bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative dissection of healthy aging using protein and peptide signatures from paired CSF and plasma
Authors: Shichkova Polina , Kamalian Aida , Tognetti Marco , Below Christopher , Bruderer Roland , Feng Yuehan , Lutz Michael W , Moghekar Abhay
Published: January 2025

Background

Despite age being the primary risk factor for Alzheimer's disease (AD), there remains a necessity for a thorough understanding of the distinct biological pathways affected in the course of healthy aging as opposed to the pathological aging that leads to neurodegeneration. As the genome remains constant throughout one's lifespan, it becomes crucial to unravel the impact of aging on the proteome. Proteins, being key players in various cellular functions, mediate the effects of environmental stimuli and epigenetic alterations. Moreover, despite the brain's protection by the blood‐brain barrier, emerging evidence suggests that systemic events like inflammation and metabolic dysfunction can significantly influence the risk of developing AD.

Method

Matched CSF and plasma samples were obtained from individuals at the same visit from the Neurology Clinic and Alzheimer’s Disease Research Center at Johns Hopkins. Samples were collected from young control subjects (n= 53), and healthy elderly subjects (n = 40). The plasma samples were depleted in 96‐well format using an automated MARS‐14 depletion system. The depleted plasma and neat CSF samples were subsequently processed to tryptic peptides and analyzed using data‐independent acquisition (DIA)‐mass spectrometry (MS). Data processing and analysis were performed using Biognosys’ Spectronaut software.

Result

Using our optimized discovery workflow, we analyzed the above‐described cohort of 93 matched plasma and CSF sample pairs. This resulted in more than 73254 quantified peptides (associated with > 4000 proteins) in CSF and 62750 quantified peptides (associated with > 2500 proteins) in plasma. The depth and breadth of protein quantification cover numerous pathological mechanisms such as AB and Tau pathology, synaptic dysfunction, neuronal injury, iron toxicity and inflammation. Harnessing the unique feature of MS‐based proteomics, we focused on the identification of differentially regulated peptides that are located in protein regions where known events such as alternative splicing, truncation or protease cleavage occur.

Conclusion

The peptide‐centric nature of our approach allowed us to assess a variety of post‐translational modifications, truncations and isoforms. We envision this unbiased profiling of proteoforms as a powerful tool to elucidate complex disease mechanisms.
Unmet Needs in the Diagnosis and Management of Early AD in Community‐Based Settings in the United States
Authors: Juday Timothy R , Holub Ashley A , Betts Keith A. , Mattke Soeren , Kitchen Sophie A , Liu Hongjiao , Malik Amyn , Batrla Richard , Frech Feride H , Khachaturian Ara S
Published: January 2025

Background

Disparities in the quality and timeliness of care for Alzheimer’s disease (AD) are well documented. This study assessed the impact of demographic characteristics on the diagnosis and management of early AD patients in community‐based settings.

Method

This cross‐sectional study abstracted medical chart data for patients aged 50‐89 years who had newly diagnosed early AD (mild cognitive impairment [MCI] or mild AD) within the past 2 years and a clinic visit within the past 12 months. Data collected included use of neurocognitive assessments, imaging/biomarker tests, laboratory tests, referrals, and treatments. Descriptive statistics were stratified by patient age at diagnosis, sex, race, and residence.

Result

A total of 1284 early AD patients (817 MCI/467 mild AD) had a mean age at diagnosis of 70 years, 43% were female, 31% were non‐white, and 17% were rural. The number of visits from initial complaint to diagnosis was lower (2.6 vs 3.0, p<0.001), and time to referral consult was faster (20.9% vs 54.4% waited ≥4 months, p<0.001) for patients ≥65 relative to <65 years. Biomarker/imaging tests were also more common (78.2% vs 72.4%, p<0.05), and beta‐amyloid medications were less frequently prescribed (3.0% vs 15.6%, p<0.001). Practices were similar for female and male patients. Non‐white patients had a longer time to diagnosis (5.5 vs 4.6 months, p<0.01) and were less likely to receive any neurocognitive assessments (80.1% vs 85.5%, p<0.05) than white patients. APOE‐e4 testing was more often used in non‐white patients (20.9% vs 17.5%, p<0.01). Urban/suburban patients were more likely to receive the ADAS‐Cog (19.2% vs 11.6%, p<0.01), while rural patients were more likely to receive the MoCA (28.2% vs 18.9%, p<0.01). Rural patients were less likely to be prescribed beta‐amyloid medications (2.3% vs. 6.5%) and more likely to wait at least 4 months for a prescription (80.0% vs.45.6%).

Conclusion

Initiatives that shorten the time to diagnosis and to referral consults in patients aged <65, and that promote the use of neurocognitive assessments in non‐white patients may help close the gap. As early detection and treatment are critical to optimize patient outcomes, more effort needs to be focused on reducing care disparities.
Unveiling the Multifaceted Neuroprotection of Dihydroxytrimethoxyflavone: Memory Enhancement Beyond Cholinergic Boost
Authors: Singh Varinder , Singh Manjinder , Shri Richa
Published: January 2025

Background

Several studies have shown the influential role of nutraceuticals on cognition and mental functions. Dihydroxytrimethoxyflavone, a natural flavone found in herbal drugs, is documented to be neuroprotective in different model systems. Nevertheless, possible memory improvement effects of dihydroxytrimethoxyflavone via nuclear factor‐E2‐related factor 2 (Nrf2) (a crucial regulator of antioxidative system) has not been systematically evaluated. Thus, the present study was aimed to investigate the memory improvement effects of dihydroxytrimethoxyflavone in mouse model of lead induced memory impairment and to reveal the possible molecular mechanism involving Nrf2, oxidative stress, cholinergic signalling and beta amyloid.

Method

Memory impairment in mice was induced by administering lead acetate for 28 days. Dihydroxytrimethoxyflavone (5‐10 mg/kg, p.o.) was administered daily to animals 60 min prior to lead acetate for 28 days. Memory functions (Morris Water Maze), brain acetylcholinesterase (AChE) activity, oxidative stress, beta amyloid and histopathological studies (H&E and congo red staining for beta amyloid) were determined to measure memory improvement effects of dihydroxytrimethoxyflavone.

Result

Dihydroxytrimethoxyflavone showed improvement in memory of animals. It reduced acetylcholinesterase activity and beta amyloid levels. Further, dihydroxytrimethoxyflavone could significantly increase antioxidant enzymes, Nrf2 expression and its nuclear translocation as well as its downstream antioxidant protein expression, NAD(P)H/quinone oxidoreductase 1 and heme oxygenase‐1.

Conclusion

Dihydroxytrimethoxyflavone improved memory in animals via activating Nrf2‐mediated antioxidant pathway, increasing antioxidant defence and inhibiting and amyloid protein burden. Thus, dihydroxytrimethoxyflavone may have beneficial effects in lowering the onset of dementia.
The Role of Blood‐Based Proteomic Biomarkers in Sleep Spindle‐Slow Oscillation Coupling and Incident Dementia
Authors: Chen Zachary Xin , Zhang Can , Mondal Prasenjit , Benitez Bruno A. , Sun Haoqi
Published: January 2025

Background

Sleep is impaired in dementia. Therefore, sleep has been proposed as an intervention target for incident dementia. The microstructures of sleep electroencephalography (EEG), such as spindle, slow oscillation (SO), and their coupling, have neuronal bases and functions in learning and memory. Higher spindle‐SO coupling is linked to lower risk of incident dementia in epidemiological studies. Here, we aim to use proteomics to explore the molecular basis of this link.

Method

This retrospective study used the Framingham Heart Study (FHS) Offspring and OMNI 1 Cohorts, accessible through BioLINCC. The inclusion criteria are (1) plasma proteomics available, where the blood was drawn at FHS‐Exam5 and profiled using SOMAscan (1373 proteins); (2) sleep EEGs from the Sleep Heart Health Study on National Sleep Research Resources obtained at FHS‐Exam6. The exclusion criteria are (1) missing covariates: age, sex, education, APOE ε4 allele, body mass index, and smoking; (2) pre‐existing dementia before sleep recording. Spindle‐SO coupling was defined as the fraction of spindles within SO at N2 or N3 stages of sleep, detected using Luna. Incident dementia was based on FHS consensus. We performed a proteome‐wide association study (PWAS) for spindle‐SO coupling using Spearman’s correlation. We also performed PWAS for incident dementia using Fine‐Gray survival analysis with death as competing risk. We then found the common proteins between the two PWASes. Since the proteins were from the blood, we filtered them by assessing their blood‐brain expression correlations using Genotype‐Tissue Expression.

Result

The PWAS for incident dementia had n=1048 (52% female) with maximum 47‐year follow‐up, revealing 35 proteins reaching Bonferroni‐corrected significance. In contrast, the PWAS for spindle‐SO coupling had n=146 (57% female), with no Bonferroni‐corrected significance. There were 28 proteins common to both PWASes before Bonferroni correction. Among them, intercellular adhesion molecule 2 (ICAM2), C‐reactive protein, and myoglobin demonstrated significant blood‐brain correlations, with ICAM2 exhibiting brain‐wide expression (Figure 1). One standard deviation increase in ICAM2 is associated with hazard ratio of 0.48 (95% confidence interval 0.23‐0.99, p=0.048) for incident dementia. ICAM2 and spindle‐SO coupling have Spearman’s correlation at 0.24 (0.08‐0.39, p=0.0036).

Conclusion

ICAM2 may serve as the proteomic basis for the association between spindle‐SO coupling and incident dementia.
Loneliness, dementia status and their association with all‐cause mortality among older US adults
Authors: Georgescu Michael F , Beydoun May A , Ashe Jason , Vieytes Christian A Maino , Beydoun Hind A , Evans Michele K , Zonderman Alan B
Published: January 2025

Background

Loneliness, dementia, and mortality are interconnected. Thus, understanding the pathways, along with their potential interaction provides a relevant area of research to be developed.

Method

The study tested bi‐directional relationships between dementia, loneliness and mortality, while examining both interactions and mediating effects in a large sample of older US adults participating in the nationally representative Health and Retirement Study. Out of ≤6,468 older participants selected in 2010, with mean baseline age of 78.3 y and a follow‐up time up to end of 2020, 3,298 died with a rate of 64 per 1,000 P‐Y. Cox proportional hazards models were used, stratifying by sex, race and interaction between loneliness scores (continuous or tertiles) and dementia status or Loge(odds) were examined. Four‐way decomposition models were also carried out to test bi‐directional mediation and interaction between dementia odds and loneliness in relation to mortality risk.

Result

Probable dementia was consistently linked to over two‐folds increased mortality risk. The presence of dementia and Loge(odds) were equally strongly related with mortality risk across tertiles of loneliness score. The study also found that the loneliness z‐score was linked to an elevated risk of mortality regardless of age, sex, or race or ethnicity, and that its total effect (TE) on mortality was partially mediated by Loge odds of dementia (z‐scored), with up to 40% of TE being a pure indirect effect. In contrast, a very small proportion (<5%) of the TE of dementia odds (Loge transformed, z‐scored) on mortality risk was explained by the loneliness z‐score.

Conclusion

transformed, z‐scored) on mortality risk was explained by the loneliness z‐score. Conclusions. In sum, dementia was positively associated with mortality risk, in similar fashion across loneliness score tertiles, while loneliness was associated with mortality risk in the overall sample. The total effect of loneliness on mortality risk was partially mediated by dementia probability, particularly when models were only adjusted for age, sex, and race/ethnicity.
Development and analytical validation of AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 in human serum, plasma, or CSF
Authors: Surls Jacqueline , Ibanez Robyn Vega , Brown Lindsey , Kemp Josh
Published: January 2025

Background

Measurement of blood‐based biomarkers for Alzheimer disease is simpler and more accessible when compared to CSF. We report the development and validation of seven Simoa® immunoassays for the detection of AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 in human serum, plasma, or CSF.

Method

Using the Quanterix® Simoa® technology (SR‐X) platform, AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 were developed and analytically validated in human serum, plasma, or CSF per CLSI standards.

Result

We have developed and analytically validated Simoa® immunoassays to detect AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 in human serum, plasma, or CSF. The assays met acceptance criteria for sensitivity, precision, stability, interference, and parallelism. The calibration curves in serum/plasma were linear from 16‐2000 pg/mL for AB40, 18‐40,000 pg/mL for AB42, 0.13‐80 ng/mL for A‐Syn, 0.012‐60 ng/mL for CD33, 0.60‐3000 pg/mL for P‐Tau 181, 0.12‐600 pg/mL for Tau, and 0.30‐38 ng/mL for TREM2. For CSF, the linear ranges were from 626‐80,000 pg/mL for AB40, 72‐160,000 pg/mL for AB42, 0.013‐8.0 ng/mL for A‐Syn, 0.012‐60 ng/mL for CD33, 30‐150,000 pg/mL for P‐Tau 181, 0.30‐1500 pg/mL for Tau, and 0.60‐76 ng/mL for TREM2. The three quality controls met inter assay precision with %CV ≤16% for levels 1 and 2, and ≤20% for level 3 across all analytes. No interference was observed with bilirubin, hemoglobin, or triglyceride. The sensitivity of the assays in human serum/plasma was demonstrated by the LLOQ values of 28 pg/mL, 47 pg/mL, 0.20 ng/mL, 0.11 ng/mL, 2.8 pg/mL, 0.22 pg/mL, and 0.59 ng/mL for AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2, respectively. For human CSF, the LLOQ values of 1139 pg/mL, 187 pg/mL, 0.020 ng/mL, 0.11 ng/mL, 142 pg/mL, 0.56 pg/mL, and 1.2 ng/mL for AB40, AB42, A‐Syn, CD33, P‐Tau 181, Tau, and TREM2 in human CSF, respectively. The stability of the analytes was established under various conditions, such as freeze‐thaw cycles, short‐term and long‐term storage.

Conclusion

These assays demonstrated acceptable performance for clinical implementation as research use only and may be useful for blood‐based biomarker studies in clinical trials.
Elevating brain GLP‐1 and GIP levels as a treatment strategy for neurodegenerative disorders
Authors: Greig Nigel H , Wang Yun , Hoffer Barry J , Sambamurti Kumar , Lahiri Debomoy K. , Tones Michael A , Zaleska Margaret M , Mattison Julie A
Published: January 2025

Background

Epidemiological studies report an elevated risk of neurodegenerative disorders, particularly Parkinson’s disease (PD), in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed incretin mimetics or dipeptidyl peptidase 4 inhibitors (DPP‐4Is). Incretin mimetic repurposing appears promising in human PD and Alzheimer’s disease (AD) clinical trials. DPP‐4Is are yet to be evaluated in PD or AD human studies.

Methods

Incretin mimetics have been evaluated in multiple cellular/animal PD models, including in 6‐hdroxydopamine (6‐OHDA) rats, and have demonstrated efficacy. The clinically approved DPP‐4Is, sitagliptin (Januvia) and PF‐00734200 (gosogliptin/Saterex) were hence evaluated in the classic 6‐OHDA unilateral medial forebrain bundle rat PD model to evaluate their repurposing potential when administered as human equivalent oral doses. Equivalent doses then were administered to naive nonhuman primates (NHPs) to evaluate whether biomarkers of efficacy in rat could be reproduced in NHPs as a further translational step towards human studies. Pharmacokinetics, DPP‐4 inhibition, GLP‐1/GIP and dopamine levels, together with dopaminergic and neuroinflammatory markers, and GLP‐1/GIP receptor levels were quantified.

Results

Sitagliptin/PF‐00734,200 pre‐ or post‐treatment mitigated 6‐OHDA‐induced dopaminergic neurodegeneration, dopamine level loss and neuroinflammation, and augmented neurogenesis in lesioned substantia nigra pars compacta and in striatum, and reduced classical methamphetamine‐induced rotation in rats. This efficacy associated with 70‐80% plasma and 20‐30% brain DPP‐4 inhibition, and with elevated plasma and brain GLP‐1/GIP levels. Alike plasma/CSF DPP‐4 inhibition and elevated GLP‐1/GIP levels were determined in NHPs administered rat equivalent (human translational) sitagliptin doses. In relation to the drug targets, brain GLP‐1/GIP receptor protein levels were age‐dependently maintained in rodents, preserved in rats challenged with 6‐OHDA, and in humans with PD. Combined GLP‐1+GIP receptor activation in neuronal cultures resulted in neurotrophic/neuroprotective actions superior to single agonists alone – particularly when combined with a DPP‐4I

Conclusions

These studies support further evaluation of repurposing clinically approved drugs that elevate plasma/brain/CSF GLP‐1/GIP as a treatment strategy for neurodegenerative disorders. Incretin mimetics are already in clinical evaluation in PD and AD. Similarly, the repurposing of gliptins warrants evaluation both alone and in combination with an effective incretin mimetic.
The role of social support and social contact in cognitive aging: A study of sex/gender and sexuality in the Health and Retirement Study
Authors: Hanes Douglas William , Stinchcombe Arne , Clouston Sean A.P.
Published: January 2025

Background

Sexual‐minority (e.g., lesbian, gay, bisexual [SM]) people may be at an increased risk of Alzheimer’s disease or a related dementia (ADRD) from stress related to experiences of minoritization. Strong levels of social contact and social support decreases dementia risk; these effects may differ by sex/gender and sexuality. The purpose of this presentation is to elucidate the relationship between cognitive function, social support, and social networks with a focus on sexuality and sex/gender.

Method

Data analyzed were from waves 8‐14 (2006‐2018) of the Health and Retirement Study, a longitudinal survey of U.S. residents aged ≥51 years (N = 18,183). Participants who reported their sexual orientation as lesbian, gay, or bisexual, or those in same‐sex relationships for at least one wave were classified as SMs. A gender/sexuality variable was created with four levels: SM‐women (n = 101), heterosexual women (n = 9,942), SM‐men (n = 106), and heterosexual men (n = 8,034). Social contact and support were reported for network size, frequency of contact, and quality of interactions across four relationships: spouses, children, family, and friends. Cognitive function was measured on a 27‐point scale. The primary analysis consisted of a series of multiple linear regression models, treating cognition as the outcome, and adjusting for age, wealth, education, and race.

Result

Descriptive analysis showed that SM‐men and SM‐women tended to be younger and join the study later than heterosexual men and women, and at baseline, heterosexual men had lower cognitive scores compared to the other three groups (F = 82.44, p<0.001). Moderation analysis showed the relationship between positive spousal support and cognition was inconsistent across gender/sexuality groups (χ2 = 11.58, p = 0.009); SM‐women did not benefit from positive spousal support as much as other gender/sexuality groups. Greater frequency of social contact was associated with higher cognitive function, except among SM‐women where greater social contact was associated with lower cognitive function (χ2 = 9.65, p = 0.023). Support from other social groups did not have differential effects across gender/sexuality groups.

Conclusion

Findings highlighted variable and gendered effects of social support and social contact on cognitive functioning in aging SM people. Examining differential effects for SM/gender groups is essential to inclusive ADRD research.
Reproducibility Challenges in Brain PET Data Analysis
Authors: Naseri Maryam , Carmichael Owen T. , Pillai Sreekrishna R.
Published: January 2025

Background

While a great deal of recent effort has focused on addressing a perceived reproducibility crisis within brain structural magnetic resonance imaging (MRI) and functional MRI research communities, less attention has been paid to reproducibility of brain positron emission tomography (PET) research.

Methods

We examined the current landscape of factors that contribute to reproducible neuroimaging data analysis, comparing brain MRI to brain PET. The factors included scientific standards, analytic plan pre‐registration, data and code sharing, containerized workflows, and standardized processing pipelines. To demonstrate the positive impact that further developing such reproducibility factors would have on brain PET research, we conducted one case study in which the brain PET processing pipeline developed for one flagship study (Alzheimer's Disease Neuroimaging Initiative, ADNI) for brain 18F‐florbetapir and 18F‐fluorodeoxyglucose (FDG) analysis was reproduced in our laboratory.

Results

Compared to fMRI, PET research encounters substantial challenges in adopting essential reproducibility practices. While 85% of fMRI studies adhere to the standardized reporting practices, PET is in the early stages of establishing reporting practices, lacking a standardized checklist. Pre‐registration is prevalent for fMRI (57.6%) but notably absent in PET, with no pre‐registered PET studies found on platforms such as the Center for Open Science. The number of shared datasets is higher for fMRI compared to PET, with 92 fMRI datasets and only 9 PET datasets on repositories like OpenNeuro. Moreover, there are very few data repositories for newer PET radiotracers. Containerized software availability also favor fMRI, with platforms like (Brain Imaging Data Structure, BIDS) apps hosting 66% dedicated fMRI tools, while no PET‐specific software is available. Standardized processing pipelines follow the same trend, with fMRI boasting optimized workflows for specific protocols, while PET has few dedicated pipelines and lacks validation studies for existing options. Furthermore, while our case study demonstrated excellent correlation results for both the 18F‐FDG and 18F‐florbetapir methods (Figure 2), the replication of the ADNI PET pipeline posed substantial challenges and implementation delays. These obstacles and delays in execution were due to incomplete documentation and ambiguities in application details.

Conclusion

PET neuroimaging lags behind its MRI‐related counterparts in achieving robust reproducibility.
History of adverse pregnancy outcomes and cognitive decline among older adults: the Adult Changes in Thought study
Authors: Tom Sarah E. , Harrington Laura B , Chau Kristi , Wartko Paige D , Muiruri Roxanne , Krakauer Chloe , McEvoy Linda K. , LaCroix Andrea Z. , Miller Eliza C.
Published: January 2025

Background

Whether history of adverse pregnancy outcomes (APOs) contributes to cognitive decline in later life is not understood because few cohorts have information on pregnancy history and later‐life cognition. We hypothesized that history of any APO would be related to lower global cognition and faster cognitive decline among older adults, compared to no APO history.

Method

The Adult Changes in Thought (ACT) Study is a prospective cohort study embedded in an integrated health care system of adults aged 65 and older without dementia at enrollment. Among ACT participants enrolled between 1994 and 2020 (n = 5,763, 58% women), women eligible for our study were born in 1940 or later, had evidence of ≥1 child or pregnancy, and had maternal or pregnancy information in their medical record (n = 444). APOs of interest were preterm birth, hypertensive disorders of pregnancy (including gestational hypertension and preeclampsia), low birth weight, small for gestational age, and stillbirth. Cognition at ACT enrollment and every two years thereafter was assessed by the Cognitive Abilities Screening Instrument, a 40‐item instrument of global cognition, further processed using item‐response theory (CASI‐IRT); points are standard deviation units of CASI‐IRT in the study population. We fit linear models using generalized estimating equations to assess associations between history of any APO with (1) cognition score and (2) cognitive decline.

Result

Among eligible participants, 13% had a history of any APO. Among people of the same age, birth cohort, education, and marital status, CASI‐IRT scores were expected to be 0.23 point lower (95% CI: ‐0.54, 0.07) among people with a history of APOs than those without; this difference did not reach statistical significance. Expected 4‐year rates of cognitive change among people with a history of APOs [‐0.01; 95% CI ‐0.25, 0.23] was not found to differ significantly from those without [0.02; 95% CI ‐0.05, 0.09].

Conclusion

There is some inconclusive evidence that history of any APO may be associated with lower cognition level in older adulthood. We failed to find any convincing evidence of the association between history of APOs and the rate of cognitive decline.
Associations Between Brain Structure and Dual Decline in Gait and Cognition
Authors: Karunarathna Sadhani , Breslin Monique , Alty Jane E , Beare Richard , Collyer Taya , Srikanth Velandai K , McDonald Scott , Callisaya Michele L
Published: January 2025

Background

Dual decline in gait and cognition is associated with an increased risk of dementia, with combined gait and memory decline exhibiting the strongest association. However, little is known about the underlying brain correlates. Therefore, we aimed to examine the associations between measures of brain structure and dual decline in gait and cognition across several cognitive domains.

Method

Participants over 60 years were randomly selected from the electoral roll into the Tasmanian Study of Cognition and Gait. We used baseline MRI and three serial gait speed and cognitive assessments (memory, processing speed‐attention, verbal fluency) performed on average 2.5 years apart. Participants were classified into four groups depending on tertiles of annual decline in gait speed and each cognitive measure (non‐decliners, gait‐only decliners, cognition‐only decliners, and dual‐decliners). Dual decliners were defined as the participants belonging to the highest tertile of annual decline in both gait speed and each of the cognitive measures. Multinomial logistic regression was used to examine the associations of baseline brain volumes (gray matter, white matter, and hippocampal) and cerebral small vessel disease (white matter hyperintensities, subcortical infarcts, enlarged perivascular spaces, and microbleeds) with dual gait and cognitive decline for each cognitive domain.

Result

The mean age of participants was 70.9 ± SD 6.7 years (n = 267). Lower baseline gray and white matter volume and higher white matter hyperintensity volume increased the risk of being a dual decliner in gait and both the memory and processing speed‐attention groups (all p < 0.05). Lower hippocampal volume (p = 0.047) was only associated with increased risk of being a dual decliner in the gait and memory group. No significant associations were found between MRI measures and the gait and verbal fluency dual decliners.

Conclusion

Neurodegenerative pathology and white matter hyperintensities are involved in dual decline in gait and both memory and processing speed‐attention domains. Smaller hippocampal volume may also contribute to dual decline in gait and memory, but not dual decline in gait and other cognitive domains.
Correlations of antemortem [18F]MK‐6240 PET with ROI‐matched postmortem biochemical assessment of total tau and tau phospho‐epitopes pThr181, pSer199, pThr231, and pSer396
Authors: Betthauser Tobey J. , Abrahamson Eric E , Chavez Elena Ruiz De , Teague Jordan P , McVea Andrew K , Deming Yuetiva , Schroeder Brooke E , Barger Madeleine R , Johnson Sterling C. , Asthana Sanjay , Villemagne Victor L , Christian Bradley T. , Salamat Shahriar , Ikonomovic Milos D
Published: January 2025

Background

[18F]MK‐6240 was developed for PET imaging of AD tau pathology, but the exact molecular signature of specific binding remains unclear. This study quantified levels of four phospho‐tau forms and total tau in postmortem brain tissues from [18F]MK‐6240 imaged cases to investigate associations with antemortem [18F]MK‐6240 PET.

Methods

This study included four participants from the Wisconsin ADRC or WRAP with antemortem [18F]MK‐6240 and [11C]PiB PET imaging and postmortem brain tissue obtained on average 32‐months after imaging (Table 1). Parametric SUVR were generated using T1‐w MRI to delineate regions matched to equivalent ROIs on fresh frozen brain tissue slabs. Tissue ROI dissected from ten brain regions per case were homogenized and ELISA was used to quantify concentrations of guanidine‐extracted total tau and tau phosphorylated at epitopes pThr181, pSer199, pThr231, and pSer396.

Results

Matched PET‐autopsy ROI analysis showed significant correlations of higher [18F]MK‐6240 SUVR with higher levels of all measured p‐tau forms or their ratios to total tau across all regions and cases. Analyses of two A+T+ cases with clinical AD dementia and postmortem Thal Phase 5/Braak NFT Stage VI showed higher [18F]MK‐6240 SUVR correlated significantly with higher levels of pThr181, pSer199, pThr231, and pSer396 tau or their ratios to total tau in a 79‐yo APOE‐ε4ε4 case, and with higher levels of pThr231 and pSer396 tau in a 78‐yo APOE‐ε3ε3 case. In two T‐ cases, we observed weak correlations of [18F]MK‐6240 SUVR with pThr181 and pSer396 tau in an A‐T‐ cognitively unimpaired case (Thal Phase 2/Braak NFT Stage II; 70‐yo; APOE‐ε3ε3), but no correlations in A+T‐ early‐onset AD dementia case with Thal Phase 4/Braak NFT Stage V (63‐yo; APOE‐ε4ε4). This latter case also had high [18F]MK‐6240 uptake outside the brain and a low tangle density outside the MTL.

Conclusions

Higher [18F]MK‐6240 PET binding reflects high brain concentrations of pThr181, pSer199, pThr231, and pSer396 tau in AD dementia cases with high AD neuropathological change. Lack of associations between PET and p‐tau biochemistry in the T‐, Braak V early‐onset dementia case suggests that the T‐ PET status is more closely associated with p‐tau biochemistry than postmortem neuropathological staging, likely due to low tangle density.
An Ethnographic Analysis of The Black and African American Adult Male Perspective on Alzheimer’s Disease and the Social Determinants of Health
Authors: Williams Lilcelia A. , Lingler Jennifer H , Terry Melita H
Published: January 2025

Background

Black and African American adult males have the worst overall health than any other race or gender in the United States. The rate of Alzheimer’s Disease is twice as high for Black and African American adults. Yet, little is known about how Black and African American adult males perceive the relationship between the social determinants of health and Alzheimer’s Disease.

Method

We conducted a secondary analysis of ethnographic interview data from ten Black and African American adult male participants at an NIA‐funded Alzheimer’s Disease Research Center. Participants included both patients (n = 6) and study partners (n = 4) who were purposively sampled to ensure that a range of perspectives were represented in the parent study, Recruitment Innovations for Diversity Enhancement (RIDE) in Alzheimer’s Disease Research. Chronological age and education were self‐reported. For the present analysis, transcripts from semi‐structured participant interviews were first examined to organize the data within categories informed the Social Determinants of Health Model. Data within each social determinant of health category were then analyzed to identify themes and explore potential relationships within the data.

Result

All participants identified as male with a mean age of 75 (SD±13); 90% reported two or more years of post‐secondary education and 100% spontaneously mentioned elements of social determinants of health in response to questions about their experiences with dementia and motivations for participation in Alzheimer’s Disease research. A relationship between Alzheimer’s Disease and the social determinants of health was demonstrated by the study participants’ endorsement in across all domains. Locus of control, perception is reality, mistrust and othering are the thematic codes that consistently emerged from both the patient and caregiver interviews. The importance of having shared social characteristics (e.g., race) with clinicians, providers and staff members was a recurrent theme among the participants.

Conclusion

Despite the shared social characteristics of race and gender among the study participants, their perception of the relationship between Alzheimer’s disease and the social determinants of health was not monolithic. Findings support the need for additional research to examine the perceptions and lived experiences of Black and African American adult males as it relates to Alzheimer’s Disease.
Central Autonomic Dysfunction and Plasma Ab42/40
Authors: Lohman Trevor , Kapoor Arunima , Engstrom Allison C , Shenasa Fatemah , Nguyen Amy , Alitin John Paul M , Gaubert Aimée , Rodgers Kathleen E. , Bradford David , Mather Mara , Han Duke , Head Elizabeth , Thayer Julian F , Nation Daniel A.
Published: January 2025

Background

Higher order regulation of autonomic function is maintained by cortical and subcortical interconnected regions within the brain, collectively referred to as the central autonomic network (CAN) (Benarroch, 1993). Despite the well‐established relationship between autonomic dysfunction and AD (Femminella et al., 2014) the relationship between CAN functional connectivity and biomarkers of AD, such as Ab42/40 ratio, remains unexplored.

Methods

76 independently living older adults were recruited from the community to undergo brain fMRI and venipuncture. Study exclusions were history of clinical stroke, dementia, major neurological or psychiatric disorder, current organ failure or other uncontrolled systemic illness. Resting state fMRI data were acquired and analyzed to quantify CAN functional connectivity from 3 previously described CAN networks with the CONN Functional Toolbox (Nieto‐Castanon, 2020). Default mode network connectivity was also included for analysis as a negative control. Plasma Aβ40 and Aβ42 concentrations were obtained by digital immunoassay with the Simoa Neurology 3‐Plex A (N3PA) Advantage Kit (Quanterix). Vascular risk factors were evaluated through interviews with the participant and informant, and included history of cardiovascular disease, hypertension, hyperlipidemia, type 2 diabetes, atrial fibrillation, and transient ischemic attack. The relationship between CAN functional connectivity and plasma Ab42/40 ratio was compared using linear regression adjusting for demographic covariates and vascular risk factor burden.

Results

CAN functional connectivity was positively associated with Ab42/40 for all three CAN models (CAN A (Beissner et al., 2013) P= .0001; CAN B (Monroe et al., 2020) P= .018; CAN C (Riganello et al., 2018) P= .006), and remained so after adjustment for age, sex, and vascular risk factor burden. Default mode network connectivity was not significantly associated with Ab42/40 (Figure 1).

Conclusion

Older adults with decreased central autonomic network connectivity exhibit lower plasma Ab42/40, indicating greater cerebral Ab1‐42 retention. This correlation could not be accounted for by age, sex, or vascular risk factor burden, suggesting a direct relationship between central autonomic function and cerebral amyloidosis. Further studies should explore the implications of CAN dysfunction for autonomic changes during the early stages of AD pathophysiology.
Alzheimer’s disease as a primary pathology in logopenic variant of primary progressive aphasia
Authors: Nevzorova Kseniya , Shpilyukova Yuliya , Akhmadullina Diliara , Shabalina Alla , Fedotova Ekaterina
Published: January 2025

Background

The logopenic variant of primary progressive aphasia (lvPPA) is a disorder centered on language impairment. Alzheimer Disease (AD) is one of the most common underlying pathologies in lvPPA. The aim of our study was to estimate frequency of AD in this phenotype and to analyze clinical features of AD‐lvPPA.

Method

We examined 20 patients (9 females and 11 males, 65.9±9.1 years) with the phenotype of lvPPA. The diagnosis was determined on clinical and imaging data according to the lvPPA criteria (Gorno‐Tempini et al., 2011). All patients underwent lumbar puncture. CSF biomarkers Abeta‐42 and p‐tau181 were analyzed. Based on the laboratory results and according to the recommendations of International Working Group (2021) we found 4 patients with established AD, 8 patients with probable AD and 8 non‐AD patients. Then we compared 2 groups (AD and non‐AD) on age of onset and cognitive features, assessed by Addenbrooke’s cognitive examination (ACE‐R) and Frontal Assessment Battery (FAB).

Result

The frequency of AD pathology in lvPPA group was 60% (20% for established diagnosis and 40% ‐ for probable). The disease onset was earlier in the group of AD lvPPA than in the non‐AD group (60.1 years vs. 65.4 years), but the difference was not statistically significant (p=0.175). We didn’t find significant differences between the groups in FAB, total ACE‐R. We revealed a higher median score in the speech ACE‐R subscale (18.5 vs. 14.5) and lower median score in the memory ACE‐R subscale (10.5 vs. 14.5) in patients with established AD group compared to non‐AD group.

Conclusion

In our study we demonstrated a high prevalence of AD pathology in lvPPA. The results showed no specific differences, but some clinical findings may predict AD on pre‐laboratory stage (such as more severe memory impairment and less speech impairment). So, it is important to analyze AD biomarkers in CSF in all cases to establish underlying pathology and to prescribe specific treatment.

The study was supported by RSF (#23‐25‐00483)
Brain structural changes in rural communities and disadvantaged neighborhoods: preliminary exploration in older adults from Southern Nevada
Authors: Zhuang Xiaowei , Cordes Dietmar , Caldwell Jessica ZK , Bender Andrew R. , Miller Justin B
Published: January 2025

Background

Rural‐dwelling older adults are at increased risk for Alzheimer’s disease (AD) and related dementia. Identifying how rural living and neighborhood disadvantage affect neurobiology may help to understand rural‐urban disparities in AD and promote healthy aging in rural communities. In this study, we characterize rural‐urban differences in cortical thickness (CT), and the association of regional CT with neighborhood disadvantage, using both clinically normal and impaired older adults.

Method

We assessed cross‐sectional data from 71 rural‐dwelling (61.97% women, 71.13±6.45 years old) and 87 urban‐dwelling (43.67% women, 72.16±6.88 years old) older adults from the Nevada Exploratory Alzheimer’s Disease Research Center and the Nevada Center for Neurodegeneration and Translational Neuroscience. The Rural‐Urban Commuting Area (RUCA) Codes score was used to determine rural‐urban residency status, and the Area Deprivation Index (ADI) was used to characterize neighborhood disadvantage. Clinical impairment status was determined by expert consensus review, and FreeSurfer‐derived CT measures were calculated from 3T structural magnetic resonance images (MRI). Analysis of covariance was used to test whether each CT measure was associated with rural‐urban living, clinical impairment status, or their interactions. Linear regressions were fitted to test the association between CT measures and ADI in clinically normal and impaired participants.

Result

For temporal and inferior frontal regions, rural‐dwelling older adults demonstrated a thinner cortex than urban older adults, and these rural‐urban differences were more pronounced in clinically normal than impaired participants. Cortical thinning of temporal regions was further correlated with advanced neighborhood disadvantages. In contrast, for superior frontal, parietal and occipital regions, rural participants showed thicker cortex than urban participants and these differences were greater in clinically impaired participants.

Conclusions

We observed extensive rural‐urban differences on CT measures with mixed directions, suggesting a complex interplay between community contexts and neurobiology in clinically normal and impaired older adults. More importantly, for regions involved in memory that are vulnerable to AD, our results suggest that living in rural areas and less advantaged neighborhoods might negatively affect subjects’ brain structures; but once clinical impairment onsets, impairment effect on these neurobiological measures tend be more dominant than the residency effect.
Genetic and Epigenetic Signatures for Cognitive Resilience in Neuropathologically Defined Alzheimer’s Disease Brains
Authors: Han Xudong , Li Donghe , Goldstein Daniel , Sahelijo Nathan J , Farrer Lindsay A. , Stein Thor D. , Mez Jesse , Jun Gyungah R
Published: January 2025

Background

Not all people with neuropathological evidence of Alzheimer’s disease (AD) manifest clinical symptoms in life (cognitive resilience). We aimed to identify genetic and epigenetic signatures of cognitive resilience, utilizing data from brain donors with neuropathological evidence of AD who were either symptomatic or asymptomatic in life.

Method

Among brain donors with neuropathologically‐confirmed AD (364 asymptomatic/cognitively resilient and 490 symptomatic) from the Boston University AD Research Center, Framingham Heart Study—where we generated our own data—as well as the Religious Orders Study and Rush Memory and Aging Project, we utilized genome‐wide genetic array data, genome‐wide DNA methylation array data and RNA sequencing data. We conducted a genome‐wide association study (GWAS) and a methylation‐wide association study (MWAS) in each dataset and meta‐analyzed. Relationships between top‐ranked CpG sites, SNPs, and expression levels of the selected genes/isoforms were further evaluated.

Result

Meta‐analysis of genome‐wide significant MWAS results revealed 3 CpG sites from 3 genes, ARHGAP22, UBAC2, and KANSL1 (top‐ranked= cg19832721: Log2 fold change [Log2FC]=‐0.12, P=2.5x10‐8). Meta‐analysis of GWAS findings identified significant ((P<1x10‐5) associations with 9 single nucleotide polymorphisms (SNPs) located in 9 different loci including APOE (top‐ranked=rs6917901 in TNFAIP3: odds ratio [OR]=0.53, 95% confidence interval [CI]=0.41‐0.67, P=3.8x10‐7). Expression of KANSL1 and its isoform ENST00000638269 were increased in symptomatic compared with cognitive resilient AD subjects (gene: Log2FC=0.082, P=5.95x10‐6; isoform: Log2FC=0.325, P=5.95x10‐4). The methylation level of cg19832721 was negatively correlated with expression of the KANSL1 isoform (Beta=‐27.13, P=0.002) but not with the gene (P>0.05). SNP rs4586175 located in the ROBO3‐ROBO4 locus was significantly associated with symptomatic AD (OR=0.58, CI=0.45‐0.74, P=9.89x10‐6) and increased expression of the ROBO3 isoform ENST00000543966 (Beta=2.72, P=0.03). A CpG site cg08770647 located 773 bp from rs4586175 was nominally associated with symptomatic AD (Log2FC=0.06, P=1.52x10‐4) and its methylation level was correlated with increased expression of the ROBO3 isoform (Beta=83.26, P=0.01).

Conclusion

Our study suggests that interactions between genetic and epigenetic signatures contribute to cognitive resilience in persons with pathologically confirmed AD. Our findings also provide insight about genetic mechanisms that could be targeted to retard or prevent onset of AD clinical symptoms.
Cross‐Cultural Adaptation of the Pool Activity Level (PAL) Checklist: From UK English to U.S. English for Enhanced Dementia Care
Authors: Gholizadeh Shadi , Sudberry Liz , Popolizio Elizabeth M. , Merz Erin L , Daniels Damaris , Pool Jackie
Published: January 2025

Background

An important aspect of quality of life is engagement in meaningful and purposeful activities. For people living with dementia (PLwD), opportunities to engage in purposeful activities can be vastly diminished. Successful engagement of individuals with dementia typically hinges upon selecting engagement targets and activities that are appropriate to the individual’s level of cognitive functioning. The Pool Activity Levels (PAL) Checklist, a strength‐based, person‐centered 9‐item checklist tool for nonclinical caregivers to assess cognitive, physical, and sensory abilities in PLwD in order to guide activity planning and engagement strategies, was originally developed in British English. The increasing use of the measure in the United States necessitates a translation into American English to ensure cultural and linguistic appropriateness. Back translation (BT) is a commonly‐used methodology of questionnaire translation. However, several problems with BT have been highlighted, including its reliance on perfect equivalence and prioritization of literal translation over conceptual and cultural equivalence. Alternatives to BT include engaging professionals with expertise in translation and the subject matter to translate the assessment and to then submit the translation to a review by an expert panel and field test or using an iterative, team based approach that involves translation, review, evaluation, pretesting, and documentation.

Method

Adopting a multidisciplinary approach, the PAL Checklist was translated from British to U.S. English. This process involved a team of professionals, including collaboration with the original author of the PAL, from various U.S. regions with expertise in care planning and assessment. The translation methodology aligned with the ISPOR Quality of Life Special Interest Group guidelines, incorporating steps like forward translation, reconciliation, back translation, cognitive debriefing, and finalization.

Result

The translation retained the original checklist’s conceptual integrity while adapting linguistic differences, such as “flannel” to “washcloth/sponge” and “cupboards” to “drawers/closet.”

Conclusion

This preliminary translation of the PAL into U.S. English lays the groundwork for future research to assess its psychometric properties in American settings. Future research will focus on extensive validation to meet psychometric criteria (e.g., internal consistency reliability, structural validity), ensuring its efficacy and reliability in the United States.