bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthetic γ‐AApeptides as Targeting Ligands for Immunomagnetic separation of Alzheimer’s disease (AD) Biomarkers
Authors: Li Yuancheng , Mao Hui , Cai Jianfeng , Ma Hedi , Padelford Jonathan 
Published: January 2025

AbstractBackgroundLiquid biopsy for Alzheimer’s disease (AD) biomarkers in cerebral spinal fluid (CSF) or blood samples is becoming a significant sector in the management of AD and AD related dementia (ADRD). Whereas different types of molecules, such as small molecules, peptides, and antibodies, have been used as ligands for targeting AD biomarkers/pathologies such as amyloid beta peptides (Aβs), current liquid biopsy approaches mostly use antibodies. However, the activity and affinity of the antibodies can vary depending on the source and preparation as well as the stability in storage. This study reports the application of Aβ40‐specific synthetic γ‐AApeptides, consisting of N‐acylated‐N‐aminoethyl amino acid units, as targeting ligands for immunomagnetic separation of Aβ40.MethodA γ‐AApeptides library was developed using combinatorial chemistry, and screened for Aβ40‐targeting candidates following published methods. Chemical structures of γ‐AApeptides were solved by nuclear magnetic resonance (NMR) spectroscopy and tandem mass spectrometry (MS/MS). Conjugation of γ‐AApeptides with ultra‐magnetic iron oxide nanorod Magfiniti® was performed using the terminal thiol groups on γ‐AApeptides and amine groups on Magfiniti®, facilitated by a sulfosuccinimidyl 4‐(N‐maleimidomethyl)cyclohexane‐1‐carboxylate (sulfo‐SMCC) linker. Conjugation was validated by the change of hydrodynamic size and zeta‐potential of Magfiniti®. Human serum spiked with fluorescence‐labeled Aβ40 (100 to 2000 pg/mL) was used to test the detection sensitivity of γ‐AApeptide‐Magfiniti®, with Aβ40‐targeting 6E10‐antibody‐conjugated Magfiniti® used as control.ResultWe found three structures of γ‐AApeptides specific for Aβ40, namely A‐28, C‐231, and F‐12, all of which contained a backbone of four monomeric γ‐peptide units but different N‐acylated‐N‐aminoethyl sidechains. With similar chemical structures, successful conjugation of each γ‐AApeptides on Magfiniti® was confirmed by the increased hydrodynamic sizes from 58.8±8.0 nm to 91.3±11.9 nm, along with the decrease of zeta potentials from 25.4±7.7 mV to 14.1±5.6 mV. The detection sensitivity for 100 pg/mL Aβ40 by each γ‐AApeptide‐Magfiniti® was 96.1±2.7% (F‐12), 92.2±4.4% (C‐231), and 78.8±6.9% (A‐28), whereas 6E10‐Magfiniti® captured 98.4±2.1% of Aβ40 under same condition.ConclusionWe synthesized and identified three Aβ40‐specific γ‐AApeptide that can be used as targeting ligands for immunomagnetic separation of AD biomarkers. The γ‐AApeptide F‐12 achieved a similar sensitivity to that of Aβ40‐targeted antibody.
BOLD fMRI signal changes in preclinical Alzheimer’s disease
Authors: Hrybouski Stanislau , Das Sandhitsu R. , Xie Long , Lyu Xueying , Wisse Laura E.M. , Kelley Melissa , Lane Jacqueline , Sherin Monica , DiCalogero Michael , Nasrallah Ilya M. , Detre John A. , Yushkevich Paul A. , Wolk David A 
Published: January 2025

AbstractBackgroundPrevious work suggests functional abnormalities in the human brain in preclinical Alzheimer’s disease. However, little has been explored about the relationship between BOLD fMRI signal amplitude/energy over time and AD pathology. In this work we analyzed the effects of AD progression on amplitude of low‐frequency fluctuations (ALFF) during resting‐state fMRI scans both at the whole‐brain level and at a more granular level, focused on regions of the medial temporal lobe (MTL) that are most vulnerable to AD pathology.MethodIn this cross‐sectional study, we analyzed data from 224 individuals from the Penn ADRC cohort (Table 1). All participants underwent structural and functional MRI on a Siemens 3T Prisma system, and 18F‐Florbetaben or 18F‐Florbetapir amyloid‐PET imaging. 125 participants also underwent 18F‐Flortaucipir tau‐PET scans. Functional images were preprocessed using a custom implementation of fMRIprep and ALFF was extracted using Conn software. In the whole‐brain analyses we performed voxelwise GLMs with age and sex as covariates.ResultsWe observed reduced ALFF in both preclinical AD (Amyloid‐positive (Aβ+) cognitively unimpaired, CU) and Aβ+ cognitively impaired (CI) individuals. Relative to Aβ‐ controls, individuals with preclinical AD displayed lower ALFF in frontal, parietal and temporal association cortices (Figure 1, top left). CI individuals displayed lower ALFF in most of the brain, except in inferior temporal cortex, temporal pole, and MTL. The effect of AD progression on ALFF was characterized by a progressive reduction primarily in frontal and parietal regions that roughly align with the anatomy of the default mode network. In contrast, transentorhinal tau pathology was negatively associated with ALFF in frontal and anterior temporal lobes, as well as insula and MTL (Figure 1 bottom right). Negative association between tau burden and MTL ALFF was observed in all main MTL subregions, and strongest in the transetorhinal cortex (Figure 2).ConclusionWe conclude that: (1) ALFF might be a promising biomarker for studying functional abnormalities in preclinical AD, and (2) based on the spatial topography of amyloid and tau effects on ALFF (Figure 1 bottom), there is likely a differential effect of of the two on ALFF that needs to be further explored.
Biomarkers, clinical status, and cognitive performance in a Caribbean Hispanic cohort
Authors: Honig Lawrence S. , Kang Min Suk , Reyes‐Dumeyer Dolly , Franco Yahaira , Medrano Martin , Piriz Angel , Recio Patricia , Mejia Diones Rivera , Soriano Belisa , Lantigua Rafael A. , Mayeux Richard 
Published: January 2025

AbstractBackgroundPlasma biomarkers may be utilized to assist in diagnosis of Alzheimer's disease. However, in a cohort of Caribbean Hispanic individuals we have shown that there are both individuals who are biomarker positive but without dementia, and biomarker negative but diagnosed with dementia. Here we examine education and neuropsychological testing performance in these subgroups with biomarker‐inconsistent dementia diagnosis.MethodAdults of Caribbean Hispanic ethnicity were recruited in both New York City and the Dominican Republic. The group reported here includes 1173 individuals. Plasma biomarkers including AB40, AB42, total tau, phosphorylated‐tau181, Neurofilament light chain (NfL), and Glial Fibrillary Acidic Protein (GFAP) were measured in samples processed, stored at ‐80°C, and thawed for analysis. Measurements were made using the Simoa Quanterix HD‐X platform.ResultIn this group of 1172 individuals, 885 (75.5%) were assessed as clinically without dementia, and 288 (24.5%) as clinically with dementia. Of those without dementia, 627 (70.8%) were biomarker negative, and 258 (29.2%) were biomarker positive for p‐tau181. Of those with dementia, 173 (60.1%) were biomarker positive, and 115 (39.9%) were biomarker negative for p‐tau181. For those without dementia, there was no significant difference in education level or performance on most neuropsychological measures between those biomarker positive or negative, except that delayed recall on the SRT word‐list‐learning test was lower in those with higher p‐tau181 (mean 4.25 ± 2.27 vs. 4.65 ± 1.98; p=0.009). For those with dementia, education was significantly lower in those that were p‐tau181 negative (2.87 ± 3.36 vs. 4.18 ± 4.73 yr;p=0.011), but these individuals also performed significantly better in neuropsychological tests including SRT immediate (p=0.003) and delayed recall (p<0.001), orientation (p=0.002), and Benton‐matching (p=0.012).ConclusionPlasma biomarkers may perform well in diagnosis of dementia in clinic populations, but less well in underserved populations, with more persons without dementia but with positive biomarkers, and with dementia but with negative biomarkers. For those without dementia but with positive biomarkers, likely many have pre‐symptomatic Alzheimer's; lower performance on memory tests supports this explanation. For those with dementia, but without positive biomarkers, explanations may include lower cognitive reserve/educational attainment level, increased comorbidities affecting functional status, and the presence of non‐Alzheimer's brain disorders.
Meta‐analysis of Alzheimer’s disease clinical trial time savings results
Authors: Hendrix Suzanne B. , Hendrix Kent , Haaland Benjamin A , O'Keefe Patrick P , Knowlton Newman , Mallinckrodt Craig , Dickson Samuel P. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) clinical trials led to the recent successes with monoclonal antibodies targeting amyloid, which opens up many new directions for research into treatment for AD in the future. Gaining greater understanding from these successes and failures will help researchers to focus their efforts on avenues that have the highest potential benefit.MethodWe performed a meta‐analysis of over a hundred studies of 70+ AD treatments. A global statistical test (GST) combining ADAS‐cog, ADCS‐ADL and CDR‐sb was used to assess the overall efficacy in these studies, in a fair way across multiple outcomes. Disease modifying treatment effects and symptomatic effects impacting all disease symptoms will perform better on this GST than treatments impacting only one symptom. In addition, a false positive effect is less likely to occur on all 3 outcomes simultaneously, making the GST a more reliable outcome for detecting true treatment effects. Composite scores, ADCOMS and iADRS, were used to target true disease progression in the lecanemab and donanemab phase 2 studies, respectively, and have similar advantages to a GST. A similar approach would have possibly averted much of the controversy surrounding the aducanumab approval.ResultSome studies that were previously determined to be failures show some indication of positive effects. And conversely, some studies previously thought to be promising are shown to be more clearly failures. Meta‐analyses combining similar treatments across programs illuminate overlooked mechanisms as well as more conclusive failures.ConclusionThe success and failure of Alzheimer’s treatments is partly hidden by including 3 different domains of clinical efficacy: cognition, function and global. True treatment efficacy and true lack of efficacy are much easier to detect with multiple, combined outcomes.
Group Singing Programs for Well‐being of Older Adults: An In‐Person Quantitative Follow‐up
Authors: Bonakdarpour Borna , Schafer Rhiana , Miller Jonathan , Miller Sandra Siegel 
Published: January 2025

AbstractBackgroundSinging improves mood, social, and physical well‐being (Pentikainen et al., 2021). Choral singing has therefore gained recognition as a highly recommended activity for older adults and persons with dementia to fight isolation (Petrovsky et al., 2020; Sakamoto et., 2023). In a previous study, using qualitative measures, we demonstrated virtual sing‐along and choral singing offered by the Chicago‐based Sounds Good Choir and were associated with improved anxiety, emotional, and physical well‐being (Schafer et al., 2023) using qualitative, but not fully quantitative measures. The goal of this study was to determine whether in‐person choral singing and virtual sing‐along programs would improve older‐adults well‐being as measures by 7 quantitative surveys.MethodsParticipants were aged 55 and older. The sing‐along program engaged participants in virtual singing‐along to familiar music weekly for a year. The choir program consisted of 14 in‐person rehearsals to learn different parts of choral pieces. Following the program, self‐report assessments were solicited via 21 Likert scale questions covering 7 areas of well‐being (Table 1). Questions were developed from previous program evaluations and modeled off existing validated assessments of well‐being (Topp et al, 2015; Barrett & Murk, 2006; Dunn, 2008). Data were compared across program types using ANOVA, with Bonferroni corrected post‐hoc pairwise t test comparisons.ResultParticipants reported improvements in all aspects of well‐being in both programs (Figure 1). Two areas improved across the board with no effect of program type ‐ normalcy/structure and emotional. ANOVA indicated four well‐being areas were improved significantly more in choir participants than sing‐along (Figure 2) ‐ social (Q2‐4, p<0.001), intellectual (Q1‐4, p<0.001), physical (Q2, p<0.01), and spiritual (Q1, p<0.01). Connection to past was endorsed significantly more by sing‐along participants (p<0.01).ConclusionBoth choral and sing‐along programs improved all aspects of well‐being with choral singing showing more effect in social, intellectual, physical, and spiritual well‐being, and sing‐along achieving more connection to the past. Our results provide preliminary evidence that our quantitative measures can capture participants’ experiences. While a larger controlled study is necessary for confirmation, our findings may suggest that depending on feasibility, either program may be utilized for measurable well‐being effects in older adults.
Limbic predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is associated with lower volume in gray and white matter of the temporal and frontal lobes and basal ganglia: A deformation‐based brain morphometry study
Authors: Tazwar Mahir , Evia Arnold M , Ridwan Abdur Raquib , Bennett David A. , Schneider Julie A. , Arfanakis Konstantinos 
Published: January 2025

AbstractBackgroundLimbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC) is common in older adults and has been associated with substantial cognitive impairment. However, the association of LATE‐NC with brain morphometry has not been thoroughly investigated. In this work, we examined the association of LATE‐NC with brain morphometric anomalies using deformation‐based morphometry (DBM) in a large community cohort of older adults that came to autopsy (N=897).MethodCerebral hemispheres were acquired from 897 deceased older adults participating in Rush Memory and Aging Project, Religious Orders Study, Minority Aging Research Study, and Clinical Core. Hemispheres were imaged ex‐vivo on 3T MRI scanners, which was followed by detailed neuropathologic examination. The participant scans were non‐linearly registered to an ex‐vivo template, and the resulting deformation fields were used to calculate the logarithm of the Jacobian determinant in each voxel (LogJ maps). Voxel‐wise linear regression was used to test the association between deformations shown in the LogJ maps and LATE‐NC stages, controlling for other age‐related neuropathologies (Alzheimer’s disease, Lewy bodies, arteriolosclerosis, atherosclerosis, cerebral amyloid angiopathy, gross and microscopic infarcts), age at death, sex, education, postmortem intervals, and scanners. To identify the earliest LATE‐NC stage exhibiting morphometric abnormalities, LogJ values were compared between LATE‐NC stages 1–5 and stage 0. Statistical significance was set at p<0.05.ResultVoxel‐wise analysis revealed an independent association of LATE‐NC with significantly lower volume in both gray and white matter regions within the temporal and frontal lobes and basal ganglia (p<0.05), including amygdala, hippocampus, entorhinal, parahippocampal, temporal pole, inferior temporal, middle temporal, fusiform, medial orbitofrontal, lateral orbitofrontal, insula, accumbens, and putamen cortices. Groupwise comparison of LogJ values revealed significant morphometric anomalies in small temporal lobe areas in stages 1–2, more temporal lobe as well as basal ganglia tissue in stage 3, and finally also included frontal lobe areas in stages 4–5.ConclusionThe morphometric anomalies were detected as early as LATE‐NC stage 1, suggesting that MRI is sensitive to the early stages of the disease. This pattern is consistent with the known pathological distribution of LATE‐NC in the brain and may potentially be used in the development of a marker of this devastating neuropathology.
Evaluating brain age using functional connectivity in autosomal dominant Alzheimer disease
Authors: Macharia Kiana Angela , Gordon Brian A. , Wisch Julie K. , Metcalf Nicholas V , Roman June , Benzinger Tammie L.S. , Cruchaga Carlos , Goate Alison M. , Hassenstab Jason J. , Ibanez Laura , Karch Celeste M. , Llibre‐Guerra Jorge J. , Morris John C. , Perrin Richard J. , Renton Alan E. , Supnet Charlene B , Xiong Chengjie ,   Dominantly Inherited Alzheimer Network (DIAN), Bateman Randall J. , McDade Eric , Ances Beau , Millar Peter R 
Published: January 2025

AbstractBackgroundBrain‐predicted age estimates are used to quantify an individual's brain age compared to a normative trajectory. We have recently shown that brain age from structural MRI is elevated in autosomal dominant Alzheimer disease (ADAD), a unique sample that allows the study of AD progression independently of age‐related confounds. Resting‐state functional connectivity (FC) may capture a biphasic response to sporadic AD, and thus may complement structural measures of brain aging in ADAD.MethodWe trained a Gaussian Process Regression (GPR) model to predict age from FC in 271 regions of interest in 779 cognitively unimpaired, amyloid‐negative, non‐ADAD participants. We applied the model in a cohort of 256 ADAD mutation carriers (MCs) and 200 familial non‐carrier controls (NCs) from the Dominantly Inherited Alzheimer Network (DIAN). We then assessed whether the brain age gap (FC‐BAG; difference between predicted and actual age) varied based on mutation status, cognitive status, or estimated years until symptom onset (EYO). We also explored its associations with markers of amyloid (PiB PET, CSF amyloid‐ß‐42/40), phosphorylated tau (CSF and plasma pTau‐181), neurodegeneration (CSF and plasma neurofilament light (NfL)), and cognition (global neuropsychological composite and CDR®‐sum of boxes).ResultThe model accurately predicted age in the training set (r = 0.77), validation set (r = 0.76), and DIAN NCs (r = 0.82), Figure 1. FC‐BAG was elevated in symptomatic MCs (p < .001), but only marginal elevation was observed in asymptomatic MCs (p = 0.047), Figure 2. In symptomatic MCs, FC‐BAG weakly associated with pTau‐181 in CSF (r = 0.34, p = 0.0046) and plasma (r = 0.26, p = 0.02), but no other associations with AD biomarkers or cognition were observed, Figure 3.ConclusionFC‐BAG was elevated in symptomatic ADAD, consistent with recent demonstrations in sporadic AD. However, we did not detect a predicted biphasic response to presymptomatic ADAD pathology. This inconsistency may be driven by differences between AD forms or by low reliability of FC, which may result in low statistical power and inconsistent brain‐behavior relationships. FC‐based BAG offers unique benefits but ultimately does not function as a reliable model for observing advanced aging in preclinical ADAD.
Correlation between ERP and CSF biomarkers in Mild Cognitive Impairment and Dementia patients in a general neurological clinic population
Authors: Levy Igor 
Published: January 2025

AbstractBackgroundWe have recently reported on the use of Event‐Related Potentials (ERP) biomarkers to separate Amyloid PET positive vs Amyloid PET negative patients with mild cognitive impairment (MCI) and dementia. A large body of evidence shows that low levels of beta amyloid and increased tau in the CSF are highly correlated with Alzheimer’s pathology in the brain. We investigated the correlation between amyloid and tau in the CSF, and ERP responses in patients with MCI and dementia.MethodPatients with MCI and Dementia in a general neurological outpatient clinic underwent ERP testing. CSF analyses for Amyloid and TAU were also performed, and the results correlated with the output from the ERP test. When CSF studies were indeterminate, readings for brain amyloid brain load were obtained through PET analysis as part of the IDEAS (Imaging Dementia ‐Evidence for Amyloid Scanning) study when feasibleResultData will be presented at the conference with correlation between ERP markers and CSF amyloid and tau levels in patients with MCI and dementia.ConclusionStudy results will provide valuable insights into the use of ERPs in a general neurological population with Alzheimer’s disease and cognitive impairment.
Auditory Intervention Program for Older Adults with Cognitive Impairment: Systematic Review and Metaanalysis
Authors: Piyajarawong Teeraya , Limkitisupasin Patcharaorn , Manum Pornnapat , Utoomprurkporn Nattawan 
Published: January 2025

AbstractBackgroundThe elderly population is particularly susceptible to the development of age‐related hearing loss and cognitive impairment. The gradual decline in auditory perception often goes unnoticed, leading to a detrimental impact on their quality of life, mental well‐being, and overall communication skills. Extensive research indicates that prolonged social isolation can exacerbate cognitive decline. Fortunately, hearing intervention has the potential to prevent this devastating consequence.MethodThree independent reviewers meticulously reviewed the selected articles. The Covidence was utilized to identify and eliminate any duplicate publications. In cases of disagreement, a fourth reviewer was consulted for adjudication. For inclusion criteria, the studies had to be in the English language and conducted on a population aged 50 years or older who were diagnosed with cognitive impairment. Animal studies and those lacking control groups (either healthy controls or pre‐ and post‐intervention tests) were excluded. We utilized the National Institute of Health (NIH) criteria for evaluating the quality of studies.ResultOut of the initial 7,069 search results, we selected 39 articles for inclusion in this study. Among these, the majority comprised randomized trials (10 out of 39) and pre‐ and post‐intervention tests (10 out of 39). The hearing interventions were categorized into four distinct groups: hearing aids, cochlear implants, medication, and sound therapy. It was observed that medication showed the least efficacy while hearing aids and cochlear implants demonstrated the most significant improvements. Following the prescription of hearing aids and cochlear implants, patients experienced enhanced quality of life, despite significant improvement not only in cognition but also in psychological and social well‐being. Additionally, sound therapy exhibited promising results in terms of stress relief and improvement in instrumental and lyric recognition among cognitively impaired patients.ConclusionOur findings indicate that hearing aids, cochlear implants, and sound therapy significantly enhance psychological and social health in individuals with cognitive impairment or dementia. Furthermore, there is a statistically significant improvement in quality of life with appropriate hearing interventions. However, we observed no substantial improvement in cognitive status as assessed by the Montreal Cognitive Assessment (MoCA) and the Mini‐Mental State Examination (MMSE), although there is a suggestive trend towards cognitive enhancement.