bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study Design of the Evaluation of Self‐Mediated Alternatives for Risk Testing Education and Return of Results ‐ E‐SMARTER: A randomized trial from the Alzheimer’s Prevention Initiative program
Authors: Langlois Carolyn , Bradbury Angela R. , Wood Elisabeth MCarty , Harkins Kristin , Erickson Claire M , Largent Emily A. , Egleston Brian L , Reiman Eric M. , Grill Joshua D , Roberts J. Scott , Karlawish Jason , Langbaum Jessica B. 
Published: January 2025

AbstractBackgroundAvailability of amyloid modifying therapies will dramatically increase the need for disclosure of Alzheimer’s disease (AD) related genetic and/or biomarker test results. The 21st Century Cares Act requires the immediate return of most medical test results, including AD biomarkers. A shortage of genetic counselors and dementia specialists already exists, thus driving the need for scalable methods to responsibly communicate test results. The current study builds off our API Generation Program in which we demonstrated the safety and effectiveness of disclosing APOE and brain amyloid results via telemedicine to cognitively unimpaired adults.MethodThe Evaluation of Self‐Mediated Alternatives for Risk Testing Education and Return of Results (E‐SMARTER) is a decentralized, randomized trial to evaluate self‐directed, scalable eHEALTH platforms for communicating APOE, brain amyloid, and plasma ptau217 test results, as well as to characterize the clinical impact of learning this information. E‐SMARTER will enroll approximately 600 cognitively normal adults aged 60‐80. Participants will be randomized to receive results either via telehealth videoconference or by eHealth platform. Participants randomized to the eHealth arm will be offered either the ADWebPortal or ADChatbot but can switch between platforms or request to speak with a healthcare provider during the sessions.ResultStudy design and available participant demographics will be presented. Participants will complete online assessments evaluating their experience with the disclosure modalities as well as the impact of AD biomarker and genetic results disclosure. Participants complete assessments at baseline, prior to the initial APOE/amyloid PET disclosure session, and at approximately 0‐2 days, 6 weeks, 6 months, and 12 months following disclosure. pTau217 plasma levels will be assessed at 6 months after APOE/amyloid disclosure. PTau217 disclosure follow‐up assessments will be collected approximately 0‐2 days and 6 weeks after disclosure of pTau217 results. A final combined APOE/Amyloid and 6‐Month pTau217 follow‐up assessment will be collected approximately 12 months following the initial APOE/Amyloid disclosure.ConclusionThe E‐SMARTER study addresses the need for practical and scalable methods to responsibly communicate AD genetic and/or biomarker results. The E‐SMARTER eHEALTH platforms will be made available to support healthcare providers in returning genetic and/or biomarker results to individuals in clinical and research settings.
Health‐Related Behaviours in Octogenarians and Nonagenarians with Robust Cognitive Longevity: Progress and Initial Data from thee SuperAging Research Initiative
Authors: Roberts Angela C , Ooteghem Karen Van , McIlroy Bill , Culum Ivan , Beyer Kit B , Thai Vanessa , Aulakh Nimrit , Li John , Dunne Ciara , Lim Andrew , Swartz Richard H , Finger Elizabeth , Maher Amanda Cook , Okonkwo Ozioma C , Goldstein Felicia , Huentelman Matthew J. , Geula Changiz , Rogalski Emily J 
Published: January 2025

AbstractBackgroundSuperAgers—individuals age 80+ with episodic memory performance at least as good as those 20‐30 years younger—provide a unique perspective on cognitive resilience and resistance in aging. The SuperAging Research Initiative (SRI), spearheaded by The University of Chicago and involving multiple academic partners, investigates factors underpinning robust cognitive aging. One key SRI project, leverages a fully remote data collection paradigm to: 1) discern activity patterns that characterize SuperAgers and 2) explore the 'complexity hypothesis in aging'—whether dynamic physiological responsiveness is a hallmark of exceptional cognitive aging. Here we report on feasibility and initial outcomes from this project.MethodParticipants don wearable sensors, including an ECG sensor (chest) and two inertial measurement units (wrist, ankle), for a 10–12‐day period of continuous data collection whilst performing their usual daily activities. The protocol includes a virtual orientation and periodic check‐ins to ensure wear‐compliance and provide technical support. Structured sensor‐wear breaks facilitate protocol compliance and acceptance.ResultTo date, recruitment efforts have led to enrollment of 91 individuals (Mean age = 84.1 years; 62 women), which approximates half of the total SRI sample. Reasons for ineligibility or non‐enrollment include dermatological contraindications, ‘busy’ lifestyles, and perceived participation burden. Initial analyses of 44/58 participants who have completed data collection show exceptional adherence (>95% sensor wear compliance) (Table 1). Limited data loss due to sensor non‐wear and/or sensor failure demonstrates high data quality (Table 1). Notably, participants demonstrate a high level of independence, with study partner assistance required in < 5% of cases. Withdrawals have been minimal (3%) and primarily attributed to skin irritation due to undisclosed dermatological contraindications. Initial data are provided in Figure 1 and Table 2 including daily activity summary data and group comparisons between SuperAgers and Controls. Updated data will be presented at the conference.ConclusionWearable technologies are feasible for remotely assessing daily activities of octogenarians and nonagenarians with high compliance. Objective quantitative data hold promise for expanding our understanding of lifestyle factors relevant to superior cognitive aging. Insights from this study may influence preventive intervention strategies against age‐associated neurological diseases and in support of enhancing cognitive longevity.
Changes in cognition of ADRD patients: effects of social isolation proxies, utilising data from UK electronic health records
Authors: Myers James A C , Stafford Tom , Vaci Nemanja 
Published: January 2025

AbstractBackgroundMarital status and living status are components of social isolation (SI), a modifiable factor thought to impact cognitive resilience, which has the potential to impact cognition throughout the course of Alzheimer’s and related dementia (ADRD) diagnosis. Electronic health records (EHRs) offer access to large scale clinical data, capable of longitudinal analyses.MethodCognitive function measurement – Montreal Cognitive Assessment (MoCA) – data, demographic (including marital and living status as SI proxies) data and ADRD diagnosis data from patients aged 50+ years from Oxford Health NHS Foundation Trust (UK) were extracted using natural language processing algorithms from EHRs dated 1995 to 2022. Longitudinal multilevel models were used to predict cognition as a function of the interaction between diagnosis duration and SI proxies, controlling for age, sex and diagnosis cause.Result‘Lifelong single’ marital status significantly predicted reduced cognition intercept scores for the MoCA dataset (𝛽 = ‐1.61, SE = 0.67, t = ‐2.42, p = 0.016). No significant marital status predictors for slope were found. Living in supported accommodation significantly predicted steeper slopes for cognition (𝛽 = ‐2.37, SE = 0.33, t = ‐7.20, p < 0.001). No living status levels significantly predicted slopes.ConclusionWorldwide ADRD incidence is predicted to increase dramatically within the next 30 years, therefore studies investigating the impact of modifiable factors on the rates of cognitive change in ADRD patients are valuable to enhancing understanding of patient care. SI data extracted from EHRs can be used to predict differences in patient cognition scores.
Cardiorespiratory Fitness Modifies the Association of Cerebral Pulsatility on CSF Biomarkers Related to Neurodegeneration, Synaptic Dysfunction, and Neuroinflammation
Authors: Brach Talia L. , Breidenbach Brianne M. , Glittenberg Matthew P , Symanski Leah E , Naren Tarun , Driscoll Ira , Lose Sarah R , Gallagher Catherine L. , Johnson Sterling C. , Asthana Sanjay , Betthauser Tobey J. , Rivera‐Rivera Leonardo A. , Hermann Bruce P , Sager Mark A. , Blennow Kaj , Zetterberg Henrik , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Cook Dane B. , Wieben Oliver , Okonkwo Ozioma C 
Published: January 2025

AbstractBackgroundCerebral pulsatility (PI) is reportedly higher in individuals with AD and MCI compared to age matched controls and has been associated with greater beta‐amyloid (Aß) burden, but its relationship to other neurodegenerative biomarkers is unknown. Higher cardiorespiratory fitness (CRF) positively affects vascular function and is associated with lower PI in several large cerebral vessels. The relationship between PI, CRF, and biomarkers for neurodegeneration have not yet been characterized. Our objective was to examine a potential CRF modification of the relationship between PI and cerebrospinal fluid (CSF) biomarkers of neurodegeneration, synaptic dysfunction, and neuroinflammation.MethodsCognitively unimpaired adults (n=32, Mean Age=64) from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center who met selection criteria were included. PI from bilateral MCA vessels were measured using 4D flow MRI and averaged (PI‐MCAAVG). CRF was measured as peak VO2PEAK during a graded exercise treadmill test. CSF was obtained via lumbar puncture and measured using the NeuroToolKit, a panel of robust prototype assays (Roche Diagnostics International Ltd). The toolkit included measures of: neurodegeneration [α‐synuclein (α‐syn) and neurofilament light polypeptide (NfL)], synaptic dysfunction [neurogranin (Ng), synaptosomal‐associated protein 5 (SNAP‐25), and neuronal activity related protein 2 (nptx2)], and neuroinflammation [glial fibrillary acidic protein (GFAP), soluble triggering receptor expressed in myeloid cells (sTREM2), and chitinase‐3‐like protein 1 (YKL‐40)]. A single multivariate regression model, adjusted for sex, age, and APOE4, examined whether the association between PI‐MCAAVG and CSF biomarkers varied as a function of CRF.ResultsThere was a significant interaction between PI and VO2PEAK on α‐syn (ß = ‐22.66, p=0.04), Ng (ß =‐171.46, p=0.01), SNAP‐25 (ß = ‐0.35, p= 0.02), STREM2 (ß =‐1.04, p=0.02), and nptx2 (ß =‐1037, p=0.04) indicating more favorable profiles of CSF biomarkers with increasing VO2PEAK despite elevated PI. No significant interactions were found for NfL, GFAP, or YKL40 (all p’s > 0.05).ConclusionOur findings support the hypothesis that increased CRF influences the relationship between cerebral PI and CSF biomarkers related to neurodegeneration, synaptic dysfunction, and neuroinflammation indicating that improved CRF may offer protection against cerebrovascular alterations known to coincide with biomolecular changes in various types of dementia.
Converging mitochondrial MicroRNA Patterns: Ischemic Stroke and Alzheimer's Connections
Authors: Vijayan Murali , Reddy Hemachandra 
Published: January 2025

AbstractBackgroundThe present study delves into the intricate molecular connections between ischemic stroke (IS) and Alzheimer's disease (AD) through an analysis of mitochondrial microRNA (miRNA) patterns. By exploring their shared signatures in the context of IS and AD, our aim is to unravel potential common pathways, understand shared molecular mechanisms, explore diagnostic and therapeutic opportunities, gain a comprehensive understanding of neurodegeneration, and advance the field of biomarker research.MethodTo explore these intriguing questions, mitochondria were isolated from postmortem brains of individuals with IS, AD, and healthy controls (n=10 each). Subsequently, miRNA extraction was carried out using the isolated mitochondria. Following this, a comprehensive analysis of global miRNA profiles in mitochondrial fractions was performed for all three groups, utilizing Hiseq 2000 or 2500 Sequencing & Pipeline filter (Illumina Inc). Furthermore, we employed the Ingenuity Pathway Analysis (IPA) software to elucidate the biological processes, cellular components, and molecular pathways associated with potential mitochondrial miRNAs.ResultOur results unveil distinct transcriptomic signatures in healthy control, IS, and AD groups. Particularly noteworthy is the identification of significant common mitochondrial miRNA alterations in both IS and AD. Furthermore, the application of IPA to mitochondrial miRNAs reveals their involvement in key signaling pathways, including calcium, Ras, P13K‐Akt, MAPK, and axon guidance. All of these pathways play central roles in the pathogenesis of both ischemic stroke and Alzheimer's disease.ConclusionOur study is the first to delineate common mitochondrial miRNA signatures in the states of IS and AD. Furthermore, this comprehensive miRNA‐seq analysis reveals the interconnectedness of these two prevalent neurological disorders at the molecular level, offering valuable insights for future therapeutic interventions and diagnostic strategies.
INTERCEPT‐AD: Understanding the Patient Experience and Expectations for Treatment Through Qualitative Interviews Among Trial Participants with Early Alzheimer’s Disease and Their Study Partners
Authors: Johnston Kelly , Presnall Carrie , Merikle Elizabeth , Cline Stephanie , Feaster Todd , Siemers Eric 
Published: January 2025

AbstractBackgroundIncorporation of the patient voice into drug development has been recognized as fundamental; recent legislation has addressed the importance of collecting patient experience data. Qualitative patient interviews conducted in tandem with clinical trials, often in later phases, are among the most common means of eliciting these data. To assess aspects of patient experience earlier in development, we conducted semi‐structured qualitative interviews following participation in the phase 1 ACU‐001 (INTERCEPT‐AD) trial, a study evaluating the safety and tolerability of the Aβ oligomer‐targeting monoclonal antibody ACU193, among a subset of participants with mild cognitive impairment (MCI) or mild Alzheimer’s disease (AD) and their study partners. Interview topics included disease experience and expectations for treatment.MethodInterviews followed the end‐of‐study visit and included both participants and study partners. Participants were asked to report their most problematic symptoms, to describe what they would hope to gain from a new AD treatment, and what changes would be meaningful. The interview guide was developed in accordance with FDA Patient Focused Drug Development guidance. Principles of qualitative thematic analysis guided the coding and analysis of transcripts, with additional features drawn from grounded theory, conforming to best practices.ResultTwenty‐eight participants and their study partners were interviewed. Participants reported a broad array of problems consistent with AD. The most frequent included difficulty with memory or cognitive functioning (96.4%), getting lost (71.4%), mood (60.7%), and difficulty communicating (57.1%). Within each of these groupings, specific problems varied among participants; higher numbers of participants reported forgetting appointments, names, and losing things (81.4%) and getting lost while driving (90.0%), while fewer reported feeling isolated (5.9%) and experiencing confusion (11.1%). Nearly every participant desired treatment that would keep the disease from getting worse or slow progression (89.3%), which was equated with maintenance of functional abilities. Maintaining the ability to recognize loved ones and communicate were also stated as important benefits of a new treatment.ConclusionProblems reported by participants were typical to AD, although there was heterogeneity in overall AD experience. Changes in mood were frequently reported. These findings highlight the need to contextualize clinical trial results by incorporating the patient voice.
Comparison of MRI T2 FLAIR White Matter Hyperintensity Segmentation Algorithms in Clinical Trials
Authors: Scheel Norman , Hubert Josh , Baker Joshua H. , Fernandez Zachary , Yanev Pavel G. , Stowe Ann M , Vongpatanasin Wanpen , Zhang Rong , Zhu David C 
Published: January 2025

AbstractBackgroundWhite Matter Hyperintensities (WMH) appear on T2‐weighted Fluid‐Attenuated Inversion Recovery (FLAIR) Magnetic Resonance Imaging (MRI) and are an important biomarker of cerebral small vessel disease (CSVD), cognitive decline, and stroke. However, manual delineation is laborious and bias‐prone, while automated segmentation has proven challenging. With the recent conclusion of the MICCAI‐Society WMH segmentation challenge, and our large clinical trials, “Risk Reduction for Alzheimer’s Disease” (rrAD) and “Hypertension, Intracranial Pulsatility and Brain Amyloid‐beta Clearance in older adults” (HIPAC), we investigated the differences in the total WMH volume segmented by various algorithms to ensure the extraction of accurate and meaningful image‐derived phenotypes.MethodsThe rrAD trial provides 512 2D axial T2 FLAIR scans, fat saturation off (ages 60‐85). The HIPAC study provides 84 3D T2 FLAIR scans, fat saturation on (ages 55‐79). The MICCAI WMH challenge provides a test set of 110 scans of 2D axial T2 FLAIR images, 30 without, and 80 with fat saturation. Our clinical trials and the MICCAI datasets comprise data from over 700 subjects, across 10 scanners and diverse sequences. Three of the best‐performing MICCAI algorithms were selected: PGS, Sysu‐Media‐2, FMRIB‐TrUE‐Net2, as well as the LPA algorithm from SPM. Segmentation results were randomized, and fully blinded expert raters scored a subset of 120 scans.ResultsFigure 1 depicts the average normalized images for each T2 FLAIR contrast. The MICCAI test set shows a median WMH burden of 10‐17 ml, while rrAD subjects presented with relative medians of ≈3−4 ml, and HIPAC subjects with ≈2−3 ml. Figure 2 shows the WMH volume for each segmentation algorithm and dataset. For HIPAC Sysu‐Media‐2 had high false pickup within grey matter regions, while LPA produced high false pickup at the posterior septum pellucidum. PGS scored best in manual ratings.ConclusionsMRI sequences that use fat saturation change the T2 FLAIR image contrast substantially and impact segmentation performance, we observed better performance with fat saturation off. The MICCAI challenge algorithms outperformed classical methods (PGS leading), detecting small lesions, away from the ventricles. As WMH distribution, shape, and longitudinal tracking are likely more sensitive biomarkers than volume alone, further analysis is warranted.
Gray Matter Alterations Associated with Aging & APOEε4 Genotype in 37,437 Participants from the UK Biobank
Authors: Gleave Emma J , Thompson Paul M. , Rajagopalan Priya 
Published: January 2025

AbstractBackgroundCarrying one or more copies of the apolipoprotein E ε4 allele represents the greatest known source of genetic risk for late‐onset Alzheimer’s disease (AD), although the mechanisms are not fully understood. Several smaller‐scale studies have analyzed APOEε4 effects on brain volume, reporting gray matter volume (GMV) alterations in medial temporal and precuneal regions in people with AD and in healthy APOEε4 carriers. Here, we analyzed brain images from a large sample of healthy elderly adults in relation to ε4 carrier status, stratifying by age to assess potential group differences.MethodThe Computational Anatomy Toolbox (CAT12) was used to perform a large‐scale voxelwise segmentation of 3D T1‐weighted brain MRI data from the UK Biobank. The statistical relationship between voxel‐wise brain GMV and APOEε4 genotype was assessed using a dominant model for presence or absence of APOEε4 allele across 37,437 subjects (51.7% female; 64.6 (7.7SD) years old), separated into three age bins (Bin1: <60 yrs old; Bin2: 60‐70 yrs old; Bin3: >70 yrs old; Table 1). Linear mixed model analyses for APOEε4 in relation to GMV were performed for the full sample and within each age bin, adjusting for age, sex, genetic ancestry, intracranial volume (ICV), and scan site.ResultLower GMV was associated with APOEε4 (standard‐FDR critical P‐value=0.0002; q=0.05), after covarying for age, sex, ancestry, and ICV. Effects were detected in the bilateral mesial temporal lobe structures including bilateral amygdala, posterior hippocampus and punctate foci within bilateral thalami. A large region of association was found in the oldest age‐group (>70yrs; Bin3). Significance maps are shown in Figure 1.ConclusionWe identified alterations in GMV related to carrying at least one APOEε4 allele in one of the largest neuroimaging samples to date. Extending prior work, even healthy adult carriers of the APOEε4 haplotype demonstrated neurostructural gray matter alterations. Such neurostructural alterations may be more salient in older age, highlighting the need for continued study of ε4 expression mechanisms and their interaction with aging
WMH and AD: is CAA the missing piece? Potential consequences at the anti‐amyloid era
Authors: Charidimou Andreas ,   Department of Neurology, Boston University School of Medicine, Boston, MA, USA
Published: January 2025

AbstractUnderlying cerebral amyloid angiopathy (CAA) is extremely common in patients with Alzheimer’s disease, contributing to cognitive impairment and hampering anti‐amyloid treatments safety. Distinct patterns of white matter hyperintensities (WMH) are supporting markers of CAA and are now included in the Boston criteria, along other hemorrhagic features of the disease. These WMH patterns includes a multispot WMH pattern in the cortical‐subcortical regions and posterior predominance of WMH. This presentation will focus on THE core imaging markers of CAA, including clinical interpretation of WMH in the context of suspected CAA, associated features and potential relevance for ARIA in anti‐amyloid treatments.