bluuebunny/crossref_metadata_2025_split huggingface dataset:
Partial inhibition of complex I restores mitochondrial morphology and mitochondria‐ER communication in hippocampus of APP/PS1 mice
Authors: Panes‐Fernandez Jessica , Nguyen Thi Kim Oanh , Gao Huanyao , Christensen Trace , Stojakovic Andrea , Trushin Sergey , Salisbury Jeffrey L , Fuentealba Jorge , Trushina Eugenia 
Published: December 2023

AbstractBackgroundAlzheimer’s Disease (AD) has no cure. We showed that partial inhibition of mitochondrial complex I (MCI) with small molecule CP2 induced adaptive stress response activating multiple neuroprotective mechanisms. Chronic treatment reduced inflammation, improved synaptic and mitochondrial functions, and blocked neurodegeneration in symptomatic APP/PS1 mice, a translational model of AD.MethodsAnalysis of mitochondrial morphology and mitochondria‐endoplasmic reticulum (ER) contacts (MERCS) was done in the hippocampal CA1 tissue from APP/PS1 mice treated with CP2 and compared to APP/PS1 and non‐transgenic mice treated with vehicle using serial block‐face scanning electron microscopy (SBFSEM) and three‐dimensional (3D) EM reconstructions combined with western blot analysis and next generation RNA sequencing.ResultsWe demonstrate that CP2 treatment restores mitochondrial morphology and mitochondria‐ ER communication, reducing ER stress in the APP/PS1 mouse brain. Using 3D EM reconstructions, we found that mitochondria in AD dendrites existed primarily as mitochondria‐on‐a‐string (MOAS), a morphological phenotype that is difficult to detect using conventional 2D EM or fluorescence spectroscopy. Compared to other morphological phenotypes, MOAS are extensively enveloped in the ER membranes forming multiple MERCS known to contribute to abnormal lipid and calcium homeostasis, and ER stress in AD. CP2 treatment specifically reduced MOAS formation, consistent with improved energy homeostasis in the brain, with concomitant reduction in MERCS, ER stress, and improved lipid homeostasis.ConclusionsThese data provide novel information on the role MOAS play in AD. Our data demonstrate that in response to energetic stress, mitochondria in dendrites acquire MOAS phenotype with increased interaction with the ER, which may synergistically contribute to the AD development. Since CP2 treatment alleviated the ER stress and improved mitochondrial dynamics and function, these data further support the development of partial MCI inhibitors as disease modifying strategy for AD.
Synaptic density is correlated with Aβ plaques and neurofibrillary tau tangles across the clinical and biologic Alzheimer’s disease continuum
Authors: DiFilippo Alexandra H , McLachlan Max , McVea Andrew K , Bettcher Brecca , Jonaitis Erin M. , Ennis Gilda E. , Pasquesi Mary‐Elizabeth , Davenport Nancy J , Thor Yer , Grover Ethan , Hudson Sarah , Barnhart Todd E , Engle Jonathan W , Betthauser Tobey J , Johnson Sterling C , Bendlin Barbara B , Christian Bradley T. 
Published: December 2023

AbstractBackgroundThe extent to which amyloid‐β burden and neurofibrillary tau tangle burden are associated with synaptic degeneration in vivo is not well known. PET imaging was used to examine the cross‐sectional relationship between neurofibrillary tau tangle burden and amyloid‐β plaque burden with synaptic density among individuals who spanned the clinical and biologic Alzheimer’s disease continuum.MethodParticipants were recruited from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Prevention study. N = 64 participants were included in the analysis based on completed cognitive testing, structural MR and PET imaging using [11C]PiB DVR for amyloid burden, [18F]MK‐6240 SUVR for regional neurofibrillary tau burden, and [11C]UCB‐J DVR for regional synaptic density burden analysis. Amyloid burden was indexed as a global [11C]PiB DVR representing the mean of brain regions that typically accumulate amyloid. UCB‐J DVR and MK‐6240 SUVR regions of interest were selected based on the histopathological staging of tau pathology in Alzheimer’s disease with a focus on regions of tau pathology described by earlier and later Braak stages. The first composite region of interest (ROI1) comprised the hippocampus and entorhinal cortex, and the second (ROI2) comprised the amygdala, fusiform, lingual gyrus, and the inferior temporal gyrus. Linear correlations (Pearson’s r) tested the relationship between UCB‐J DVR and PiB DVR, as well as UCB‐J DVR and MK‐6240 SUVR.ResultGlobal [11C]PiB DVR showed a moderate negative relationship with UCB‐J DVR in ROI1 (r = ‐0.42, p = 0.0006) and a weak relationship with UCB‐J DVR in ROI2 (r = ‐0.33, p = 009). [18F]MK‐6240 SUVR and UCB‐J DVR were negatively correlated in ROI1 (r = ‐0.44, p = 0.0003) and in ROI2 (r = ‐0.42, p = 0.005).ConclusionBoth amyloid burden and tau pathology were associated with lower synaptic density. Tau and synaptic density appeared to show moderate correlations among brain regions involved in both earlier and more advanced tau pathology, whereas amyloid burden appeared to be more strongly related to synaptic density in brain regions where more advanced disease is typically observed.
Pathogenesis of ARIA
Authors: Carare Roxana O. O 
Published: December 2023

AbstractBackgroundAD is characterised pathologically by the deposition of amyloid‐beta peptides in the extracellular spaces of the brain as plaques and cerebral amyloid angiopathy (CAA). Observations on human post‐mortem brains and experimental studies in mice demonstrate that amyloid‐beta is deposited in the basement membranes of capillaries and basement membranes of arterial smooth muscle cells, within the Intramural Periarterial Drainage (IPAD) pathways.MethodPathological studies performed on human post‐mortem brains from the first ELAN trial demonstrated that after active immunization against amyloid‐beta, despite the disappearance of plaques, CAA worsened and both Abeta 40 as well as Abeta42 were present in the vascular wall. This suggests that Abeta42 solubilised from plaques has become entrapped in the IPAD pathways.ResultExperimental immunization in rodents against a cerebral protein demonstrate that within 24h, immune complexes are formed in the basement membranes of capillaries, impairing IPAD. By 7 days after immunization, inflammatory cuffs of perivascular cells are present, but, in a normal adult mouse, IPAD is restored.ConclusionThis suggests that clearance of fluid and solutes can be restored even in the context of immune cell recruitment if the vascular wall is healthy.
Network‐based Genetic Subtyping for Target Prioritization and Drug Repositioning: The Artificial Intelligence for Alzheimer’s Disease (AI4AD) Consortium
Authors: Jun Gyungah R 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) is a progressive neurodegenerative disease with complicated underlying disease mechanisms. The clinical and neuropathological heterogeneity of AD may be explained by specific disease mechanisms at a brain cell‐level. We postulate that the path to effective treatment of AD depends on identifying distinctive subtypes linking to specific disease mechanisms at brain cellular level.MethodWe developed a novel precision medicine framework using polygenic risk scores defined by co‐regulated cellular networks to stratify individuals into low and high‐risk groups (genetic subtypes) for brain cell‐type specific networks. We prioritized genes from the cell‐based networks using a graph‐based ranking (PageRank) algorithm. We investigated molecular signatures of the prioritized genes for the subtypes using autopsied brains from the Framingham Heart Study (FHS). We validated the signatures using isogenic APOE lines of human pluripotent stem cell (hiPSC)‐derived astrocytes. Existing drugs targeting for the genetic subtypes were identified using drug perturbation database and clustering algorithms using compound structures from the PubChem databaseResultWe identified six preserved and AD associated co‐expressed gene networks for astrocytes, oligodendrocytes, and oligodendrocyte progenitor cells. The top‐ranked astrocyte network was enriched with Parkinson’s disease, Alzheimer’s disease, mineral absorption, and ribosome pathways. The most important gene in the astrocyte network was the APOE gene, which its expression was increased in AD compared in control brains with elevated complement C4A level. We confirmed elevated expression of both APOE and C4A levels in APOE4 compared in APOE3 hiPSC‐derived astrocytes. We identified three drugs targeting the astrocyte subtype, all of them previously modulated expression of the prioritized genes in the drug perturbation database. Clustering algorithm identified multiple compounds targeting the prioritized genes in the astrocyte network with at least 80% similarity in structure.ConclusionThe newly established framework provided the potential implication in genetic subtype driven drug repositioning in AD. In future, we will develop novel graph neural network approaches to identify comprehensive genetic subtypes and drugs targeting the subtypes in collaboration with internal and external members from the AI4AD consortium.
A review of recommended outcomes and measurement tools within Core Outcome Sets (COS) developed for dementia
Authors: Tran Hanh Dao 
Published: December 2023

AbstractBackgroundA core outcome set (COS) is a minimum set of health outcomes to be measured for a given condition. COS can be developed for specific populations, interventions, or settings, so several COS may exist for a condition e.g., dementia. Comparison of the outcomes and measurement tools informs which outcomes should be considered by stakeholders when assessing quality of care.MethodCOS developed for people living with any type of dementia were identified through the COMET database1 and handsearching references of eligible papers. Data was extracted on COS scope (population, intervention), stakeholders, development methods, and the outcomes and tools recommended within each COS. Recommended outcomes were classified against COMET’s taxonomy2 and tools were grouped by outcome across COS.ResultTen papers outlining 14 COS were identified (Table 1). Nine included people living with dementia, carers or care organisations in the consensus process. Eleven specified use for a disease stage or intervention. Eleven COS were for research use, one for routine care, and two for both settings. 87 outcomes covering a range of domains were recommended (Table 2). Function/Activities of Daily Living, Cognition, Patient behaviour/ neuropsychiatric symptoms, QoL, and Family Carer QoL were all recommended by at least four COS. Eight COS included recommendations of how to measure the outcomes, but tools differed across the COS.ConclusionMultiple COS for dementia have been identified. Most of these have been developed for research, specific interventions, or stages of dementia. Although the majority involved people with dementia or their carers, further quality assessment is needed. Evaluation of recommended outcomes and quality of COS development is required where multiple COS exist, or COS scope does not directly match the proposed area of application. This information can be used by stakeholders from the intended setting to select or ratify the most pertinent outcomes instead of creating additional COS.
1
https://www.comet‐initiative.org/

2Dodd S et al. A taxonomy has been developed for outcomes in medical research to help improve knowledge discovery. J Clin Epidemiol. 2018;96:84‐92.
Cerebral Blood Flow and Arterial Transit Time Variations in Elders with Long COVID
Authors: Patel Milan , Cohen Alexander D , Pommy Jessica , Umfleet Laura Glass , Franczak Malgorzata , Swanson Sara J , Obarski Shawn , Agarwal Mohit , Wang Yang 
Published: December 2023

AbstractBackgroundMany COVID‐19 patients experience persistant neurological symptoms that often extend beyond the period of acute infection, referred to as “Long COVID”, where most patients reported brain fog and cognitive dysfunction. While elderly individuals are more vulnerable to possible enduring cognitive impairments after acute COVID‐19 requiring hospitalization, there is increasing concern that older patients with Long COVID will be at high risk for developing Alzheimer’s disease (AD) and dementia. Although there is emerging recognition of Long COVID, its underlying neuropathology remains unknown. This study aimed to investigate neurovascular function using advanced MRI perfusion in elder patients with Long COVID.MethodWell‐matched elderly Long COVID patients (n = 14, mean age = 60.1±4.3 years, 12F, 2M) and control subjects (n = 25, mean age = 60.4±7.2 years, 19F, 6M) underwent neurocognitive testing as well as neuroimaging. Patients were seen 711.57 ± 165.02 days after the initial mild non‐hospitalized COVID‐19 infection. Clinical cognitive complaints of Long COVID patients included memory changes (n = 12, 85.7%), attention (n = 12, 85.7%), speech/writing (n = 9, 64.3%), and multitasking (n = 9, 64.3%). Brain perfusion was evaluated using an advanced 3D pseudo‐continuous arterial spin labeling (pCASL) sequence with Hadamard encoded multiple post‐labeling delays (PLDs), enabling estimation of Cerebral Blood Flow (CBF) and Arterial Transit Time (ATT) ATT and ATT corrected CBF.ResultConventional MRI scans (T1, T2, and FlAIR) appear normal in all subjects. Voxelwise comparisons between Long‐COVID and control subjects showed a significant global decrease in the ATT (p < 0.05, cluster corrected at α < 0.05), along default mode and other key networks, where there is a trend of decreased CBF (p<0.05, uncorrected) specifically in the frontal lobe in those with Long COVID.ConclusionThese preliminary results in an aging group indicate that neurocognitive effects of Long COVID could be attributed to neurovascular dysfunction, even in those cases with initial non‐hospitalized mild COVID‐19 of more than 500 days. The novel finding of diffusely decreased ATT could be something attributable to the unique neurovascular mechanism of Long COVID. Future longitudinal research following the progression of those elderly Long COVID patients with known abnormal neurovascular function to fully evaluate their risk for developing AD and dementia.
Mechanistic modeling of tau biomarkers for amyloid load. A Quantitative Systems Pharmacology study of amyloid‐tau interaction.
Authors: Geerts Hugo , Bergeler Silke , Walker Mike , Van der Graaf Piet 
Published: December 2023

AbstractBackgroundRecent clinical trials with amyloid antibodies have suggested a beneficial effect on cognitive scales after clearing most of the amyloid load. Interestingly, substantial reduction in plasma or CSF tau biomarkers were documented providing interesting insights into the amyloid‐tau interactions in the human AD patient.MethodWe developed a Quantitative Systems Pharmacology (QSP) platform for late MCI‐prodromal AD subjects that combined an earlier published Physiology‐Based Pharmacokinetic (PBPK)‐ QSP model of amyloid aggregation with a novel QSP model describing the impact of amyloid monomers on glutamatergic and nicotinic neurotransmission and neuronal firing, the neuronal activity‐dependent tau release, subsequent tau uptake in the afferent neuron and dynamics of tau biomarkers in CSF and plasma.ResultThe combined model quantitatively reproduced (1) the cortical hyperactivity and higher tau biomarker levels associated with increasing amyloid deposition in observational studies, (2) the differential decrease in CSF and plasma tau biomarkers in clinical trials with various amyloid antibodies. Dynamics of monomeric brain Ab40 and Ab42 and their effect on neuronal firing, rather than reduction in SUVR can better explain the clinically observed changes in CSF or plasma tau between aducanumab, lecanemab, donanemab and gantenerumab. The range of commonly used comedications and common dopaminergic and serotonergic genotype variants affecting neuronal activity can partially explain the variability of tau biomarkers response as downstream effects of amyloid removal.ConclusionThis study suggests a direct link between amyloid dynamics and plasma / CSF tau levels through modulation of neuronal activity. The calibrated QSP model sets the stage for modeling long‐term effects of amyloid therapy on tau pathology progression and identification of optimal trial design for combination therapies.
Preparation of Novel Donepezil Long‐Acting Injectable, IVL3003, and its Pharmacokinetic Study via Subcutaneous Injection in Dogs and Monkeys
Authors: Lee Mase , Lee Sangno 
Published: December 2023

AbstractBackgroundDonepezil is a selective oral acetylcholinesterase inhibitor to treat Alzheimer’s disease (AD). Most patients with AD need help with taking oral donepezil for forgetfulness etc. Therefore, long acting injectables (LAIs) can improve patient’s compliance and quality of life. Because of narrow therapeutic window of donepezil, precisely size controlled microsphere technology is needed for drug release control. We have developed IVL3003 as a novel sustained release monodisperse subcutaneous (SC) LAI of donepezil for one month using IVL‐DrugFluidics® technology. The purpose of this study is to evaluate the physicochemical characteristics of IVL3003 and investigate the inter‐species pharmacokinetic profile differences in beagle and monkey models.MethodVarious one month formulations of donepezil microspheres were prepared by IVL‐DrugFluidics®. Characterization of IVL3003 was performed by scanning electron microscopy (SEM), and the size distribution was measured by laser particle size analyzer (PSA). The amount of donepezil and encapsulation efficiency (EE, %) was determined by HPLC. Size distributions were expressed as span value and CV(%). Non‐clinical models were used to optimize formulations and to evaluate their pharmacokinetic properties. IVL3003 was administered to male beagle dogs (n = 3/group, 11 months old, body weight 9∼11 kg) and male cynomolgus monkeys (n = 3/group, 30∼50 months old, body weight 2.6∼3.3 kg). Plasma concentrations were monitored for one month.ResultsThe SEM images of the microspheres appeared spherical and smooth. Donepezil was well encapsulated and homogeneously. The EE(%) of microspheres was 97.5% and the residual solvent was 232.2 ppm. The span value was 0.25 and CV(%) was 10.01%. The plasma concentrations of donepezil were maintained for 28 days without any initial burst and had small individual variation. There was no big difference between species in plasma concentration and showed a similar PK profile in both.ConclusionsAs we postulated, narrow distribution of the particles was led to improvement of controlled‐release characteristics. These results proved the excellence of IVL‐DrugFluidics® as an ideal microsphere fabrication method in manufacturing uniform and monodispersed microspheres. Long‐acting injectable, IVL3003 is expected to increase the compliance and the safety in the treatment of Alzheimer’s patients. We have filed Ph I for IVL3003 recently as the 1st donepezil containing LAI.
Identification of leukocyte surface biomarkers associated with late‐onset Alzheimer’s disease
Authors: Li Yihan , Huang Xin , Fowler Christopher J , Trounson Brett , Pertile Kelly , Wang Haihua , Wiley James S , Masters Colin L , Gu Ben J 
Published: December 2023

AbstractBackgroundAltered innate immunity has been long associated with late‐onset Alzheimer’s disease (AD) and its associated blood‐based biomarkers are important for AD diagnosis and prognosis.MethodWe collected 38 participants from the AIBL study, including 22 cognitive normal (CN) individuals with negative amyloid burden (Centiloid [CL] < 15), 5 CN individuals with positive amyloid burden (CL > 15), and 11 mild cognitive impairment (MCI) and AD cases. A total of 17 leukocyte surface antigens were examined by flow cytometry immunophenotyping and compared between healthy controls (CN Ab ‐ve), pre‐clinical patients (CN Ab +ve), and clinical cases (MCI & AD), including CD36, MerTK, Clec7a, RAGE, Tyro3, CR1 (CD35), CX3CR1, CCR2, Axl, LILRB2, LILRB3, LILRB4, PILRA, and P2×7.ResultWe identified leukocyte surface markers differentially expressed between HC, pre‐clinical patients, and clinical cases. Mean fluorescence intensities of CD85d and CD85k were significantly reduced in pre‐clinical patients and cases compared with HC, implicating CD85d and CD85k downregulation in AD pathogenesis. Significant upregulation of RAGE, Tyro3, CCR2, CD85a, and PILRA was also noted in cases compared with HC. Leukocyte surface expressions of RAGE, CCR2, PILRA, and CD85k were significantly associated with the Preclinical Alzheimer’s Cognitive Composite (PACC), which is one of the most accurate estimates of cognition in AD diagnosis.ConclusionOur preliminary investigations into these leukocyte markers demonstrated their dysregulations in pre‐clinical stage of AD, implicating early deficits in innate immunity, as supported by genomic studies of AD. This project will continue collecting more AIBL participants up to 200 to evaluate leukocyte surface markers more comprehensively, which would benefit AD screening and diagnosis.
Exploring older people’s attitudes and preferences around the use of their routinely collected healthcare data in brain health research
Authors: Prieto Cristian Andres Gonzalez , Yates Susan , Rodriguez Claudia Rivera , Wilson Daniel , Dobbie Gillian , Cullum Sarah J 
Published: December 2023

AbstractBackgroundOver 50% of dementia in NZ may be due to high prevalence of risk factors such as hypertension, diabetes and cardiovascular disease. If so, a better understanding of the relationships may present ways to mitigate the risk of dementia. Community‐based epidemiological studies would provide definitive evidence but are resource‐intensive so we need to explore alternative sources of data such as routinely collected health information.The overarching aim of our research is to use a machine learning model to identify population groups at high risk of cognitive decline and/or dementia. But first we need to gauge the appetite of service users to have their personal data used in this way. This study aimed to explore the attitudes and preferences of people aged 55+ living in Counties Manukau regarding the use of their de‐identified health data and understanding their concerns and degree of comfort in different scenarios.MethodAn anonymous online survey was conducted with people aged 55+ from NZ European, Māori, Pacific, Chinese and Indian communities currently engaged with older adult health services in Counties Manukau District in 2022. We offered service users the opportunity to complete the survey by telephone if preferred, and the opportunity to be interviewed in languages other than English to ensure adequate representation of the local population.ResultOver 85% of the participants were aware of how their health information was used for service development and assessing population trends, and about 80% were comfortable or very comfortable with data being used in this way, assuming data were stored securely and confidentiality was assured. Participants generally felt that patients’ permission was required if data were being analysed by people other than health professionals or being used by commercial companies, and that there should be transparency about these uses. There were some specific cultural concerns about patients’ data being used after their death.ConclusionThis study supports the idea that the local population are generally supportive of researchers using their de‐identified routinely collected data for research purposes that will benefit the population from which the data were taken, but specific cultural concerns need to be addressed.