bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating the role of SORL1 as an APOE receptor using iPSC‐derived astrocytes
Authors: Lee Hyo , Pan Cheryl , Goberdhan Sri , Young Jessica E. , Young‐Pearse Tracy 
Published: December 2020

AbstractBackgroundApolipoprotein E (APOE), the strongest genetic risk factor in late‐onset AD (LOAD), encodes a protein that can interact with Aβ and regulate its clearance. Interestingly, SORL1, another AD risk gene, belongs to the family of APOE receptors involved in Aβ clearance. SORL1 is the only APOE receptor gene that has been identified as a genetic risk factor in LOAD. Recent studies identified SORL1 loss‐of‐function variants in familial AD patients, suggesting that SORL1 may be a causal gene for AD. Here, we investigated the potential convergent mechanisms of APOE and SORL1 function in the brain by examining the novel function of SORL1 in human astrocytes in Aβ clearance.MethodiPSC‐derived astrocytes were generated from individuals with 1) different APOE isoforms 2) SORL1 knock out (KO), risk SNPs and missense mutations and 3) other AD risk SNPs using two astrocyte differentiation protocols. Aβ clearance assays were performed by treating the astrocytes with synthetic or cell derived Aβ, then monitoring the Aβ level in both media and lysate over time to determine the ability of astrocytes to uptake and clear Aβ.ResultWe have generated iPSC‐derived astrocytes from multiple lines to characterize whether SORL1 functions as an APOE receptor in human astrocytes. We determined that SORL1 is highly expressed in astrocytes, both in cytoplasmic and cell surface compartments, and SORL1 can interact with APOE in iPSCs as shown by co‐immunoprecipitation. Further, our preliminary data show that SORL1 KO astrocytes show elevated endogenous extracellular Aβ levels, and impaired Aβ clearance ability when treated with exogenous or cell derived Aβ. Lastly, when Aβ uptake was examined using APOE isogenic astrocytes, APOE KO show impaired clearance, supporting a role for endogenously secreted APOE in Aβ uptake in human astrocytes. Ongoing studies are interrogating the contribution of SORL1 in APOE‐mediated Aβ clearance.ConclusionHere, I have utilized iPSC‐derived astrocytes to examine the novel role of SORL1 as an APOE receptor in astrocytes, and investigate a potential convergent mechanism that APOE and SORL1 play in Aβ clearance.
TREM locus methylation in Alzheimer’s disease
Authors: Weber Grace E. , Khrestian Maria , Shao Yvonne , Tuason Elizabeth D. , Rao Stephen M. , Pillai Jagan A. , Leverenz James B. , Bekris Lynn M. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neurodegenerative disorder, and currently lacks a blood‐based biomarker of neuroinflammation. The triggering receptor expressed on myeloid cells 2 (TREM2) R47H genetic variant is associated with increased risk for AD. TREM2 mRNA has been described as elevated in AD leukocytes, and associated with a decrease in TREM2 DNA methylation. In contrast, TREM2 hypermethylation has been described as associated with increased expression in the brain, suggesting differences in DNA methylation of TREM2 according to the tissue microenvironment. DNA methylation can dynamically regulate clusters of genes according to the needs of the cellular microenvironment. The TREM2 gene is part of a complex cluster genes that also includes other TREM and TREM‐like (TREML) genes. Understanding its DNA methylation signature is important to decipher any change in its regulatory state in AD. We hypothesized that TREM locus genes are differentially methylated in whole blood among AD patients compared to cognitively normal controls.MethodParticipants included age‐matched cognitively normal controls (HC), mild cognitive impairment related to AD (MCI‐AD) and AD dementia (confirmed by CSF AD biomarkers). Peripheral blood was collected for DNA extraction. Methylation of peripheral blood DNA was measured using Illumina 450k methylation chip. Percent methylation of CpG sites across the TREM locus were grouped into regions based on genomic context. Hierarchical clustering was used to evaluate relationships between genomic regions.ResultGenomic regions across the TREM locus exhibited differential methylation where in general promoters are hypomethylated while other non‐promoter regions are hypermethylated. Although levels of methylation were similar between groups, regions within the TREM locus correlated differently between the groups.ConclusionsTaken together, the results suggest that differential methylation exists at the TREM locus that is genomic region and AD specific. We anticipate that future studies will contribute to a better understanding of TREM2 and its role as a biomarker to aid in earlier diagnosis and interventions of AD.
Use of in‐home remote sensing to measure dietary behavior and weight in aging and cognitive decline: A pilot study
Authors: Wright Kirsten M , Mattek Nora , Gothard Sarah , Beattie Zachary , Sharma Nicole , Dodge Hiroko H , Kaye Jeffrey 
Published: December 2020

AbstractBackgroundWeight loss has been associated with earlier onset of dementia and accelerated cognitive decline. Current methods of assessing nutritional health, including body mass and dietary habits, occur in clinic settings semiannually to annually. A home‐based non‐invasive system allows for continuous data collection that could generate clinically meaningful and reliable data providing insight into subtle changes in disease progression, nutritional health and response to treatment. To properly utilize remote sensing approaches in assessing dietary behavior, potentially more sensitive, objective and ecologically valid measures need to be longitudinally acquired and analyzed for feasibility and acceptability in real world, home environments.MethodA cohort analysis of 66 participants enrolled in prospective longitudinal aging studies with in‐home digital monitoring was performed. Contact sensors attached to refrigerator doors were used to assess the number of door openings per day as a measure of dietary frequency. Daily weight measurements were collected using an in‐home wireless bioimpedence scale. Correlations between dietary frequency and cognitive status (Mini Mental State Examination; MMSE) were performed within 30 days of cognitive assessment.ResultThere is a positive correlation between cognitive status and average number of refrigerator door openings per day (n=66, r=0.31, p=0.01). Remote measures of body weight show increases around known periods of increased food consumption.ConclusionDietary frequency, as measured by refrigerator door openings, and weight are feasible to collect in elders using a non‐invasive home‐based remote system. Continued longitudinal measurements and analysis are needed to determine long‐term feasibility, adherence and acceptability of remote measures of nutritional health.
Sensory‐evoked gamma frequency oscillations in Alzheimer’s disease patients: Biomarker and therapeutic applications
Authors: Hajos Mihaly , Harvey Brian D. , Mortimore Hailey , Strozewski Nathan , Kolin Katharine , Boasso Alyssa , Cimenser Aylin , Marin Anna , Hajos Gabor P , Palumbo Rocco , Spencer Kevin M. , Malchano Zach , Budson Andrew 
Published: December 2020

AbstractBackgroundAs a potential neurophysiology‐based biomarker of cortical neuronal network integrity, visually evoked steady‐state oscillations (SSVEPs) are investigated in healthy young and elderly subjects, and mild cognitive impaired (MCI) and Alzheimer’s disease (AD) patients. Based on recent findings from the Li‐Huei Tsai Laboratory (Picower Institute, MIT) showing that 40 Hz audio/visual stimulation reverses AD‐related pathologies in transgenic mice, we are evaluating the effects of 40 Hz audio/visual stimulation on brain neurophysiology in healthy subjects, and MCI and AD patients (together with clinical trials assessing impact on severity of clinical symptoms and Aβ PET signals) at Cognito Therapeutics.MethodWe are testing SSVEPs, including 15, 30 and 40 Hz light stimulations, and evoked steady state oscillations in response to combined 40 Hz audio/visual stimulation using 128 or 64 channel EEG recordings, respectively. We analyze phase‐locked evoked potentials, inter‐trial coherence, induced oscillations and network coherence in young subjects, MCI and AD patients and age‐matched healthy elderly individuals.ResultSSVEPs have been observed in healthy subjects and MCI/AD patients in response to 3 second flashing light using 15, 30 and 40 Hz stimulation frequencies. High test/re‐test reliability has been established in healthy young subjects. Compared to healthy young subjects (< 30 years), diminished inter‐trial coherence in healthy elderly (> 65 years) subjects, and impaired sensory responses in MCI and AD patients were found to light stimulation. Simultaneous audio/visual 40 Hz stimulation, using Cognito Stimulation System elicited 40 Hz entrainment of cortical activity over the entire 1‐hour session in healthy subjects, MCI and AD patients, without adverse events either during or following SSEVP. Cortical 40 Hz entertainment was accompanied with high‐intensity alpha oscillation. Following the audio/visual stimulation, the augmented alpha band power was associated with increased alpha coherence between fronto‐occipital and fronto‐temporal regions.ConclusionReliable 40 Hz steady‐state oscillations can be elicited and maintained in MCI and AD patients, providing an opportunity to evaluate symptomatic and disease‐modifying effects of this therapy. Detecting disease relevant and individual SSVEP abnormalities can support precision medicine by customizing therapy.
Gray and white matter metabolite differences in Alzheimer’s disease and normal human brain tissue
Authors: Hammond Tyler C. , Xing Xin , Nelson Peter T. , Ham Stephanie , Lin Ai‐Ling 
Published: December 2020

AbstractBackgroundGray matter atrophy and white matter alteration are key neurological features of Alzheimer’s disease (AD), but very little has been reported about the biochemical profile of the gray and white matter in AD. Here we measure the metabolites of AD brains and control brains in the gray and white matter to understand what differences are present.MethodThe global biochemical profiles of post‐mortem human brain tissue from Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 53 subjects with AD and 46 cognitively normal subjects were analyzed. Metabolites in gray and white matter were compared. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch’s two‐sample t‐test and random Forest.ResultGray and white matter metabolites differed in both the AD and the control brains. The gray matter had more metabolites associated with anaerobic metabolism including increased glycine, serine and threonine metabolism, alanine and aspartate metabolism, dipeptides, glycolysis, gluconeogenesis, and pyruvate metabolism, pentose metabolism, BCAA metabolism, phosphatidylcholine, phosphatidylethanolamine, sphingolipid synthesis, ceramides, nicotinate and nicotinamide metabolism, and vitamin B6 metabolism. The white matter had more metabolites associated with aerobic metabolism including oxidative phosphorylation, fatty acid metabolism, long chain monounsaturated fatty acid, Acyl Carnitine Fatty Acid Metabolism, Glycerolipid Metabolism, Monoacylglycerol, Hexosylceramides (HCER), Sterols, and Pantothenate and CoA Metabolism in the white matter vs the gray matter. White and gray matter differences were dependent on disease status for the following metabolites: N‐acetylserine – part of serine metabolism, 1‐arachidonoyl‐GPA (20:4) – a lysophospholipid, Valylleucine – a dipeptide, and octadecenedioate (C18:1‐DC) and oleoylcarnitine (C18:1) – both fatty acids.ConclusionIn our cohort, gray matter showed more metabolite differences dependent on anaerobic metabolism and white matter showed more metabolite differences dependent on aerobic metabolism. Some metabolite differences were dependent on disease status. Researchers using brain metabolomics data should be aware of these gray and white matter differences so that their results aren’t due simply to differences in concentration of gray and white matter between samples. An understanding of how the brain metabolites differ depending on AD disease status can give important insights into disease pathology.
Evidence that semaphorin 4D is upregulated in neurons in Huntington’s and Alzheimer’s diseases: Effects of a SEMA4D blocking antibody on FDG‐PET in a clinical trial, and treatment rationale for its use in AD
Authors: Evans Elizabeth E. , Fisher Terrence L. , Leonard John E. , Reader Alisha M. , Mishra Vikas , Mallow Crystal L. , Balch Leslie , Howell Alan , Smith Ernest S. , Feigin Andrew , Siemers Eric R. , Zauderer Maurice 
Published: December 2020

AbstractBackgroundPepinemab (VX15/2503) is a humanized IgG4 monoclonal antibody that blocks the binding of semaphorin 4D (SEMA4D) to its plexin B1 and plexin B2 receptors. SEMA4D is upregulated in neurons and oligodendrocytes in response to stress and triggers inflammatory activation of plexin B1/B2 positive astrocytes with concomitant loss of some normal astrocyte functions. Blocking antibody to SEMA4D has been shown to reduce neurodegenerative processes in preclinical models, including Huntington’s disease (HD) and Alzheimer’s disease (AD). SIGNAL‐HD is a double‐blind, placebo‐controlled study of pepinemab in HD. Given previous studies of fluorodeoxyglucose (FDG) positron emission tomography (PET) loss in HD and the mechanism of action of pepinemab, FDG‐PET imaging was included in the SIGNAL‐HD study.MethodTransgenic mouse models for HD (Q175) and AD (CVN) as well as human pathological tissue was used for immunohistochemistry. The SIGNAL‐HD study includes participants with late prodromal and early manifest HD. Results from 36 subjects in Cohort A informed group size and treatment duration in Cohort B. A subset of participants in Cohort A underwent PET scanning using FDG at baseline, at the end of the 6‐month placebo‐controlled period and at 12 months at the end of the open‐label treatment period.ResultSEMA4D was upregulated and astrocyte activation was present for HD and AD based on samples from transgenic models and staged patient autopsy samples. SIGNAL‐HD Cohort A (n=36) has been completed and Cohort B (n=265) is fully enrolled. For participants in Cohort A undergoing FDG‐PET imaging (n=19), those in the pepinemab group showed increases in FDG uptake compared to baseline (median 8.6%, range: 0.5‐20.4%) while participants taking placebo showed the expected decrease after 6 months. Nominal statistical significance (p<0.05) pepinemab compared to placebo was achieved for 11/14 frontal and parietal brain regions.ConclusionTransgenic mouse models and human neuropathological analyses are consistent with an upregulation of SEMA4D in HD and AD. The increase in FDG‐PET signal in SIGNAL‐HD Cohort A suggests central target engagement and improvement in brain metabolic activity. SIGNAL‐AD, a randomized, placebo‐controlled, phase 1b/2 study of pepinemab in early AD, will also incorporate FDG‐PET and is planned to begin mid‐2020.
Lipid profiles of extracellular vesicles are distinct for Alzheimer’s disease cases
Authors: Martins Tânia Soares , Magalhães Sandra , Rosa Ilka Martins , da Cruz e Silva Odete , Nunes Alexandra , Henriques Ana Gabriela 
Published: December 2020

AbstractBackgroundExtracellular vesicles (EVs) are secreted by most of the cells and their content can reflect physiological and pathological stages, making them attractive biomarker sources for a wide range of diseases, including Alzheimer’s disease (AD). AD molecular‐based diagnosis in cerebrospinal fluid is a powerful approach nonetheless the identification of biomarkers in peripheral biofluids represents an attractive clinical tool. The procedure to isolate blood‐derived EVs is less invasive, cost‐effective and can be widely available. In addition, Fourier Transformed Infrared (FTIR) Spectroscopy is a highly reproducible, rapid and inexpensive technique. This study addressed the value of FTIR and serum‐derived EVs in AD.MethodSerum was obtained from the pcb‐Cohort (primary care‐based cohort), established by the group (Rosa I.M.et al.2017, Dement Geriatr Cogn Disord;43:15–28). Serum‐derived EVs enriched in exosome‐like vesicles were isolated using Exosome Precipitation Solution (ExoQuick); characterized by Nanoparticle Tracking Analysis and Transmission Electron Microscopy, as described (Soares Martins T.et al.2018, PLoS One;13:e0198820). The FTIR spectra of serum‐derived EVs from AD cases and Controls were acquired (ATR‐FTIR spectrometer); data analysed using multivariate (PCA‐LDA, PCA‐QDA) and univariate (second derivative peak area calculation) approaches.ResultFocus was given to FTIR spectra of lipid regions (3000‐2888 cm‐1 and 1767‐1721 cm‐1). Differences were observed between the average spectra of EV’s from AD and Controls, for both normalized spectra and second derivative spectra. PCA‐LDA and PCA‐QDA revealed that FTIR spectra, in the lipid absorption regions, of serum‐derived EVs has potential disease discriminatory value. In accordance, the second derivative peak area calculation of EVs spectra also revealed significant differences among Controls and ADs. This is in line with previous work where distinct nucleic acid profiles were reported for EVs from AD vs Controls (Soares Martins T.et al.2020, J Alzheimers Dis; in press).ConclusionTaken together data suggests to that metabolic profile of EVs has AD diagnostic potential. To this end research was funded by PTDC/DTPPIC/5587/2014, supported by iBiMED‐UIDB/04501/2020, FCT, COMPETEprogram, QREN, European Union; “pAGE” (CENTRO2020‐CENTRO‐01‐0145‐FEDER‐000003), Centro2020program, Portugal2020, European Union. Conference participation is supported by MEDISIS (CENTRO‐01‐0246‐FEDER‐000018), Centro2020program, European Union, FEDER. We thank volunteers, their families and health professionals. Health Ethics Committee (CES) ARS Centro (No.012804‐04.04.2012) and CNPD (No.369/2012).
Graphical user interfaces for regulatory‐endorsed quantitative drug development tools in Alzheimer’s disease
Authors: Romero Klaus , Hanan Nathan J. , Sivakumaran Sudhir , Sinha Vikram , Haeberlein Samantha Budd , Gold Michael 
Published: December 2020

AbstractBackgroundModel‐informed drug development (MIDD) can improve cost effectiveness of research and development (R&D) decision‐making. The Critical Path for Alzheimer’s Disease (CPAD) Consortium has developed a mild‐to‐moderate Alzheimer’s disease clinical trial simulator, which is intended to optimize clinical trial design in this target population, when using ADAS‐Cog as the primary endpoint. This tool represented the first‐ever FDA and EMA‐endorsed quantitative drug development tool. The CPAD team has also developed a pre‐dementia disease progression model, which received an EMA letter of support, as a trial enrichment tool for pre‐dementia trials that use CDR‐SB as the primary endpoint. In order to democratize the use of these tools, graphical user interfaces (GUIs) were developed for these two models.MethodThe GUIs were developed using R‐Shiny, focusing on the drug‐disease‐trial model aspects of the clinical trial simulator for mild‐to‐moderate AD, with emphasis on the sources of variability (APOE4, sex, baseline MMSE and age); and focusing on the disease progression predictors of the trial enrichment model for pre‐dementia (baseline MMSE, age and hippocampal volume, APOE4 and sex).ResultThe GUIs were beta‐tested by pharmacometricians, statisticians, clinical trialists and clinicians. Their feedback was used to further improve the functionality of the GUIs. Focus was put on the ability of the users to intuitively set up the simulation framework for specific studies, the underlying assumptions, and the graphical and tabular output of simulated results.ConclusionThe publicly accessible GUIs will increase the usability of these quantitative drug development tools. Examples of their application include informing stage‐gate decisions; optimization of study design; patient selection; and sample size estimations.
Effect of polyphenol treatment for mild cognitive impairment (MCI) and diabetes
Authors: Pasinetti Giulio Maria , Iqbal Umar Haris , Rosenberg Paul B. 
Published: December 2020

AbstractBackgroundAs the prevalence of Alzheimer’s disease (AD) continues to rise, alternative approaches are sought to have a greater understanding of this neurological disease. One approach of interest would be to identify individuals who are at risk of Alzheimer’s disease (AD) and determine the efficacy of a selected therapeutic. Persons with Mild Cognitive Impairment (MCI) are at risk of incident dementia, and being coupled with deficits in short‐term recall, significantly increases their risk of incident AD. In addition, having risk factors of the metabolic syndrome, such as prediabetes, has also been found to augment the risk of incident cognitive impairment. This is further strengthened by evidence showing neurons in AD brains being insulin resistant. Previous animal studies have found that a nutraceutical containing grape seed polyphenol extract (GSPE) and resveratrol to be associated with improved cognition and lowering brain amyloid and tau burden. The current clinical study is being taken as a first step to investigate the safety and tolerability of GSPE and resveratrol in patients who have Mild Cognitive Impairment (MCI) and diabetes. In addition, this study will also quantify the bioavailability of selected polyphenols and their metabolites, and determine if any changes are seen between the treatment and placebo group at the end of the study in regards to cognitive test scores, and CSF content of tau/β‐amyloid 42.MethodParticipants were entered into a 4 month double‐blinded study and given either a placebo, or a mixture containing 450 mg of GSPE and 125 mg of resveratrol. Serum samples were taken at baseline, 2 months, and 4 months, whereas CSF samples were taken at the start and end of the study.ResultThe study is still ongoing and additional individuals are enrolling in the study. No adverse events related to GSPE and resveratrol have been observed from the participants to date, and compliance has been good.ConclusionAt the conclusion of this clinical trial, in addition to determining the safety and tolerability of GSPE and resveratrol, a greater understanding will be attained as to the potential association of selected polyphenol metabolites and biomarkers of AD neuropathology in CSF.