bluuebunny/crossref_metadata_2025_split huggingface dataset:
Establishment and application of a microglial phagocytosis/cell health high content assay for Alzheimer’s disease drug discovery targeting microglia
Authors: Mason Emily R , Soni Disha , Chu Shaoyou ,   Cellular Pharmacology lab/TREAD‐AD center, Clinical Pharmacology/Dept. of Medicine
Published: December 2023

AbstractBackgroundTargeting microglial phagocytosis has been proposed as a therapeutic strategy for Alzheimer’s disease drug discovery. A reliable cellular assay capable of measuring drug‐regulated phagocytosis activity while simultaneously measuring treatment‐caused cell stress and toxicity is needed for drug discovery research targeting microglia. This need motivated us to develop and establish a high content microglial phagocytosis/cell health assay to meet the challenge.MethodThe assay uses 384‐well cellular imaging plates, microglial cell lines (HMC3 and BV2) and mouse primary microglia, pHrodo‐myelin/membrane debris as ligand, and a high content imaging system for imaging and analysis. Assay procedures include 1) plate cells on day 1 and incubate cell plates overnight in 37oC; 2) treat cells with compounds on day 2; 3) add pHrodo‐myelin/membrane debris to cell plates on day 3 and incubate in 37oC for 20 hours; 4) stain cell nuclei with Hoechst‐33342 for 30 min before performing high content imaging and analysis on day 4. Three selected parameters are measured from cell images: 1) mean total fluorescence intensity per cell of pHrodo‐myelin/membrane debris in phagocytosis vesicles to quantify phagocytosis; 2) cell counts per well (assessing effects on proliferation and cell death); and 3) average nuclear intensity (detecting induced apoptosis).ResultVarious treatments targeting different mechanisms regulating microglial phagocytosis were tested; we observed that Cytochalasin D inhibited phagocytosis, LPS stimulated phagocytosis in BV2 cells but not HMC3 cells, Idelalisib (PI3Kd inhibitor) inhibited HMC3 cell phagocytosis, and Saracatinib (Src/abl family of kinases inhibitor) stimulated HMC3 phagocytosis. These results validated the assay for use in drug discovery targeting microglial phagocytosis. With the assay, we identified some INPP5D inhibitors and some PLCG2 activators stimulated phagocytosis in a concentration range without significant cell stress/toxicity with all three cell types tested.ConclusionA microglial phagocytosis/cell health assay was established. The simultaneous measurement of phagocytosis and cell health allows for the distinction of drug effects on regulation of phagocytosis from cellular stress/toxicity‐related changes, a distinguishing feature of the assay, which helped compound selection of drug discovery projects targeting INPP5D and PLCG2 respectively.
Exploring gray matter volume atrophy associations with hearing in the UK Biobank
Authors: Fitzhugh Megan C , Pa Judy 
Published: December 2023

AbstractBackgroundHearing impairment was recently recognized as a modifiable risk factor for dementia. Theories to explain this relationship propose that hearing impairment results in reduced sensory input across the brain, which negatively affects brain structure. Therefore, large exploratory studies are needed to examine potential relationships between hearing and brain volume.Method2,000 participants (age = 63±7 years, 50% female) from the UK Biobank were include in this study. Voxelwise multiple regression models examined the association between hearing and baseline MRI gray matter volume. Hearing was assessed using a speech‐in‐noise task, with positive scores reflecting poorer hearing. Interactions between hearing and sex on brain volume were also explored. Covariates included age, sex (except in model with sex interaction), socioeconomic status, and total intracranial volume. Given the exploratory aim of the analysis, a threshold of p<0.001 was used.ResultThe multiple regression model results showed that poorer hearing is associated with lower gray matter volume in bilateral temporal auditory regions (Heschl’s gyrus, superior temporal gyrus) and left amygdala. While hearing scores did not significantly differ by sex, there were significant hearing‐by‐sex interactions. In women, poorer hearing was associated with lower volume in bilateral auditory regions. In men, poorer hearing was associated with lower volume in right hippocampus and higher volume in posterior cingulate cortex.ConclusionThis study sought to address a major gap in the current literature and explored voxelwise associations between hearing and brain volume in a large sample. The results show that poorer hearing is associated with lower brain volume in lateral and medial temporal regions, which differed by sex. Poorer hearing in women was associated with lower volume in auditory regions, while in men, poorer hearing was associated with lower volume in regions similarly affected by Alzheimer’s disease and dementia. Together, these data provide support for a potential mechanistic explanation for the association between hearing loss and dementia through increased brain atrophy.
C/EBPβ/δ‐secretase Signaling Drives Neurodegenerative Diseases
Authors: Ye Keqiang 
Published: December 2023

AbstractBackgroundC/EBPb/AEP pathway are escalated in the brain in an age‐dependent manner and proteolytically cleaves APP and Tau and a‐Synuclein, facilitating AD and PD pathologies.MethodC/EBPb/AEP pathway couples different risk factors that elicit inflammation to Alzheimer’s disease. To explore why women are more vulnerable for AD, we investigated different hormones altered during menopause and found FSH (follicle‐stimulating hormone) strongly activated this signalling, leading to AD pathogenesis in different mouse models. Employing immuno‐EM and knockout tissues, we demonstrated that FSHR is expressed in mouse and human brain neurons. Notably, FSH administration drives AD onset in young male and female mice, whereas anti‐FSH robustly diminishes AD progression in overiactomized female 3xTg mice. Moreover, deletion of FSHR or C/EBPb from the neurons of 3xTg mice attenuates AD pathologies.ResultElevated FSH during menopause activates C/EBPb/AEP signalling, which subsequently cleaves both APP and Tau, triggering AD onset. Blockade of FSH abrogates overiactomy‐induced AD pathologies and restores the cognitive dysfunctions in AD mouse models.ConclusionFSH elevation after menopause elicits women susceptibility to AD via activating C/EBPb/AEP pathway. Inhibition of FSH/FSHR may provide an innovative therapeutic strategy for treating AD.
Sex Differences in Behavioral and Psychological Symptoms in Institutionalized Patients with Advanced Alzheimer’s Disease
Authors: Choudhury Samira , Colman Sarah , Chu Li , Davies Simon , Derkach Peter , Elmi Sarah , Fischer Corinne E. , Gerretsen Philip , Graff‐Guerrero Ariel , Hussain Maria , Ismail Zahinoor , Khan Shehroz , Kim Donna , Krisman Linda , Moghabghab Rola , Mulsant Benoit H. , Nair Vasavan , Pollock Bruce G. , Rej Soham , Rostas Aviva , Streiner David , Van Bussel Lisa , Rajji Tarek K. , Kumar Sanjeev , Burhan Amer M. ,   StaN study Group
Published: December 2023

AbstractBackgroundBehavioral and psychological symptoms in dementia (BPSD) are highly prevalent in patients with Alzheimer’s dementia (AD). We examined sex differences in the frequency and severity of BPSD in patients with advanced AD residing in long term care or admitted to inpatient psychiatric units. Also, sex differences in the frequency and severity of BPSD symptom clusters were explored.MethodWe analyzed data from the Standardizing Care for Neuropsychiatric Symptoms and Quality of Life in Dementia (StaN) study (ClinicalTrials.gov/NCT03672201). BPSD was assessed with the Neuropsychiatric Inventory Clinician rating scale. Chi‐squared tests and Mann‐Whitney U tests were used to determine sex differences in frequency and severity of BPSD, respectively. Bonferroni correction was used for multiple comparisons. Generalized linear models were performed to examine effect of sex on severity of BPSD while controlling for age and residence. BPSD symptom clusters were defined as: (1) psychosis (hallucinations and delusions), (2) emotional distress (depression and anxiety), and (3) agitation (agitation, aggression, irritability, aberrant motor behavior, and aberrant vocalizations).Result194 participants (99 female, 95 male) were included. Females had higher frequency of delusions (X2(N = 176) = 8.47, p = .004) and males had higher frequency of sleep disturbances (X2(N = 176) = 9.89, p = .002). Further, females had greater severity of delusions (N = 176, U = 2976, p = .001), and sleep disturbances (N = 176, U = 2950, p = .002). In generalized linear models, sex was associated with severity of delusions (Wald X2 = 3.97, N = 176, p = .046), but not with sleep disturbances. Examination of clusters revealed that females had higher frequency of psychosis (X2(N = 176) = 4.25, p = .039).ConclusionWe observed sex differences in the frequency and severity of specific BPSD. Future studies should aim to understand potential mechanisms underlying these differences, and to study their relevance for screening, and individualized management of BPSD.
Findings from IDEA Café, the first pilot intervention for sexual and gender minority older adults living with dementia with no care partner
Authors: Fredriksen‐Goldsen Karen I , Kim Hyun‐Jun , Teri Linda , Jones Brittany R , Petros Ryan , Berridge Clara , Emlet Charles A 
Published: December 2023

AbstractBackgroundDue to our aging population and changing demographics, there are an increasing number of older adults with dementia with no care partner in the U.S., a trend more pronounced among sexual and gender minority (SGM) older adults. To our knowledge there are no extant interventions for SGM older adults with dementia and few dementia interventions that do not rely on the presence of a care partner.MethodWe tested an innovative group adaptation of Innovations in Dementia Empowerment and Action (IDEA), IDEA Café. SGM older adults with dementia (including mild cognitive impairment) and no care partner were enrolled and randomly assigned to IDEA Café (n = 15) or routine medical care (RMC; n = 15). IDEA Café participants attended a 9‐session virtual group program emphasizing exercise, pleasant events, social support, and stress management. The goal was to improve the health‐related quality of life of SGM older adults with dementia and no care partner. We aimed to assess the intervention’s feasibility, acceptability, and preliminary efficacy.ResultWe met enrollment goals and had good adherence, compliance, and participation, demonstrating feasibility. Participants and interventionists found the intervention acceptable. Within‐group tests revealed the RMC group showed no statistical changes from pre‐test to post‐test, while the IDEA Café treatment group showed significant improvement in primary outcomes, including physical functioning and depressive symptomology with medium effect sizes, and quality of life with small effect size. Between‐group tests found the IDEA Café group had significantly higher physical functioning and quality of life and lower microaggression scores than the RMC group at posttest, all with large effect sizes. In secondary outcomes, IDEA Café participants’ microaggression scores, perceived stress, and social isolation scores significantly decreased with medium effect size, and informational and social support increased with medium affect size.ConclusionOur results offer preliminary evidence for a group‐based virtual intervention for this health disparate, underserved population. Our significant findings support IDEA Café’s mechanisms of change: increasing physical activity and mobilizing social support, while addressing SGM risk and protective factors. Future research should examine treatment effects over time with a larger sample size, and the moderating and mediating effects of background characteristics.
The prevalence of and risk factors for sleep disturbances: a systematic review and meta‐analysis
Authors: Butris Nina , Tang Evan , Pivetta Bianca , He David , Saripella Aparna , Yan Ellene , Englesakis Marina , Boulos Mark I , Nagappa Mahesh , Chung Frances 
Published: December 2023

AbstractBackgroundDetermining the prevalence and risk factors related to sleep disturbance is beneficial for risk stratification, preventative interventions, and care planning. The objectives of this systematic review and meta‐analysis are to determine the prevalence and risk factors of sleep disturbances and their associated postoperative complications in surgical patients.MethodA systematic search of the databases MEDLINE, MEDLINE ePubs Ahead of Print and In‐ process, Embase Classic+Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials from inception to February 23, 2022, was conducted. The inclusion criteria were: (1) adult patients undergoing a surgical procedure; (2) in‐patient population; (3) assessed for pre‐ and postoperative sleep disturbances using the Pittsburgh Sleep Quality Index (PSQI) and/or objective sleep assessment tools, and (4) English language articles. The pooled prevalence of sleep disturbances was calculated using inverse‐variance random‐effects model. The 95% confidence interval (CI) was calculated using normal approximation calculation. Sensitivity analysis was performed to determine the effect of each study on the meta‐analysis estimates.ResultThe systematic search resulted in 21,951 articles. Twelve studies involving 1,497 patients were included. The pooled prevalence of sleep disturbances at preoperative assessment was 60% (95% CI: 50%, 69%) (Figure). Risk factors for postoperative sleep disturbances were preexisting disturbed sleep and preoperative anxiety. Patients with postoperative delirium had a higher prevalence of pre‐ and postoperative sleep disturbances. Patients with postoperative delirium also had higher wake after sleep onset percentage (WASO%) in preoperative assessment using actigraphy.ConclusionThe prevalence of preoperative sleep disturbances is high at 60%. In adult surgical patients undergoing inpatient surgery, preoperative sleep disturbance and anxiety were the two main risk factors for postoperative sleep disturbance. Surgical patients with postoperative delirium were associated with a higher prevalence of pre‐and postoperative sleep disturbances. Preventing sleep disturbances in surgical patients may be important for postoperative outcomes.
Assessing caregiver burden
Authors: Bakkali Leen , Renzulli Brenda 
Published: December 2023

AbstractCaregiver burden is an unfortunate reality which can impact negatively on the health of the caregiver and the appropriate care the patient with dementia needs.The Zarit Burden interview provides an objective measure of caregiver’s burden which alerts the healthcare provider and the caregiver for the need to intervene to prevent deleterious consequences.Our practice regularly assesses caregiver’s burden and looks in ways to lessen care giver burden using different tools and approaches.Caregiver burden can improve by education, emotional support, change in environment and planning.
Do Mouse Data Lie? For Buntanetap, They Totally Predict Human Outcome
Authors: Maccecchini Maria L. , Fang Cheng 
Published: December 2023

AbstractBackgroundOverexpression of neurotoxic proteins drives downstream events that dysregulate axonal transport, lead to inflammation, nerve cell death, and loss of function (Chen et al. 2021). By inhibiting the translation of neurotoxic aggregating proteins ‐ amyloid precursor protein, tau, alpha‐synuclein etc., buntanetap restores axonal transport, lowers inflammation, and protects nerve cells from dying. In three double‐blind, placebo controlled, phase 1/2 clinical studies in both Alzheimer (AD) and Parkinson (PD) patients buntanetap showed statistically significant improvement in movement in PD and cognition in AD (Fang et al. 2023).MethodHere we want to compare our animal data with our human data to evaluate if animal models are predictive of human outcomes. We are comparing data from APP/PS1 AD mice (Teich et al. 2018), Ts65Dn Down Syndrome mice (Chen et al. 2020), and two Phase 1 /2 double‐blind, placebo‐controlled human AD studies: Discover study run by ADCS and AD/PD study run by Annovis.Result1. Buntanetap is a translational inhibitor of APP by pulse‐chase experiment in mice and by stable isotope labeling kinetics (SILK) in humans (Galasko et al. 2022).2. Our drug inhibits APP/Abeta, tau/pTau in a dose‐dependent manner in animals (Lahiri et al. 2007; Teich et al. 2018; Chen et al. 2020) and humans (Maccecchini et al. 2012).3. The biomarker dose‐response is seen at a much higher dose than the efficacy dose‐response.4. We see a statistical improvement in cognition in animals and in humans (Teich et al. 2018; Fang et al. 2023).ConclusionIn all our studies conducted to date in AD mice and humans, we have obtained consistent data on the mechanism of action, consistently lowered levels of neurotoxic aggregating proteins, and consistent improvements in cognition.
Increased neural activity relates to greater neuropsychiatric symptoms and beta‐amyloid plaque load in cognitively normal older adults
Authors: Oh Hwamee , Razlighi Qolamreza R , Rogers Annika , Sharp Elizabeth 
Published: December 2023

AbstractBackgroundEpidemiological studies have shown that individuals predisposed to experiencing psychological stress, and those affected with diseases associated with chronic stress such as depression and anxiety have an increased risk of developing Alzheimer’s disease (AD). These findings may imply that poor resilience to psychological stress is not simply a characteristic of dementia, but may reflect mechanisms involved in disease etiology. In this study, we examined the level of neural activity as a potential mechanism of linking individual susceptibility to psychological stress and AD‐related neuropathology across the spectrum of AD.MethodsA total of 166 participants (mean age = 74.21; 90 Females) spanning diagnostic spectrums along cognitively normal (CN) individuals and AD patients was selected for analysis from the ADNI2 database based on the availability of resting state fMRI and AV45 PET data. Neural activity was quantified by applying the amplitude of low frequency fluctuations (ALFF) method to time series of fMRI blood oxygenation‐level‐dependent signals (in the frequency range of 0.01‐0.08 Hz) obtained during resting‐state fMRI (rsfMRI) scan. Amyloid pathology was quantified by AV45‐SUVR measures that were normalized to the cerebellum. Mini‐Mental State Exam (MMSE) and the total Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores were used as cognitive and stress susceptibility measures.ResultsBehavioral measures of stress were significantly associated with brain Aβ indices and neural activity across the entire cohort, spanning from CN older adults to AD patients (ps<0.05). Relationships between the neural activity, stress responses, and Aβ deposition, however, differ by diagnostic groups. As stress indicators increased, CN subjects exhibited increased activity in several brain regions including the regions within the default mode network (DMN), while AD participants exhibited decreased activity across the brain. Moreover, as brain Aβ load increased, CN participants experienced DMN hyperactivity, while AD participants experienced hypoactivity.ConclusionThese results indicate a potential link between heightened stress responses and increased susceptibility to the development of AD pathologies through neuronal hyperactivity, especially in the preclinical stage of AD. Alleviating stress and regulating stress responses may be important modifiable factors and intervention strategies that could help prevent and intervene the development of AD pathology.
Development of an Algorithm for Real‐time Delivery of Automated Intervention Boosters to Support Long‐term Use of an Electronic Memory Aid
Authors: Schmitter‐Edgecombe Maureen , Luna Catherine , Farias Sarah Tomaszewski , Cook Diane J 
Published: December 2023

AbstractBackgroundElectronic memory aids can facilitate positive health outcomes in older individuals experiencing memory difficulties. Despite this, long‐term maintenance of device use is often limited. Delivery of automated boosters has the potential to enhance use of these aids and retention of compensation training goals, but questions remain regarding optimal timing of boosters. For example, if delivered too frequently recipients will habituate. Here we describe our process for developing an automated schedule that will detect when use of an electronic memory aid has started to decline so that an automated booster can be delivered. We start by unobtrusively observing use patterns and generating initial delivery rules based on clinical judgement, and then apply these rules to develop an automated algorithm.MethodsWe used three months of post‐training data from 28 older adults with mild cognitive impairment who learned to use an electronic memory and management aid (EMMA) application. Two clinicians examined graphs of each users’ daily interactions with EMMA to identify specific days when device interactions had declined and iteratively developed a set of rules that identified the best time points to deliver boosters. The algorithm was then applied to data from an entirely different cohort of 50 older adults engaged in an intervention utilizing the EMMA app. We then compared when the clinician would have boosted vs when the algorithm would deliver a boost.ResultsFollowing 4 iterations of clinicians examining graphs with possible boost points from the first set of users, an algorithm was developed. When applied to the second data set, the algorithm identified 371 boost points, with a false positive rate of 11% and false negative rate of 3%. It was also deemed that the timing of approximately 28% of the correctly identified boost points by the algorithm were off by +/‐ 2 days.ConclusionNext steps will be to further modify the algorithm and then formally test the impact of boosts at different time points to empirically evaluate their impact on usage. Our ultimate goal is to deliver boosters in real time and as early as possible when usage wanes to improve intervention outcomes.
APOE‐4 dependent dysfunctional neutrophil‐microglia crosstalk accelerates Alzheimer’s disease
Authors: Rosenzweig Neta , Kleemann Kilian , Grucci Madeline , Aronchik Micheal , Butovsky Oleg 
Published: December 2023

AbstractBackgroundAPOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD). The role of human APOE variants in AD has been studied extensively in the regulation of brain cells but not in peripheral immunity. APOE is also expressed in neutrophils and controls their activation. Moreover, neutrophils have been shown to play a negative role in AD mice via the induction of neutrophil extracellular traps (NETs)MethodHere we aimed to dissect the impact of APOE4‐neutrophils on AD pathology, using Ly6g‐CRE mice crossed to APOE‐KI(E3 and E4)fl/fl:APP/PS1.ResultWe identified a cell intrinsic role of APOE3 in controlling neutrophil maturation and degranulation, which is exacerbated in APOE4‐KI neutrophils and reduced in APOE4‐KO neutrophils. Moreover, APOE4 neutrophils accumulated in the brains of AD mice and in AD patients, associated with microglia at sites of plaque pathology. Here we show that genetic deletion of APOE4 in neutrophils suppressed their activation and reduced their recruitment to the brains of APP/PS1 mice. RNAseq analysis showed increased proportion of disease associated microglia (DAM/MGnD) in APP/PS1: Ly6g‐CRE:APOE4fl/fl mice, associated with reduced plaque pathology. Furthermore, we show impaired induction of MGnD signature in AD brains of APOE4 carriers. Our findings show that APOE4‐induced inflammatory neutrophils are recruited to the diseased brain and impair MGnD response leading to accelerated AD pathology.ConclusionTaken together, these findings identify a cell‐intrinsic role of APOE4 in the induction of hyperactivated neutrophils recruited to the brain, which may provide new molecular targets to modulate and restore functional microglia in AD.