bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single‐cell network biology characterizes cell type gene regulation for drug repurposing and phenotype prediction in Alzheimer’s disease
Authors: Gupta Chirag , Xu Jielin , Jin Ting , Khullar Saniya , Liu Xiaoyu , Alatkar Sayali Anil , Cheng Feixiong , Wang Daifeng 
Published: December 2022

AbstractBackgroundDysregulation of gene expression in Alzheimer’s disease (AD) remains elusive, especially at the cell type level. Gene regulatory network, a key molecular mechanism linking transcription factors (TFs) and regulatory elements to govern target gene expression, can change across cell types in the human brain and thus serve as a model for studying gene dysregulation in AD. However, it is still challenging to understand how cell type networks work abnormally under AD.MethodTo address this, we integrated single‐cell multi‐omics data and predicted the gene regulatory networks in AD and control for four major cell types, excitatory and inhibitory neurons, microglia and oligodendrocytes. Importantly, we applied network biology approaches to analyze the changes of network characteristics across these cell types, and between AD and control.ResultWe found that many hub TFs target different genes between AD and control (rewiring). Also, these cell‐type gene networks show strong hierarchical structures in which top TFs (master regulators) are largely common across cell types, whereas different TFs operate at the middle levels in some cell types (e.g., microglia). The regulatory logics of enriched network motifs (e.g., feed‐forward loops) further uncover cell‐type‐specific TF‐TF cooperativities in gene regulation. The cell type networks are highly modular. Several network modules with cell‐type‐specific expression changes in AD pathology are enriched with AD‐risk genes and putative targets of approved and pending AD drugs, suggesting possible cell‐type genomic medicine in AD. Finally, using the cell type gene regulatory networks, we developed machine learning models to classify and prioritize additional AD genes. We found that top prioritized genes predict AD and clinical phenotypes (e.g., cognitive impairment).ConclusionOverall, this single‐cell network biology analysis provides a comprehensive map linking genes, regulatory networks, cell types and drug targets and reveals mechanisms on cell‐type gene dysregulation in AD.
Impact of therapeutic plasma exchange on amyloid plaque load and vascular health in APP/PS1 mice
Authors: Cover Christopher G , Peretin Jenna , Lopez Oscar L. , Vazquez Alberto L 
Published: December 2022

AbstractBackgroundTherapeutic plasma exchange (TPE) has been shown to be a beneficial treatment for Alzheimer’s disease (AD) to both humans and mice; however, little is known about TPEs impact on preserving vascular function. Since AD pathology is usually associated with vascular dysfunction, the current study investigates the therapeutic potential of TPE on preserving vascular reactivity in young APPswe/PS1dE9 AD mouse model.MethodBi‐monthly TPE began at 6‐months of age (mo) in the treatment APP/PS1 group (n = 6), exchanging 300‐400 µL of plasma from a 2‐3 mo donor, wild‐type (WT) mouse. The control groups, APP/PS1 (n = 6) and WT group (n = 5), received no treatment. All mice were implanted with a 5mm cranial window and head‐fixed conditioned for awake optical imaging. Wide‐field optical imaging (WFOI) at 620nm light was used to assess vascular function. To this end, changes in optical imaging signal sensitive to blood oxygenation (OIS‐BOLD) produced by a 90‐sec hypercapnic stimulus (10% CO2 in air) delivered by nose cone. Peak changes from baseline OIS‐BOLD were measured (Fig. 1). Images of cortical amyloid plaques were obtained monthly using fluorescence microscopy 6‐24 hrs after Methoxy‐X04 administration (1 mg/kg, IP; Fig. 2). To account for between mouse variability in plaque accumulation, plaque data were normalized to their value immediately prior to their treatment (i.e., 6 mo data). An analysis of covariance was used to assess statics for vascular reactivity and plaque load.ResultTPE shows a trend towards reduced cortical plaque load in 8‐12 mo treated APP/PS1 mice (Fig. 2; p = 0.1658 ± 0.023). Vascular reactivity values measured by OIS‐BOLD also show a trend towards improved vascular function although our treated group measurements did not sample older ages (Fig. 3; F(2,134) = 2.08,p = 0.124).ConclusionOur findings showed that there is a trend to a decrease cortical amyloid plaque load in young‐middle aged AD mice treated with TPE, as well as a trend for improved vascular function. Further studies on old‐aged mice will provide additional information about the effects of TPE on AD and vascular function.
Deconvolving Cerebrospinal Fluid Soluble TREM2 Signal and Longitudinal Associations with Cognition
Authors: Weiner Rebecca L , Dumitrescu Logan , Blennow Kaj , Zetterberg Henrik , Gifford Katherine A. , Pechman Kimberly R. ,   The Alzhemer's Disease Neuroimaging Initiative, Jefferson Angela L. , Hohman Timothy J. 
Published: December 2022

AbstractBackgroundCerebrospinal fluid (CSF) soluble triggering receptor expressed on myeloid cells‐2 (sTREM2) is an emerging biomarker of neuroinflammation in Alzheimer’s disease (AD). Yet, sTREM2 expression has not been systematically evaluated in relation to concomitant drivers of neuroinflammation. We previously found a novel association between high Aβ40 (but not Aβ42) and high sTREM2 levels at baseline and replicated additional associations between a fluid biomarker of blood‐brain barrier (BBB) integrity and CSF biomarkers of neurodegeneration. Therefore, we sought to determine the relative contributions of these biological correlates to CSF sTREM2 levels during the prodromal stages of AD. Additionally we investigated whether the residual variance in sTREM2 level correlated with each biomarker predicted future cognitive performance.MethodLeveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6, male=67%, mild cognitive impairment=47%), previously established associations between baseline CSF sTREM2 concentrations and CSF AD biomarkers (Aβx‐40, total tau, phosphorylated tau, and neurofilament light) and BBB integrity (CSF/plasma albumin ratio) were examined via hierarchical linear regression using sTREM2 as an outcome variable. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status. Baseline CSF sTREM2 levels and corresponding residual components when adjusting for other biomarker levels in independent models were used in longitudinal mixed effects models predicting an episodic memory composite calculated as a z‐score from independent tests. Participants had up to five visits (mean±sd=2.63±1.30 visits).ResultHigh baseline CSF sTREM2 levels predicted slower longitudinal memory decline in VMAP (β=1.442e‐05, p=0.035). Additionally, the component of sTREM2 signal correlated with Aβx‐40 best predicted future memory performance (β=2.217e‐05, p=0.007). Together, Aβx‐40, phosphorylated tau, and the CSF/plasma albumin ratio jointly explained 36% of variance in sTREM2 levels. Aβx‐40 levels and the CSF/plasma albumin ratio explained sTREM2 signal above and beyond established associations with tau (R2=0.21; R2=0.21; and R2=0.17, respectively).ConclusionWe highlight potential contributions of Aβ homeostasis and BBB integrity to elevations in CSF sTREM2, underscoring novel biomarker associations relevant to disease progression. Results suggest that the tight correlation between baseline CSF sTREM2 and Aβx‐40 levels may have notable importance to cognitive trajectory in an aged cohort enriched for mild cognitive impairment.
The novel M4 PAM PET tracer [11C] MK‐6884: a novel biomarker for measuring target engagement of muscarinic M4 positive allosteric modulators (PAMs) as well as cholinergic tone in patients with Alzheimer’s disease
Authors: Li Wenping , Basile Anthony S , Tong Ling , Van Laere Koen , Masdeu Joseph C. , Hostetler Eric D , Marshall Fiona , Uslaner Jason M. 
Published: December 2022

AbstractBackgroundThe muscarinic acetylcholine receptor 4 (M4) has attracted attention as a target for treating neuropsychiatric symptoms, such as agitation and aggression, associated with Alzheimer’s disease. We have developed novel selective, potent, and in vivo suitable M4 positive allosteric modulators (PAMs) and demonstrated robust pharmacology in preclinical models predictive of antipsychotic and pro‐cognitive effects. Importantly, we have also shown that these selective M4 PAMs produce greater therapeutic margins for cholinergic adverse effects compared to less selective muscarinic receptor agonists.MethodsTo enable translation in the clinic, we set out to discover an M4 PAM PET tracer suitable for measuring central receptor occupancy (RO).Result[11C]MK‐6884 binds with high affinity and selectivity to the allosteric site on the M4 receptor that our other M4 PAMs bind. The affinity of [11C]MK‐6884 was found to be influenced by the concentration of orthosteric agonist in vitro and in vivo, consistent with the high cooperativity of the molecule in vitro. PET studies successfully determined the target engagement of PAMs to enable modeling the relationship between drug plasma exposure, RO, and pharmacodynamic activity. Donepezil increased the tracer binding potential of [11C]MK‐6884 in rhesus and healthy human subjects, confirming in vivo the influence of cholinergic tone on [11C]MK‐6884 binding that was observed in vitro. Consistent with a presumed cortical deficit in synaptic acetylcholine, [11C]MK‐6884 PET studies in AD patients showed lower cortical binding potential compared to healthy elderly participants, as well as notable cortical heterogeneity and bilateral asymmetry of M4 receptor binding in AD patients. Striatal binding potential was unchanged in these different populations.ConclusionOur findings demonstrate that the M4 PAM PET tracer [11C]MK‐6884 is a useful tool for determining target engagement of M4 PAMs, as well serving as a unique probe to study changes in cholinergic neurotransmission in neurodegenerative disease. The Enigma Biomedical Group has an exclusive license agreement with Merck & Co., Inc., for the global development and commercialization of MK‐6884. This allows Enigma and its partner, Cerveau Technologies Inc. to provide biomarkers to industry and academia to accelerate research in the field of neurodegenerative and neuropsychiatric diseases.
Chronic Treatment Study Using Class C CpG ODN in Aged Non‐Human Primate Model of Sporadic CAA (Saimiri boliviensis boliviensis).
Authors: Patel Akash G , Karimi Sohail , Nehete Pramod N , Nehete Bharti P , Murray Sean , Levine Dafna T , Soliman Muhammad T , Llanos Michael , Hopkins William D , Williams Lawrence E , Wisniewski Thomas , Scholtzova Henrieta 
Published: December 2022

AbstractBackgroundTherapeutics that target innate immunity present promising avenues for the treatment of Alzheimer’s disease (AD) neuropathology. Our recently published study using squirrel monkeys (SQMs), a non‐human primate model of sporadic AD with extensive cerebral amyloid angiopathy (CAA), demonstrated that treatment with TLR9 agonist, Class B CpG ODN, safely reduces cognitive deficits and pathological features including parenchymal amyloid deposits, tau pathology, and CAA. Subsequently, we initiated the first chronic treatment study using Class C CpG ODN, and demonstrated its safety and efficacy in eliciting an immune response in a geriatric SQM population. Here, we assess the efficacy of Class C CpG ODN by evaluating plasma biomarkers of neurodegeneration and cognitive status using an innovative computerized testing system.MethodGeriatric SQMs received monthly injections of Class C CpG ODN or saline. Plasma biomarkers of neurodegeneration (NfL, GFAP), neuroinflammation (YKL‐40/CHI3L1), and Aβ40/42 autoantibodies were detected longitudinally using Luminex, SIMOA, or ELISA assays. Furthermore, we have implemented an innovative, touchscreen‐based Automated Cognitive Testing System (ACTS) among socially living SQMs to monitor behavioral changes. Actical® activity monitors recorded general activity parameters (step count, activity count, energy expenditure, and intensity level).ResultPlasma levels of NfL, GFAP, and YKL‐40 were significantly increased in saline‐administered monkeys compared to CpG ODN‐treated cohort. No changes were observed in both treatment groups in general activity parameters. Longitudinal plasma hematological/biochemical parameters and Aβ40/42 IgG and IgM titers revealed no differences between treatment groups, further validating the safety of our immunomodulatory approach. Geriatric SQMs completed the ACTS SHAPE training tasks to a 95% criterion of success within 10 days and are progressing through advanced cognitive tests [Match‐to‐Sample (MTS) and Two‐Choice Discrimination]. Preliminary MTS testing revealed that CpG ODN‐treated group performed with a greater response accuracy than saline controls over the last 1000 trials. Additional biofluid biomarkers and cognitive assessments are being finalized. Longitudinal gene expression profiles (RNA‐seq and NanoString analyses) involved in CpG ODN pathways using PBMCs are underway.ConclusionOur findings enhance the translational value of the SQM model for preclinical research on AD and CAA pathogenesis, as we continue to demonstrate Class C CpG ODN’s safety and therapeutic efficacy in geriatric SQMs.
Amyloid Negative, Highly Tau Positive: Clinical Characterization of a Rare Biomarker Profile
Authors: Windon Charles , Iaccarino Leonardo , Mundada Nidhi S. , Apostolova Liana G. , Carrillo Maria C. , Dickerson Brad C. , Grant Harli E. , Miller Bruce L. , Shankar Ranjani , Soleimani‐Meigooni David N. , Joie Renaud La , Rabinovici Gil D. ,   ADNI and LEADS
Published: December 2022

AbstractBackgroundThe majority of individuals with unambiguously positive tau biomarkers (T++) have positive amyloid biomarkers. Here we describe cases with clinical features associated with an unusual biomarker profile: very high tau PET binding and negative amyloid PET (A‐T++).MethodWe searched the Longitudinal Early‐Onset Alzheimer’s Disease (AD) Study, University of California San Francisco AD Research Center and the AD Neuroimaging Initiative cohorts on 09/01/2021 for participants with completed amyloid PET (Florbetapir, Florbetaben, Pittsburgh Compound B) and Tau PET (Flortaucipir (FTP)) scans and identified 1420 participants (mean age 69, 49.7% male). Using a pathology‐based, neocortical centiloid threshold of 24.4 (amyloid positivity) and a pre‐defined region of interest (Temporal MetaROI) standardized uptake value ratio (SUVR) > 1.27 threshold (tau positivity), we identified 64 amyloid negative, tau positive cases. An additional MetaROI FTP‐SUVR threshold > 2.0 (based on visual plot of data) was then applied to identify 7 A‐T++ cases (Figure 1).ResultAmong A‐T++ individuals mean age was 66.2 (range 53.8 ‐ 77.1), 4/7 were female, mean years of education was 15 (range 12 ‐ 20), mean MMSE was 20 (range 14‐29), 3/7 were APOE e3/e4 and clinical phenotypes included amnestic and atypical AD phenotypes (Table 1).Mean neocortical centiloid value was 11.4 (range: ‐1.39 ‐ 17.11) among A‐T++ cases and 4/7 had centiloid values between 12.2 ‐ 24.4 (may be indicative of early positivity). Mean FTP SUVR was 2.28 (range 2.03 ‐ 2.63) (Table 2). All A‐T++ cases demonstrated FTP tracer binding within the middle temporal cortex, medial temporal structures, and posterior cingulate regions (Figure 2). Neuropathological data from 1 case (UCSF3) revealed frequent CERAD Neuritic Plaques, Thal Amyloid Plaque Phase 5, and Braak Neurofibrillary Degeneration Stage 6 (autopsy performed 1 year after amyloid PET).ConclusionA‐T++ individuals were heterogeneous clinically but all displayed FTP tracer binding in AD‐signature regions. Four cases had amyloid centiloid values above 12.2 (threshold to detect moderate‐to‐frequent CERAD scores) but below 24.4 (threshold to detect intermediate‐to high Alzheimer’s disease neuropathologic change (ADNC) levels). Pathological data available for 1 case revealed a high level of ADNC. False negative amyloid PET in A‐T++ individuals is an important consideration; future studies are needed.
Transcranial direct current stimulation (tDCS) in cognitively symptomatic older adults
Authors: Hampstead Benjamin M. , Iordan Alexandru , Peltier Scott , Ploutz‐Snyder Robert 
Published: December 2022

AbstractBackgroundtDCS offers an inexpensive, portable, well‐tolerated, and safe approach to neuromodulation. These benefits led to a rapid increase in its use as a potential treatment for those with Alzheimer’s disease and related dementias (ADRD), yet were accompanied by a number of methodological gaps that limit its current translational potential. This session will introduce and evaluate several such methodological factors including potential mechanisms of action, dose‐response relationships, session frequency and duration, and individual factors that may account for variable treatment response.MethodData from over 300 participants across the ADRD spectrum and 2,500 tDCS sessions who were enrolled at the Research Program on Cognition and Neuromodulation Based Interventions will be used to demonstrate the potential impact of the above noted methodological factors. Structural and functional neuroimaging data will be included to demonstrate both theoretical and empirical effects of tDCS.ResultAcross studies, our results demonstrate that targeted, multi‐electrode tDCS can alter underlying neurotransmitter levels and potentially “normalize” patterns of “activation” and functional connectivity in those with cognitive impairment. However, there is remarkable variability in the amount of electrical current delivered to the brain across participants (>600%) as well as the targeted brain region, which require reconsideration of the traditional dosing at the scalp approach. Moreover, there are apparent polarity‐dependent effects as well as differences between passive versus active (i.e., cognitive task performance) measurements. Ongoing work evaluates the additional impact and nature of disease pathology on these factors.ConclusionThe combination of results highlights the complex and multifaceted nature of tDCS and may translate to other forms of neuromodulation.
Regional pattern of cortical microstructural alterations along the AD continuum and association with plasma neurofilament light
Authors: Torso Mario , Ridgway Gerard R , Valotti Michele , Chance Steven A ,   for The Alzhemer's Disease Neuroimaging Initiative
Published: December 2022

AbstractBackgroundMicrostructural changes associated with the progression of Alzheimer's disease (AD) precede macrostructural atrophy. We investigate cortical microstructural changes along the AD continuum in patients with cerebrospinal fluid (CSF) AD biomarkers and plasma neurofilament light chain (NfL).MethodThree hundred fifty‐one participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with CSF amyloid‐beta 42 (Aβ42) and Phosphorylated Tau 181 (pTau181) were included. The CSF pTau181‐Aβ42 ratio was used to assess the presence (+/‐) of the pathophysiological hallmarks of AD and classify the participants into four groups: 149 cognitively normal biomarker negative (CN‐), 61 cognitively normal positive (CN+), 73 patients diagnosed with Mild Cognitive Impairment positive (MCI+) and 68 AD positive (AD+).Structural and diffusion MRI (dMRI) were used to calculate cortical mean diffusivity and three novel cortical diffusivity measures: the angle between the radial minicolumnar direction and the principal diffusion direction (AngleR); the principal diffusion component parallel with the minicolumns (ParlPD), and the diffusion components perpendicular to the minicolumns (PerpPD+).Clinical, demographic and MRI data were used to characterize groups. Group differences in diffusion metrics were tested with a linear model, adjusting for age, sex and site‐ID, with false discovery rate correction (pFDR<0.05). The association between cortical diffusivity and NfL was investigated in a subset of 111 participants.ResultAt whole‐brain level, the AD+ group exhibited significantly higher AngleR, PerpPD+, ParlPD and MD values compared to the other groups. PerpPD+ was the only measure able to differentiate between all subsequent disease stages (CN‐ and CN+ vs MCI+, and MCI+ vs AD+); regional results are presented in the Figure. Along the AD continuum, the results revealed a widespread progressive pattern of higher PerpPD+, involving mainly fronto‐temporal and occipital regions. Correlation analysis showed significant association between cortical diffusivity measures (PerpPD+ and ParlPD) and NfL values.ConclusionCortical diffusivity measures can detect progressive microstructural changes along the AD continuum and are significantly associated with NfL. Cortical diffusion MRI offers a microstructural marker of neurodegeneration within the ATN framework (Jack et al. 2018); as an imaging measure, regional patterns can provide disease specificity that is lacking for fluid measures like NfL.
Reduced CSF Aβ42 and Aβ42/Aβ40 ratio during early cerebral amyloid deposition in the AppNL‐F knock‐in mouse model of Alzheimer’s disease
Authors: Andersson Emelie , Saito Takashi , Saido Takaomi C. , Blennow Kaj , Zetterberg Henrik , Hansson Oskar 
Published: December 2022

AbstractBackgroundThe concentration of Aβ42 in cerebrospinal fluid (CSF) is decreased at least a decade before cognitive symptoms caused by Alzheimer’s disease (AD) manifest. This drop in concentration has been suggested to occur before abnormal levels of fibrillar Aβ in the brain are reached, but the underlying cause is not well understood. The present study aims to explore the translational potential of the App
NL‐F knock‐in mouse model, and compare it to transgenic App‐overexpressing 3xTg mice, for investigation of the early events in Aβ pathology that associates with reduced CSF Aβ42 in preclinical AD.MethodCSF and brain tissue was collected from 3‐18 months old App
NL‐F knock‐in mice (n=56) and 3‐24 months old 3xTg mice (n=74). CSF Aβ40 and Aβ42 concentrations were measured using Single Molecule Array (Simoa) technology and immunohistochemistry was performed on brain sections for detection of cerebral Aβ deposition.ResultIn App
NL‐F knock‐in mice, CSF Aβ40 remained unchanged while CSF Aβ42 and Aβ42/Aβ40 ratio were reduced from 12 months of age after which a plateau was reached (Fig.1). The initial reduction coincided with early deposition of cortical Aβ42 in the brain that gradually increased with age (Fig.2). Accordingly, in the whole study population, CSF Aβ42 and Aβ42/Aβ40 ratio showed a moderate negative hyperbolic association with cortical Aβ42 load (Fig.3). In comparison, increased CSF Aβ40 and Aβ42 was observed in 3xTg mice prior to Aβ plaque deposition, although the Aβ42/Aβ40 ratio remained stable. These changes coincided with the accumulation of cerebral intracellular Aβ. Once Aβ plaques started to deposit in the brain from 12 months of age, a subsequent reduction of CSF Aβ42 and Aβ42/Aβ40 was observed (Fig.4).ConclusionIn line with clinical findings, CSF Aβ42 and Aβ42/Aβ40 ratio are reduced in App
NL‐F knock‐in mice and seem to reflect pathological processes that occur slightly before deposition of amyloid in the brain is widespread. This reduction quickly starts to stabilize towards a plateau, although accumulation of cerebral amyloid steadily continues to increase. In contrast to 3xTg mice, no initial increase in CSF Aβ40 and Aβ42 was observed and further studies are needed to elucidate these differences and their translational implication.