bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comorbidity burden in Alzheimer’s disease clinical trials
Authors: Fowler Mackenzie E. , Murchison Charles F. , Cutter Gary R. , Schneider Lon , Kennedy Richard 
Published: December 2020

AbstractBackgroundIndividuals with AD may be healthier than the general older adult population. Clinical trials for AD have been known to enroll individuals who are not representative of the general population, but it is unclear to what extent comorbidity affects cognitive outcomes in clinical trials.MethodsWe included 10 studies with 4,002 subjects with AD from our meta‐database of 18 ADCS studies and ADNI. Comorbidity was measured using the RxRisk‐V, which provides a count of the total number of comorbid conditions based on medication data. Cognition was measured using the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog). We used linear mixed effects models to examine the rate of cognitive decline by total comorbidity count, by individual disorders, and by presence of hypertension plus diabetes as known AD risk factors.ResultsAcross all participants, the mean RxRisk comorbidity score was 1.90 (SD 2.04). Approximately 27% had 0 comorbidities, 27% had 1 comorbidity, and 46% had 2+ comorbidities. Across all studies, for each additional comorbidity, the rate of progression on the ADAS‐cog increased by 0.11 point/year (95% CI ‐0.05, 0.26), reflecting a non‐significant worsening of cognition (Figure). After adjusting for other comorbidities, the rate of progression was not significant for congestive heart failure (‐0.5 point/year, 95% CI ‐1.3, 0.3), COPD (‐0.1 point/year, 95% CI ‐1.6, 1.3), diabetes (‐1.2 point/year, 95% CI ‐2.5, 0.1), hypertension (0.7 point/year, 95% CI ‐0.1, 1.6), or ischemic heart disease (‐0.3 point/year, 95% ‐0.9, 0.4). The rate of progression was also not significant for the combination of hypertension plus diabetes (0.1 point/year, 95% ‐0.7, 0.9).ConclusionsComorbidity did not have a significant effect on rate of cognitive decline across AD clinical trials. As several comorbidities are known to affect the rate of AD progression, these findings suggest that AD clinical trials enroll participants with less severe comorbidities that do not affect cognitive decline. Further study of the effects of comorbidities on AD clinical trial outcomes are warranted, particularly study of severity of comorbidities.
Signatures of disrupted synaptic maintenance in the entorhinal cortex of both pathology‐free APOE4 carriers and aged APOE4 mice
Authors: Arain Hirra A. , Kumar Gautam , Figueroa Helen Y. , Cookson Mark R. , Mathews Paul , Duff Karen E. , Nuriel Tal 
Published: December 2020

AbstractBackgroundThe greatest genetic risk factor for late‐onset Alzheimer’s disease (AD) is the possession of the apolipoprotein E4 (APOE4) variant. Yet the mechanism by which APOE4 increases AD susceptibility is unclear. The entorhinal cortex (EC) is one of the first region of the brain to succumb to AD pathology, and previous studies in our lab have revealed unique APOE4‐assocated effects on the regulation of important biological processes in the EC of aged APOE4 mice. In this study, we further elucidated APOE4‐associated vulnerability in the EC by investigating such alterations in AD pathology‐free brain tissues from human APOE4 carriers.MethodUsing both confirmed pathology‐free human brain tissue genotyped for APOE status and brain tissue from aged APOE targeted replacement mice, we investigated the effects of APOE4 expression in the EC using a combination of transcriptomic analysis, immunohistochemistry and biochemical assays.ResultDifferentially expressed genes present in both human and mouse samples revealed APOE4‐associated alteration of transcripts in the EC related to both the maintenance and the structural integrity of synapses. Follow up studies have elucidated the ways in which the alterations of these transcripts affects synapse integrity and causes dysregulation of vital biological processes in the EC. Additional studies are currently underway to understand how such pathway dysregulations are related to one another and how they are instrumental in the AD pathology that accumulates early on in the EC.ConclusionOur studies reveal novel insights into the ways in which APOE4 expression may increase AD risk by revealing region‐specific alterations in vital biological processes present in both humans and mice that possess the APOE4 allele. We believe that these results will point to novel ways in which AD can be slowed or prevented, especially among APOE4 carriers.
Artificial intelligence‐led decision support services to reduce caregiver load related to persons with cognitive impairment
Authors: Dorai Chitra , Stern Edith 
Published: December 2020

AbstractBackgroundThe number of people in the US living with cognitive impairment (including Alzheimer’s Disease and other dementia) is over 5.8M today, and is expected to increase to nearly 14M by 2050 [c.f. alz.org]. The rapidly growing population of informal caregivers is subject to high stress due to patient behavioral symptoms, increased demands on caregiver time, and lack of knowledge about new care giving tasks. Many of these tasks are complex and time consuming such as determining and coordinating services/resources for the patients, seeking information and talking with the clinical team about patient conditions and care plans, and arranging for someone to care for their charge.MethodWe hypothesize that the power of artificial intelligence (AI) technology can be harnessed to meaningfully support caregivers in time consuming, complex tasks encountered in care giving and thereby reduce their load before, during and after diagnosis. We have developed a set of ARTful (accountable, responsible, and transparent) AI services to support informal caregivers of patients with mild cognitive impairment who are being diagnosed and treated at a hospital Memory Clinic. Barriers to adoption of AI technology services include usability (as defined in the System Usability Scale), acceptability (fear of AI) and experience (digitally unprepared) on the part of patient/caregiver pairs.ResultIn this paper, we present case studies covering service onboarding, caregiver exploration and patterns of use of the AI technology, and initial assessment of its impact on adherence to care plans and on caregiver burden. Preliminary findings indicate that well‐thought out AI‐led solutions can reduce caregiver load and increase care plan adherence. A double‐blind study is planned to quantitatively assess impact as measured by scores on the Oberst Caregiver Burden Scale.ConclusionA demonstration of the effectiveness of this technology in reducing caregiver load will lead to a scalable, cost‐effective solution that raises the standard of current practices in neurodegenerative care, and leads to improved health outcomes.
Effects of a high‐fat diet on the brain in FRGN mice with humanized livers
Authors: Edlund Anna K. , Giannisis Andreas , Patra Kalicharan , Morrema Tjado H.J. , Hoozemans Jeroen J.M. , Bial Greg , Foquet Lander , Nielsen Henrietta M. 
Published: December 2020

AbstractBackgroundDiets rich in fat lead to high levels of circulating free fatty acids that induce systemic inflammation, which contribute to systemic insulin resistance and consequently impaired glycemic control. Both of these conditions are associated with brain glucose hypometabolism [1, 2] and an increased risk of neurodegenerative dementias such as Alzheimer’s disease. Mice on a high‐fat diet (HFD) were reported to show signs of brain insulin resistance with coinciding cognitive impairment [3]. Due to the significant difference in lipid metabolism between mouse and man, its poorly understood how the effects of a HFD on mice brains translate to human brain. We therefore employ a mouse model with humanized livers resulting in a more human‐like peripheral lipid profile [4] to study the effects of a HFD on the mice brain.MethodFRGN mice with humanized livers were fed either normal chow or a 12‐week HFD. Brains were harvested and divided with a sagittal cut. The right hemispheres were used for immunohistochemical analysis and the left hemisphere was macro‐dissected to retrieve the hippocampus and the cortex which were fractionated into nuclei‐ and synaptosome enriched as well as synaptosome‐depleted tissue fractions using an established differential centrifugation protocol. Tissue fractions were used for western blotting assessment of various markers relevant to insulin signalling, glucose uptake, synaptic integrity and neuroinflammation.ResultInitial results from the immunohistochemical analysis of the cortex reveal near‐abolished levels of the microglial marker IBA1 (model effect) and increased accumulation of reactive astrocytes around blood vessels in FRGN mice compared to WT mice. The GFAP signals were slightly reduced in FRGN mice with humanized livers. Both observations were unrelated to the HFD.ConclusionInitial results from our immunohistochemical evaluation of the cortex suggest a model‐specific decrease in microglial cells in the FRGN mice, and modest changes in the presence of astrocytes in FRGN mice with humanized livers that appeared unaffected by a HFD. References: (1) Burns, C.M., et al.,Neurology, 2013. 80(17): p. 1557‐64. (2) Baker, L.D., et al., Arch Neurol, 2011. 68(1): p. 51‐7. (3) Kothari, V., et al., Biochim Biophys Acta Mol Basis Dis, 2017. 1863(2): p. 499‐508. (4) Ellis, E.C., et al., PLoS One, 2013. 8(11): p. e78550.
Soccer heading and cognitive performance in professional soccer players: One‐year longitudinal data
Authors: Caramelli Paulo , Lima Mariana D. M. , Palma Giovanni B. , Furtado Celso , Lasmar Rodrigo P. , Rodrigues Ana Carolina O. 
Published: December 2020

AbstractBackgroundSoccer is the most popular sport worldwide and the only sport in which participants purposely hit the ball with their head. Although researchers have focused on the effects of concussions in contact sports, the role of sub‐concussive impacts (e.g. heading), has gained attention. The aim of this ongoing longitudinal study is to investigate the effects of soccer heading on cognitive functioning in active soccer players.MethodMale professional soccer players (n=22), from two teams playing in the Brazilian championship, and non‐athletes (n=37), matched by age and education, were submitted to computerized (E‐Prime software) and conventional (NEUPSILIN battery) cognitive assessment. All subjects were tested on two occasions – T0 and T1 – separated by a one‐year interval.ResultIn T0, players performed better than controls on three variables of computerized testing – reaction time and accuracy in executive functioning tests – and on two variables of NEUPSILIN battery – scores in memory and arithmetic abilities tests. In T1, soccer players outperformed controls on three variables of the computerized testing – reaction time in general motor coordination test and accuracy in executive functioning tests – and on one variable of the NEUPSILIN battery – score in arithmetic abilities test. Intragroup analyses revealed that while controls improved their performance on three variables from T0 to T1 – reaction time in attention test, accuracy in executive functioning test and score in memory test – no improvement was observed among soccer players. However, a comparison involving variation in performance between T0 and T1 showed no significant differences between groups. Among soccer players, no significant correlations were found between self‐reported number of headings per game and cognitive performance in T0 and T1, controlling for concussion history.ConclusionThere was no evidence of cognitive impairment in soccer players, compared to non‐athletes, in T0 and T1. Soccer players even outperformed controls on some tests. The change in cognitive performance from T0 to T1 was similar between groups. Moreover, estimate of exposure to heading did not correlate with performance of soccer players in tests. Further longitudinal investigations are needed to clarify the relationship between soccer heading and cognition.
Frequency of familial Alzheimer’s disease gene mutations within the Alzheimer Disease Sequencing Project (ADSP)
Authors: Scalici Alexandra , Peloso Gina M. , Wang Yanbing , Lin Honghuang , Sarnowski Chloé , Pitsillides Achilleas N. , Dupuis Josée , Seshadri Sudha , Destefano Anita L. ,   CHARGE ADSP FUS Group
Published: December 2020

AbstractBackgroundMutations within the amyloid precursor protein (APP), presenilin‐1 (PSEN1), and presenilin‐2 (PSEN2) genes are known to cause familial Alzheimer’s disease (AD). Our goal is to examine the distribution of clinical variants in these genes within the ethnically diverse participants in the Alzheimer Disease Sequencing Project (ADSP) whole genome sequence (N = 4789) and whole exome sequencing (N = 20,158) data.MethodWe aggregated mutations reported in APP, PSEN1, and PSEN2 from the Alzheimer’s disease and Frontotemporal Dementia Mutation Database, ClinVar, and the Online Mendelian Inheritance in Man, and selected rare variants (minor allele frequency < 1%) described as pathogenic and related to AD or dementia yielding 304 variants (53 in APP, 233 in PSEN1, 18 in PSEN2). We counted the presence of these clinically implicated variants in the currently available ADSP data.ResultAmong 22,558 ADSP subjects passing quality control filters we observed 16 PSEN1, 5 PSEN2 and 6 APP variants. We identified 48 individuals (13 controls, 30 AD cases, 5 missing AD diagnosis) that were heterozygous for one of these variants. An additional AD case was a compound heterozygote for two APP variants. Out of the total sample, 0.06% of African Americans (AA), 0.21% of whites (non‐Hispanic white or white with ethnicity unknown), and 0.33% of Hispanics (HI) were carriers. In contrast, AA, white, and HI represented 21%, 63%, and 15% of the sample, respectively. The carriers included two pairs of second‐degree relatives: one Hispanic pair and one pair consisting of one Hispanic and one white/ethnicity unknown individual.ConclusionA reported mutation in APP, PSEN1 or PSEN2 was observed in 0.22% of ADSP participants, with the lowest carrier rate in AA. Studies in other diseases indicate that disparities in inclusion in genomic sequencing may result in misclassification or higher rate of uncertain significance for patients in underrepresented populations (e.g. Manrai et.al. 2016, Spratt et.al. 2016). It is unknown if the current difference in observed carrier rate by ancestry reflects study design, a true difference in frequency of AD causal APP, PSEN1, and PSEN2 mutations across populations, or limitations in identified pathogenic mutations due to populations historically included in genetic studies of AD.
A preliminary assessment of longitudinal amyloid status in the ongoing open‐label extension phase in subjects with early Alzheimer’s disease
Authors: Swanson Chad J. , Zhang Yong , Dhadda Shobha , Wang Jinping , Kaplow June , Bradley Heather , Rabe Martin , Lai Robert Y.K. , Gordon Robert , Kramer Lynn D. 
Published: December 2020

AbstractBackgroundBAN2401 is a humanized IgG1 monoclonal antibody that selectively binds large soluble Aβ aggregates over monomers and fibrils. We have previously shown that amyloid reduction over 18 months of BAN2401 treatment at 10 mg/kg‐biweekly persists at baseline in an open label extension (OLE) following long‐term withdrawal from BAN2401. Here, we present preliminary data on the early longitudinal effects of BAN2401 on brain amyloid in the OLE of BAN2401‐G000‐201.MethodsSubjects who fulfilled OLE inclusion/exclusion criteria were eligible. Amyloid positivity was required at baseline of the core Phase 2 study. Amyloid PET status was determined by visual read using an identical approach to that conducted at baseline in the core. The OLE was initiated after analysis of the core study showed clinical potential for BAN2401, thus, individuals were off drug for variable periods of time prior to entering the OLE. All subjects received 10 mg/kg biweekly in the OLE. Data for longitudinal PET standard uptake value ratio (SUVr) were collected in subjects at either 3mo and 6mo assessment. Piecewise regression was used to predict change from OLE baseline over 6mo.ResultsA total of 105 subjects from the core study have undergone an amyloid PET at OLE baseline with florbetatpir (mean duration off drug: ∼24mo; min=9.2mo; max=59.7mo). OLE baseline SUVr for those with longitudinal OLE assessments in the core phase for placebo, 10mg/kg‐monthly, and 10mg/kg‐biweekly were 1.46 (N=5), 1.21 (N=7), and 1.09 (N=8), respectively. Mean PET SUVr change from OLE baseline at 6mo was ‐0.26 (N=5), ‐0.09 (N=7), and ‐0.01 (N=8), with predicted slopes for 6 mo change of ‐0.042, ‐0.012, and ‐0.005 for subjects treated in the core phase with placebo, 10mg/kg‐monthly, and 10mg/kg‐biweekly, respectively. Three (3) of 5 subjects in the core placebo group became amyloid negative by visual read at 3mo treatment in OLE, with 5/5 subjects amyloid negative at 6mo.ConclusionsIn this preliminary analysis, 10 mg/kg‐biweekly BAN2401‐mediated amyloid reduction in the OLE was dependent on core treatment/SUVr at OLE baseline, and was apparent by 3mo with amyloid negativity achieved at 6mo (visual read) in placebo‐treated subjects from the core. Updated data will be presented as available.
Quantitative susceptibility mapping of substantia nigra in dementia with Lewy bodies
Authors: Chen Qin , Boeve Bradley F. , Arani Arvin , Senjem Matthew L. , Jack Clifford R. , Przybelski Scott A. , Lesnick Timothy G. , Fields Julie A. , Schwarz Christopher G. , Gunter Jeffrey L. , Graff‐Radford Jonathan , Savica Rodolfo , Knopman David S. , Ferman Tanis J. , Graff‐Radford Neill R. , Petersen Ronald C. , Kantarci Kejal 
Published: December 2020

AbstractBackgroundNeurodegeneration of the substantia nigra in dementia with Lewy bodies is associated with iron deposition, which increases the magnetic susceptibility of the substantia nigra on MRI. The objective of this study was to measure the magnetic susceptibility of the substantia nigra in patients with dementia with Lewy bodies (DLB) and patients with mild cognitive impairment with at least one core feature of DLB (MCI‐DLB) compared to cognitively unimpaired controls (CU) by quantitative susceptibility mapping (QSM).MethodWe studied clinically diagnosed patients with DLB (n=36), patients with MCI‐DLB (n=16), and age‐, gender‐matched CU (n=104) in a case‐control study. MR images used for QSM were performed on 3T MRI with a multi‐echo (5 echoes) 3D gradient recalled echo sequence with a bipolar‐readout. Three‐dimensional regions of interest (ROIs) of bilateral substantia nigra, based on the DISTAL atlas, were propagated from the Mayo Clinic Adult Lifespan Template (MCALT) to each subject’s T1 image using ANTs nonlinear registration. The mean susceptibility values of the substantia nigra were extracted by aligning each subjects QSM image to their T1 image and corresponding ROIs with a 6 DOF rigid registration.ResultThe mean susceptibility values of the substantia nigra bilaterally was 0.110 ± 0.026 for DLB, 0.099 ± 0.028 for MCI‐DLB and 0.091 ± 0.025 for controls (Figure 1). No difference was found across the mean susceptibility from left, right and combined bilateral substantia nigra. Compared to controls, patients with DLB had higher susceptibility in the substantia nigra (p<0.001). The susceptibility of substantia nigra showed an increasing trend from controls to MCI‐DLB and to DLB (p<0.001). There was no correlation between the Unified Parkinson's Disease Rating Scale (UPDRS) and the mean susceptibility in the substantia nigra in patients with MCI‐DLB and DLB (r=0.03; p=0.82).ConclusionQuantitative susceptibility mapping is sensitive to the increased magnetic susceptibility due to higher iron content in the substantia nigra in DLB. The trend of increasing susceptibility from CU to MCI‐DLB and to DLB suggests that iron deposition in the substantia nigra starts to increase as early as the prodromal stage in DLB and continues to increase as the disease progresses independent of the severity of Parkinsonism.
Computer device and phone utilization trends among a cohort of older adults
Authors: Bouranis Nicole , Gothard Sarah , Mattek Nora , Kaye Jeffrey 
Published: December 2020

AbstractBackgroundSurveys assessing rates of technology adaptation among older adults are cross‐sectional in nature, but few studies assess usage among a single older adult cohort. This study analyzes rates of computer device utilization among community‐dwelling older adults age 62 and older who are enrolled in longitudinal technology studies at the Oregon Center for Aging and Technology in Portland, Oregon.MethodWe reviewed four years of data (2016‐2019) from a cohort of 113 community‐dwelling individuals age 62 and older and two years of data (2018‐2019) for 158 community‐dwelling low‐income individuals, veterans and spouses of veterans age 62 and older enrolled in a different study. We identified trends in computer device and phone ownership and utilization. Basic descriptive statistics were analyzed.ResultAmong the first cohort there was an increase in the percentage of older adults who own multiple devices (59.7%, up from 37.2%) and a decrease of those who use a desktop computer as their primary device (16.9%, down from 45.2%) between 2016 and 2019. The percentage of participants who own a landline decreased (75.3%, down from 86.7%) while those who own a cell phone increased (84.4%, up from 71.7%). The percentage of participants who do not use a cell phone decreased (8.3%, down from 24.8%). There was an increase in the percentage of participants who own a cell phone with internet access (64.1%, up from 48.1%) and text messaging capabilities (64.1%, up from 43.2%). Among the second cohort, the percentage of people who use desktops, laptop, and smartphones remained constant, but there was an increase in tablet users (37.3%, up from 21.5%) between 2018 and 2019.ConclusionThese findings indicate a shift from using landlines and desktop computers and an increase in the use of smartphones and tablets among older adults. The majority of older adults own multiple devices and use mobile devices. These findings have implications for communication styles, application development and data collection in studies that analyze computer usage among older adults. Future analyses will include data from the 2020 survey and identify and compare trends among demographic groups, including age, gender, locality, veteran status, and socioeconomic status.