bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gradient Analysis for the Study of Alzheimer's Disease
Authors: Camargo Aldo , Wang Ze 
Published: January 2025

AbstractBackgroundDys‐connectivity has been repeatedly shown in Alzheimer’s Disease (AD) but the change of connectivity gradient across the brain is under‐studied. In this study, we used resting state fMRI (rsfMRI) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to build a whole brain functional connectivity matrix. We then compared the major connectivity gradients decomposed from the connectivity matrix from normal controls (NC), mild cognitive impairment (MCI), and AD patients.Method30 NC, 11 MCI, and 40 AD were included in the analysis. Data preprocessing including motion correction, slice time correction, normalization, and artifact component removal, was performed using SPM12 and FSL. Mean rsfMRI time series was extracted from each of the 400 segments in the Schaefer atlas. A 400x400 functional connectivity matrix was calculated for each subject. Connectivity gradients were subsequently calculated using the BrainSpace toolbox. A mean connectivity matrix and its gradients were calculated for NC, MCI, and AD separately. Individual subject’s gradients were then aligned to those population level ones and compared across groups through two‐sample t‐test. Our analysis limits to the first three gradients as the corresponding eigenvalues explained >39 % of the original matrix variance. Multiple comparison correction was performed using Bonferroni correction.ResultFigure 1 shows the first gradient map for each sub‐group. The gradients were lowest in occipital cortex, and increased in the motor network and temporal cortex, and then gradually went down toward prefrontal cortex. Figure 2‐4 are the statistical comparison results. The first gradient map showed the largest cross‐sectional changes. Compared to NC, MCI had reduced gradients in occipital cortex, motor cortex, and temporal cortex. Gradients in occipital cortex and posterior part of temporal cortex further reduced in AD compared to MCI, and AD patient showed gradient reduction in prefrontal cortex.ConclusionWe found consistent functional connectivity gradient reduction in the AD continuum in occipital cortex and temporal cortex, suggesting a common pathway of AD‐related impairment to functional connectivity. Gradient reduction was identified in motor cortex in MCI compared to NC and was found in prefrontal cortex in AD compared to MCI, likely related to the escalated cognitive control and working memory decline in AD.
Exploring Polygenic Risk and Neuroimaging Parameters across the Alzheimer's disease Spectrum
Authors: Pandya Snehal , Venneri Annalena , De Marco Matteo 
Published: January 2025

AbstractBackgroundSporadic Alzheimer’s disease (AD) accounts for >90% of AD cases, of which 70% are thought to be due to a combination of several risk genes. Of these, Apolipoprotein E (APOE) is the most studied gene. Given that the APOE ɛ4 risk variant is found in ∼14% of the general population and ∼37% of the AD population, APOE ɛ4 is neither necessary nor sufficient to cause AD on its own. Investigating polygenic scores may lead to a better predictive model of AD, by studying many genes simultaneously, and increase understanding of how gene‐gene interactions may contribute to AD. The aim of this research was to review systematically papers exploring polygenic risk and neuroimaging parameters across the AD spectrum.MethodLiterature searches were conducted on three online databases: PubMed, Scopus, and Web of Science, between January–March 2023. All articles and early access papers, written in English, and on humans, were included. Reviews and systematic reviews were excluded. Papers were cross‐checked by three independent reviewers. Selected papers were assessed with a customised set of criteria to determine quality papers for this review and to avoid biases.Result3264 papers were found, of which 66 were eligible for review. Some papers used more than one imaging modality, therefore, there were a total of 80 studies: 49 structural, 8 functional, and 23 neuromolecular, covering regional and whole‐brain metrics. Polygenic risk scores and polygenic hazard scores are associated with regions vulnerable to AD, e.g., hippocampi, and entorhinal cortices. These findings are consistent across the three imaging modalities, and across the AD spectrum. In some cases, significant associations between polygenic scores and neuroimaging parameters are only present when including, or excluding, APOE. There are discrepancies in whether APOE increases, or decreases, strength of associations.ConclusionThis review demonstrates that attention must divert away from APOE since numerous genes impact brain architecture and connectivity, and it is their combined effect that is of key interest in sporadic AD. It highlights the challenges faced, and the intricacies that must be thought about, when constructing polygenic scores.
Design of A Phase 1 Trial for Safety, Tolerability, Single‐ascending Dose, Multiple‐ascending Dose, Food Effect, and Pharmacokinetic Study of TML‐6, A Novel Oral Multi‐Target Drug, in Healthy Volunteers
Authors: Lin Chien Hong , Chen Shang Hung , Yu Hsu Chia‐ , Wang Hui‐Chen , Su Ih‐Jen 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is complex in pathogenesis and related to aging biology, especially in late‐onset AD. We identified a novel synthetic curcumin analog TML‐6 through the platform of 6 biomarkers of anti‐aging, anti‐inflammation, and anti‐Aβ as the potential AD drug candidate. TML‐6 exhibits multi‐target effects on AD pathogenesis, including the activation of NrF‐2, the regulation of autophagic machinery through mTOR, the inhibition of APP synthesis and reduction of Aβ, the upregulation of ApoE, and the inhibition of microglial activation. In the past years, we conducted series of preclinical studies on TML‐6 which showed satisfactory bioavailability and sufficient safety. US pre‐IND consultation has been completed, and IND/ phase I trial is expected to be approved on February, 2024.MethodPhase 1 trial was designed into 5 parts containing 8 cohorts on 72 healthy subjects, including single ascending doses and multiple ascending doses. The food effect, the elderly subjects, the plasma pK analysis, and the CSF pK analysis were studied.ResultThe final phase I trial protocol was shown in the flow chart. The phase 1 trial will be conducted by CRO in Glendale Adventist Medical Center, LA, USA. According to pre‐clinical data, we anticipate good tolerability and safety of phase 1 trial through TML‐6 oral administration in healthy adults. The pK data will be analyzed for the design of dosing regimens in phase 2.ConclusionTML‐6 exhibits a multi‐target action mechanism meeting the new era strategy to develop AD drug. The combined data of phase 1 trial and 9‐month chronic toxicology in dogs will be applied to US FDA for global phase 2a trial, with integration of blood biomarkers. We look forward to the success of TML‐6 in clinical trials that will provide an ideal therapy, with potential of combining with anti‐amyloid drug, for Alzheimer’s disease.Key Words: TML‐6; curcumin analogue; Alzheimer’s disease; amyloid‐beta; aging biology
Sex Differences in the Associations of Cardiorespiratory Fitness with Executive function, Episodic Memory, and Global Cognition in Older Adults with Mild Cognitive Impairment
Authors: Yu Fang , Salisbury Dereck L. , Pituch Keenan A , Lin Feng Vankee 
Published: January 2025

AbstractBackgroundA potential mechanism underpinning the cognitive benefits from physical activity and aerobic exercise is cardiorespiratory fitness (CRF). Greater cardiorespiratory fitness (CRF) was associated with better executive function, short‐term memory, and global cognition in older adults without cognitive impairment. Sex differences in CRF has been established in adults. However, sex differences in the associations between CRF and cognition have been limitedly studied among older adults with mild cognitive impairment (MCI).MethodThis study examined sex differences in the associations of CRF with executive function, episodic memory, and global cognition in community‐dwelling older adults with amnestic MCI. Baseline data from the Aerobic exercise and Cognitive Training (ACT) Trial that tests the cognitive effects and mechanisms of 6‐month combined aerobic exercise and cognitive training were used. CRF was measured by peak oxygen consumption (VO2peak) in a laboratory‐based symptom‐limited peak cycle‐ergometer test. Executive function was measured with the EXAMINER that calculates 3 sub‐domain composite scores on working memory, cognitive control, and fluency, episodic memory with the Brief Visuospatial Memory Test‐Revised learning and delayed recall, and global cognition with Montreal Cognitive Assessment. Covariates included demographics, body‐mass index, comorbidities, activities of daily living, depression, and premorbid intellect. Regressions were performed.ResultOn average, the participants (N = 142) were 73.8±5.8 years of age with 16.9±2.9 years of education, 87.3% White, 51.4% male, and 69.7% married. Their VO2peak was 17.1±5.0 mL/kg/min. After controlling for covariates, VO2peak was related to executive function (β = 0.037, SE = .015, p<.05) and episodic memory (b = .590, SE = .226, p<.05), but not global cognition (b = .074, SE = .055, p > .05). The associations of VO2peak with executive function (b = .063, SE = .024, p<.05) and episodic memory (b = 1.008, SE = .312, p<.01) were significant for males only.ConclusionOur findings show that VO2peak was associated with executive function and working memory in the overall sample and males. Future studies need to examine longitudinal changes of CRF in preclinical AD and MCI to better understand of its sex‐differential impact on cognition and personalize exercise interventions on targeted cognitive domains based on sex.
Assessment of Interest and Resources Needed for the Development of Scalable Healthcare Professionals Facilitated Strategies to Diversify Alzheimer’s Disease Research Participation
Authors: Parker Monica W , Glover Crystal M , Johnson David K , Rentería Miguel Arce , Biber Sarah A , Wang Sophia 
Published: January 2025

AbstractBackgroundIncreasing underrepresented racial and ethnic minority group (URG) participation in early‐stage Alzheimer’s disease and related dementias (ADRD) research is critical to inclusive characterization of underlying pathology and testing of disease‐modifying treatments. One promising recruitment strategy to accelerate URG participation is for healthcare professionals (HCPs) to facilitate referrals. The use of HCP‐facilitated recruitment strategies across the Alzheimer’s Disease Research Center (ADRC) network, a major referral source for ADRD multisite observational and clinical trials, has not been examined. We hypothesized that there would be interest in the development of scalable HCP‐facilitated recruitment strategies to accelerate URG participation across the ADRC network.MethodsWe emailed Outreach, Recruitment and Engagement (ORE) Cores within the NIA‐funded ADRC network to complete a web‐based REDCap™ survey on their current HCP‐facilitated recruitment strategies for URG participants, resources enhancing use of these strategies, and their interest in strategy development. We conducted descriptive statistics using SPSS 29.0.ResultsOut of 37 ADRCs, 27 (73.0%) completed the survey. Although the majority of ADRCs (66.7%, N = 18) reported HCPs referring URG participants (Table 1), they mostly relied on HCP faculty based at the ADRC (48.1%, N = 13) or the ADRC affiliated academic medical center (51.9%, N = 14) (Table 2). Nearly all (92.5%, N = 25) ORE Cores expressed interest in participating in or learning more about future efforts to develop HCP‐facilitated recruitment strategies for increasing URG participation. Resources which would increase use of HCP‐facilitated strategies for URG referrals included guidance on outreach and engagement strategies (70.4%, N = 19), culturally tailored resources for HCPs to refer participants (59.3%, N = 16), technology and informatic recruitment strategies (63.0%, N = 17), and staff effort (63.0%, N = 17) (Table 3).ConclusionsOur survey identified key opportunities to develop novel scalable HCP‐facilitated recruitment strategies to accelerate URG participation. Although most ORE Cores expressed interest in expanding their HCP‐facilitated recruitment strategies to have more inclusive research participation, there is need for both higher‐level strategic guidance and ready‐to‐use resources to implement these strategies. Future studies will need to develop and test scalable HCP‐facilitated strategies and resources to systematically accelerate URG research participation.
DA‐7503, a novel tau aggregation inhibitor, ameliorates tau pathology and reduces CSF tau in transgenic mouse models of Alzheimer’s disease and primary tauopathies
Authors: Lee Min Jung , Choi Song‐hyen , Moon Jun‐Hwan , Lee Hyangsoo , Kim Eunjin , Lee Dae Young , Lim Sungsu , Kim Yun Kyung , Pae Ae Nim 
Published: January 2025

AbstractBackgroundElevation of cerebrospinal fluid (CSF) tau is a feature of Alzheimer’s disease (AD) and is being explored as a biomarker of AD and other tauopathies. The aim of this study was to elucidate the in vivo effects of DA‐7503, a potent and selective tau aggregation inhibitor, and its pharmacodynamics on CSF tau in transgenic mouse models of Alzheimer’s disease and primary tauopathies.MethodTauP301L‐BiFC mice expressing full‐length human tau with the P301L mutation were orally administrated with DA‐7503 for 1 month. CSF, plasma, and brain homogenates were collected at 4 time points from the last dosing. Total tau in CSF was measured using an AlphaLISA, and the concentrations of DA‐7503 in CSF and plasma by time were determined using LC‐MS/MS. To further evaluate the effectiveness of DA‐7503, neurobehavior and tau pathology were investigated after oral administration of DA‐7503 in TauP301L‐BiFC mice. The effect of DA‐7503 on tau pathology was also determined in human Tau (hTau) transgenic mice expressing all six isoforms of human tau combined with a knockout of murine tau.ResultIn a TauP301L‐BiFC AD mouse model, DA‐7503 showed not only a significant reversal of memory and recognition deficits but also an attenuation of tau aggregation and phosphorylation in the cortex and hippocampus. In these mice, DA‐7503 caused a significant reduction of CSF tau in a drug concentration‐dependent manner. DA‐7503 also reduced phosphoSer202‐tau in the brain cortex of hTau transgenic mice.ConclusionDA‐7503 restores the impairments of memory and recognition, and ameliorates the aggregation and hyperphosphorylation of tau in transgenic mouse models of AD and other tauopathies. The inverse correlation between total Tau in CSF and DA‐7503 exposure in plasma suggests that DA‐7503 induces an increase of tau clearance from the brain and CSF tau may be explored as a biomarker in clinical development of DA‐7503. Our findings indicate DA‐7503 is a promising agent for the treatment of AD and primary tauopathies.
Predictors of Life Expectancy in Community‐Dwelling People with Dementia – The Role of Social Support
Authors: Blotenberg Iris , Boekholt Melanie , Michalowsky Bernhard , Platen Moritz , Rodriguez Francisca S , Teipel Stefan , Hoffmann Wolfgang , Thyrian Jochen René 
Published: January 2025

AbstractBackgroundThe aim of the present study was twofold: First, to examine the validity of previously reported sociodemographic (age, sex) and clinical predictors (cognitive status, functional status, comorbidities) for the life expectancy in people with dementia in a community sample. Second, to investigate the role of social support beyond individual predictors.MethodThe study utilizes data from 500 individuals living in the community who were diagnosed with dementia. These participants were monitored over a period of up to eight years. The research focused on assessing life expectancy in connection with established sociodemographic factors (such as age and sex), clinical predictors (including cognitive status, functional status, and comorbidities), and also considered the impact of social support. This was analyzed using Cox regression.ResultAdvanced age increased the risk of mortality (hazard ratio [HR], 1.08; 95% CI, 1.05–1.11), while being female was associated with a lower mortality risk (HR, 0.65; 95% CI, 0.49–0.87). Higher cognitive (HR, 0.95; 95% CI, 0.93–0.98) and functional status at baseline (HR, 0.91; 95% CI, 0.86–0.97) were linked to increased life expectancy. Greater support from the social environment reduced the risk of mortality (HR, 0.79; 95% CI, 0.64–0.99), even after accounting for clinical variables.ConclusionPreviously reported sociodemographic and clinical predictors were confirmed within a community sample. Additionally, social support was found to predict life expectancy in individuals with dementia. Our findings highlight the crucial role of the social environment for the well‐being of individuals with dementia and emphasise the need for interventions that specifically address these factors.
Association and multimodal model of retinal and blood‐based biomarkers for detection of preclinical Alzheimer’s disease
Authors: Ravichandran Swetha , Snyder Peter J. , Alber Jessica , Jeromin Andreas , Chaby Lauren E , Arthur Edmund 
Published: January 2025

AbstractBackgroundThe potential of plasma Aβ42/Aβ40 ratio, NfL, p‐tau 181, and p‐tau 217 has been extensively discussed in the literature. Our previous study explored the association between retinal biomarkers and preclinical AD. The goal of this study was to evaluate the association and a multimodal model of retinal and plasma biomarkers for detection of preclinical AD.MethodsWe included 81 cognitively unimpaired (CU) participants (139 eyes; mean age: 67 years; range: 56‐80) from the Atlas of Retinal Imaging in Alzheimer's Study (ARIAS). Blood samples were assessed for concentrations of Aβ42/Aβ40 ratio, NfL, p‐tau 181, and p‐tau 217 (ALZpath, Inc.) using SIMOA technology. Spectralis II instrument was used to acquire macular centered SD‐OCT images for evaluation of putative retinal gliosis surface area and macular retinal nerve fiber layer (RNFL) thickness. A subgroup cohort of 57 eyes (32 preclinical, 25 controls; mean age: 69 vs 66, p = 0.06) were included for assessment of a multimodal model to distinguish between preclinical AD (PET Aβ+ve) and controls (PET Aβ‐ve). For all participants, partial correlations (accounting for age) were assessed between retinal and blood‐based biomarkers. For the subgroup cohort, an ROC analysis was performed to compare a multimodal model of the retinal and plasma biomarkers vs. each biomarker alone to distinguish between the two groups.ResultSignificant positive partial correlation was found between putative retinal gliosis and p‐tau 217 (ρ = 0.27, p = 0.001) but not for the other plasma biomarkers. The multimodal ROC model based on retinal (gliosis area, inner inferior RNFL thickness, inner superior RNFL thickness, and inner nasal RNFL thickness) and plasma biomarkers (p‐tau 217 and Aβ42/Aβ40 ratio) had an excellent AUC of 0.97 (95% CI = 0.93 – 1.01; p < 0.001) compared to unimodal models of gliosis and RNFL thickness; AUC = 0.68 (95% CI = 0.54 – 0.82, p = 0.01), ptau 217; AUC = 0.87 (95% CI = 0.78 ‐ 0.97, p < 0.001), and Aβ42/Aβ40 ratio; AUC = 0.54 (95% CI = 0.38 – 0.70, p = 0.67).ConclusionOur analysis shows the potential of integrating retinal and blood‐based biomarkers for improved detection and screening of preclinical AD.
A cross‐linguistic test of automated speech and language analysis for detecting Alzheimer’s disease: Machine learning evidence from English and Spanish speakers
Authors: Perez‐Toro Paula Andrea , Ferrante Franco Javier , Pérez Gonzalo Nicolás , Slachevsky Andrea , Nöth Elmar , Schuster Maria , Maier Andreas , Arroyave Juan Rafael Orozco , Garcia Adolfo M. 
Published: January 2025

AbstractBackgroundDigital health research on Alzheimer’s disease (AD) points to automated speech and language analysis (ASLA) as a globally scalable approach for diagnosis and monitoring. However, most studies target uninterpretable features in Anglophone samples, casting doubts on the approach’s clinical utility and cross‐linguistic validity. The present study was designed to tackle both issues.MethodThe study included 178 native English speakers from the Pitt corpus (134 with AD, 44 controls) and 39 native Spanish speakers from a Chilean cohort (21 with AD, 18 controls). Participants were audio‐recorded as they described the Cookie Theft picture. Recordings were used to extract speech timing features (reflecting semantic memory retrieval effort), whereas their transcriptions were used to derive vocabulary selection features (revealing lexicon navigation patterns). We first trained classifiers with English‐speaking AD patients and controls, and then tested them in (a) a within‐language setting (with English‐speaking patients and controls as testing folds) and (b) a between‐language setting (with Spanish‐speaking patients and controls as testing folds). To discriminate between groups, in each case, we ran a separate classifier per modality (timing, vocabulary) and then another combining both modalities via early fusion. Finally, we explored whether the most sensitive features in each setting could predict patients’ clinical severity, as indexed through the Mini‐Mental Status Examination (MMSE).ResultWithin‐language analysis showed that discrimination between AD patients and controls was good when based on speech timing (AUC = 0.75) and vocabulary (AUC = 0.79) features alone, and excellent when upon combining both modalities (AUC = 0.91). Between‐language analyses yielded maximal discrimination for the speech timing classifier (AUC = 0.79), surpassing vocabulary features (AUC = 0.60), and the fusion of both dimensions (AUC = 0.66). Patients’ MMSE scores were robustly predicted by speech timing features in both the within‐language (ρ = 0.41, p < .001) and the between‐language (ρ = 0.60, p < .001) settings.ConclusionInterpretable ASLA features capturing semantic memory processes can robustly identify AD patients, with speech timing measures showing greater potential for cross‐linguistic generalization and severity prediction. Our approach paves the way for novel studies bridging the gap between ASLA and global approaches to dementia.