bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational profiling identifies sex‐specific metabolic and epigenetic reprogramming of microglia in cerebral amyloidosis models with an antibiotic‐altered gut microbiome
Authors: Shaik Shabana M , Cao Yajun , Dodiya Hemraj B. , Zhang Xulun , Boutej Hejer , Han Weinong , Kriz Jasna , Sisodia Sangram S. 
Published: December 2022

AbstractBackgroundMicroglia, the brain‐resident macrophages perform immune surveillance and engage in pathological processes by changing their phenotype and maintain homeostasis. Previously, we showed that antibiotic‐mediated changes in the gut microbiome of APPPS1‐21 transgenic mice resulted in significant decrease in amyloidosis and altered microglial phenotype that are specific to male mice. The molecular events underlying microglial phenotypic transition remain unclear due to lack of models that allow reliable in vivo proteomics. Here, we generated ‘APPPS1‐21‐CD11br’ microglia reporter mice and assessed their protein networks during their phenotypic transition in a sex‐specific manner.MethodSix groups of mice that included WT‐CD11br, antibiotic (ABX) or vehicle‐treated APPPS1‐21‐CD11br male and female were sacrificed at 7‐weeks of age (n=15/group) and used for immunoprecipitation of microglial polysomes from cortical homogenates using anti‐FLAG antibody. Liquid chromatography coupled to tandem mass spectrometry (LC‐MSMS) and label‐free quantification was used to identify newly synthesized peptides extracted from polysomesResultWe showed ABX‐treatment led to reduced Ab levels in male APPPS1‐21‐CD11br mice with no significant changes in the females. We first identified sex‐specific oxidative stress induced by Ab peptides leading to mitochondrial dysfunction and altered calcium signaling. Notably, the female mice also showed dysregulation of ribosomal machinery. Further, microglial polypeptides were associated with FcgR‐mediated phagocytosis in male mice and actin organization in female mice. Interestingly, ABX‐treatment resulted in substantial remodeling of epigenetic landscape for metabolic shift to accommodate increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex‐specific manner. The male mice showed glycolytic shift for neuroprotective phenotype to promote Aβ clearance. However, the female mice showed loss of energy homeostasis due to persistent mitochondrial dysfunction associated with impaired lysosomal clearance and inflammatory phenotype.ConclusionOur studies provide first snapshot of the dynamic translational state of microglial cells in a sex‐specific manner. We identified that antibiotic‐mediated changes in gut microbiome results in metabolic reprogramming of microglial phenotypes to modulate immune responses and amyloid clearance. This microglial plasticity to support neuro‐energetic homeostasis for its function based on sex, paves the path for therapeutic modulation of immunometabolism for neurodegeneration.
Dementia Care Coordination: Evaluating a Program to Support Caregivers through Collaboration with the Alzheimer’s Association and Health Care Partners
Authors: McGurin Nicole E , McCarthy Liz , Arsenault Lisa , Showalter Elizabeth , Patterson Brooke 
Published: December 2022

AbstractBackgroundA dementia diagnosis presents a myriad of non‐medical needs that are burdensome to caregivers and critical for disease management. Most medical professionals lack the time and training to meet these needs for support, education, and resources. The Alzheimer’s Association MA/NH Chapter has developed the Dementia Care Coordination program that partners health care providers and payors with dementia care consultants to improve outcomes for caregivers. Dementia Care Coordination is a telehealth‐based program that has provided invaluable support and tools for caregivers to manage the increased challenges and isolation of the COVID‐19 pandemic. This caregiver support and efficacy are vital to the health and well‐being of a person living with dementia.MethodsA mixed‐methods approach was used to evaluate Dementia Care Coordination. Program data were analyzed. A survey measuring self‐efficacy, unmet needs, and satisfaction was distributed to caregivers at baseline and three months and six months post‐referral. Key informant interviews with caregivers supplemented survey results. A survey measuring provider confidence in dementia management and program impact and satisfaction was distributed to referring partners. Case studies with several referring partners provided additional descriptions.ResultsTotal Referrals for Dementia Care Coordination have increased 91% since the pandemic. Surveys for both caregivers and referring partners found high satisfaction with the program. Key informant interviews with caregivers and case studies with referring partners described the positive impact of the program. Ongoing analyses of the quantitative data from the surveys indicate improvement in unmet needs and self‐efficacy among caregivers and improved provider confidence to manage dementia.ConclusionsDementia Care Coordination is a successful program to meet the needs of and improve outcomes for caregivers. The support, education, and resources were pivotal in managing the additional stresses of the COVID‐19 pandemic for dementia caregivers. The Alzheimer’s Association New England Chapters will use the evaluation data to further improve the program, expand healthcare partners, serve more families, and develop a tool kit for replication in other chapters.
Effects of Alzheimer’s Disease Risk Factors on Cerebrovascular Dynamics in Gray Matter
Authors: Kim Donghoon , Hughes Tim M. , Kim Jeongchul , Harvey Danielle J. , Lockhart Samuel N. , Craft Suzanne , Baker Laura D. , Whitlow Christopher T. , Okonmah‐Obazee Stephanie E. , Hugenschmidt Christina E , Bobinski Matthew , Jung Youngkyoo 
Published: December 2022

AbstractBackgroundCerebrovascular functional parameters such as cerebral blood flow (CBF), cerebrovascular reactivity (CVR), and arterial transit time (ATT) may play an essential role in understanding the vascular contributions to dementia (VCID). We investigated the relationships between cerebrovascular functional parameters and AD risk factors, including APOE genotype, hypertension, and diabetes.MethodSixty‐five subjects (Table 1) enrolled in the Wake Forest Alzheimer’s Disease Research Center (ADRC) Clinical Core cohort underwent MRI, including pseudo‐continuous ASL (PCASL). CVR maps were obtained under a hypercapnic challenge using a computer‐controlled gas blender. A multi‐TI PCASL sequence was also employed to obtain resting CBF and ATT. Separate linear regression models were tested with response variables of quantitative CBF, CVR and ATT in whole brain gray matter (GM) and AD‐prone GM regions including hippocampus, parahippocampal, entorhinal, inferior parietal lobule, precuneus, and cuneus, adjusted for covariates: age, sex, and years of education. To investigate the effects of a risk factor on the interrelated vascular dynamic parameters, a cerebrovascular composite was created with the implementation of the weighting factors, obtained from covariates adjusted logistic regression, for each AD risk group and mild cognitive impairment (MCI). The factor score p‐values were calculated from two‐sample t‐tests with the cerebrovascular composite.ResultIn both whole brain GM and AD‐prone GM regions, subjects with the risk factors generally had lower resting CBF, but differential relationship with CVR. Subjects with hypertension had significantly higher CVR, while APOE e4 carriers showed significantly lower CVR (Figure 1 and 2). From the cerebrovascular composite analysis, CVR showed higher weights in hypertension and APOE e4 carrier groups in both whole brain GM and AD‐prone GM regions (Table 2) although there still were fractions of linear weights of CBF or ATT, which were not negligible.ConclusionHypertension and APOE e4 carrier showed group differences of CVR in both whole brain GM and AD‐prone GM regions and the directions were opposite, implying their pathophysiological mechanisms may differ. As resting CBF and ATT showed lower weights in the composite than CVR, CVR may be a more sensitive brain perfusion parameter relating VCID.
Effects of blood pressure lowering for the prevention of dementia: meta‐analysis of individual patient data from five seminal randomised controlled trials involving 28008 participants
Authors: Peters Ruth , Xu Ying , Fitzgerald Oisin , Aung Htein Linn , Beckett Nigel S. , Bulpitt Christopher J. , Chalmers John , Forette Françoise , Gong Jessica , Harris Katie , Humburg Peter , Matthews Fiona E , Staessen Jan , Thijs Lutgarde , Tzourio Christophe , Warwick Jane , Woodward Mark , Anderson Craig S. 
Published: December 2022

AbstractBackgroundObservational studies indicate U‐shaped associations of blood pressure (BP) and incident dementia in older age, but randomised controlled trials of BP lowering treatment show mixed results on this outcome in hypertensive patients. We undertook a pooled individual participant data analysis of five seminal double‐blind placebo‐controlled randomised trials to better define the effects of BP lowering treatment for the prevention of dementia and cognitive decline.MethodsMultilevel logistic regression was used to evaluate the treatment effect on incident dementia. Effect modification was assessed for key population characteristics including age, baseline systolic BP, sex, and presence of prior stroke. Mediation analysis was used to quantify the contribution of trial medication and changes in systolic and diastolic BP on risk of dementia.ResultsThe total sample included 28,008 individuals recruited from 20 countries. After a median follow‐up of 4.3 years, there were 861 cases of incident dementia. Multilevel logistic regression reported an adjusted odds ratio 0.87 (95% confidence interval 0.75, 0.99) in favour of antihypertensive treatment reducing risk of incident dementia with a mean BP lowering of 10/4mmHg. Further multinomial regression taking account of death as a competing risk found similar results. There was no effect modification by age or sex. Mediation analysis confirmed the greater fall in BP in the actively treated group was associated with a greater reduction in dementia risk.ConclusionUsing data from double‐blind placebo‐controlled clinical trials, we provide evidence in the first single‐stage individual participant meta‐analysis to support benefits of antihypertensive treatment in late‐mid and later life to lower the risk of dementia. Questions remain as to the potential for additional BP lowering in those with already well‐controlled hypertension and of antihypertensive treatment commenced earlier in the life‐course to reduce the long‐term risk of dementia.
Live‐cell imaging of internalised oligomeric tau reveals differences between neuronal cell types
Authors: Lyu Chen 
Published: December 2022

AbstractBackgroundIt has recently been established that pathological forms of aggregated tau spread from affected to recipient cells in the brain, facilitating disease progression. Here we have applied live‐cell imaging to visualise internalised tau in recipient neuronal cells.MethodRecombinant human 2N4R tau was aggregated using heparin and dithiothreitol, sonicated, and labelled with the fluorescent dye, Cy5. Differentiated SH‐SY5Y human neuroblastoma cells (dSH‐SY5Y), mouse primary cortical neurons (PCNs) and human induced pluripotent stem cell‐derived neurons (iPSCs) were exposed to Cy5‐tau for up to 7 days. Confocal microscopy was used to visualise internalised Cy5‐tau in live‐cells and paraformaldehyde‐fixed cells. BODIPY 493/503 and Lysotracker dyes were used to label neutral lipids and lysosomes, respectively.ResultLive‐cell imaging showed rapid (within five minutes) internalisation of Cy5‐tau by all cell types, appearing as small speckles (<0.1µm diameter), with larger masses (>0.5 µm diameter) forming over time. In contrast, only small speckles of Cy5‐tau were detectable inside fixed cells. The size of Cy5‐tau accumulations in PCNs, but not in dSH‐SY5Y or iPSCs, increased further over time, reaching up to 6 µm diameter after 7 days. Lysotracker labelling of live cells indicated significant colocalisation with Cy5‐tau in all three cell types. BODIPY also partially colocalised with both Lysotracker and Cy5‐tau in PCN and iPSCs, but not in dSH. Furthermore, some large (>5 µm diameter) Cy5‐tau spheres in PCNs were Lysotracker‐negative, indicating that incorporation of Cy5‐tau may deacidify lysosomes.ConclusionLive‐cell imaging of neuronal cells has revealed previously unreported internalised tau structures that are not detectable in fixed cells. The sizes of tau spheres that form inside cells exposed to oligomeric tau differ between neuronal cell types, which is a consideration for selecting the most appropriate disease model. The colocalisation between Cy5‐tau and specific organelle labelling indicated tau intracellular trafficking pathway.
Plasma neurofilament light chain in cognitively unimpaired late middle‐aged & older adult APOE ε4 homozygotes, heterozygotes, & non‐carriers from the Arizona APOE Cohort
Authors: Ghisays Valentina , Su Yi , Malek‐Ahmadi Michael H. , Jansen Willemijn J. , Protas Hillary D. , Chen Yinghua , Lee Wendy , Luo Ji , III Robert J. Bauer , Chen Kewei , Caselli Richard J. , Zetterberg Henrik , Blennow Kaj , Reiman Eric M. 
Published: December 2022

AbstractBackgroundAPOE4 gene dose, the number of apolipoprotein E ‐ɛ4 (APOE4) ɛ4 alleles in a person’s genotype, is associated with higher Alzheimer’s disease (AD) risk and younger median age at dementia onset. We previously found relationships between PET, plasma, and measurements of core AD CSF biomarkers in APOE4 gene dose. Here, we characterize longitudinal neurofilament light chain (NfL) changes in the Arizona APOE cohort, including cognitively unimpaired participants, with longitudinal plasma NfL measurements in APOE4 homozygotes (HMs), heterozygotes (HTs) and non‐carriers (NCs).MethodPlasma NfL measurements were performed at the University of Gothenburg using a Single molecule array (Simoa) immunoassay. Annual log‐transformed plasma NfL changes were compared with linear‐tend and univariate ANOVA adjusted for age, sex, and education in 45 HMs, 107 HTs, and 201 NCs who were cognitively unimpaired, 47‐85 years old and did not differ significantly in their age, sex, or educational level. Pearson r correlations with age and annual log‐transformed NfL changes were assessed in 353 participants with at least 2 visits (range 2‐6 visits with an average of ∼3) and an average follow‐up of ∼7 years (range 1‐12 years).ResultAnnual log‐transformed NfL changes were linearly associated with APOE4 gene dose (linear trend HM>HT>NC, P=0.01) and positively associated with age (r = 0.31, P<0.0001). Pairwise comparisons from the univariate ANOVA adjusted for age, sex, and education (P=0.001) showed significantly higher annual NfL changes in HM and HT groups versus NC controls (P=0.01).ConclusionAge and APOE4 gene dose are associated with greater annual plasma NfL changes in CU subjects close to their estimated ages at clinical onset. Studies are needed to better elucidate relationships between different Aβ, tau, inflammatory, and other CSF, or blood‐based biomarkers, and APOE4 gene dose at other ages and in larger subject groups.
Association between late‐life air pollution exposure and medial temporal lobe atrophy in older women
Authors: Wang Xinhui , Salminen Lauren , Petkus Andrew J. , Driscoll Ira , Millstein Joshua , Beavers Daniel P. , Espeland Mark A. , Braskie Meredith N , Thompson Paul M , Gatz Margaret , Chui Helena C , Resnick Susan M. , Kaufman Joel D. , Rapp Stephen R. , Shumaker Sally A. , Younan Diana , Chen Jiu‐Chiuan 
Published: December 2022

AbstractBackgroundAmbient air pollution exposures increase the risk of Alzheimer’s disease (AD) and related dementias, which may be driven by structural brain alterations in the medial temporal lobe (MTL). The MTL consists of subregions critical for memory and vulnerable to AD neuropathology, including the hippocampus, parahippocampal gyrus (PHG), entorhinal cortex (ERC), and amygdala. However, previous structural MRI studies examining the hypothesized adverse effects of exposure on MTL were cross‐sectional and largely focused on hippocampus which yielded mixed results, failing to provide insights on the underlying neuropathological processes affected by air pollution exposures.MethodWe conducted a longitudinal study including 653 cognitively‐normal community‐dwelling women from the Women’s Health Initiative Memory Study with two MRI brain scans (MRI‐1: 2005‐6; MRI‐2: 2010‐11; Meanage at MRI‐1 = 77.3±3.5). Using regionalized universal kriging models, exposures at residential locations were estimated as 3‐year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2; traffic‐related pollution) prior to MRI‐1. Volumes of the total MTL and MTL subregions were derived using multi‐atlas region segmentation with ensembled registration. We used linear regressions to estimate exposure effects on 5‐year standardized volume changes, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics. We also examined if associations differed between APOE4 carriers (n = 123) and non‐carriers (n = 463).ResultMTL volume decreased by 0.53±1.00cm3 over 5 years. For each interquartile increase of PM2.5 (3.26µg/m3) and NO2 (6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3 (95%CI = [‐0.43,‐0.21]) and 0.12cm3 (95%CI = [‐0.23,‐0.01]) over 5 years, equivalent to respectively 17% (95%CI = [11%, 24%]) and 6% (95%CI = [0.6%, 12%]) increased dementia risk. For PHG, we found loss of 0.24cm3 (95%CI = [‐0.30,‐0.19]) and 0.09cm3 (95%CI = [‐0.14,‐0.04]) associated with PM2.5 and NO2 respectively. There was loss of 0.06cm3 (95%CI = [‐0.10,‐0.01]) in ERC associated with PM2.5, but not with NO2. No associations were found with amygdala or hippocampal atrophy. The observed adverse exposure effects on MTL atrophy did not differ by APOE4 genotype.ConclusionMTL atrophy in older women was associated with late‐life exposures to PM2.5 and NO2, and the putative adverse effects varied across brain subregions. The PHG and ERC—the MTL subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity.
Functional Neurophysiological Biomarkers of Early‐Stage Alzheimer’s Disease: An Experimental Perspective of Network Hyperexcitability in Disease Progression and Pharmacological Interventions
Authors: Drinkenburg Wilhelmus (Pim) , Tok Sean , Ahnaou Abdel 
Published: December 2022

AbstractBackgroundNeuronal network hyperexcitability and related alterations in the excitation‐inhibition balance hold promise as early functional biomarkers of network dysfunction and as prodromal indicators of Alzheimer’s disease (AD) pathogenesis. However, the translational validity of hyperexcitability as found in some AD pathology animal models seems restricted by their limited capacity to encompass the complexity of clinical AD.MethodA comparison was made between different AD pathology mouse models with respect to the development of neuronal network hyperexcitability (LFPs) and epileptiform EEG. To this end, amyloid APP‐KI and APP/PS1 mice were assessed with and without hippocampal seeding of (human‐derived) pathological tau conformers at different ages (3‐6 months) and post‐seeding periods (1‐5 months) concerning alterations in amyloid and tau pathology in relation to hyperexcitability‐related, vigilance‐controlled neurophysiological changes.ResultsAnimals from both AD models progressively developed AT8‐tau pathology that is amplified by the presence of amyloid pathology, but that only in APP/PS1 is further intensified by the starting amount of amyloid pathology. Alterations in EEG gamma oscillations appears to be associated with the development of amyloid and tau pathology, and may be an indicator of neuropathology, of neuronal network dysfunction, and of a potential disposition to future deposition of pathogenic amyloids. Immediate localized alterations in hippocampal EEG power spectra associated with tau seeding were found, while a lack of longitudinal changes in neuronal hypersynchrony was noted: hyperexcitability as indicated by increased broadband power spectra was noted in APP/PS1 but not APP‐KI animals at baseline. These differential findings between AD models exemplify the difficulty and complexity associated with identifying physiologically relevant and translatable early biomarkers of AD dysfunction.ConclusionFunctional neurophysiological biomarkers based on early alterations in neuronal circuits, including hyperexcitability, in combination with dysfunctional (GABA‐ergic) inhibitory control of cortical pyramidal neurons should be assessed and validated in the complex context of neurodegeneration, specific amyloid/tau pathology, as well as neuroinflammation and disturbed sleep‐related processes like glymphatic clearance. This complexity constitutes both an additional challenge and a novel opportunity to AD pathology rodent models, in which such an integrative approach is feasible, but whose translational validity is still to be determined in the development of neuroprotective and neurorestorative therapeutic strategies.
A changing diagnostic paradigm of Alzheimer’s disease; an introduction to IWG and NIA‐AA criteria
Authors: van der Flier Wiesje M. , Scheltens Philip 
Published: December 2022

AbstractBackgroundWith the introduction of the NINCDS‐ADRDA criteria in 1984, Alzheimer’s disease (AD) could for the first time be diagnosed with high probability during life. The pathological characteristics of AD were not mentioned at all however, since they could not yet be measured in living individuals.MethodIn the following decades, advances in MRI measures, markers in Cerebrospinal Fluid (CSF), and amyloid‐imaging using PET can be counted among the largest successes of AD research. As a result, the AD disease process can now be demonstrated during life. In addition, these novel diagnostic tests allow the measurement of Alzheimer’s pathology before the stage of dementia. Nonetheless, until well into the 21st century, the 1984 criteria remained common standard.ResultThe publication of the IWG‐criteria in 2007 was a first attempt to integrate biomarker knowledge into diagnostic criteria. These criteria allowed a diagnosis of AD before dementia. In 2011 a roundtable under auspices of NIA‐AA published separate sets of criteria for dementia and MCI due to AD, and even for preclinical AD –the latter reading more like a research agenda than a set of criteria. The 2018 NIA‐AA research framework defines AD as a biological construct, independently of clinical staging. A diagnosis of AD can hence entirely be based on biomarkers. The most recent publication of the IWG in 2021 however proposes that a diagnosis of AD should be reserved to those with symptoms only, otherwise individuals should be considered ‘at risk’ of progression to AD.ConclusionQuestions remain with respect to operationalization, e.g. choices and cut‐offs, for the biomarkers of use. Among the most fundamental questions is the question whether you can have disease but no symptoms, and when disease is symptomatic. Ultimately, truly longitudinal studies are needed to answer the question whether everybody with abnormal amyloid and tau will develop dementia, given enough time of life. This is particularly important now disease modifying treatment are at the horizon. In this presentation, I provide an overview of the different sets of criteria, outlining a number of open questions to be addressed before these criteria can be fully used in clinical practice.