bluuebunny/crossref_metadata_2025 huggingface dataset:
The relationship between neighborhood disadvantage and the brain age gap
Authors: Martin Yolana C , Adluru Nagesh , Nair Veena A. , Prabhakaran Vivek , Alexander Andrew L , Johnson Sterling C. , Asthana Sanjay , Powell W. Ryan , Kind Amy J.H. , Bendlin Barbara B.
Published: January 2025

Background

Accelerated aging is strongly linked to adverse social exposome and accelerated aging of the brain may be a dementia risk factor. Machine‐learning can estimate the biological “brain age” from neuroimages, which provides complementary information to the chronological/calendar age. The difference between biological and chronological age is referred to as the “brain age gap.” The Area Deprivation Index is a metric representing 17 indicators of neighborhood level poverty, education, employment, and physical environment, and provides a robust measure of the social exposome. The purpose of this work was to test the relationship between neighborhood‐level disadvantage and accelerated brain aging using brain age gap estimates in a Wisconsin cohort.

Method

Brain age was estimated using T1‐weighted MR images from 1052 participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention or Wisconsin Alzheimer’s Disease Research Center studies. Brain age was estimated using a publicly available deep learning model called the two‐stage‐age‐network (TSAN) that was pre‐trained on >4000 scans from OASIS, ADNI‐I, and PAC‐2019 datasets. Average brain age was used when multiple images were available at the same time point. Participants’ addresses were geolinked to their statewide ranking of neighborhood disadvantage using a time‐concordant ADI. Participants were binned by quintile based on state ADI rank, where Quintile 5 comprised of participants with highest ADI (Table 1). In the analyses, Quintile 5 was compared to a grouped category of Quintiles 1‐4. A marginal means test was conducted on a fitted one‐way ANOVA model to assess differences in mean brain age gaps between Quintile 5 and Quintiles 1‐4. The ANOVA model used quintile as a fixed effect predictor variable of brain age gap and a random effect of participant ID to account for participants with multiple visits.

Result

The mean brain age gap for Quintile 5 was 0.96 years (‐0.79, 2.71), and for Quintiles 1‐4 was 0.27 years (‐0.12, 0.66) (Figure 1).

Conclusion

This analysis found that the mean brain age gap does not significantly differ between Quintile 5 and Quintiles 1‐4 (p≤0.45), however statistical power was low given very broad confidence intervals. Future work will test for longitudinal effects and incorporate a larger sample.
Biomarker Evaluation in Young Onset Dementia from Diverse Populations
Authors: Barragan Eden V. , Heuer Hilary W. , Nosheny Rachel L. , Camacho Monica R. , Navarra Krista , Aisen Paul S. S. , Rahman‐Filipiak Annalise , Roberts J. Scott , Ajayi Adeyinka , Byrd Desiree , Mindt Monica Rivera , Rabinovici Gil D. , Boxer Adam L.
Published: January 2025

Background

Early onset dementia (EOD) affects people at the peak of their personal and professional responsibilities and economic productivity. Alzheimer’s disease (AD) and Frontotemporal Dementia (FTD) are the most common EOD etiologies in Non‐Latinx White adults (NLW). Black and Latinx older adults bear a disproportionate burden of dementia compared to NLW, likely due to vulnerabilities that confer increased risk, such as cardiovascular factors, socioeconomic stressors, and structural racism. Little is known, however, about the prevalence and causes of EOD in Black, Latinx, and other diverse populations (DP) because most EOD studies have primarily recruited NLW individuals. Many barriers impede research participation in DP, but community‐engaged research (CER) strategies to collect diagnostic data, like blood‐based biomarkers and digital assessments, may increase access and convenience of research participation in DP.

Method

The BEYONDD study (www.beyonddproject.org), a new NIH‐funded study, is recruiting 200 DP individuals to evaluate the use of remote assessments and the impact of returning diagnostic information to participants as a more accessible research framework to understand the etiology of EOD in DP. Participants are recruited using CER strategies and screened via online platform for eligibility (age 40‐64, with concerns about cognitive or behavioral function). Participants complete the following procedures remotely and receive gift cards after completion: online questionnaires, self‐administered tablet‐based cognitive testing (Brain Health Assessment), and an in‐home blood draw for standard labs and plasma biomarkers of AD and neurodegeneration (Aβ and P‐tau217 ratios, NfL). Participants can learn their results remotely or in person. Participants are invited for more comprehensive onsite evaluation at one of 10 BEYONDD clinical centers, followed by appropriate referral to other NIH‐funded research programs.

Result

The study has recruited its first participants. Early participant feedback suggests that remote, accessible procedures may increase DP engagement and participation in EOD research. We expect substantial enrollment by July and will report initial results and plans for refinement of study procedures.

Conclusion

The importance of surmounting historic barriers to DP participation in EOD research is clear. We plan to build on the experience of this project to improve DP enrollment into ongoing and future observational research and clinical trials.
Characterizing plasma biomarkers of Alzheimer’s disease in three non‐human primate species: marmosets, titi monkeys, and capuchins
Authors: Rothwell Emily S. , Lau Allison , Sosnowski Meghan , Bales Karen L. , Brosnan Sarah , Silva Afonso C , Rizzo Stacey J Sukoff
Published: January 2025

Background

Studies of aging in non‐human primates are important to elucidate primate‐specific mechanisms underlying human aging, including pathological trajectories like Alzheimer’s disease (AD). Evidence of AD‐like brain aging has been reported across the primate order including amyloid beta (AB) deposits, but blood‐based biomarkers are less well‐studied. The goal of this project was to explore the use of validated assays for plasma biomarkers in two new non‐human primate species: coppery titi monkeys (Plecturocebus cupreus) and brown capuchins (Sapajus apella). We aimed to 1) assess the utility of the assay, 2) establish normative values, and 3) explore age‐related differences in biomarker levels. For each species, we assessed biomarkers sensitive to physiologic aging and pathological conditions including neurodegeneration/neuronal injury (neurofilament light chain, NfL), neuroinflammation (glial fibrillary acidic protein, GFAP), neuropathology (AB40, AB42, pathological tau).

Method

Plasma samples were obtained from males and females of adult common marmosets (Callithrix jacchus) (n=85), titi monkeys (n= 33), and capuchins (n=19), and evaluated using MesoScale Discovery (MSD): AB Peptide 4G8 Panel & Neurology Panel 1multi‐plex ELISAs. Samples from genetically engineered marmosets with early onset familial mutations in the presenilin 1 (PSEN1) gene were included as positive controls and benchmarks (Sukoff Rizzo et. al, 2023).

Result

AB40, AB42, Tau, GFAP, and NfL were detectable in plasma from titi monkeys and capuchins. Biomarker levels across ages of each species had comparative values and overlapping ranges with wildtype (WT) adult marmosets. Consistent with previous data PSEN1 knock‐in marmosets had the expected increase in plasma AB42 relative to WT, with some individuals of each species showing naturally elevated levels. For both marmosets and titis, NfL was found to increase with advancing age. Titi monkeys also showed increases in AB40 and GFAP with age.

Conclusion

The present data are the first to demonstrate normative values for plasma biomarkers of neurodegeneration, neuroinflammation, and neuropathology in capuchin and titi monkeys. Preliminary results show comparative values and aging trajectories across three species of non‐human primates. Ongoing studies are evaluating additional individuals and species, to longitudinally track aging which will facilitate understanding primate‐specific mechanisms underlying healthy human aging as well as AD.
Associations of cerebral amyloid and tau with neurocognitive performance: Findings from the 90+ Study
Authors: Fletcher Evan , Sapkota Shraddha , Martinez Oliver , Corrada María M. M. , Woodworth Davis C. , Sajjadi S. Ahmad , Decarli Charles
Published: January 2025

Background

Associations between cognition and brain markers of amyloid, tau, and neurodegeneration are poorly understood in the oldest‐old (>90 years) compared to younger populations. Prior work suggests that the link between neuropathology and cognition may become weaker in advanced old age, reducing the applicability of accepted biomarker cascade models of Alzheimer’s disease progression. Addressing this question in the oldest‐old is challenging, partly due to limited data and methodological challenges of neuroimaging analysis. In this study, we examine the associations of (1) cerebral amyloid and tau, (2) amyloid and cognitive performance, and (3) tau and cognitive performance, in the overall group and as stratified by amyloid positivity.

Method

Participants were from the oldest‐old cohort from the 90+ Study at University of California, Irvine (N=98; mean age at assessment=92.04 years; %female=53,). We used MRI‐free analyses of PET imaging to investigate the relations among amyloid (AV45), tau (AV1451) in Braak regions 1/2, 3/4 and 5/6, and cognitive measure (Mini‐Mental State Exam [MMSE]). Native PET images were warped directly to an appropriate PET template, yielding SUVRs computed using cerebellar reference means. Amyloid positivity used an SUVR cutoff of 1.11, computed over a standard index region. All regressions were controlled for age, sex, education, and Apolipoprotein E status.

Result

Group characteristics are in Table 1. In the amyloid positive group (N=61), we found significant associations for amyloid with tau in Braak 1/2 (p=0.03; Figure 1), and MMSE (p=0.045; Figure 2). Associations of MMSE with tau Braak regions varied (Braak 1/2: p=0.086, Braak 3/4: p=0.018, Braak 5/6: p=0.061; Figure 3). We observed no significant associations in the full cohort or in the amyloid negative group.

Conclusion

MRI‐free PET processing yielded results in the oldest‐old that are consistent with expected relations among amyloid, tau and cognition. Accurate SUVR measurement requires rigorous template registration and quality control. All significant associations occurred in the amyloid positive group, showing expected relations of amyloid to cognition and early Braak stage tau, and tau to cognition, consistent with accepted models. However, small sample size limited our findings. Further studies are needed to clarify the applicability of amyloid‐tau models in this age group.
Association between Default Mode Network Connectivity Compared Between Two Tau Tracers (Flortaucipir vs. MK6240) – HEAD Study
Authors: Karim Helmet T. , Povala Guilherme , Bauer‐Negrini Guilherme , Lussier Firoza Z , Pascual Belen , Gordon Brian A. , Lowe Val J. , Oh Hwamee , soleimani‐meigooni David N. , Rosa‐Neto Pedro , Jagust William J. , Klunk William E , Baker Suzanne L. , Pascoal Tharick Ali
Published: January 2025

Background

Default mode network (DMN) resting state connectivity has been correlated with heightened amyloid and tau – hallmarks of Alzheimer's Disease (AD). Tau is postulated to impact a meta‐temporal area including DMN‐associated regions like amygdala, entorhinal cortex, fusiform gyrus, parahippocampus, inferior temporal, and middle temporal gyrus. We recruited individuals with varying cognitive status to undergo resting state connectivity and imaging with two tau tracers (Flortaucipir and MK6240). We investigated the association between DMN connectivity and both global and regional (meta‐temporal) tau.

Methods

We studied 149 adults who were young cognitively healthy (n=10, 21‐25 years, 5F), older cognitively healthy (n=85, 50‐83 years, 51F), had MCI (n=43, 53‐84 years, 23F), or had AD (n=11, 62‐84, 6F). All individuals underwent resting state imaging and PET imaging with both Flortaucipir and MK6240 tau tracers. Resting data was preprocessed and DMN connectivity was estimated using bilateral posterior cingulate gyrus as region of interest. Tau tracer uptake was preprocessed (Pascoal. et al), and voxel‐wise standardized uptake value ratio (SUVR) was computed using inferior cerebellar gray matter as reference. We computed universal and meta‐temporal uptake for both tracers. We conducted four voxel‐wise associations between DMN connectivity and uptake in each tracer. We corrected for multiple comparisons using SnPM13 to estimate non‐parametric p‐values (10,000 permutations), we used a cluster forming threshold of p=0.001 and corrected for multiple comparisons by controlling the family‐wise error rate (FWE) at p=0.05.

Results

Greater universal Flortaucipir uptake was associated with lower within‐network DMN connectivity (bilateral posterior cingulate, precuneus, angular/supramarginal gyrus, and inferior parietal) but greater between‐network DMN connectivity (superior parietal, postcentral gyrus; Figure 1A). Greater universal MK6240 uptake was associated only with greater DMN‐cerebellum connectivity (Figure 1B). Greater meta‐temporal Flortaucipir was associated with lower within‐network DMN connectivity similar to universal uptake with addition of medial prefrontal cortex and middle temporal gyrus (Figure 2A). Greater meta‐temporal MK6240 was only associated with greater DMN‐superior parietal connectivity (Figure 2B).

Conclusions

These preliminary findings show that uptake using different tau tracers may lead to varying conclusions on association with connectivity. This may have implications for understanding the role of tau in altering resting state connectivity findings.
Plasma pTau217 Predicts AD and Disease Progression in a Diverse Cohort
Authors: Lah James J. , Roberts Blaine Russell , Watson Caroline M , Johnson Erik C.B. , Hales Chadwick M , Qiu Deqiang , Wingo Thomas S. , Seyfried Nicholas T , Jeromin Andreas , Levey Allan I.
Published: January 2025

Background

Plasma pTau217 detects AD pathology and show longitudinal changes dependent on baseline pathology. However, previous studies have been restricted to cohorts with limited diversity. We evaluated performance of plasma pTau217 in detecting AD and predicting disease progression in a diverse cohort from the Emory Goizueta ADRC.

Method

We analyzed plasma pTau217 levels using AlzPath antibody and the Simoa HD platform. The cohort includes 410 Controls, 100 MCI, and 249 AD cases with research consensus diagnoses, 38.4% self‐identified African American (AA) individuals, with a subset of 478 cases with CSF AD biomarkers. Baseline plasma samples were analyzed for accuracy in classifying diagnosis and predicting progression (i.e., Control to MCI or MCI to AD). Paired samples for 244 participants were used to determine longitudinal changes.

Result

In baseline samples, median pTau217 levels were 0.318 pg/ml in Controls, 0.678 pg/ml in MCI, and 1.151 pg/ml in AD. Differences between Control, MCI, and AD were significant (p<0.0001 for all pairwise comparisons) for the entire cohort and within self‐identified AA and White subgroups. Group comparison by race revealed lower pTau217 in AA vs. White individuals among Controls (0.297 vs. 0.351; p<0.0001) and AD (1.046 vs. 1.266; p<0.05) groups. In longitudinal samples, progressors had higher pTau217 at baseline compared to non‐progressors (Controls: 0.939 vs. 0.336, p<0.0001; MCI: 1.056 vs. 0.678, p=0.040). Plasma pTau217 increased across all longitudinal samples at 0.020 pg/ml/yr. Rate of increase in pTau217 was higher among those with AD at baseline compared to Control non‐progressors (0.077 vs. 0.017; p=0.035). No other group differences reached statistical significance but analysis was limited by small sample sizes.

Conclusion

Baseline plasma pTau217 levels are different among Control, MCI, and AD cases for AA and White individuals, and higher baseline levels are associated with higher rate of longitudinal increase and predict disease progression. However, AA individuals collectively have lower pTau217 levels than White individuals regardless of disease status. Self‐identifies racial differences in plasma pTau levels must be addressed when using cut‐points for both research and clinical applications.
Age‐related differences in the relationship between sleep quality and cortical thickness
Authors: Kim Hyun , Zhang Yisha , Huber Benjamin , Rueppel Elizabeth , Goldberg Terry E. , Lee Seonjoo ,   human connectome project
Published: January 2025

Background

While the association between sleep quality and brain health is well established, the role of aging in this relationship is largely unknown. This study aimed to examine the interaction between sleep and age on cortical thickness using samples from large‐scale cohort studies. Age was examined in both linear and non‐linear (quadratic) terms, in order to determine the presence of critical age ranges that may exhibit more significant sleep‐related brain structural changes.

Method

Sample included 700 adults (mean age 59.63 [age range 36‐90], 55.9% female) from the Human Connectome Project‐Aging (HCP‐A). Sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI). Magnetic resonance imaging (MRI) data was obtained from T1‐weighted structural images using a 3T scanner, and cortical thickness indices were derived using the FreeSurfer pipeline. The interaction between sleep and age on cortical thickness was tested using the moderation analysis using linear regression models, with sex, race, and use of sleep medication as covariates. The same analyses are planned on a separate dataset from the Nathan Klein Institute (NKI) cohort in order to replicate these findings.

Result

There was a significant interaction term between the PSQI and non‐linear age term (age2) on the insula (b=0.67, CI=0.03‐1.30, p=.04) and the middle temporal cortical thickness (b=0.58, CI=0.03‐1.13, p=.04), indicating that sleep quality may be associated with cortical thickness distinctly in different age groups. A visual examination of this relationship indicated that cortical thickness for individuals between the ages 53 and 78.

Conclusion

Age may have a significant role in the relationship between sleep and cortical thickness. Middle‐aged and older adults may be most vulnerable to sleep‐related changes in the brain structures. These findings will be tested using a separate dataset.
Prevalence of Oropharyngeal Dysphagia in Patients With Advanced Cognitive Impairment
Authors: de Miranda Souza Ana Carolina Borges , Morillo Lilian Schafirovits
Published: January 2025

Introduction

Patients with severe cognitive impairment, with the progression of the disease, show behavioral impairments, loss of functionality and, in many cases, swallowing changes (dysphagia). Dysphagia comes with serious complications that can cause health damage, such as malnutrition, dehydration and serious lung damage secondary to aspirations. Eating process goes beyond nutritional intake, as it has a social, cultural, behavioral, physical and cognitive component. OBJECTIVE: To correlate swallowing changes with the severity of symptoms that are present in patients with advanced cognitive impairment, monitored by the multidisciplinary team at an University hospital in the state of São Paulo.

Method

This is a longitudinal observational retrospective study, carried out through analysis of medical records of patients followed at the Advanced Cognitive Impairment Outpatient Clinic (ACCA) over a period of one year. A comparison was made between the swallowing functionality scale (ASHA NOMS) and clinical dementia rating sum of boxes score (CDR‐SB).

Results

The prevalence of patients with Alzheimer’s disease was 33.3% of the sample of this population, followed by mixed dementia (Alzheimer’s and vascular). In August 2022, 27.5% of patients had ASHA 6 or 7, 23.5% had ASHA 5, 47.1% had ASHA 4 or less and 25.5% of the patients had CDR 3 (sum of boxes 17). After a year, only 11.7% had ASHA 6 or 7 (normal and/or adapted swallowing), 33.3% of patients had ASHA 5 and 49% had ASHA 4 or less (needs restrictions and adaptations of consistencies, use of strategies, food supplementation and/or use of alternative feeding routes), despite dementias progression CDR 3 (sum of boxes 18) in 31.4% of the total amount. Comparing 2022 datas of ASHA and CDR scale, an inverse proportionality relationship was found with statistical relevance (p = 0.05), but this finding did not remain in 2023 (p = 0.73).

Conclusion

Oropharyngeal dysphagia is present in many cases of cognitive impairment and speech therapy assessment is essential to identify changes in swallowing, manage and make dietary adaptations aiming to maintain, for nutrition or comfort, a safe oral route, avoiding respiratory infections and, consequently, mortality.
Dynamics of Handwriting for Cognitive Assessment
Authors: Chavez Gabrielle , Thebaud Thomas , Butala Ankur , Dehak Najim , Moro‐Velazquez Laureano , Oh Esther S
Published: January 2025

Background

Previous studies have shown that motor dysfunction can be an indicator of AD. We measured the observable and dynamic characteristics of spirals drawn by people with AD.

Method

We instructed 23 AD and 40 healthy control (CTRL) participants to perform a range of handwriting tasks on a digital tablet using a pen. We instructed the participants to draw spirals in three different ways with: i) left hand; ii) right hand; iii) dominant hand while repeating the occlusive word “Pa‐ta‐ka.” From the drawing samples of 63 participants collected over multiple sessions, we computed 14 time‐independent, explainable features from the shape of the spirals and the dynamics of the drawings (duration, fundamental frequencies using Fourier transform etc.). Those features were compared between the two studied groups using Welch's t‐test with a false discovery rate (FDR) correction.

Result

Right Spirals

We found there is a significant difference (p‐value<0.01) for the Duration and Fundamental Frequency (FF) with respect to Origin vs Total Number of Points, and FF with respect to Center vs Total Number of Points. Furthermore, the Average Loop Speed is significant (p‐value<0.05).

Left Spirals

We found there is a significant difference (p‐value<0.05) for all features.

Pataka Spirals

Additionally, there is a significant difference (p‐value<0.05) for AD and CTRL participants concerning the Duration, Average Loop Speed, and FF Origin and FF Center.

All Spirals

We compared all spiral samples based on only their group type, either AD or CTRL. We found that all features resulted in a significant difference (p‐value<0.01).

Conclusion

Though there was no notable visual variation between AD and CTRL spirals, we did find there were significant differences among dynamical characteristics like duration, loop speed, and frequencies. We can conclude that AD participants tend to take longer drawing spirals which result in lower Average Speed per Loop than their CTRL counterparts. Additionally, the FF extracted from both groups indicate that higher frequencies are found in AD participants.
Patterns of Tau Deposition by Cognitive Subtype in the Alzheimer's Disease Neuroimaging Initiative
Authors: Scollard Phoebe , Gibbons Laura E. , Choi Seo‐Eun , Lee Michael L. , Klinedinst Brandon S , Trittschuh Emily H. , Mez Jesse , Saykin Andrew J. , Nakano Connie , Sanders Elizabeth , Lila Eardi , Risacher Shannon L. , Mormino Elizabeth , Smith Viktorija , Carlson Mackenzie L. , Young Christina B. , Crane Paul K. , Mukherjee Shubhabrata
Published: January 2025

Background

Cognitive subtypes of Alzheimer’s Dementia (AD), defined by a relative impairment in a particular domain of cognition, have previously been shown to be associated with patterns of gray matter atrophy. Here we assessed the association of these subtypes with patterns of tau deposition measured in vivo using tau PET imaging in the Alzheimer’s Disease Neuroimaging Initiative (ADNI).

Method

We included amyloid positive individuals with AD and Mild Cognitive Impairment (MCI). We selected the first diagnosis visit for AD and the most recent visit for MCI. Previously, AD individuals were categorized into AD‐Memory, AD‐Language, AD‐Executive, AD‐Visuospatial, AD‐Multiple domains, or AD‐No domain subtypes based on a relative cognitive impairment. These methods were extended to categorize MCI individuals. The AD/MCI‐Memory, AD/MCI‐Visuospatial, and AD/MCI‐No domain groups were large enough for our analyses. The tau PET scan closest to the subtyping visit was selected (median 49 days between scan and visit). Tau deposition for 35 brain regions (left and right sides averaged) were included as predictors. Separate five‐fold cross validated LASSO regressions were run for each of the three pairwise comparisons. Each model was repeated 100 times with different random fold selections to assess the stability of results.

Result

We included 240 individuals (118 AD; 122 MCI) in our analyses (Table 1). There was some variation in the chosen models across repetitions with the AD/MCI‐Visuospatial versus AD/MCI‐No domain comparison varying the most (Table 2). We limit interpretation to those regions that appeared in ≥70% of repetitions. The amygdala was consistently selected in all pair‐wise comparisons. Higher tau deposition in this region was associated with a higher likelihood of being in AD/MCI‐Memory. Higher tau deposition in the postcentral region was associated with a lower likelihood of being in AD/MCI‐Memory compared to AD/MCI‐Visuospatial. Coefficients on consistently selected regions in the AD/MCI‐visuospatial versus AD/MCI‐No domain comparison were small. Figure 1 summarizes the top results from our analyses.

Conclusion

We found heterogeneity in regional tau deposition among three cognitive subtypes. Future work will make use of additional cohorts with harmonized cognitive and imaging data. We plan to incorporate all cognitive subtypes and evaluate lateral asymmetry.
Impact of TDP‐43 co‐pathology on limbic cortical microstructure in Alzheimer’s disease: evidence from an autopsy‐confirmed cohort with in vivo diffusion MRI
Authors: Torso Mario , Ridgway Gerard R , Hardwidge Jamie , Hardingham Ian , Chance Steven A ,   National Alzheimer’s Coordinating Center,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2025

Background

TDP‐43 (TAR DNA‐binding protein 43) is one of the most frequently observed co‐pathologies in Alzheimer's disease (AD). Recognizing the diversity of pathological features in individuals with AD, including the presence of TDP‐43, may lead to more personalized and effective treatment approaches.

We investigate ante‐mortem cortical microstructural changes in MRI with subsequent autopsy confirmation of Alzheimer’s disease neuropathological changes (ADNC) with and without TDP‐43 comorbidity.

Method

Participants with ADNC and ante‐mortem MRI were obtained from the National Alzheimer's Coordinating Center (NACC; n=46) and the Alzheimer's Disease Neuroimaging Initiative (ADNI; n=8). Participants were grouped based on TDP‐43 presence (36 AD “pure” and 18 AD with TDP‐43). Thal phase, CERAD neuritic plaque assessment, Braak NFT, and combined ABC score, were used as AD neuropathological hallmarks. Cases with TDP‐43 ≥ Stage 2 were considered AD with TDP‐43.

Structural and diffusion MRI were used to calculate cortical diffusivity measures in five functional macroregions: Primary Sensory, Unimodal, Limbic/Proisocortex, Heteromodal and Primary Motor (Ffytche & Wible 2014, PMID:24936089; Mesulam 1998, PMID:9648540).

Cortical mean diffusivity and three minicolumn‐inspired cortical diffusivity measures were calculated: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+) (Torso et al. 2022, PMID:36281682).

Groups were characterized using clinical, demographic, and neuropathological data (see table). Differences in diffusion metrics were tested adjusting for interval between MRI scan date and autopsy date, scanner manufacturer, diffusion b‐value, age and sex, with FDR correction (pFDR<0.05).

Result

The Limbic/Proisocortex macroregion exhibited significantly higher AngleR (F1,36= 7.978; pFDR=0.04) in AD with TDP‐43 (AngleR mean 1.135) compared to the AD pure group (1.055).

Conclusion

Diffusion MRI can detect differences in cortical microstructure of AD with TDP‐43 co‐pathology, suggesting more extensive cortical damage in AD with TDP‐43 comorbidity that involves Limbic cortical areas (cingulate, entorhinal, parahippocampal, and temporal pole).

Consistent with previous findings regarding early cortical changes associated with amyloid deposition and neuroinflammation (Torso et al. 2022, PMID:36281682 Torso et al. 2323 PMID:37794477), the diffusion‐derived metric AngleR appears particularly sensitive to subtle effects, such as the impact of TDP‐43 in addition to ADNC.
White Matter Integrity of Age‐Related Hearing Loss and Cognitive Impairment
Authors: Nemati Samaneh , Arjmandi Meisam , Newman‐Norlund Roger , Newman‐Norlund Sarah , Fridriksson Julius
Published: January 2025

Background

Emerging research, underscored by the UK National Institute of Health and Care Excellence and the US National Institutes of Health, suggests that age‐related hearing loss (ARHL) is linked to the development of dementias such as Alzheimer's disease (AD). In this study, we aim to investigate the neural correlates of ARHL and cognitive impairments based on the changes in white matter (WM) microstructures in a population of non‐demented adults.

Method

129 participants (94 female) aged between 20‐79 years old (Mean = 51.35 ± 20.65) were recruited as part of the Aging Brain Cohort at the University of South Carolina (ABC@UofSC). Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). Hearing ability was evaluated by measuring pure‐tone thresholds (PTT) and words‐in‐noise (WIN) thresholds. Structural T1 weighted and diffusion tensor imaging (DTI) scans were administered, and data preprocessing was performed with our nii_preprocess automated pipeline, available for public use. Changes in the WM integrity were measured using fractional anisotropy (FA) and mean diffusivity (MD). Finally, we examined the relationship between DTI metrics (FA and MD) and hearing and cognitive performance using region‐of‐interest‐based regression analysis.

Result

Our investigation identified a constellation of brain regions where lower FA and higher MD were significantly associated with both poorer auditory and cognitive processing. Specifically, poorer cognitive performance, as reflected by lower MoCA total scores, was associated with lower FA and higher MD values across major interconnecting pathways, including superior longitudinal fasciculus, fornix, corona radiata, and splenium of corpus callosum. Individuals with poorer hearing sensitivity and difficulty in words‐in‐noise recognition showed reduced FA and increased MD in fornix, superior longitudinal fasciculus, optic tract, and corona radiata (anterior and posterior sections).

Conclusion

Our findings reveal that the integrity of the white matter tracts across multiple brain regions is correlated with both auditory and cognitive performance, suggesting that these tracts may underlie a shared neural substrate for hearing and cognitive processes. The identified brain regions offer promising neural targets for the early detection of ARHL and cognitive impairments, as well as potential neural substrates for applying effective intervention strategies aimed at reducing the risk of dementia.
ATN plasma biomarkers and digital cognitive performance in adults with type 1 diabetes: data from the GluCog study
Authors: Fonseca Luciana Mascarenhas , Beeri Michal S , Hawks Zoë W , Jung Laneé , Cleveland Michael , Delgado Nikki , Bulger Jane , Grinspoon Elizabeth , Janess Kamille , Sliwinski Martin J. , Weinstock Ruth S , Chhatwal Jasmeer P. , Kivisäkk Pia , Germine Laura Thi , Chaytor Naomi Sage
Published: January 2025

Background

Highly specific ATN plasma biomarker assays for neurodegenerative diseases have been developed, but their associations with cognition vary in different populations. Kidney disease, common in diabetes, may decrease the predictive precision of those biomarkers. The aim of this study was to characterize for the first time the relationships between plasma ATN biomarkers and cognitive function in adults with T1D.

Method

Adults with T1D mean age 49 years (range 19‐84), 53% female, mean HbA1c 7.6% who participated in the Glycemic Variability and Fluctuations in Cognitive Status in Adults with T1D study and had plasma β‐amyloid42/40, p‐tau181, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels measured using Quanterix, and p‐tau217 using AlzPath assays, were included (N=114). Self‐administered online cognitive tests (TestMyBrain.org) were used: Digit Symbol Matching (processing speed), Gradual Onset Continuous Performance (cognitive control, attention), Multiple Object Tracking (visual working memory); Vocabulary (verbal reasoning), Matrix (non‐verbal reasoning), Simple Reaction Time (psychomotor speed), Letter‐Number Switching (cognitive flexibility), Visual Paired Associates (visual memory), Flicker (working memory), and Paced Serial Addition Test (PSAT, working memory, attention). Bivariate correlation analyses between cognitive function and biomarkers were performed. Significant correlations after false discovery rate were re‐analyzed using linear multiple regression with biomarker assigned as outcome and cognitive function as predictors in separate models, adjusting for age, sex and education.

Result

All biomarkers were correlated with cognitive function in bivariate analysis. Multivariate analyses revealed that higher concentrations of ptau181 and GFAP were associated with longer reaction time for correct responses, PSAT (β=0.002, p=0.011 and β=0.057, p=0.012, respectively), and higher β‐amyloid42/40 concentration was associated with better vocabulary performance (β=0.028, p=0.009). Associations remained significant after including kidney‐related disease or other diabetes features as adjustments.

Conclusion

PTau181, GFAP and β‐amyloid42/40 were associated with cognitive performance in adults with T1D. Working memory speed was related to ptau181 and GFAP, suggesting it may be an early indicator of neurodegeneration in this population. The positive association between β‐amyloid42/40 and Vocabulary, a measure of crystalized cognitive ability, suggests protective mechanisms related to cognitive reserve. Investigation on ATN biomarkers and longitudinal cognitive decline is crucial for disentangling their role in T1D.
Serum Soluble CD14 is Associated with Insulin Resistance and Cortical Inflammation in Nonhuman Primates Consuming Western versus Mediterranean Diets
Authors: Frye Brett M. , Negrey Jacob D. , Sutphen Courtney L. , Craft Suzanne , Shively Carol A. , Register Thomas C.
Published: January 2025

Background

Diet composition is associated with neurodegenerative disease risk including Alzheimer’s Disease (AD). The adverse effects of Western‐style diets may be moderated, in part, by systemic as well as central inflammation, whereas the neuroprotective effects of Mediterranean diets may work through mechanisms that promote anti‐inflammatory phenotypes. Systemic inflammation also may induce insulin resistance, another risk factor for AD. However, controlled trials of human dietary patterns are not available nor has the impact of such diet patterns on systemic and central inflammation been examined in nonhuman primates.

Method

Here we determine the effects of long term (31 months) consumption of a Mediterranean (n=16) or Western (n=21) diet in cynomolgus monkeys (Macaca fascicularis). We examined relationships between the circulating marker of monocyte activation soluble CD14 (sCD14) and lateral temporal cortical transcriptional profiles associated with proinflammatory (Cyclin dependent kinase 14 [CDK14]), and anti‐inflammatory/neuroprotective (lunatic fringe [LFNG], mannose receptor C type 2 [MRC2], solute carrier family 3 member 2 [SLCA32], butyrophilin subfamily 2 member A1 [BTN2A1], katanin regulatory subunit B1 [KATNB1], transmembrane protein 268 [TMEM268]) transcripts. We also analyzed associations between sCD14 and insulin and glucose responses in an intravenous glucose tolerance test (ivGTT).

Result

On average, individuals in the Mediterranean diet group showed decreased signatures of monocyte activation, reflected by lower levels of circulating sCD14 compared to the Western group (mean difference±SE: 137.2±70.01, t=1.960, p=0.058). Serum sCD14 was negatively associated with anti‐inflammatory/neuroprotective brain transcripts: SL3CA2 (R=‐0.359, p=0.029), MRC2 (R=‐0.437, p=0.007), TMEM268 (R=‐0.304, p=0.067), BTN2A1 (R=‐0.300, p=0.071). sCD14 also was positively related to fasting insulin levels (R=0.401, p=0.021) and insulin area under the curve (R=0.350, p=0.046) in the ivGTT.

Conclusion

These results demonstrate relationships between sCD14, a circulating marker of monocyte activation, insulin resistance, and a neuroinflammatory transcriptional profile in the temporal cortex. Mediterranean diet consumption was previously shown in these subjects to significantly alter circulating monocyte profiles toward an anti‐inflammatory phenotype and to preserve insulin sensitivity relative to Western diet consumption. The findings support multisystem anti‐inflammatory effects of Mediterranean diet consumption which may be mediated via integrated pathways. This work captures the complex interplay of diet composition, insulin resistance, inflammation, and brain health.
p‐tau217 in a large Peruvian cohort phenotyped for Alzheimer’s Disease
Authors: Pandey Neetesh , Honig Lawrence S. , Reyes‐Dumeyer Dolly , Cieza Basilio , Montesinos Rosa , Cespedes Jennifer , Soto‐Añari Marcio F. , Custodio Nilton , Tosto Giuseppe
Published: January 2025

Background

Blood‐based Alzheimer's disease (AD) biomarkers have been increasingly employed for diagnostic and prognostic purposes, thanks to high diagnostic accuracy in distinguishing AD from healthy controls or other dementia types. p‐tau217 exhibits stronger associations with AD hallmarks in CSF and brain, compared to other p‐tau isoforms. Furthermore, the majority of these studies have been conducted in non‐Hispanic Whites, limiting our understanding of the performances and utility of these biomarkers across ethnicities.

Method

We employed a cohort of Peruvians from the GAPP study, a recently‐established cohort of Peruvian mestizos from Lima and indigenous groups from Southern Peru (Aymaras and Quechuas). We generated p‐tau ALZPATH217 in 561 samples, and tested the association between p‐tau217 and clinical diagnosis (healthy controls n=359 vs. AD n=92) using regression models adjusting for sex, age, education and study site. We also explored the biomarkers level in MCI (n=100). The receiver operating characteristics area under the curve (ROC‐AUC) was used to evaluate the biomarker’s classification performances.

Result

p‐tau217 was significantly associated with AD (higher quartile vs. lower quartile: OR=6.49 95%CI 2.91‐14.90) while it did not differ between controls and MCI (p=0.33; Figure 1). p‐tau217 levels were also increasingly higher in participants carrying one or two APOE‐e4 alleles (ANOVA p‐value<0.001). When classification accuracy was considered, the resulting ROC area for p‐tau217 was 74%.

Conclusion

To our knowledge, this is the largest study conducted in a Hispanic cohort phenotyped for AD with available p‐tau217. We confirmed the robust performances of the blood biomarker in a non‐White population; studies on Hispanic individuals with clinical AD diagnosis reported AUC as low as 52% vs. our robust finding of 74%. Previous investigations have mostly focused on highly selected cohorts with established AD‐endophenotypes (CSF, autopsies, PET etc.), while data on population cohorts with clinical assessment are currently lacking, especially in minoritized groups.
Attenuated neural activity in processing decision‐making feedback in uncertain conditions in patients with mild cognitive impairment
Authors: Zhang Mang , Zhang Ying , wang luchun , Zheng Yaonan , Li Huizi , Xie Yuhan , Lv Xiaozhen , Yu Xin , Wang Huali
Published: January 2025

Background

Individuals with mild cognitive impairment (MCI) have decreased cognitive function, which makes them prone to making inappropriate decisions in complex and uncertain situations. However, there is currently no study being undertaken to investigate the potential neural mechanisms for processing decision‐making feedback in MCI patients. The present study aimed to explore the potential neural correlates during feedback evaluation during decision‐making under risk and ambiguity in MCI.

Method

Nineteen individuals with MCI and twenty age‐matched HCs were enrolled. Decision‐making performance under risk and ambiguity was examined with the modified game of dice task (GDT) and an Iowa gambling task (IGT). Using task‐related EEG data, reward positivity (RewP) and feedback P3 (fb‐P3) were used to characterize participants’ motivation and allocation of cognitive resources. Also, response time and event‐related oscillation (ERO) was used to evaluate information processing speed, and the potent of post‐feedback information integration and behavioral modulation.

Result

MCI patients had lower RewP (p = 0.022) and fb‐P3 (p = 0.045) amplitudes in the GDT than HCs. Moreover, the amount and valence of feedback modulated the RewP (p = 0.008; p = 0.017) and fb‐P3 (p < 0.001; p < 0.001). In the IGT, in addition to the significantly reduced fb‐P3 observed in MCI patients (p = 0.010), the amount and valence of feedback modulated the RewP (p = 0.002; p = 0.020). Furthermore, MCI patients took longer to make decisions (t = 2.15, p = 0.041). The ERO analysis revealed that delta power was reduced in MCI (GDT: p = 0.045; p = 0.011).

Conclusion

The findings suggest that, during feedback evaluation when making risky and ambiguous decisions, motivation, allocation of cognitive resources, information processing and neuronal excitability were attenuated in MCI. It implies that neural activity related to decision making was compromised in MCI.
Association between Stress and White Matter Hyperintensity Volume in Diverse Populations: A HABS‐HD Study
Authors: Trammell Antoine R , Lah James J. , Parker Monica W , Goldstein Felicia , Hales Chadwick M , Davis Crystal P , Dorbin Cornelya D , Saleh Sabria , Murphy‐Tchivzhel Elizabeth , Rose Alecia Michella , Osborne Amber , Ahmad Adiva , Al‐Amin Jahmila , O'Bryant Sid E.
Published: January 2025

Background

Older African American (AA) and Hispanic American (HA) adults have a higher risk for Alzheimer’s disease and related dementias (ADRD) than older non‐Hispanic white (NHW) adults. Adverse experiences like stress and discrimination may contribute to the higher vascular disease burden observed in AA and HA persons. Cerebrovascular disease reflected by white matter hyperintensity (WMH) lesions on magnetic resonance imaging (MRI) may affect ADRD risk in older AA and HA adults. As stress may influence vascular disease and thus ADRD risk, this study explores associations between stress and WMH burden in a diverse cohort.

Method

We analyzed stress scores and WMH volume data from self‐reported NHW, AA, and HA participants in the Health and Aging Brain Study: Health Disparities. Data obtained at the baseline study visit includes the Clinical Dementia Rating (CDR), Chronic Stress Scale (CSS), Everyday Discrimination Scale (EDS), Penn State Worry Questionnaire (PSWQ), Geriatric Depression Scale (GDS), and MRI brain scans. With this data, we used global CDR scores (normal=0, impaired≥0.5) and race to create race/cognitive groups (white/normal, white/impaired, AA/normal, AA/impaired, HA/normal, HA/impaired). We compared baseline characteristics, stress and GDS scores, and WMH burden in the groups with ANOVA and chi‐square. Next, we performed linear regression adjusted for age, education, and sex to test associations between stress scores and WMH burden.

Result

Data from 3,035 participants was analyzed (mean age: 65.2; female: 62.3%; impaired: 20.1%). Compared to the NHW and HA groups, AA participants had higher CSS scores (NHW: 7.44, HA: 7.1, AA: 8.42, p=.0003), EDS scores (NHW: 5.59, HA: 6.2, AA: 9.47, p<.0001), and WMH volume (NHW: 4.16, HA: 3.18, AA: 18.4, p<.0001). The HA group had higher GDS scores (NHW: 4.86, HA: 6.71, AA: 5.61, p<.0001). Regression showed that higher EDS scores were associated with higher WMH volume in the AA/impaired (β=3.48, p=.02) and HA/impaired (β=.27, p=.002) groups.

Conclusion

Our results suggest that higher discrimination scores may be linked to higher WMH volume in older AA and HA adults with cognitive impairment. As vascular disease may contribute to their higher ADRD risk, further study of stress, microvascular brain disease, and ADRD risk is needed.
Evaluation of Type 2 diabetes mellitus, Alzheimer's disease, and olfactory dysfunction relationships
Authors: Gutierrez‐Malacara Andres‐Ivan , Gomez‐Virgilio Laura , Silva‐Lucero Maria‐del‐Carmen , Lora‐Marin Obed‐Ricardo , Cardenas‐Aguayo Maria‐del‐Carmen
Published: January 2025

Background

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and insulin resistance. Historically, it is linked to greater cognitive decline and risk of Alzheimer's dementia. Although deregulations in the insulin signaling pathway have been identified, further investigation is needed. Diabetic patients over 60 years of age, in addition to facing cognitive risks, show olfactory deficits like AD. Neuronal precursors in the olfactory epithelium (hONE NPCs) offer a valuable model for studying the connection between T2DM and AD. Nasal exfoliates and plasma samples were collected from diabetic patients with or without cognitive decline and healthy controls. Assessment of biomarkers, the insulin signaling pathway and the posttranslational modification OGlacNac were done.

Method

We divided our study groups into apparently healthy subjects (AHS), subjects with cognitive impairment (SMCI), subjects with T2DM without cognitive impairment (ST2DM), and subjects with type 2 diabetes with cognitive impairment (ST2DM‐SMCI). We obtained hONE NPCs cell cultures from the volunteers through a non‐invasive nose exfoliate, those cells were characterized by WB and ICC. We obtained blood samples for the detection of HbA1c and AD biomarkers. We performed MoCA Test, medical interview and an olfactory test for each volunteer.

Result

We isolated and cultured human hONE NPCs from a Mexican cohort of 60 individuals over 50 years old diabetic and nondiabetic with or without MCI. We collected clinical data, performed MoCA test, and an olfactory test, collected blood samples, and evaluated glucose levels to search for possible correlations among these variables.

Our results showed increased expression of IRS‐1 between control subjects (AHI) vs subjects with SMCI+ST2DM and a significant increase in OGlacNac of the IRS‐1 receptor between the control (AHI) group versus the SMCI and SMCI+ST2DM.

Conclusion

We obtained a positive correlation between the olfactory and MoCA test and a non‐significant trend of negative correlation between the MoCA score and the HbA1c. A significant increase in IRS‐1 expression between AHI vs. subjects with SMCI+ST2DM was detected, and a significant increase in OGlacNac of the IRS‐1 receptor between the AHI versus the SMCI and SMCI+ST2DM. Thus, the hONE NPC cells constitute an accessible model to study the relationship between T2DM, AD, and olfactory dysfunction.