bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the Utility of a Knowledge Based Algorithm for Classifying Alzheimer disease and Mild Cognitive Impairment in the Recruitment and Retention for Alzheimer’s Disease Diversity Cohorts in the ADSP (READD‐ADSP) Project
Authors: Zaman Andrew F. , Mena Pedro R. , McInerney Katalina F , Celis Katrina , Adams Larry D. , Duke Tina , Sanchez Jose Javier , Chavez Jenny , Cespedes Jennifer , Starks Takiyah D. , Laux Renee A. , Hamilton‐Nelson Kara L. , Rajabli Farid , Byrd Goldie S. , Reitz Christiane , Tosto Giuseppe , Ogrocki Paula K. , Caban‐Holt Allison M , Haines Jonathan L. , Vance Jeffery M. , Pericak‐Vance Margaret A , Cuccaro Michael L.
Published: January 2025

Background

Over 13,000 individuals from both domestic and African sites will be collected for the READD‐ADSP study. Adjudicating this number of individuals is challenging, so we evaluated knowledge‐based decision tree algorithms to predict clinical diagnoses using nationally representative norms and standard cut‐offs. Additional models were constructed using culturally adjusted cut‐offs, domain average cut‐offs, and exclusion of the Trail Making Test (TMT) which performed poorly. Our aim was to evaluate the accuracy of these decision tree models in the READD‐ADSP dataset.

Method

Clinically adjudicated diagnoses by at least two neuropsychologists and/or neurologists were available for 150 individuals from the READD‐ADSP sample (44%‐Unaffected, 36%‐MCI, 9.3%‐AD, 2.7%‐Dementia not AD, 8%‐Cognitively Impaired– Vascular; 19% Hispanic, 81% African‐American, 76%‐Female, Age: 73.0 years, Education: 13.7 years). Eight models were used to classify our sample into the diagnostic categories above and varied in test cut‐offs (standard vs. culturally adjusted), use of domain average cut‐offs (no average vs. average), and use of TMT (inclusion vs. exclusion). Model accuracy was assessed using the F1 score (which balances precision and sensitivity). F1 scores >0.9 are considered excellent, >0.8 are good, and those between 0.6‐0.8 are acceptable.

Result

The two models that used culturally adjusted cut‐offs and domain average cut‐offs performed best (with TMT, F1 = 0.81; without TMT, F1 = 0.78). All other models had F1 scores ranging from 0.63‐0.73. While the two best models were similarly accurate based on F1 scores, the difference in the frequency of diagnoses between them was notable. In the model that excluded TMT, 38% of the sample were classified as Unaffected vs. 30% in the model that included TMT; (41% and 47% were classified MCI, respectively).

Conclusion

Our findings show that culturally sensitive adjusted cut‐offs and inclusion of domain average cut‐offs improved the accuracy of decision tree model classifications. These findings suggest that implementation of decision tree model approaches in the READD‐ADSP dataset can accurately and efficiently classify individuals. Finally, we plan improve overall accuracy by using a hybrid method where models classify individuals who are clearly Unaffected or AD while more complex cases will be assigned to human adjudication.
The auditory phenotype of behavioural variant and right temporal variant frontotemporal dementia
Authors: Johnson Jeremy , Levett Benjamin Aaron , Requena‐Komuro Mai‐Carmen , Benhamou Elia , Jiang Jessica , Bamiou Doris‐Eva , Hardy Chris JD , Warren Jason D
Published: January 2025

Background

Patients with behavioural variant frontotemporal dementia (bvFTD) and right temporal variant frontotemporal dementia (rtvFTD) commonly exhibit abnormal hedonic and other behavioural responses to sounds, however hearing dysfunction in this disorder is poorly characterised. Here we addressed this issue using the Queen Square Tests of Auditory Cognition (QSTAC) – a neuropsychological battery for the systematic assessment of central auditory functions (including pitch pattern perception, environmental sound recognition, sound localisation and emotion processing) in cognitively impaired people.

Method

The QSTAC was administered to 12 patients with bvFTD, 7 patients with rtvFTD and 24 patients with comparator dementia syndromes (primary progressive aphasia and typical Alzheimer’s disease) and 15 healthy age‐matched individuals. Participants also underwent pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.

Result

After accounting for nonverbal executive and peripheral hearing performance, patients with bvFTD and rtvFTD showed deficits of environmental sound and auditory emotion recognition and sound localisation, compared both with healthy controls and patients with Alzheimer’s disease. Patients with bvFTD showed a deficit in dichotic listening compared with the rtvFTD group.

Conclusion

bvFTD and rtvFTD have distinct phenotype of auditory cognitive dysfunction which likely contributes to the hearing alterations that many patients with this diagnosis experience in daily life. Our findings call attention to an under‐recognised issue in frontotemporal dementia that warrants further clinical interpretation and the development of management strategies tailored to real‐world acoustic environments.
Vascular risk factors, subjective cognitive decline, and mild behavioral impairment: A CAN‐PROTECT study
Authors: Guan Dylan X. , Aundhakar Aditya , Farias Sarah Tomaszewski , Smith Eric E. , Ismail Zahinoor
Published: January 2025

Background

Subjective cognitive decline (SCD) and mild behavioral impairment (MBI) identify older persons that are more likely to be at preclinical stages of Alzheimer’s disease (AD) than those without SCD and MBI. However, vascular co‐pathologies may also contribute to new onset and persistent cognitive and behavioral symptoms. We investigated vascular risk factor associations with SCD and MBI in older persons without mild cognitive impairment or dementia.

Method

Data for 1285 participants from the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN‐PROTECT) study were analyzed [Figure 1]. Vascular risk factors were body mass index (normal, overweight, obese), hypertension, high cholesterol, diabetes, and smoking (never, past, active). Outcomes were measured using the Everyday Cognition (ECog‐II) scale and MBI Checklist (MBI‐C). SCD was operationalized based on a score of ≥2 (i.e., consistently a little or much worse) on any ECog‐II item. MBI+ status was defined by MBI‐C total scores ≥8. Propensity scores were used to balance age, sex, years of education, marital status, and ethnocultural origin across exposure groups using inverse probability of treatment weighting. Weighted negative binomial and logistic regressions were used to model vascular risk factor (exposure) associations with ECog‐II and MBI‐C total scores, and SCD and MBI+ statuses, respectively.

Result

Participant characteristics are summarized in Table 1. As shown in Table 2, all vascular risk factors assessed in the study were associated with higher ECog‐II total score, with the exception of past (i.e., not active), smoking behavior. Diabetes and active smoking showed the largest magnitudes of effect in relation to ECog‐II total scores. Active smoking and obesity showed the largest magnitudes of effect in relation to MBI‐C total scores. When assessing outcomes as categorical variables (i.e., SCD+ and MBI+), the same associations were found.

Conclusion

Vascular risk factors were associated with poorer everyday cognition, more severe MBI symptoms, and greater odds for classification as SCD+ and MBI+ in a sample of older persons without objective cognitive impairment. These findings suggest potential vascular contributions to cognitive and behavioral markers traditionally linked to AD.
ROCK inhibitors alter brain proteomic profiles and tau phosphorylation in iPSC‐derived human neurons and mouse model of Alzheimer’s disease
Authors: Collu Roberto , Giunti Elisa , Yin Zheng , Daley Sarah , Chen Mei , Li Qinqing , Morin Peter J , Killick Richard , Wong Stephen T.C. , Xia Weiming
Published: January 2025

Background

We aim to investigate efficacies of Ras homolog (Rho)‐associated kinases (ROCK) inhibitors on Alzheimer’s disease (AD) pathological proteins in human induced pluripotent stem cell (iPSC)‐differentiated human neurons and the P301S tau transgenic mouse model (PS19).

Method

Quantitative liquid chromatography‐mass spectrometry (LC‐MS/MS) and targeted ELISA were implemented to investigate the effect of treatment with fasudil or its derivatives on the human neurons and brains from PS19 mice. We explored the efficacy of these ROCK inhibitors in reducing tau phosphorylation, and the brain proteomic profiles after their administration in mice.

Result

We found a significant negative correlation between the brain levels of phosphorylated tau (pTau) and both fasudil and its metabolite hydroxyfasudil. Human neuronal culture exposed to selective ROCK inhibitors exhibited similar efficacies. Proteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood‐brain barrier (BBB) gap junction metabolic pathways.

Conclusion

Our results provide evidence to support the development of ROCK inhibitors as AD therapeutics.
The dynamics of auditory working memory impairment in logopenic variant primary progressive aphasia and typical Alzheimer’s disease
Authors: Levett Benjamin Aaron , Novoa Catalina , Core Lucy , Jiang Jessica , Warren Jason D , Hardy Chris JD
Published: January 2025

Background

Impaired auditory verbal working memory is a diagnostic hallmark and integral driver of the clinical phenotype in logopenic variant primary progressive aphasia (lvPPA). However, the physiology of the working memory buffer in this syndrome is poorly characterised. Here we addressed the temporal dynamics of auditory verbal working memory in patients with lvPPA and typical Alzheimer’s disease (tAD).

Method

In a cohort of 8 patients with lvPPA, 17 patients with tAD and 18 healthy age‐matched controls, we assessed how temporal manipulations of a standard auditory verbal working memory tasks (forward digit span and phrasal repetition) affected performance. We varied tempo of delivery and inter‐trial gap and performed a detailed analysis of error types. Participants also underwent pure tone audiometry to assess peripheral hearing function and a comprehensive general neuropsychological assessment.

Result

Compared with healthy controls, patients with lvPPA and tAD showed increased sensitivity to temporal manipulation of auditory verbal working memory tasks and error profiles suggesting a dynamic physiological lesion of the working memory buffer. These effects were particularly marked in the lvPPA group.

Conclusion

Our findings open a novel physiological window on working memory dynamics in Alzheimer’s disease syndromes. Further work is warranted to assess how this dynamic deficit impacts communication in patients’ daily lives, how it can best inform management interventions and its potential as a novel, rapid read‐out of neural function in the era of disease‐modifying therapies.
Serial‐position effect in participants cognitively unimpaired with Subjective Cognitive Complaints (SCCs) and with Mild Cognitive Impairment (MCI) that revert, remain stable or worsen: Evidence from the Compostela Aging study (CompAS)
Authors: Rozas Arturo X. Pereiro , Campos‐Magdaleno Maria , Lojo‐Seoane Cristina , Pérez‐Blanco Lucía , Mallo Sabela Carme , Arora Sonali , Fernández‐Feijoo Fátima , Facal David
Published: January 2025

Background

Higher recency effect in episodic memory (EM) has been found for MCI and dementia (Martin et al., 2013; Campos et al., 2016). Additional research should be conducted on the pre‐symptomatic stages and on their ability to predict progression to cognitive decline. Our aim is to analyze the differences in the serial‐position effect in cognitively unimpaired and MCI participants that revert, remain stable or worsen.

Method

A sample of 162 participants from the CompAS were classified in five groups considering change or stability from its baseline diagnoses to the 2nd follow‐up (48‐76 months after baseline) as follows: Stable‐SCC (SCC who remain stable; N = 97), Worsen‐SCC (SCC who worsening to MCI/dementia; N = 32), Stable‐MCI (MCI who remain stable; N = 13), Worsen‐MCI (MCI who worsening to dementia; N = 8), and Reverters (participants who revert from MCI; N = 12). The Spanish version of the CVLT were administered and corrected regional scores were computed (see Campos et al., 2016). A mixed model was carried out to test group differences considering the intrasubject factors Regions (Primacy, Middle, Recency) and Measurements (baseline, 1st follow‐up, 2nd follow‐up).

Results

Significant effects was found for the interaction between Group*Region*Measurement also achieved significance (F(16,628) = 1.87; p<.021; ηp
2
= .045, observed power = .957). Differences between Measurements were not found in any Region for Reverters and Stable‐SCC. In both, Stable‐MCI and Worsen‐SCC groups differences showed better performance in 1st than in 2nd follow‐up in Middle and poor retrieval in Baseline than in 2nd follow‐up in Recency regions. Worsen‐MCI showed better retrieval in Baseline than in 2nd follow‐up for the Middle region but poor retrieval in Baseline than in 1st and 2nd follow‐up for the Recency region (see Figure 1). Group differences were found mainly in Middle and Recency regions (see Table 1) and in the 1st and particularly 2nd follow‐up showing poor retrieval particularly for the Worsen‐MCI.

Conclusions

Recency effect becomes prominent compensatory mechanism as cognitive decline progress. Retrieval in Middle region decrease only MCI participants. Poor retrieval in Middle region scores could be useful to improve identification of SCC at risk.
The Impact of Spatial Navigation Task Types: Moderator Analysis in Meta‐Analysis on Mild Cognitive Impairment
Authors: Kossowska‐Kuhn Dorota , Gouveia Gillian , Charness Neil
Published: January 2025

Background

Dementia exerts a significant global impact on societies and individuals. Spatial disorientation emerges as one of the initial symptoms of Alzheimer’s Disease (AD) (Coughlan et al., 2018). In our Meta‐analysis on spatial navigation in Mild Cognitive Impairment (MCI) we obtained the standardized mean difference (Hedge’s g) between this population and cognitively healthy older adults at the level of g = .88, which corresponds to the large effect size.

Method

The potential moderators such as year of study publication, country of study, age of participants in each population, gender, education, forms of test administration (i.e., real‐world, virtual reality), type of measure (time, accuracy), type of task (i.e., A Maze, Environment Navigation, Money Road Map Test) were coded for moderator analysis.

Result

Moderator analysis for 125 effect sizes across 47 studies, involving 2916 participants (1415 with MCI, 1501 cognitively healthy older adults) revealed that both age and the type of task were statistically significant (p < .05).

Conclusion

Further discussion on the definition of spatial navigation skills is essential to reach a consensus regarding the tasks used for assessments. Given the potential role of spatial navigation as an early marker of dementia, the significance of understanding this complex skill is paramount.
Loss of presenilin 2 function increases susceptibility to kainate‐induced status epilepticus and attenuates associated increases in hippocampal kainate‐type glutamate receptor expression
Authors: Robinson‐Cooper Larissa , Davidson Stephanie , Koutoubi Rami , Barker‐Haliski Melissa
Published: January 2025

Background

Presenilin 2 (PSEN2) is one of three deterministic risk genes that increases the risk of early‐onset Alzheimer’s Disease. People with PSEN2 variants have increased risk of unprovoked seizures versus age‐matched unaffected individuals yet few studies have interrogated the contributions of PSEN2 on seizure susceptibility. Critically, PSEN proteolytic capacity may be a novel regulator of hippocampal kainate‐type glutamate receptors (KARs), with PSEN deletion reducing KAR availability and synaptic transmission in vitro (Barthet et al 2022). Kainic acid (KA) is a naturally occurring agonist for KARs that evokes sustained, severe seizures and status epilepticus (SE). We thus hypothesized PSEN2‐KO mice would demonstrate reduced KA‐SE latency, increased SE severity, worsened outcomes 7‐days later, and have altered hippocampal KAR expression versus similarly treated WT mice.

Method

Using a repeated low‐dose systemic KA administration model to evoke SE, we quantified the latency to SE and extent of SE‐induced neuropathology in 3–4‐month‐old male and female PSEN2‐KO versus WT mice (n = 10‐16 mice/group/sex). GluK5, a KAR subunit, expression was colocalized in astrocytes and neurons by immunohistochemistry 7 days after KA‐SE or sham to define the impacts of PSEN2 deletion and SE on hippocampal KAR expression.

Result

Regardless of sex, PSEN2‐KO mice were more susceptible to KA‐SE than WT mice. Male PSEN2‐KO mice progressed to SE faster than WTs (78.6±25.3 versus 98.2±16.0 min; t = 2.43, p = 0.027); female PSEN2‐KO mice were also more susceptible to KA‐SE relative to WTs (85.3±32.2 versus 112.2±15.4 min; t = 2.45, p = 0.022). Basal GluK5 expression did not differ between sexes or genotypes. However, in male mice 7‐days post‐KA‐SE insult GluK5 expression was significantly increased over basal levels in WT mice (p = 0.0028), but PSEN2‐KO mice GluK5 levels were unchanged from basal expression (p = 0.9819). Regardless of genotype, female mice GluK5 levels were unchanged from basal expression at 7‐days post‐KA‐SE insult, revealing sex differences in post‐SE outcomes.

Conclusion

Loss of normal PSEN2 function increases susceptibility to KA‐induced seizures and SE, which cannot be explained by basal GluK5 expression differences. However, increased GluK5 expression in male WT relative to PSEN2‐KO mice 7‐days post KA‐SE, further substantiates a role of PSEN2 in KAR availability. Sex differences in GluK5 and GFAP were also apparent post‐SE.
Validation of Various Pan‐ApoE and Isoform‐Specific ApoE Antibodies
Authors: Siano Dahlia , Golden Lesley R , MacLean Steven M , Hernandez Gabriela , Johnson Lance A
Published: January 2025

Background

Apolipoprotein E (ApoE) exists in three protein isoforms: E2, E3, and E4, which differ by only one or two amino acids. These slight differences profoundly effect protein structure and function, allowing each isoform to differentially impact Alzheimer’s Disease (AD) risk. Relative to the most common E3 isoform, E4 dramatically increases risk, while E2 confers a substantial decrease in risk. The close similarity between protein isoforms makes it difficult to develop isoform‐specific antibodies that are reliable and selective. Here, we aim to validate and optimize a number of common, commercially available ApoE antibodies to determine isoform specificity.

Method

Control samples included plasma and brain collected from APOE knockout (KO), homozygous E2, E3 and E4 humanized APOE (hAPOE) mice, and human plasma from all 6 possible APOE genotypes. Western blotting was used on plasma and brain homogenates to determine isoform specificity of E2, E3, or E4 antibodies. Commercial antibodies tested included pan‐ApoE antibodies from Cell Signaling Technologies (CST) and Abcam, ApoE4 antibodies from Novus and CST, ApoE2 antibodies from CST, and ApoE3 antibodies from Abcam and Novus. Additionally, pan‐ApoE antibodies were kindly gifted to us by collaborators (Drs. Lammich and Haass, LMU) and tested. Antibodies were also tested for use in immunohistochemistry (IHC) using hAPOE and APOE KO mouse brain sections (30 uM).

Result

Despite the ApoE3 antibodies being marketed as isoform‐specific, they did not show efficacy in either application. Commercial pan‐ApoE antibodies were outperformed by the LMU antibodies, but still showed efficacy. When used for western blotting, the CST ApoE4 and ApoE2 antibodies showed clear isoform specificity in hAPOE mouse and human samples. While none of the isoform‐specific antibodies passed controls for IHC purposes, multiple pan‐ApoE antibodies were variably effective for staining of brain tissue.

Conclusion

These data identify several isoform‐specific ApoE antibodies that are reliable and selective across multiple sample types and applications; albeit some display higher affinity for one application over another. Overall, we hope these results will provide AD researchers with important resources that are crucial for visualizing and quantifying ApoE isoform distribution in heterozygote individuals and across a number of AD models, systems, and studies.
TabCAT Brain Health Assessment: Preliminary validation in a multicultural Israeli population
Authors: Haddad Rafi , Tsoy Elena , Tanne David , Ayoub Rawan , Shihada Essam , Natalya Yarovinsky , Erlhoff Sabrina J , Fisher Tali , Aharon‐Peretz Judith , Ben‐Hayun Rachel , Valcour Victor , Possin Katherine L
Published: January 2025

Background

The Israeli population, primarily comprised of Israeli Jews (74%) and Arabs (21%), is one of the most diverse aging societies around the world. The need for brief, accurate, and culturally appropriate cognitive measures in Israel is high, as they can facilitate early detection of cognitive disorders across clinical settings. We examined the discrimination accuracy and concurrent validity of the brief Tablet‐based Cognitive Assessment Tool (TabCAT) Brain Health Assessment (BHA) battery in a multicultural Israeli sample.

Methods

Participants were 79 Hebrew and Arabic speaking older adults (age: 67±6; 58% female; education: 15±4). Clinically normal participants (n = 63) were community‐dwelling individuals with no self‐ or informant‐reported cognitive symptoms or functional decline. Cognitively impaired participants (n = 16) with diagnoses of mild cognitive impairment (n = 15) or dementia (n = 1) were recruited from a large neurology center. Diagnoses were based on the published clinical criteria, and all patients underwent comprehensive neurological and neuropsychological evaluations independent of study procedures. All participants completed the TabCAT‐BHA and the Montreal Cognitive Assessment (MoCA) in their primary language. Logistic regressions with ROC curves were used to examine discrimination accuracy, controlling for age, sex, education, and testing language. Concurrent validity was evaluated against the MoCA indices for the same domains.

Results

The TabCAT‐BHA battery showed excellent discrimination accuracy (AUC = .99, sensitivity = .81, and specificity = .95) outperforming the MoCA (AUC = .94, sensitivity = .63, specificity = 0.97). Moderate associations were observed between TabCAT Favorites (associative memory) and MoCA Memory Index (r = .49, P < .001), and between TabCAT Match (executive functions) and MoCA Executive Index (r = .64, P < .001). Weaker associations were found between TabCAT Line Orientation (visuospatial skills) and MoCA Visuospatial Index (r = ‐.27, P = .02).

Conclusions

Our preliminary findings support the validity of the 10‐minute TabCAT‐BHA battery in culturally diverse Israeli older adults. The battery exhibited excellent performance in detecting cognitive impairment in our sample outperforming a widely used brief cognitive assessment tool, the MoCA. Future studies, including development of Israel‐specific normative data and replication of these results in larger samples, are ongoing.
Using a novel cognitive screening test to identify dementia risk amongst community‐dwelling cognitively unimpaired older adults from underserved populations.
Authors: Parra‐Rodriguez Mario A , Gonzalez‐Hernandez Alfredis , Bonilla‐Santos Jasmin , Cala Dorian , Gomez Duvan , Forero Eduardo A
Published: January 2025

Background

Recent studies suggest that among cognitively unimpaired older adults, there are individuals who might present with subtle cognitive impairments suggesting the risk of Alzheimer’s disease (AD; Bos et al., 2018). The Visual Short‐Term Memory Binding Test (VSTMBT) identifies older adults who are accumulating AD pathology even though they are otherwise cognitively unimpaired (Parra et al., 2024). We investigated whether community dwellers from different socioeconomic groups above their 60s and displaying subtle VSTMB impairments also present neuropsychological profiles compatible with dementia risk.

Methods

A sample of 235 community‐dwelling older adults were assessed with an extensive neuropsychological battery (Bonilla‐Santos et al., 2023) and a sensitive scale of functional abilities (T‐ADLQ; (Muñoz‐Neira et al., 2012). We divided the sample following recent recommendations drawn from the VSTMBT (Parra et al., 2024). We found that out of the total sample, 43 participants were classified as normal binders (performance on two VSTMBT above cut‐off), 99 were classified as suspicious binders (performance on at least one VSTMBT below cut‐off), and 93 were classified as weak binders (performance on both VSTMBT below cut‐off).

Results

Group comparisons revealed that relative to normal and suspicious binders, weak binders have poorer performance on cognitive screening tools (MMSE, F(2,230) = 4.01, p = 0.019; ACE‐R F(2,230) = 3.4, p = 0.035) and functional scales (T‐ADLQ, F(2,230) = 4.53, p = 0.012). Such effects were unaccounted for by years of education, gender, socioeconomic status, comorbidities, or toxic habits. Age was a significant predictor with weak binders being older (F(2,234) = 6.31, p = 0.002). Assessment of subjective cognitive experiences (SCD) revealed no group effects (F(2,202) = 0.57, p = 0.566). Standard neuropsychological tests from the CERAD revealed marginal group effects for variables previously acknowledged as markers of AD.

Conclusions

The VSTMB test identified AD risk profiles in community‐dwelling older adults from an underserved population. The fact that such a test proved insensitive to gender, education, socioeconomic status, comorbidities and toxic habits, suggests that this assessment tool can be reliably used to identify, in community settings, older adults who are at risk of dementia even if they have not yet complained about their cognitive abilities or sought medical help.
Remote Naturalistic Speech Analysis as a Tool to Classify Behavioral Variant Frontotemporal Dementia
Authors: Vonk Jet M. J. , Morin Brittany T. , Dhanam Sreya , Clark Annie L. , Young J. Clayton , Taylor Jack C. , Rosado‐Rolon David , Heuer Hilary W. , Forsberg Leah K. , Boeve Brad F. , Rosen Howard J. , Tempini Maria Luisa Gorno , Boxer Adam L. , Staffaroni Adam M.
Published: January 2025

Background

Frontotemporal dementia (FTD) is a diverse spectrum of neurodegenerative disorders impacting the frontal and temporal lobes, primarily manifesting as behavioral and/or language issues. Accurate diagnosis is crucial for effective management, potential treatment, and care planning. While speech analysis has shown promise in detecting cognitive markers of Alzheimer’s disease (AD), its exploration in FTD is limited. This study examined if linguistic features from remote, app‐based speech collection can differentiate healthy controls (HC) from individuals with behavioral variant FTD (bvFTD), the most common FTD variant.

Method

Participants included 15 bvFTD (mean age = 64.3, SD = 9.1 years) and 19 HC (mean = 55.8, SD = 14.2) from the ALLFTD Consortium. Participants were prompted to talk freely about a happy memory; audio recordings were collected with the ALLFTD Mobile App, transcribed using OpenAI’s large Whisper model, and manually quality‐checked. We extracted 98 linguistic features using our in‐house pipeline (Fig 1). Features were selected for classification analysis if they differed between groups based on a MANCOVA adjusted for age, sex/gender, and education, with feature reduction in case of collinearity. We then determined if these features could classify groups using multi‐variable logistic regression models, and subsequently calculated its ROC‐AUC score to measure sensitivity/specificity.

Result

Based on the MANCOVA, three features were selected for classification analysis: average seconds of non‐speech (i.e., silence), ratio of number of complex nominal clauses to total clauses, and number of restarts (i.e., disfluency). The logistic model showed that this set could distinguish between groups (Omnibus p = .001; Nagelkerke R2 = .499), and their saved prediction probabilities indicated a ROC‐AUC score of 84.8% accuracy (Fig 2).

Conclusion

Leveraging a flexible speech capture app with remote accessibility and state‐of‐the‐art automated speech analysis, we identified linguistic features that can distinguish HC from bvFTD. This approach presents a promising screening tool for detecting bvFTD, offering quick, easily administered assessments with the potential for scalable implementation outside of clinical settings. Next steps are to investigate linguistic changes in presymptomatic mutation carriers and compare speech profiles between FTD and AD. These results hold meaningful implications for addressing current challenges in FTD therapeutics, potentially offering sensitive outcome measures for clinical trials and future tools for personalized cognitive assessment and long‐term monitoring.
Effect of administration of vitamin D3 alone or combined with donepezil on the memory of adult and aged ovariectomized rat
Authors: Danielski Lucineia , Medeiros Eduarda Behenck , Zabot Gabriel Casagrande , Vargas Adrielly , Fenilli Gabriela Piovesan , De Jesus Laura Ceolin , Silveira Gustavo De Bem , Giridharan Vijayasree V , Barichello Tatiana , Budni Josiane
Published: January 2025

Background

The increasing prevalence of neurodegenerative diseases, particularly among women post‐menopause, is linked to the decline in 17 β estradiol (E2). Vitamin D deficiency, common in older individuals, exacerbates this risk due to its anti‐inflammatory and neuroprotective properties. Hypovitaminosis D is associated with age‐related conditions, including cognitive decline. Donepezil, an acetylcholinesterase inhibitor used for Alzheimer’s dementia, targets cholinergic dysfunction in normal aging and prodromal states of this disease, suggesting a potential intervention for early disease modification.

Method

Adult female Wistar rats aged 60 or 120 days were used, submitted to ovariectomy (OVX) for 1, 4, or 8 months, supplemented with vit D, at doses of 42 and 420 IU/kg, or water or combined with DONE (1 mg/kg) orally by gavage for 21 days. The open field test (OFT) and Y‐maze test were performed.

Result

Ovariectomized rats at 60 and 120 days of age exhibit deficits in short‐term spatial reference memory, as evidenced by performance in the Y‐maze task. In the OFT, 60‐day‐old rats subjected to OVX for four months displayed impairment, a trend also observed in rats of the same age undergoing OVX for eight months, both in the control and OVX groups. Notably, 120‐day‐old rats subjected to OVX for 4 and 8 months failed to learn, along with their respective control groups. However, the majority of interventions successfully reversed these memory impairments, with particular efficacy observed in treatments involving vitamin D at 42 IU/kg and the combination of vitamin D with DONE.

Conclusion

Memory impairment occurs as a result of ovariectomy (OVX). This effect persists with aging, and vit D, either alone or in combination with DONE, emerges as a significant alternative for reversing or mitigating this cognitive decline.
Exploring selective neuronal vulnerability in Alzheimer’s disease – key pathways are downregulated in vulnerable subpopulations of RORB and CDH9 excitatory neurons of the entorhinal cortex at Braak 0
Authors: Soloviev Alexander V. , Pereira Felipe Luiz , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Leng Kun , Kampmann Martin , Grinberg Lea T.
Published: January 2025

Background

Understanding the molecular mechanisms underlying selective neuronal vulnerability is crucial for developing effective treatments for Alzheimer’s disease (AD). Our group has shown that RORB/CDH9‐positive excitatory neurons in the entorhinal cortex (EC) display selective vulnerability as early as Braak stage (BB) 2. However, not all RORB/CDH9‐positive neurons are vulnerable. By further leveraging single‐nucleus RNA sequencing (snRNA‐seq) data, we aimed to identify molecular signatures of selective neuronal vulnerability. This involved comparing resilient‐like subpopulations (BB0 cells with RNA expressions similar to BB6) and vulnerable‐like subpopulations (BB0 cells with different RNA expressions than BB6) within each RORB and CDH9 subpopulation.

Method

Bioinformatic analyses were conducted using the Seurat R library on a published snRNA‐seq dataset of isolated nuclei extracted from the EC of postmortem brain tissue from healthy controls and AD patients (BB0 [n = 3], BB2 [n = 4], and BB6 [n = 3]) (Fig. 1). The Wilcox statistical test (p‐adjusted <0.05) was applied throughout the FindMarkers function to identify differentially expressed genes (DEGs) on vulnerable‐ and resilient‐like cells.

Result

From the original dataset, with EC excitatory neurons (11488 nuclei), we found one RORB‐ and two CDH9‐positive (CDH9.2 and CDH9.9) vulnerable‐like neuronal subpopulations (Fig. 1). In RORB neurons, downregulated genes are involved in insulin signaling, autophagy, and ErbB signaling pathways (Fig. 2A). In CDH9.2 neurons downregulated genes are involved in membrane trafficking, axon guidance, proteasome‐mediated ubiquitin‐dependent protein catabolic process, and protein polyubiquitination (Fig. 2B). Additionally, in CDH9.9 neurons downregulated genes are involved in membrane trafficking, Ras protein signal transduction, GTPase activator activity, and ubiquitin‐like protein ligase binding (Fig. 2C). These three susceptible subpopulations share eight downregulated genes, some of which are highly involved in the Heme Biosynthetic Process. Heme is a common element linking various metabolic disruptions in AD, including oxygenase, mitochondrial dysfunction, and inhibition of muscarinic acetylcholine receptor binding.

Conclusion

Our analyses suggest that changes in metabolic, ubiquitin‐proteasome, and cell growth/survival pathways occur in vulnerable‐like cells of the EC in BB0. Therefore, these pathways may be potential therapeutic targets in the earliest stages of AD. By looking into younger cohorts, we will further investigate if the molecular differences between these neuronal subpopulations are canonical (indicating a pathological predisposition) or an early pathological response.
Contribution of neuropathological changes to cognitive decline in late life; The 90+ Study
Authors: Yu Jiaxin , Woodworth Davis C. , Bukhari Syed A. , Ezzati Ali , Montine Thomas J. , Kawas Claudia H. , Corrada María M. M. , Qian Tianchen , Sajjadi S. Ahmad
Published: January 2025

Background

Cognitive impairment and dementia in late life are often due to co‐occurrence of multiple neuropathologic changes (NC) leading to multiple etiology dementia (MED). Our aim was to assess the contribution of these NCs by first studying the shape of cognitive trajectories in the absence of pathology and then to capture the association between longitudinal change in cognition and multiple common age‐related NCs in an oldest‐old cohort.

Method

415 participants from The 90+ Study with longitudinal evaluations and autopsy data were included. The following criteria were used for NC presence: moderate or severe likelihood of Alzheimer’s disease NC (ADNC) according to NIA‐AA criteria; hippocampal or cortical limbic‐predominant age‐related TDP‐43 encephalopathy (LATE‐NC); presence of hippocampal sclerosis; limbic/neocortical Lewy bodies disease (LBD); moderate/severe scoring for cerebral amyloid angiopathy (CAA), atherosclerosis, and arteriolosclerosis, and ≥2 microvascular lesions (MVLs). We considered longitudinal scores of the clinical dementia rating sum of boxes (CDR‐SB), global cognition measured by mini mental state examination (MMSE), and composite scores for 6 cognitive domains (Figure 1). We quantified the time‐varying relationship between each of clinical and cognitive measures, as outcome, and the neuropathologic changes, as independent variables, using varying‐coefficient mixed effects models that can identify nonlinear relationships and account for within‐subject repeated measures. The models were adjusted for age at death, sex, and education.

Result

Table 1 summarizes the demographic and neuropathologic characteristics of the participants. Mean age at death was 97.2, 68% were female, and 50% were college graduate. Most NCs were significantly more frequent in the dementia group. Figure 1 shows the trajectories of CDR‐SB and various cognitive domains in a hypothetical individual with no NCs. Attention and executive function showed early decline while CDR and cognitive domains showed an NC independent decline around five years before death. Figure 2 demonstrates the significant associations of NCs with decline in CDR‐SB and cognitive domains. LATE‐NC was the strongest predictor of CDR and cognitive outcomes closely followed by ADNC, HS, LBD, and MVL.

Conclusion

Our results demonstrate the contribution of various NCs to trajectories of cognitive outcomes in the oldest old and highlight the importance of non‐Alzheimer’s NCs in this age group.
Association Between Incident Neuropsychiatric Symptoms and Cognitive Decline in Cognitively Unimpaired Older Adults
Authors: Kim Therese H , Head Elizabeth , Stark Craig EL , Sordo Lorena , Sultzer David L
Published: January 2025

Background

Neuropsychiatric symptoms (NPS) are highly prevalent in older adults. While the association between NPS and cognitive decline in older adults is widely acknowledged, there remains a lack of specificity regarding emerging NPS and cognitive outcomes in cognitively unimpaired older individuals. Our study assessed the incidence of NPS development, its link to cognitive decline, and other factors associated with development of MCI among cognitively unimpaired older adults without NPS at baseline.

Method

Utilizing data from the UCI ADRC cohort, we included cognitively unimpaired participants without neuropsychiatric symptoms at baseline, followed longitudinally for at least 5 years. Comprehensive clinical assessments and expert diagnostic classifications occurred annually. NPS were evaluated using the Neuropsychiatric Inventory (NPI), the Mild Behavioral Impairment Checklist (MBI‐C), and the Geriatric Depression Scale (GDS). Demographic characteristics, cognitive test scores, ApoE genotype, CSF pTau181 level, and progression to MCI were compared between NPS developers and non‐developers. Logistic regression analysis, with progression to MCI as a dependent variable, was employed to explore factors influencing the likelihood of cognitive decline.

Result

Participants were followed for an average of 8.4 years. The rate of NPS development was 32.4%, and 13.1% of participants progressed to MCI. There was no significant difference in demographic characteristics, baseline cognitive test scores, or biological markers between NPS developers and non‐developers. NPS developers exhibited a significantly higher rate of progression to MCI compared to non‐developers (24.6% vs. 7.6%, p = 0.002). In logistic regression analysis to predict progression to MCI, NPS development emerged as the most significant factor (OR = 5.209, p<0.001), followed by high CSF pTau181 level (OR = 1.122, p = 0.012), ApoE4 carrier status (OR = 2.928, p = 0.027), and low 5‐minute recognition score on the CERAD Word List Test (OR = 0.405, p = 0.029).

Conclusion

These findings underscore the importance of assessing cognitive change in cognitively unimpaired older adults with recent‐onset NPS. Additionally, they indicate the potential benefits of combining NPS assessments with biological markers and cognitive test scores to predict those at risk of cognitive decline. These results further support the role of NPS in the pathophysiology of cognitive decline.
Correlation between changes in apathy and cognition in Alzheimer’s disease associated apathy: analysis of the Apathy in Dementia Methylphenidate Trial 2 (ADMET 2)
Authors: Sankhe Krushnaa , Tumati Shankar , Perin Jamie , Rivet Luc , Vieira Danielle , Rosenberg Paul B. , Herrmann Nathan , Shade David , Lerner Alan J. , Padala Prasad R , Brawman‐Mintzer Olga , van Dyck Christopher H. , Porsteinsson Anton P. , Craft Suzanne , Levey Allan I. , Mintzer Jacobo , Lanctôt Krista L.
Published: January 2025

Background

Apathy in Alzheimer’s disease (AD) is associated with cognitive impairment, particularly executive functions such as selective attention, making it unclear whether apathy should be a separate treatment target. Apathy in Dementia Methylphenidate Trial 2 (ADMET 2) is the largest and most recent trial assessing apathy and cognition. This analysis assessed whether changes in apathy correlated to changes in various cognitive domains in ADMET 2.

Method

In this multicentre, randomized, placebo‐controlled trial, 200 participants with mild to moderate AD received 20 mg methylphenidate (MPH) or placebo (PLB) for 6 months. The Neuropsychiatric Inventory apathy (NPI‐A) subscale measured apathy. Cognitive tests included Mini‐Mental State Exam (MMSE), Hopkins Verbal Learning‐immediate (HVLT‐I) and delayed (HVLT‐D), Digit Span forward (DF) and backward (DB), Trail Making (TMT A and B), Action Verbal Fluency (AV), Category Fluency (CF), and Boston Naming Test (BNT). Linear mixed models were conducted with cognitive change scores as the dependent variable and time and change in NPI‐A as the independent variable, overall and in each treatment group. All models were adjusted for baseline cognitive test score and NPI‐apathy, age, sex, diabetes, and treatment group.

Result

199 ADMET 2 participants (131 (66%) male) were included. For all participants, worsening apathy was associated with worsening MMSE (B (SE) = ‐0.10 (0.03), p = 0.003), CF (B (SE) = ‐0.13 (0.04), p = 0.0009), and HVLT‐I (B (SE) = ‐0.13 (0.05), p = 0.005). In the MPH group (n = 98), worsening apathy was associated only with worsening CF (B (SE) = ‐0.21 (0.06), p = 0.0008). In the PLB group (n = 101), worsening apathy was associated with worsening MMSE (B (SE) = ‐0.13 (0.05), p = 0.006), HVLT‐I (B (SE) = ‐0.30 (0.06), p = 0.000002), and HVLT‐D (B (SE) = ‐0.06 (0.02), p = 0.002). Changes in apathy were not associated with performance on the remaining cognitive tests.

Conclusion

Changes in apathy are associated with changes in cognition as part of the natural history of AD. However, this association is disrupted by MPH treatment and suggests that improvements in apathy in AD with MPH were not driven by cognitive changes. These results are consistent with the view that apathy as a syndrome is related to, but distinct from cognition.
Gender differences in the association of depressive symptoms with neuroimaging outcomes in the LifeAfter90 Study
Authors: Posis Alexander Ivan B. , Lor Yi , George Kristen M. , Gilsanz Paola , Maillard Pauline , Decarli Charles , Kawas Claudia H. , Corrada María M. M. , Whitmer Rachel A.
Published: January 2025

Background

Depressive symptoms are associated with reduced brain integrity. However, it is unclear if this association holds among a racially and ethnically diverse population aged ≥90 years and if there are differences by gender.

Method

The LifeAfter90 Study enrolled 212 long‐term members of Kaiser Permanente Northern California who were ≥90 years old, without dementia diagnosis, and received neuroimaging via 3T MRI. Depressive symptoms were measured using the 15‐item Geriatric Depression Scale (GDS). Neurodegeneration outcomes included volumetric measures (residual values accounting for total cranial volume) of total and bilateral hippocampus, regional cortical volume, and lateral and third ventricular volume, as well as amyloid PET, quantified as mean SUVR and amyloid positivity. Vascular injury outcomes included fractional anisotropy, free water, and log‐transformed total white matter hyperintensities. We used multivariable linear or logistic regression models to estimate associations between GDS and MRI outcomes adjusted for age at neuroimaging scan, gender, race/ethnicity, and education. We assessed effect measure modification by testing a gender‐by‐GDS interaction and gender‐stratified models.

Result

Participants had a mean age of 93.1±2.2 years, 58% were women, 22% African American/Black, 27% Asian, 17% Hispanic/Latino, 28% White, and 5% Other/Multiracial. Average GDS score was 2.1±2.0 (women = 2.1±2.1; men = 2.1±1.9), and 16% had scores ≥4 (range = 0‐11), which suggests significant depressive symptoms. While increased GDS scores generally trended with poorer neuroimaging outcomes (e.g., βFrontal Cortex = ‐0.29, 95% CI ‐0.88,0.30; except for occipital cortex volume, third ventricle volume, or vascular injury outcomes), associations were not significant in unadjusted (Figure) or multivariable models (p’s>0.05). There were differences by gender for third ventricle volume (p‐interaction = 0.01), such that increasing GDS scores were associated with lower third ventricle volumes among men only (β = ‐0.06; 95% CI ‐0.11,‐0.01). Increased GDS was associated with higher lateral ventricle volume among women only (β = 1.24; 95% CI 0.01,2.46), however the gender‐by‐GDS interaction was not significant (p‐interaction = 0.13).

Conclusion

In this study of diverse adults aged 90+, increased depressive symptoms were associated with lower third ventricle volume among men and higher lateral ventricle volume among women. Results support future longitudinal study to understand change in neuroimaging outcomes that may be impacted by depression and gender among the oldest‐old.
Comparing Psychometric Characteristics of a Computerized Cognitive Test (BrainCheck‐Assess) against the Montreal Cognitive Assessment (MoCA)
Authors: Huynh Duong , Ghomi Reza Hosseini , Huang Bin , Patterson Mary
Published: January 2025

Background

Previous validation studies demonstrated that BrainCheck Assess (BC‐Assess), a computerized cognitive test battery, can reliably and sensitively distinguish individuals with different levels of cognitive impairment (i.e., normal cognition (NC), mild cognitive impairment (MCI), and dementia). Compared with other traditional paper‐based cognitive screening instruments commonly used in clinical practice, the MoCA is generally accepted to be among the most comprehensive and robust screening tools, with high sensitivity/specificity in distinguishing MCI from NC and dementia. In this study, we examined: (1) the linear relationship between BC‐Assess and MoCA and their equivalent cut‐off scores, and (2) the extent to which they agree on their impressions of an individual’s cognitive status.

Method

A subset of participants (N = 55; age range 54‐94, mean/SD = 80/9.5) from two previous studies who took both the MoCA and BC‐Assess were included in this analysis. Linear regression was used to calculate equivalent cut‐off scores for BC‐Assess based on those originally recommended for the MoCA to differentiate MCI from NC (cut‐off = 26), and dementia from MCI (cut‐off = 19). Impression agreement between the two instruments were measured through overall agreement (OA), positive percent agreement (PPA), and negative percent agreement (NPA).

Result

A high Pearson correlation coefficient of 0.77 (CI = 0.63 ‐ 0.86) was observed between the two scores. According to this relationship, MoCA cutoffs of 26 and 19 correspond to BC‐Assess scores of 89.6 and 68.5, respectively. These scores are highly consistent with the currently recommended BC‐Assess cutoffs (i.e. 85 and 70). The two instruments also show a high degree of agreement in their impressions based on their recommended cut‐offs: (i) OA = 70.9%, PPA = 70.4%, NPA = 71.4% for differentiating dementia from MCI/NC; (ii) OA = 83.6%, PPA = 84.1%, NPA = 81.8% for differentiating dementia/MCI from NC.

Conclusion

This study provides further validation of BC‐Assess in a sample of older adults by showing its high correlation and agreement in impression with the widely used MoCA.