bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 2 PIONEER Trial of Oral T3D‐959 for the Treatment of Patients Diagnosed with Mild‐to‐Moderate Alzheimer’s Disease: New Results in a Modified Intent‐to‐Treat Population
Authors: Stanek Jessica , Swearingen Blake , Strittmatter Warren , Chamberlain Stan , Gabriel Hoda , Coutlee Christopher , Lineberry Charles , Didsbury John 
Published: January 2025

AbstractBackgroundPIONEER was a Phase 2 randomized, placebo‐controlled, multi‐center trial evaluating efficacy and safety of the dual PPARδ/γ agonist T3D‐959 in patients with mild‐to‐moderate Alzheimer’s disease (AD).MethodEnrolled patients (N = 250) had mild‐to‐moderate AD per NIA‐AA criteria. No AD biomarker enrollment criteria were defined. Study data revealed a cluster of sites with common data irregularities, including (1) no drug in plasma at end of treatment in patients assigned to drug (2) baseline p‐tau217 ratio inconsistent with biological AD, and (3) placebo response outside of historic norms for mild‐to‐moderate AD. These sites were excluded to form an mITT study population. Primary endpoints were ADAS‐Cog11 and ADCS‐CGIC. Secondary endpoints were plasma Aβ42/40 ratio and Digit Symbol Coding Test. Proteomic biomarkers including p‐tau217 and neurogranin were exploratory endpoints. Efficacy was evaluated as least‐squares mean changes from baseline to week 24.Result141 patients were included in the mITT population randomized to placebo (n = 32) or T3D‐959 (15mg, n = 38; 30mg, n = 39; or 45mg, n = 32). Both primary endpoints were met, approaching statistical significance, ADAS‐Cog11 in the 30mg group (0.73 vs 2.70; p = 0.073) and ADCS‐CGIC in the 15mg group (0.39 vs 0.86; P = 0.060), consistent with slowing of clinical decline. Secondary endpoint plasma Aβ42/40 ratio was met, with significant improvement in the T3D‐959 30mg and 45mg groups vs placebo (30mg: P = 0.011; 45mg: P = 0.033), with a similar magnitude of effect as lecanemab at 6‐months. T3D‐959 30mg and 45mg groups significantly improved on neurodegeneration biomarker neurogranin (T3D‐959 30mg: P = 0.035; T3D‐959 45mg: P = 0.051) and changed proteomic markers suggesting pluripotent effects on dysregulated AD pathways including inflammation, oxidative stress and metabolism. T3D‐959 was safe and well‐tolerated.ConclusionCo‐primary endpoints ADAS‐Cog11 and ADCS‐CGIC were met per protocol, approaching statistical significance at week 24. T3D‐959 demonstrated significant improvement over placebo in plasma Aβ42/40 ratio and in plasma neurogranin. Biomarkers of all three AD diagnostic criteria, Amyloid/Tau/Neurodegeneration, were improved, as well as markers of inflammation, insulin resistance and dysfunctional lipid metabolism. Results demonstrate a strong safety profile and evidence of slowing of clinical and biological decline.
Lower dorsal raphe nucleus activity reflects resilience to Aß‐related cognitive decline in preclinical Alzheimer’s disease individuals with mild depressive symptoms
Authors: Lawn Timothy , Prokopiou Prokopis C. , Heinrich Lukas , Nancy Donovan , Papp Kathryn V , Rentz Dorene M , Sperling Reisa A , Johnson Keith A , Jacobs Heidi I.L. 
Published: January 2025

AbstractBackgroundThe neuromodulatory subcortical systems are among the earliest brain regions to accrue pathology in Alzheimer’s disease (AD), contributing to cognitive and non‐cognitive symptoms. Monoaminergic nuclei, such as the dorsal raphe (DRn), modulate mood, cognition, and arousal. Their pathological perturbation is proposed to induce initial hyperexcitability followed by decreased activity, which may therefore be associated with the neuropsychiatric and cognitive symptoms of preclinical AD. Here, we associated novelty‐related activity of the DRn to longitudinal neuropsychiatric and cognitive changes in preclinical AD.MethodNinety‐two older adults from the Harvard Aging Brain Study (mean age = 69.4±10, 51 females, Table 1) underwent baseline functional MRI where they were presented unfamiliar and familiar face‐name pairs organized within blocks of novelty and repetition to extract DRn novelty‐related activity. They additionally completed 11C PiB‐PET scanning to assess neocortical Aβ (cut‐off: 1.324 DVR, PVC) as well as annual neuropsychological testing (mean = 5.21±1.91 years). Robust linear regressions tested cross‐sectional associations, and robust linear mixed effects models assessed longitudinal associations, of DRn activity with cognitive decline or increases in depressive symptoms, in interactions with PiB (adjusted for age, sex, and years of education).ResultDRn and PACC5 were not associated at baseline nor in interaction with PiB (p<0.05). Longitudinally, lower DRn activity was associated with steeper cognitive decline at elevated PiB (Figure 1A,
B = 0.092, t(374) = 2.65, p = 0.008). This was particularly driven by the category fluency and logical memory components of PACC5 (Figure 1B). Conversely, higher DRn activity was associated with worsening of depressive symptomatology at high PiB (Figure 2A, B = 0.42, t(373) = 2.7, p = 0.007). To reconcile these opposing findings, we related both slopes: in preclinical AD with increasing depressive symptoms, individuals with higher DRn activity exhibited steeper cognitive decline, compared to those with lower DRn activity (N = 92, B = ‐0.48, t(81) = ‐5.43, p = 0.000).ConclusionThese findings indicate that lower DRn activity may reflect resilience to cognitive decline in preclinical AD individuals with worsening depressive symptoms. However, high DRn activity in those with worsening depressive symptomatology signifies cognitive deterioration. Future work including serial imaging is required to model the temporal evolution of serotonergic neuromodulation and its relation to disease progression.
The monoclonal antibody 17E1 selectively labels GFAP in 5xFAD mice
Authors: Norris Christopher M. , Kraner Susan D 
Published: January 2025

AbstractBackgroundOur lab recently developed 2 mouse monoclonal antibodies that preferentially react with “distressed astrocytes”. One monoclonal, 26A6, was found to react preferentially with a form of the Ca2+/calmodulin‐dependent protein phosphatase, calcineurin (CN), that has been cleaved by calpain, to generate a 48 kDa CN fragment (∆CN). We recently published a characterization of this antibody. Surprisingly, the second antibody (17E1), generated to the same antigen used to create 26A6, preferentially binds to GFAP and is present at elevated levels in the 5xFAD mouse strain.MethodA peptide encompassing the calpain sensitive region of the CN carboxyl terminus was used for mouse monoclonal antibody generation.ResultWe identified 2 monoclonal antibodies: 26A6 and 17E1. The 26A6 antibody binds to a recombinant CN fragment (48 kDa) that is generated by calpain‐mediated proteolysis. We’ve shown that this antibody selectively labels subsets of reactive astrocytes in human brain in conjunction with Alzheimer’s and cerebrovascular pathology, but provides very little labeling in healthy control brain tissue. The 17E1 antibody also labels a 48 kDa protein, but does not label recombinant CN, nor does it label calpain generated CN fragments. Western blot analyses found that the 17E1 and 26A6 antibodies exhibit differential labeling of a 48 kDa protein found in 5xFAD mice. Specifically, 26A6 showed no labeling while 17E1 exhibited highly selective labeling. The 48 kDa band was also detected with a commonly used commercial CN antibody from EMD Millipore (1492) that labels full length CN and multiple C terminus truncation products of CN. To our surprise, immunoprecipitation experiments followed by Western and mass spectroscopy showed that the 48 kDa fragment bound by both 17E1 and 1492 was actually GFAP. Both the 17E1 and 1492 Abs label recombinant GFAP, but 26A6 did not. 26A6 also exhibited no substantial labeling in 5xFAD brain tissue.ConclusionBoth 26A6 and 17E1 preferentially interact with “distressed astrocytes”. However, 26A6 labels proteolyzed CN, while 17E1 labels GFAP. The results emphasize the importance of using the correct antibodies to evaluate the role of CN in neurodegenerative disease. Further characterization of 17E1 in human brain tissue and rodent models of disease is underway.
Expo‐AD: An Innovative Alzheimer’s Disease and Related Dementias (ADRD) Research Infrastructure for Secure Data Integration and Exposome Linkage
Authors: Cheng Yixuan , Lyons David , Thursday Nyla , DeWitt Amanda , Bendlin Barbara B. , Kind Amy J.H. 
Published: January 2025

AbstractBackgroundResearch is needed to understand the impact of the exposome on ADRD, and development of a secure research infrastructure that facilitates linkage of exposome metrics to biological outcomes is critical. Such linkages are challenging because they often require working with protected health information (PHI) covered under the Health Insurance Portability and Accountability Act (HIPAA). In response, we have developed a robust administrative, legal, and cybersecurity infrastructure at the University of Wisconsin (UW) to establish a novel, PHI‐capable, multi‐site service for exposome data linkage for the ADRD research community: “Expo‐AD”.MethodExpo‐AD is a scalable, cloud‐based environment created and maintained by UW. Data sharing agreements with 22 academic institutions and a specially designed and carefully curated cybersecurity platform provide a secure, PHI‐compliant computing environment.Expo‐AD utilizes cloud‐based virtual machines (VMs) to ensure isolation of sensitive PHI, maintaining HIPAA compliance and preventing unauthorized access. Data transfer leverages Globus, a research cyberinfrastructure used to reliably and securely share data across institutions. VMs provide a scalable resource which is crucial for managing large datasets and adjusting computational power as needed in exposome research. They also provide disaster recovery capabilities which ensure minimal disruption and safeguard data over time. Access is controlled through both technical and procedural methods and overseen by an external advisory committeeResultsExpo‐AD is currently storing personal identifiers and neuropathology data of 10,875 brain donors acquired from 22 participating brain banks and the National Alzheimer’s Coordinating Center. Residential addresses are geocoded and linked to the Area Deprivation Index to characterize the exposome. Curated data will be released through Globus after each data freeze to requesting researchers. Life course residential history construction for brain donor cases is ongoing.ConclusionExpo‐AD is one of the largest multi‐site infrastructures designed specifically to enhance life course exposome intake and linkage to biological ADRD data. Its design facilitates future broad scale sharing of deidentified exposome metrics to non‐PHI capable research resources. Expo‐AD holds the promise of expanding exposome data access across the ADRD field, bringing benefits to the research community and catalyzing collaborative and reproducible exposome research.
Alterations in protein conformation assessed by FTIR in EVs from an AD mimicking model
Authors: Vaz Margarida , Martins Tânia Soares , da Cruz e Silva Odete , Nunes Alexandra , Henriques Ana Gabriela 
Published: January 2025

AbstractBackgroundAβ peptide is a central player in Alzheimer’s disease (AD) pathogenesis, which once generated rapidly tends to aggregate, from oligomers to fibrils and finally deposits into senile plaques, one of the disease hallmarks.Extracellular vesicles (EVs) are secreted by all cell types and recognized as key intercellular communication mediators. In AD, it has been reported that EVs can carry Aβ and may potentially accelerate its aggregation, thus contributing to the seeding of the toxic peptide.Hence, the main goal of this work was to evaluate if Aβ itself can impact the secondary structure of proteins carried by EVs, using Fourier Transform Infrared (FTIR) spectroscopy.MethodN2a neuroblastoma cells were treated with 10 µM of Aβ25‐35 peptide for 48 h, after which EVs were isolated from cell culture medium by ultracentrifugation and then characterized by TEM, NTA and WB. For FTIR analysis, cell suspension samples were also prepared and the FTIR spectra was acquired for N2a and N2a‐derived EVs. The data analysis was focused in the 1700‐1500 cm−1 spectral region, which is mostly assigned to protein conformation.ResultDifferences in peak intensities of this spectral region were observed. After Aβ treatment a tendency for an increase in protein aggregation was observed in N2a cells, whereas for EVs a tendency for an increase in protein secondary structures associated with native proteins and oligomers was mostly evident.ConclusionThese results demonstrated that Aβ can alter the secondary structure of proteins in cells but can also have an impact on the proteins carried by the EVs, affecting protein structures differently. Data reinforces that EVs may be key players in signaling events, involving proteins misfolding, that leads to AD.This work was funded by Instituto de Biomedicine (iBiMED) under Grant UIDB/04501/2020 and UIDP/04501/2020; MV is supported by the individual PhD grant UI/BD/151354/2021.
Comorbidity of frontotemporal dementia in the bone evidenced as, gender‐specific alterations in the bone microarchitecture, composition, and biomechanical properties observed in MAPT P301S transgenic mouse model
Authors: Suryadevara Vidyani , Valiya Anuradha Kambrath , Krehbiel Connor J , Karra Swathi , Kluppel Michael , Miller Lisa , Monte Willis S 
Published: January 2025

AbstractBackgroundComorbidities are becoming increasingly evident during various Alzheimer’s disease related pathologies. It was found that patients with AD have a higher risk for fractures and falls. Further people who have an incident of falls/fractures have a higher risk for cognitive decline. This study is focused on investigating the alterations in the bone at the structural and functional level in MAPT P301S Tg+ mouse, a preclinical model for frontotemporal dementia.MethodsThe MAPT P301S Tg+ mouse expresses a human 4‐repeat mutant MAPT P301S and was developed to model NFTs secondary to tau aggregations. The femur from N = 20 (equal number of male and female) MAPT P301S Tg+ and C57BL/6J mice at 12‐months age were scanned with µCT to characterize the bone microarchitecture. Further three‐point bending test was performed to assess the biomechanical properties and FTIR was used to determine the material properties of the bone. The expression of genes regulating the bone matrix composition was determined by using RTPCR.ResultsThe male MAPT P301S Tg+ mice have a significant decrease in bone geometrical parameters (both cortical and trabecular properties) than the females, as compared to their respective wild type. Interestingly the biomechanical properties were altered in both the males and females, wherein there was an increase in the pre‐yield properties, but decrease in the post‐yield properties. This correlated with the alterations in the material properties of the male bone determined by FTIR and the changes in the genes regulating the extracellular matrix of the bone. Tauopathies lead to loss of bone structure and functionality by altering it’s material composition. Further, we found protein expressionConclusionThis is a first study indicating the presence of Tau in the bone, which impacts the function and this opens up the prospective of Tau impacting other organs, in addition or concurrently with neurodegenerative diseases.
Alzheimer’s Caregiver Psychoeducation‐Based Psychological Support Telerehabilitation
Authors: Doğan İdil Arasan , Sayar Feride Gökben Hızlı 
Published: January 2025

AbstractBackgroundAlzheimer’s Caregiver Psychoeducation‐Based Psychological Support Telerehabilitation; is an online program where the caregiver is educated about the disease and processes and supported therapeutically. This program also aims to promote the psychological well‐being of the caregiver and ensure a positive prognosis.MethodThe study was conducted with 20 caregivers (relatives of patients) who applied to various branches of the Alzheimer Association of Turkey and received services, in a group setting using the Zoom Platform online. The control group consisted of 20 people who attended the association’s routine information meetings. Data collection tools were determined as the Sociodemographic Form, Brief Symptom Scale, Psychological Resilience Scale, and Zarit Caregiver Burden Scale. The study, based on psychoeducation, utilized Cognitive Behavioral Therapy Techniques and Positive Psychology Positive Interventions as therapeutic methods. The program was structured to last 6 weeks, with 12 sessions, twice a week for 90 minutes each. The telerehabilitation applied in a group setting was also supported with individual sessions. One support session per month was organized for 6 months following the completion of the program.ResultThe age distribution of the caregivers was predominantly in the 45‐54 range, with a majority being female. In the experimental group, the scores for psychological symptoms such as Depression, Anxiety, Negative Self, Somatization, and Hostility in the final test were significantly lower compared to the pre‐test. No significant difference was observed in this context in the control group. Zarit Caregiver Burden scores in the experimental group also significantly decreased compared to the pre‐test. Regarding Psychological Resilience scores in the experimental group, the final test results showed an increase in psychological resilience levels.ConclusionAs a result of the implementation of the telerehabilitation program, caregivers' knowledge and awareness of Alzheimer’s Disease and the care process increased, their psychological resilience was strengthened, and their social support networks expanded. Additionally, the caregivers' burden of care decreased, and symptoms of depression and anxiety were alleviated. These findings emphasize the importance of accessible, applicable, and sustainable telerehabilitation programs.
Passive amylin immunotherapy improves brain function and reduces brain β‐amyloid pathology in APP/PS1 mice
Authors: Kotiya Deepak , Despa Florin 
Published: January 2025

AbstractBackgroundAmylin is a systemic hormone that is co‐secreted with insulin from pancreatic β‐cells. Amylin co‐aggregates with brain parenchymal and vascular β‐amyloid in persons with Alzheimer’s dementia. The present pilot study sought to assess the safety and side effects during and after the treatment period of passive amylin immunotherapy in the APP/PS1 mouse model of Alzheimer’s disease.MethodWe have generated a polyclonal anti‐amylin antibody (P2) in rabbits using the N‐terminal of amylin peptide as an immunogen. In this pilot study at 5 months of age, male APP/PS1 mice were randomly assigned into rabbit Ig‐G vehicle‐control and P2 amylin antibody injected group (n = 4/group). Anti‐amylin antibody was injected at a dose of 10 mg/kg of body weight three times a week for six weeks. During the six weeks of amylin immunotherapy, we monitored the mice for visible side effects and immunocomplex disease‐related visible symptoms. Six weeks later, we assessed body weight, blood glucose level, and brain function with the novel object recognition test and performed comparative immunochemical Aβ analyses of hippocampal tissue by using MSD ELISA.ResultDuring the period of passive amylin immunotherapy, we did not observe visible symptoms of immunocomplex disease such as rash, urticaria, and malaise along with any sudden drop in body weight. Mice with anti‐amylin antibody injected showed an enhanced trend of recognition memory index (p = 0.1121) along with a lower blood glucose level (p = 0.2602) as compared to those that were injected with rabbit Ig‐G vehicle control. This was associated with decreasing trend of hippocampal levels of Aβ42 (p = 0.7872), Aβ40 (p = 0.4609), Aβ38 (p = 0.4473) in brain sup fraction, and Aβ42 levels (p = 0.6336) in brain pellet fraction measured by MSD ELISA.ConclusionPassive amylin immunotherapy in APP/PS1 mice shows that used immunotherapy procedure might be safe for further investigation. Future experiments will be performed in APP/PS1 mouse model in which the mouse amylin gene is replaced by the human amylin gene in the pancreas and is conditionally downregulated by tamoxifen (TMX) injection, intraperitoneally.
Assessing Sleep hours in Participants with Alzheimer’s Disease: Findings from a Phase I MAD Study of IGC‐AD1
Authors: Venegas Margarita , Tangarife Maria Alejandra , Delgado‐Murillo Laura , Gutiérrez Evelyn , Naranjo María Paula , Rao Jagadeesh S , Shahnawaz Saadia , Sánchez Laura Tatiana , Ghazaryan Varduhi , Camargo Fabio , De Jesus William Julio , Hong Elliot , Grimaldi Claudia , Mukunda Ram , Arbelaez Maria Juanita 
Published: January 2025

AbstractBackgroundSleep disturbances are prevalent in Alzheimer’s disease (AD), impacting cognition and quality of life. Trials have also shown increased subjective sleepiness with melatonin doses compared to placebo. High melatonin doses may increase drowsiness, headache, and dizziness, as indicated by a systematic review. A Phase I trial assessed the safety and tolerability of IGC‐AD1, comprising delta‐9 tetrahydrocannabinol (THC) and melatonin. Preliminary findings suggest IGC‐AD1’s safety, with fewer reports of somnolence and dizziness than placebo and no increase in sleep hours. Concerns about melatonin’s sedative properties are addressed through sleep duration assessment.MethodData is presented from a Phase 1 Multiple Ascending Dose MAD trial. Caregivers reported participant sleep hours and nocturnal awakenings during daily safety calls. Average sleep hours for each cohort were computed, calculating nightly averages over the 14‐day drug intake period, and then by cohort and treatment group (1 ml for cohort 1, 2 ml for cohort 2, and 3 ml for cohort 3).ResultVariations in average sleep duration across cohorts were observed. Cohort 1 showed average sleep hours of 8.97 (active) and 8.77 (placebo), while cohort 2 exhibited averages of 8.11 (active) and 9.43 (placebo). Cohort 3 displayed averages of 7.90 (active) and 9.24 (placebo). These findings suggest that the administration of IGC‐AD1 did not meet expectations regarding increased sleep duration, despite containing melatonin.ConclusionAlthough exogenous melatonin is often associated with sedation, the study indicates that IGC‐AD1, containing melatonin, did not lead to the anticipated increase in sleep duration. Further research is needed to understand the underlying mechanisms and optimize therapeutic interventions for sleep disturbances in AD patients.