bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is there still a rationale for BACE‐inhibition in Alzheimer’s disease? A quantitative systems pharmacology analysis
Authors: Geerts Hugo , Spiros Athan 
Published: December 2020

AbstractBackgroundSo far all clinical trials with BACE inhibitors have failed to generate a cognitive benefit and many have demonstrated a reversible cognitive worsening. Lack of understanding of the biological reason for this clinical effect hampers the study of which patient subpopulations might still benefit from lower levels of target exposure.MethodWe present computer‐based Quantitative Systems Pharmacology (QSP) simulations of cognitive ADAS‐Cog readouts to identify relevant PD‐PD interactions between comedications, common genotype variants, disease state and amyloid modulating agents, in particular BACE inhibition. This platform is based on a computer model of biophysically realistic neuronal cortical microcircuit with 35 CNS targets and calibrated for ADAS‐Cog. Long and short amyloid peptides affect glutamate and nAChR neurotransmission differentially that reproduces three clinical datasets. APOE, COMTVal158Met and 5‐HTTLPR rs23351 genotype are introduced using human imaging studies.ResultThe 5‐HTTLPR rs23351 L/L genotype defines a set of responders that are more resilient to amyloid increase with a 3‐4 point smaller worsening on ADAS‐Cog. Differential interaction with tau pathology can further reduce the effect with up to a 0.5 point. When simulating 2 year BACE‐I treatment in MCI, the platform predicts a worsening of up to 3 points compared to baseline on ADAS‐Cog for subjects with 5‐HTTLPR s/s genotype and slow amyloid progression while placebo deteriorates only 2 points. Conversely, BACE‐I is anticipated to improve cognition by about 0.4 point compared to baseline in subjects with 5‐HTTLPR L/L genotype and fast amyloid progression with placebo deteriorating 0.1 point. Lower levels of target engagement slightly improve the effect of BACE‐I but only in subjects with already elevated amyloid baseline levels. This is likely because of the beneficial effect of low doses of short amyloid forms that are also reduced by BACE‐I.ConclusionQSP is a hypothesis‐generating engine based on mechanistic, integrative and quantitative modeling of pharmacological and biological data and is particular informative at the individual patient level. The platform explains the reversible worsening of cognition with high exposure levels of BACE‐I in prodromal AD. Further simulations suggest that BACE inhibition can have modest benefits at lower levels of target engagement and in well‐defined patient populations.
Which tau target to select for drug discovery? Insights from an advanced quantitative systems pharmacology model
Authors: Spiros Athan , Geerts Hugo 
Published: December 2020

AbstractBackgroundAlthough tau pathology is a major driver of Alzheimer’s Disease (AD) pathology and remains a very interesting target, the mere complexity of tau biology significantly hampers the identification and validation of the most impactful target.MethodWe developed a Quantitative Systems Pharmacology (QSP) platform integrating diverse preclinical and clinical knowledge about tau biology processes in an actionable computer model. The computer model includes tau species diversity, activity‐dependent tau secretion, tau binding to HSPG at the synaptic cleft and along the axonal membrane following a diffusion gradient and subsequent internalization, slow axonal transport over microtubules, intracellular degradation and templating of monomeric tau by seed‐competent tau into aggregates and insoluble Neurofibrillary Tangles. Polysynaptic progression is implemented by modeling secretion into the second synapse and subsequent uptake in the second axon.ResultThe platform was calibrated with preclinical experiments from in‐vitro cellular assays and injected brain extract in transgene mouse models. The model reproduced experimentally determined in vivo monomeric tau progression speeds at 0.25 mm/day; the rate of oligomerization was estimated to not less than 58 nM/year and the presence of each additional synapse reduces the peak of oligomeric tau about tenfold. We modified the platform to reproduce clinical AD pathology, based on stationary levels of seed‐competent tau from experimental measures in post‐mortem brains at diverse Braak stages. Using sensitivity analysis on this in silico platform we rank ordered various possible therapeutic interventions on the accumulation of seed‐competent tau in distal regions such as passive immunization using antibodies with different epitopes on the tau protein, reduced binding to HSPG, reduction of oligomerization, decreased secretion and increased degradation and identified interesting synergistic interactions. Interestingly this order was not the same as for the simulated conditions of injected brain extract in mouse models, possible identifying another problem of translationability.ConclusionAdvanced computer modeling allows to ‘humanize’ preclinical experiments and can be an additional tool to support innovative disease modifying tauopathy R&D projects.
Assessing the longitudinal relationship between theta‐gamma coupling and working memory performance
Authors: Brooks Heather J. , Wang Wei , Kumar Sanjeev , Goodman Michelle S. , Zomorrodi Reza , Blumberger Daniel M. , Daskalakis Zafiris J. , Mulsant Benoit H. , Voineskos Aristotle N. , Rajji Tarek K. 
Published: December 2020

AbstractBackgroundIndividuals with a history of depression exhibit cognitive deficits and are at high‐risk for developing dementia. In particular, they show deficits in prefrontal cortical function, e.g. executive functioning and working memory. Theta‐gamma coupling (TGC) is a neurophysiologic marker of prefrontal cortical function. In cross‐sectional studies, TGC is associated with performance on several prefrontal cortex dependent cognitive tasks. Thus, it is a promising target for interventions to enhance cognition and possibly prevent cognitive decline. However, the relationship between change in TGC and change in cognitive performance is not yet characterized. The aim of this study is to determine whether change in TGC over repeated assessments is associated with change in working memory performance at these assessments.MethodsTwenty‐seven older individuals with a history of depression (mean age = 66.18, SD = 5.43) completed the N‐back, a working memory task, at three time‐points (T0, T1 (2 weeks post T0) and T2 (90 days post T0). TGC was recorded using electroencephalography during the N‐back task. Change in TGC and N‐back performance among the three time‐points was calculated for each participant. Regression analyses were run, with change in N‐back dprime as the dependent variable, change in TGC as the independent variable, and time‐point as the fixed factor. To control for any effect of change in theta and gamma oscillations, we included also changes in theta and gamma powers as covariates.ResultsWe found a positive association between change in TGC and change in N‐back dprime (B = 96.5, p = 0.006), but no association between change in theta (B = 7.66e‐6, p = 0.28) or gamma (B = 1.96E‐6, p = 0.93) power. There was also no effect of time‐point (B = ‐0.32, p = 0.07), and no interaction between time‐point and TGC (B = ‐67.17, p = 0.23).ConclusionOur results suggest enhancing TGC could enhance working memory performance irrespective of whether this enhancement happens over days or weeks. They also further support the use of TGC as a target for intervention to enhance prefrontal cortical function in individuals at high‐risk for cognitive decline, and potentially prevent decline and dementia.
Genetic analysis of biobank data: Familial history aggregation‐based tests (FHAT) with application to Alzheimer's disease
Authors: Wang Yanbing , Chen Han , Peloso Gina M. , Destefano Anita L. , Dupuis Josée 
Published: December 2020

AbstractBackgroundBiobanks provide great resources for genetic association analysis. To increase power of genetic association analysis, we propose a novel approach to exploit family history of disease that is often available in biobanks. While methods have been proposed to incorporate family history in single variant analysis, methods to incorporate this information in gene‐based tests, such as the Sequence kernel association test (SKAT), are not available. The goal of this project is to develop a familial history aggregation‐based test (FHAT) to improve power to detect rare variant associations in gene‐based tests, and to apply this method to detect genes associated with Alzheimer’s Disease (AD).MethodWe assume that participants’ genotypes, and phenotypes of participants’ and their relatives, such as parents, are available from a large cohort. We first assess the association between participants’ genotypes and their phenotypes. Then we evaluate the association between participants’ genotypes and a set of relatives’ disease status conditional on the participants’ disease status. We use a weighted meta‐analysis to combing the score statistics from probands and their relatives. We evaluate the FHAT in simulations, and we apply our novel method to detect associations of gene regions with Alzheimer’s Disease (AD) in the UK Biobank data incorporating parental disease history.ResultOur simulation results showed that the type I error of FHAT is well controlled with disease prevalence of 10% and 20%. We obtained corrected type I error rate at various alpha levels using 10,000 simulation replicates with a sample size of 5,000. Out of seven genes previously implicated in AD susceptibility, six showed evidence of association using FHAT in UK Biobank. These six genes had improved significance after incorporating parental phenotype information.ConclusionWe proposed a novel approach to include family history, as is often available from medical charts, and showed improved power to detect aggregates of rare variant genetic associations with AD in large cohorts or biobanks.
Best practices for rehabilitation for older adults with dementia
Authors: McGilton Katherine S , Vellani Shirin , Zheng Nancy , Wang Daniel , Yeung Lydia , Escrig‐Pinol Astrid 
Published: December 2020

AbstractBackground and ObjectivesDespite emerging evidence that older adults with cognitive impairment including those with dementia can be rehabilitated following a hip fracture, there is a paucity of research on strategies staff use and the support required to effectively rehabilitate this cohort. This qualitative study explores healthcare professionals’ perspectives of providing rehabilitation for older adults with cognitive impairment.MethodsAn in‐depth qualitative exploration of one site selected for its excellent outcomes in rehabilitation of older adults with cognitive impairment. Sixteen healthcare professionals with various backgrounds (occupational therapists, nurses, physiotherapists, and one social worker) were purposively sampled using a maximum diversity sampling strategy. Four focus groups were conducted to explore the experiences of professionals providing rehabilitation to this population. A hybrid inductive‐deductive approach was used to analyze the data.ResultsParticipating healthcare professionals acknowledged that older adults with cognitive impairment deserved a chance at inpatient rehabilitation and favourable outcomes were achievable; however, their knowledge, skills, and attitudes required reframing. Analysis identified three essential components to rehabilitating this cohort: i) staff’s need for education, mentorship, and support to facilitate positive outcomes for persons with dementia, as well as for the healthcare team ; ii) the importance of knowing each patient to individualize rehabilitation approaches that encourages participation in rehabilitation; and iii) the need for care partner involvement by making contributions to rehabilitation care while in the hospital as well as continue to support recovery when they returned home, with support and education from the rehabilitation staff.ConclusionsRehabilitation of older adults with cognitive impairment is achievable and healthcare professionals can learn how to modify their practices to achieve positive patient outcomes. However, support and involvement of management to help create a vision for success is essential.
Are life events differentially associated with dementia risk by gender?
Authors: Kim Alice J. , Beam Christopher R. 
Published: December 2020

AbstractBackgroundGender differences in the association between life events and dementia have rarely been explored. Mixed findings exist regarding the role of gender in stress exposure, generation, and reactivity. Gender may affect the pathways through which different life events correlate with dementia risk. We hypothesized that life events would differentially associate with dementia risk by gender via both familial confounding and causal processes in a sample of older Swedish adults.MethodWe analyzed data from 885 twin families (>= 50 years; 57.81% women; N = 1,742) in the Swedish Adoption/Twin Study of Aging. Six life event domains were constructed from variables measuring ever‐occurrence of life events through 1990 (general loss, negative child events, self‐illness, family strife, negative spousal events, positive life events). Models were run separately by gender. Dementia diagnoses occurring after 1990 were made via clinical assessment and national registry linkage (15.06% diagnosed). Biometric regression models were used to evaluate confounding and quasi‐causal effects of life events on dementia status.ResultFor women, the total effect of life events on dementia was detected for general loss (B = 0.19, SE = 0.06, p = .001); for men, family strife was associated with dementia (B = 0.22, SE = 0.10, p = .027). After adjusting for shared genetic and environmental factors, there were no associations between these life events and dementia, indicating little evidence for quasi‐causal effects. The associations were best explained by familial confounding.ConclusionGender differences were found in the association between life events and dementia such that general loss in women and family strife in men were predictors of dementia risk. Familial confounding explained these associations. Rather than attempting to minimize dementia incidence by mitigating impacts of life events, future research could examine the kinds of genotypes and environments that increase the risk of experiencing both negative life events and dementia by gender (e.g., for men, social environments inducing hostility may engender risk of both family strife and dementia). By preventing or intervening in impacts of these mechanisms, it may be possible to decrease the incidence of both negative life events and dementia.
CSF p‐Tau/AΒ40 ratio adjusts for the variance of CSF production and predicts brain tau accumulation in Alzheimer’s disease
Authors: Guo Tengfei , Korman Deniz , Shaw Leslie M. , Trojanowski John Q , Jagust William J. , Landau Susan M. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2020

AbstractBackgroundAlzheimer’s‐related tauopathy can be measured with CSF p‐Tau and tau PET, but the associations between them as well as in relation to prospective tau PET and cognition are not well understood. Furthermore, recent studies observed CSF p‐Tau is positively associated with CSF Aβ42 in the normal range, which presumably reflects individual differences in CSF production rather than pathology and adds noise to CSF p‐Tau measurements.MethodWe analyzed 345 participants with Aβ PET, 18F‐flortaucipir PET, and CSF measurements and from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). We observed that the use of a CSF p‐Tau/Aβ40 ratio to define CSF tauopathy reduced noise related to the presumably artifactual positive correlation between CSF p‐Tau and Aβ42 among Aβ PET‐ individuals (Fig.1). We investigated inter‐relationships associations between continuous and dichotomous Aβ PET, CSF p‐Tau/Aβ40 and flortaucipir as well as their prediction of subsequent flortaucipir increase and cognitive decline.ResultThe CSF p‐Tau/Aβ40 ratio also increased associations (relative to p‐Tau alone) with flortaucipir uptake across 34 Freesurfer‐defined cortical regions and amygdala. The highest CSF p‐Tau/Aβ40 associations were observed primarily in Temporal‐metaROI (Fig.2), so this region was selected to detect tau deposition for further analyses. Among Aβ+ participants (who drove all associations), Aβ PET was associated (p<0.001) with both CSF p‐Tau/Aβ40 and flortaucipir, and “abnormal CSF p‐Tau/Aβ40 only” were 4 times more prevalant (p<0.001) than “abnormal tau PET only” (Fig.3); in multivariate analyses predicting longitudinal flortaucipir and cognitive changes, CSF p‐Tau/Aβ40 was the strongest predictor of subsequent flortaucipir increase while flortaucipir was the strongest predictor of longitudinal cognitive change(Fig.4).ConclusionIn summary, we found that CSF p‐Tau/Aβ40 may reduce individual variability related to CSF production and improve the accuracy of tau detection in CSF. Our findings support a model in which Aβ PET positivity precedes abnormal CSF p‐Tau/Aβ40 and is subsequently followed by abnormal Temporal‐metaROI tau PET and cognitive decline. The temporal sequence of abnormal tau biomarker changes may provide insight into pathological changes that precede cognitive decline in Alzheimer’s disease.
Anemia, mild cognitive impairment, and dementia among rural‐dwelling older adults: A population‐based study
Authors: Jiang Ziying , Han Xiaolei , Wang Yongxiang , Hou Tingting , Cong Lin , Tang Shi , Qiu Chengxuan , Du Yifeng 
Published: December 2020

AbstractBackgroundEvidence has emerged that anemia is associated with cognitive impairment and dementia in older people. However, their relationship has been rarely examined among people in low‐ and middle‐income countries. We aimed to investigate the associations of anemia and hemoglobin with mild cognitive impairment (MCI) and dementia among rural‐dwelling Chinese older adults.MethodThis population‐based cross‐sectional study included 4,838 participants (age ≥65 years; 57.0% women) who were living in the rural communities in western Shandong Province. Data on demographics, lifestyle, clinical conditions, and cognitive function were collected through face‐to‐face interviews, physical examinations, and laboratory tests. Anemia was defined as hemoglobin levels <13 g/dl in men and <12 g/dl in women. Cognitive function was evaluated using the Mini‐Mental State Examination (MMSE) and neuropsychological test battery. We defined MCI using Petersen’s criteria and dementia according to the DSM‐IV criteria. Data were analyzed using multiple multinomial logistic and general linear regression models.ResultsThe overall prevalence of anemia was 20.1%, with the prevalence in people with normal cognition, MCI, and dementia being 19.2%, 22.8%, and 26.3%, respectively. Anemia was associated with a multiple‐adjusted odds ratio of 1.28 (95% CI: 1.04‐1.57) for MCI and 1.27 (95% CI: 0.87‐1.85) for dementia, and a multiple‐adjusted β‐coefficient of ‐0.60 (95% CI: ‐0.94 to ‐0.27) for MMSE score. Furthermore, a higher hemoglobin level was significantly associated with a greater C‐MMSE score (P for trend <0.001), but not with dementia.ConclusionsAnemia is associated with MCI and poor global cognitive performance, but not with dementia among rural‐dwelling Chinese older adults. Furthermore, a higher hemoglobin level is correlated with better cognitive performance.
Memory clinics as vehicles of research into dementia: The NACC example
Authors: Kukull Walter A. ,   National Alzheimer's Coordinating Center
Published: December 2020

AbstractBackgroundAlzheimer’s Disease Research Centers (ADRC) in the U.S, (N∼30) all enroll participants through similar clinical settings while applying a variety of active and passive recruitment methods. Thus, the voluntary enrollment and other characteristics of participants may resemble many referral‐based memory clinics not at ADRCs. In most cases however, the enrollee may not reflect the composition of the general population. When standardized clinical examination and data are applied across these independent case series valuable research data can be collected and both cognitively normal and cognitively impaired groups can be compared cross‐sectionally and longitudinally. The National Alzheimer’s Coordinating Center (NACC) receives, curates, stores and distributes the aggregate data to researchers on request. https://www.alz.washington.edu
MethodThe Uniform Data Set (UDS) was established in 2005 and applied in the clinics of the ADRCs. By December 2019, data from 42,022 participants were included; 6,056 of those participants had also died and completed standardized neuropathology exam and data collection. In addition 28,519 UDS participants have data on 2 or more clinic visits.ResultThis conglomerate “case series” is comprised of cognitively normal through demented individuals etiologically classified by underlying disease (e.g., AD, VaD, LBD et al). The value of common data collection is also highlighted as DNA are made available for genomic studies resulting in new genetic associations with disease. In addition the overall data have led researchers to produce some 500 research publications.ConclusionCombination of standardized data across independent memory clinic settings can lead to valuable research findings. While population‐based research is still most valuable for inferring the occurrence of various conditions in the community, these clinic‐based case‐series can provide valuable insights and comparisons to further our knowledge of Alzheimer’s disease and related dementias.
Dementia care practice: Integrating medical and caregiver support in a community‐based program
Authors: Templeton Virginia H , Noel Margaret A 
Published: December 2020

AbstractBackgroundDementia is among the most challenging health issues of our time and affects not only the person with dementia (PWD) but their family and other caregivers as well. With no cure or effective disease modifying treatments currently available, having affordable models of care that address caregiver needs as an integral part of medical management of the PWD is widely seen as essential to maximize quality of life, manage safety concerns, plan for future care needs and provide highest quality care. Data is limited regarding cost effectiveness or caregiver and PWD experience of such care models. MemoryCare is a community‐based, out‐patient nonprofit organization serving a largely rural area of western North Carolina for 19 years with a model of care that integrates education, training and support of caregivers with the medical care of persons with Alzheimer’s disease and other types of dementia. Caregivers participate in all clinic visits offering valuable history that informs medical decisions and, with the PWD, contribute to development of care plans. Alongside provision of medical care for the PWD, caregivers receive dementia education, training in behavioral management, resource matching and support specific to their individual needs. In 2019, 1,020 PWD and 3,372 caregivers enrolled at MemoryCare for care services as a supplement to primary care. For the past 5 years, observational data regarding hospitalization rates, 30‐day readmission rates, and ED utilization was collected for PWD seen in MemoryCare’s clinic setting who had been enrolled for at least one year and lived in a defined region where health care utilization could be independently confirmed. Caregiver satisfaction was assessed for the same 5‐year period through anonymous self‐report surveys. Data collected reveal high levels of caregiver satisfaction, increased dementia‐specific knowledge, and perceived improvement in ability to manage dementia‐related behaviors and lengthen time in the home setting. Data shows lower hospitalization and ED visit rates as well as reduced length of stay and readmission rates when compared to published norms. Findings suggest that inclusion of caregivers in the medical model of care for PWD may improve overall outcomes and warrant further study of integration of caregivers into clinical care models.