smartphone sensor data. We aimed to clarify which intrinsic and extrinsic factors are associated with digital phenotyping versus traditional cognitive measures in a cohort of older adults.

Methods

34 participants (Mage = 71.6±5.5; Meducation = 16.4±2.7; 57% non‐Hispanic White; 88% native English language) with normal cognition or Mild Cognitive Impairment used an open‐source smartphone application (mindLAMP) to passively capture GPS trajectories for one month. Baseline neuropsychological tests were collected as external validators along with self‐reported sociodemographics (intrinsic) and technology habits/phone type (extrinsic). GPS data were processed into monthly feature estimates of activity, routine, and location diversity. Correlations and univariate ANOVAs were used to examine relationships between GPS features, z‐transformed neuropsychological tests, and intrinsic/extrinsic factors.

Results

Consistent with prior findings, greater monthly GPS activity (radius of gyration), less routine (physical circadian routine), and more location diversity (significant locations visited) associated with higher scores on measures of attention, executive functioning, and language (.36≤|r’s|≤.50, p’s<.05). Several sociodemographic factors associated with cognitive scores but not with GPS features; these included age, education, living alone (.34≤|r’s|≤.47, p’s<.05) and race (3.8≤F(2,30)≤ 5.5, .20<η2<.27, p’s<.05). Higher lifetime income and native English language associated with better cognitive scores and with more GPS activity/less routine (.35≤|
r’s|≤.57, p’s<.05). Sex and current occupational status were not associated with cognitive tests or GPS features. iPhone vs. Android ownership associated with cognitive tests but not GPS metrics (.35≤r’s≤.37, p’s<.05), whereas more habitual smartphone use associated with less location diversity but not with other GPS metrics or cognitive tests (r = ‐.40, p<.05).

Conclusions

Passively‐obtained mobility phenotypes were significantly and moderately correlated with gold standard neuropsychological tests commonly used for clinical assessment and clinical trial endpoints. Several factors pertinent to social determinants of health were related to neuropsychological tests but not GPS features, suggesting naturalistic assessment via digital phenotyping may be less biased by these factors. On the other hand, other important factors including lifetime income and native English language impacted both methods of assessment.
Comparing the utility of mean versus intraindividual variability metrics in the relationship between mobility‐based digital phenotypes and cognition
Authors: Hackett Katherine , Xu Shiyun , McKniff Moira , Barnett Ian , Giovannetti Tania
Published: January 2025

Background

Intraindividual variability (IIV) on neuropsychological task performance has demonstrated enhanced sensitivity to neuropathological decline compared to mean performance. It is currently unknown whether increased IIV in everyday behaviors may also lend added sensitivity to detect early subtle changes seen in pre‐clinical ADRD.

Methods

In a pilot smartphone digital phenotyping study, 34 participants (Mage = 71.6±5.5; Meducation = 16.4±2.7; 68% female 57% non‐Hispanic White) with healthy cognition or Mild Cognitive Impairment downloaded an open‐source smartphone application (mindLAMP) to passively capture GPS trajectories for 4 weeks. Monthly mean and day‐to‐day standard deviation (IIV) metrics for three GPS features were generated to test a priori hypotheses based on a conceptual framework. Correlations examined the relationship between mean versus IIV mobility metrics and 11 baseline neuropsychological T‐scores adjusted for age, sex, education, and estimated premorbid IQ. Hierarchical linear regressions examined whether mobility IIV was independently associated with cognition after adjusting for mean mobility, and vice versa, for relationships in which both mean and IIV were significantly correlated with the same cognitive outcome.

Results

Greater mean GPS activity (radius of gyration), less mean GPS routine (physical circadian routine), and greater IIV in these two GPS features were both significantly associated with a neuropsychological measure of language (Boston Naming Test; .39≤|r’s|≤.55, p’s<.05). IIV in GPS routine did not explain a significant amount of additional variance in Boston Naming scores after controlling for mean GPS routine, whereas mean routine explained an additional 11% of variance after controlling for IIV (Overall model: R2 = .34, F(2,31) = 8.07, p = .002). Unique associations were identified between IIV in GPS routine and animal fluency scores (r = .44, p<.05) and IIV in GPS location diversity and Boston Naming (r = .35, p<.05), whereas mean metrics of these features were not associated with corresponding outcomes.

Conclusions

Mobility‐based digital phenotyping features appear to be selectively associated with demographically‐corrected neuropsychological measures of language. Considering IIV in everyday mobility behaviors – in addition to overall mean mobility features ‐ may lend added value. Next steps will evaluate and compare a greater array of digital phenotyping features (mean and IIV) in predicting cognition and other relevant outcomes.
Interaction between polymorphisms in MBP and EIF2B5 genes is significantly associated with Alzheimer’s disease
Authors: Yashin Anatoliy I , Wu Deqing , Arbeev Konstantin , Duan Hongzhe , Holmes Rachel , Bagley Olivia , Ukraintseva Svetlana
Published: January 2025

Background

Results of recent analyses indicate that axon demyelination may play an important role in AD pathology. The MBP gene encodes a myelin basic protein involved in axon myelination in the nervous system including the central nervous system. Polymorphisms in this gene, as well as variations in expression, have been associated with multiple sclerosis (MS). Evidence of the involvement of this gene in Alzheimer’s disease (AD) is emerging. The EIF2B5 gene codes for a subunit of eukaryotic translation initiation factor 2B (eIF2B), a master regulator of translation. Recent studies connected EIF2B5 and its polymorphisms with various health disorders including MS and AD, as well as hypomyelination. The latter was also associated with reduced MBP. Considering this, and that both MBP and EIF2B5 have been associated with AD, we hypothesized that the interplay between these two genes might also be associated with AD.

Methods

To test this hypothesis, we analyzed data on genotyped individuals (males and females combined) from the Health and Retirement Study using a logistic regression model with the interaction term. Education, smoking status, sex, and the first five principal components were included as observed covariates. The binary AD trait was defined as “0” if AD onset was observed at any age, and as “1” if a person survived to age 85 and did not get AD during their life. Linkage disequilibrium (LD) test and SNP‐clumping procedures were used to reduce the number of tests in SNPxSNP interaction analysis and make Bonferroni correction less conservative.

Results

We found a statistically significant positive association of the interaction between intronic rs12959006 in MBP gene and missense variant rs843358 in the EIF2B5 gene with AD. The rs12959006 was associated with MS and rs843358 in survival from cancer in the literature. Several other SNPs that are in high LD with the SNPs found in this study have also been separately associated with health traits in the literature.

Conclusion

The results of this study support the hypothesis that the interaction between MBP and EIF2B5 variants is significantly associated with AD. Our finding implies that regulation of translation and axon demyelination jointly contribute to AD.
Investigating the microvascular dysfunction in the Frontotemporal Dementia using a progranulin‐deficient mice model
Authors: Chakraborty Supriya , Franciosa Sofia , Bracko Oliver
Published: January 2025

Background

Despite being the second most common form of dementia, vascular contributions of Frontotemporal Dementia are understudied. Recent data from patients and preliminary experiments have indicated that in progranulin‐deficient mice, an increased number of cortical capillaries are stalled, and cerebral blood flow is reduced. Here, we examined the underlying mechanism contributing to microvascular dysfunction in FTD.

Method

Blood‐brain barrier (BBB) integrity was examined using immunohistochemistry and protein analyses. We compared PGRN‐deficient mice to controls and tested for the tight junction proteins Claudin‐5, Occludin, and markers of BBB leakage, such as Albumin. High Resolution in vivo two‐photon Imaging was utilized to detect the capillary stalls and capillary blood flow in the cortical capillaries, and the images were analyzed using MATLAB and ImageJ software.

Result

We discovered that the number of blood vessels significantly decreased in the 10‐11 month‐old PGRN‐deficient mice compared to controls. Furthermore, the tight junction protein levels of Claudin‐5 and Occludin are significantly reduced in PGRN‐deficient mice compared to age and sex‐matched controls. Finally, in‐vivo multiphoton experiments revealed a reduction in cerebral blood flow associated with a increased number of capillary stalling.

Conclusion

This study shows that the BBB is damaged in PGRN‐deficient mice, accompanied by microvascular dysfunction and hypoperfusion. The data suggest that PGRN‐deficient mice could be an ideal model to investigate vascular contributions to FTD.
Early menopause and cognitive impairment: Insights from the ELSI‐Brazil Study
Authors: Franco Alvaro de Oliveira , Leotti Vanessa Bielenfeldt , Zimmer Eduardo R. , Castilhos Raphael Machado
Published: January 2025

Background

Dementia and cognitive impairment, primarily linked to aging, are increasingly recognized as multifactorial conditions. Emerging research has pointed to early menopause as another potential risk factor. However, its relationship with cognitive impairment needs further investigation, especially in low‐ and middle‐income countries. Therefore, this study aims to analyze the effect of early menopause on cognitive impairment in the Brazilian population.

Methods

We analyzed data from the Brazilian Longitudinal Study of Aging (ELSI‐Brazil), a nationally representative study of individuals older than 50 years. In this analysis, we included only women (n = 4,494) and defined early menopause as when its age of onset occurred before 45 years. A Global Cognitive Score (GCS) was computed by standardizing Z scores yielded by the assessment of four cognitive subdomains (orientation, fluency, episodic memory, and semantic memory). Depression was assessed using the Epidemiological Scale‐Depression 8 (CES‐D8), with scores of 3 or higher indicating depression. High cardiovascular risk (HCR) was defined by a history of stroke or heart attack. We conducted a general linear model with GCS as the dependent variable, and early menopause, age, HCR, and depression as covariates. Statistical analyses were performed in the R environment, and significance was set at p < 0.05.

Results

Of the 4,494 women included in the study, 1,218 (27.1%) had early menopause. Age between groups is not different, but the group with early menopause had fewer years of education than women with normal menopause (p < 0.001) (Table 1). Early menopause is significantly and independently associated with lower scores in GCS (β: ‐0.112, p <0.001), implying a lower performance in the cognitive assessment. Seemingly, depression (p < 0.001), age (p < 0.001), and high cardiovascular risk (p = 0.009) negatively impact GCS.

Conclusions

Our study shows early menopause as an independent factor associated with cognitive impairment in a representative sample of the Brazilian population. Further research is warranted to elucidate the underlying mechanisms linking early menopause to cognitive impairment and to develop effective interventions that can optimize cognitive health in this vulnerable population.
Molecular Significance of Sorbs2 in Alzheimer’s Disease
Authors: Rocco Grace , Lin Henry , Boudreau Ryan L , McLendon Jared M
Published: January 2025

Background

Sorbs2 is a cytoskeletal adaptor protein that is expressed in hippocampal neurons, but its mechanistic role in these cells is not yet fully understood.

Method

We created two groups of mice for our study: whole‐body Sorbs2‐Knockout (KO) mice and Sorbs2‐Flox mice, which had neuronal knockout via AAV‐PHP.eB‐hSyn1‐Cre virus injection. We assayed mixed‐sex littermate cohorts at 6 months of age (n = 24 each, WT/KO; n = 8 each ± CRE) with behavior tests. We used postmortem brain samples to visualize and quantify Sorbs2 expression and microtubule stability.

Result

Our preliminary results suggest that female Sorbs2‐KO mice have a decrease in freezing time during contextual fear conditioning at 6 months of age. We next tested an independent cohort of females (n = 8v8) and the data show reduced freezing time in cued fear conditioning and decreased interaction time with the displaced object in Spatial Object Recognition tests after 24 hours. From the above‐mentioned experiments, we have collected tissue samples for molecular and histological analysis. Preliminary results show that global Sorbs2‐KO mice have a complete loss of an immunoreactive band specific to neuronal Sorbs2 isoform at ∼150 kDa, whereas AAV‐Cre injected Sorbs2‐flox mice have > 50% reduction in neuronal Sorbs2. In preliminary studies, we assessed microtubule stability in hippocampus homogenates from global Sorbs2‐KO or WT mice and showed an increase in the amount of free tubulin and a decrease in the amount of polymerized tubulin in the knockout samples. These data suggest that loss of Sorbs2 may destabilize microtubules in the hippocampus.

Conclusion

Our results suggest that Sorbs2 may regulate microtubule stability in the brain and be involved in memory formation or retrieval. In future studies, we plan to identify populations of Sorbs2‐expressing cells in the brain, interrogate neuronal‐specific Sorbs2 deletion, and assess the intersection between Sorbs2 and AD‐related phenotypes in mouse models of neurodegeneration.
Targeting cannabinoid type 2 receptors alters human tau levels in ex vivo brain slice cultures
Authors: Joers Valerie L , Bagheri Ila , Coronado Jazmyn , Hillard Cecilia , Tansey Malu Gámez
Published: January 2025

Background

The presence of Tau pathology is strongly associated with the clinical symptoms and cognitive decline found in Alzheimer’s disease (AD), suggesting that targeting pathological tau may be a more effective therapeutic approach. Microglia have been implicated in tauopathies as their activation is strongly related to the progression of tau phosphorylation and aggregation potentially due to dysfunctional lysosomal activity. Cannabinoid type 2 receptors (CB2) are highly expressed in immune cells and upregulated in activated microglia under conditions of neurologic disease, such as AD. CB2 deficient models have demonstrated a reduction in inflammation and amyloid plaque deposition, suggesting a role of CB2 on the immune system to influence AD‐related pathologies. However, there are limited findings on the CB2 regulation of tau accumulation.

Method

We have generated organotypic brain slice cultures from CB2‐EGFP/f/f and CB2‐knockout mice and transduced with human wild‐type and mutant (P301L or P301L/S320F) tau viruses, previously shown to accumulate total and phosphorylated human tau and develop insoluble tau aggregates. As a complimentary approach, slices were treated with CB2‐selective ligands. Slices were evaluated for tau aggregation and microglial phenotypes using biochemical fractionation and western immunoblotting analyses.

Result

In our hands, brain slice cultures overexpressing human P301L‐tau generate soluble total and phosphorylated tau species but do not produce urea‐soluble aggregates. Our preliminary work demonstrated that P301L expressing brain slice cultures deficient in CB2 do not have altered high‐salt soluble total or phosphorylated tau compared to CB2‐EGFP/f/f slices. Yet, treatment with CB2 inverse agonist SR144528 reduced phosphorylated tau (Ser202/Thr205) in the soluble fraction (p = 0.0011) in CB2‐EGFP/f/f brain slices over‐expressing P301L/S320F human tau compared to vehicle treatment. Further evaluations on tau aggregation are being conducted on brain slice cultures from CB2‐EGFP/f/f and CB2‐knockout mice overexpressing P301L/S320F tau.

Conclusion

These results suggest that CB2 alters the function of immune cells to reduce tau species in a stimulation dependent‐manner. Future studies will evaluate microglia‐restricted CB2 knock‐out brain slices to advance our understanding of the role of brain CB2 in the microglial contribution to pathologic tau removal and potentially highlight CB2 as a therapeutic target against tauopathies.
Measurements of decision‐making ability in middle to late adulthood: a multi domain scoping review from the ARMCADA study
Authors: Ho Emily , Ece Berivan , Hosseinian Zahra , Mather Molly A , Dworak Elizabeth , Novack Miriam , Karpouzian‐Rogers Tatiana , Pila Sarah , Weintraub Sandra , Gershon Richard C.
Published: January 2025

Background

Deficits in decision‐making (DM) can lead to adverse outcomes across multiple domains such as financial management and medical care. By hindering such DM abilities, cognitive impairment (CI) often affects quality of life. Routine screening for CI, however, does not include systematic and comprehensive assessment of DM ability. While there are many measures of DM ability, there is considerable heterogeneity in what constructs are measured and the populations in which they have been validated. This scoping review assessed what decision‐making measures were present in the literature and their validation evidence, across the domains of financial, functional outcomes, health care, end‐of‐life, and affective.

Method

We adhered to established scoping review methodology and included keywords pertaining to measurement, technology, decision‐making, and age across a variety of databases. A total of 16278 articles were identified, and of those, 1654 passed title and abstract screening, and were deemed eligible for full‐text review. Seven‐hundred eighty six studies were included for consideration of full‐text extraction; currently, 581 were identified for full‐text extraction.

Result

Preliminary findings suggest that across domains, there were more measures for functional outcomes (25%), health‐care decision‐making (19%), followed by financial decision‐making (15%), affective (15%), and end‐of‐life (3%), though there were many measures rated as encompassing more than one category. Measures are overwhelmingly in‐person (69%), while 16% could be administered remotely, although many of them were computer‐based tasks. Common decision‐making tasks included tests of risk (e.g., gambling tasks), semi‐structured interviews of assessment, and brief cognitive screenings. Such measures were presented with a variety of clinical populations.

Conclusion

Many measures of decision‐making ability identified were used in laboratory or research settings, or measured one construct. Future work will investigate adaptation, validation, and development of existing decision‐making measures, for early detection of preclinical dementia.
Evaluation of novel metrics derived from a brief smartphone cognitive task for predicting disease severity in frontotemporal dementia
Authors: Taylor Jack C.
Published: January 2025

Background

Sensitive assessments capable of detecting cognitive changes are important for improving early identification of symptoms in frontotemporal dementia (FTD). The ALLFTD Mobile App features smartphone cognitive tests that capture a range of FTD symptoms. We have previously shown that the flanker task from this battery is reliable and capable of detecting early changes in FTD. Here we generate features from the digital flanker task and utilize machine learning algorithms to test their incremental utility for detecting cognitive changes in FTD.

Method

Sample included 50 symptomatic and 70 prodromal, sporadic and familial FTD participants (CDR®+NACC‐FTLD = 1 or 0.5, respectively) with a range of FTD syndromes, and 70 controls (CDR®+NACC‐FTLD = 0, no pathogenic mutation) from the ALLFTD Consortium. Participants completed a two‐minute, 100‐trial digital flanker assessment on the ALLFTD Mobile App. We extracted 301 distribution metrics, based on reaction time and trial type, and 15 traditional metrics using an in‐house pipeline. Random forest models were trained using 5‐fold cross validation to classify controls from prodromal or from symptomatic individuals. The top 10 metrics of importance based on SHAP value were then entered as predictors in a standard logistic regression model and compared to a logistic model including only total score (speed + accuracy) as the predictor.

Result

In all comparisons, logistic regressions achieved higher classification accuracies than the random forest models. When using random forest to classify controls vs prodromal and controls vs symptomatic, AUCs were 0.69 and 0.81, respectively. Logistic model AUCs for classifying controls vs prodromal were 0.85 using total score alone and 0.81 using all top 10 metrics. When classifying controls vs symptomatic, model AUCs were 0.84 using total score alone and 0.91 using all top 10 metrics.

Conclusion

We tested the use of experimental features derived from a brief two‐minute test to distinguish healthy individuals from prodromal or symptomatic FTD. Classification accuracies were moderate to high, suggesting that while traditional measures continue to perform well, novel features provide an improvement in accuracy. Future directions include analogous investigations of other smartphone cognitive tasks collected through this battery.