bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial pathway‐specific Alzheimer’s disease polygenic risk scores are associated with increased risk of Alzheimer’s disease
Authors: Paliwal Devashi , Andrews Shea J , Easteal Simon , McInerney Timothy 
Published: December 2020

AbstractBackgroundIncreasing evidence from genetic, biomolecular, cell biology, clinical endophenotypes, animal, and epidemiological studies suggest a potential role of mitochondria in Alzheimer’s disease (AD). Here we investigate the association of AD‐associated polygenic risk scores (PRS) composed of genetic variation within genes associated with known mitochondrial pathways (pathway‐PRS) with AD risk.MethodUsing data from the Alzheimer’s Disease Neuroimaging Initiative we constructed mitochondrial pathways‐specific AD PRS in 698 non‐Hispanic whites (AD = 463, Controls = 235) and investigated their association with AD. We constructed thirteen PRS in total – a whole genome PRS, a nuclear‐encoded mitochondrial genome (nMT‐DNA) geneset (comprising of all nMT‐genes) and eleven mitochondrial pathways based on genesets obtained from the Molecular signatures database (MsigDB). PRS were constructed using the ‘standard weighted allele’ method, with SNPs weighted by their effect size from a GWAS of clinical AD. P‐value thresholding (p ≤ 0.5) and LD clumping for the whole genome and set‐based LD clumping for pathway‐specific PRS (250 kb window, r2 < 0.1) was performed. A competitive empirical p‐value approach was applied as a correction for the multiple testing burden. Finally, logistic regression was used to assess the association of pathway‐PRS with AD, adjusting for age, sex, APOE, and ancestry.ResultWe found that nMT‐DNA PRS was significantly associated with AD risk (OR: 2.12 [95% Cl: 1.77, 2.57], p < 0.001). In pathway analyses, three biological pathways showed significant association with increased AD risk: (i) cellular response to oxidative stress (OR: 2.11 [95% Cl: 1.75, 2.56], p < 0.001); (ii) mitochondrial transport (OR: 1.89 [95% Cl: 1.58, 2.28], p < 0.001); and (iii) Hallmark oxidative phosphorylation and respiratory chain (OR: 1.27 [95% Cl: 1.08, 1.49], p < 0.05).ConclusionOur findings suggests that higher baseline genetic risk conferred by AD‐associated SNPs within genes involved in three pathways ‐ cellular response to oxidative stress, mitochondrial transport, and oxidative phosphorylation significantly contributes to higher AD risk. This is the first study to demonstrate these findings and suggests the therapeutic potential of targeting these pathways. Further investigations are required to validate and establish the causal role of these pathways in AD pathology.
Effect of combined WeChat video and comprehensive medical therapy on severe COVID‐19 with moderate Alzheimer's disease: A case report
Authors: Zhang Fengxia , Lu Yinshan , Hu Jun , Hu Mengting , Ma Siliang , Zhu Shanshan 
Published: December 2020

AbstractObjectiveWe present a case report of recovery from severe COVID ‐ 19 (novel coronavirus 2019) in a patient with cognitive decline (84‐year old, female), behavioral and psychiatric symptoms, hip arthroplasty, sacroiliac decubital necrosis, cachexia, after comprehensive therapy.BackgroundBecause of cognitive and behavioral disorders, patients with Alzheimer’s disease have poor coordination of treatment especially in an unfamiliar environment. Communicating with close family members through WeChat video can relieve patients' anxiety and other mental symptoms, leading to better cooperating with drug treatment and nasal feeding diet.MethodsPatient received 1 hour daily WeChat video communication with her son at isolation ward, including psychological comfort, care and positive words. The WeChat video communication were last for 4 weeks, during this time, the elderly patient was also treated with methylprednisolone (for 5 days), immunoglobulin (for 5 days), ulinastatin, thymus methoxide (for twice a week), acetylcysteine, antibiotics, low molecular weight heparin, probiotics, nutrition and other symptomatic support therapy.ResultsBefore WeChat video communication about 4 weeks, the patient refused medical treatment, consisting of extraction of infusion set and removal of gastric tube, which greatly affects the treatment of drugs and the nutritional intake of patients; and the state of the patient’s condition became even worse. However, after 4 weeks WeChat video communication, the patient showed a significant improvement in the Mini‐mental state examination scores from 8 to 12 (Education: illiterate) and in the Neuropsychiatric questionnaire scores from 35 to 10. Besides, after 4 weeks WeChat video communication and comprehensive therapy, the patient’s pneumonia improved significantly and the nucleic acid test turned negative.ConclusionsWeChat video communication may be a promising noninvasive approach for patients with Alzheimer’s Disease, which may help alleviate neuropsychiatric behavioral symptoms and can be more cooperative with medical workers.
Chimera traumatic brain injury induces tauopathy in the RTG4510 mice
Authors: Cheng Wai Hang , Wilkinson Anna , Cheung Honor , Barron Carlos J , Cripton Peter A , Wellington Cheryl L 
Published: December 2020

AbstractBackgroundTraumatic brain injury (TBI) is a major cause of death and disabilities in developed countries. We have previously designed an animal TBI model called Closed Head Injury Model of Engineered Rotational Acceleration (CHIMERA). CHIMERA has the advantage of inducing precise non‐surgical head impacts without restricting head motion, thus inducing TBI relevant to a real‐world scenario. Using CHIMERA, we showed that repetitive mild TBI in a mouse model of amyloidosis led to neuropathological changes including neuroinflammation, fear memory deficits, and accumulation of soluble high molecular weight Aβ oligo/fibril. In the current study, we aim to study if CHIMERA TBI exacerbates tau pathologies, by inducing moderate/severe TBI (msTBI) to rTg4510 mice.Method4‐mo male rTg4510 mice were used for this study. For the test group, a single msTBI TBI was induced at 4.0 J impact energy, with CHIMERA interface. For sham group, the animals received only anesthesia but no impact. 8 out of 13 animals survived the moderate/severe TBI procedure (38% mortality). The surviving animals were kept for 2‐mo, and the brain tissues were harvested for analysis using immunohistochemistry and Western blotting for multiple tau epitopes, neuroinflammation, and axonal injury. Blood samples were collected biweekly for biomarker analysis.ResultTBI animals showed a significant increase duration of loss of righting. Histological analyses indicated significant microgliosis (Iba1) and axonal injury (Neurosilver) at white matter (optic tract), but no significant change in neuronal number (NeuN), astrocytes (GFAP), endothelial cells (CD31), or blood brain barrier integrity (IgG). There was a significant increase of one p‐tau epitope (PHF1), but not others (CP13, AT8, MC1, RZ3, or DA9). TBI also reduced the level of an inactive form of GSK‐3b (p‐GSK‐3b at S9). Interestingly, TBI animals showed a significant increase of P62 signals particularly at hippocampus, suggesting impaired autophagy.ConclusionOur current findings suggest a single msTBI is sufficient to induce p‐tau in rTg4510 mice, possibly through a reduction of inactive GSK‐3b. In addition, increased P62 signals may indicate impaired autophagy, which may lead to increased accumulation of neurodegenerative proteins at a later stage. More work has to be done to confirm long‐term tau and autophagy changes after TBI.
The effects of increasing dementia knowledge on alleviating stigmatizing attitudes among elementary school students in Taiwan
Authors: Kuo Ching‐Yi 
Published: December 2020

AbstractObjectivesBased on the published research that disseminating dementia knowledge reduced stigmatizing attitude toward persons with dementia, this project is going to carry out the research results into dementia care practice through disseminating dementia knowledge to school age children in Taiwan.BackgroundStigma attached to dementia is a common theme across cultures as reported in the literature. Despite retaining cultural adherence to filial piety, which includes respect for the aging, stigmatizing attitudes toward dementia remain a hindrance to timely diagnosis and services utilization in Asian communities (Chiu et al., 2014). Community education about dementia may be helpful to lower this barrier to early detection and intervention (Cheng et al., 2011; Devlin et al., 2007). Most studies focus on the impact of disseminating knowledge to adults. Little is known regarding its effects of increasing dementia knowledge in school age children on combating dementia stigma and mental health issues in aging populations in Asia.MethodsA Quasi‐experimental design will be employed in this study. The third and fourth graders in selected elementary schools in southern Taiwan will be administered a questionnaire eliciting current understanding of dementia prior to a power point introducing dementia, and followed by the repetition of the questionnaire for a pre and post‐ test elicitation and identification of concepts grasped and concepts missed.ResultsThis is an on‐going research project and the results are in process. Implications: Young children often help older family members care for older persons with dementia who are home‐bound; they may be more empathetic if they know more about the condition affecting their relative.
Self‐administered gerocognitive examination for the early detection of cognitive impairment at primary care provider visits
Authors: Scharre Douglas W. , Vrettos Nicole E , Nagaraja Haikady N 
Published: December 2020

AbstractBackgroundCurrently 50%‐75% of dementia cases are undiagnosed, untreated, and unmanaged. The average diagnosis time is 32 months after symptom onset. Primary Care Providers (PCP) are critical for case finding of cognitive impairment to provide management, referrals, and treatments. Cognitive assessments are time consuming and difficult to incorporate into time‐limited PCP visits. Self‐Administered Gerocognitive Examination (SAGE) is a reliable, valid, pen and paper, cognitive assessment that is easily incorporated into PCP visits without needing staff administrators. PCP visits with and without SAGE were compared to determine differences in diagnoses, treatment, and management of new cognitive disorders.MethodSubjects without diagnosed cognitive disorders and with acceptable reading, vision and English language comprehension, aged 65‐89 who completed a non‐acute office visit were enrolled. Two physically separate PCP offices conducted their visits as they normally would for 100 consecutive subjects each. One office, in an additional 100 subjects, used SAGE and asked an informant, if available, to ascertain if the subject experienced significant cognitive change (based on PCP opinion) over the previous year. Chart reviews were conducted 60 days from the initial visit. One‐way analysis of variance and Fisher exact tests were used to compare the groups and outcomes.ResultThere were no differences in age, race, or gender between the intervention (n=100) and control (n=200) subgroups. When SAGE was utilized, the PCP documented detection of new cognitive conditions/concerns six times (9% versus 1.5%) as often (p=0.003). In the intervention group, detection rate was nearly 4‐fold higher when SAGE scores were in the cognitively impaired range (p=0.034). New cognitive conditions/concerns were recorded by the PCP in 31% of 16 cases where informants noticed cognitive changes and in none of 22 where informants noted no changes (p=0.009). Combining low SAGE scores and informant concerns, those with one of the factors were 15‐fold as likely to have new cognitive conditions/concerns documented (p=0.007).ConclusionSAGE was easily incorporated into PCP visits and resulted in significantly increased awareness of new cognitive conditions/concerns leading to new diagnoses, treatment, and management changes, which increased 4‐fold when combined with informant reports of significant cognitive declines over a year.
Emerge and Engage topline results: Phase 3 studies of aducanumab in early Alzheimer’s disease
Authors: Haeberlein Samantha Budd , von Hehn Christian , Tian Ying , Chalkias Spyros , Muralidharan Kumar Kandadi , Chen Tianle , Wu Shuang , Skordos LeAnne , Nisenbaum Laura , Rajagovindan Raj , Dent Gersham , Harrison Katie , Nestorov Ivan , Zhu Ying , Mallinckrodt Craig , Sandrock Alfred 
Published: December 2020

AbstractBackgroundAducanumab is a human monoclonal antibody that selectively targets aggregated forms of Aβ, including soluble oligomers and insoluble fibrils. EMERGE and ENGAGE are two 18‐month, randomized, double‐blind, placebo‐controlled, global Phase 3 studies with identical design that evaluated the efficacy and safety of aducanumab in patients aged 50–85 years with early Alzheimer’s disease (MCI due to AD or mild AD dementia).MethodKey inclusion criteria included positive amyloid PET, MMSE score of 24–30, CDR Global score of 0.5, and an RBANS‐DMI score ≤85. During the 18‐month placebo‐controlled period, patients were randomized 1:1:1 to low‐dose aducanumab, high‐dose aducanumab, or placebo, administered via IV infusion every 4 weeks. The primary endpoint for EMERGE and ENGAGE was change from baseline at Week 78 on the CDR‐SB. Secondary endpoints included change from baseline on MMSE, ADAS‐Cog13, and ADCS‐ADL‐MCI.ResultFollowing pre‐planned futility analysis, analysis of the data from the final database lock showed that EMERGE met its primary endpoint, based on the pre‐specified statistical analysis plan. Patients treated with high dose aducanumab showed a significant reduction of clinical decline from baseline in CDR‐SB scores at 78 weeks (22% versus placebo, P = 0.01). ENGAGE did not meet its primary endpoint. However, data from patients in ENGAGE who achieved sufficient exposure to high dose aducanumab supported the findings of EMERGE.ConclusionEMERGE met its primary endpoint, based on the pre‐specified statistical analysis plan. Data from a subset of patients in ENGAGE support the results of EMERGE. The safety and tolerability profile of aducanumab in EMERGE and ENGAGE was consistent with previous studies of aducanumab.
ATP as a catalyst for amyloid fibrillation of tau protein
Authors: Heo Chae Eun , Kim Hugh Inkon 
Published: December 2020

AbstractBackgroundIntracellular tau protein tangle is a hallmark of various neurodegenerative diseases, which include Alzheimer’s disease (AD). For this reason, characterizing the physiological factors associated with tau aggregation and the aggregation mechanism has been considered crucial for understanding tau pathology. Recent evidence implies that (i) intracellular ATP level may be dysregulated and (ii) the increased ATP level may have an influence on the tau aggregation. However, the effects of ATP on tau fibrillation and its mechanistic details are not fully elucidated.MethodsFor characterizing K18 fibrillation mechanism catalysed by ATP, we performed multiple biophysical experiments such as thioflavin assays, circular dichroism, small‐angle X‐ray scattering, and native mass spectrometry. We further measured cellular ATP amount in presence of TNFα, and intracellular tau aggregation was examined by bimolecular fluorescence complementation experiments.ResultsHerein, we report the catalytic role of ATP and its mechanistic details in tau aggregation at a molecular level for the first time. Using multiple approaches including solution small angle X‐ray scattering (SAXS), native mass spectrometry (MS) and molecular dynamics (MD) simulations, we observed that nonspecific electrostatic interactions between negatively charged triphosphate moiety in ATP and basic residues in tau K18 (i.e. four‐repeat domain of tau) direct the dimerization of K18 by charge neutralization of the protein in the early stage of the aggregation. We observed that ATP was excluded in the late stage of fibrillation and acted to accelerate K18 fibrillation even at lower stoichiometric ratios for the charge neutralization, indicating that ATP acted as a catalyst for K18 fibrillation. Moreover, our bimolecular fluorescence complementation (BiFC) and immunoblotting (IB) experiments suggested a correlation between ATP dyshomeostasis and tau aggregation in cellular environment.ConclusionWe believe that our observations would provide valuable insights into the mechanism of tau aggregation and the importance of ATP in tauopathies.
Psychotherapeutic interventions in individuals at risk for Alzheimer’s dementia: A systematic review
Authors: Rostamzadeh Ayda , Kahlert Anna , Kalthegener Franziska , Jessen Frank 
Published: December 2020

AbstractBackgroundExpanding technologies of early detection of Alzheimer’s disease (AD) allow to identify individuals at‐risk in very early and asymptomatic disease stages. Neuropsychiatric symptoms, such as anxiety and depression, are common in in the course of AD and may be clinically observed many years before the onset of significant cognitive symptoms. To date, therapeutic interventions for AD focus on pharmacological and non‐pharmacological strategies. However, despite good evidence for psychotherapy in late‐life depression, evidence for such therapeutic options in the course of cognitive decline related to AD is sparse.MethodA systematic review was conducted in PUBMED, PsycINFO and Web of Science to summarize the state of evidence on psychotherapeutic‐psychoeducational interventions for individuals at‐risk for Alzheimer’s dementia. Eligible articles needed to apply a manualized and standardized psychotherapeutic or psychotherapeutic‐psychoeducational intervention administered by trained professionals for individuals with subjective cognitive decline (SCD) or mild cognitive impairment (MCI).ResultThe literature search yielded 35 studies that were included in this narrative summery. The data illustrates heterogeneous therapeutic approaches with mostly small sample sizes of study participants and short follow‐up monitoring. There is evidence that interventions have an antidepressive effect and a positive impact on disease acceptance, including positive effects on life quality. However, specific therapeutic determinants of efficacy have not been identified to date.ConclusionThis review underlines the need of specific psychotherapeutic‐psychoeducational therapeutic approaches for individuals at‐risk of Alzheimer’s dementia, particularly in terms of early interventions aiming at improving well‐being, mental health and quality of life in the course of the neurodegenerative disease. One paramount challenge is the modification of psychotherapeutic techniques according to the different stages of cognitive decline in the course of AD, which is needed to be sensitive to the individual needs and preferences.
Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in Alzheimer's disease patients
Authors: Llorens‐Martin María 
Published: December 2020

AbstractBackgroundMemory impairment in Alzheimer’s Disease (AD) can be attributed to a significant decline in the functioning of the hippocampal formation, a brain region crucial for learning and memory. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely the addition of new neurons throughout lifetime. While synapse loss and consequent death of mature neurons may be responsible for much of the hippocampal malfunctioning in AD, studies in mice suggest that the disease could also target the generation of new neurons – or adult hippocampal neurogenesis (AHN). Nonetheless, direct evidence of AHN in humans has remained elusive.MethodWe have developed a novel reliable method to study AHN in post‐mortem human brain samples. We revisited the occurrence of continued neurogenesis in the human hippocampus of aged healthy subjects and AD patients, using brain material obtained under tightly controlled conditions and applying state‐of‐the‐art tissue processing methods.ResultWe observe a dynamic population of immature neurons in the human dentate gyrus at least until the tenth decade of life. Slight variations in histological and tissue processing methodologies have a great impact on the study of AHN in the human DG. AHN is dramatically impaired in AD patients.ConclusionOur data evidence that AHN is a robust phenomenon in the human brain, and points to impaired neurogenesis as a potentially relevant mechanism underlying AD that may be amenable to novel therapeutic strategies.
Oligomeric amyloid‐beta 1–42 inhibits antigen presentation
Authors: Gericke Christoph , Mallone Anna , Engelhardt Britta , Nitsch Roger M , Ferretti Maria Teresa 
Published: December 2020

AbstractBackgroundBeyond microglia, the involvement of other immune cell types and immune functions in Alzheimer’s disease (AD) is not well understood. Here, we investigated the potential immunomodulatory properties in vivo and in vitro of oligomeric species of beta‐amyloid‐peptide (Aβ) on microglia and other putative antigen presenting cells (APCs).MethodsWe used multicolour flow‐cytometry, confocal microscopy and MSD biochemical analysis to characterise amyloid deposition and brain immunephenotype of APP‐PS1‐dE9 mice of 3, 6, 12 and 20 months of age. Next, we applied a customised in vitro systems (using OT‐II ovalbumin‐specific transgenic CD4+ T cells and ovalbumin as antigen) to study the effect of recombinant, oligomeric preparations of human Aβ1‐42 on antigen presentation by primary dendritic cells. Finally, via RNAseq, we investigated the effect of oligomeric Aβ 1‐42 on the transcriptome of primary dendritic cells.ResultsWe show that, in the APP‐PS1‐dE9 mouse model, the deposition of the first beta‐amyloid plaques at 6 months of age is accompanied by a significant reduction in MHC class II surface levels on brain APCs, suggesting impaired antigen presentation capability induced by beta‐amyloid. This hypothesis was confirmed by our in vitro experiments, using the prototypical antigen presenting cells, primary bone‐marrow derived dendritic cells. Incubation with a preparation containing various forms of oligomeric Aβ1‐42 (but not of scrambled peptide) inhibited antigen presentation by primary dendritic cells, in a dose‐dependent manner. Finally, we found that human oligomeric Aβ 1‐42 alters the transcription of key immune mediators in dendritic cells, including cytokines, chemokines and adhesion molecules.ConclusionsOur results suggest that, beyond their well‐characterised neurotoxic effects, oligomeric forms of Aβ 1‐42 exert hitherto unknown immunomodulatory properties. By inhibiting antigen presentation by cerebral APCs, Aβ 1‐42 might interfere with physiological brain immune surveillance, thus facilitating Aβ 1‐42 and tau spreading in AD.