bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptomic profiling in mild cognitive impairment using peripheral blood gene co‐expression networks
Authors: Sanjay Apoorva Bharthur , Correia Rion Brattig , Rocha Luis M. , Apostolova Liana G. 
Published: December 2021

AbstractBackgroundIn an effort towards AD prodromal risk assessment, precision medicine and biomarker development, we evaluated the efficacy of characterizing and clustering peripheral blood transcriptomic data by constructing gene‐coexpression networks from differentially expressed genes between normal controls and MCI subjects.MethodData from the ImaGene study (Imaging and Genetics Biomarkers study of Alzheimer’s Disease, ImaGene) was used. This included 160 subjects clinically diagnosed with amnestic MCI (n=70), non‐amnestic MCI (n=38) and normal controls (n=52) (Table 1). Quantile‐normalized and log‐transformed mRNA levels were obtained from peripheral blood. In a preliminary analysis we selected 2062 genes (out of HOW MANY) which were significantly differentially expressed between normal controls and MCI (two sample t‐test, pfdr<0.05). Gene‐coexpression networks were built by creating correlation matrices of the differentially expressed mRNA values. Network backbones were then built using the shortest path computation to remove redundancy and identify important edges. Hierarchical clustering was performed on the co‐expression matrix to identify important communities or clusters within the network. We identified the strongest cluster associated with amnestic MCI phenotype (pfdr<0.0001) by using the first principal component of the cluster as the eigen gene. The genes within the cluster and edges within the backbone were investigated.ResultUpon backbone computation, the number of edges compared to original correlation matrix were significantly reduced (Figure 1). Hierarchical clustering yielded 42 clusters of genes. One cluster (eigen gene) had the strongest association with amnestic MCI phenotype (r=0.45, pfdr<0.0001). This cluster consisting of 46 genes warrants further investigation for specific function and interactions with other nodes in the cluster backbone. Two of the driver genes ADRA1A and ARHGAP4 were involved in noradrenergic receptor signaling pathway and PDGF signaling pathway, both of which are dysregulated in AD pathogenesis.ConclusionA large noisy transcriptomic data was reduced to a critical number of mRNA measures from peripheral blood. The backbone method pruned the gene coexpression network significantly. The cluster analysis identified a set of genes which had highly significant association with amnestic MCI. This approach can also help build models for risk assessment, gene therapy and help identify novel therapeutic targets/ dysregulated pathways.
Healthcare costs incurred by patients before entering GERAS‐US, a prospective, observational study of early Alzheimer’s disease: Impact of disease severity and amyloid status
Authors: Chandler Julie , Zimmer Jennifer A , Kubisiak Emily , Kubisiak Joanna 
Published: December 2021

AbstractBackgroundGERAS‐US (NCT02951598) is a longitudinal, prospective US cohort study assessing healthcare resource use (HCRU) and costs in clinician‐diagnosed, early‐stage Alzheimer’s disease (AD). This study analyzed HCRU and costs incurred by patients before and after cognitive impairment (CI)/AD diagnosis, before entering the GERAS‐US study.MethodData of GERAS‐US participants who consented for this addendum study were linked to Medicare claims data, for up to 5 years before baseline study visit (2013–2017). GERAS‐US study classified severity using Mini‐Mental State Examination (MMSE) and Functional Activities Questionnaire (FAQ) scores. Mild cognitive impairment (MCI) was defined as MMSE: 24–30 and FAQ: <6, and mild dementia (MILD) was defined as MMSE: 20–30 and FAQ: ≥6. Amyloid status (positive/negative) was determined by PET scan. Participants selected in this analysis required Medicare fee‐for‐service eligibility (Parts A and B enrollment) for ≥1 month before baseline visit. Mean HCRU and costs before and after CI/AD diagnosis were compared by severity and amyloid status, adjusting for length of fee‐for‐service history before or from the month of first CI/AD diagnosis, respectively. Differences in costs were assessed using general linear model regression analyses and healthcare costs per patient per month (PPPM) were calculated. Descriptive, Chi‐square (categorical variables), and t‐test (continuous variables) analyses were conducted.ResultHealthcare costs of 174 patients were assessed by severity and amyloid status (Table). Mean total all‐cause healthcare cost incurred PPPM post CI/AD diagnosis was greater for MILD versus MCI cohort (P=.067), and for patients with amyloid‐negative versus ‐positive status (P<.05). Post CI/AD diagnosis, patients in the MILD cohort with amyloid‐negative status incurred greatest mean PPPM total healthcare costs (MILD amyloid‐negative, $1842; MILD amyloid‐positive, $695; P=.014; not shown). Home health cost post CI/AD diagnosis was a significant factor driving differences between MCI and MILD cohorts ($9 vs. $120, P=.014), and between amyloid‐negative and ‐positive cohorts ($124 vs. $19, P=.022) (not shown).ConclusionDifferences in total healthcare costs were greatest post CI/AD diagnosis, with greater costs being incurred by MILD versus MCI, and amyloid‐negative versus amyloid‐positive cohorts. After diagnosis, home health cost was a major factor significantly driving cost differences.
Interval‐specific likelihood ratios for improving differential diagnosis of Alzheimer’s disease using biomarkers in cerebrospinal fluid
Authors: Poesen Koen , Dubin Jonas , Vandenberghe Rik 
Published: December 2021

AbstractBackgroundSingle cutoff values are currently applied to interpret Alzheimer biomarker results. Yet these cutoffs are not uniform among centers, nor highly specific to discriminate AD from other disorders. We examined if the likelihood of AD was higher when biomarker levels deviated more from normal levels. For this purpose, we constructed interval‐specific likelihood ratios (LRs) for CSF biomarkers amyloid Aβ1‐42, total Tau protein (tTau) and hyperphosphorylated Tau protein (pTau181).MethodThis retrospective single center study included 208 patients who 1) attended the Neurology Memory Clinic of the University Hospital Leuven in the period of September 2011 till July 2017, 2) underwent CSF AD biomarkers assessment in the diagnostic workup (Innotest, Fujirebio) and 3) had a stable clinical diagnosis for at least three years after diagnosis. For each biomarker, we calculated LRs for AD for different test result intervals, based on 2 methods, including intervals with boundaries equal to limited multiples of previously published cutoff values (method 1), or to generate intervals well distributed over the entire dynamic range of biomarker levels (method 2). In a graphical representation, post‐test probability of AD was related to pre‐test probability and test result interval for each biomarker.ResultBoth methods for constructing intervals showed that for any of the biomarkers the LR increased significantly once deviating from normal values. Further dividing these aberrant levels into additional intervals (method 2) further increased the LR. Further dividing normal levels into more intervals did further decrease the LR, except for Aβ1‐42. No LRs > 10 or < 0.1, suggesting clinically meaningful differences between pre‐test and post‐test probability, were encountered. LRs between 0.1 – 0.2 or 5 – 10, suggestive of modest clinical differences, were seen for normal Aβ1‐42 levels (800 – 1,000 pg/mL; LR = 0.168), and aberrant tTau levels (≥ 1,000 pg/mL; LR = 5.540) and pTau181 levels (≥ 80 pg/mL; LR between 5.936 and 7.420).ConclusionThe likelihood of AD changed as CSF levels of AD biomarkers deviated more outspoken from normal range, yet related to a modest clinical significance given the partial overlap between AD and non‐AD of biomarker values that deviated from normal values.
The design of Dominantly Inherited Alzheimer Disease Trial of the anti‐tau antibody, E‐2814, on the DIAN‐TU Tau Next Generation Platform
Authors: Schneider Lon S. , Bateman Randall J. , Clifford David B. , McDade Eric , Wang Guoqiao , Llibre‐Guerra Jorge J. , Li Yan , Mills Susan , Santacruz Anna , Sachdev Pallavi , Li David JianJun , O'Sullivan Stacie , Yagi Takuya , Koyama Akihiko , Irizarry Michael C. , Reyderman Larisa 
Published: December 2021

AbstractBackgroundTau pathology is closely associated with the onset and progression of Alzheimer’s disease. Recent advances in drugs that target tau suggest the potential to prevent or attenuate the pathophysiology and pathology of tau. Novel CSF and blood tau species including specific phospho‐tau (p‐tau) and truncated species containing the microtubule binding region of tau (MTBR‐tau) which aggregates in tau tangles, increases 10 years or more before tau tangles are detected by tau‐PET. Two stages of AD are identified and studied using soluble p‐tau and MTBR‐tau forms in the asymptomatic stage and Tau PET in the post‐tangle symptomatic stage. E2814, an anti‐tau monoclonal antibody targets MTBR‐tau and decreases tau pathology in animal models.MethodWe designed an anti‐tau trial to target soluble tau species in two cohorts including pre‐tangle asymptomatic and post‐tangle symptomatic participants in dominantly inherited AD (DIAD). We analyzed longitudinal clinical, cognitive, tau PET and CSF measures of tau species including, multiple p‐tau species (e.g., p‐tau217, 231, 181, 205), total tau, MTBR‐tau (e.g., MTBR‐tau243, MTBR‐tau299, and MTBR‐tau354), and NfL in DIAD cohorts from DIAN and DIAN‐TU. Novel trial design and statistical approaches have been developed to address primary and secondary outcomes, magnitude of effect by stage of disease (pre‐tangle vs. post‐tangle), and potential for prevention.ResultWe designed a trial of two cohorts, each powered, with different biomarker outcomes: in the pre‐tangle, tau‐PET negative cohort, CSF ptau217/tau217 is the endpoint; for the post‐tangle tau‐PET positive cohort, tau‐PET is the endpoint. Further, each cohort will measure target engagement by CSF MTBR‐tau and downstream effects on soluble total tau, p‐tau and MTBR tau with common measures of neurodegeneration by CSF and blood NfL, atrophy by MRI, hypometabolism by FDG‐PET, effects on amyloid by abeta42/40 and amyloid‐PET, and cognitive and clinical measures. This design is facilitated by the predictable pattern of biomarker changes observed in DIAD allowing appropriate powering of the study even in this rare condition.ConclusionThe Tau Next Generation Platform will address disease progression, before and after tangle formation begins, assessing when an anti‐MTBR tau monoclonal antibody will have the largest effects. It is the first anti‐tau trial for DIAD.
Caring for residents with dementia during a COVID‐19 outbreak in a long‐term care home
Authors: Hung Lillian 
Published: December 2021

AbstractBackgroundAlthough there have been considerable public concerns about the impact of COVID‐19 on residents living in long‐term care homes, much less attention has focused on lessons learned from staff experiences about caring for people with dementia during outbreaks. The outbreaks added significant additional stress to the nursing workforce, which has historically experienced high turnover, chronic staffing shortages, and increased burnout in long‐term care settings. We conducted focus groups (n=20) and individual interviews (n=10) to investigate critical challenges, experiences, and support needed for frontline staff in a long‐term care home in British Columbia, Canada. A total of 30 staff in multiple disciplines participated in the study. They included Registered Nurses, Licenced Practical Nurses, care staff, recreational staff, and unit clerks. We applied qualitative thematic analysis and identified four themes: (a) I am proud, (b) we become stronger, (c) I am nervous (d) the vaccine helps. The frontline staff's voices provided a detailed description of their emotional experiences, creative coping strategies and positive stories about caring for the most vulnerable population in extraordinary situations. In our poster, lessons learned and implications for future research and practice will be explored and discussed.
The screening and enrollment of underrepresented ethnoracial and educational populations in the Alzheimer's Disease Neuroimaging Initiative
Authors: Ashford Miriam T , Miller Garrett , Raman Rema , Donohue Michael C , Okonkwo Ozioma C , Mindt Monica Rivera , Nosheny Rachel L , Petersen Ronald C , Aisen Paul S , Weiner Mike W 
Published: December 2021

AbstractBackgroundAn analysis of the ethnoracial and educational composition of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants, and the relationship between ethnoracial/education and screening, enrollment, dropout, and biomarkers is needed to assess the generalizability of ADNI data to diverse populations, and to inform efforts to increase diversity.MethodData from all 4 ADNI phases were used to determine ethnoracial and educational breakdown and differences of the following ADNI participation metrics: screening, screen fails, enrollment, as well as drop‐out within and between ADNI phases. Multivariable logistic regression was used to analyze the association between ethnoracial and educational group and either amyloid positivity or ApoE e4 status, adjusting for age, gender, and diagnostic group.ResultAcross the 4 ADNI phases (screened: n=3,739; enrolled: n=2,286), 11% of screened and enrolled participants identified as Latinx, non‐Latinx Black, or non‐Latinx‐Asian and 16% of the screened and 15% of the enrolled participants reported having =<12 years of education. In contrast, the 2019 US Census American Community Survey for adults 60+ reports 25% non‐White, and 44 % =< 12 years of education. There were no observed differences between participants from historically underrepresented ethnoracial groups and NLW participants in screen fail and dropout rates. We found that individuals with =<12 years of education failed screening at a significantly higher rate (p=.01) and rolled‐over significantly less to subsequent ADNI phases (p<.001) compared to individuals with an education >12 years. Identifying as non‐Latinx Asian was associated with lower odds of being amyloid positive (OR=0.36; p=.014) and an ApoE4 carrier (OR=0.36; p=.008) compared to NLW. Identifying as Latinx was associated with being less likely to be amyloid positive than NLW participants (OR=0.54; p=.031).ConclusionCompared to the US Census, ADNI underrepresents enrollment of Latinx, non‐Latinx Black, and non‐Latinx Asian participants and those with low educational attainment. Hence, ADNI reflects the on‐going challenges with recruiting and enrolling underrepresented populations into most AD research. Our findings highlight the need for ADNI to increase enrollment and engagement of underrepresented ethnoracial and educational populations. ADNI is actively undertaking steps to implement improved recruitment approaches aimed at increasing ethnoracial and socioeconomical representation in multi‐center cohort studies.
ACI‐24 in adults with Down syndrome: Results of a phase 1b, randomized, placebo‐controlled study
Authors: Rafii Michael S , Sol Olivier , Mobley William C , Skotko Brian G. , Burke Anna D , Sabbagh Marwan N. , Yuan Shauna , Rissman Robert A. , Delpretti Saskia , Beth Greg , Gray Julian JG , Melo dos Santos Antonio , Hliva Valerie , Vukicevic Marija , Kosco‐Vilbois Marie , Streffer Johannes , Pfeifer Andrea , Feldman Howard 
Published: December 2021

AbstractBackgroundThe APP gene is located on chromosome 21 and thought to lead to overproduction of beta‐amyloid (Aβ) in persons with trisomy 21 (Down syndrome, DS). As a result, individuals with DS are at high risk for developing Alzheimer’s disease (AD). ACI‐24 is a liposomal, T‐cell independent, anti‐Aβ vaccine which was assessed in a world’s first clinical phase 1b study in adults with DS.MethodThe primary objectives of this randomized, double‐blind, placebo‐controlled, dose‐escalation, phase Ib multi‐center study were to assess the safety and tolerability of ACI‐24 in adults aged 25‐45 years with DS and its effect on the induction of serum anti‐Aβ antibody titers. The secondary objectives were to explore the effect of ACI‐24 on cognition, behavior, AD biomarkers, T‐cell activation, and brain volumes assessed by MRI. Participants received subcutaneous injections of ACI‐24 (300 µg or 1000 µg) or placebo (3:1 ratio) at different timepoints up to week 48 before entering a 48‐week safety follow‐up period.ResultSixteen participants (9F/7M; mean age 32.9 [25‐41]) were randomized into 2 dose‐level cohorts (n=8 each; 6 ACI‐24 and 2 placebo). Treatment compliance was 100%. The safety and tolerability were very good with no serious adverse events reported and no withdrawals due to adverse events. Most adverse events were mild in intensity and unrelated or unlikely related to ACI‐24. No amyloid‐related imaging abnormalities (ARIA) or changes in markers of CNS inflammation were observed. Increases in anti‐Aβ antibody titers were observed in selected participants in both treatment arms receiving ACI‐24 as compared to placebo. In addition, an increase in plasma Aβ1‐40 and Aβ1‐42 levels compared to placebo was observed in active groups. As expected, no consistent changes between treatment and placebo groups were observed in other biomarkers or clinical measures in this small study.ConclusionACI‐24 was safe and well‐tolerated in adults with DS. Evidence of immunogenicity was observed with this T‐cell independent vaccine along with pharmacodynamic and target engagement effects as measured by an increase in plasma Aβ 1‐40 and Aβ 1‐42 levels in treated groups as compared to placebo. These results support the pursuance of an accelerated clinical development with an optimized formulation of ACI‐24.
Rationale for an anti‐inflammatory insulin sensitizer in a phase 3 Alzheimer's disease trial
Authors: Reading Chris L , Ahlem Clarence N , Parameswaran Narayanan 
Published: December 2021

AbstractBackgroundNE3107 (3α‐ethynyl‐androst‐5‐ene‐3β,7β,17β‐triol), shows safety, antiinflammatory and insulin‐sensitizing activities in vitro, in animals, and humans. NE3107 binds ERK1/2 and inhibits inflammatory, but not homeostatic NFkB/ERK signaling in vitro, in animals and in humans. NE3107 is blood‐brain permeable, and does not affect neurotransmitter receptors. NE3107 inhibits TNFα‐stimulated NFκB transcription in human macrophages. It also inhibits NFκB nuclear translocation and LPS‐stimulated inflammatory signal transduction. NE3107 prevented IκBα proteolysis in murine macrophages. NE3107 decreased EAE optic nerve microglia, and increased nuclear NFκB in collicular and retinal neurons (homeostatic), but decreased optic nerve head glial nuclear NFκB (inflammatory) in a glaucoma model. NE3107 preserved dopaminergic neurons in MPTP‐treated mice and marmosets. In obese impaired glucose tolerance (IGT) humans, NE3107 decreased CRP, which is involved in AD inflammation and tissue damage, and increased antiinflammatory HDL, which decreases risk of AD pathogenesis. NE3107 increased adiponectin, which suppresses insulin resistance, inflammation, and AD pathology. In obese, inflamed IGT and type 2 diabetes (T2D) subjects, NE3107 decreased insulin resistance, which drives neurodegeneration and AD. Importantly, in obese inflamed T2D subjects, NE3107 decreased inflammation‐driven systems deregulation, known to contribute to AD progression.MethodSafety and activity data from preclinical, toxicology, human clinical trials, and a protocol synopsis for a pivotal trial in AD were submitted, and the FDA allowed NeurMedix to proceed with the NM101 trial.ResultA Phase 3, Double Blind, Randomized, Placebo Controlled, Parallel Group, Multicenter Study of NE3107 in Subjects Who Have Mild to Moderate Alzheimer's Disease (NCT04669028) will evaluate safety and efficacy of oral 20 mg BID NE3107 vs. placebo in 316 subjects with mild to moderate AD. Two coprimary outcome measures ADAS Cog12 and ADCS CGIC will be evaluated as the change from Baseline to Week 30. Secondary endpoints include measures of neuropsychological deficits, functional performance, glycemic control and resource utilization. A subset of patients may volunteer for exploratory vMRI and FDG‐PET scans at baseline and week 30.ConclusionInflammation and insulin resistance drive AD. NE3107 decreases these insults that drive systems dysregulation in AD. This trial is well‐positioned to examine the effects of NE3107 on progression of AD dementia, affecting more than 40 million people globally.
Subgroup analyses of the amyloid PET substudies from EMERGE and ENGAGE, phase 3 clinical trials evaluating aducanumab in patients with early Alzheimer’s disease
Authors: Rajagovindan Raj , Chen Tianle , Wu Hao , Tian Ying , Nisenbaum Laura , Castrillo‐Viguera Carmen , He Ping , Haeberlein Samantha Budd 
Published: December 2021

AbstractBackgroundAducanumab, a human monoclonal antibody that selectively targets aggregated forms of beta amyloid (Aβ), is under investigation for the treatment of Alzheimer’s disease (AD). EMERGE and ENGAGE were 2 identically‐designed, randomized, double‐blind, placebo‐controlled Phase 3 trials that evaluated the efficacy and safety of aducanumab in participants with mild cognitive impairment (MCI) due to AD or mild AD dementia and confirmed amyloid pathology. These studies were initiated following the Phase 1b PRIME study in which aducanumab reduced amyloid burden and slowed decline on exploratory clinical endpoints. In both EMERGE and ENGAGE, dose‐ and time‐dependent reductions in amyloid positron emission tomography (PET) composite standard uptake value ratio (SUVR) were observed at Week 78 in the amyloid PET biomarker substudies.MethodParticipants were randomized (1:1:1) to receive high‐dose aducanumab, low‐dose aducanumab, or placebo via intravenous injection every 4 weeks for 18 months. Longitudinal amyloid PET imaging using 18F‐florbetapir was performed in a subset of patients (n=488 in EMERGE; n=585 in ENGAGE) at screening, Week 26, and Week 78.Subgroup analysis of amyloid PET SUVR for 6 prespecified factors including age (≤64, 65 to 74, or ≥75 years), sex (male or female), ApoE ε4 status (carrier or noncarrier), baseline clinical stage (MCI due to AD or mild AD dementia), baseline Mini‐Mental State Exam (≤26 or ≥27) and use of AD symptomatic medications at baseline (yes or no) for a total of 13 subgroups was conducted for each study.ResultAn advantage of high‐dose and low‐dose aducanumab over placebo was observed in the 13 subgroups, with time‐ and dose‐dependent Aβ reduction observed in each subgroup. These results were consistent with the overall results of the amyloid PET biomarker substudies in which aducanumab treatment was associated with robust dose‐dependent reduction in brain Aβ levels.ConclusionAmyloid PET SUVR subgroup analysis revealed a consistent dose‐ and time‐dependent advantage of high‐dose and low‐dose aducanumab over placebo in the prespecified subgroups.