bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimodal Analysis of Behavior During Stroop Test for Characterization of Alzheimer’s Disease Signs
Authors: Meyer Trevor , Favaro Anna , Oh Esther S , Irazoqui Pedro , Dehak Najim , Moro‐Velazquez Laureano
Published: January 2025

Background

Clinical rating scales and neuropsychological tests are commonly used for assessing sign and disease severity, yet lack detail in the early stages Alzheimer’s Disease (AD). Existing evaluation methods can be subjective, nonlinear, expensive, or reliant on anecdotal evidence making objective and consistent characterization and phenotyping of AD difficult. Multimodal analysis of patient behavior, rather than scoring of patient‐generated output which can be skewed by compensation strategies, presents a unique opportunity to objectively quantify AD related changes. Using the Stroop Test (ST), we present a multimodal analysis of eye movement and spoken responses during completion of ST tasks, with the goal to characterize patient behavior.

Method

17 individual AD subjects and 24 age‐matched cognitively normal controls (CTL) were recruited from the Johns Hopkins Memory and Alzheimer’s Treatment Center and the Movement Disorders Clinic at the Johns Hopkins University School of Medicine. Eight subjects returned for two or three follow up sessions at least 20 weeks apart, totaling 29 AD recording sessions. An Eyelink Portable Duo in head‐free‐to‐move mode was used to record eye movements and spoken responses. We analyzed subjects' interaction with ST using several metrics relating to blinking, saccade, fixation, gaze, prosodic, accuracy, and timing characteristics. We summarize patient behavior abnormality by scaling behavioral metrics into positive z‐scores using CTL performance and summarize the overall abnormality as the average z‐score across 45 metrics.

Result

The average deviation across metrics correlates with MoCA scores (p<0.001). These metrics display significantly different distributions between the AD from CTL subjects (p<0.001). A visualization we've coined as a “sign profile” summarizes patient behavior abnormality during ST. In all subjects our abnormality measurement closely matches MoCA scores and clinician observations.

Conclusion

AD subjects execute the ST with eye movement and speech behaviors which significantly differ from CTL subjects, and subjects with longitudinal recordings show encouraging results for the use of this analysis in monitoring. By utilizing measures from more than one feature, we detect early clinical changes a single‐score test might miss. This analysis offers comprehensive patient profiling, providing an intuitive and quantitative understanding of patient signs enabling more accurate detection and management of disease.
A machine learning approach to predict amyloid and tau positivity using clinical features
Authors: Arnold Daniel , Borelli Wyllians Vendramini , Machado Luiza Santos , Rahmouni Nesrine , Therriault Joseph , Servaes Stijn , Stevenson Jenna , Macedo Arthur C. , Schumacher‐Schuh Artur Francisco , Mattjie Christian , Barros Rodrigo C. , de Bastiani Marco Antônio , Lussier Firoza Z , Chamoun Mira , Bezgin Gleb , Benedet Andrea L. , Pascoal Tharick , Rosa‐Neto Pedro , Zimmer Eduardo R. ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2025

Background

Screen failure due to amyloid negativity is yet a problem in clinical trials for anti‐amyloid drugs. In this context, clinical characteristics of patients presenting with cognitive decline may decrease the screen failure ratio by increasing the odds of selecting individuals with brain amyloid pathology. Herein, we aimed at estimating amyloid and tau positivity in individuals using clinical variables in a machine learning model of prediction.

Method

We selected 1694 participants with amyloid and tau status from ADNI, TRIAD, PPMI databases. Commonly shared clinical features selected between datasets were age, total MOCA scores, clinical diagnosis, sex, education, BMI, heart disease, stroke, hyperlipidemia and diabetes. Amyloid positivity was defined by amyloid‐PET (PIB‐PET, FBB‐PET or AZD4694‐PET) or CSF AB42 and Tau positivity defined by Tau‐PET (MK6240‐PET or AV1451‐PET) or CSF p‐tau181. The dataset was split into training (49%), validation (21%), and testing datasets (30%). A XGBoost model was tuned, and then used to predict the tau status outcome in the testing dataset.

Result

A total of 927 men and 767 women were included with mean MOCA 25.7 ± 3.8 scores (Table). The population consisted of 1276 CN, 290 MCI and 128 dementia individuals (1357 A‐T‐ and 337 A+T+). The receiver‐operator characteristic (ROC) analysis showed that the area under the curve (AUC) was 0.86 for discriminating A‐T‐ vs. A⁺T⁺, with 0.82 as sensitivity, specificity as 0.90 and accuracy as 0.88. The top 3 most impactful features were found to be age, diagnosis and MOCA score through a SHAP value analysis (Figure).

Conclusion

Predicting amyloid and tau positivity with clinically collectible variables may improve selection of individuals for anti‐amyloid trials. A two‐step workflow using this approach may significantly reduce the costs of AD trials. The following studies may incorporate an individualized calculator using clinical variables to estimate amyloid and tau positivity.
Investigating heterogeneity of cognitive and functional decline using Subtype and Stage Inference machine learning
Authors: Petersen Kellen K. , Nallapu Bhargav Teja , Demirsoy Idris , Lipton Richard B. , Grober Ellen , Rabin Laura , Ghanbarian Elham , Ezzati Ali
Published: January 2025

Background

Alzheimer’s disease (AD) is a heterogeneous disease with different clinical phenotypes and pathophysiological subtypes. Identifying cognitive/functional subtypes in AD could elucidate the diverse clinical progression patterns. The Cognitive Function Index (CFI), a 15‐item questionnaire completed by participants and study partners, captures aspects of cognitive and functional decline. We investigated participant heterogeneity using the CFI and compared differences between subtypes based on participant or study partner reports.

Methods

Participants were 4486 cognitively unimpaired older adults from the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Study. All participants and study partners completed the CFI. Participants had baseline demographics, neuropsychological test scores, and amyloid PET measures available. The Staging and Subtype Inference (SuStaIn) algorithm was independently applied to participant (PT) and study partner (SP) CFI reports to identify subtypes. Differences between subtypes were assessed using Analysis for Variance (ANOVA) with post hoc analysis.

Results

Table 1 summarizes participant characteristics. Analysis of PT and SP CFI responses independently identified three subtypes with distinct progression patterns. Notably, 35.2% and 57.5% of participants showed no progression based on PT and SP reports, respectively. All subtypes, except SP‐2, had CFI items related to difficulties with recall, needing written reminders, and misplacing items as the first items of suspected decline (Figure 1). Clusters PT‐1 (66.5%) and SP‐1 (45.8%) were the subtypes with most frequent progression pattern (Figure 1). Subtypes PT‐2 and SP‐2 had the highest scores on Digit Symbol Substitution test, walked the most, and for SP‐2 lowest Geriatric Depression Scores (p<0.05 for all; Figure 3). Subtypes PT‐3 and SP‐3 scored lowest on the participant Activities of Daily Living (ADL; p<0.05). Additionally, PT‐3 scored lowest on the Study Partner ADL.

Conclusion

We identified distinct subtypes from both participant and study partner CFI reports. Post hoc analysis indicated consistency within subtypes identified from the two sources of information. Subjective reports on cognitive decline could serve as a valuable tool for classifying participants into different risk groups.
Virtual support for family caregivers to reduce hospitalization and fall risk in people with Alzheimer’s disease
Authors: Laird Rosemary D. , Abrevaya Jason
Published: January 2025

Background

The Florida Department of Elder Affairs and Navigating Aging Needs, LLC (NAN) recently formed a public‐private partnership providing virtual support to family caregivers of people with Alzheimer’s disease (AD) living at home. The program targets a diverse population with high‐level daily care needs and at increased risk for continuing decline and costly Medicaid‐supported care. Objectives To reduce the risk of hospitalizations and falls for people living with Alzheimer’s disease.

Methods

Family caregivers were offered a virtual support program that included regular meetings (Zoom or phone) with a personal licensed social worker. Of the 50 family caregiver participants, 45% were Black and 12% were Hispanic. The initial assessment included 80 questions on the AD patient’s medical, emotional, social, and legal/financial well‐being and the validated battery of 12 questions comprising the Zarit Burden Scale. Following the assessment, the social worker provided the family caregiver with a personal plan that identified areas of risk that “need attention,” along with resources to address identified needs. The social worker and family caregiver then met monthly to resolve areas identified as high risk and discuss other relevant issues as they arose. Every 3 months the social worker re‐assessed patient status with the family caregiver.

Results

After 9 months of virtual support, family caregivers reported 75% fewer falls and 68% fewer hospitalizations. Average number of falls fell from 2.2 at baseline to 0.54 (p = 0.004), and average number of hospitalizations fell from 0.90 at baseline to 0.28 (p = 0.006). Caregiver assessments also demonstrated a positive impact on AD patients' depression, anxiety, advanced directives, and financial planning over the course of the program. Zarit Burden Scale scores for family caregivers remained stable despite AD progression.

Conclusion

Providing virtual support to family caregivers of people with AD was correlated with reduced hospitalizations and falls for people living at home with AD in this pilot program. The next step for the Florida Department of Elder Affairs and NAN is to assess the cost implications of expanding this approach on a larger scale.
Diagnostic performance of online cognitive assessment and plasma biomarkers in Alzheimer’s Disease and Subjective Cognitive Impairment using the Oxford Cognitive Testing Portal
Authors: Toniolo Sofia , Scholcz Anna , Amein Benazir , Ganse‐Dumrath Akke , Thompson Sian , Manohar Sanjay , Zetterberg Henrik , Husain Masud , Zhao Sijia
Published: January 2025

Background

Plasma biomarkers have emerged as a promising tool to detect the presence of Alzheimer’s disease (AD) when cognitive symptoms have not yet emerged. However, there is also a pressing need to detect and track subtle cognitive change at the preclinical stage of AD for population screening purposes and to monitor disease progression at scale. A potential solution is remote cognitive assessment, yet it is still not extensively employed.

Method

114 participants (37 AD, 22 subjective cognitive impairment (SCI) patients and 55 age‐matched controls) were recruited from the Oxford Centre for Cognitive Disorders. They were tested on a newly developed, fully remote online cognitive assessment tool, Oxford Cognitive Testing Portal (OCTAL), which hosts a wide range of validated cognitive tasks, such as the Rey‐Osterrieth Complex Figure (ROCF), Trail Making Task (TMT), Digital Symbol Substitution task (DSST)), Corsi Block Task (CORSI), as well as novel visual short‐term memory (Oxford Memory task) and visual long‐term memory (Object‐in‐Scene task) tasks (Figure 1). All participants underwent standard in‐person cognitive testing, i.e. Addenbrooke’s Cognitive Examination‐III (ACE). Plasma p‐tau181, GFAP, NFL, Aß42/40 ratio were also measured. Logistic regression was used for group classification.

Result

Performance on OCTAL was able to discriminate between SCI from healthy controls with an AUC of 0.78 (Figure 2a), statistically outperforming standard neuropsychological testing (ACE), which had an AUC of 0.65. Combining plasma biomarkers to OCTAL further increased diagnostic accuracy, reaching an AUC of 0.82 in group classification. OCTAL also outperformed ACE in distinguishing individuals with AD from SCI (Figure 2b), where adding plasma biomarkers to performance at OCTAL achieved a perfect separation (AUC of 1) between the groups.

Conclusion

These findings demonstrate the potential of OCTAL for widespread, cost‐effective cognitive testing. They also emphasise the utility of combining plasma biomarkers and digital cognitive tests to improve diagnostic accuracy across different stages of the disease. These accessible tools could pave the way to more scalable protocols for screening, stratification and monitoring of patients with preclinical AD.
Computerized testing to detect cognitive decline in biomarker‐confirmed Alzheimer’s disease: Longitudinal findings from the ARMADA study
Authors: Jutten Roos J , Ho Emily , Karpouzian‐Rogers Tatiana , Van Hulle Carol A. , Dodge Hiroko H , Nowinski Cindy J. , Gershon Richard C. , Weintraub Sandra , Rentz Dorene M
Published: January 2025

Background

The National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) was developed to address the need for a brief yet comprehensive instrument to facilitate more uniform assessment in large‐scale research studies. Here, we investigated whether the cognitive measures of the NIHTB detect cognitive decline in biomarker‐confirmed Alzheimer’s disease (AD).

Method

We used data from N = 178 participants (age 76.5±8; 53% female) from the Assessing Reliable Measurement in Alzheimer’s Disease and Cognitive Aging (ARMADA) study, who were recruited across nine research centers in the United States and had amyloid PET or amyloid‐beta42/tau CSF data available within two years of their baseline NIHTB assessment. Participants' cognitive status (normal (CN) or impaired (CI), based on standardized protocols) and amyloid status (Aß‐/Aß+, based on site‐specific cut‐offs) were combined to create three groups: healthy controls (CN Aß‐, n = 113), asymptomatic AD (CN Aß+, n = 24), and prodromal‐to‐mild AD (CI Aß+, n = 34) (Table 1). The NIHTB was assessed at baseline, 12 and 24 months and includes five tasks measuring fluid cognition (attention, executive functions, processing speed, working memory, and episodic memory) and two tasks reflecting crystallized cognition (oral word reading and auditory word comprehension). Linear mixed‐effect models correcting for age, sex, and education were used to examine cross‐sectional and longitudinal NIHTB scores in the three study groups.

Result

Compared to healthy controls, the prodromal‐to‐mild AD group had lower baseline scores on most NIHTB fluid tasks (Flanker Inhibitory Control and Attention, Dimensional Change Card Sort, Picture Sequence Memory, List Sort Working Memory) and showed accelerated decline over 12‐24 months on Pattern Comparison Processing Speed, List Sorting Working Memory and Picture Vocabulary (Figure 1). None of the NIHTB tasks detected cross‐sectional or longitudinal differences in the asymptomatic Aß+ group compared to healthy controls over the course of this study.

Conclusion

The NIHTB detects cross‐sectional impairment in episodic memory, attention, executive functions and working memory and longitudinal change in processing speed, working memory and auditory word comprehension in prodromal‐to‐mild AD. These findings further support the use of the NIHTB in AD research, but also imply that the optimal NIHTB composite to detect cognitive decline may differ across AD clinical stages.
The electronic Person‐Specific Outcome Measure (ePSOM) in the US population: What matters to individuals the most about their brain health
Authors: Saunders Stina , Jannati Ali , Gomes‐Osman Joyce Rios , Pobst Jeff , Morrow William Isaiah , Tobyne Sean , Showalter John , Pascual‐Leone Alvaro
Published: January 2025

Background

It is essential that both drug and lifestyle‐based interventions aimed at delaying the functional decline in conditions like Alzheimer’s disease and related dementias (ADRDs) capture change in functioning that incorporates the person’s voice. Such brain health priorities can vary across populations and it is unclear to what degree findings from the ePSOM program in the UK might apply to the US.

Methods

We conducted an online nationwide study to understand what matters to people aged 50 and older about their brain health in the US. The ePSOM US survey (May 2023‐Jan 2024) collected primarily free‐text responses, alongside sociodemographic information, self‐reported neurodegenerative disease diagnosis, and self‐reported confidence in managing personal priorities. We examined [1] the difference in relative frequency of specific words for key sociodemographic groups and comparable UK/US populations, and [2] compared the differences in confidence scores between the diagnosis and non‐diagnosis groups (gender and age controlled) using the Mann–Whitney U test.

Results

A total of 764 participants provided over 11,522 free text responses. Most were female (69%), married (63%), had higher education (64%) and did not report neurodegenerative disease diagnosis (93%); mean age 63.17 (SD = 8.52) in women, 62.99 (SD = 8.30) in men. There were statistically significant differences (p<0.05) in the pattern of responses between sub‐groups: younger/older; male/female; higher/lower education and UK/US populations but not between those with and without a diagnosis. Individuals with a diagnosis rated their confidence significantly lower (median score 20/25, IQR = [17,23]) than those without a diagnosis (median score 24/25, IQR = [22,25]; U = 8908, p<0.05).

Conclusion

Our study demonstrates that there is heterogeneity in the outcomes that matter to individuals about their brain health across sociodemographic groups and UK/US populations. These findings support the notion that emerging treatments in ADRD should be developed with a person‐centred approach that accounts for sociodemographic factors, and that confidence may be an appropriate construct to measure self‐perceived ability. Efforts such as the ePSOM program offer an evidence‐based method to capture and monitor personally meaningful treatment targets.
Can a picture description differentiate the nonfluent/agrammatic and logopenic variants of primary progressive aphasia?: Evidence from Catalan‐Spanish bilinguals
Authors: Pugalenthi Lokesha , Montagut Núria , Marques‐Kiderle Sonia Karin , Rodriguez Camille Wagner , Iyer Ami , Chaires Jan Christian Holst , Motta Whendy Avila , Filella‐Merce Júlia , Zhu Nuole , Rubio‐Guerra Sara , Illán‐Gala Ignacio , Borrego‐Écija Sergi , Lladó Albert , Fortea Juan , Lleo Alberto , Sanchez‐Valle Raquel , Santos‐Santos Miguel A , Grasso Stephanie M
Published: January 2025

Background

Primary progressive aphasia (PPA) is a language‐based dementia linked with underlying Alzheimer’s disease (AD) or frontotemporal dementia. Clinicians often report difficulty differentiating between the logopenic (lv) and nonfluent/agrammatic (nfv) subtypes, as both variants present with disruptions to “fluency” yet for different underlying reasons. In English, acoustic and linguistic markers from connected speech samples have shown promise in machine learning (ML)‐based differentiation of nfv from lv. To our knowledge, this approach has not been evaluated in other languages nor in the context of bilingualism.

Method

Twenty‐four Spanish‐Catalan bilingual patients (lv = 15, nfv = 9) were asked to describe a picture (WAB Picnic Scene) in both their dominant and non‐dominant language. From the participant’s recorded response, 10 acoustic features were derived with PRAAT and 15 linguistic features were derived with the Natural Language Processing (NLP) tools SpaCy and CLAN. A similarity score between the image and patient’s transcription was derived with the Vision‐Language model CLIP. The acoustic features, linguistic features, and CLIP scores, were separately fed into ML classification algorithms for differentiating nfv from lv in participants' dominant and non‐dominant samples.

Result

The acoustic‐based classifiers achieved classification accuracy (F1 score) of 59% in the dominant and 86% in the non‐dominant language, respectively. The linguistic‐based classifiers achieved F1 scores of 73% in the dominant and 77% in the non‐dominant language, respectively. The CLIP‐based classifier achieved F1 scores of 82% in the dominant and 82% in the nondominant language, respectively. The acoustic and linguistic classifier performed 25% (p = 0.077) and 4% (p = 0.18) better given only non‐dominant samples compared to only dominant samples.

Conclusion

Taking advantage of recent advances in multilingual NLP, we achieved promising and effective differentiation of nfv from lv for Spanish‐Catalan bilingual patients using a nearly automated pipeline. Interestingly, our acoustic and linguistic‐based classifiers performed better given responses from a patient’s non‐dominant language, and the acoustic feature set was more accurate in discriminating between nfv and lv compared to the linguistic model. Future directions include examining patterns in a larger sample size and comparison of performance on different types of connected speech tasks.
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 (ß = ‐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 (ß = 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.
Association between medial temporal and neocortical Tau SUVR across tau imaging agents: HEAD Study
Authors: Rahmouni Nesrine , Tissot Cécile , Hosseini Seyyed Ali , Macedo Arthur C. , Servaes Stijn , Therriault Joseph , Lussier Firoza Z , Arias Jaime Fernandez , Wang Yi‐Ting , Stevenson Jenna , Trudel Lydia , Gauthier Serge , Baker Suzanne L. , Pascoal Tharick Ali , Rosa‐Neto Pedro
Published: January 2025

Background

The association between medial temporal and neocortical SUVR depends on availability of cortical tau. However, tracer differences in affinity and off‐target binding might interfere in these associations. Here, we examined the association between medial temporal and neocortical SUVR using voxel‐based approach.

Method

We included 92 individuals (46 Cognitively Unimpaired and 46 Cognitively Impaired) from the HEAD Study recruited at McGill University. All individuals were assessed for amyloid‐ß (Aß) deposition using [18F]AZD4694‐PET and at least two tau‐PET ligands ([18F]MK6240 and [18F]Flortaucipir). A subset of 25 individuals had 2 additional tau‐PETs scans: [18F]RO948 and [18F]PI‐2620. Voxel‐based regression models evaluated the relationship between PET tracers’ uptake in the entorhinal cortex (EC) and its association with the tracer’s uptake in later Braak regions. All models include Aß‐PET, age, and sex as covariates and RFT was used to account for multiple comparisons. Additionally, we extracted the number of significant voxels in the associations within each Braak regions.

Result

Positive associations were observed between tau‐PET SUVR in the EC (Figure 1). [18F]MK6240 EC was correlated with tracer uptake in the whole cortex. [18F] Flortaucipir was associated with tracer uptake in similar regions, albeit showing a lower t‐value. [18F]PI2620 EC uptake correlated with binding in regions Braak II‐V. Finally, [18F]RO948 was associated with uptake in regions Braak II‐IV. We further validated our results by extracting the number of significant voxels in each Braak regions. [18F]MK6240 showed the highest percentage of spatial extent of tau spreading in all Braak regions, followed by [18F]Flortaucipir and [18F]RO948. [18F]PI2620 demonstrated the lowest spatial extent.

Conclusion

[18F]MK6240 SUVR better predicted the spatial extent of tau spreading in the whole cortex. Results were concordant at the voxel and region‐on‐interested levels. [18F]Flortaucipir showed similar results, in lower magnitude. Finally, [18F]PI2620 and [18F]RO948 were further lower. Nevertheless, the later analyses were conducted in a smaller sample. Our results support the concept that MK6240 affinity possibly explain these results.
Driving Tau Pathogenicity Seeding ‐ How Fibril Structure and Post‐Translational Modifications Alter Seeding Capacity
Authors: Kasen Alysa , Breton Libby , Meyerdirk Lindsay , Lövestam Sofia , McPhail Jacob , Louwrier Ariel , Scheres Sjors , Henderson Michael
Published: January 2025

Background

The accumulation of hyperphosphorylated, aggregated tau in neurons is one of the hallmarks of Alzheimer’s disease (AD). Recent work in structural biology has solved the structure of tau fibrils in several tauopathies and found that the structure of the tau fibrils varies between diseases, but fibril structure is conserved among patients within the same disease, suggesting fibril structure relates to its pathogenicity. Tau fibrils derived from AD brain (AD PHFs) seed AD‐like pathology in wild‐type mice, yet efforts to recapitulate this seeding with recombinant fibrils have failed. The differential capacity of tau fibrils to seed pathology also supports the relevance of tau structure to its pathogenicity. We hypothesized that recombinant fibrils that recapitulate the core region structure of AD tau will show similar seeding capacity to AD tau, with PTMs playing a modulatory role.

Methods

We took advantage of recently developed recombinant tau fibrils with diverse structures to investigate how tau fibril structure and PTMS are related to tau seeding capacity in primary cortical neurons. Fibrils of interest from the screen were then assessed through hippocampal injection into wild‐type and MAPT knock‐in mice.

Results

In‐vitro screening showed that fibrils more closely resembling the core structure of an AD PHF had a higher seeding capacity than other fibrils. However, the replication of the core structure alone in truncated fibrils is not sufficient to fully replicate the seeding capacity of AD PHFs, indicating that the region outside of the core structure, containing PTMs, likely plays an essential role in pathology seeding. This finding was replicated in the seeding model into wild‐type and MAPT KI mice. We also found that tau fibrils containing PTMs had a higher seeding capacity than full length fibrils without PTMs. However, the presence of PTMs alone was not enough to fully replicate the seeding capacity of AD PHFs.

Conclusions

The structure and PTM patterns of tau fibrils appear to be closely tied to fibril pathogenicity, with recombinant fibrils more closely resembling AD PHFs having a more similar seeding capacity. We believe that the generation of fibrils closely resembling AD PHFs can lead to improved model systems of tau pathology in AD.
APOEε4, blood glucose levels, peripheral inflammation, and cognitive change among postmenopausal women in the Women’s Health Initiative
Authors: Klinger Hannah M , Coughlan Gillian T , Hayden Kathleen M. , Manson JoAnn E. , Wild Robert A , Jung Su Yon , Casanova Ramon , Liu Longjian , Shadyab Aladdin H. , Wactawski‐Wende Jean , Schembre Susan M , Liu Simin , Rapp Stephen R. , Resnick Susan M. , Baker Suzanne L. , Buckley Rachel F
Published: January 2025

Background

Older women have a higher prevalence of Alzheimer’s disease relative to comparably aged men. Although the biological mechanisms driving this sex difference remain elusive, emerging data suggest that longevity, APOEε4, inflammation, and blood glucose levels may play roles. Our objective was to examine the associations of APOEε4, high sensitivity‐C‐reactive protein (hs‐CRP), and fasting blood glucose levels with cognitive changes over time among women enrolled in two ancillary studies of the Women’s Health Initiative (WHI).

Method

We identified 2,534 women from WHIMS‐ECHO (Enrollment agemean(SD) = 70(4) years) and 400 women from WHIMS‐Y (Enrollment agemean(SD) = 52(1) years) with baseline data available for APOEε4 carriage, plasma hs‐CRP, and serum‐measured fasting blood glucose, and longitudinal cognitive measures, including the TICSm, EBMT, EBMT‐recall, verbal fluency, Digit Span Backwards, and CVLT scores. A series of linear mixed‐effects models were used to examine these three predictors’ main and interactive effects on longitudinal cognition changes, adjusting for age, education level, body mass index, diabetes status, WHI randomization arm, and cohort (including random intercepts and slopes). Hs‐CRP levels were log transformed and glucose levels were inverse transformed. All data were z‐scored.

Result

APOEε4 carriage was associated with steeper cognitive decline on the TICSm, EMBT, EBMT‐recall, verbal fluency, Digit Span Backwards, and CVLT‐correct scores compared to non‐carriers (Table 1). APOEε4 carriers with lower blood glucose levels showed steeper cognitive decline on TICSm and EBMT‐recall scores but less intrusions on the CVLT compared to APOEε4 carriers with higher glucose levels. Additionally, APOEε4 carriers with higher levels of hs‐CRP demonstrated a steeper decline on CVLT‐correct scores relative to APOEε4 carriers with lower hs‐CRP levels. Women with higher levels of hs‐CRP alone exhibited steeper cognitive decline on the EBMT and Digit Span Backwards test compared to women with lower hs‐CRP. Women with higher levels of both hs‐CRP and blood glucose also showed significantly faster rates of decline on TICSm and verbal fluency scores relative to women with higher hs‐CRP who had lower blood glucose levels. Three‐way interaction tests (APOEε4*CRP*glucose) did not yield significant results.

Conclusion

These findings underscore the complex interplay between genetic risk, metabolic and inflammatory health, and their associations with cognitive decline among older women.
A polygenic score for executive function correlates with differential rates of cognitive decline
Authors: Dehghani Nadia , Massimo Lauren , Rhodes Emma , Cousins Katheryn A Q , Boyle Rory , Emrani Sheina , Phillips Jeffrey S , Ohm Daniel T , Matyi Melanie A , Van Deerlin Vivianna M , Irwin David J , McMillan Corey T
Published: January 2025

Background

Executive dysfunction is a hallmark clinical feature of frontotemporal degeneration (FTD). Genome‐wide association studies have identified genetic variants, and resulting polygenic scores (PGS), related to executive function (EF) in population studies. We evaluated whether EF‐PGS correlates with differential rates of cognitive decline in FTD.

Method

We computed an EF‐PGS based on a prior EF‐GWAS for 375 individuals genotyped in the Penn Integrated Neurodegenerative Disease Database with a diagnosis consistent with FTD including bvFTD, naPPA, svPPA or cognitively normal. We investigated the association between EF‐PGS tertiles and cognitive decline over time (letter‐guided fluency, n = 257; semantic fluency, n = 185 with animals, n = 171 with vegetables; backwards digit span, n = 140; Boston Naming Test, n = 179) in linear mixed effects models adjusting for age at baseline, sex, education years and baseline cognitive score.

Result

Overall, the low‐PGS tertile exhibited faster decline over time in letter‐guided fluency assessed by the number of correct words beginning with the letter “F” produced in 1‐minute (t = −2.77, df = 96, p = 0.007 compared to the intermediate‐PGS tertile; t = −2.41, df = 99, p = 0.018 compared to the high‐PGS tertile). There was no significant differential rate of decline between EF‐PGS tertiles in measures of semantic fluency, confrontation naming (Boston Naming Test) or working memory (backwards digit span), with the caveat that fewer participants in our cohort had these measures.

Conclusion

Our results suggest that lower EF‐PGS correlates with faster cognitive decline over time, particularly specific to letter‐guided fluency. This PGS, based on genetic variants associated with EF, may reflect the domain‐specific decline in cognitive performance observed across FTD syndromes.
Associations of Vision Impairment with Cognitive Impairment Among Stroke Survivors in the Atherosclerosis Risk in Communities Study
Authors: Hreha Kimberly , Ashner Marissa , Peskoe Sarah , Downer Brian , Reistetter Timothy , Whitson Heather
Published: January 2025

Background

Vision impairment is a common complication of stroke, which has been linked to cognitive decline in stroke survivors. Little is known about how specific types of vision impairment influence the relationship between stroke and dementia. The aims of this project were: (1) to characterize the prevalence of both pre‐stroke and stroke‐related vision impairment(s) among stroke survivors with and without mild cognitive impairment (MCI) or dementia, and (2) to determine associations of vision impairment with cognitive impairment, depression, and physical performance.

Methods

Data from the Atherosclerosis Risk in Communities Study (ARIC) were studied. Our analytic cohort included ARIC participants who had both a stroke hospitalization captured via surveillance prior to dementia and cognitive measures from Visits 5‐6. Participants without a retinal exam prior to their stroke were excluded. We determined the prevalence of specific types of vision impairments and ocular conditions as well as patient‐level demographics, stratified by cognitive status. Multivariable linear and logistic regressions, controlling for age, sex, and education, modelled the relationship between types of vision impairment and each outcome.

Results

Our final cohort contained n = 227 individuals, with mean (standard deviation [SD]) age of 78.5 (5.56) years. Participants were primarily male (54.2%) and white (73.6%), with a mean of 14.5 (SD = 4.24) years of education. 15.9% had a pre‐existing vision impairment (e.g., glaucoma), and 18.5% developed a stroke‐related vision impairment (e.g., diplopia). Vision impairment (all types) was significantly associated with dementia (adjusted odds ratio (OR) = 2.17, 95% confidence interval (CI) = 1.07‐4.41), but not MCI (OR = 1.23, 95% CI = 0.07‐2.20). In assessing pre‐stroke vision impairment and stroke‐related vision impairment separately, there were no statistically significant associations with any outcomes.

Conclusions

This study informs the rates of types of well‐characterized vision impairments in a group of stroke survivors. There is a 2‐fold increase in the likelihood of dementia among stroke survivors with vision impairment as compared to those without vision impairment, defined as either pre‐stroke or stroke‐related impairment. Future data collection in larger, more diverse populations is needed to determine how specific types of vision impairments in stroke survivors associate with cognitive impairment as well the likelihood of depression or worse functional status.
The impact of dementia medications on medical outcomes in older adults
Authors: DeMercy Haylie M. , Brenner Colleen A.
Published: January 2025

Background

Dementia often includes behavioral and psychological symptoms such as behavioral excitement, mood disorders and psychosis. Antipsychotic drugs are often prescribed alone or in conjunction with cognitive enhancers, however, these drugs can increase risk for adverse cardiovascular/cerebrovascular events (MACCE) and mortality. This study investigated whether those prescribed antipsychotics and/or cognitive enhancers experienced a MACCE more quickly and if medication dosage impacts survival time.

Methods

Data from 1,126 patients aged ≥ 50 or older, with a diagnosis of dementia and behavioral symptoms were studied. We compared four different models of BPSD treatment using Cox Regression Analyses.

Results

Results indicated that there was a significant effect of type of medication on duration until MACCE, (p < .001). The odds of experiencing a MACCE were 96.3% higher for individuals treated with both antipsychotics and cognitive enhancers (p < .001), 78.7% higher for those treated with only antipsychotics (p < .001), and 31.9% higher for those treated with only cognitive enhancers (p = .003). There was also a significant effect of dosage on duration until MACCE, p < .001. The odds of experiencing a MACCE sooner were 238% higher for those on high doses of antipsychotics (p < .001), and 48% higher for individuals on a medium dose (p < .001) compared to low doses. There was also a significant effect of cognitive enhancer dosage on duration until a MACCE, (p < .001). The odds of experiencing a MACCE were 76% higher for individuals on high doses of cognitive enhancers (p < .01) and 38% higher for those on a medium dose (p < .05) compared to low doses.

Conclusion

There is a clear increased risk of adverse medical outcomes when using antipsychotic and cognitive enhancing drugs in the treatment of dementia with behavioral symptoms. The use of antipsychotic medication, particularly at high doses, was associated with the greatest risk of an adverse medical outcome. Use of antipsychotic medications in this population should include close monitoring for cardiovascular/cerebrovascular events.
Differential associations between plasma p‐tau181 and hippocampal subfield integrity across the Alzheimer’s disease diagnostic continuum
Authors: Rich Adea , Oh Hwamee
Published: January 2025

Background

Plasma p‐tau181 is an increasingly established diagnostic marker for Alzheimer’s disease (AD); however, its precise relationship with brain tau pathology and the neural mechanisms underlying its association with cognitive impairment remain elusive. Our objective was to assess the association between plasma p‐tau181 and hippocampal (HC) subfield integrity and to investigate whether the subfields mediate the relationship between plasma p‐tau181 and cognition.

Method

A total of 213 participants (57 cognitively normal, 109 mild cognitive impairment, and 47 AD) with plasma p‐tau181 measurements and high‐resolution T2‐weighted scans were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). HC subfield volume was measured at baseline using the Automatic Segmentation of Hippocampal Subfields (ASHS) software. Follow‐up HC subfield volume collected around one year was measured for eighty‐nine participants. A linear regression adjusted for age and sex evaluated the relationship between plasma p‐tau181 and HC subfields at baseline, as well as HC volume rate of change over one year. A mediation model assessed whether HC subfields mediate the association between plasma p‐tau181 and memory and executive functioning.

Result

Our findings indicate that increasing levels of plasma p‐tau181(pg/mL) are associated with decreased volume in the left CA1 (β = ‐0.119, p = 0.019, Fig. 1a), right CA1 (β = ‐0.154, p = 0.005, Fig. 1b), left dentate gyrus (β = ‐0.120, p = 0.016, Fig. 1g), right dentate gyrus (β = ‐0.146, p = 0.005, Fig. 1h), and right entorhinal cortex (β = ‐0.091, p = 0.048, Fig. 1l). Moreover, these subfields partially mediate the relationship between plasma p‐tau181 and memory and executive functioning composite scores. Baseline plasma p‐tau181 did not predict longitudinal atrophy of the HC subfields across diagnostic groups.

Conclusion

Our study reveals consistent associations between plasma p‐tau181 levels and vulnerable HC subfields, including CA1, entorhinal cortex, and dentate gyrus, collectively implicated in normal aging and Alzheimer’s disease pathologies. Volumetric changes in CA1, dentate gyrus, and right entorhinal cortex were shown to underlie the association of plasma p‐tau181 with both memory and executive functioning. Together, our findings indicate that selective changes in HC subfield volume serve as a neural basis underlying the relationship between plasma p‐tau181 levels and cognitive impairment.
Development of a prototype ChLIA and a research‐use only ELISA for the detection of light chain neurofilament (NfL) in CSF
Authors: Zeplin Katharina , Niewand Julia , Franco Stephanie , Borchardt‐Lohölter Viola , Herbst Victor
Published: January 2025

Background

Increased levels of the light chain of neurofilament (NfL) in human cerebrospinal fluid indicate axonal damage. Their determination can support laboratory diagnosis and monitoring of neurological diseases associated with axonal damage. We developed a prototype chemiluminescence assay (ChLIA) and an enzyme‐linked immunoassay (ELISA, research use only) to detect NfL and report their analytical agreement with an established ELISA.

Method

Agreement between the established NF‐light ELISA (UMANDiagnostics) and the Neurofilament Light (NfL) ELISA (EUROIMMUN) as well as the prototype NfL ChLIA (EUROIMMUN) was determined using 19 internal reference samples containing native NfL, with NfL levels distributed across the measurement range of the NF‐light ELISA. Possible bias between methods was estimated with Passing‐Bablok regression and Kolmogorov‐Smirnov CUSUM test.

Result

Comparison of NF‐light ELISA and Neurofilament Light (NfL) ELISA indicated a small proportional deviation with NF‐light ELISA values being higher than Neurofilament Light (NfL) ELISA values (regression: y = ‐63.9+0.97x, 95% CI intercept: [‐490.8, ‐79.67], CI slope: [0.89, 1.05], r = 0.08, CUSUM test p = 0.6). Comparison of Neurofilament Light (NfL) ELISA and prototype NfL ChLIA indicated a small shift with ChLIA values being higher than ELISA values, especially in the upper end of the measurement range (regression: y = 13.73+1.14x, CI intercept: [‐140.9, 97.05], CI slope: [1.07, 1.23], r = 0.98, CUSUM test p = 0.6).

Conclusion

The results of analytical agreement between NfL levels determined by the ELISA and the prototype ChLIA in comparison to the established ELISA show promise regarding their performance characteristics. Being limited by the small sample size, these results will be followed up by a larger method comparison and validation study.
Peripheral parenchymal organ volume plays a role in neurodegenerative diseases: A Mendelian Randomization Study
Authors: An Dinghao , Xu Yun
Published: January 2025

Background

Some studies have reported that neurodegenerative diseases can have different effects on the structure and function of peripheral organs, including organ volumes, and we wondered whether there is a genetic causal relationship between the two and whether changes in the volumes of parenchymal organs can affect the risk of developing neurodegenerative diseases.

Method

Our SNP data were obtained from several different databases, including UKB and IEU OpenGWAS, and we analyzed them using bidirectional Mendelian randomization followed by comprehensive robustness analysis.

Result

For traditional genetic threshold: belly subcutaneous fat tissue volume can increase the risk of Alzheimer’s disease. Spleen volume can decrease the risk of amyotrophic lateral sclerosis. Pancreas volume may decrease the risk of amyotrophic lateral sclerosis. Dementia with Lewy bodies can decrease the risk of visceral fat tissue volume change while increasing the risk of spleen volume change. Alzheimer’s disease can decrease the risk of lung volume change, liver volume change, visceral fat tissue volume change, and pancreas volume change while increasing the risk of spleen volume change. For expanded genetic threshold: lung volume change can increase the risk of amyotrophic lateral sclerosis. Alzheimer’s disease can decrease the risk of belly subcutaneous fat tissue volume change, and visceral fat tissue volume change, and increase the risk of lung volume change.

Conclusion

We found that some neurodegenerative diseases affect parenchymal organ volumes and that changes in the volumes of some organs increase the risk of developing neurodegenerative diseases, particularly the volumes of lung, spleen, pancreas, viscera fat tissue, and belly subcutaneous fat tissue. This may provide some new evidence and insights into the pathogenesis and comprehensive management of neurodegenerative diseases.
The Brain Tissue Properties Within the Cerebellum Play Role in Executive Functioning and Memory Performance in Healthy Older Adults
Authors: Moallemian Soodeh , Dapnée Chylinski , Van Egroo Maxime , Justinas Narbutas , Salmon Eric , Pierre Maquet , Collette Fabienne , Gilles Vandewalle , Phillips Christophe , Bastin Christine
Published: January 2025

Background

Cognitive function alterations are a feature of the cognitive aging process. Additionally, aging is marked by macro‐ and micro‐structural changes in the brain, such as gray matter (GM) atrophy, iron accumulation, and demyelination. This study explores the association between cognitive function and cooccurrence of brain micro‐ and macro‐structural changes in healthy older adults.

Method

One hundred and one participants (32% men, age range: 50‐69 years) were included in this study. All participants completed a cognitive assessment resulting in composite scores with mean = 0.00, s.d. = 0.99 for attention, executive functions, and memory. The preclinical Alzheimer’s cognitive composite (PACC5) was calculated for all participants (mean = 0.00, s.d. = 2.99). Quantitative magnetic resonance imaging (MRI) data were obtained using multiparametric mapping protocol. The association between cognitive composite scores and combinations of tissue properties was tested using multivariate generalized linear models (GLM) in Statistical Parametric Mapping (SPM) software.

Result

Voxel‐wise multivariate GLM analyses revealed significant associations after family‐wise error rate correction between executive functions and the combination of macro‐ and micro‐structural changes within the cerebellum including right crus I and II, VII‐b (see Figure 1‐A). As illustrated in Figure 1, panels B and C, we also detected a correlation between memory and combined microstructural alterations in the in the left Cerebellum VIII‐b, as well as bilaterally within the cingulate gyrus and insula.

Conclusion

These findings highlight the role of the cerebellum in cognition besides the complex relationship between cognition and brain micro‐ and macro‐structural properties in aging. As such, the involvement of the cerebellum in motor coordination and procedural memory may potentially influence executive functions