bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Multi‐disciplinary Team Approach for Educating Providers to Recognize Delirium in the Post Anesthesia Care Unit
Authors: Chapin Benjamin Albert , Radhakrishnan Nila , Perera Estefania , Kimmett Faith , Mortimer Brenda , Crescioni Charles , Price Catherine C. 
Published: December 2023

AbstractBackgroundPostoperative delirium is common in older adults and has significant associated morbidity and mortality. However, screening is rarely performed in the post anesthesia care unit (PACU). For this reason, clinical researchers of delirium and a tertiary care interdisciplinary delirium Task Force Team proposed to address this area of patient safety.MethodA multidisciplinary team met to complete 3 hospital learning objectives. First, to develop an educational toolkit on PACU delirium identification with feedback from hospital stakeholders on topics to be trained, implementation into medical records, and finalizing training videos/powerpoint/quiz modules. Second, to train every PACU nurse on delirium identification. An EPIC form was created with detailed instructions for completing and documenting the CAM‐ICU and included in the PACU discharge checklist. All PACU nursing staff were assigned the module, and delirium screening was made mandatory for all patients aged 65 years or older. Following module assignment, perceived value, satisfaction, and barriers were surveyed to inform modification of training and implementation. Third, delirium screening rates were monitored.ResultsNurses (n = 110) were assigned postoperative delirium training modules across 3 PACUs starting July 2022 with a 2‐week deadline. Training completion rate was 83% after 3 months. Nurses provided positive feedback on the importance of delirium. Compliance in delirium screening in the PACU was low (<10%). After meeting with nursing staff to hear concerns/barriers to training and implementation, 1 on 1 training with research staff was initiated and all PACU nursing staff completed additional training between September and October. Before project implementation, no delirium screening was performed in the PACU. Over 3 months following completion of training, of 683 patients aged 65 years and older discharged from the PACU, 83 (12%) had delirium screening documented, and 0% were flagged as positive. Rate of screening differed by surgical service and hospital location.ConclusionThis hospital learning study documents the challenges and promise of implementing a PACU delirium screening program in a tertiary care academic medical center. We present data on improved delirium recognition at the hospital level, but variation in compliance rates by surgical service. Future research needs to examine reasons for variable delirium compliance screening.
Low‐Frequency Oscillations During Resting and Task Differentially Associate with Working Memory Performance in Older Adults
Authors: Venkatesan Tharunika , Fei Ellen , Hammond Tyler C , Zhao Xiaopeng , Thibault Olivier , Sompol Pradoldej M , Norris Christopher M. , Jicha Gregory A , Jiang Yang 
Published: December 2023

AbstractBackgroundIncreased intrinsic slow delta oscillations during resting state are associated with brain aging and increased Alzheimer’s disease/related dementia pathologies, i.e., synaptic network dysfunctions and astrocyte over‐reactivity in human (Wiseman et al., 2022) and animal models (Sompol et al., 2023). Here we examined the relations of working memory performance (accuracy and reaction time) with low frequency electroencephalogram (EEG) oscillations during resting and task.Method34 cognitively normal adults (26 female; mean age 77, education 17 years) from UK‐ADRC participated in the study. EEG was recorded using a wireless headset while participants performed a visual working memory task (Borhani et al., 2021), first using their dominant hand (DH, better cognitive motor) then using their nondominant hand (NDH) to indicate a working memory target. Additionally, they participated in resting state eyes closed (EC) and eyes open (EO) pre‐ and post‐task (Fig. 1). EEG data was cleaned and extracted for frequency power using a program developed by Zhao Lab. Pearson correlations were applied.ResultUnder EC resting state, longer reaction times (during retrieval of memory target) positively correlated with increased Delta power in the left frontal site (FC5) during pre‐task (0.34) and the left parietal site (P7) during post‐task (0.35) (Fig. 2). In contrast, increased Theta power in the left frontal site (F3) associated with faster reaction times (‐0.32) during pre‐task EC.Under EO and the task, shorter reaction times negatively correlated with increased Delta power at F3 during post‐task EO (‐0.31) (Fig. 3) and the right frontal site (F4) during task NDH (‐0.33). At P7 (0.31) and F3 (0.32), increased Delta positively correlated with higher retrieval accuracy during pre‐task EO. Conversely, longer reaction times at F4 during task NDH (0.30) and decreased accuracy at P7 during pre‐task EO (‐0.31) correlated with increased Theta.ConclusionIncreased intrinsic slow Delta (0.5‐3.5 Hz) during eyes closed is associated with longer working memory retrieval time but during eyes open or task correlates with faster reaction times. Increased Theta power (4‐7 Hz) showed opposite relations with working memory performance compared to Delta power. Low frequency neural slowing has emerged as promising indicators of pathophysiological changes during brain and cognitive aging.
FDA‐approved carbonic anhydrase inhibitors rescue brain Aβ overload, cerebrovascular pathology and gliosis in Alzheimer’s disease model
Authors: Canepa Elisa , Vazquez‐Torres Rafael , Guzman‐Hernandez Roberto A , Debure Ludovic , Angiulli Federica , Parodi‐Rullan Rebecca M , Lemon Nicole L , Fossati Silvia 
Published: December 2023

AbstractBackgroundMost of Alzheimer’s disease (AD) cases present cerebrovascular dysfunction (CVD) and neuroinflammation, at both early and late stages of AD progression. Dysfunctional vasculature and glial cells favor Aβ deposition, inducing brain cell stress, neuroinflammation, impaired clearance/ metabolic waste accumulation, blood‐brain barrier permeability, and ultimately leading to neurodegenerative processes and cognitive impairment. Endothelial cells (ECs) and microglial cells are major players in mediating vascular and glial fitness, and therefore clearance and inflammatory response. Our previous findings in vitro demonstrated that Aβ elicits mitochondrial dysregulation and caspase‐mediated apoptosis in ECs and glial cells. We also showed that FDA‐approved carbonic anhydrase inhibitors (CAIs), acetazolamide (ATZ) and methazolamide (MTZ), employed in non‐AD related conditions, hinder these pathological events.MethodTgSwDI mice, expressing human Amyloid‐β Precursor Protein, APP, carrying the Swedish, Dutch and Iowa mutations, were employed as AD/CAA (Cerebral Amyloid Angiopathy) model. The model is characterized by fibrillar Aβ burden in the cerebral microvasculature and in the parenchyma, starting at 6 months, as well as abundant gliosis. 8‐month‐old Tg animals were fed 8‐month‐CAI‐diet, following which we harvested the brains for biochemical and immunohistochemical assessments.ResultCAIs significantly reduced brain amyloidosis, and vascular and microglial Aβ accumulation. In addition, CAIs prevented caspase‐3 activation in ECs and microglia, ameliorating vascular and glial fitness, as we observed less microhemorrhages, reduced microgliosis, and microglial pro‐clearance phenotype. We also unveiled a critical novel druggable target, showing that the mitochondrial isozyme Carbonic Anhydrase (CA)‐VB is specifically upregulated in human cerebral endothelial and microglial cells challenged by Aβ, and most importantly is overexpressed in TgSwDI mouse brains, and in human brains of CAA and AD (with CAA) patients.ConclusionCAIs promote vascular health, glial anti‐inflammatory/pro‐healing phenotype and Aβ phagocytosis, which may underlie Aβ deposition reduction. This work paves the way for the application of CAIs in clinical trials for AD and CAA, and uncovers CA‐VB as a mediator of cerebral Aβ toxicity in endothelial and microglial cells.
Gut microbial composition mediates the relationship between intestinal inflammation and amyloid burden before cognitive decline
Authors: Heston Margo B. , Hong Qilin , González Antonio , Betthauser Tobey J , Chin Nathaniel A. , Hanslik Kendra L. , Zarbock Katie R , Kerby Robert L. , Asthana Sanjay , Johnson Sterling C , Knight Rob , Kaddurah‐Daouk Rima F. , Tang ZhengZheng , Ulland Tyler K. , Rey Federico E. , Bendlin Barbara B 
Published: December 2023

AbstractBackgroundGut microbial composition is associated with Alzheimer’s disease (AD) pathology, and recent findings (Heston et al, medRxiv 2022) have identified an increase in intestinal inflammation with greater age and with higher cortical amyloid burden. Although gut microbiome composition and intestinal inflammation have independently been linked to AD pathology, it remains unclear whether the microbiome and gut inflammation are interrelated in the context of preclinical AD. Here we used phylogenetically‐based mediation (PhyloMed) to test whether the gut microbiome mediates the relationship between gut inflammation and cortical amyloid burden, and to highlight bacterial clades that may be specifically implicated as mediators.Method78 participants (Table 1) were enrolled in the Wisconsin Alzheimer’s Disease Research Center and Wisconsin Registry for Alzheimer’s Prevention, collected fecal samples, and completed C11‐PiB PET. Figure 1 illustrates the processing and analysis for each data stream. Fecal calprotectin was measured to quantify intestinal inflammation, and 16S rRNA sequencing characterized the fecal microbiome. Testing the full cohort and the cognitively unimpaired (CU) subset separately (n = 73), PhyloMed was performed at every taxonomic level, resulting in 14 models. Covariates included age, sex, body mass index, Bristol Stool Scale score, cognitive diagnosis/amyloid status, pseudocontinuous APOE AD risk score, and age difference between PET scan and fecal sample.ResultFor both the full and CU cohorts, models at the amplicon sequence variant (ASV) level showed that gut microbiome composition was a significant mediator (p<0.05); species‐ and genus‐level models were marginally significant (p<0.1, Benjamini‐Hochberg FDR) (Table 2). ASVs from the family Lachnospiraceae (Figure 2A) were highlighted as significantly mediating taxa (p<.05, FDR). Interestingly, these taxa were negatively associated with calprotectin, while they were positively associated with PiB DVR (Figures 2B, 2C).ConclusionEven before cognitive decline, the gut microbiome mediated the relationship between calprotectin, a measure of gut inflammation, and cortical PiB DVR, a measure of amyloid burden. Taxa within Lachnospiraceae were implicated as specific mediators, linked with lower inflammation and higher amyloid burden. Future work will use germ‐free mouse models to functionally elucidate the role of these bacteria in inflammation and AD.
Genome‐wide association meta‐analysis of plasma neurofilament light levels in high‐risk adults with Down Syndrome
Authors: Dang Lam‐Ha T , Petersen Melissa , Xicota Laura , O'Bryant Sid E. , Krinsky‐McHale Sharon J , Mapstone Mark , Kamboh M. Ilyas , Cruchaga Carlos , Handen Benjamin L. , Pang Deborah , Silverman Wayne , Schupf Nicole , Lee Joseph H. 
Published: December 2023

AbstractBackgroundOnly a few studies in the general population have investigated genetic contributions to variation in levels of neurofilament light (NfL), which is a general marker of axonal damage and is predictive of Alzheimer’s disease (AD). To our knowledge, no studies have examined this relation in people with Down Syndrome (DS), a population at high risk of developing AD. We performed a genome‐wide search for SNPs associated with plasma NfL levels. We paid special attention to genetic variants identified in the general population to be associated with AD risk and NfL to evaluate whether those variants contributed to AD in DS by altering NfL levels.MethodsWe performed a meta‐analysis using two datasets (N = 455): the omicsADDS and ABC‐DS studies. Levels of plasma NfL were measured using the Simoa platform and genotyping was performed using an Illumina Infinium General Screening Array v2. Imputation on autosomal chromosomes other than 21 was performed using the TOPMed Imputation Server. We first assessed the association between SNPs and plasma NfL levels in each dataset using a multivariable linear regression model that included age, sex, dementia status, and genetic ancestry. We then performed meta‐analysis using sample size weighting. We restricted our meta‐analysis to variants that had study‐specific P<5×10−4, to minimize potential false positives.ResultsOur genome‐wide scan, after Bonferroni correction, identified 33 novel SNPs contributing to variation in plasma NfL (28 variants with elevated plasma NfL and 5 variants with decreased plasma NfL). Three AD‐risk variants previously identified in the general population (UNC5CL/rs10947943, USP6NL/rs7912495, FOXF1/rs16941239), were found to be associated with variation in plasma NfL levels at nominal Pmeta < 0.05. Candidate variants associated with NfL in the general population were not replicated in the current meta‐analysis. The novel genes identified have been implicated in tau neuropathology, variation in lipid levels, insulin regulation, and neurotransmitter release.ConclusionThis genome‐wide meta‐analysis revealed multiple novel genetic loci associated with NfL levels in plasma in adults with DS. We additionally found supporting evidence for three known variants. The genes identified here may lead to insight into underlying mechanisms of neurodegeneration and AD in adults with DS.
Using neuroimaging biomarkers to define plasma thresholds in a community dwelling cohort
Authors: Rudolph Marc D. , Sutphen Courtney L. , Register Thomas C. , Whitlow Christopher T. , Sai Kiran K. Solingapuram , Hughes Timothy M. , Bateman James R. , Dage Jeff L. , Russ Kristen A. , Mielke Michelle M. , Craft Suzanne , Lockhart Samuel N. 
Published: December 2023

AbstractBackgroundAD Imaging biomarkers (IBM) include measures of amyloid (A) on PET, and neurodegeneration (N) on MRI, with thresholds for classification of imaging A/N positivity commonly used at research centers. Novel AD plasma biomarkers (PBM) can potentially enhance neuropathological characterization; however, knowledge regarding which thresholds to use to characterize PBM abnormalities is limited.MethodWe evaluated a range of PBM thresholds based on (1) plasma data alone (gaussian mixture models [GMM]), and (2) when classifying A/N IBM using both existing and data‐driven cutoffs (ROC analyses). Baseline plasma and imaging data were obtained in a community‐dwelling cohort enrolled in the Wake Forest ADRC, including cognitively normal participants (N = 300) and individuals with consensus diagnosis of mild cognitive impairment (N = 192) or dementia (N = 64; Table 1). We examined PBMs (Quanterix SIMOA HD‐X from NCRAD: Aβ42/40, GFAP, NfL, p‐tau181) and IBM measures of A (global PiB PET; A+>1.21 SUVR) and N (FreeSurfer temporal cortical thickness; MAYOTHCK), N+≤2.68mm; FreeSurfer hippocampal volume, N+≤0.454% head size; HPC‐VOL).ResultsOptimal/low/high GMM‐derived thresholds based on PBM distributions (Figure 1a) are provided in Figure 1b. ROC analysis using existing IBM cutoffs are in Figure 1c, with details (sensitivity/specificity/AUC) in Figure 1d. GMM‐ and ROC‐derived p‐tau181 thresholds were highly aligned (range 3.698‐4.071 pg/ml). For NfL and GFAP, imaging ROC‐derived thresholds were lower than GMM‐derived thresholds. AUCs were highest when PBM classification was used to predict A‐PET using existing PET‐positivity cutoffs, with PBM performing more poorly for MRI‐based cutoffs. A/N IBM histograms and current/optimal/low/high GMM‐derived thresholds for each IBM are in Figure 2a. Figure 2b represents how different data‐driven IBM cutoffs impact PBM thresholds in ROC analyses, with AUC statistics for these ROC analyses in Figures 2c‐e. Notably, GMM‐optimal IBM cutoffs performed similarly to current cutoffs for defining PBM thresholds, especially when using A‐PET (AUCs for current and GMM‐optimal >0.747).ConclusionWhile use of existing and data‐driven IBM cutoffs to define PBM thresholds in a community‐dwelling cohort is feasible, some plasma assays (e.g., p‐tau181) are more consistent than others, and caution is warranted against selecting a single threshold. To facilitate clinical use, future work will focus on establishing confidence intervals for PBM abnormalities.
Novel systemic delivery of a peptide‐mediated anti‐sense oligonucleotide to reduce α‐synuclein in a mouse model of Alzheimer’s Disease
Authors: Leitao Andre Direito Goulart , Spencer Brian , Wu Chengbiao , Masliah Eliezer , Rissman Robert A 
Published: December 2023

AbstractBackgroundNeurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α‐synuclein (α‐syn) and amyloid beta (Aβ). Misfolded and aggregated α‐syn has been implicated in neurological disorders such as Parkinson’s disease (PD), and Dementia with Lewy Bodies (DLB), but less so in Alzheimer’s Disease (AD). However, accumulation of α‐syn has been confirmed in over 50% of postmortem brains of AD patients. To date, no therapeutic strategy has consistently downregulated α‐syn in AD.MethodHere we tested the hypothesis that using a peptide (ApoB11) that binds a modified antisense oligonucleotide (2’‐O‐methyl si α‐syn or 2’‐OMe) for transport across the blood‐brain barrier following systemic administration, would downregulate α‐syn expression in an AD mouse model and improve behavioral and neuropathologic phenotypes. We tested the efficacy of the ASO in knocking down α‐syn both in vitro, using neuronal cell lines, and in vivo by measuring α‐syn levels in brains of treated mice with 2mg/kg at 6, 7 and 8 months of age.ResultWe found that treatment of APP transgenic mice with systemic delivery of ApoB11:ASO‐α‐syn reduces expression of α‐synuclein in specific regions of hippocampi of 9 month‐old APP transgenic mice. Downregulation of α‐syn led to a significant reduction of Aβ plaques burden, rescued neuronal loss and prevented astrogliosis, as compared to untreated PSAPP mice. Importantly, we found that AD mice treated with the ASO‐syn had greatly improved hippocampal and spatial memory function as shown by Morris Water Maze tests.ConclusionCollectively, the data shown in this work supports the use of ApoB11:ASO α‐syn conjugates delivered systemically to downregulate α‐syn as a promising future therapeutic strategy in AD. Our work suggests that knocking down α‐syn could be necessary to prevent neuropathology and prevent spatial memory loss.
Investigating mechanisms of sporadic progressive supranuclear palsy in autopsy‐validated human iPSC‐derived midbrain organoids and human brain tissue
Authors: Whitney Kristen R. , Krassner Margaret M. , Delica Sean Thomas , Farrell Kurt W. , Kim SoongHo , Dangoor Diana K. , Sharma Abhijeet , Song Won‐Min , Christie Thomas D. , Iida Megan A , Walsh Hadley A. , Sarrafha Lily , Parfitt Gustavo , Walker Ruth H. , Riboldi Giulietta M. , Frucht Steven J. , Ahfeldt Tim , Zhang Bin , Pereira Ana C. , Temple Sally , Crary John F. 
Published: December 2023

AbstractBackgroundProgressive supranuclear palsy (PSP) is the most common primary tauopathy, with a constellation of pathological features including 4R‐tau positive neurofibrillary tangles and tufted astrocytes. Most PSP cases are sporadic and associated with common structural variation in the 17q21.31 MAPT locus as well as other risk loci, including EIF2AK3 which is critical for the unfolded protein response (UPR). Despite these known genetic risk associations, mechanisms underlying disease pathogenesis are unclear. To investigate candidate mechanisms, there is a critical need for model systems that better recapitulate the cellular complexity of the human brain. Human induced pluripotent stem cell (hiPSC) patient‐derived organoid models have emerged as powerful tools to study molecular and cellular changes in a disease‐relevant genomic context.MethodFibroblasts grown from sporadic PSP patient skin cells were cultured in vitro and reprogrammed into hiPSCs. HiPSC‐derived midbrain organoids were generated in suspension spinner flasks through pharmacological directed differentiation, processed and screened for patterning using qRT‐PCR, immunohistochemistry (IHC), and quantitative immunoblot. Total tau, tau isoform, hyperphosphorylated tau (p‐tau), and UPR activation markers were assessed in organoids and human brain tissue. Single‐nucleus RNA sequencing (snRNA‐seq) was performed on the subthalamic nucleus and adjacent structures in autopsy‐validated PSP brain tissue and clinically normal controls.ResultPSP and control organoids displayed a cytoarchitectural and gene expression pattern consistent with the developing neuroectoderm and midbrain. We observed disease‐relevant differences between PSP and control organoids, including increased high molecular weight p‐tau, a higher ratio of p‐tau:total tau, and increased levels of 4R‐tau in the PSP organoids. Human PSP brain snRNA‐seq data showed dysregulation of the UPR in astrocytes and neuronal subpopulations. We also observed different UPR activation levels in PSP organoids. These findings were validated by neurohistological characterization of the UPR in autopsy brain tissue.ConclusionSingle nucleus transcriptomic and neurohistological data reveals dysregulation of the UPR in key cell types affected in PSP. PSP patient‐derived organoids develop a characteristic midbrain cellular composition and recapitulate key disease‐relevant features, including elevation of toxic tau proteoforms and UPR dysregulation. This sporadic PSP organoid model will provide insight into cell‐type specific drivers of neurodegeneration that underlie sporadic tauopathy.