bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cerebrovascular amyloid angiopathy in bioengineered vessels is reduced by high‐density lipoprotein particles enriched in apolipoprotein E
Authors: Robert Jerome , Button Emily B. , Martin Emma , McAlary Luke , Gidden Zoe , Gilmore Megan , Boyce Guilaine K. , Caffrey Tara M. , Agbay Andrew , Clark Amanda , Silverman Judith M , Cashman Neil R. , Wellington Cheryl L. 
Published: December 2020

AbstractBackgroundSeveral lines of evidence suggest that high‐density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta‐amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood.MethodsHere we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding.ResultsWe demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)‐BI, in contrast to the SR‐BI‐dependent mechanism by which HDL prevents Aβ‐induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen‐I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen‐I protein levels produced by smooth‐muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE.ConclusionThe findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally‐acting apoE in AD.
Exploring the pathologic synergy between amyloid β and tau
Authors: Ibanez Kristen R. , Koller Emily J. , De La Cruz Elsa Gonzalez , Weinrich Mary J. , Ryu Daniel H. , Giasson Benoit I. , Borchelt David R. , Chakrabarty Paramita 
Published: December 2020

AbstractBackgroundAlzheimer’s disease is mainly characterized by amyloid β (Aβ) plaques and tau neurofibrillary tangles (NFTs). The amyloid cascade hypothesis provides a hypothetical link between these two proteinopathies and posits that Aβ can trigger tauopathy.MethodTo understand the temporal relationship between Aβ and tau and also to probe whether specific forms of misfolded tau preferentially interact with Aβ to induce the neurodegenerative cascade, we used an adeno‐associated model (AAV) of tauopathy combined with the TgCRND8 mouse model of Aβ deposition. We used three different types of tau variants in TgCRND8 mice – wild type (WT) tau, FTD‐associated P301L mutant tau and Pick’s disease‐associated S320F mutant tau. In prior studies, we demonstrated that while both WT and P301L tau expression results in accumulation of soluble phosphorylated tau in nontransgenic mice, only the S320F mutant readily formed insoluble intracellular NFTs allowing us to test the relative vulnerability of the Aβ mouse model to different types of misfolded tau.ResultIn the first cohort, we injected the AAV‐tau constructs into the brains of neonatal TgCRND8 mice. At 3 months post‐injection, when Aβ deposits first begin to appear, we found ‐ that expression of S320F tau produced NFT and surprisingly also exacerbated Aβ deposition. Expression of WT or P301L tau had no effect. The intracellular tau pathology in all these mice resembled the patterns observed in nontransgenic CRND8 littermates, suggesting no obvious cooperativity between Aβ and tau. In the second cohort, we delivered these AAV‐tau in the hippocampus of adult TgCRND8 mice with pre‐existing Aβ pathology and analyzed after three months of AAV expression. Here, we observed that the presence of pre‐existing Aβ induced formation of NFT pathology in the P301L tau expressing mice but not in the WT tau expressing mice. The levels of tau pathology from expression of S320F tau induced NFTs were essentially similar to that found in the first cohort that was injected neonatally.ConclusionTaken together, our data demonstrate gradations in the ability of pre‐existing Aβ deposits to secondarily induce tau misfolding, with the P301L tau variant showing the greatest response.
Engaging the Down syndrome community: Overcoming barriers to clinical trial recruitment
Authors: Hendrix James A. 
Published: December 2020

AbstractBackgroundWith improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly with a life expectancy of >55 years of age compared to just 25 year of age in the 1980’s. It is estimated that there are 210 K people with DS in the USA and 40% are over the age of 30 years old.1 However, with longevity comes a very high risk of Alzheimer’s disease (AD). It is estimated that by age 55–60 years at least 70% will develop Alzheimer’s dementia.2, 3 Despite the Alzheimer’s crisis facing the DS population, very few people with DS have participated in clinical trials.MethodThis talk will explore common barriers and potential solutions to the recruitment of adults with DS. DS organizations, such as LuMind IDSC, continuously work to gain the trust of participants and their families in ethical research which is a key component for successful recruitment.ResultThe NIH, LuMind IDSC, and other DS advocacy organizations are developing tools to engage, support and educate adults with DS and their caregivers about the risk of AD to help solve the issue of DS recruitment into trials.ConclusionUnique recruitment strategies are needed for successful enrollment of adults with DS in AD trials. References: 1. de Graaf, G.; Buckley, F.; Skotko, B. January 28, 2019 | https://dsuri.net/us‐population‐factsheetLemere, al. Neurobiol Dis, 1996, 3(1):16‐32. 2. Hartley, al. Alzheimer’s Dementia, 2015, 11(6):700‐9.
Functional considerations in the conduct of clinical investigations in the adult Down syndrome population
Authors: Bell Joanne M. 
Published: December 2020

AbstractBackgroundWith a lifespan buildup of amyloid beta in individuals with Down Syndrome (DS), comes the opportunity to study Alzheimer’s disease (AD) related pathological processes in potentially smaller sample sizes and shorter duration trials.MethodThere are multiple differences between these groups that require attention in designing investigational trials in the DS population. Primary is that DS participants constitute a vulnerable population.ResultThere is a wide range of intellectual disability (ID), and not all participants will have similar understanding of the informed consent/ assent process. Respecting the individuals perspective will be necessary to ensure open communication and build trust. These differences in ID translate into cognitive capacity which reflects upon reaction time, verbal working memory and mental flexibility. The variation in ID applies to mental health concerns as anxiety over novel situations and depression over life/environmental changes are frequent and require accommodation by both the family and the trial site. While many physical problems associated with DS are corrected in childhood, more problems arise during succeeding decades: obstructive sleep apnea, epilepsy (bimodal occurrences), poor visual and/or auditory acuity, and heightened immune responses are some co‐morbidities which will need to be addressed.ConclusionMore overwhelmingly is a need for the investigational site to build a strong, long‐term trusting relationship with DS individuals and their families or caregivers. Investigators will need to encourage DS parents or their study partners to take an active role in preparing and soothing the participants while allowing some degree of autonomy to boost confidence and increase tolerance to clinical assessments.
APOE genotype and multimorbidity in the FINGER multidomain lifestyle trial
Authors: Turunen Heidi , Marengoni Alessandra , Antikainen Riitta , Helisalmi Seppo , Laatikainen Tiina , Soininen Hilkka , Strandberg Timo , Kivipelto Miia , Solomon Alina , Ngandu Tiia 
Published: December 2020

AbstractBackgroundA growing burden on healthcare systems is the increasing amount of chronic diseases in single person (multimorbidity), especially in the elderly population. Multimorbidity leads to many problems, such as higher use and cost of healthcare, polypharmacy and poorer quality of life. The present study reports exploratory analyses of APOE genotype and multimorbidity in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER, ClinicalTrials.gov NCT01041989).MethodFINGER was a 2‐year randomized controlled trial with 1260 participants at risk for dementia from the general Finnish population, aged 60‐77 years. Beneficial effects of the multidomain intervention (diet, exercise, cognitive training and monitoring of vascular risk factors) versus control (regular health advice) have been previously reported on the primary cognitive outcome and several secondary outcomes. APOE and multimorbidity data at baseline and the 2‐year follow‐up were available for 532 participants in the intervention group and 527 in the control group. Multimorbidity was assessed through a standardized questionnaire, and an interview by the study physicians. The questionnaire entailed 17 diseases. Associations between APOE genotype (carrier vs non‐carrier of the ε4 allele) and multimorbidity after 2 years were assessed using logistic regression analyses, adjusted for randomization group, age, sex, education, smoking, alcohol consumption and baseline multimorbidity.ResultAt baseline APOE was not related to multimorbidity. However, in longitudinal analyses carriers of the APOE4 allele were more likely to develop 3 or more new chronic diseases during follow‐up, with OR (95%CI) 2.2 (1.04‐4.87), p=0.04. No significant associations were found between APOE and multimorbidity defined as one or more new chronic diseases (p=0.21) or 2 or more new chronic diseases (p=0.59).ConclusionPreliminary findings from the FINGER trial suggest that in this at‐risk general older population the APOE4 allele was related to multimorbidity defined as 3 or more new chronic diseases. To our knowledge this is the first study to link APOE to multimorbidity in the context of a lifestyle intervention to prevent cognitive decline. This is in line with previous findings linking APOE4 to cardiovascular and metabolic conditions.
In‐silico high throughput whole transcriptome screening implicates cardiovascular disease and the immune system in the mechanism of action underlying adverse effects of atypical antipsychotics
Authors: Creese Byron , Malekizadeh Yasaman , Williams Gareth , Whitfield David , Kelson Mark , Ballard Clive , Mill Jonathan , Jeffries Aaron 
Published: December 2020

AbstractBackgroundRisks of stroke/thromboembolic events, infections and death are all significantly increased by antipsychotics in people with dementia but specific mechanisms are unclear. In a novel application of a drug repurposing paradigm, we aimed to identify candidate underlying mechanisms in‐silico by leveraging publicly available transcriptomic data.MethodsWhole transcriptome signatures were first generated for three antipsychotics (amisulpride, risperidone and volinanserin) using RNA‐sequencing in SHSY‐5Y cell lines. These compounds were chosen to represent a range of mechanisms of action relevant to clinically used compounds and novel compounds in development. An unbiased high throughput screen generated correlations between each compound and a public repository of over 100,000 human disease samples. From a long list of statistically significant hits, correlations between each antipsychotic and conditions/diseases related to known side effects of antipsychotic use in dementia were identified and gene set enrichment analysis performed.ResultsStatistically significant associations were found between antipsychotic transcriptional signatures and atherosclerosis (amisulpride p=0.002; risperidone p=6.98x10‐6; volinanserin p=5.5x10‐8), venous thromboembolism (risperidone p=8.13x10‐7; volinanserin p=0.002) and influenza (amisulpride p=0.002). Pathways enriched in antipsychotic signatures were linked to the cardiovascular system, the immune system and inflammation (including brain derived neurotrophic factor, platelet derived growth factor receptor beta, tumor necrosis factor alpha signalling).ConclusionUsing a novel, high throughput approach, these findings implicate cardiovascular disease and the immune system in the mechanisms of action of atypical antipsychotics, providing a list of priority candidate mechanisms of harm relevant to dementia research. This approach could have implications for drug safety screening of psychotropic drugs in dementia.
Synaptoprotective effects of the novel TNF inhibitor XPRO1595 in 5xFAD mice: Interactions between Western diet and sex
Authors: Weiss Blaine E. , Gollihue Jenna L. , Farr N. Drew , Sompol Pradoldej , Artiushin Irina A. , Kraner Susan D. , Tansey Malu Gamez , Norris Christopher M. 
Published: December 2020

AbstractBackgroundThe western diet has been repeatedly shown to trigger inflammation and has been implicated as an environmental factor in cerebrovascular disease and Alzheimer’s disease (AD) pathology. Our previous work has shown that inhibition of neuroinflammation by the selective anti‐TNF biologic, XPro1595, ameliorates neurologic dysfunction in a mouse model of amyloid pathology. Unlike other TNF inhibitors, XPro1595 targets only the soluble form of TNF (sTNF), preserving the neuroprotective transmembrane TNF signaling pathways. Here, we investigate whether western diet‐induced chronic inflammation accelerates AD‐like pathology in a mouse with genetic predisposition for amyloid development and the extent to which this synergy is dependent on sTNF signaling.MethodThree‐month‐old 5xFAD mice received Teklad high fat and high fructose (HFHF) diet (TD 150111) or a balanced control diet (TD 150112) over a two‐month period. At four‐months‐of‐age and halfway through dietary intervention, subcutaneous injections of XPro1595 (10mg/kg, 2x/week) or saline were started and continued for another 4 weeks along with the dietary regimen. At endpoint, brain slices were prepared for electrophysiologic analyses of basal synaptic function and long‐term potentiation (LTP) in hippocampal CA1. Synaptic parameters were compared across diet and drug treatment conditions (n= 9‐14 mice/condition) using ANOVA and, where appropriate, Tukey’s post hoc test.ResultSlices from XPro1595‐treated mice exhibited an increase in both synaptic strength and LTP, regardless of diet. However, these effects also depended strongly on sex. LTP in males was similar across treatment groups (125‐130% of baseline), but females treated with HFHF showed nearly no LTP. LTP deficits in HFHF‐treated females were reversed by XPro1595 adminitration in vivo. In fact, HFHF females treated with XPro1595 showed the highest LTP levels (∼140% of baseline) of all groups investigated.ConclusionAberration of sTNF pathways have a differential effect on synapse physiology depending on sex and diet. Protective effects of XPro1595 on synapes materialize predominantly in females under conditions of dietary stress, while males responded modestly to treatment regardless of diet conditions. Studies are underway to establish whether sex‐specific differences reflect differences in amyloid burden between the sexes known to occur in this model, or are related to other differences unrelated to amyloid burden.
Exercise intervention differentially induces the expression of cystathionine beta synthase (CBS) in African American with MCI: Implication for endogenous H2S generation and component of aging pathway
Authors: Bedada Fikru B. , Ntekim Oyonumo , Johnson Steven P. , Turner Jillian , Nadarajah Sheeba R. , Ngwa Julius S. , Bond Vernon , Kwagyan John , Obisesan Thomas O. 
Published: December 2020

AbstractBackgroundDecline in metabolic fitness, accumulation of undesirable metabolic changes and cellular senescence are the hallmarks of aging [1,2]. The incorporation of lifespan‐extending platforms such as exercise can promote metabolic fitness and delay the process of aging [3]. However, the mechanisms involved are unclear. We hypothesized that exercise intervention can drive beneficial outcome by increasing expression of two enzymes; CBS and CTH involved in the production of H2S, glutathione and taurine as well as splice factors; SRSF2 and HNRNPD [4,5] in African American with MCI.MethodWe used TaqMan gene expression assay to investigate mechanistic link between exercise and components of aging pathway by evaluating CBS and CTH, enzymes metabolizing sulfur containing amino acid. We also evaluated if CBS and CTH expression correlate with SRSF2 and HNRNPD splice factors by virtue of endogenous H2S production.ResultComparison of CBS and CTH at baseline, 3‐ and 6‐month exercise time points revealed that 3‐month exercise intervention doubled the expression of CBS. However, CTH showed a decreasing trend, suggesting differential expression. Interestingly, expression of CBS correlated with SRSF2 splice factor whereas expression of CTH correlated with HNRNPD at all time points tested.ConclusionIn this study, we provided mechanistic insight through which exercise drive beneficial outcome by investigating component of aging pathway at baseline and exercise intervention in African American with MCI. Our data suggest differential effect of exercise on the expression of CBS, CTH; and the splice factors linked to delay pace of cellular senescence and aging by way of H2S [4,5]. Thus, our study implicates exercise‐induced CBS expression and endogenous H2S as drivers of benefit of fitness adaptation on metabolic fitness and life span with potential for clinical translation.
Longitudinal change in cortical thickness and hippocampal volume predicts cognitive decline
Authors: Chen Gengsheng , McKay Nicole Sarah , Gordon Brian A. , Liu Jingxia , Dincer Aylin , Keefe Sarah J. , LaMontagne Pamela J. , Koenig Lauren N. , Schultz Stephanie A. , Hassenstab Jason , Morris John C. , Benzinger Tammie L.S. 
Published: December 2020

AbstractBackgroundUsing biomarkers for early detection of Alzheimer disease (AD) is crucial for developing potential treatments. It has been hypothesized that longitudinal change in cortical thickness and hippocampal volume could be used to predict cognitive decline in individuals with AD. Here, using longitudinal MRI data, we evaluated whether changes in cortical thickness and hippocampal volume predicted changes in cognition, as measured by a battery of standardized tests.Method152 Participants (aged: 45‐86) who were enrolled in studies at the Knight ADRC at Washington University were included. Data was obtained through OASIS (www.oasis‐brains.org). Participants were classified as having normal cognition or early symptomatic AD, and were followed for 1‐8 years. Hippocampal volume was extracted, and cortical thickness measures were derived as an average of a set of FreeSurfer cortical regions (Figure 1). A random coefficient model was used to calculate longitudinal change in these biomarkers, and to assess whether these measures predict cognitive decline. Additional correlations between longitudinal changes in cognition and changes in cortical thickness, and hippocampal volume, were calculated using Spearman correlations.ResultWe found that longitudinal change in cortical thickness and hippocampal volume significantly predicted the rate of decline measured from a battery of standardized cognitive tasks (Figure 2). Furthermore, longitudinal changes in these structural biomarkers were strongly correlated with cognitive decline measured by the Logical Memory IIA‐Delayed (Figure 3).ConclusionLongitudinal changes in cortical thickness and hippocampal volume significantly predict cognitive decline on neuropsychological tests that address cognitive domains that are typically impacted by AD. To evaluate brain atrophy in a manner that could easily be examined in a clinical context, we did not limit the study to participants with known amyloid biomarker status. It has been postulated that once therapeutic agents for AD become available, we will have difficulty providing large scale screening tests in populations at risk due to limited availability of PET centers. As MRI is widely available, longitudinal volumetric MRI may potentially be used in the future to screen patients as a first step in a workup and evaluation for participation in clinical trials or, once approved, evaluation for therapy.
Early developmental exposure to air pollution increases the risk of Alzheimers disease and amyloid production: Studies in mouse and Caenorhabditis elegans
Authors: Haghani Amin , Johnson Riachard G. , Dalton Hans , Feinberg Jason I. , Lewis Kristy C. , Ladd‐Acosta Christine , Woodward Nicholas C. , Safi Nikoo , Jaffe Andrew E. , Allayee Hooman , Sioutas Constantinos , Campbell Daniel B. , Volk Heather E. , Curran Sean P , Finch Caleb E. , Morgan Todd E. 
Published: December 2020

AbstractBackgroundExposure to air pollution (AirP) as adults increases the risk for dementia in human populations and increases the production of amyloid‐beta peptides in mouse models (Cacciottolo et al 2017 PMID28140404). Gestational exposure to AirP adversely alters early human neurodevelopment and increases risk for cognitive and behavioral disorders. It is unknown if gestational or developmental exposure to AirP can increase the risk for or accelerate cognitive aging or Alzheimer’s disease (AD) in later adulthood.MethodsTo approach this gap, we examined the developmental effects of nano‐sized urban particulate matter (nPM), a subfraction of AirP, on later life stages of mice and nematodes. In C57BL/6J mice, initial transcriptional changes in the cerebral cortex or hippocampus were studied by RNAseq and tested for association with long‐lasting phenotypic effects of gestational nPM exposure. Experiments on Caenorhabditis elegans addressed developmental effects of nPM on AD‐related genes and Aß production in later adulthood.ResultsGestational exposure to nPM caused sex‐specific gene expression changes in the cerebral cortex of pups at postnatal day 5. The changes included DNA damage, oxidative stress, and immune responses. The top potential upstream regulators of these transcriptome changes included APP, Psen1, and Tau. At age 5 months, neuroinflammatory gene expression in the hippocampus was associated with depressive behavior, weight and fat gain, and increased glucose intolerance. Similarly, the initial responses of the L1 larval stage of C. elegans to nPM included an increase of mRNA levels in genes related to inflammation (e.g. abf‐2) and AD‐gene homologs (e.g. sel‐12/PSEN1). In an AD nematode model, developmental exposure to nPM in the L1 stage resulted in an accelerated paralysis phenotype in adults which is an indicator of increased Aß42 production.ConclusionsThis novel experimental evidence suggests mechanisms by which the developmental exposure to AirP could increase AD risk in later ages. Further studies may reveal the effects of gestational nPM exposure on later‐life cognition, Aß plaque formation, and neuropathology.