bluuebunny/crossref_metadata_2025_split huggingface dataset:
MRI and PET findings with long‐term gantenerumab treatment: results from the DIAN‐TU trial
Authors: Benzinger Tammie L.S. , Gordon Brian A. , McCullough Austin A. , Hornbeck Russ C. , Flores Shaney , Koeppe Robert A. , Jack Clifford R. , Li Yan , McDade Eric , Llibre‐Guerra Jorge J. , Clifford David B. , Mills Susan , Santacruz Anna , Wang Guoqiao , Supnet‐Bell Charlene , Ibanez Laura , Klein Gregory , Baudler Monika , Doody Rachelle S. , Kerchner Geoffrey A. , Atri Alireza , Bateman Randall J. ,   The DIAN‐TU Study Team
Published: January 2025

AbstractBackgroundAnti‐amyloid monoclonal antibody therapies for AD have documented plaque removal on amyloid PET scans. We evaluate the findings for amyloid PET, tau PET, FDG PET and volumetric MRI over the course the open label extension (OLE) for the DIAN‐TU gantenerumab treatment, compared to the last imaging obtained prior to the OLE (to evaluate for potential rebound effects) and in comparison to longitudinal imaging in the DIAN Observational study.MethodThis double‐blind, phase 2/3 trial (2012‐2019), followed by open‐label extension (OLE), investigated varying gantenerumab doses up to 1500 mg SQ q2 weeks [NCT NCT01760005]. We report long‐term amyloid‐plaque removal by PET and findings for metabolic FDG PET and tau PET, and additionally changes of atrophy on volumetric MRI. Imaging measures were secondary outcome analyses. Comparison is made between the treatment cohort and controls (DB placebo participants who didn’t enter OLE, plus external controls from the DIAN OBS). Estimated years to onset was included as a covariate. The gap period of ∼1 year is specifically analyzed to estimate any “rebound” effect on amyloid or tau accumulation or neurodegeneration. Volumetric MRI measures include hippocampal volumes, lateral ventricular volumes, and white matter hyperintensities.ResultIn participants who were asymptomatic at baseline and treated with gantenerumab (n = 53), amyloid‐plaque removal measured by PIB‐PET in Centiloids was dose‐dependent. Few participants had reached completely negative levels (below 24). No statistical significance was found for FDG PET, tau PET, or volumetric MRI, including hippocampal volumes. Impact of the gap period of ∼1 year (gap in treatment) on the rate of amyloid accumulation compared to the rate of accumulation predicted in observational studies of this cohort is under evaluation, as are the other imaging measures.ConclusionWhile no overall effect was observed in the total group for non‐amyloid measures, results suggest dose dependent clearance of amyloid plaque in asymptomatic DIAD mutation carriers following long‐term, high‐dose gantenerumab. The potential “rebound effect” of elevated amyloid accumulation for participants for whom there was a significant gap in therapy between the trial and the OLE is under evaluation and will be presented, as will the variables for FDG PET, tau PET, and volumetric MRI.
Comparison of Relative Change with Effect Size Metrics in Alzheimer’s Disease Anti‐amyloid Clinical Trials
Authors: Goldberg Terry E. , Lee Seonjoo , Devanand Davangere , Schneider Lon S. S. 
Published: January 2025

AbstractBackgroundPercent slowing of decline is frequently used as a metric of outcome in Alzheimer’s disease (AD) clinical trials, but it may be misleading. Our objective was to determine whether percent slowing of decline or Cohen’s d is the more valid and informative measure of efficacy.MethodOutcome measures of interest were percent slowing of decline; Cohen’s d effect size, and number‐needed‐to‐treat (NNT). Data from a graphic were used to model the inter‐relationships among Cohen’s d, placebo decline in raw score units, and percent slowing of decline with active treatment. NNTs were computed based on different magnitudes of d. Last, we tabulated recent AD anti‐amyloid clinical trials that reported percent slowing and for which we computed their respective d’s and NNTs.ResultWe demonstrated that d and percent slowing were independent. While percent slowing of decline was dependent on placebo decline and did not include variance in its computation, d was dependent on both group mean difference and pooled standard deviation. We next showed that d was a critical determinant of NNT, such that NNT was uniformly smaller when d was larger. In recent AD associated trials including those focused on anti‐amyloid biologics (aducanumab, lecanemab, gantenerumab, and donanemab), d’s were below 0.23 and thus small, while percent slowing was in the 12%‐27% range and NNTs ranged from 14‐34.ConclusionStandardized effect size is a more meaningful outcome than percent slowing of decline because it determines group overlap, which can directly influence NNT computations, and yield information on the likelihood of minimum clinically important differences. In AD, greater use of effect sizes, NNTs, rather than relative percent slowing, will improve the ability to interpret clinical trial results and evaluate the clinical meaningfulness of statistically significant results.
Large‐scale proteomic and genomic analysis identify plasma proteins influencing human brain structure and Alzheimer’s disease risk
Authors: Ayubcha Cyrus , Sun Benjamin B , Ge Tian , Chen Chia‐Yen 
Published: January 2025

AbstractBackgroundRecent advances in proteomics technology enable us to comprehensively examine the impact of the proteome on Alzheimer’s disease (AD) and intermediate phenotypes, such as brain imaging measures. Here, by leveraging large‐scale proteomic, brain imaging, and AD genome‐wide association studies (GWAS), we performed Mendelian randomization (MR) and colocalization analysis to investigate the impact of plasma protein levels on brain imaging measures and the link between plasma protein levels, brain imaging, and AD.MethodWe leverage the protein quantitative trait loci (pQTL) datasets from the UK Biobank Pharma Proteomics Project (UKB‐PPP; 2,625 proteins by Olink assay) and deCODE genetics (Ferkingstad et al. 2021; 4,472 proteins by SomaLogic assay). UKB‐PPP and the deCODE study represent the largest plasma proteomics GWAS to date based on two different proteomics platforms, where the total sample sizes are over 30,000 for each. For the brain imaging and AD genetic datasets, we used the brain imaging GWAS from UKB (453 T1 MRI and DTI imaging; Smith et al. 2021), and AD GWAS from Bellenguez et al. 2022.ResultAfter extensive data processing and quality control, we performed two‐sample MR and identified significant associations in 170 protein‐DTI imaging pairs and 38 protein‐MRI pairs for 60 unique proteins from UKB‐PPP and 41 unique proteins from deCODE. Colocalization analysis further prioritized proteins related to AD implicated in previous studies. We further extended the association between plasma protein and brain imaging to AD by performing MR and colocalization analyses using pQTL and AD GWAS. As an example, we showed that plasma progranulin (P28799) level showed a significant effect on AD risk (P = 6.79×10−12), while supported by associations between plasma progranulin level and caudate volumes (right and left T1 DTI, P = 8.41×10−6).ConclusionIn summary, we presented the largest to date study for the impact of plasma protein levels on brain imaging measures and a novel approach to identify biomarkers for AD. Overall, the integration of large‐scale MRI, proteomics, AD phenotype, and genome‐wide data holds great promise for enhancing our understanding of AD, and ultimately facilitates biomarker discovery and therapeutic development.
Blood‐based Proteomic Profiling for the Progression of Cognitive Decline, Neuropsychiatric Symptomatology, and Neuroimaging Outcomes within an Asian Memory Clinic Cohort
Authors: Sim Ming Ann , Choi Hyung Won , Cai Yuan , Richards Arthur Mark , Chen Christopher 
Published: January 2025

AbstractBackgroundThe prognostic performance of plasma proteomics for longitudinal changes in (i)cognition (ii)neuropsychiatric symptomatology and (iii)neuroimaging outcomes within South East Asia, where prevalence of cerebrovascular disease is high, remains un‐investigated.MethodsA prospective cohort of Singaporean memory clinic attendees was followed‐up for 4 years. Annual neurocognitive and neuropsychiatric assessments were performed alongside 2‐yearly brain magnetic resonance imaging (MRI) scans. Incident cognitive decline was defined as a Clinical Dementia Rating Scale Sum‐of‐Boxes (CDR‐SB) ≥3 increment from baseline. Significant neuropsychiatric symptomatology progression was defined by a Neuropsychiatric Inventory score increment of ≥4 from baseline.Neuroimaging outcomes evaluated included (i)rates of progression of cerebral small vessel disease (white matter hyperintensity volume) and (ii)hippocampal atrophy on 2‐yearly MRI scans.1536 plasma proteins (encapsulating all major biological pathways including neurological, immune‐oncological, cardiovascular and inflammatory pathways) were profiled at baseline using the Olink Explore 1536 platform. Their associations with cognitive, neuropsychiatric and MRI outcomes were subsequently evaluated in multivariable regression models, with correction for false‐discovery rate.ResultsOf 528 subjects (mean age 72.83±7.81years, 43.8% male, 57.9% cerebrovascular disease, 22.4% NCI, 40.3% CIND, 37.3% dementia), the incidence of cognitive decline was 31.6% (167/528). Among 245 proteins significantly associated with cognitive decline, GFAP and NEFL were the most powerfully prognostic (Fig. 1).The incidence of significant progression of neuropsychiatric symptomatology was 55.68% (294/528). Among 310 proteins significantly associated with the progression of neuropsychiatric symptoms, NEFL and DCBLD2 were the most prognostic (Fig. 1).NEFL and TNFRSF11B were the most significantly dysregulated proteins for cerebral small vessel disease progression, while GFAP and NEFL significantly associated with rate of hippocampal atrophy. These top proteins also significantly associated with the rates of domain‐specific decline in 4 or more cognitive domains assessed over 4 years (Fig. 2).The top two gene ontology biological pathways identified from all data on significantly dysregulated proteins, were (i)cell adhesion and (ii)signal transduction, in both clinical entities (Fig. 3).ConclusionOur findings, upon interrogation of a biobank from a well‐annotated cohort, identifies late‐stage protein biomarkers and biological pathways for a suite of longitudinal cognitive, neuropsychiatric and neuroimaging outcomes. These biomarkers warrant further validation and mechanistic elucidation as potential therapeutic targets.
Effects of APOE e4 and Neuropathological Diagnoses on Neuropsychiatric Symptoms: Mediation Analyses and Likely Causation in an Integrated NACC Database
Authors: Goldberg Terry E. , Kim Hyun , Devanand Davangere , Lee Seonjoo 
Published: January 2025

AbstractBackgroundOur goal in this study was to identify paths from APOE e4 to neurobehaviors itemized on a neuropsychiatric inventory that involved neuropathologies associated with e4 (amyloid, tau, cerebral amyloid angiopathy, and Lewy bodies) or cognition mediators (memory or global cognitive status), as well as direct paths from e4 to cognition or neurobehaviors.MethodA total of 1199 cases with available neurobehavioral, cognition and neuropathological data were included. We then conducted a series of causal mediation analyses in R in which e4 always served as the independent variable and Neuropsychiatric Inventory (NPI) neurobehavioral items, when included in the mediation, the outcome. Neuropathologies or cognition served as mediators.ResultMultiple significant indirect paths from e4 through neuropathologies to neurobehaviors were identified. More refined analyses indicated that neuritic plaques and Braak stage, but not extent of diffuse amyloid plaques, drove the findings. A significant direct effect of e4 to memory was also identified. Additionally, Lewy body disease, when treated as an exposure, had a direct effect on hallucinations in keeping with known features of the disease.ConclusionWe found strong evidence for partial mediation of NPI symptoms by cognition, suggesting that cognitive limitations that may have influenced understanding (or misunderstanding) the environment with impacts on maladaptive behavior. In addition, neuritic amyloid plaque levels and Braak stage, but not diffuse amyloid plaque extent, were key in NPI mediated associations suggesting the possibility that synaptic failure play an important role in multiple neurobehavioral symptoms in dementia, including psychosis. Last, we found strong evidence that e4 may have direct effects on cognition when we used verbal episodic memory as an outcome, suggesting that medial temporal regions that support memory may be sensitive to non‐amyloidogenic and non‐tau related pathophysiological processes.
Evaluation of serum level of seven Sirtuins in Alzheimer’s Disease patients: Biomarker based on the Translational Research
Authors: Singh Abhinay Kumar , Pradhan Rashmita , Chatterjee Prasun , Dey Sharmistha 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Dysfunction of mitochondria and oxidative stress are known to aggravate the disease pathology. Sirtuins, NAD‐dependent deacetylases, have a well‐defined role in this pathway and thus can serve as a potential biomarker for the early detection of the disease.MethodThis study evaluated the level of serum Sirtuins (SIRT1–SIRT7) in three study groups: AD, mild cognitive impairment (MCI) and geriatric control (GC) by the label free surface plasmon resonance (SPR) technology and was further validated by the Western blot experiment. ROC analysis was performed to differentiate the study group based on the concentration of serum SIRT proteins.ResultOut of seven Sirtuins, serum level of SIRT1, SIRT3 and SIRT6 (mean ± SD) were significantly decreased in AD (1.65 ± 0.56, 3.15 ± 0.28, 3.36 ± 0.32 ng/μl), compared to MCI (2.17 ± 0.39, 3.60 ± 0.51, 3.73 ± 0.48 ng/μl) and GC (2.84 ± 0.47, 4.55 ± 0.48, 4.65 ± 0.55 ng/μl). ROC analysis showed the cut‐off value with high sensitivity and specificity for cognitive impairment (AD and MCI). The concentration declined significantly with the disease progression. No specific difference was observed in the case of other SIRTs between the study groups.ConclusionThis study for the first time reports the concentration of all seven Sirtuins in serum of AD and MCI patients and reveals an inverse relationship between serum level of SIRT1, SIRT3 and SIRT6 and AD. The cut‐off values with sensitivity and specificity shows the clinical relevance of SIRT3 and SIRT6 as serum protein markers for AD.
Human‐specific α7nAChR‐dependent adaptation to mechanical properties of the extracellular environment
Authors: Szombathy Anna Marie , Ihnatovych Ivanna , Dorn Ryu , Nimmer Erik , Heo Yuna , Bae Yongho , Szigeti Kinga 
Published: January 2025

AbstractBackgroundCHRFAM7A is a human‐restricted gene associated with neuropsychiatric and neurodegenerative disorders. The translated CHRFAM7A protein incorporates into the α7 nicotinic acetylcholine receptor (α7nAChR) leading to a hypomorphic receptor. Mechanistic insight from isogenic iPSC derived neuronal and mononuclear cells demonstrated that CHRFAM7A affects Ca2+ signaling and activates small GTPase Rac1 leading to an actin cytoskeleton gain of function. Fundamental differences in tissue stiffness in human and rodent brain are emerging as a translational gap. Since the actin cytoskeleton is a driver of adaptation to tissue stiffness, we explored the role of CHRFAM7A in mechanobiology.MethodNeuronal progenitors and monocytes were differentiated from isogenic iPSCs (null and CHRFAM7A knock‐in (KI)). Polyacrylamide hydrogels corresponding to Young’s modulus 2 kPa (soft) and 5 kPa (stiff) were used to model the mechanical properties of the tissue environment. Actin immunofluorescent morphological analysis and atomic force microscopy (AFM) were utilized to characterize cellular adaptation.ResultAFM demonstrated intracellular stiffness adaptation to the soft and stiff environment in CHRFAM7A KI neuronal progenitors and monocytes. In CHRFAM7A KI neuronal progenitors, growth cone (GC) morphology adapted to the stiffness by reinforcing lamellipodia and maintaining directionality. In null MGE progenitors filopodia remained the actin structure in both the soft and stiff environment resulting in GC curvature in the stiff hydrogel. Polarization pattern favored the bipolar morphology in both the neuronal and monocytic lineage of CHRFAM7A KI cells in the stiff environment, while null cells retained the multipolar pattern. Cell polarity correlated with small GTPase activity: in null MGE progenitors, multipolar morphology is associated with high RhoA activity in the stiff environment. In contrast, CHRFAM7A KI MGE progenitors adapted to stiffness by activating both CDC42 and Rac1.ConclusionHuman specific CHRFAM7A facilitates adaptation to matrix stiffness in both the neuronal and mononuclear lineage, bridging the gap between rodent and human brain stiffness and holding implications for physiological and pathological conditions. Human‐restricted CHRFAM7A needs to be taken into account to overcome the translational gap in drug development for neurodegenerative and neuroinflammatory diseases.
A Thematic Analysis of the Patient Centered Outcomes Research Institute’s (PCORI) Stakeholder Identified ADRD Research Priorities
Authors: Philips Joanna , Audley John , Akinbami Yewande , Majid Tabassum , Arora Neeraj , Penuela‐Wermers Sarah 
Published: January 2025

AbstractBackgroundNational and international organizations, including the United Nations, Center for Disease Control, Agency for Healthcare Research and Quality, and the US Surgeon General’s Office have highlighted the need for a comprehensive approach to caring for the growing number of older adults in the U.S. Furthermore, advancements in both non‐pharmacological and pharmacological treatments for Alzheimer’s Disease and Related Dementias (ADRD), coupled with the CMS initiative on improving dementia care management (GUIDE), have intensified national attention on the needs of older adults living with ADRD. Acknowledging this convergence of factors and with the input of stakeholders, PCORI identified “Promoting the Health of Older Adults” as one of 12 topic themes for future research. As the leading funder of Clinical Comparative Effective Research (CER), PCORI has invested $88 million to support 15 CER studies focused on ADRD and 10 awards on engagement related initiatives to advance ADRD research interests.MethodTo further identify funding gaps and understand CER priority areas related to ADRD, we conducted in‐depth analyses of PCORI’s ADRD portfolio and of discussions on ADRD with diverse stakeholder partners (i.e. patients, clinicians, researchers, nursing organizations, payers, advocacy groups). An analysis of 24 ADRD‐related stakeholder convenings using open‐ended unstructured interview questions was done and common themes of priority CER areas were identified.ResultThe thematic analysis revealed three ADRD CER priority areas related to: (1) Sensory impairment in ADRD patients, (2) Coordination of healthcare services and (3) Support for caregivers of ADRD patients. Moreover, stakeholders identified the need for interventions that address health inequities in underserved populations affected by ADRD and innovative approaches to navigating a fragmented health care system highlighted by the COVID‐19 pandemic.ConclusionEvaluation of PCORI’s ADRD portfolio and engagement discussions provide important insights on current critical evidence gaps and real‐world decisional dilemmas. The engagement discussions illuminate priority areas for research that will holistically address those impacted by ADRD at the patient, caregiver, health system, and community level. These insights reveal a need for research that will focus on underserved older adults and their caregivers, as well as optimizing the coordination and integration of care for this population.
Decrowding Expansion Pathology for Visualization of Herpes Simplex Virus Type 1 and Tau Interaction in Alzheimer’s Disease
Authors: Araya Katherine , Valdes Pablo , Taglialatela Giulio 
Published: January 2025

AbstractBackgroundChronically reactivating Herpes Simplex Virus Type 1 (HSV1) infection has been shown to produce key molecular and behavioral markers of Alzheimer’s disease (AD). Most notably, the accumulation of neurotoxic tau isoforms, neurofibrillary tangles (NFTs), and Amyloid‐beta plaques. Our study takes a unique approach to the systematic characterization of HSV1 biomarkers within the brain. We introduce the novel application of decrowding expansion pathology (dExPath) for immunofluorescent studies, a technique that sheds new light on the interactions between HSV1 proteins and tau. This innovative use of dExPath provides a visualization of HSV1 protein in the context of AD pathology, offering a fresh perspective on the hypothesized interactions between HSV1 proteins and Tau.MethodWe aim to overcome the limitations of traditional imaging protocols, which are often hindered by spatial resolution and tissue density. To achieve this, we utilize dExPath, a technique that physically expands hippocampal tissue fourfold in an isotropic manner. This approach reveals disease biomarkers that are not visible with conventional staining techniques, allowing us to visualize HSV1 protein within AD clinical hippocampal specimens. Through this, we seek to establish a new understanding of the role of viral factors in the development of AD pathology.ResultOur research has yielded a significant breakthrough. We have successfully identified viral proteins within clinical AD hippocampal specimens using dExPath, a feat that was not possible with traditional immunofluorescent staining techniques.ConclusionThe findings of our research offer significant implications for the understanding of Alzheimer’s disease. By opening new avenues for therapeutic intervention targeting the interaction between HSV1 protein and tau, we provide potential insights into the disease’s etiology and potential treatment strategies. This could potentially lead to groundbreaking advancements in the treatment of Alzheimer’s disease.