bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of mRNA isoform diversity in a transgenic model of tau pathology using targeted long‐read sequencing
Authors: Leung Szi Kay , Jeffries Aaron , Hannon Eilis , Castanho Isabel , Moore Karen , Murray Tracey K. , Ahmed Zeshan , Collier David A. , Mill Jonathan 
Published: December 2020

AbstractBackgroundAn increasing number of studies implicate a role for alternative splicing in the development and neuropathology of Alzheimer’s disease (AD). However, it has been historically challenging to characterise splicing events, due to the limitations of short‐read RNA‐sequencing (RNA‐Seq) for the capture full‐length transcripts critical for transcriptome assembly. In this study, we used Pacific Biosciences long‐read isoform sequencing (Iso‐Seq) to enrich and comprehensively characterise isoform diversity for AD‐associated genes in entorhinal cortex samples from a well‐validated AD transgenic mouse model.MethodWe used Pacific Biosciences Targeted Iso‐Seq to investigate splicing of 20 AD‐associated genes (including TREM2, BIN1, and APOE) in entorhinal cortex of a well‐characterised mouse model of tau pathology, rTg4510. Sequence data was processed using the Iso‐Seq3 pipeline, followed by downstream analysis using other publically available resources and customised scripts. The same samples have additionally been sequenced using whole transcriptome Iso‐Seq and RNA‐Seq as validation.ResultWe obtained deep sequencing coverage of full‐length transcripts for each of the AD genes, revealing complex usage of alternative start sites and splicing events, as well as many novel 5′starts and 3’ends not previously annotated in existing genomic datasets. We identified differential transcript expression and isoform usage between transgenic and wild‐type mice, with highly‐correlated gene expression between Iso‐Seq and short‐read RNA‐seq data.ConclusionThis study highlights the application of long‐read sequencing approaches to assess splicing variation and isoform diversity in AD by selective gene enrichment. Results suggest differential splicing events associated with AD pathology, supporting a role for transcriptomic dysregulation in development of AD. Further work will be undertaken to characterise other AD‐associated genes, and to extend these analyses to human post‐mortem brain samples.
Change in 12‐month health care utilization patterns among persons living with dementia who received a comprehensive home‐based dementia care coordination program: Mind at home
Authors: Samus Quincy M , Amjad Halima , Huang Jin , Leoutsakos Jeannie‐Marie S , Lyketsos Constantine , Johnston Deirdre 
Published: December 2020

AbstractBackgroundMIND at Home, a value‐based innovation, is a comprehensive, home‐based care coordination program for people with dementia and their carers to identify and address a broad set of health determinants to improve health, clinical outcomes, and reduce costs. We present pooled trial data evaluate change in 12‐month health care utilization patterns among a racially and cognitively diverse group of persons living with dementia who received MIND at Home.MethodPre‐post, adjusted Poisson regression models were used to evaluate health care utilization patterns for a pooled sample of persons with dementia receiving MIND at Home (n=391) in the 12 month period after enrollment in the program with the 12 month period prior to enrollment. Hospitalizations, ED visits, outpatient visits, home and community‐based services (HCBS) were ascertained via proxy‐report from carers.ResultThe mean number of hospital admissions decreased by 27% in the one year period after baseline (95% CI: 6%, 44%, p=0.01) compared with the year prior. Adjusted rates of one or more hospitalizations declined from 36.8% to 32.5%, with a crude rate reduction of 11.6% (unadjusted) between pre‐and post‐periods. Mean number of HCBS services used increased by 70% (95% CI: 54%, 88%, p<0.01) and mean number of outpatient specialties seen in the post period increased by 52% (95% CI: 43%, 62%, p<0.01) compared with the year before baseline. Average number of outpatient provider visits remained the same (p=0.76). Mean number of ER visits decreased by 16% (95% CI: ‐8%, 34%) but was not statistically significant (p=0.18).ConclusionResults provide compelling new quasi‐experimental data that supports the impact of the MIND at Home program on changing health care utilization patterns and is in line with our prior findings. Persons who received MIND at Home were less likely to use high cost acute health services (inpatient) and more likely to use more cost‐efficient services like home and community based services and physician services in the year after enrollment compared to the year prior. These data imply a potential cost benefit of the MIND at Home dementia care coordination program.
Development and implementation of a training program to facilitate community partnerships in the Indigenous Cultural Understandings of Alzheimer’s Disease and Related Dementias – Research and Engagement (ICARE) project
Authors: Blind Melissa J , Pitawanakwat Karen , Koski Jessica , Lambrou Nickolas H , Lemieux Andrine , Jacklin Kristen , Warry Wayne 
Published: December 2020

AbstractBackgroundIndigenous Cultural‐understandings of Alzheimer’s – Research and Engagement (ICARE) is a program of research investigating the lived experiences of family and professional care providers for Indigenous people with dementia involving three diverse sites in Canada and the United States. We employ a community‐based participatory research (CBPR) approach that includes hiring Indigenous community‐based researchers to assist with community engagement, subject recruitment, data collection, analysis, and dissemination. This poster describes the development and deployment of a training program designed to build capacity and support community participation in the ICARE project.MethodThe goal was to design culturally safe training that would support community participation in the study, build research capacity in local community members, and improve standardization of protocols across the sites. The training objectives were to teach the basics of CBPR, administrative tasks, basics of qualitative research, protocols of the study, including research ethics and compliance. To accomplish this, we used a Two‐Eyed seeing approach and cultural safety lens. The training encompasses four modules, with online active and reflective learning, mandatory readings, and videotaped interviews. Five community researchers completed the training. Post‐training debriefing interviews and written review of lessons learned were conducted four months after the training was completed.ResultAt completion of the training, community researchers could define the key tenets and methodological procedures used in CBPR, including the unique ethical considerations for completing research related to dementia within Indigenous communities, the administrative duties required to produce reliable data, and demonstrate key qualitative research. Trainees reported the videotaped interviews conducted with a senior community were the most important to their learning, as the videos gave concrete examples of what to expect in conducting research within their own communities. They wished we had more content and videos on accessing and using the technology associated with the administrative tasks.ConclusionHiring and training community‐based researchers is considered best practice in Indigenous Health research, yet there are few guidelines on how to develop local capacity to fill these roles. The ICARE training provided community‐based researchers with critical skills to facilitate community involvement in the research process and grounding in academic protocols and methods.
Diagnostic differentiation by NIH Toolbox‐Cognition (iPAD) for Alzheimer’s disease, mild cognitive impairment (MCI), and healthy control participants
Authors: Bhaumik Arijit K. , Reader Jonathan M. , Rahman‐Filipiak Annalise , Kairys Anson , Duda Bryant , Heidebrink Judith L. , Hampstead Benjamin M. , Paulson Henry L. , Giordani Bruno 
Published: December 2020

AbstractBackgroundAge‐associated impairment among older adults is a significant public health concern. The NIH Toolbox for Assessment of Neurological and Behavioral Function® (NIHTB) was developed for use in studies for which standardized, computer‐based measurement of cognitive, motor, sensory, and behavioral processes is of importance. The NIH Toolbox–Cognition battery measures both crystallized and fluid cognitive functions. The goal of this study was to compare performance of the newly available tablet‐version of the Cognition battery across healthy and impaired older adults and to analyze if race and gender effects would be evident even when using NIHTB fully‐adjusted T‐scores.MethodA total of 104 individuals (28 men, 56 women; 45% African American) completed the NIH Toolbox–Cognition as part of a National Alzheimer’s Disease Coordinating Center (NACC) longitudinal study of memory and aging through the Michigan Alzheimer’s Disease Research Center (Michigan ADRC). All participants received the Unified Data Set (UDS) and consensus diagnosis of normal cognition (NL), amnestic mild cognitive impairment (aMCI), or Alzheimer’s dementia (AD). Univariate analyses of variance with post‐hoc comparisons were used to compare fully adjusted (age, gender, race/ethnicity, education) Toolbox T‐Score performance across the groups.ResultsUnivariate ANOVAs revealed significant findings for the Total and Fluid composites (both p<0.001) and Crystallized Composite (p<0.05). For Crystallized subtests, only Oral Reading demonstrated group differences, with NL>AD. Though NL and aMCI groups performed similarly, both groups outperformed AD on Dimensional Card Sort, Flanker, and Pattern Comparison Fluid subtests. NL>aMCI>AD on List Sorting Working Memory and Picture Sequence Memory. Main effects for race or gender were not seen for comparisons of NL to aMCI, but some group sizes were too small for adequate testing in the AD participants.ConclusionsAs expected, NL, aMCI, and AD demonstrated significant performance differences on NIH Toolbox—Cognition composite and scale scores. As expected, Crystallized tasks were least effective, traditionally representing cognitive areas least sensitive to neurologic dysfunction. Fluid tasks were noticeably more effective, with the working memory and learning measures showing a significant tiered difference, with NL highest and AD lowest. The fully adjusted scores were successful in accounting for demographic variables.
Distinct patterns of gray matter atrophy in hippocampal sclerosis of aging and Alzheimer’s disease neuropathology
Authors: Woodworth Davis C. , Scambray Kiana Alexis , Phelan Michael , Corrada Maria M.M. , Kawas Claudia H. , Sajjadi S. Ahmad 
Published: December 2020

AbstractBackgroundHippocampal sclerosis of aging (HS) and Alzheimer’s Disease Neuropathology (ADNP) both contribute to dementia in the elderly but are difficult to distinguish in vivo. Currently, there are no established biomarkers for HS, and few studies have investigated the distinction between HS‐ and ADNP‐related patterns of brain atrophy. We hypothesized that HS‐related atrophy would be restricted to the hippocampus and surrounding structures, while ADNP‐related atrophy would be most pronounced in the lateral temporal and parietal lobes.MethodWe used data from the National Alzheimer’s Coordinating Center (NACC) (09/2005‐03/2017) and identified 134 participants with suitable 3D T1w MRI and autopsy data. HS pathology was available as present/absent and we defined ADNP as present by a combination of high Braak stage (V/VI) and CERAD neuritic plaque score (3). We used the Computational Anatomy Toolbox (CAT12) to segment the MRI scans into tissue types and generate gray matter density maps. We examined the following regions of interest (ROIs): hippocampus, parahippocampus, amygdala, temporal and parietal regions, and global tissues measures. Additionally, we performed a voxel‐based morphometry (VBM) analysis. We studied the relationship between volumes/densities and neuropathologies using multiple linear regression models while adjusting for sex, age, education, dementia status, years from MRI to death, and intracranial volume.Result
Table 1 depicts participant characteristics. We found that HS, but not ADNP, was associated with the volumes of the hippocampus (HS P<0.001, ADNP P=0.4), parahippocampus (anterior only, HS P=0.007, ADNP P=0.8), and amygdala (HS P=0.009, ADNP=0.2, Table 2). ADNP was significantly associated with lateral temporal lobe volumes, most strongly the inferior/middle temporal gyri. We found a trend of association between ADNP and gray matter atrophy (P=0.051). HS was significantly associated with white matter atrophy (P=0.001). We display the VBM results in Figure 1, which largely confirm the ROI results. Additionally, we found HS was associated with bilateral thalamic and insular regions and ADNP with the left amygdala and hippocampal tail atrophy.ConclusionWhile HS is strongly associated with atrophy of the hippocampus and surrounding structures, ADNP is associated with atrophy of lateral temporal lobe regions. These diverging atrophy patterns are potential biomarkers for differentiating these two clinically indistinguishable conditions during life.
Lithium protects against lipopolysaccharide‐induced cytotoxicity in SH‐SY5Y cells expressing Alzheimer’s presenilin 1 mutation by ameliorating calcium dysregulation
Authors: Sun Liang , Liang Ge , Wei Huafeng 
Published: December 2020

AbstractBackgroundLipopolysaccharide is a crucial mediator of neuroinflammation in sepsis. Neuroinflammation is implicated in normal brain aging and neurodegeneration in various neurodegenerative disorders including Alzheimer's disease. We examined the effect and mechanisms of lithium protection against lipopolysaccharide‐induced cytotoxicity in human neuroblastoma SH‐SY5Y cells expressing familial Alzheimer’s disease mutant presenilin‐1 (PS1) and compared to wide type control.MethodHuman neuroblastoma SH‐SY5Y cells transfected with human wild type or point mutant PS1 (M146L) were pretreated with lithium chloride (1 mM) for 1 week, and then challenged with lipopolysaccharide for 24 h. Cell viability was determined by the 3‐(4,5‐dimethylthiazol‐2yl)‐2,5‐diphenyltetrazolium bromide (MTT) reduction assay. Alterations of cytosolic Ca2+ concentrations were measured using jellyfish specific photo protein aequorin‐based probes.ResultLipopolysaccharide resulted in a dose‐dependent cytotoxic effects (starting from the concentration of 400 μg/ml) in both types of cells. Moreover, lipopolysaccharide (400 μg/ml) caused significantly more cytotoxicity in M146L than its corresponding wild type control cells, which could be inhibited significantly by lithium (1 mM) pretreatment. Lipopolysaccharide induced significantly more elevation of peak cytosolic Ca2+ concentrations in M146L cells than in wide type control cells, which could be abolished by lithium (1 mM) pretreatment.ConclusionsOur results suggest that lithium pretreatment at clinically relevant concentrations could effectively mitigates lipopolysaccharide mediated cytotoxicity, especially in Alzheimer’s PS 1 mutated cells, possibly by ameliorating the abnormally elevated cytosolic Ca2+ concentration.
Neuropathology and immune biomarker discovery in a rat model of Alzheimer's disease, TgF344‐AD, with controlled cortical injury model of traumatic brain injury
Authors: Wang Athena Ching‐Jung , Adame Vanesa , Markham Neil , Potter Huntington , Boyd Timothy 
Published: December 2020

AbstractBackgroundIndividuals with a history of traumatic brain injury (TBI) have a higher risk of developing Alzheimer’s disease (AD) and AD‐related dementias (ADRD), such as chronic traumatic encephalopathy (CTE). However, the relationship(s) between TBI, AD, and CTE remain poorly understood and markedly understudied. Because transgenic mouse models of AD that develop amyloidosis do not readily develop pathological tauopathy that is commonly found in ADRD, we used the TgF344‐AD transgenic rat model of AD in which amyloid deposition drives endogenous tauopathy and neurodegeneration for our TBI studies.MethodWe used the closed‐head controlled cortical impact (CCI) model of TBI, performed either once (1X‐CCI) or twice over two weeks (2X‐CCI) in both 6‐ and 12‐month‐old TgF344‐AD and wild‐type (F344) rats to investigate the effects of TBI on acute and chronic neuroinflammation, on blood brain barrier (BBB) integrity, and on ADRD‐associated neuropathology. Whole brains and terminal blood draws were collected at different time points following the 1X‐ or 2X‐CCI TBI procedures at 3, 15, 30, 60, and 120 days after the final CCI procedure. Thus, the tissue collection ages of animals across the project allow for TBI‐induced ADRD‐related pathological analyses at 6, 7, 8, 10, 12, 13, 14, and 16 months of age. MRI scans were conducted at 30‐days post‐CCI to examine BBB leakage and chronic inflammation, with subsequent post‐mortem histochemical confirmation. Terminal blood draw samples were used for complete blood cell counts with differential and multiple biomarker analyses.ResultThis project is ongoing, but interim analyses reveal chronic neutrophil percentages remaining consistent in both TgF344‐AD and wild‐type 12‐month‐old cohorts undergoing either 1X‐ or 2X‐CCI at all post‐injury time points. Also, the upright time for the animals does not appear to differ based on impact type or genotype so far. However, histochemical pathological analyses of the 12‐month‐old AD rats have demonstrated changes in Aβ pathology and astrogliosis markers. MRI analyses have not yet been completed.ConclusionWe are continuing to carry out detailed analyses of changes in ADRD‐related pathology and blood biomarkers. These animal models should help provide an increased understanding of chronic neuroinflammation and other pathological mechanisms associated with TBI and risk for ADRD.
iPSC‐derived neurons and microglia with an African‐specific ABCA7 frameshift deletion have impaired function
Authors: Cukier Holly N. , Laverde‐Paz Juliana , Ramirez Juliana , Adams Larry D. , Starks Takiyah D. , Vance Jeffery M. , Cuccaro Michael L. , Blurton‐Jones Mathew , Haines Jonathan L. , Byrd Goldie S. , Pericak‐Vance Margaret A , Dykxhoorn Derek M. 
Published: December 2020

AbstractBackgroundThe ATP‐binding cassette, sub‐family A (ABC1), member 7 (ABCA7) gene has been implicated as a risk factor in Alzheimer’s disease (AD) across populations. However, the risk effect of ABCA7 in African Americans (AAs) is stronger than in non‐Hispanic white (NHW) populations. We identified a 44 base pair deletion in AA significantly associated with disease (cases = 15.2%, controls = 9.74%, p = 1.414 × 10−5, Cukier, et al, 2016). The deleted allele is predicted to produce a frameshift mutation (p.Arg578Alafs), resulting in a truncated protein that may interfere with its normal functions, including APP processing and Aβ clearance.MethodTo further understand the mechanism by which the ABCA7 deletion may be acting, induced pluripotent stem cells (iPSC) lines were developed from the blood of two unrelated AA AD individuals heterozygous for the deletion, as well as age matched cognitively normal individuals. The iPSC lines were differentiated into cortical neurons and microglia, as both cell types endogenously express ABCA7.ResultEach iPSC line generated was karyotyped and validated for pluripotency through immunocytochemical staining. RNA from the cases demonstrated that a stable RNA transcript is produced from the ABCA7 deletion allele. Preliminary results from iPSC‐derived neurons and microglia identified impaired functions in both cells types. Cortical neurons from patients produced higher levels of Aβ40 and Aβ42 compared to controls. In addition, while the patient‐derived microglia had normal rates of phagocytosis, they were impaired in the uptake and clearance of fibrillar Ab. Furthermore, when exposed to the proinflammatory stimulus lipopolysaccharide (LPS), the patient‐derived microglia had decreased cytokine responses.ConclusionThis deletion in ABCA7 is an ethnic specific, pathogenic alteration in AD that may result in an increased production of toxic β‐amyloid production in neurons and a depressed ability to clear Ab and impaired responsiveness to proinflammatory signals in microglia.
AL001 restores CSF PGRN levels and normalizes disease‐associated biomarkers in individuals with frontotemporal dementia due to heterozygous mutations in the progranulin gene
Authors: Haynes Beth Ann , Rhinn Herve , Yeh Felix L , Long Hua , Ward Michael , Hagey Mackenzie , Siddiqui Omer , Paul Robert 
Published: December 2020

AbstractBackgroundAL001 is a recombinant humanized anti‐Sortilin monoclonal antibody in development for frontotemporal dementia (FTD). Mutations in a single copy of the progranulin gene (GRN) leads to a 50% or greater decrease in the level of circulating progranulin (PGRN) protein levels and are causative of FTD. The disease is associated with increased inflammation and impaired lysosomal function in the brain. The INFRONT Phase 1/1b clinical study AL001‐1 investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenously administered AL001 in healthy volunteers (HV) and participants with a GRN mutation causative of FTD (FTD‐GRN). In addition, the study investigated the effect of AL001 on disease‐associated biomarkers.MethodA total of 64 participants were enrolled in the AL001‐1 study. In the single dose ascending part of the study, 50 healthy volunteer participants were enrolled with 38 exposed to AL001 and 12 exposed to placebo. The study enrolled 6 asymptomatic FTD‐GRN and 8 symptomatic FTD‐GRN participants. The 8 symptomatic FTD‐GRN participants received 3 doses of 30 mg/kg of AL001 over 4 weeks.ResultTreatment of symptomatic FTD‐GRN participants with AL001 over 4 weeks restored PGRN levels in the cerebrospinal fluid (CSF) to normal levels for more than 8 weeks. To further investigate the effects of restoring PGRN levels, partial normalization of a FTD disease proteomic signature was observed in the CSF 4 weeks after the last dose in multidose treatment group. Compared to healthy volunteers, AL001 treatment rescued cathepsin B (CTSB), a marker of lysosomal function, by 58%. AL001 treatment also partially normalized markers of inflammation and gliosis, osteopontin (SPP1) and chitotriosidase (CHIT1) by 52% and 22%, respectively. In addition to the reversal of these disease phenotypes, a 14% reduction (n.s.) in plasma neurofilament light chain (NfL), a marker of neuron injury and stress, was observed after 8 weeks after the last dose.ConclusionAL001 treatment resulted in a sustained increase in plasma and CSF PGRN in FTD‐GRN mutation carriers. New data showed reduction of NfL and normalization of proteins associated with the disease after one month of dosing. These results have supported progressing AL001 to Phase 2 and pivotal Phase 3 studies.