bluuebunny/crossref_metadata_2025_split huggingface dataset:
NFT maturation and tau mediated neurodegeneration in Alzheimer’s disease with concomitant LATE
Authors: Arezoumandan Sanaz , Emrani Sheina , Capp Noah , Ohm Daniel T , Phillips Jeffrey S , McMillan Corey T , Lee Eddie B , Wolk David A , Irwin David J 
Published: January 2025

AbstractBackgroundLimbic predominant age‐related TDP‐43 encephalopathy (LATE) is a common co‐pathology in Alzheimer’s disease (AD) and is associated with advanced cognitive impairment and severe atrophy in limbic regions. In AD, various maturation stages for tau neurofibrillary tangles have been characterized and can be selectively marked by monoclonal tau antibodies, providing insight into disease progression. Indeed, AD tau pathology progresses from an early “paperclip” conformation, marked by the MC1 epitope to a C‐terminally truncated form of tau, marked by MN423 epitope. Moreover, MC1‐reactive inclusions in AD largely take the form of pre‐tangles/threads and are less prominent in patients with more advanced AD, where there is a higher burden of MN423‐reactive inclusions that largely take the form of extracellular ghost tangles. In this study we tested the hypothesis that hippocampal tau maturation is more advanced in AD with concomitant LATE compared to the pure AD.MethodIndividuals with neuropathological diagnoses of pure AD (N = 63) and AD+LATE (N = 66) were selected. Hippocampal sections were immunohistochemically stained with MC1 and MN423. We measured percent area‐occupied by tau pathology in CA1 of hippocampi by employing validated digital histopathology methods. Additionally, we used ordinal ratings (0‐3) of TDP‐43 pathology from adjacent sections to test the association between tau and TDP‐43 pathology in the AD+LATE group. We compared pathology burden between groups using linear regression models controlling for age, disease duration, sex, and Braak stage.ResultThere were lower levels of early conformations of tau detected by MC1 in the AD+LATE group in contrast to the pure AD group (p = 0.01). Moreover, we found a similar burden of late conformation of tau associated with ghost tangles between the AD+LATE and pure AD group (p = 0.2) (Fig. 1A). However, among individuals with AD+LATE, higher TDP‐43 pathology was associated with greater burden of MN423 immunoreactive tau (p = 0.03) (Fig. 1B).ConclusionThe presence of increasing TDP‐43 pathology in AD+LATE is associated with maturation of tau NFT and could potentiate tau‐mediated neurodegeneration.
Association between remote Traumatic Brain Injury and AD pathology, vascular injury, and cognitive decline among Veterans and non‐Veterans
Authors: Van Hulle Carol A. , Zylstra Hanna , Betthauser Tobey J. , Du Lianlian , Cole Aleshia , Cronin Katherine , Rivera‐Rivera Leonardo A. , Gleason Carey E. , Johnson Sterling C. , Zetterberg Henrik , Carlsson Cynthia M. 
Published: January 2025

AbstractBackgroundEach year, millions of Americans experience mild traumatic brain injury (mTBI). Current research on the long‐term effects of mTBI vary considerably. Several mechanisms linking mTBI to dementia have been proposed including amyloid plaque formation and cerebrovascular injury following mTBI. Veterans have higher rates of mTBI than non‐Veterans. As efforts to increase Veteran enrollment in clinical trials and studies related to Alzheimer disease expand, it is critical to understand the potential impact of mTBI on cognitive ability and factors related to risk for AD. This study leveraged two cohorts to examine the association between history of mTBI and white matter hyperintensity lesion volume (WMLV), CSF pTau181, total tau, and Aβ42, and cognitive ability.MethodThe sample comprises, N = 131 VA eligible Veterans without memory impairment enrolled in the Brain Amyloid and Vascular Effects of Eicosapentaenoic Acid (BRAVE) clinical trial (NCT02719327) and N = 320 participants in the Wisconsin ADRC clinical core, including n = 36 identified as Veterans. BRAVE participants reported if they had experienced symptoms of mTBI (e.g. loss of consciousness, dizziness, headache). ADRC participants indicated if they had a recent or remote mTBI; participants with a recent mTBI were excluded (n = 6).CSF samples were assayed using elecsys® beta‐Amyloid(1_42) CSF II, phopho‐Tau (181P), and Total tau assays (Roche Diagnostics International, Switzerland) and log‐transfomed prior to analyses. WMHLV adjusted for TIV was binarized to WMH presence or absence. Separate Preclinical Alzheimer’s Cognitive Composite scores were created for BRAVE and were analyzed separately. Regression models included gender, age at study visit, clinical status and education level (PACC only) as covariates.ResultDemographics and study outcomes stratified by cohort and Veteran status are shown in Table 1 and 2. Veterans had higher rates of mTBI than non‐Veterans. History of mild TBI status was unrelated to study outcomes (see Figure 1; WMH presence: p = .06; CSF biomarkers: ps = .50 to .88; BRAVE‐PACC: p = .15, ADRC‐PACC, p = .48).ConclusionHistory of mild TBI had no long‐term impact on cerebrovascular dysfunction, AD biomarkers or baseline cognitive performance. Further analyses will explore severity of TBI (with or without loss of consciousness) on study outcomes as well asexamine the impact of mTBIon change in cognitive performance and biomarkers of neuroinflammation.
Cerebral and cognitive correlates of olfactory functioning in older adults at risk of Alzheimer’s disease: preliminary results from the CIMA‐Q Cohort
Authors: Jobin Benoît , Frasnelli Johannes , Boller Benjamin , Group CIMA‐Q 
Published: January 2025

AbstractBackgroundOlfactory identification is impaired in the early stages of Alzheimer’s disease (AD), including mild cognitive impairment (MCI). This early sensory impairment could result from several factors such as early cognitive or structural cerebral damages caused by the disease. It is however not clear which factors are contributing the most to the olfactory impairment in older people at risk of developing AD. The aim of this study was to explore and determine the cerebral and cognitive correlates of olfactory identification functioning in a cohort of older adults at risk of developing AD.MethodHere we report preliminary data on 16 participants with subjective cognitive decline (SCD) (mean age: 76.58, SD: 5.53) and 17 patients with MCI (mean age: 79.94, SD: 7.06) from the Consortium for the Early Identification of Alzheimer’s Disease‐Quebec (CIMA‐Q). Olfactory assessment was completed using the University of Pennsylvania Smell Identification Test (UPSIT), while episodic memory was assessed using the Logical Memory subtests of the Wechsler Memory Scale. All participants underwent a clinical examination and neuropsychological assessment. Further, grey matter volume (GMV) of olfactory‐related structures was extracted using CAT12 in a subgroup of 16 participants for whom MRI data were available.ResultThe UPSIT score was significantly correlated with the Logical Memory immediate recall score in the MCI group (r = .53, p = .03) but not in the SCD group (r = ‐.26, p = .33). No significant differences were found regarding olfactory identification between both groups (p = .75). Bilateral middle cingulate cortex (r = .51, p = .04) and caudate (r = .51, p = .04) GMV were correlated to the UPSIT score, while no significant correlation was found for other structures (p > .05).ConclusionThese preliminary data suggest that short‐term episodic memory, as well as GMV of middle cingulate cortex and caudate are related to olfactory identification in older adults at risk of AD. Future studies to validate these findings will incorporate more participants from the CIMA‐Q cohort.
Investigating the stability of SuperAging over time
Authors: Loxton Caitlin C , Fong Tamara G. , Jones Richard N , Marcantonio Edward R , Schmitt Eva M , Katsumi Yuta , Barrett Lisa F , Touroutoglou Alexandra , Dickerson Bradford C. , Inouye Sharon K. , Wong Bonnie 
Published: January 2025

AbstractBackground“SuperAgers” (SA) are older adults who perform significantly better than their peers and comparable to young adults on objective memory measures. Longitudinal studies show that many do not maintain their SA status over time. The fluctuation in SA stability may reflect changes in executive functioning, hypothesized to contribute to variance of episodic memory scores in SA. In the present study we analyzed longitudinal neuropsychological performance of SAs in the Selective Aging After Elective Surgery (SAGES) study to examine SA stability. We hypothesized that losing SA status over time will reflect a decline in executive function.Methods17 SAs (criteria defined by Katsumi, Wong et al., 2022) (mean age 75.4, 12 females) identified in the SAGES Study were tested annually (up to 84 months). Neuropsychological data for baseline and follow‐up at years 1, 2, and 3 were analyzed. Performance of SAs who no longer met SA criteria after baseline (non‐stable SAs) were compared to that of SAs who maintained their status (stable SAs). A mixed factorial ANOVA was run with Trail Making Test B (TMTB) scores as the dependent variable to determine differences over time between stable and non‐stable SAs.Results7/17 non‐stable SAs were identified. Analyses revealed a significant group x timepoint interaction [F(3, 39) = 3.152, p < 0.05]. Assessment of the coefficient of variation calculated across time points revealed that non‐stable SAs showed greater variability in TMB performance (M = 0.21, SD = 0.059) than stable SAs (M = 0.15, SD = 0.064). A significant difference was found between stable SA and non‐stable SA for TMT‐B performance [F(1, 13) = 13.237, p < 0.01. Both groups were similar in age at baseline (p < 0.19).ConclusionsThese findings suggest that current SA definitions need refinement as SA reflects more than superior memory. Ongoing analyses include 7‐year data from the current sample, replication of findings in an independent SA cohort, and examination of the neuroanatomical correlates of the observed differences between stable and non‐stable SAs. Enhancing our understanding of SAs will deepen our knowledge of resilience to decline in aging.
The Impact of Test‐Scoring Models on MCI Diagnosis
Authors: Woods David L. , Baldo Juliana , Hall Kathleen , Blank Michael , Geraci Kristin , Miranda Miranda , Chok Jas M. , Lwi Sandy J. , Jaramillo Isabella , Schendel Krista , Spinelli Maria G , Herron Timothy J , Johnson David K 
Published: January 2025

AbstractBackgroundCognitive‐test scores in the bottom 7% of a normative distribution (z‐score < ‐1.50) are an essential component of the diagnosis of Mild Cognitive Impairment (MCI). However, different patients show MCI‐compatible performance when evaluated using scoring models that account for the influences of different demographic variables (e.g., Age only, Age and Gender, Age, Education, and Gender). Most conventional models exclude many factors (e.g., vocabulary, comorbidities, race, functional impairment, emotional status, etc.) that correlate significantly with test scores. As a result, they reduce score precision, inflate racial disparities in MCI classification, and compromise the detection of MCI in high‐functioning individuals.Method415 older participants (mean age 70.1 years) completed three 90‐minute enrollment test sessions using the California Cognitive Assessment Battery (CCAB). Omnibus z‐scores were obtained by averaging z‐scores from 70 performance measures. Stepwise linear regression was used to identify factors that contributed significantly (p<0.01) to the solution, after outliers (typically ∼3% of scores) were eliminated. We compared MCI classification using unadjusted performance scores and models with different predictors including (1) Age, (2) Age and Gender; (3) Age, Education, and Gender (AEG), and (4) a Comprehensive model that included 15 demographic factors (see Table 1). All models were tested for heteroskedasticity, multicollinearity, and normality.ResultTable 1 shows Pearson correlations with omnibus z‐scores (averaged over test scores) of the 15 demographic factors included in the Comprehensive model. The five factors that contributed significantly (p< 0.01) and independently to the model were included in the final model solution. Figure 1 shows omnibus z‐scores calculated with AEG and Comprehensive models. Table 2 shows the model root mean squared error and the racial bias of MCI classification for each of four models, along with the percentage of patients with identical MCI classifications on the different models. Less than one‐third of participants with MCI‐level performance on the Comprehensive model showed MCI‐level performance on other models.ConclusionMCI classification is strongly influenced by the model used to score performance. Compared to other models, a Comprehensive model accounted for more variance, reduced racial bias in MCI classification, and identified different participants with performance in the MCI range.
Preservation amidst decline: wake‐promoting histaminergic system provides a novel target to mitigate sleep/wake dysfunction in Alzheimer’s disease
Authors: Satpati Abhijit , Pereira Felipe Luiz , Soloviev Alexander V. , Mladinov Mihovil , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Rodriguez Roberta Diehl , Paes Vitor Ribeiro , Walsh Christine M , Spina Salvatore , Seeley William W. , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Neylan Thomas C. , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundExcessive daytime sleepiness is a common and early symptom of Alzheimer’s disease (AD). The subcortical wake‐promoting neurons in the lateral hypothalamic area, tuberomammillary nucleus (TMN), and locus coeruleus synchronize to maintain wakefulness/arousal. Although significant neuronal decline occurs in wake‐promoting regions, the TMN histaminergic neurons remain relatively more intact than orexinergic and nor‐adrenergic neurons. The preserved histaminergic neurons could be a potential target for addressing sleep dysfunction when neurons in the wake‐promoting system degenerate. We aimed to map neuropathological and molecular events in poorly understood histaminergic neurons across AD progression in the human TMN to help understand pathogenic features and guide therapeutic strategies.MethodWe used unbiased stereology and double‐immunohistochemistry to quantify pTau (CP13) accumulation, the number of histaminergic, and total neurons in the TMN in subjects across progressive Braak stages (n = 20). Data were analyzed using the Wilcoxon signed‐rank test. We used a customized Neuropathology nCounter® (Nanostring) panel for proteomic analysis. Wald statistical test was used to compare the groups, and the genes were considered differentially expressed when the p‐value was <0.05.ResultTMN total neuronal count remained constant across Braak groups (BG), underscoring TMN’s resilience to AD compared to other wake‐promoting neurons. Histaminergic (HDC+CP13‐) neurons declined between BG 0‐2 and 5‐6 (p = 0.013). The number, proportion, and density of pTau inclusions in histaminergic and total TMN neurons increased across BG (p<0.05) (Fig. 1, Table 1). In Braak 5‐6 over 0‐2, we found 284 differentially expressed genes in TMN, of which 171 were upregulated. Gene ontology analysis demonstrated upregulation of cytokine‐cytokine receptor interaction pathways (p = 0.015). In Braak 5‐6 over 0‐2, histamine decarboxylase (HDC) expression was downregulated (lfc = ‐0.819, p = 0.37) with increased expression of histamine receptors HRH1 (lfc = 1.26, p = 0.028) and HRH2 (lfc = 1.76, p = 0.019) (Fig. 2).ConclusionStereological data revealed that the decline in histaminergic neurons is associated with pTau accumulation and reduced histamine synthesis rather than neuronal loss. This is corroborated by a decrease in HDC expression and an upregulation of histaminergic receptor expression (potentially compensatory) in late Braak stages. Interventions focused on pTau removal may succeed in reinstating histaminergic neuro‐transmission/‐modulation, improving cognition, and restoring sleep‐wake dysfunction in AD patients.
Behavioral and metabolic profiles in an aged, humanized APP/APOE mouse model of Alzheimer’s Disease risk
Authors: McLean John W. , Bhattrai Avnish , Brinton Roberta Diaz 
Published: January 2025

AbstractBackgroundResearch into Alzheimer’s Disease (AD) pathomechanisms frequently utilizes animal models with dominant mutations; however, the vast majority (>95%) of AD cases are idiopathic. Animal models with AD risk factors represent an approach with potentially greater translational validity. The predominant genetic risk factor for AD is the Apolipoprotein E ε4 (APOE4) polymorphism, with APOE4 homozygosity conferring approximately 15‐fold higher risk relative to the normative APOE3/3 genotype. Additionally, women are nearly twice as likely to develop AD. To address the translational validity of a risk factor model approach for AD research, we investigated behavioral and metabolic differences in a novel mouse model with homozygous expression of humanized (h) amyloid precursor protein (hAPP), encoding the precursor of the major protein in amyloid plaques, and replacement of murine Apoe with humanized hAPOE3 or hAPOE4.MethodAged (22‐24 months) hAPP/APOE3 and hAPP/APOE4 mice underwent open field (OF), novel object recognition (NOR), EchoMRI body composition analysis, fasting blood glucose (FBG) and ketone body (FKB) determinations. Data were analyzed by 2‐way ANOVA for effects of biological sex and APOE genotype followed by post‐hoc t‐tests and considered significant at p<0.05.ResultFemale mice traveled significantly farther and for a greater percentage of time during both OF and NOR, and interacted more with both familiar and novel objects during NOR. There were no group differences in either thigmotaxis or novelty recognition. EchoMRI body composition analysis revealed significant weight reduction in both male and female APP/APOE4 mice. While weight loss included a decline in both lean and adipose mass, greater loss of adipose tissue in APP/APOE4 mice resulted in lower body fat percentage and was the major contributor to weight loss.ConclusionMetabolically, female mice had lower FBG and higher FKB relative to males. The sex difference was greater in APP/APOE4 females, which had the lowest FBG and highest FKB. The hAPOE4‐driven reduction in body weight, especially in adipose tissue, further indicates a metabolic consequence in mice expressing the AD risk gene. Collectively, this program of research contributes to the determination of the translational validity of the humanized APOE and APP mouse model for preclinical target identification and therapeutic development for AD.
Brain Health Screening in Israel’s Diverse Population
Authors: Haddad Rafi , Ben‐Hayun Rachel , Ayoub Rawan , Natalya Yarovinsky , Shihada Essam , Shor Merav , Levavi Michal , Fisher Tali , Aharon‐Peretz Judith , Tanne David 
Published: January 2025

AbstractBackgroundIsraeli population is primarily comprised of Jews (74%) and Arabs (21%). Previous studies suggested a higher incidence of cerebrovascular risk factors (CVRF) and dementia among Israeli Arabs. We evaluated potential cognitive disparities between community‐dwelling Arabs and Jews diagnosed with at least one CVRF.Method96 participants (age: 66.6± 5.3; education: 14.8± 4.1), 52 Arabs (age: 64.4± 5; education: 15.3±2.6), and 44 Jews (age: 69.1± 4.4; education: 14.8± 4.1) without known cognitive impairment and with at least one CVRF were prospectively enrolled. All participant completed a cognitive symptoms questionnaire (in their primary language) and underwent the Montreal Cognitive Assessment (MoCA) and the Tablet‐based Cognitive Assessment Tool (TabCAT) Brain Health Assessment (BHA) battery, including the TabCAT Favorites (associative memory), Match (executive functions and processing speed) and Line Orientation (visuospatial skills) tasks. Demographic and clinical characteristics were analyzed using the Student’s t‐test for continuous variables and Chi‐squared tests for categorical data.ResultsArab participants were younger (p≤0.001) than Jews, education was similar (p = 0.26). Cognitive complaints were reported by 32 (33%) participants, (24% Arab,9% Jews). Participants with cognitive complaints exhibited significantly lower scores on Match (p = 0.005), but not on Favorites (p = 0.28), Line Orientation (p = 0.48), and MoCA (p = 0.62). Arabs scored significantly worse on Match (p = 0.006) while Jews scored worse on Line Orientation (p = 0.004). Performance was similar on the Favorites (p = 0.4) and MoCA (p = 0.2). When focusing on participants with cognitive complaints Arabs exhibited significantly lower scores on Match (p = 0.036) while Jews had lower scores on Line Orientation (p = 0.06). No significant differences were observed on Favorites (p = 0.4) or MoCA (p = 0.2). Among participants without cognitive complaints no significant differences were observed between Jews and Arabs on Match (p = 0.29), Favorites (p = 0.99) or MoCA (p = 0.65). Jews had lower scores on Line Orientation (p = 0.04).ConclusionTabCAT‐BHA proved superior to MoCA in depicting subtle cognitive impairment in people with CVRF. Despite being younger, Arabs exhibited higher prevalence of cognitive complaints and were more impaired on executive functions while Jews on visuospatial tasks.
Multi Site Comparison of Participant Profiles in the South Texas Alzheimer’s Disease Research Center
Authors: Bosque Jennifer G Del , Wang Chen‐Pin , Fernandez Roman A. , Tanner Jeremy A. , Sullivan A. Campbell , Savoia Sarah E. , Parker Alicia S. , Salardini Arash , de Erausquin Gabriel A. , Goss Monica , Trevino Hector A , Patel Aishwarya N. , Katragadda Haritha V. , Seidl Amaya M , Saklad Amy R. , Werry Amy , Gonzales Mitzi M. , Pirela‐Mavarez Rosa P. , Mejia‐Arango Silvia , Lavigne Shannon , Hromas Gabrielle , Santiago‐Mejias Stephanie , Satizabal Claudia L , Hilsabeck Robin C. , Maestre Gladys E. , Seshadri Sudha , LaRoche Ashley 
Published: January 2025

AbstractBackgroundHispanic adults comprise 19% of the US population, yet <8% of Alzheimer’s Disease and Related Dementia (ADRD) research cohorts. Hispanic adults in the US are 1.5 times more likely to develop ADRDs compared to Non‐Hispanics. Considering the projected growth in Hispanics in the US, a >400% increase in ADRDs in this population is anticipated over the next twenty‐five years. Knowledge is limited on the prevalence and influence of social determinants of health (SDoH) and modifiable risk factors on cognition in ethnically diverse groups. The South Texas Alzheimer’s Disease Research Center (STAC, P30AG066546) is a collaboration between UT Health San Antonio (UTHSA) and UT Rio Grande Valley (UTRGV) with a primary aim to better understand ADRDs in Hispanic adults. Our objective is (1) to describe differences in SDoH, modifiable risk factors, and cognitive performance in cognitively unimpaired adults in STAC, and (2) to assess differences between sites to better understand the risk factors in ADRDs in Hispanics by location.MethodParticipants in San Antonio, Tx, and Rio Grande Valley, Tx completed cognitive testing and questionnaires of medical history, SDoH, and modifiable ADRD risk factors. The two sites were compared between sites with Wilcoxon and T‐Tests. Differences in neurocognitive performance was further assessed with linear regression adjusting for age, sex, and education.ResultCognitively unimpaired adults were enrolled at UTHSA (n = 180, mean(SD) age 71(10), 36% male, 47% Hispanic) and UTRGV (n = 45, age 63(12), 33% male, 71% Hispanic). Participants at UTRGV were younger and more frequently identified as Hispanic. Site differences were seen on Trails B (p < 0.001), and Number Span Total Forward (p = .001) and Total Backward (p = 0.009) after adjusting for age, sex, and education. Sites showed differences in risk factors including hyperlipidemia (p = <.001), hearing loss (p = .022), Sleep Apnea (p = .006), and alcohol use (p = .022). Other risk factors were similar across sites.ConclusionOverall, there were significant differences in the risk factors between locations, supporting the value of recruiting participants at both sites to assess the spectrum of risk factors and SDoH in Hispanic adults.