bluuebunny/crossref_metadata_2025_split huggingface dataset:
Importance of functional outcome measures when evaluating the efficacy of tau immunotherapies
Authors: Ji Changyi , Lin Yan , Sigurdsson Einar M. 
Published: December 2023

AbstractBackgroundTau immunotherapies are promising approaches to treat Alzheimer’s disease and other tauopathies. Using in vivo two‐photon calcium imaging, we have observed altered neuronal calcium activity in behaving JNPL3 tauopathy mice at both early and advanced stage of tauopathy. We have also shown that two mouse monoclonal antibodies, targeting phosphorylated tau‐Ser396/Ser404, partially restored these neuronal deficits (Wu Q et al Neurobiol Dis 2021, Ji C et al Alzheimers Dement AAIC 2022). Recently, we reported that novel single domain antibodies (sdAbs) and their divalent derivatives conjugated to Fc fragment showed varied efficacy to reduce tau pathology in culture, and to clear tau in brain interstitial fluid by in vivo microdialysis. Whether these sdAbs restore tauopathy‐induced neuronal deficits warrants further evaluation.MethodSomatic calcium activity in the motor cortex of homozygous 6‐month‐old JNPL3 mice was imaged by two‐photon microscopy when animals were either quiet or running. Two doses (100 µg each) of a tau IgG1‐(sdAb)2 or a control IgG1 were administered intravenously four days apart after the first imaging session. Somatic calcium activity was assessed again four days later, and compared to profile before treatment. Tau pathology was then analyzed in the mouse brain lysates by immunoblotting.ResultAbnormal cortical calcium activity was observed in resting and running JNPL3 mice at 6 months of age. Acute treatment with the tau IgG1‐(sdAb)2 did not normalize the frequency, amplitude or total activity of calcium transients in motor cortical neurons. Littermate mice treated with control IgG1 showed worsening of the tauopathy‐induced calcium dysfunction in the resting condition, and no improvement in the running condition. Interestingly, tau IgG1‐(sdAb)2 treatment decreased soluble phosphorylated tau in the treated mice, although it did not improve neuronal function. Additional analyses are ongoing, including of antibody target engagement.ConclusionThese findings confirmed neuronal calcium dysregulation in young JNPL3 mice. The failure of this particular acute tau antibody treatment to restore neuronal function is in contrast to our prior findings on two other tau antibodies targeting a different epitope, although all reduced soluble phospho‐tau. Therefore, these results highlight the importance of including a functional readout during preclinical development of tau antibodies.
Specific damages to olfactory‐related structures and their relation to episodic memory in Individuals at Risk of Alzheimer’s Disease.
Authors: Jobin Benoît , Frasnelli Johannes , Boller Benjamin ,   CIMAQ group
Published: December 2023

AbstractBackgroundOne of the major challenges in the diagnosis of Alzheimer’s disease (AD) is to increase the specificity of the early diagnosis. While episodic memory impairment is a sensitive marker of AD, other markers are needed to improve diagnostic specificity. A promising biomarker might be a cerebral atrophy of the central olfactory processing areas in the early stages of the disease since an impairment of olfactory identification is present at early clinical stages of AD. Our goal was to evaluate whether reduced grey matter volume (GMV) in the central olfactory processing regions could be observed in early and preclinical stages of AD. We also aimed to verify if GMV of central olfactory processing regions is associated with episodic memory performance.Method166 participants from the Consortium for the Early Identification of Alzheimer’s Disease‐Quebec (CIMA‐Q) (92 with subjective cognitive decline ‐ SCD, 40 with mild cognitive impairment ‐ MCI and 34 cognitively healthy controls) were included. We performed regions of interest (ROI) analysis using a mask of the regions that are activated during olfactory stimulation. We also extracted GMV outside ROIs, representing non‐olfactory areas of these regions, i.e., regions which do not respond to olfactory stimulation. Verbal episodic memory was assessed using a free word recall task from Memoria Word Recall test.ResultCompared to controls (p = .019) and participants with SCD (p = .003), participants with MCI exhibited a smaller total GMV of central olfactory processing regions, with a significant interaction effect between region and group (p = .004). Specifically, the piriform cortex, amygdala, entorhinal cortex, and left hippocampus were significantly smaller in individuals with MCI (p≤.05, corrected). In contrast, when comparing GMV outside ROIs between the three groups, there was no such interaction between region and group (p = .428). Additionally, GMV in the olfactory areas of the piriform cortex, amygdala, and left hippocampal gyrus was correlated with episodic memory performance, while GMV in the non‐olfactory areas of the left hippocampus and left parahippocampal gyrus was correlated with episodic memory performance (p≤.05, corrected).ConclusionThere is a specific neurodegeneration of limbic and medial‐temporal olfactory‐structures in MCI, GMV of these regions being related to cognitive performance.
Structural brain network degeneration associated with agitation in dementia
Authors: Jenkins Lisanne M , Gupta Sonya M , Kouchakidivkolaei Maryam , Sridhar Jaiashre , Rogalski Emily J , Weintraub Sandra , Popuri Karteek , Rosen Howard J. , Wang Lei 
Published: December 2023

AbstractBackgroundAgitation is a behavioral syndrome involving increased motor activity, restlessness, aggressiveness and emotional distress. Its has a 30% prevalence across multiple types of dementia and is associated with negative outcomes, including reduced quality of life, caregiver distress, and mortality. Pharmacological treatment risks serious side effects, including mortality. Understanding brain network topology could provide insights into novel treatment methods.MethodParticipants comprised 600 subjects from 3 existing databases: the Alzheimer’s Disease Neuroimaging Initiative (ADNI), Frontotemporal Lobar Degeneration Neuroimaging Initiative (NIFD) and the Mesulam Center for Cognitive Neurology and Alzheimer’s Disease at Northwestern University.Participants were clinically diagnosed with either behavioral variant frontotemporal dementia (bvFTD), mild cognitive impairment (MCI), dementia of the Alzeheimer type (DAT) or cognitively normal (CN). The Neuropsychiatric Inventory Questionnaire (NPI‐Q) caregiver rating was used to determine whether individuals were agitated or not.Morphometric similarity networks (MSNs) were generated from Freesurfer statistics calculated from T1‐weighted MRIs. 7 surface‐based cortical metrics (e.g. gray matter volume, surface area) were calculated for each of 360 parcels. Pairwise inter‐parcel Pearson correlations of feature vectors were calculated to produce a morphometric similarity matrix for each individual. We calculated sub‐matrices for salience (SN) cognitive control (CCN) and default mode networks (DMN). Brain Connectivity Toolbox calculated transitivity and global efficiency of each network. Metrics were calculated at different thresholds to ensure the results were not threshold‐dependent.We calculated 2 (Agitation present/absent) x 4 (Diagnosis) repeated measures ANCOVAS for transitivity and global efficiency for each network. Covariates were age, sex, race, database, education, ICV, CDR‐SB and days MRI‐NPI‐Q.ResultFor the SN, people with Agitation had significantly lower global efficiency than people without Agitation (Figure 1). There were no significant effects of diagnosis or interaction.For the CCN, people with agitation had significantly lower transitivity than people without Agitation (Figure 2). There were no significant effect of diagnosis or interaction.ConclusionAcross different forms of dementia, Agitation is associated with reduced integration (global efficiency) of the salience network, and reduced segregation (transitivity) of the cognitive control network. Interventions that alter these topological network features may be effective in reducing agitation in dementia, regardless of clinical diagnosis.
Genetic associations with mixed neuropathologies in the aging brainGenetic associations with mixed neuropathologies in the aging brain
Authors: Katsumata Yuriko , Fardo David W. , Abner Erin L , Nelson Peter T 
Published: December 2023

AbstractBackground““Mixed” neuropathologies (NPs) are common in aged brains. Classic Alzheimer’s disease neuropathologic change (ADNC) proteinopathies are amyloid‐β plaques and tau neurofibrillary tangles (NFTs). In addition, α‐synuclein and TDP‐43 are also key proteinaceous disease markers, and cerebrovascular diseases (CVDs) often coexist. Although the scientific problems regarding mixed NPs are increasingly recognized, genetic associations with mixed NPs have not been well‐investigated. In this study, we applied item response theory (IRT) to optimize the clustering and combination of mixed NPs and examined the genetic associations.MethodNP data were drawn from the National Alzheimer’s Coordinating Center (NACC) NP v10‐11 forms through the March 2022 data freeze, including Thal phase ratings (A score); Braak NFT stage (B score); CERAD neuritic plaque scores (C score); Lewy bodies (LBs); TDP‐43; hippocampal sclerosis (HS); cerebral amyloid angiopathy (CAA); infarct and lacunes; microinfarcts; atherosclerosis of the circle of Willis; and brain arteriolosclerosis. We determined dominant pathology patterns in 1,228 participants who had no missing data using a multidimensional graded response model within the IRT framework. The NACC NP data were linked to the U.S. Alzheimer’s Disease Research Centers genetic data provided by the Alzheimer’s Disease genetic Consortium.ResultFrom the leave one out cross validation simulation, the model fitness tests showed that the 4‐factor model had fewer differences from the data than the other models. As shown in Figure, the predominant NPs were TDP‐43 and HS for factor 1 (F1), CVDs other than CAA for factor 2 (F2), A, B, and C scores and CAA for factor 3 (F3), and LBs for factor 4 (F4). The TMEM106B locus was genome‐wide significant with F1 (TDP‐43/HS) and the APOE locus was genome‐wide significant with F3 (ADNC/CAA) after adjusted for age at death, sex, and other factor scores. The SDK1 and FMNL2 loci were not genome‐wide significant, but had noteworthy associations with F2 (CVDs).ConclusionOur new approach to create mixed NP scores could detect the TMEM106B and APOE loci as TDP‐43/HS related and ADNC related regions, respectively. Although previous studies reported SDK1 as an ADNC related gene, we showed that the gene may be associated with CVDs.
An Investigational RNAi Therapeutic for Tau Lowering
Authors: Farley Jonathan , Haines Jeffery D , Gannon Sean , Nguyen Tuyen , Abbott Stephen , Darcy Justin , Tymon Roxanne , Cha Diana , Schlegel Mark , Castoreno Adam , Bisbe Anna , Zlatev Ivan , Rollins Jeff , Bostwick Bret , Avbersek Andreja , Macdonald Lynn , Gao Min , Anderson Matthew , Brown Kirk 
Published: December 2023

AbstractBackgroundThe hyperphosphorylation, mislocalization, and aggregation of the microtubule associated protein Tau (MAPT) is a driving force in tauopathies, a class of progressive neurodegenerative disorders. These pathogenic intracellular aggregates, known as neurofibrillary tangles (NFTs), are a hallmark in several diseases such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and Alzheimer’s Disease (AD). There is a high unmet medical need for new approaches to target Tau in these numerous tauopathies. While anti‐Tau immunotherapies emphasize the clearance of extracellular Tau aggregates, they do not address the intracellular accumulation of NFTs.MethodHere, using our lipophilic C16‐conjugated siRNA for CNS delivery, we identified potent molecules targeting the MAPT gene in both in vitro and in vivo models.ResultsOur RNAi molecules targeting the MAPT gene durably reduce MAPT mRNA and Tau protein levels in both in vitro and in vivo model systems. Furthermore, in a 16‐week non‐human primate study, we observed robust target engagement resulting in sustained reduction of MAPT transcript and Tau protein in brain tissue and cerebrospinal fluid.ConclusionTogether, these results suggest that RNAi lowering of Tau could be a novel strategy to address both intra‐ and extra‐cellular accumulation of Tau aggregates, which could have therapeutic advantages for treating tauopathies.
Development of the COMET tool: Caregiver‐reported Outcome Measure for Emergency care Transitions
Authors: Gettel Cameron , Galske James , Uzamere Ivie , Serina Peter , Hernandez‐Bigos Kizzy , Mane Sahil , Chen Kelly , Ottilie‐Kovelman Sierra , Sandoval Jacqueline , Venkatesh Arjun , Cohen Andrew , Monin Joan , Fried Terri , Hwang Ula 
Published: December 2023

AbstractBackgroundDespite a recognized need for more robust metrics, caregiver‐reported outcome measures have not been developed for care partners of persons living with cognitive impairment (PLWCI) navigating emergency department (ED)‐to‐community care transitions. Our objective was to develop the Caregiver‐reported Outcome Measure for Emergency care Transitions (COMET) tool through a 5‐phase process.MethodsThe study was conducted in four EDs and included care partners of PLWCI discharged from the ED identified by validated screening tools. In Phase 1, 25 participants completed semi‐structured interviews to identify barriers experienced during ED‐to‐community care transitions. In Phase 2, research team members performed item generation, in which candidate items were developed through findings from Phase 1 qualitative interviews and adaptation of items on existing outcome measures. In Phase 3, we utilized member checking, in which 27 new participants ranked candidate items they felt important for inclusion within the final COMET tool. Phase 4 included 10 cognitive debriefing interviews, in which participants assessed candidate items for comprehensiveness, content validity, and comprehension. In Phase 5, 19 multidisciplinary stakeholders participated in a modified Delphi approach to generate the COMET tool.ResultsPhase 1 identified four major barriers experienced by care partners of PLWCI during ED‐to‐community care transitions: 1) unique care considerations while in the ED setting impact the perceived success of the care transition, 2) poor communication and lack of care partner engagement was a commonplace during the ED discharge process, 3) care partners experienced challenges and additional responsibilities when aiding during acute illness and recovery phases, and 4) navigating the health care system after an ED encounter was perceived as difficult by care partners. Phase 2 generated 50 candidate items grouped into 3 domains: discharge process, care transition, and impact on the caregiver. Phase 3 quantitatively identified high‐ and low‐scoring candidate items for inclusion in the final COMET tool. Phase 4 resulted in revisions to the wording of several candidate items. Phase 5 resulted in the 19‐item COMET tool.ConclusionsDevelopment of the COMET tool will provide a means for caregiver‐centric outcome assessment of interventions targeting ED‐to‐community care transitions among PLWCI.
Dementia prevention strategies in Low and Middle Income Countries: A systematic review
Authors: Jeraldo Rosario Isabel Espinoza , Chandra Avinash , Anjum Rifah , Bothongo Phazha L K , Waters Sheena , Uchegbu Ijeoma , Byford Michelle , Marshall Charles R , Cooper Claudia 
Published: December 2023

AbstractBackgroundAmidst the global efforts to target potentially modifiable dementia risk factors, Low and Middle Income Countries (LMIC) have been described as having considerable potential for prevention. Although there is growing interest in the design, testing and implementation of preventive strategies, most of the existing literature focuses on countries with higher income levels. This systematic review aims to 1) describe the approaches that have been tried in LMIC to prevent dementia in adults over 50 years old at high risk 2) explore the key potential mechanisms and contexts associated with a positive outcome.MethodWe conducted our search on appropriate electronic databases for articles published between January 2010 to January 2023. We included all primary research intervention studies meeting a priori criteria. Our primary outcomes were any change in cognition, and/or dementia diagnosis. Two authors are independently reviewing articles and assessing study quality using the Mixed Methods Appraisal Tool (MMAT). We will narratively synthesise results.ResultIn line with current literature on dementia prevention, and due to both the diversity of populations and the broad range of possible approaches, we expect heterogeneity of studies with mixed results. We also expect multi‐domain interventions to be reported as the most effective.ConclusionThis project will add to current knowledge on how dementia prevention is being approached in the context of LMIC. Findings will allow us to understand which factors make local interventions work and inform the implementation of preventive strategies for people at high risk of dementia.
Impact of mobile research unit in SKYLINE trial to broaden trial access in traditionally underrepresented communities
Authors: Croney Ruth , Jan Adam Y , Hurley Vicki , Markham‐Coultes Kelly , Smith Jill , Batchuluun Dawn , Jaime Lucia , Fils‐Aime Lucie , Pingshaw Astrid , Ostrowitzki Susanne 
Published: December 2023

AbstractBackgroundThe SKYLINE prevention trial (NCT05256134) aimed to enroll cognitively unimpaired, elderly, amyloid‐positive adults, which is known to be challenging. Additionally, it is essential to address disparities of access to trials, particularly in underrepresented populations (URPs) where the need to travel to a research site and lack of comfort or distrust of medical providers have been identified as barriers to participation (Alzheimers Dement 2021;17:327‐406). Potential participants in URPs may have limited experience/knowledge of clinical research; therefore, additional community‐based initiatives were launched to improve awareness and education.MethodA mobile research unit (THOR) was designed to visit selected communities and provide education on memory loss and initial access to screening for the SKYLINE trial. THOR was designed to optimize participant experience and study visit flow (Figure), and was strategically operationalized in Florida due to the large prevalence of older adults, high proportions of URPs, and concentration of Alzheimer’s research centers. Two multilingual personnel, representative of the targeted populations and with expertise in outreach within URPs, managed the unit. Community‐based settings were targeted, including community centers, churches, retirement communities, restaurants, and doctors’ offices. In addition to SKYLINE prescreening, THOR offered community‐based memory screenings and memory loss education to help build relationships and trust with communities. A survey was used to assess site staff perceptions of the implementation of THOR.ResultBetween July and November 2022, THOR was deployed at 20 community outreach events; 325 participants were prescreened for SKYLINE (Table 1). Race and ethnicity data were provided by 127 participants at 12 events from Global Alzheimer’s Platform (GAP) Foundation‐partnered sites; 64/127 (50.4%) participants were from an URP. Overall, 80% of surveyed site staff agreed/strongly agreed that THOR had a positive impact on relationship‐building and prescreening rates in URPs (Table 2).ConclusionTHOR was an innovative, strategic way to increase access to SKYLINE by raising awareness of brain health and clinical research in the community. Site survey responses indicated utilization of THOR improved engagement with URPs. Implementation of a mobile research unit with capabilities to perform trial prescreening activities was an effective way to engage potential trial participants including URPs.
Blood‐derived mitochondrial DNA copy number is associated with Alzheimer’s Disease through the regulation of plasma lipid and amino acid metabolism
Authors: Tong Tong , Zhu Congcong , Farrell John , Khurshid Zainab , Martin Eden R. , Pericak‐Vance Margaret A. , Wang Li‐San , Schellenberg Gerald D. , Haines Jonathan L. , Lunetta Kathryn L. , Farrer Lindsay A. , Zhang Xiaoling 
Published: December 2023

AbstractBackgroundBlood‐derived mitochondrial DNA copy number (mtDNA‐CN) is the proxy measurement of mitochondrial function in the peripheral and central systems. Abnormal mtDNA‐CN not only indicates impaired mtDNA replication and transcription machinery but also dysregulated biological processes such as energy and lipid metabolism. However, the relationship between mtDNA‐CN and Alzheimer’s Disease (AD) and the underlying mechanisms of mitochondrial dysfunction in the pathogenesis of AD are still unclear.MethodTo investigate the causal relationship between mtDNA‐CN and AD, we performed two‐sample Mendelian randomization (MR) using publicly available summary statistics from GWAS for mtDNA‐CN and AD. Further, we estimated mtDNA‐CN using whole‐genome sequence data from blood samples of 1,521 ADNI participants and used a Cox proportional hazard model, adjusted for age, sex, and study phase, to assess the association between mtDNA‐CN and AD risk. The association of AD biomarkers measured in brain and plasma metabolites with mtDNA‐CN was evaluated using linear regression. We conducted causal mediation analysis to test the natural indirect effects of mtDNA‐CN change on AD risk through the significantly associated biomarkers and metabolites.ResultMR analysis using a profile likelihood approach suggested a causal relationship between decreased blood‐derived mtDNA‐CN and increased risk of AD (OR = 0.71; P = 0.023). Survival analysis showed that decreased mtDNA‐CN was significantly associated with increased risk of conversion from mild cognitive impairment to AD (HR = 0.80; P = 0.0017). We also identified significant associations between mtDNA‐CN and brain glucose metabolism (β = 0.050; P = 0.047) and amyloid‐β (Aβ) (β = 0.069; P = 0.015) and CSF Aβ (β = ‐0.051; P = 0.048). Plasma Aβ was, however, not associated. Several lipid species, amino acids, biogenic amines, and inflammatory proteins in plasma were also significantly associated with mtDNA‐CN. Finally, causal mediation analyses showed that the effect of change in mtDNA‐CN on AD risk is mediated by plasma neurofilament light (β = ‐0.055; P = 0.010), glycine (β = 0.016; P = 0.044), and hexadecenoylcarnitine (β = ‐0.017; P = 0.049).ConclusionOur study indicates that mtDNA‐CN measured in blood is predictive of AD risk. Associations of mtDNA‐CN with Aβ in CSF and brain, but not plasma, suggest cross‐tissue regulation of mitochondria. Decreased mtDNA‐CN might increase AD risk through lipid and amino acid metabolism. These results also suggest potential development of mtDNA‐CN as a blood‐based biomarker.