bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain tocopherol levels are associated with lower activated microglia density in elderly human cortex
Authors: de Leeuw Francisca A , Schneider Julie A , Agrawal Sonal , Leurgans Sue E , Morris Martha Clare 
Published: December 2020

AbstractBackgroundHigher intake of vitamin E has been associated with a lower risk of Alzheimer’s disease (AD), however the underlying mechanisms are unclear. One explanation might be that anti‐inflammatory properties of tocopherols prevent microglia activation. In this study we investigated the association of brain tocopherol levels with microglia activation in elderly humans.MethodWe included 113 deceased participants (88.5±6 years, 60% female) from the prospective Memory and Aging Project. Brain levels of α‐ and γ‐tocopherol were measured by HPLC coupled to electrochemical detection. Microglia presence was assessed in three stages of activation, based on morphology; i.e. I – not activated, II – activated, III – most activated. Microglia densities and tocopherol levels were log‐transformed when not normally distributed, standardized and averaged across two cortical and two subcortical brain regions. Linear regression analyses examined associations between tocopherol levels and microglia densities (outcome) in two models; a model adjusted for age, sex, education, APOE ε4 genotype and post mortem time interval (model 1), and a model additionally adjusted for total amyloid load and neurofibrillary tangles severity (model 2).ResultTotal microglia density (stage I‐III) was lower in cortical versus subcortical brain regions (153.2 (111.2‐194.0); 209.2 (175.8‐224.1), p<0.001). Levels of α‐ and γ‐tocopherol and activated microglia (II/III or III only) density did not differ between brain regions. Higher α‐ and γ‐tocopherol levels were associated with lower total and activated microglia densities in cortical (range (B(SE) ‐0.25,‐0.19 (0.09,0.10) p<0.05) but not in subcortical brain regions (range B(SE) ‐0.01, 0.12 (0.09,0.10) p>0.05). When we additionally adjusted for AD neuropathology effect estimates diminished and lost significance except for the association between α‐tocopherol and total microglia density in cortical brain regions (B(SE) ‐0.20 (0.09), p=0.03).ConclusionThese results suggest that the relation between tocopherols and AD might be partly explained by the alleviating effects of tocopherols on microglia activation.
Gene‐diet interaction and dementia risk: The example of coffee and CYP1A2 gene
Authors: Lefèvre‐Arbogast Sophie , Dartigues Jean‐François , Tzourio Christophe , Berr Claudine , Helmer Catherine , Samieri Cécilia 
Published: December 2020

AbstractBackgroundCoffee consumption has been associated with a decreased risk of dementia, although findings have been inconsistent. Among the numerous coffee bioactives, caffeine may improve neurotransmission by acting as antagonist of adenosine receptors. There exists a large inter‐individual variability in caffeine metabolism in relation to the cytochrome P450 1A2 (CYP1A2), and some studies suggest that specific genes of CYP1A2 may module the relationship between coffee and chronic diseases (cancer, cardiovascular disease, Parkinson’s disease). Our objective was to evaluate the association between coffee consumption and dementia risk in the French Three‐City (3C) cohort of older persons, taking into account the potential modulatory effect of CYP1A2 rs762551 genotype.MethodWe included 5,963 participants, free of dementia at baseline when they reported their daily coffee consumption and who were followed for incidence dementia up to 14 years. All included participants had available genome‐wide genotyping. We tested the interaction between coffee consumption (number of cups/day) and CYP1A2 rs762551 (number of alternative allele C) on the risk of dementia using Cox proportional hazard models adjusted for age (as time scale), sex, level of education and ApoE‐ε4. Multivariate associations between coffee consumption and the risk of dementia were then investigated according to CYP1A2 rs762551 genotype that induce “faster” caffeine metabolism (A/A) or “slower” caffeine metabolism (C/A‐C/C).ResultParticipants were 74 (sd 5) years‐old on average at baseline and 61% were women. The mean coffee consumption was 1.6 cups/day (sd 1.3; min 0; max 10 cups/d) and 78% of participants reported the consumption of at least 1 cup/d. In total, 52% of participants were carriers of at least one rs762551 C allele. Over a median follow‐up of 8.6 years, 756 cases of dementia were diagnosed. Daily coffee consumption was associated with a decreased risk of dementia only among carriers of the CYP1A2 rs762551 C allele, with each additional cup of coffee being associated with a 10% reduced risk of dementia (95%CI: 2‐18%; p for interaction=0.007).ConclusionIn our study, coffee consumption was associated with a reduced risk of dementia among older persons with a genetic predisposition towards a slow caffeine metabolism.
Alzheimer’s disease brain atrophy subtypes are associated with incident dementia in subjective cognitive complaint and mild cognitive impairment
Authors: Planche Vincent , Bouteloup Vincent , Mangin Jean‐Francois , Dubois Bruno , Habert Marie‐Odile , Tison François , Chêne Geneviève , Dufouil Carole ,   MEMENTO
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) brain atrophy subtypes on structural MRI have been associated with rate of cognitive decline in AD and prodromal AD. However, previous works were based on selected amyloid‐positive and/or cognitively‐impaired patients. The clinical relevance of brain atrophy subtypes categorization in people referred to Memory Clinics for subjective cognitive complaint (SCC) or mild cognitive impairment (MCI), without any a priori assumptions regarding their amyloid status, is currently unknown.MethodsWe investigated 2118 subjects from the French Memento cohort presenting either with SCC or MCI and for whom both hippocampal and cortical volumes were available at baseline. Among them, 883 also had Amyloid‐PET and/or CSF biomarkers. They were prospectively followed during 4 years for dementia status and neuropsychological performances. MRI scans at baseline were used to define groups with “limbic predominant atrophy”, “hippocampal sparing atrophy”, “typical/diffuse atrophy” and “no evidence of brain atrophy”, based on previously described algorithms.ResultsIn Cox proportional‐hazards models, “typical/diffuse atrophy” and “limbic predominant atrophy” were associated with an increased risk of developing dementia over time (HR=3.67; 95%CI 2.63–5.13 and HR=1.77; 95%CI 1.05–2.98 respectively), independently of age, gender, educational level, ApoE4 genotype and CDR‐SB at baseline. Brain atrophy subtypes categorization was more informative than hippocampal and/or cortical volumes separately, when comparing Akaike information criteria of Cox models. Very similar results were found when analyses were restricted to the sample of amyloid‐positive participants (n=236) (HR=3.69; 95%CI 2.03–6.70 for “typical/diffuse atrophy” and HR=2.40; 95%CI 0.96–5.96 for “limbic predominant atrophy”).ConclusionAD brain atrophy subtypes are associated with conversion to dementia in patients with SCC or MCI consulting in Memory Clinics, agnostic of any a priori assumptions regarding their amyloid status. Because this categorization based on structural MRI is more informative than hippocampal and/or cortical volumes, it could be widely used as a biomarker in future epidemiological and clinical studies.
Utility of DTI as a prognostic biomarker in MCI: Beyond AD biomarkers
Authors: Pillai Sheela Kumari Raghavan , Przybelski Scott A. , Reid Robert I. , Graff‐Radford Jonathan , Lesnick Timothy G. , Zuk Samantha M. , Knopman David S. , Machulda Mary M. , Mielke Michelle M. , Petersen Ronald C. , Jack Clifford R. , Vemuri Prashanthi 
Published: December 2020

AbstractBackgroundGiven that a proportion of mild cognitive impaired (MCI) individuals are amyloid negative and have cerebrovascular disease (CVD), there is a need for biomarkers that can complement AD biomarkers (amyloid and neurodegeneration) for the prediction of future cognitive decline in MCI. The aim of our study was to determine the utility of diffusion tensor imaging (DTI) as a CVD marker for prediction of future cognitive decline in individuals with MCI in conjunction with amyloidosis and neurodegeneration.MethodWe identified 132 MCI individuals ≥60 years old (55 % were amyloid positive and 59 % were male) from the population based sample of Mayo Clinic Study of Aging (MCSA) who had structural MRI, DTI, amyloid PET, and at least one clinical follow‐up after the imaging at the time of their clinical visit as MCI. All imaging scans were acquired and processed using in house developed protocols and pipelines. We used fractional anisotropy in the genu of corpus callosum (FAGCC), as a CVD marker, education/occupation score as a resilience variable, and global cognitive z‐score as the cognitive outcome. Using mixed effect models for cognitive decline, we evaluated three models to test the prognostic ability of (i) DTI marker alone, (ii) DTI marker and amyloid PET, (iii) DTI marker, amyloid PET, and neurodegeneration (cortical thickness). The final parsimonious models included the significant interactions of potential predictors with time, main effects nested within those interactions, and other significant main effects. Since the adjustment for conventional CVD measures like WMH was important to determine the utility DTI over traditional measures, we further assessed the value of FAGCC in conjunction with white matter hyper intensity (WMH).ResultWe found: i) FAGCC was associated with cognitive decline after adjusting for amyloid PET neurodegeneration (Figure 1 and Table 1) and ii) FAGCC was associated with cognitive decline even after controlling for WMH and WMH was no longer significant after accounting for FAGCC (Table 2).ConclusionDTI has significant utility for prediction of cognitive decline in MCI from population‐based samples and will provide complementary information to AD biomarkers.
Hyperhomocysteinemia as a model of VCID
Authors: Weekman Erica M. , Lee Tiffany , Price Brittani R. , Woolums Abigail E. , Hawthorne Danielle , IV Charles E. Seaks , Wilcock Donna M. 
Published: December 2020

AbstractBackgroundVascular contributions to cognitive impairment and dementia (VCID) are increasingly recognized as a significant cause of dementia. Furthermore, VCID co‐morbid with Alzheimer’s disease (AD) is estimated to occur in at least 60% of AD cases. While the contribution of VCID to clinical dementia is increasingly recognized, the mechanistic underpinnings of VCID has been lacking.MethodWe have previously shown that induction of hyperhomocysteinemia (HHcy) via diet in both wildtype (WT) and APP/PS1 mice produces cerebrovascular pathologies. While the pathological characteristics of HHcy have been identified in both models, the time course for these changes is unclear. We examined neuropathological changes along a time course of 2, 4, 6, 10, 14 and 18 weeks on diet in our models.ResultIn both the WT and APP/PS1 mice on the HHcy diet, increased microglial staining began at 6 weeks and was accompanied by a significant increase in several pro‐inflammatory markers. Several astrocytic end feet markers were significantly decreased at 10 weeks in the WT mice on HHcy diet. Cognitive decline also began at 10 weeks on diet in both models. Prussian blue staining revealed a significant increase in microhemorrhages starting at 14 weeks on the HHcy diet. Finally, in the co‐morbidity model, induction of HHcy resulted in redistribution of amyloid from the parenchyma to the vasculature starting at 14 weeks on diet.ConclusionOverall, induction of HHcy in both WT and APP/PS1 mice leads first to neuroinflammation, followed by astrocytic end foot disruption and cognitive decline, and finally, microhemorrhages, and redistribution of amyloid to the vasculature in the APP/PS1 mice. Taken together, this data suggests that neuroinflammation is an initiator in HHcy mediated VCID alone and when amyloid plaques are present, providing a possible common target for therapeutics in both VCID and co‐morbid patients.
Anatomical correlates of age‐related basal forebrain dysfunction
Authors: Somera Brandy Lynn , Woodruff Jennifer L. , Grillo Claudia A. , Reagan Lawrence P. , Fadel James R. 
Published: December 2020

AbstractBackgroundThe basal forebrain (BF) is comprised of several nuclei including the substantia innominata, medial septum, nucleus basalis and diagonal band of broca, which are involved in cognitive functions including attention, motivation, and arousal. BF neurons are particularly vulnerable to dysfunction and degeneration in aged humans and, more dramatically, in diseases such as Alzheimer's disease (AD). Age‐related BF dysfunction may reflect diminished afferent regulation, as well as an altered local glial environment. We have previously shown reduced orexin/hypocretin innervation of BF in aging, a phenomenon that may link afferent dysfunction with altered microglial homeostasis. There is little research examining these relationships involving afferent neuronal and glial cell populations in the BF as it relates to aging. The purpose of this study is to compare specific neuronal and glial populations to identify anatomical factors susceptible to age‐related homeostatic dysfunction in the BF.MethodsSeveral lines of evidence demonstrate the responsiveness of the BF to homeostatic stimuli including food related stimuli. Using a food‐paired stimulus to examine effects of aging on physiologically‐relevant afferent stimulation, we deposited the retrograde neuronal tracer cholera toxin B (CTb) in BF of aged (26‐28 months) and young (2‐3 months) F344/Brown Norway F1 hybrid rats and trained them for 7 days. We then combined neural tract‐tracing with functional and phenotypic markers of activation to elucidate neural circuits that may underlie age‐related loss of activation of BF neurons using immunohistochemistry. Additionally, to show that loss of orexin afferents affects inflammation in the BF via microglial dysregulation, we administered a miRNA‐expressing lentivirus designed to knock down Orexin Receptor 2(OXR2) expression in the BF in young and aged rats. We then analyzed phenotypic changes in microglia using immunohistochemistry and ELISA against a panel of inflammatory cytokines.ResultsAged rats showed altered activation of BF afferents located in the medial prelimbic cortex, infralimbic cortex, nucleus accumbens, and ventral tegmental area. Furthermore, changes in morphological and cytokine correlates of microglial activation following OXR2 loss can be seen in aged rats.ConclusionTogether, these studies compare specific neuronal and glial populations of young and aged rats to identify anatomical factors susceptible to age‐related dysfunction.
Little progress in reducing relative racial disparities in the incidence and prevalence of dementia in the United States, 2000‐2016
Authors: Power Melinda C , Bennett Erin , Ciarleglio Adam , Glymour M Maria , Turner Robert , Dowling Maritza , Gianattasio Kan Z 
Published: December 2020

AbstractBackgroundIn the United States (U.S), risk of dementia is higher in non‐Hispanic black or African American populations than in non‐Hispanic white populations. Recent reports suggest declining or stable dementia prevalence and incidence, which may impact the degree of racial disparities. Our objective was to examine whether racial disparities in dementia prevalence or incidence have changed in the U.S. from 2000 to 2016.MethodWe leverage data from non‐Hispanic white and non‐Hispanic black participants ages 70 and older from the 2000 to 2016 waves of the U.S. nationally‐representative Health and Retirement Study (HRS). For analyses of secular trends in racial disparities in dementia prevalence, we consider each HRS wave separately. For analyses of secular trends in racial disparities in dementia incidence, we created seven sub‐cohorts, which followed all eligible persons without dementia classification at baseline for seven distinct four‐year intervals: 2000‐2004, 2002‐2006, 2004‐20108, 2006‐2010, 2008‐2012, 2010‐2014, and 2012‐2016. Participant race/ethnicity was based on participant response to closed‐ended survey questions. We determined dementia status for all HRS participants at each wave using three previously developed and validated algorithms designed for use in HRS‐based studies of racial/ethnic disparities in dementia. These algorithms assign dementia status based on information gathered at HRS study visits, and were designed to have similar out‐of‐sample sensitivity and specificity across non‐Hispanic white and non‐Hispanic black subgroups. We characterized disparities using ratio measures.ResultWhile overall dementia prevalence declined from 2000 to 2016 in age‐ and sex standardized analyses, overall dementia incidence remained stable from 2000 to 2016. There was no evidence of secular trends in the magnitude of relative racial disparities in dementia prevalence or incidence. The prevalence of dementia in older non‐Hispanic black Americans remained approximately twice the prevalence in non‐Hispanic white Americans, and the incidence of dementia in non‐Hispanic black Americans was approximately 50‐60% greater than that observed in non‐Hispanic white Americans from 2000 to 2016ConclusionThere is no evidence to suggest U.S. racial/ethnic disparities in dementia risk changed between 2000 and 2016. Additional efforts to identify and mitigate the source of these disparities is warranted.
Assessing accelerometric, gait and physiological parameters of induced spatial orientation in people with MCI or mild dementia and older healthy cohorts
Authors: Hinz Charlotte Alexandra , Amaefule Chimezie O , Lüdtke Stefan , Kirste Thomas , Teipel Stefan J 
Published: December 2020

AbstractBackgroundPersons with dementia often experience spatial disorientation. They may benefit from the use of assistive technological devices to support outdoor navigation. One requirement for such systems is the automated detection of spatial disorientation to provide real time support. Previous studies showed that accelerometry and physiology signals could be informative in detecting phases of disorientation in real time. In an earlier field study, we developed a pattern recognition model of disorientated behavior based on accelerometric data from a real‐word environment. Here, we use the hybrid virtual and real‐world environment of the Gait Real‐Time Analysis Interactive Lab (GRAIL) (Figure one) to investigate accelerometric, gait and physiological parameters of induced spatial orientation among people with dementia and older healthy people.MethodWe implemented a 3D virtual environment (VE) of the Rostock city center into the GRAIL system, which consists of an instrumented treadmill and a 180° projection screen. Cognitively healthy older participants (age: 60‐85, MMSE ≥ 28) and PwD (age: 60‐85, MMSE ≥ 15 und ≤ 27) are included in this ongoing study. Participants walk a predefined route in the VE twice. In the first walk, they learn the route guided by the experimenter and then are asked to find the way to the goal destination unguided. Spatial disorientation is induced by manipulating landmarks in the 3D environment (for only the healthy older subjects in the experimental group), and resulting phases of spatial disorientation are video recorded for later offline annotation using a customized annotation scheme. Participants are equipped with wearable sensors which record heart rate, accelerometry and skin conductance. Afterwards, participants fill questionnaires examining usability and immersion.ResultRecruitment is currently ongoing. Four old healthy participants (mean age = 67.5 , SD = 3.69) (3 female) and one (male) PwD (age = 79) have been measured so far. All participants completed the experiment. Evaluation of questionnaire responses indicates an overall suitability of our setup. Further results will be presented at the conference.ConclusionOur study serves as a basis for the development of situation‐aware sensor‐based ATD that support PwD in wayfinding. This study contributes towards improving independent mobility among PwD.
Deep volumetric super‐resolution improves the detection of amyloid‐related cross‐sectional group differences in MCI
Authors: Hesterman Jacob , Avants Brian , Greenblatt Elliot , Tustison Nicholas J. 
Published: December 2020

AbstractBackgroundSuper‐resolution (SR) methodology has emerged as a practical tool that may improve the interpretability and reliability of clinical MRI [Zhao2019, Xie2019] for structural measurements. Despite promise in neurodegenerative disease populations, relatively little work has been performed to validate SR image analysis. We hypothesize that deep learning SR methodology will improve inference about the relationship between surrogate measurements of AD pathology and in vivo measurements of cortical thickness. We test this hypothesis in ADNI subjects with baseline measurements of AV45 PET and diagnosis of mild cognitive impairment.MethodWe employ a 3D variant of the deep back projection network optimized with both distortion minimizing and perceptual losses [Haris2018]. The network was not optimized in any way for ADNI data. ANTsR and ANTsRNet [Muschelli2019] were used onT1w MRI for brain extraction, registration, anatomical labeling, bias correction, segmentation, and cortical thickness estimation. Segmentation and thickness estimation were done at the resolution of the native or SR image, respectively (Figure 1). Demographic data for the ADNI cohort (n=120) used in this study are shown in Figure 2. We interrogate p‐values of both the AV45 PET SUVR predictor and the data collection site predictor, enabling evaluation of the effect of SR on both predictors of interest and nuisance variables. We also control for age at baseline, gender and APOE status.Result(1) The model relating APOE, gender, age and SUVR in left temporal lobe explained 42.9% of the variance using native resolution estimates compared to 47.1% for SR. All predictors were significant. The p‐value for SUVR was 5e‐4 for native resolution and 9e‐5 for SR. (2) MR sequence effect mitigated by super‐resolution (p = 6.7e‐7 ). (3) Main biological effects are improved (gender, APOE4, AV45, age) while nuisance (site and quality) effects are reduced. (4) SR thickness predicts amyloid level ‐ after controlling for low resolution estimate of thickness.ConclusionVolumetric super‐resolution methodology may provide a useful preprocessing step in the structural analysis of neuroimages in MCI populations. Future work should evaluate impact on longitudinal processing, quantification of functional data, optimization for clinical signal detection, and additional validation efforts in other AD and non‐amyloid pathology.