bluuebunny/crossref_metadata_2025_split huggingface dataset:
Panel discussion: DIAN‐TU trial collaborative effort
Authors: Bateman Randall J. , Ryan Laurie M. , Carrillo Maria C. , Kerchner Geoffrey A. , Farlow Martin R. , Salloway Stephen P. , Yaari Roy 
Published: December 2020

AbstractBackgroundDr. Bateman is principal investigator of a therapeutic trial evaluating two investigational drugs, gantenerumab and solanezumab, for dominantly inherited Alzheimer’s disease. Washington University is also the regulatory sponsor for this trial. Funding for DIAN‐TU clinical trials includes the National Institute on Aging of the National Institutes of Health, Alzheimer's Association, Eli Lilly and Co, Hoffman La‐Roche/Genentech, Janssen, Avid Radiopharmaceuticals, GHR Foundation, and an anonymous foundation. Discussion session with leaders from the collaborative group: Randall Bateman (DIAN‐TU, PI), Laurie Ryan (NIH/NIA), Maria Carrillo (Alzheimer’s Association), John Sims (Eli Lilly and Co.), Geoff Kerchner (F. Hoffman‐La‐Roche, Ltd.), Marty Farlow (DIAN‐TU Project Arm Leader, Sola), and Steve Salloway (DIAN‐TU Project Arm Leader, Gant). Trial results discussed.
The Generation program: Baseline characteristics of cognitively unimpaired APOE4 carriers recruited for Generation study 1 and Generation study 2
Authors: Tariot Pierre N. , Borowsky Beth , Liu Fonda , Riviere Marie‐Emmanuelle , Rouzade‐Dominguez Marie‐Laure , Cazorla Pilar , Quinn Matt , Ricart Javier , Langbaum Jessica B. , Viglietta Vissia , Sui Yihan , Caputo Angelika , Reiman Eric M. , Graf Ana 
Published: December 2020

AbstractBackgroundThe Alzheimer Prevention Initiative (API) Generation Program evaluated the effectiveness of the BACE1 inhibitor, umibecestat, and the active immunotherapy, CAD106, in delaying the onset of AD symptoms in APOE4 carriers. The Generation Program included two studies implemented in 23 countries at 207 sites. Recruitment in the program and treatment with umibecestat was terminated in July 2019 after detecting an early signal of mild worsening in some measures of cognitive function with umibecestat. We will summarize the baseline characteristics of participants in the Generation Program.MethodTreatment duration was planned for 5‐8 years in two double‐blind, placebo‐controlled, parallel design studies (Lopez Lopez et al., 2019) in cognitively unimpaired participants aged 60‐75 years, at risk for onset of clinical symptoms due to AD. Generation Study 1 (NCT0256551) recruited APOE4 homozygotes (HMs) while Generation Study 2 (NCT03131453) enrolled both HMs as well as APOE4 heterozygotes (HTs) if they also had elevated brain amyloid (assessed by either PET and/or CSF). Both studies included a 12‐week screening phase starting with genotyping. Amyloid testing was the last screening assessment performed before randomization.ResultAmong the 9623 participants recruited, more than 2700 completed the 12‐week Screening phase with amyloid testing. Approximately 27% were HMs. About 60% of HMs and 35% of HTs had elevated brain amyloid. A total of 1623 participants were randomized: 478 to Generation Study 1 (all HMs) and 1145 to Generation Study 2 (including 20% HMs and 80% HTs with elevated amyloid). Education, sex, family history of AD, clinical scales (including MMSE, RBANS total score and indices, CDR sum of boxes, and ECog), brain volumes and amyloid status will be shown. Scores from cognitive scales will be presented by sex, genotype (E4/E4, E3/E4, E2/E4), age group and amyloid status.ConclusionThe Generation program collected a broad set of parameters for the world’s largest cohort of cognitively unimpaired APOE4 carriers. Baseline characteristics of participants enrolled in the Generation Program were consistent with the target population at risk for AD. Findings in relation to genotype, age, sex and amyloid status will be discussed.
Umibecestat in the API Generation program: Worsening in RBANS and/or CDR on treatment reverses after wash‐out
Authors: Graf Ana , Riviere Marie‐Emmanuelle , Liu Fonda , Rouzade‐Dominguez Marie‐Laure , Cazorla Pilar , Quinn Matt , Arkuszewski Michal , Ricart Javier , Langbaum Jessica B. , Piccard Hernan , Sui Yihan , Quarg Peter , Caputo Angelika , Reiman Eric M. , Tariot Pierre N. 
Published: December 2020

AbstractBackgroundRecruitment in the API Generation program and treatment with umibecestat were terminated in July 2019 after detection of an early signal of mild worsening in some measures of cognitive function with umibecestat. Participants were followed to assess the reversibility of these and other observed effects. We will summarize the key clinical results for umibecestat vs placebo during treatment and follow up.MethodFollowing randomization to umibecestat or placebo, clinical assessments were scheduled at month 3, month 6 and every 6 month thereafter. After discontinuation of study medication, participants underwent a full evaluation within 3 months of the last dose. Data will be presented for visits on‐ and off‐treatment. For visits off‐treatment, results will be compared for visits occurring before vs after wash‐out of umibecestat (> 31 days after last dose). Analysis of cognitive scales in relation to age, sex, genotype and amyloid status, and a safety summary will also be presented.ResultAt termination about 650 participants had reached week 26. The final evaluation was performed on most of the 1561 ongoing participants (45% after wash‐out). Worsening was detected in a group‐level comparison at month 3 and month 6 in both studies for the two doses of umibecestat (effect size 0.2‐0.3 for RBANS Total, Immediate and Delayed Memory indices). Analysis from the visits conducted after wash‐out indicated that key cognitive findings seen before wash‐out were reversible: we saw no more between‐group differences in RBANS and no more imbalance in the proportion of participants having a >14‐point decrease in total RBANS or > 1‐point increase in CDR‐SB after wash‐out. Similar findings were also seen in homozygotes without elevated amyloid.ConclusionThe negative effect of umibecestat vs placebo on RBANS and CDR‐SOB was detected as early as month 3 and was detectable throughout the treatment period, but was no longer present after wash‐out of umibecestat. This effect seems to be independent of the presence of brain amyloid. Confirmation of the contemporary reversibility of worsening in measures of cognition is an important result to inform development of future prevention therapies for Alzheimer’s disease (AD).
Persistent challenges in Alzheimer’s disease modeling: Pragmatic solutions to inform the road forward
Authors: Herring William L , Mauskopf Josephine M 
Published: December 2020

AbstractBackgroundThe credibility of economic evaluations of emerging Alzheimer’s disease (AD) therapies will depend on addressing persistent structural and data challenges with transparent and evidence‐based approaches. This study describes methodological challenges recurring throughout the AD modeling literature and recommends practical solutions for future researchers.MethodSystematic literature reviews of economic models in AD were supplemented by a targeted review of recently published models. The findings from the reviews and the approaches used in recent models were synthesized to identify remaining structural and data challenges. Data availability and anticipated health technology assessment requirements were used to inform potential solutions to these challenges.ResultWe identified four fundamental challenges for models used to evaluate emerging AD therapies: (1) quantifying heterogeneity in population characteristics and the natural history of disease progression and dementia onset; (2) assembling evidence supporting the extrapolation of short‐term trial endpoints to long‐term benefits; (3) addressing data gaps in costs, utilities, and mortality by disease severity accounting for age; and (4) bridging differences in populations, endpoints, and care settings across datasets and markets. We recommend analyses of existing longitudinal datasets to understand variability and prognostic factors within and between datasets, matching patient characteristics and progression patterns across datasets and clinical trials (challenges 1, 4). Existing longitudinal datasets also can be used to generate evidence of correlation between short‐term clinical trial endpoints and long‐term progression in support of model extrapolations (challenge 2). Long‐term follow‐up of clinical trial participants should be planned to validate findings from these analyses. Previously collected data on costs, utilities, and mortality should be reanalyzed to isolate AD‐specific estimates across disease severity levels accounting for the impact of aging (challenge 3). Crosswalks between study populations, symptom measures, and biomarker criteria should be created to support adaption of economic models to local markets (challenges 1, 3, 4). Finally, models should be developed with flexibility in their structural assumptions to address uncertainty inherent in these recommended solutions.ConclusionPragmatic solutions tailored to the available data and the anticipated profiles of therapies in late‐stage development should be pursued to support near‐term decision making and inform the design of long‐term evidence‐generation efforts.
Sensory gamma frequency stimulation in cognitively healthy and AD individuals safely induces highly coordinated 40 hz neural oscillation: A preliminary study of non‐invasive sensory stimulation for treating Alzheimer’s disease
Authors: Suk Ho‐Jun , Chan Diane , Jackson Brennan , Fernandez Vanesa , Stark Danielle , Milman Noah , Beach Sara , Uitermarkt Brandt , Gander Phillip , Boes Aaron D , Brown Emery , Boyden Ed , Tsai Li‐Huei 
Published: December 2020

AbstractBackgroundOur lab previously showed that 40 Hz sensory stimulation can modulate neural oscillations, ameliorate Alzheimer’s disease (AD) pathology, and improve cognition in AD mouse models (Iaccarino, Singer et al., Nature, 2016; Martorell, Paulson et al., Cell, 2019; Adaikkan et al., Neuron, 2019). To determine the safety and feasibility of 40 Hz sensory stimulation as a potential therapeutic for AD, human subjects, including AD patients, were exposed to various stimulation modalities and their electrophysiological responses were studied.MethodWe developed a device that delivers light and sound at desired frequencies for human use. Cognitively healthy (24 males, 22 females; age range 20‐75) and AD subjects (7 males, 10 females; age range 55‐88) were stimulated with our device while their scalp electroencephalogram (EEG) was recorded. Epilepsy patients with intracranial electrodes (1 male, 1 female; age 19) were also exposed to our device for sensory stimulation while recording the intracranial EEG (iEEG). The EEG signals were screened for interictal/ictal spikes and analyzed to evaluate spectral characteristics.ResultThe EEG signals from cognitively healthy and AD subjects as well as epilepsy patients did not show any interictal/ictal spikes during or after the stimulation. In all subject groups, our sensory stimulation increased the spectral power and coherence at 40 Hz, with the concurrent visual and auditory stimulation leading to more widespread and coordinated 40 Hz oscillations than visual or auditory stimulation alone. iEEG signals showed that our sensory stimulation can entrain deeper brain regions. An hour‐long continuous 40 Hz stimulation using concurrent visual and auditory stimuli in healthy older subjects showed 40 Hz power and coherence both increasing over time. Following the hour‐long stimulation, gamma power and coherence were elevated compared to the pre‐stimulation levels.ConclusionOur non‐invasive sensory stimulation at gamma frequency safely induces highly coordinated 40 Hz oscillations in cognitively healthy and AD subjects. This serves as a preliminary study for a placebo‐controlled, randomized control trial to test the effect of our sensory stimulation on AD. The application of non‐invasive techniques to modulate gamma oscillations in the human brain is a novel and potentially very powerful disease modifying therapeutic for the treatment of dementia.
White matter hyperintensities, gray matter atrophy and cognitive deficits in Parkinson’s disease
Authors: Dadar Mahsa , Gee Myrlene , Duchesne Simon , Camicioli Richard 
Published: December 2020

AbstractBackgroundMRI features of grey matter atrophy and White Matter Hyperintensities (WMHs) of cerebrovascular origin have been linked to cognitive symptoms in Parkinson’s disease (PD) (Yau 2018, Dadar 2018). Here we assess the relationship between WMH burden, gray matter atrophy in the Hippocampi and cognitive symptoms in PD.MethodData included 50 PD patients and 45 age‐matched controls with T1‐weighted and FLAIR scans at baseline, month18, and month36. WMHs were segmented using T1‐weighted and FLAIR images and a random forests classifier (Dadar et al. 2017, Figure 1.a). SNIPE (Scoring by Nonlocal Image Patch Estimator) was used to measure Alzheimer’s‐disease‐like atrophy patterns in the left and right hippocampi (Figure 1.b, Coupé et al. 2019). The relationship between MRI features and clinical scores was assessed using mixed‐effects models: where Cohort denotes a categorical variable contrasting PD versus controls, and ID denotes the categorical random effects. The variables of interest were MRI‐Feature (implying an overall association between the MRI feature and clinical score of interest) and the interaction term Cohort:MRI‐Score (implying an additional PD‐specific impact of the MRI‐Feature on the Clinical‐Score). Log‐transformed WMH volumes and SNIPE grading in the left and right Hippocampi were used as MRI features. Total Dementia Rating Scale (DRS) was the dependent variable of interest reflecting cognitive performance.ResultWMH load significantly increased with age in both groups (t=9.95, p<0.0001). We did not find a significant group difference in WMH volumes. We did not find a significant association between WMH load and Total DRS score in either group. Total DRS significantly decreased with age (t=‐2.23, p<0.04) and decrease in Hippocampal grading (tLeftHC=2.83, pRighHC=0.005, tLeftHC=2.55, pRighHC=0.01), with a marginally greater impact in PDs (Figure 2, tLeftHC=1.80, pRighHC=0.07, tLeftHC=1.58, pRighHC=0.10).ConclusionIn our cohort, hippocampal atrophy was significantly associated with cognitive deficits in both controls and PD patients, with a slightly greater impact in the PD group. We did not observe an impact of vascular disease burden on cognitive performance.
Mechanisms of neuroinflammation with APOE4 implicate CPLA2
Authors: Wang Shaowei , Solomon Victoria A. , Sullivan Patrick M. , Yassine Hussein N. 
Published: December 2020

AbstractBackgroundAPOE4 is the strongest genetic risk factor for late‐onset Alzheimer’s disease (AD) and is associated with increased susceptibility to neuroinflammation, however the reasons for this association are not very clear. Increased phosphorylation of calcium‐dependent cytosolic PLA2 (cPLA2) is evident in amyloid plaques of human brains. Enhanced cPLA2 activity promotes the release of arachidonic acid (AA) and prostaglandin E₂ (PGE2) to initiate an inflammatory response. Our primary aim is to determine if ApoE4 increases cPLA2 activity.MethodCellular, animal models and human brain tissue were employedResultWe found greater cPLA2 expression and phosphorylation in ApoE4 immortalized and primary astrocytes compared to ApoE3. Greater levels of phosphorylated cPLA2 and higher cPLA2 activity were found in the brains of ApoE4‐TR mice (vs ApoE3) at 8‐months of age. In addition, phosphorylated cPLA2 level was increased in hippocampus of APOE4/E4 carriers with AD compared to cognitive healthy APOE3/E3 carriers. To examine the mechanisms for phosphorylation of cPLA2, we examined its regulation by the mitogen‐activated protein kinase (MAPK) pathway. We found that the p38 pathway (but not ERKs pathway) was more activated in cells, mouse and human brain samples with ApoE4 genotype compared to ApoE3.ConclusionOur research implicates an ApoE4‐driven cPLA2 activation as a mechanism for the increased susceptibility to neuroinflammation in AD and a potential target for treatment.
A systematic review of short cognitive assessments for diagnosing dementia and MCI in clinical settings in Chinese‐speaking countries
Authors: Yu Ruan‐Ching , Lai Jen‐Chieh , Mukadam Naaheed , Kapur Narinder , Stott Joshua , Livingston Gill 
Published: December 2020

AbstractBackgroundMandarin Chinese is one of the most widely spoken languages in the world, and is used as a primary or secondary language in China, Hong Kong, Singapore and Taiwan. These countries differ in historical, economic and societal contexts so that cognitive assessments validated in one country may not be valid in another. The aims of this study are to compare the short diagnostic assessments (<15 minutes) used to assist in diagnosing dementia and Mild cognitive impairment (MCI) in Chinese‐speaking countries through rating the translation and cultural adaptation and reporting the sensitivity and specificity of assessments.MethodWe searched for terms relating to "assessments" and "dementia" or "MCI" and "Chinese‐speaking populations” in electronic bibliographic databases, including Embase, Ovid MEDLINE(R), PsycINFO, PsycTESTS, Web of Science, The Cochrane Library from inception to 3th July 2019. Two raters independently screened titles and abstracts, rated the translation and cultural adaption according to published guidelines by judging whether the details described are sufficient for replication and evaluated the quality of studies with a diagnostics critical appraisal sheet developed by the Centre for Evidence‐Based Medicine (CEBM).ResultThe searches retrieved 11763 articles, of which 74 articles were included after full‐text screening: 29 articles from China, 18 articles from Hong Kong, 12 articles from Singapore and 15 articles from Taiwan. We found 41 different short cognitive assessments used, but only two assessments ‐ the Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) have been validated in the four countries. The NUCOG cognitive screening tool in China specifically was shown to have the highest validity in screening 44 dementia diagnosed with DSM‐IV from 260 normal controls with a sensitivity of 100% and specificity of 98.5%. Reporting of cultural adaptation was achieved in approximately two third of the studies analysed.ConclusionThere are wide range of tools available to assess cognitive impairment in the Chinese‐speaking populations most of them are not validated in all Chinese speaking populations. Their psychometric properties vary and translation and cultural adaptation procedures are poorly reported.
Protective low expression of PU.1 reduces microglial inflammatory and phagocytic response
Authors: Pimenova Anna A. , Herbinet Manon , Gupta Ishaan , Machlovi Saima , Marcora Edoardo , Goate Alison M. 
Published: December 2020

AbstractBackgroundThe genetic risk for sporadic Alzheimer’s disease (AD) is polygenic, driven by more than 40 loci. Pathway analysis implicates immune response in the etiology of AD, and given that genetic risk alleles are enriched in myeloid cell types, it has been proposed that impaired microglial function is a major contributing factor to AD risk. Microglial homeostasis is affected by the myeloid lineage‐determining transcription factor SPI1/PU.1, with lower SPI1 expression associated with protection and higher expression with risk for AD based on the rs1057233 genotype.MethodsTo understand how modulation of PU.1 expression affects microglial function we generated stable Spi1/PU.1 overexpression and knock‐down BV2 mouse microglial cell lines and assessed their response in functional assays under baseline and challenged conditions using staurosporine, rotenone and LPS.ResultAnalysis of RNA sequencing data from BV2 lines showed that knock‐down of PU.1 repressed the microglial homeostatic gene signature in a manner similar to that described in disease‐associated microglia in AD mouse models. Pathways of LXR/RXR signaling, antioxidant action and protein translation were upregulated, while inflammatory gene expression was decreased, which may underlie the protective effect of microglia with reduced PU.1 expression. BV2 microglial cells with PU.1 overexpression showed increased, while PU.1 knock‐down led to decreased phagocytosis of bioparticles independent of their type, e.g. zymosan, myelin, early or late apoptotic cells. PU.1 overexpression led to resistance to staurosporine‐induced apoptosis because of decreased caspase cascade activity, while PU.1 knock‐down cells were more susceptible to apoptosis‐induced cell death independent of caspase activation. Increased viability of PU.1 overexpressing cells resulted in potentiation of production of reactive oxygen species, nitric oxide and inflammatory cytokines under stimulated conditions. Furthermore, conditioned media from these cells led to propagation of the reactive phenotype to mouse primary astrocytes in culture. In contrast, PU.1 knock‐down repressed the inflammatory response of BV2 cells after LPS stimulation, and repressed the reactive phenotype in astrocytes.ConclusionReduced expression of PU.1 represses the homeostatic signature of microglia and decreases stimulus‐mediated cell viability, phagocytic and inflammatory responses, which may lead to increased turnover of microglia in the brain underlying the protective effect of SPI1 genotype against AD risk.
Relationship between serum TSH level and Alzheimer disease pathology
Authors: Choi Byung Wook , Kang Sungmin , Kim Hae Won 
Published: December 2020

AbstractBackgroundThyroid dysfunction is one of the risk factors associated with cognitive impairment, including Alzheimer disease (AD). The aim of this study was to evaluate the association between serum TSH level and AD pathology through biochemical assays, positron emission tomography (PET) imaging, and cognitive performance tests.MethodSixty‐nine subjects without overt hypothyroidism who underwent [18F]‐florbetaben PET were included in this prospective cross‐sectional study. The serum levels of free thyroxine (fT4) and thyroid stimulating hormone (TSH) were quantified using radioimmunoassays. The Mini‐Mental State Examination, Digit Span Memory Test, Boston Naming Test, and the Rey‐Osterrieth Complex Figure Test and Recognition Trial were performed to assess cognitive function. Differences in cerebral amyloid‐β (Aβ) burden, which is represented by standardized 18F‐florbetaben uptake value ratio (SUVR), were compared between high‐normal TSH (TSH ≥ 2.5 μIU/mL) and low‐normal (TSH < 2.5 μIU/mL) groups. Multiple linear regression analyses, adjusted for age and sex, were performed to evaluate the relationship between thyroid hormone levels and cerebral Aβ burden, and between thyroid hormone levels and cognitive function.ResultThe cerebral Aβ burden in the high‐normal TSH group was significantly higher than in the low‐normal TSH group (SUVR 1.53 vs. 1.35, p = 0.009). The fT4 levels were negatively correlated with cerebral Aβ burden (β = ‐0.250, p = 0.033), and TSH levels were positively correlated with cerebral Aβ burden (β = 0.243, p = 0.018). The fT4 level was also positively associated with cognitive function, as inferred from cognitive performance evaluation.ConclusionSerum TSH level is associated with cerebral Aβ burden. The fT4 and TSH levels showed negative and positive correlation with cerebral Aβ burden, respectively. Our findings suggest that serum TSH level, especially in subject with high‐normal serum TSH level, may contribute to AD development.