bluuebunny/crossref_metadata_2025_split huggingface dataset:
A novel anti‐amyloid‐beta oligomer antibody reduces plaque burden and slows cognitive decline in 5xFAD mice
Authors: Wang Yubin , Huang Lei , Bujold Matthew , Tang Lingyun , Du Xin 
Published: December 2023

AbstractBackgroundThe soluble amyloid‐beta (Aβ) oligomers are the more toxic form of Aβ as compared with monomers and insoluble fibrils. Lecanemab, a humanized monoclonal antibody (mAb) with high affinity for Aβ oligomers, reduced cognitive decline in patients with early Alzheimer’s disease in a phase 3 clinical trial. Here we report a novel fully‐human anti‐Aβ oligomer mAb with profiles similar to Lecanemab.MethodAlivaMab human F(ab’)2 transgenic mice were immunized with Aβ oligomers to generate Aβ oligomer selective mAbs. The antibodies were screened for, and ranked, based on their selectivity for Aβ oligomer over monomer and ability in mediating the uptake of Aβ oligomers by microglia. Pharmacokinetics (PK) and brain penetration of lead mAb candidates was determined in mice. In vivo efficacy was evaluated in 7‐month old 5xFAD mice with weekly intraperitoneal injection of antibody lead at 1, 3, or 10 mg/kg dose levels for 4 months. After completion of dosing, open field and novel object recognition tests were performed on the treated mice and amyloid plaque burden in the brain was measured by Campbell‐Switzer stain and ELISA.ResultLead antibody 17P04 exhibited higher oligomer selectivity than that of mAb158 (mouse parental antibody of Lecanemab which served as reference antibody control) and induced antibody‐dependent cell‐mediated phagocytosis of Aβ oligomers in mouse microglia cells. PK study in mice showed that 17P04 had longer half‐life in the plasma and the brain, and demonstrated higher brain penetrance in comparison with mAb158. Subchronic treatment of 5xFAD mice with 17P04 reduced Aβ plaque burden in the brain in a dose dependent manner, reversed the abnormal activity of 5xFAD mice in open field test, and reduced cognitive decline as evaluated by novel object recognition.ConclusionWe identified a novel fully‐human anti‐Aβ oligomer antibody with superior Aβ oligomer selectivity, half‐life and brain exposure. Lead antibody 17P04 demonstrated high efficacy in plaque clearance and cognitive protection in 5xFAD mice.
Exploring the Social Connection of Young Caregivers of People Living with Dementia in Ontario
Authors: Redublo Tyler Christian , Alvares Allison , Farahani Mehrdad 
Published: December 2023

AbstractBackgroundCaregiving at a young age can have negative effects on relationships, mental health, and emotional regulation. Notably, dementia caregivers are at higher risk of experiencing social isolation due to their caregiving responsibilities (1‐3). However, there is a lack of knowledge of the experiences of young caregivers of people living with dementia (YCPLWD). Our project is the first to recognize YCPLWD as a unique population and seeks to improve their social connection, which is how individuals connect with each other, and it is comprised of multiple aspects (4) (Figure 1). Our project goals are to:1.	Describe the experiences of social connection among YCPLWD.2.	Identify barriers and facilitators to social connection.MethodOur project applies the Toronto Translational Framework (5) (Figure 2), a patient‐centric approach to identify person‐centered needs in healthcare and co‐create innovative solutions. Qualitative data will be collected through 2‐4 focus groups, each with 6‐8 YCPLWD. Participant criteria include English‐speaking post‐secondary students (aged 18‐24 years) who have provided care to a person(s) living with dementia in the past 12 months and are currently living in the Greater Toronto and Hamilton area. Participants will be recruited using both convenience and snowball sampling. Focus groups will be audio‐recorded, transcribed verbatim, then analyzed using Braun & Clarke’s thematic analysis (6) to identify significant themes.ResultFocus group discussions will focus on (1) experiences with and the impact of social connection, and (2) facilitators and barriers to social connection. These sessions will enable YCPLWD to co‐create knowledge with their peers and share unique insights about the social experience of caregiving. Moreover, focus group findings will be mapped onto Liougas et al.’s framework (4) to verify how YCPLWD experience and articulate different aspects of social connection, including resources, activities, and subjective feelings.ConclusionThis project will recognize YCPLWD as a vulnerable population with unique and specific needs. Given the heterogeneity of dementia caregiving experiences, YCPLWD may face various challenges that can be further understood. Moreover, by exploring barriers and facilitators to social connection, this project will inform the development of novel resources to educate and support YCPLWD.
Evaluation of the association between circulatory markers of neuroinflammation and Alzheimer’s disease pathology
Authors: Peretti Débora Elisa , Ribaldi Federica , Boccalini Cecilia , Marizzoni Moira , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Frisoni Giovanni B , Garibotto Valentina 
Published: December 2023

AbstractBackgroundIncreasing evidence suggests that neuroinflammation and astrogliosis have a prominent role in the spread of pathology and the development of cognitive impairment in Alzheimer’s disease (AD). Circulating plasma markers of neuroinflammation, such as the glial fibrillary acid protein (GFAP), have recently become available, and early observations suggest a robust association with brain pathology. Positron emission tomography (PET) is a molecular imaging technique that allows visualisation and quantification of AD pathology in vivo. The aim of this study was to evaluate the association between GFAP and AD pathology, and its interaction with cognitive decline.Method121 subjects from the Geneva Memory Centre underwent amyloid and tau PET, blood collection, and mini‐mental state examination (MMSE). Amyloid uptake was calculated as centiloid whereas tau was quantified as standardised uptake value ratio. Association of centiloid and tau with GFAP was assessed using a multivariate linear regression model, corrected for age, gender, and MMSE. Mediation analysis described the mediating effect of GFAP on the association between centiloid and tau. Ninety‐four subjects had a follow‐up MMSE after at least 12 months. Linear regression was used to assess the effect of GFAP on the annual rate of change of MMSE (corrected for centiloid, global tau, age, and gender). Mediation analysis was used to test whether the relationship between rate of MMSE change and tau could be explained by a mediation of GFAP.ResultThe mean (SD) age of the participants was 72.6 (7.6) years, and 61 of 121 subjects were men. GFAP was significantly associated with increased tau, but not with centiloid. GFAP partially mediated the effect of centiloid on global tau (mediated proportion = 14%, p = 0.03). The rate of MMSE change was significantly associated with GFAP, and global tau, but not with centiloid. Moreover, GFAP partially mediated the effect between global tau SUVR and change of MMSE scores (52%, p<0.01).ConclusionElevated GFAP is associated with tau. GFAP also partially explains the effect of amyloid pathology on tau accumulation and of tau pathology on subsequent cognitive decline. These results support neuroinflammation and astrogliosis as a relevant contributor to AD pathology, which can be monitored in blood.
White matter changes with cerebrovascular disease and Alzheimer’s disease pathologies
Authors: Raghavan Sheelakumari , Tian Jianqiao , Reid Robert I. , Przybelski Scott A. , Lesnick Timothy G. , Lowe Val J. , Machulda Mary M. , Kantarci Kejal , Knopman David S. , Petersen Ronald C. , Jack Clifford R. , Radford Jonathan Graff , Vemuri Prashanthi 
Published: December 2023

AbstractBackgroundWhite matter (WM) plays an important role in cognitive function and undergoes substantial changes due to aging and increase in AD and AD related dementia (AD/ADRD) pathologies. While recent work proposed measurement of global WM changes from diffusion MRI as biomarkers for Cerebrovascular disease (CVD) such as PSMD and free water, there needs to be a better understanding of WM changes due to AD/ADRD pathologies. The goal of our recent work was to understand white matter changes with CVD and AD – common pathologies in AD/ADRD ‐ utilizing data from Mayo Clinic Study of Aging and Mayo ADRC.MethodUsing diffusion MRI (dMRI) in 718 participants from Mayo Clinic Study of Aging (mean age = 71.1 years, 56% male), we investigated relationships between commonly used dMRI measures and vascular risk as well as global amyloid PET. In a subset of 233 participants who were amyloid‐PET positive and also competed Tau‐PET (flortaucipir) from Mayo Clinic Study of Aging and Mayo ADRC, we investigated associations between regional flortaucipir SUVRs in Braak stages and regional WM changes.ResultsWe found greater frontal lobe WM damage with increasing vascular risk across all dMRI measures. We previously validated the strong relationship between the genu of the corpus callosum (anterior interhemispheric connections) dMRI measurements made on antemortem scans and cerebrovascular pathology observed on postmortem tissue (Nguyen et. al. Acta Neuropathologica 2022) supporting the utility of genu of the corpus callosum dMRI measures as a potential CVD biomarker. Also, we found greater posterior WM damage with increasing amyloid burden. Among the 233 amyloid positive participants, we found spatially dependent WM degeneration associated with regional flortaucipir SUVRs in Braak stages with greater extent of posterior WM damage. Further, dMRI measurements of the WM damage provided complementary information about disease staging and progression of AD in addition to flortaucipir SUVR measurements.ConclusionsAnterior WM measurements may be more specific to CVD and posterior WM changes are seen with increasing AD pathological burden. Our results suggest that WM changes observed with CVD and typical AD may be different and have clinical utility for differential diagnosis and disease staging.
PHysical ACtivity and Aminoacids in MCI: their role in progression towards DEmentia. Study design for “PHACADE”: a monocentric, prospective, non‐pharmacologic interventional study
Authors: Villani Emanuele Rocco , Manni Barbara , Galli Chiara , Fabbo Andrea 
Published: December 2023

AbstractBackgroundMild cognitive impairment (MCI) is a condition in which individuals shows overt cognitive impairment with minimal impairment of instrumental activities of daily living (IADLs). Individuals with MCI have a 10‐fold increased risk of developing dementia as compared to cognitively normal individuals. Several factors are involved into progression from MCI to dementia and sarcopenia is one of them. Hence, physical exertion is an appropriate treatment for people with MCI. But older adults should integrate physical activity with a nutritional programme. The aim of our project is to evaluate the effect of physical training alone and combined physical training and dietary intervention on MCI progression towards AD.Methodopen‐label single centre trial. It compares two cohorts of patient with MCI during a follow‐up period of 2 years: 200 participants are divided in two cohorts (50 intervention group, 150 control group, 1:3 ratio). Inclusion criteria are being > = 65 years old with a diagnosis of MCI made upt to 6 months before the enrolment. Exclusion criteria are Tinetti Scale score of > = 24, Clinical Frailty Scale (CFS) < = 5 and concomitant psychiatric disorders or chronic alcoholism. For each participant in the control group, a twice a week plan of up to 40 minutes of aerobic exertion is conducted by a technician with a degree in sports science belonging to the UOC Medicina dello Sport of AUSL Modena Physical activity programme lasts two months and is scheduled at month 4, and then rescheduled at month 10, month 16 and month 21. In addition to the same twice‐a‐week physical activity exertion plan scheduled for the control group, a supplementation of essential amino acids pharmacological preparation, according to WHO daily ratio is furnished for participants in the intervention group. The main endpoint is to evaluate the efficacy, in terms of incidence rate ratio of developing an overt AD over a 24‐months period.Resultcurrently, the project has been approved by the ethic committe (AOU 0026789/22)) and the enrolment is ongoing.Conclusionthis study will provide more evidence about the efficacy and the feasibility of integrated physical exertion and nutrition programme in MCI population.
Clinical correlates of psychotropic therapy use in early‐onset Alzheimer’s disease ‐ experiences from the Serbian Centre for Memory Disorders
Authors: Stojmenovic Gorana Mandic , Stojkovic Tanja , Stefanova Elka , Obradovic Dragan , Šarčević Maksim , Kostic Vladimir S 
Published: December 2023

AbstractBackgroundEarly‐onset dementia (EOD) is conventionally considered to include patients with disease onset before 65 years of age, with Alzheimer’s disease (AD) being the most common form of EOD. Our aim was to investigate the clinical correlates of psychotropic therapy use in early onset AD (EOAD).MethodThis observational retrospective study included 135 consecutive EOAD patients who were diagnosed according to current criteria from April 1, 2012. until April 1, 2017. year at the Neurology Clinic, University Clinical Centre of Serbia. Neuropsychiatric symptoms were assessed using Neuropsychiatric inventory, Hamilton scale for depression and anxiety, and apathy scale.ResultThe frequency of psychotropic therapy use in our EOAD group was high with 85.18% patients receiving these drugs. Patients often received combinations of psychotropic drugs, 40% of patients received two psychotropic drugs (the most common was a combination of antidepressants and benzodiazepines). Clinical correlates of benzodiazepine administration in our group were agitation, irritability and anxiety. Antipsychotics use correlated with hallucinations, anxiety, irritability and sleep disorders. Psychotropic therapy was not associated with faster cognitive deterioration in EOAD patients, while more frequent functional deterioration correlated with the use of antipsychotics. The use of antipsychotics in patients with EOAD was not associated with serious side effects and reduced life expectancy.ConclusionThe frequency of psychotropic therapy use in our EOAD group was high. Psychotropic therapy was not associated with faster cognitive deterioration, serious side effects and reduced life expectancy in our EOAD patients.
An Integrated Approach to Dementia Support: Sage House
Authors: King Rachel , Surrell Isabelle , Sharpe Benjamin , Pereira Antonina 
Published: December 2023

AbstractThe rising prevalence of dementia, economic costs and growing demand on secondary care services has highlighted the need to start evaluating how we support individuals with dementia and their care givers (Wittenberg et al., 2019). In 2016 the World Alzheimer’s report recommended a shift to post‐diagnostic support services being based in primary and community led care (Prince et al., 2016). As outlined in the WHO global action plan these services need to be accessible, integrated and comprehensive, empowering people with dementia to live in the community for longer (World Health Organisation, 2017).A model of support that meets this directive is an Integrated Dementia Support Approach (IDSA), exemplified by a centre called Sage House. Sage House is an integrated hub for dementia support, offering a range of services for individuals with dementia and caregivers that spans across the dementia journey from diagnosis to day care. This provision includes access to assessment, information, cognitive and social enrichment, and care services in one carefully designed setting.In order to gain a better understanding of the potential of IDSA, a series of research projects were co‐designed with Dementia Support as part of their National Ambition Programme. Three research projects were developed to examine the impact of this integrated approach on outcomes such as wellbeing, quality of life and health economics. The first of these studies is a mixed‐method exploratory service evaluation, that combines survey and interview methods to understand the lived experience of attending Sage House for individuals with dementia and caregivers.Overall, the integrated approach was rated highly, with participants highlighting how the approach was practical and helped to reduce stress. This included reducing the load related to locating services and optimising time by being able to access multiple services in the same visit. Moreover, the continuity helped to facilitate the development of friendships and a sense of familiarity and safety. The evaluation also gave insight into how this innovative approach can impact well‐being, quality of life and engagement with health and social care services. Findings are discussed in light of the potential of this impactful integrated approach to Dementia care.
SUMOylation impact on synaptotoxicity of tau oligomers
Authors: Fraser Paul , Argyrousi Elentina K , Arancio Ottavio , Fioriti Luana 
Published: December 2023

AbstractBackgroundTau oligomers (oTau) secreted by neurons and astrocytes are linked to the propagation of pathology and negatively affect neuronal activity and viability. oTau‐mediated synaptic loss leads to cognitive deficits and manifests the clinical outcomes of Alzheimer’s disease and related tauopathies. Small Ubiquitin‐like MOdifier (SUMO) proteins regulate multiple cellular events and SUMOylation plays pivotal roles in synaptic biology. Changes in SUMO conjugation and function are also linked to AD and related neurodegenerative disorders such as Huntington’s and Parkinson’s disease. The goal of this investigation is to determine the impact of the two main SUMO isoforms, SUMO1 and SUMO2, on oTau related synaptotoxicity.MethodSUMO1 and SUMO2 transgenic mice were generated with expression regulated by the neuron‐specific prion cos‐tet promoter. These in vivo models were used to generate double transgenic mice expressing human SUMO proteins and P301S mutant Tau. Changes in synaptic density and activity and the effects of oTau pathology were investigated with respect to cognitive deficits and long term potentiation (LTP).ResultElevated expression of human SUMO1 lead to impaired synaptic development and increased tau aggregation. SUMO1 transgenics crossed to Tau mutant mice resulted in an accelerated synaptic loss and a more severe disease phenotype as evidenced by LTP impairments and rapid cognitive decline. Conversely, SUMO2 conjugation levels were decreased in the presence of oTau and phospho‐tau pathology indicating a down‐regulation of its function. Enhanced SUMO2 expression in a mouse model of Tau pathology reversed this process and resulted in a significant reduction in oTau‐mediated synaptotoxicity and the associated LTP and cognitive impairments.ConclusionCumulatively, our findings indicate that SUMO1 negative impacts and exacerbates oTau‐related synaptic dysfunction. In contrast, SUMO2 confers substantial neuroprotection and represents a potential therapeutic avenue to counteract oTau‐induced synaptotoxicity in AD.
Crosstalk between tau and alpha7 nicotinic acetylcholine receptors at the synapse
Authors: Tropea Maria Rosaria , Puma Domenica Donatella Li , Melone Marcello , Gulisano Walter , Vacanti Valeria , Arancio Ottavio , Grassi Claudio , Conti Fiorenzo , Puzzo Daniela 
Published: December 2023

AbstractBackgroundThe failure of cholinergic transmission and the increase of amyloid‐β peptide (Aβ) and tau protein are key players in Alzheimer’s disease (AD). The interaction between α7 nicotinic acetylcholine receptors (α7‐nAChRs) and Aβ has been previously investigated, but few studies have focused on the crosstalk between α7‐nAChRs and tau. We previously reported that Aβ and tau might act independently or concomitantly to impair synaptic plasticity and memory, converging onto common targets such as amyloid precursor protein (APP). Here we investigated the role of α7‐nAChRs on tau‐mediated impairment of synaptic plasticity and memory, tau neuropathology, and their interplay with APP.MethodWe used WT (C57Bl6/J) and α7 KO at different ages. 3XTg models of AD were used as positive controls. We performed electrophysiology to investigate synaptic transmission and plasticity at the CA3‐CA1 synapses from hippocampal slices, and behavioral studies (Novel Object Recognition and Location, Fear Conditioning) to evaluate memory. We used western blot for the expression of APP, tau (Ser199, Ser396, Thr205) and GSK‐3β (Ser9) phosphorylation. Formation of tau paired helical filaments (PHFs) and neurofibrillary tangles (NFTs) were evaluated by immunohistochemistry and Bielschowsky staining. Immunoreactivity for NeuN was measured to assess neuronal loss.ResultWe found that α7 KO mice presented an AD phenotype characterized by the impairment of Long‐Term Potentiation and Paired Pulse Facilitation, and the reduction of different types of memory starting at 12 months of age. This age‐dependent phenotype was paralleled by an increase of APP expression, hyperphosphorylation of tau, and a decrease of GSK‐3β (Ser9) phosphorylation. α7 KO hippocampi presented a marked tau neuropathology with an increase of PHF‐1 immunoreactivity, the presence of PHFs and NFTs, and neuronal loss.ConclusionIn summary, the lack of α7‐nAChRs was sufficient to trigger an AD‐like phenotype characterized by a marked tau pathology. Our data also suggest that the concomitant increase of APP expression might contribute to tau neurotoxicity.