bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of Inflammasome Activation through the Modulation of b‐hydroxybutyrate Levels In vivo Decreases Alzheimer’s Disease Pathology
Authors: Shippy Daniel , Hanslik Kendra , Wilhelm Connor , Patel Viharkumar , Zarbock Katie R , Bendlin Barbara B. , Rey Federico E. , Raife Thomas , Ulland Tyler K. 
Published: December 2022

AbstractBackgroundUsing gnotobiotic models, our research group has demonstrated that specific changes in the gut microbiome modulate serum and brain b‐hydroxybutyrate (BHB) levels. BHB levels measured in blood also differ in Alzheimer’s disease (AD), and BHB has been linked with immune function. Recently, microglial activation of the nod‐like receptor family pyrin domain containing protein 3 (Nlrp3) inflammasome—a multi‐protein complex that when activated results in apoptosis specks‐like protein containing a caspase recruitment domain (Asc)‐speck accumulation—has been recognized as feature of AD (extracellular Asc‐specks can nucleate Ab plaques and enhance AD pathology). Given that gut microbiome modulates immune function and may impact inflammasome activation, here we tested the extent to which BHB differs in AD brain, impacts the Nlrp3 inflammasome and impacts AD pathology.MethodsBrain samples and red blood cells from N = 10 individuals with AD and N = 10 controls were obtained from the Wisconsin ADRC and subjected to untargeted metabolomics. For mouse experiments 5XFAD mice, a model for Ab plaque formation, and wild type controls were treated with oral BHB in drinking water. Mice were maintained on BHB drinking water from 8 weeks of age until 4 months of age. Upon harvest half of each mouse brain was fixed, sectioned, stained, and imaged on a confocal microscope. The levels of BHB in the other half of each brain were assessed.ResultsWe found that individuals with AD have lower levels of BHB in both their red blood cells and their brains. As BHB is known to inhibit Nlrp3 inflammasome activation we hypothesized that increasing BHB levels would result in the inhibition of the Nlrp3 inflammasome and subsequent reduction in AD pathology in vivo. To test this, we administered BHB orally to 5XFAD mice. BHB administration increased brain BHB levels, reduced plaque load, microgliosis, inflammasome activation, and Asc‐spec formation.ConclusionsOur findings demonstrate that BHB levels are lower in the brains of individuals with AD and BHB administration in 5XFAD mice reduces AD pathology by inhibiting Nlrp3 inflammasome activation and Ab plaque formation. Taken together, our data suggest future studies exploring the role of BHB in humans with AD are warranted.
Comparison between plasma, serum and cerebrospinal fluid glial fibrillary acidic protein in Alzheimer’s Disease and Dementia with Lewy bodies and the effect of age and sex on diagnostic performance
Authors: Honey Madison I. J. , Wesenhagen Kirsten E. J. , Willemse Eline A.J. , Verberk Inge M.W. , Boonkamp Lynn , Killestein Joep , Visser Pieter Jelle , Tijms Betty M. , Teunissen Charlotte E. 
Published: December 2022

AbstractBackgroundGlial fibrillary acidic protein (GFAP) is a novel Alzheimer’s Disease (AD) biomarker that associates with amyloid pathology and pathology‐related changes can be detected in different biofluids. We studied how the performance of GFAP to distinguish between controls, AD and dementia with Lewy bodies (DLB), depends on the studied biofluid (cerebrospinal fluid (CSF), serum or plasma) and the confounding effects of age or sex.MethodFrom the Amsterdam Dementia Cohort and a local repository of healthy controls we included 372 cognitively normal individuals (CN), 255 patients with AD and 120 patients with DLB (Table 1) and GFAP levels were measured in one (n=322), two (n=416) or three (n=9) biofluids. GFAP was measured using Simoa in CSF (n=473), plasma (n=257) and serum (n=451) samples. For individuals with DLB, GFAP was measured in CSF and serum only. Effects of clinical diagnosis, age and sex on GFAP levels in each body fluid were estimated with linear models. Estimated differences between diagnostic groups were corrected for age and sex, age effects were corrected for sex and diagnostic group, and sex effects were corrected for age and diagnostic group.ResultGFAP levels were increased in AD relative to controls in all biofluids (fold change (FC): 1.6(CSF), 1.9(plasma) and 1.4(serum), p‐values<0.001) and increased in AD relative to DLB (FC: 1.7(CSF) and 1.3(serum), p‐values<0.001, Figure 1). No difference was found between DLB and controls. CSF GFAP levels increased with age in all clinical groups (range of standard deviation protein level increase per year (SD/year): 0.020‐0.024), while plasma GFAP levels increased with age only in CN (SD/year: 0.032). Serum GFAP levels increased with age in CN and DLB (SD/year: 0.058(CN) and 0.074(DLB), Figure 2). CSF GFAP showed sex effects in AD only (FC in males compared to females: 1.1), whereas serum GFAP showed sex effects in all clinical groups (FC in males: 0.83(AD), 0.85(NC) and 0.72(DLB)), and plasma GFAP showed no sex effects (Figure 3A‐C).ConclusionDifferences in GFAP levels between clinical diagnoses showed the same trend for all three matrices. With older age, differences in GFAP levels between controls and AD become harder to detect.
A systematic approach to reduce cultural bias: An illustration from the adaptation of the Addenbrooke’s Cognitive Examination III for the Bengali speaking population in India
Authors: Dutt Aparna , Nandi Ranita , Rao P.Sulakshana , Bhargava Pallavi , Gopalkrishnan Subha , Bose Arpita , Ghosh Amitabha , Evans Jonathan J. 
Published: December 2022

AbstractBackgroundA systematic approach is vital for adapting neuropsychological tests developed and validated in the western, educated and English populations. However, rigorous and uniform methods are often not implemented during adaptation of neuropsychological tests and cognitive screening tools across different languages and cultures. This has serious clinical implications. The naming test from the Addenbrooke’s Cognitive Examination (ACE) III will be presented as an example to illustrate a systematic approach for selecting culturally appropriate and psychometrically reliable items for a literate Bengali speaking population in India.MethodTwo studies were conducted in seven phases for adapting the ACE III naming test. Twenty‐three items from the naming test in the English and the different Indian ACE‐R versions were administered to healthy Bengali speaking literate adults for determining image agreement, naming and familiarity of the items. Eleven items were identified as outliers. We then included 16 culturally appropriate items that were semantically close to the items in the selected ACE‐R versions of which 3 were identified as outliers. The final corpus consisting of 24 items was administered to 30 patients with mild cognitive Impairment, Alzheimer’s disease and vascular dementia, and 60 healthy controls matched for age and education to determine which items in the corpus best discriminated patients and the controls, and also their difficulty levels.ResultThe ACE III Bengali naming test with an internal consistency of .87 included 12 psychometrically reliable, culturally relevant high naming‐high familiarity and high naming‐low familiarity living and non‐living items. Item difficulty ranged from .47 to .88 and had discrimination indices ≥.44.ConclusionA systematic approach helps to determine whether a test is appropriate for the cultural context (within nations also) in which it is intended to be used, and also the possible reasons if inappropriate, which subsequently determines the principle/framework for test adaptation. Adaptation of neuropsychological tests based on familiarity driven approach helps to reduce cultural bias at the content level. This coupled with appropriate item selection statistics helps to improve the validity of the adapted tests and ensure cross‐cultural comparability of test scores both across and within nations.
Structural Basis and Mechanism of Cyclophilin A‐Tau Interaction in Alzheimer’s Disease and Neuroinflammation
Authors: Murray Anqesha L , Wang Chunyu , Gibson James 
Published: December 2022

AbstractBackgroundTau protein that comprises neurofibrillary tangles in Alzheimer’s Disease (AD) interact with the abundant immunophilin protein Cyclophilin A (CypA) due to its peptidyl‐prolyl cis‐trans isomerase activity.MethodUsing surface plasmon resonance (SPR), nuclear magnetic resonance (NMR) and cell culture, structural details of CypA/tau interaction and its functional consequences are characterized.ResultUsing SPR, we observed a binding equilibrium constant (KD) of full‐length tau at ∼10 µM and identified the tau binding pocket on CypA using NMR. CypA and tau uptake by microglia was measured by immunofluorescence microscopy and flow cytometry. CypA‐tau interactions within microglia cell lines affect neuroinflammation by altering proinflammatory and anti‐inflammatory cytokine secretion responses.ConclusionCypA binds to tau with high affinity and specificity, which has functional significance in tau conformation, interaction, aggregation, and in neuroinflammation.
The Lived Experience Of Latinx‐Americans And How Researchers Can Build Stronger Partnerships To Improve Research
Authors: Flores Melissa , Walter Sarah , Seshadri Sudha 
Published: December 2022

AbstractBackgroundThe Latinx population is growing in the United States, and yet recruiting participants at representative rates into research for dementia is an ongoing challenge. This group is additionally facing the largest increase in Alzheimer’s Disease and related dementia diagnoses; however, literature indicates their contribution is regularly absent from related research and clinical trials. Representative recruitment to research is critical to ensure the outcomes of research are applicable and generalizable to this large population group. Hearing and understanding the lived experience of individuals from Latinx communities is key to addressing barriers to participation. Literature around increasing minority participation notes approaches of personalization are essential in reaching Latinx groups. This session will assist researchers in tailoring strategies of recruitment and methods of engaging with the latinx population by providing the necessary platform and direct connection to this community.MethodThe panelist, selected by the Biggs Institute research team, will share their lived experience with ADRD diagnosis, care, and/or research participation. As part of the South Texas ADRC, the Biggs Institute selected panelist will provide the perspective of Latinxs living in south Texas and along the border, specifically addressing the unique challenges faced in accessing care and research. They will communicate their connection to research, personal and potential cultural barriers to research involvement, and share what researchers can do to build better partnerships with Latinx communities.ResultThis session will highlight the Latinx perspective related to dementia research and will offer the opportunity for further understanding around the experience of individuals in minoritized communities. Attendees will hear the perspective of the Latinx community to prompt improved methods of inclusion. This session aims to benefit researchers, and those in the field of aging and dementia research, by providing perspectives crucial to the development of strategies to facilitate engagement with a more demographically diverse community.ConclusionThe voice of Latinx individuals is essential to include when discussing research priorities and addressing the challenges to increase diverse research participation. Improving inclusivity in ADRD research will improve relevance of findings, and sharing diverse perspectives is a first step to build meaningful partnerships with the latinx community.
Why and how to engage with African American faith communities in brain health research?
Authors: Epps Fayron , Moore Miranda , Chester Mia , Gore Janelle , Aycock Dawn 
Published: December 2022

AbstractBackgroundDisparities in brain health outcomes often involve African American individuals. To achieve the highest impact for health care initiatives; effectively engaging with African American communities is crucial. One method to reach African American communities is to effectively collaborate with churches. Churches are often seen as the cornerstone of African American communities and should be regarded as a key partner in health care research. Churches have opportunities to respond to the health needs of their respective congregation and communities. For this presentation, we will outline effective strategies for engaging African American churches in promoting behavior change to enhance health equity for health care research.MethodsStrategies include: a) Learning the history of the church, b) Selecting the best person to represent your organization, c) Having a clear ask, d) Engaging in honest conversations with leadership, e) Being persistent and engaging in church sponsored activities, and f) Offering a sustainability plan.ResultsThe implementation of these strategies requires planning, time, and commitment. For example, Alter (nurse‐led dementia‐friendly congregation program) has implemented these strategies over a 2‐year period and excelled in promoting brain health and reducing dementia stigma in African American communities.ConclusionHealth professionals and researchers can use these strategies within their practices and research to improve health and promote health equity for African American individuals and communities.
APOE e4 dependent deficits in brain DHA phospholipids and mfsd2a in Alzheimer’s disease patients with severe cerebral amyloid angiopathy
Authors: Nkiliza Aurore , Evans James , Ringland Charis , Daniel Niedospial , Huguenard Claire , David Roderick , Ojo Joseph , Crawford Fiona , Mullan Michael , Bachmeier Corbin , Abdullah Laila 
Published: December 2022

AbstractBackgroundThe apolipoprotein E e4 allele (APOE4) is a major risk factor, contributing to vascular pathologies in AD which include CAA, BBB dysfunction and reduced cerebral vascular integrity. The diminished capacity of APOE4 to transport docosahexaenoic acid (DHA), an essential fatty acid required for the structural and functional maintenance and vascular integrity of the brain, could also contribute to AD pathogenesis. However, it remains undetermined if changes in the brain DHA content of phospholipids (PL) and DHA transporters exist in relation to APOE4, AD diagnosis and CAA pathology.MethodWe performed liquid chromatography/mass spectrometry‐based PL analysis of the cerebrovascular and parenchymal fractions from autopsied human brain of pathologically confirmed AD cases and controls. We performed an antibody‐based examination of the major facilitator superfamily domain containing 2A (mfsd2a) protein in the cerebrovasculature from these subjects and brain homogenates from transgenic mice with human APOE (APOE‐TR) and APOE‐TR crossed with mice with five AD mutations (EFAD). We performed proteomic analyses of the cerebrovascular and parenchymal fractions of the brains from 50‐week‐old APOE‐TR.ResultIn the cerebrovasculature and parenchyma, DHA containing PL species were lower in ε4 carriers with AD compared to control ε4 carriers. We observed an ε4‐dependent decrease in mfsd2a level in the cerebrovasculature of ε4 carriers compared to non‐carriers. Stratification of DHA containing PL by CAA showed that these PL levels were reduced in ε4 positive AD patients with severe CAA. In addition, brain levels of DHA containing PC species and mfsd2a were lower in APOE4‐TR and E4FAD mice compared to other genotypes in each mouse model. Furthermore, protein levels of glucose transporter 1 (Glut1) and a metabolite transporter, monocarboxylate transporter 1 (MCT1), were lower in the cerebrovasculature of APOE4‐TR relative to APOE3‐TR and APOE2‐TR mice.ConclusionThese findings demonstrate that brain DHA deficiencies in ε4 carriers may be due to reduced mfsd2a expression and partly associated with severe CAA. Thus, targeting this transport mechanism may improve the bioavailability of DHA into the brains of ε4 carriers who are at risk of developing AD.
Different atrophy profiles detected in AD patients who carry APOE4 versus non‐carriers: An ENIGMA‐VBM Multicohort Analysis (N=1,893)
Authors: Rajagopalan Priya , Tennant Victoria R , Thomopoulos Sophia I , Owens‐Walton Conor , Kempton Matthew , Si Shuqing , Thompson Paul M 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is the most common neurodegenerative disorder and apolipoprotein E (APOE) ε4 allele is the greatest common genetic risk factor for late‐onset AD. In one of the largest multi‐cohort VBM analyses to date, we aimed to a) map regional brain cortical volume deficits in people with dementia vs controls (CTL) and b) investigate how atrophy patterns in AD were modulated by carrying the APOE4 genotype.MethodThe ENIGMA voxel based morphometry (VBM; https://sites.google.com/view/enigmavbm) pipeline was used to perform a mega‐analysis and a multi‐cohort meta‐analysis on T1‐weighted brain MRI data from 1,893 subjects (Table 1) across four different cohorts, namely the Alzheimer’s Disease Neuroimaging Initiative (ADNI), phases 1, GO/2, 3, and the Open Access Series of Imaging Studies (OASIS3). 488 participants with AD had APOE genotype data with 172 non‐carriers (ε3/3) and 316 carriers (ε3/4, ε4/4). Protective APOE ε2 carriers were excluded. Within the 488 participants with AD, effects of carrying the APOE4 allele were tested using a VBM analysis adjusting for age, sex, intracranial volumes and differences in cohorts.ResultAs expected, compared to controls (CTL), participants with dementia demonstrated cortical brain volume deficits in medial temporal lobes, notably the bilateral hippocampus, entorhinal cortex, amygdala and fusiform gyrus in Mega‐ & Meta‐analysis (Fig. 1). In those with AD, APOE4 carriers demonstrated relatively higher gray matter volumes in the primary motor cortex, medial frontal gyrus and posterior middle temporal gyrus, compared to non‐carriers (P<0.001, uncorrected; Fig. 2). As expected, APOE ε4 carriers demonstrated lower medial temporal lobe and precuneal gray matter volumes.ConclusionAn expected strong pattern of medial temporal lobe volume reduction was noted in the dementia group compared to CTL. Interestingly, within the dementia group, APOE ε4 carriers showed higher gray matter density in the primary motor cortex, a region not routinely associated with AD nor with amyloid deposition, as shown in a smaller prior study. APOE ε4 carriers showed typical medial temporal and precuneal volume reductions which commonly show amyloid deposition, consistent with the notion that APOE ε4 mediates atrophy mainly via an amyloid dependent mechanism.References: 1) Ashburner J, Friston KJ. doi:10.1006/nimg.2000.0582. 2) Liu, Ying. doi:10.1016/j.neuron.2014.11.020. 3) La Joie, Renaud. doi:10.1126/scitranslmed.aau5732. 4) Gutiérrez‐Galve L. doi:10.1159/000258100 et al. 2009;28(5):461‐70.
Cellular network perturbations point to a new microglia‐astrocyte community accelerating Alzheimer’s disease progression
Authors: Green Gilad Sahar , Fujita Masashi , Yang Hyun‐Sik , McCabe Cristin , Taga Mariko , Cain Anael , Zeng Lu , Regev Aviv , Bennett David A , Menon Vilas , Habib Naomi , De Jager Philip L 
Published: December 2022

AbstractBackgroundAlzheimer’s Disease (AD) is a fatal neurodegenerative disease where abnormal accumulation of amyloid‐β and tau aggregates drive neurodegeneration and leads to cognitive impairment, dementia and eventually death. Combining results from recent studies, each finding a novel AD‐associated cell state of different non‐neuronal cell types, suggests a system level change of the cellular environment of the AD brain and its potential role in disease outcome.MethodTo better understand the dynamics of the cellular environment in aging human brains and AD, we applied single‐nucleus RNA‐sequencing to profile 424 aging brains of individuals across different clinicopathological characteristics. We characterized the cellular diversity within the aging human prefrontal cortex, resulting in a detailed atlas of ∼1.7 million cells classified into 95 cellular subsets of different cell types, including rare populations of microglia and astrocytes.ResultsQuantifying variations across individuals, we uncovered multiple cell subsets associated with disease pathologies and cognitive impairment. Of these, we prioritize an uncommon Microglial subset 13 (Mic.13, average 3.2% of microglia) and Astrocyte subset 10 (Ast.10, average 3.8% of astrocytes). Mic.13 expresses AD risk gene TREM2 and microglial markers linked to AD (e.g. APOE, SPP1), and its proportion is strongly associated with AD pathologies, amyloid‐β plaques and neurofibrillary tangles, and cognitive decline. Applying a mediation model, we showed that Mic.13 partially mediates the effect of amyloid‐β on tau (proportion mediated [p.m.] = 18%). While the impact of Mic.13 on cognitive decline is largely mediated by tau (p.m. = 43%), an additional subset highlighted by our analysis Ast.10, associated with both tau and cognitive decline, partially mediates the impact of tau and Mic.13 on cognitive decline (p.m. = 7.2% and p.m. = 12% respectively). Integration of all cellular states revealed an intricate network of multi‐cellular communities, each composed of multiple states of different cell types. Investigating the dynamics of the cellular communities in the aging brain and along disease progression, uncovered unique trajectories spanning from a healthy to diseased brains.ConclusionOur charted atlas of the cellular environment and modelling of the cellular dynamics supports a system level change underlying AD, with an active role for multiple cell types in disease progression, and highlights novel research directions and potential therapeutic targets.
Present mind in aging brain: Neural associations of dispositional mindfulness in cognitive decline
Authors: Sumec Rastislav , Filip Pavel , Vyhnalek Martin , Katina Stanislav , Hort Jakub , Sheardova Katerina 
Published: December 2022

AbstractBackgroundSubjects at risk of dementia, such as subjective cognitive decline (SCD) and mild cognitive impairment (MCI), present with specific clinical symptoms, as well as functional and structural changes within the brain. Dispositional mindfulness (DM) has been linked to better cognitive performance and is associated with activation and grey matter volume of specific brain regions. It is yet unknown how DM is related to cognitive and neural parameters of those at risk of dementia.ObjectiveTo estimate the association of DM with cognitive functions, brain volumetry, functional connectivity and gray matter integrity in key regions relevant for cognition (hippocampus, anterior cingulate cortex) and self‐awareness (ventromedial prefrontal cortex (vmPFC), posterior cingulate cortex) in SCD and MCI subjects.Methods79 non‐demented older adults with memory complaints ((SCD = 48, MCI = 31) were assessed by neuropsychological tests, MRI volumetry, resting‐state fMRI‐derived connectivity and DTI. Dispositional mindfulness was examined with Breath Counting Task (BCT).ResultsParticipants with MCI showed significantly worse BCT performance in comparison to SCD (p˂0.001). In MCI, BCT performance was positively associated with connectivity (p˂0.001) and negatively related to mean gray matter diffusivity (p˂0.05) in vmPFC. No other significant associations were found between DM, MRI measures and neuropsychological variables in either group.ConclusionWorse cognition in subjects at risk of dementia may be reflected in changes in DM. Lower connectivity and worse gray matter integrity of vmPFC in MCI could play a role in the worsening of DM in this population. Longitudinal studies are needed to further clarify the relatedness of DM and neural changes elicited by neurodegeneration in people at higher risk of dementia.