bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diesel exhaust particle role on gut microbiome and onset of Alzheimer disease neuroinflammation
Authors: Naughton Sean X , Westfall Susan , Pasinetti Giulio Maria 
Published: December 2020

AbstractBackgroundRecent evidence has emerged to show that diesel exhaust particulate (DEP) pollution can double the risk of getting dementia. Evidence suggest that exposure to high levels of air pollution are significantly more likely to develop dementia‐related diseases including Alzheimer’s disease. DEP is primarily composed of polycyclic aromatic hydrocarbons (PAHs) and nitro‐substituted polycyclic aromatic hydrocarbons (n‐PAHs). PAHs have previously been shown to undergo biotransformation through interactions with human colonic microbiota. The goal of the present study is to determine if DEP may influence selective gut microbiota. We will eventually identify gut‐brain‐axis mechanisms associated with DEP mediated neuroinflammatory mechanisms through microbiota dysbiosis.MethodUsing an in vitro model of the human gastrointestinal tract, EBIOME, we are exploring the human gut bacteria exposed to various concentrations of diesel exhaust particulate matter. Bacterial species were quantified over an extended time‐course to monitor log‐scale changes in colony survival and growth. In order to obtain higher resolution of gut microbiome species meta‐genomic analysis will be also conducted.ResultThe current studies have identified concentration dependent changes in microbiome biodiversity. Through ongoing analysis, it is anticipated that altered biodiversity will lead to decreases in the production of brain penetrant metabolites, such as short‐chain fatty acids including butyrate, acetate, and propionate.ConclusionOur studies provide novel information regarding the role of the gut‐brain‐axis in neuroinflammation in Alzheimer’s disease and other forms of dementia.
Benefits of a novel highly bioavailable resveratrol formulation, JOTROL, for Alzheimer’s disease
Authors: Volmar Claude‐Henry , Dennison Jessica , Ricciardi Natalie R. , Janczura Karolina J. , Walker Brittni R. , Brown Jonathan M. , Stahl Jack , Hayward Marshall A. , Brothers Shaun P. , Wahlestedt Claes 
Published: December 2020

AbstractBackgroundWith the recent Alzheimer’s disease (AD) clinical trial shortcomings, we and colleagues agree that an epigenetic approach is needed to address the polygenicity of AD. Recently, a randomized clinical trial with the SIRT1 activator resveratrol (3,5,4’‐trihydroxy‐trans‐stilbene) has shown positive effects in AD patients (Turner et al., 2015; Moussa et al., 2017). However, the high dose needed due to low bioavailability has been reported to cause a GI side effect. To increase bioavailability, JOTROL, a new oral formulation of resveratrol that shows significantly better pharmacokinetic properties than non‐formulated resveratrol, was manufactured by Jupiter Orphan Therapeutics. We hypothesize that equimolar concentrations of JOTROL, compared to non‐formulated resveratrol, will result in greater brain exposure to resveratrol and more efficacious responses on AD biomarkers, allowing for a reduction in dose regimen.MethodsFor acute studies, Sprague Dawley rats or C57B6 mice (n = 3/treatment) were administered a single oral dose of 50 mg/kg JOTROL 30 minutes prior to being euthanized. Blood, buffy coat and brains were harvested. For AD‐related studies, 15‐month‐old male triple‐transgenic (APPSW/PS1M146V/TauP301L; 3xTg‐AD) AD mice were treated by daily oral gavage with 50 mg/kg JOTROL (n = 5) or vehicle (n = 5) for 36 days. Animals were euthanized after behavior tests. The expression of AD‐related genes and proteins in brain, liver and spleen were analyzed using RT‐qPCR, Western blots and ELISAs. Effects on mitochondrial biogenesis were also investigated.ResultsJOTROL (50 mg/kg) increases brain and plasma resveratrol bioavailability in animals, significantly increases both SIRT1 (P<0.0001) and α‐secretase ADAM10 (P<0.0001) gene expression in rat brain, but significantly decreases Tau gene expression (P<0.05). 36‐day treatment of 3xTg‐AD mice with 50 mg/kg JOTROL decreases expression of IL6 (P<0.001 in liver, P<0.05 in spleen) and TNFα (P<0.001 in liver and P<0.01 in spleen), concurrent with a marked decrease of splenomegaly. Increased mitochondrial biogenesis is also observed in the brain (P<0.05) and in the liver (P<0.05) of these mice.ConclusionsJOTROL has a strong anti‐inflammatory effect in the brain and peripheral organs, promotes non‐amyloidogenic processing of the amyloid precursor protein and increases mitochondrial biogenesis. Further investigation is underway to determine prophylactic effects of JOTROL for AD pathogenesis.
Transcription of nicotinic acetylcholine receptor A7 in monocytic and patient‐derived microglial cell lines
Authors: Torsetnes Silje Bøen , Nordengen Kaja , Wettergreen Marianne , Gisladottir Berglind , Sharma Kulbhushan , Larsen Laila Norrheim , Glover Joel , Christensen Erik , Jaenisch Rudolf , Fladby Tormod 
Published: December 2020

AbstractBackgroundInnate immune genetics contribute to Alzheimer’s disease (AD) risk. Innate immune cholinergic activation is implicated in CNS immune regulation, and nicotinic acetylcholine receptor α7 (CHRNA7) activation may alleviate macrophage/monocyte and microglial inflammatory activation. Functional CHRNA7 (“N”) gene‐expression is negatively regulated by transcription or expression of the CHRFAM7‐gene (“M”), which is a uniquely human gene composed of elements from the N genes and FAM7 genes giving rise to truncated and altered α7 N subunits. As polyunsaturated fatty acids are proposed to ameliorate inflammation we hypothesized that docosahexaenoic acid (DHA) in combination with agents for nicotinic activation (positive allosteric modulators; PAMs) might influence N/M transcription patterns.MethodWe investigated the N and M transcription in two innate immune cell models; the human acute monocytic leukemia cell line THP‐1 and AD patient‐derived iPSC microglial cells. The patient‐derived iPSC microglial cells were differentiated according to the Douvaras‐protocol (Douvaras, 2017), and showed ramified morphology, motile processes, the ability to phagocytose amyloid beta (Aβ) 42 and presence of the microglial markers P2Y12, PU.1 and TMEM119. THP‐1 cells were differentiated to macrophages by a 48h treatment of 100 nM TPA (12‐O‐tetradecanoylphorbol‐13‐acetate). The THP‐1 cells were also used for intervention stimulation experiments, and treated with DHA, Aβ40, in addition to type I and type II PAMs and in combinations (see Figure 1). QPCR was performed on the intervention samples after preamplification. Absolute quantification was performed using M and N synthetic oligonucleotides standards. All samples were ran in triplicates.ResultRoughly similar levels of transcription of both N and M genes are found in both unstimulated microglia and monocytes. However, the stimulation experiments imply that N/M transcription ratio may be altered by intervention through an observed relative increase of N/M by DHA stimulation (N/M ratio>1.2), and a larger increase when combining DHA with either or both Aβ40 and the PAMs (N/M ratios>1.4, see figure).ConclusionWe show that CHRNA7 and CHRFAM7A subclasses are transcribed in monocytes and patient‐derived iPSC microglia in comparable amounts, and that CHRNA7/CHRFAM7A ratio transcription can be modified by combining DHA with a7‐PAMs. Putatively, this mechanism may be a therapeutically effective way to ameliorate CNS inflammation.
Synbiotic‐derived metabolites reduce neuroinflammatory symptoms of Alzheimer’s disease
Authors: Smith Chad 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a multifaceted disorder and recent advancements suggest that the gut microbiota and its metabolites play a critical role in the progression and potential treatment of AD. Synbiotics, the combination of probiotics and prebiotics, can be designed to produce specific bioavailable metabolites that penetrate the blood‐brain‐barrier and actively reduce the neuropathologies associated with AD. Recently, we designed an in vitro model of the human gastrointestinal tract that can be used to optimize the production of metabolites from synbiotic formulations using machine learning algorithms that can then be tested in animal models of AD. The objective of this study is to optimize and characterize a synbiotic’s metabolite production using an in vitro bioreactor that could be used as a therapeutic tool against AD. We hypothesize that a synbiotic designed towards the production of specific brain‐bioactive metabolites will synergistically mitigate the neuro‐ and systemic‐pathologies associated with AD.MethodUsing the in vitro model of the human gastrointestinal tract, we have used this optimized combination of polyphenols and tested 15 combinations of 6 probiotic bacteria as a synbiotic to optimize metabolite production using a multivariate regression algorithm (MARS) and found that three probiotic bacteria, Lactobacillus plantarum, Bifidobacterium infantis and L. salivarius together synergistically improve the production of brain bioavailable metabolites including quercetin, kamferin, 4‐hydroxyphenylpyruvic acid and 4‐hydroxyphenylacetic acid.ResultWe have found that two polyphenolic metabolites 3‐hydroxybenzoic acid and 3‐(3’‐hydroxyphenyl) propionic acid derived from a grapeseed polyphenolic extract (GSPE) can penetrate the blood‐brain‐barrier and in vitro,inhibit the aggregation of amyloid plaques and tau fibrils. By increasing the diversity of the polyphenolic pool by adding a concord grape extract and resveratrol to the GSPE, we provided greater protection against cognitive impairment and amyloid aggregation in an AD mouse model than the components alone.ConclusionWhile bioavailability studies have shown that these metabolites cross the blood‐brain‐barrier, in vitro studies have confirmed that these metabolites have potent anti‐inflammatory activity. This synbiotic combining potent grape‐derived polyphenolic precursors with bioactive probiotic bacteria has the potential to slow the progression and treat AD by synergistically targeting multiple of its neuropathologies including inflammation, amyloid aggregation and tau fibril formation.
Genome‐wide analysis of longitudinal Alzheimer’s disease biomarker endophenotypes
Authors: Jacobson Tanner Y. , Nho Kwangsik , Risacher Shannon L. , Gao Sujuan , Saykin Andrew J. 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is characterized by a pathophysiological cascade, in part detectable using imaging and fluid biomarkers, that evolves over many years. Our goal was to study the interaction between genetic risk and longitudinal trajectories of selected AD endophenotypes using the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset.MethodLongitudinal data included amyloid beta (PET and CSF), total tau and phosphorylated tau (CSF), FDG PET (3 ROIs), MRI measures of atrophy (8 ROIs) and white matter hyperintensities (WMHI), and composite scores from cognitive tests for memory and executive function (full list of endophenotypes, sample size, and covariates in Table 1). Genetic association with longitudinal phenotypes was performed using Linear Mixed Modelling (LMM; LME4 R package), modeling the SNP main effect and SNP x time effects, with time x subject as a random effect and participant age as the time variable. SNP P‐values from the LMM were analyzed for gene enrichment using MAGMA, with a 10kb boundary around genes for SNP to gene assignment. A stringent significance threshold was set to P ≤ 6.25 × 10−9 based on Bonferroni correction for the top 8 principal components explaining 85% of variance across all tested phenotypes. LD trimming was performed to identify top SNPs for genetic regions. MAGMA gene based association was FDR corrected to P ≤ 0.05.ResultMultiple genetic regions (26) were associated with the main SNP effect, including the APOE ε4 locus, which was significant on all measures except WMHI. Time interaction identified the APOE ε4 allele as study wide significant with cognitive measures and 5 MRI ROIs. Apart from APOE, 7 SNPs were identified that met genome‐wide significance, including SNPs intronic to BORCS5, HLA‐DPA1, and GRIN3A (Figure 1). Gene based association identified 21 genes, 14 primarily associated with MRI atrophy measures, 3 WMHI, 2 with CSF tau, 1 with amyloid PET, and 1 with cognitive measures (Figure 2).ConclusionGenetic association analysis of longitudinal trajectories of AD biomarker phenotypes identified both genes and pathways previously implicated with AD, as well as several novel loci. These findings may point to new targets for diagnostic and therapeutic development.
Cortical atrophy signatures and machine learning MR‐based classification of primary progressive aphasia variants
Authors: Ezzo Rania , Cordella Claire , Dickerson Brad C. , Collins Jessica A. 
Published: December 2020

AbstractBackgroundPrimary Progressive Aphasia (PPA) is a rare neurodegenerative disorder characterized by progressive language impairment and three clinical phenotypes: semantic variant (svPPA), logopenic variant (lvPPA) and non‐fluent variant (nfvPPA). The goals of the present study were to 1) identify the group brain atrophy “signatures” of each PPA clinical phenotype, 2) determine the degree of individual variability in the spatial extent of atrophy within each clinical phenotype, and 3) explore the ability of a machine learning algorithm to classify patients based on regional atrophy values.MethodAnatomical MRIs were collected from patients with a clinical diagnosis of svPPA (N=22), lvPPA, (N=21), nfvPPA, (N=18), and age‐matched healthy controls (N=25). Group‐level atrophy “signatures” were created using whole‐brain group GLMs comparing cortical thickness of each PPA variant to the control group. Next, group percent overlap maps were created by binarizing each patient’s z‐normalized atrophy map (relative to the control group, thresholded z<‐1.5), adding those maps together, and then dividing by each group’s N. Finally, a linear support vector machine (SVM) was applied to w‐scored atrophy values (controlling for intracranial volume, age, and sex), from brain regions identified as being most frequently affected within each patient group.Result100% of svPPA patients demonstrated atrophy in the left anterior temporal lobe. Atrophy patterns in the lvPPA and nfvPPA groups were more heterogeneous; 80% of lvPPA patients demonstrated atrophy in the left posterior superior temporal, middle temporal, inferior temporal, and fusiform gyri; and 60% of nfvPPA patients demonstrated atrophy in the left pars opercularis, caudal middle frontal, and superior frontal gyri. The linear SVM classified individual patients with a total precision (true positives/true positives+false positives) = 91.6% (svPPA=98.4%, lvPPA=88.2%, nfvPPA=78.3%) and a recall, or sensitivity (true positives/true positives+false negatives) = 90.0% (svPPA=95.45%, lvPPA=88.25%, nfvPPA=76.25%). The features identified as most important for classification were the left temporal pole, middle temporal gyrus, and insula.ConclusionOur results provide further evidence that the PPA variants have distinct neuroimaging profiles that can support diagnosis, with svPPA and lvPPA patients exhibiting fairly homogenous atrophy signatures. We further showed that a linear SVM applied to regional atrophy values can classify individual patients with high accuracy.
Clinician‐reported features in MBI/MCI and early dementia in genetic FTLD
Authors: Gottesman Reena T. , Barker Megan S. , Cosentino Stephanie , Manoochehri Masood , Boeve Bradley F. , Boxer Adam L. , Rosen Howard J. , Forsberg Leah , Heuer Hilary W. , Brushaber Danielle , Huey Edward , Rascovsky Katya ,   the ARTFL/LEFFTDS Consortium
Published: December 2020

AbstractBackgroundFrontotemporal dementia (FTD) can present with significant phenotypic heterogeneity. Most cases of sporadic FTD do not present for diagnosis until functional impairment is evident, making it difficult to identify and characterize the earliest features of FTD. Focusing on participants from families with known FTD‐causing pathogenic mutations allows for the characterization of the earliest features of FTD in genetic carriers.MethodThe ARTFL and LEFFTDS consortia (AG063911, AG045390, NS092089, AG016976) are joint, multi‐center cohort studies of patients with FTLD, including symptomatic and asymptomatic family members. For this study, a subset of ARTFL/LEFFTDS participants from families with known genetic mutations were selected if they were determined by a study physician to have (a) a phenotype of Mild Behavioral / Cognitive Impairment (MBI/MCI) and CDR®+NACC‐FTLD = 0.5 (44 participants, 19 C9orf72, 12 GRN, 13 MAPT mutations), or (b) CDR®+NACC‐FTLD = 1 (33 participants, 16 C9orf72, 10 GRN, 7 MAPT mutations). We examined the NACC Uniform Data Set (UDS) B9F form, bvFTD criteria. Pearson chi‐squared tests compared the frequency of identified bvFTD features between MBI/MCI and bvFTD participants.ResultThe most common bvFTD diagnostic criteria features questionably or definitely present in the 44 MBI/MCI participants were Apathy and Disinhibition, both at 30% (Within the early FTLD group: Apathy at 70% and Disinhibition at 72%). Neuropsychological testing deficits consistent with bvFTD were present in 27% (72%), and loss of empathy in 25% (72%). Impaired daily functioning was next at 16% (81%), Ritualistic behaviors were observed in 7%, (36%) and Hyperorality in 5% (33%). Chi‐squared tests revealed significant differences between the two groups for all features, with the largest numerical and statistical difference in impaired daily functioning.ConclusionApathy and Disinhibition were the most common neuropsychiatric symptoms noted in FLTD MBI/MCI. Development of impairments in daily functioning best distinguished the MBI/MCI and FTLD groups. This may be related to the requirement of functional impairment for the diagnosis of dementia. The relative frequency of different features in early dementia of genetic FTLD is similar to that reported in sporadic bvFTD. As more longitudinal data is collected, within‐subject assessment of the development of features in genetic bvFTD over time will be instructive.
White matter disintegration along tracts measured by diffusion tensor imaging in people with MCI
Authors: Haddad Seyyed Mohammad Hassan , Faria‐Pieruccini Frederico , Montero‐Odasso Manuel , Bartha Robert 
Published: December 2020

AbstractBackgroundGradual disintegration of white matter (WM) tracts has been observed in Alzheimer’s disease (AD) by postmortem histological analyses and in‐vivo neuroimaging. Previous diffusion tensor imaging (DTI) studies have shown changes in fractional anisotropy (FA) and radial diffusivity (RD) indicative of microstructural changes in select WM regions in AD and mild cognitive impairment (MCI). However, the precise location of microstructural damage along WM tracts at the early stages of cognitive decline is still unknown. In the current study, DTI metrics along the major WM tracts were measured and compared in healthy elderly and MCI subjects to localize microstructure changes.MethodDiffusion tensor images (32 directions, b=1000 s/mm2) were acquired on a 3 Tesla Siemens Tim Trio and a 3 Tesla Siemens Prisma Fit MRI scanner in healthy elderly (N=40) and people with MCI (N=44) as part of the Gait and Brain Study in London, Ontario. FA and RD were quantified along 18 major WM tracts in each subject using TRACULA in FreeSurfer. The average FA and RD of each tract were compared between groups using a MANOVA (for FA and RD separately) adjusted for age, sex, education, comorbidity, and MoCA score. If the MANOVA was significant (p<0.05), post‐hoc tests were conducted to identify the tracts on which the DTI metrics differed between the groups. Then, the DTI metrics were examined along these identified tracts to localize observed differences.ResultThe MANOVA detected significant differences in both FA (p‐value=0.018) and RD (p‐value=0.019) in the 18 tracts studied between controls and MCI subjects. Post‐hoc tests showed that specifically, FA in right cingulum‐cingulate gyrus endings (rh_ccg) (Fig. 1) and in left superior longitudinal fasciculus‐parietal endings (lh_slfp), and RD in rh_ccg and left uncinate fasciculus (lh_unc) (p‐value < 0.05) differed between the groups. Comparison along the rh_ccg using t‐test (p‐value < 0.05) revealed that FA and RD differed significantly between the groups in the posterior portion of this tract (Figures 2 and 3).ConclusionTract specific white matter disruption in the cingulum gyrus in people with MCI was localized in the posterior part of the rh_ccg tract adjacent to the posterior cingulate (Fig. 1).
Targeting mitochondrial complex I enhances reserve capacity through super‐complex structural assembly
Authors: Flannery Padraig Flannery , Pichurin Nicholas , Trushin Sergey , Trushina Eugenia 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neuropathological condition where age is the greatest risk factor. There is currently an estimated global prevalence upward of 46.8 million individuals and recent efforts to combat the clinical presentation of AD through late‐stage Amyloid‐beta (Aβ) targeted therapeutic intervention has not been successful, underscoring the need for novel approaches to slow disease progression. Accumulating evidence proposes that mitochondrial and metabolic homoeostasis is an early dysfunction which occurs decades before the presentation of clinical symptoms. Indeed AD has been classified as type‐3 diabetes, suggesting the need to target metabolic modifiers to slow or even abrogate neurodegeneration. We have recently reported that targeting the oxidative phosphorylation (OXPHOS) system through mild inhibition of NADH dehydrogenase (Complex I) with our small molecules partial Complex I inhibitors (MCIi) can halt the development of cognitive and behavioral phenotypes associated with AD. We have also demonstrated that this modulation of mitochondrial complex I, through reversible inhibition at the Flavin Mononucleotide (FMN) domain, serves to enhance mitochondrial bioenergetics and function and protects against oxidative stress. We hypothesize that this mechanism of improved bioenergetics may be due to transformed OXPHOS super‐complex assembly, which can lead to a more efficient bioenergetics system and protect against extrinsic stress.MethodsTo test this hypothesis, we examined bioenergetics and the assembly of mitochondrial OXPHOS complexes and super‐complexes in mitochondria from primary cortical neurons and synaptosomes isolated from the brain tissue of non‐transgenic and 3xTgAD mice treated with MCli using respiratory XF Seahorse analysis, BNPAGE and 2D‐BNPAGE.ResultsOur analyses demonstrates that MCIi can acutely alter the assembly of super‐complexes within the OXPHOS system and protect against stress through enhanced spare respiratory capacity while preserving ATP level, which may aid in the enhancement of mitochondrial bioenergetics and function in AD.ConclusionPartial complex I inhibitors can induce positive bioenergetics through super‐complex assembly