bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alzheimer’s Disease as an Autoimmune Disease
Authors: Weaver Donald F , Meek Autumn , Reed Mark , Barden Christopher 
Published: June 2023

AbstractBackgroundThe identification of new exploitable molecular pathogeneses (beyond the conventional amyloid hypothesis) for Alzheimer’s disease (AD) is a continuing neurotherapeutic priority, and has yielded a range of mechanistic proposals including immunopathy, gliopathy, mitochondriopathy, synaptopathy. However, as these new hypotheses emerge, they are often regarded as mutually exclusive and even in competition. Rather than unconditionally rejecting the role of amyloid‐β (Aβ) (or any other proposed mechanism), the need for a broadly‐encompassing model of AD, which harmonizes multiple divergent theories into a single unified explanation emerges as a much‐needed goal.MethodWe performed a comprehensive series of in silico, in vitro and in vivo studies explicitly evaluating the atomistic‐molecular mechanisms of cytokine‐mediated and Aβ‐mediated neurotoxicities in AD. Next, new chemical entities were synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small molecule therapeutics.ResultIn response to various stimuli (e.g. infection, trauma, ischemia, air pollution, depression), Aβ is released as an early responder immunopeptide triggering an innate immunity cascade in which Aβ exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon ‘self’ neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane‐penetrating attack by antimicrobial peptides (AMPs) such as Aβ. Following this self‐attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aβ, leading to a chronic self‐perpetuating autoimmune cycle. AD thus emerges as a brain‐centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti‐Alzheimer’s molecules capable of chemical modification into multi‐site therapeutic modulators targeting AD’s complex immunopathic‐proteopathic pathogenesis.ConclusionConceptualizing AD as a brain‐centric autoimmune disease of innate immunity (with Aβ as an immunopeptide), and identifying endogenous regulators of this autoimmunity, represents a novel comprehensive conceptualization approach to AD with therapeutic implications.
ABTEST‐IA: A new reliable tool for the quantification of Aβ40 and Aβ42 in CSF
Authors: Fandos Noelia , Romero Judith , Pascual‐Lucas María , Alcolea Daniel , Castillo Sergio 
Published: June 2023

AbstractBackgroundThe ratio Aβ42/Aβ40 in cerebrospinal fluid (CSF) is considered one of the most reliable biomarkers of Alzheimer’s Disease. ABtest40‐IA and ABtest42‐IA have been widely used for amyloid‐β (Aβ) quantification in plasma samples. The aim of this study was to validate these tests for the quantification of Aβ40 and Aβ42 in CSF.MethodAnalytical validation of ABtest40‐IA and ABtest42‐IA was accomplished following FDA and EMA reference guidelines. Calibration curves, sensitivity, specificity, accuracy, precision, recovery and dilution linearity were evaluated.Correlations between ABtest‐IA and an independent fully automated IVD test, (Lumipulse ® G β‐amyloid 1‐40 and 1‐42, Fujirebio), were estimated using 93 CSF samples of PET‐Aβ positive (75%) and PET‐Aβ negative (25%) individuals. Differences in CSF Aβ42/Aβ40 levels between both PET‐Aβ groups were analyzed (Mann Whitney test).The ability of CSF Aβ42/Aβ40 ratio to discriminate between PET‐Aβ positive and PET‐Aβ negative subjects was evaluated by means of Receiver Operating Characteristic (ROC) curve analysis, considering PET‐Aβ the gold standard.ResultCalibration curves ranges were set at 43.9 to 500 pg/mL for ABtest40‐IA and 5 to 100 pg/mL for ABtest42‐IA. Intra‐assay, inter‐assay and inter‐lot coefficients of variation were below 5.2% and 7.4% for ABtest40‐IA and ABtest42‐IA respectively. Accuracy evaluation provided mean relative errors of 4.6% and 7.5%.Spearman correlation coefficients between ABtest‐IA and Lumipulse® were 0.96, 0.95 and 0.93 for Aβ40, Aβ42 and Aβ42/Aβ40 respectively (p values < 0.0001). As expected, Aβ42/Aβ40 ratio levels were significantly lower in the PET‐Aβ positive group (p < 0.0001).ROC analysis of CSF Aβ42/Aβ40 gave an AUC of 0.85 (95% CI 0.74 to 0.97), very similar to that obtained with Lumipulse®: 0.84 (95% CI 0.72 to 0.98). The overall agreement of PET‐Aβ and ABtest‐IA Aβ42/Aβ40 was 90%, being false positives the majority (78%) of the misclassified subjects. Results are supporting that CSF Aβ42/Aβ40 is an early biomarker of cerebral amyloid deposition.ConclusionABtest40‐IA and ABtest42‐IA were successfully validated as new precise and accurate tools for the quantification of Aβ40 and Aβ42 in CSF samples. ABtest‐IA measures of Aβ42/Aβ40 ratio in CSF identified individuals with brain amyloid deposition with equivalent ability to other test commercially available.
Neurogranin and BACE1 as biomarkers for early detection of Alzheimer’s disease
Authors: Wang Xiao , Priller Josef , Schneider Anja , Fliessbach Klaus , Wiltfang Jens , Jessen Frank , Duzel Emrah , Buerger Katharina , Perneczky Robert , Teipel Stefan , Laske Christoph , Spottke Annika , Heneka Michael T. , Peters Oliver 
Published: June 2023

AbstractBackgroundA major goal on Alzheimer’s disease (AD) is to identify the disease in its earliest stages to provide optimal care for patients as soon as possible. Currently, the initial clinical diagnosis of AD is substantiated by the quantitative analysis of amyloid β (Aβ) peptide and Tau protein (Tau) in the cerebrospinal fluid (CSF). However, when AD becomes manifest in mental disturbances, Aβ and Tau levels have already become static. Thus, the identification of biomarkers within the earliest stages of AD are of utmost interest.This study aimed to investigate the postsynaptic proteins neurogranin and beta‐secretase 1 (BACE1) for early discrimination in AD spectrum.MethodWe analyzed the data from DELCODE, a multicenter prospective cohort study. CSF levels of neurogranin and BACE1 were measured using ELISA and compared in participants with unimpaired cognition, subjective cognitive decline (SCD), mild cognitive impairment (MCI), mild AD dementia and first‐degree relatives of patients with AD dementia. To explore differences between earlier groups, we further divided SCD into two groups based on Aβ42/pTau181: Aβ42/pTau181‐SCD, Aβ42/pTau181+SCD. Differences between the groups were analyzed with non‐parametric tests. The significance values of group‐wise comparisons were adjusted by Bonferroni correction for multiple tests.ResultA total of 530 participants were finally enrolled, including 91 healthy controls, 212 SCD (155 Aβ42/pTau181‐SCD, 57 Aβ42/pTau181+SCD), 114 MCI, 67 AD dementia and 46 first‐degree relatives. The comparisons between different groups showed CSF levels of neurogranin and BACE1 were significantly higher in Aβ42/pTau181+SCD (503.08 ± 202.89 pg /ml and 2406.39 ± 613.89 pg /ml, respectively) than those in Aβ42/pTau181‐SCD (330.94 ± 134.02 pg /ml and 1972.19 ± 561.94 pg /ml, respectively, both P < 0.0001). The AD group showed higher neurogranin levels than all other groups except Aβ42/pTau181+SCD (all P < 0.05). Furthermore, the CSF levels of Neurogranin were correlated with baseline MMSE scores (spearman r = ‐ 0.16, P < 0.001).ConclusionThis study reveals that neurogranin and BACE1 provide new perspectives for discriminating AD, which may open up possibilities of new therapeutic targets for AD.
Hippocampal BDNF encapsulated cell bio‐delivery improves spontaneous behavioral alternations in the Y‐maze test in AppNL‐G‐F mice.
Authors: Tambaro Simone , Mitra Sumonto , Gera Ruchi , Linderoth Bengt , Wahlberg Lars , Behbahani Homira , Darreh‐Shori Taher , Nilsson Per , Eriksdotter Maria 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is an age‐related disease characterized by synaptic dysfunction, brain inflammation, and neurodegeneration against which there is no effective cure available. Brain‐Derived Neurotrophic Factor (BDNF) is a key molecule involved in the learning and memory process, with a crucial role in synaptic plasticity and neuronal survival. Several findings support that a reduced BDNF expression in the human brain is associated with AD pathogenesis. BDNF has been proposed as a potential therapy for AD, but BDNF has low brain permeability. In this study, we used an innovative encapsulated cell biodelivery (ECB) device containing cells capable of locally delivering BDNF to characterize its neuroprotective effects in the novel AD APP‐knock‐in mouse model AppNL‐G‐F.MethodECB devices with human ARPE‐19 cells modified to release BDNF were surgically bilaterally implanted in the hippocampus of 3‐month‐old AppNL‐G‐F mice. BDNF effects on AD pathology were evaluated after 1, 2, and 3 months of treatment by immunohistochemical and biochemical analysis. In the 3‐month‐treated groups, exploratory and memory performances were also evaluated using Elevated Plus Maze (EPM) and Y‐maze tests.ResultThe ECB implants were well tolerated with no signs of unwanted side effects or weight loss. A high BDNF staining was detected in most of the brains in the area surrounding the devices at 1‐3 months, but retrieved devices showed variability of BDNF release. Interestingly, three months of BDNF treatment significantly improved AppNL‐G‐F mice´s anxiety behavior in EPM and improved the spontaneous behavioral alternations in the Y‐maze test.ConclusionThe results of this study are encouraging and support the BDNF device as a promising approach for treating cognitive AD decline. Optimization of the mouse‐sized devices to reduce the variability of BDNF release is needed for future experiments and translated to larger devices for clinical translation.
Effect of alpha‐Synuclein on the binding of [18F]MK‐6240 and [18F]AV‐1451
Authors: Kunach Peter , Moquin Luc , Hopewell Robert , Aliaga Arturo Aliaga , Tissot Cécile , Therriault Joseph , Zimmermann Maria , Kulasek Michal , Soucy Jean‐Paul , Massarweh Gassan , Rosa‐Neto Pedro 
Published: June 2023

AbstractBackgroundBinding in alpha‐synuclein containing brain regions have been described for both Flortaucipir ([18F]AV‐1451) and [18F]MK‐6240. Here we assessed whether alpha‐Synuclein constitutes a target for these tau imaging agents.MethodWe used autoradiographic dot blot to validate specific and evaluate off‐target interactions of [18F]MK‐6240 and [18F]AV‐1451 using sarkosyl‐insoluble extracts from PSP, CBD, PiD, and AD cortical tissue which contain fibrillar forms of tau. Tissue concentrations of alpha‐Synuclein are orders of magnitude lower than NFTs leading us to use recombinant alpha‐Synuclein PFFs to evaluate potential off‐target interactions.Briefly, 1:100 dilutions of each preparation were incubated with 82 fmol of mass in a 30uL total volume. Samples were incubated for 90 minutes at 37°C. Reactions were terminated by pipetting the solution in triplicate onto a glass fiber filter held within a 96‐well dot‐blot aspiration device and the samples were immobilized. Unbound ligand was washed three times with ice cold PBS. The glass fiber filters were transferred to a cassette for exposure to autoradiographic film for 90 minutes and the activity in photostimulated luminescence units per mm2 was calculated using ImageJ software v.1.8.0.ResultDisintegrations were corrected for decay and normalized to cerebellar extracts for both ligands. [18F]MK‐6240 demonstrated high specificity, binding in AD extracts and AD extracts subject to trypsin treatment. [18F]AV‐1451 demonstrated similar binding in both native and trypsinized AD extracts, while also showing overlapping binding profiles in human alpha‐synuclein PFFs but not in mouse alpha‐synuclein PFFs.Conclusion[18F]AV‐1451 binds to recombinant human alpha‐Synuclein PFFs as it does to native AD‐tau PHFs. Future experiments should assess patient derived alpha‐Synuclein aggregates as a potential off target binding to [18F]AV‐1451.
Relation of different CSF biosignatures to clinical phenotypes in a memory clinic cohort
Authors: Alanko Vilma , Mravinacová Sára , Kivipelto Miia , Månberg Anna , Nilsson Peter , Sandebring‐Matton Anna 
Published: June 2023

AbstractBackgroundThe heterogeneity of a multifactorial disease like Alzheimer’s disease (AD) cannot be captured solely with ATN biomarkers. Previous research has identified mixed neuropathologies as well as subtypes discovered by brain scans and cerebrospinal fluid (CSF) proteomics in AD cohorts. Still, we need a better understanding of how clinical characteristics distribute between subgroups of AD. Additionally, various approaches determining subgroups need to be evaluated. AD, which falls under the umbrella term dementia, could in fact also be considered an umbrella itself with distinct subgroups.MethodAltogether 288 CSF samples from patients from the Karolinska University Hospital memory clinic in Solna, Sweden, were analysed. Patients in the cohort were diagnosed with subjective cognitive impairment (SCI), mild cognitive impairment (MCI), and different dementias, mainly AD. Using an antibody‐based suspension bead array, levels of 75 proteins were measured. Clustering analysis methods were used to identify subgroups.ResultThe assessed panel reveals differences in patterns of protein levels within diagnostic groups and by applying clustering analyses subgroups across the dementia spectrum can be identified. Furthermore, Gene Ontology search implies differences in plausible underlying disease mechanisms between the distinct subgroups. It is of interest to explore to what extent, e.g., cardiovascular conditions or psychological burden are represented in the subgroups.ConclusionIdentifying subgroups within different diagnostic groups may prove to be crucial for finding the most suitable prevention and treatment options, particularly when disease modifying drugs are developed and tested.
Perceived usefulness of a shared journal feature to support coordination and communication across dementia care networks
Authors: Linden Anna , Jolliff Anna , Werner Nicole , Elliott Christian , Zuraw Matthew 
Published: June 2023

AbstractBackgroundCare partners (family and friends) for people living with Alzheimer’s Disease and related dementias (ADRD) often provide care within a care network of both informal (e.g. family, friends) and formal (e.g. home aides, respite care) supports. Care networks can improve care but are often associated with increased communication and coordination demands. Technology interventions have potential to support care networks, but evidence is limited. This study explored care network use of a shared communication platform to identify care partner’s perceptions of the platform’s usefulness.MethodThis study used data from a feasibility trial for CareVirtue, a web application designed to support care partners in storing and sharing information with members of their network. Fifty‐one care networks comprised of a primary care partner and other network members (N = 61) in California and Wisconsin used CareVirtue for 60 days and completed a post‐trial semi‐structured interview. This analysis focused on CareVirtue’s journal feature, which allows users to share daily experiences through written posts published to a newsfeed that care network members can view and comment on. We exported the text of these journal entries and conducted team‐based content analysis. We performed a thematic analysis on interview transcripts to identify themes related to the journal’s usefulness.ResultIn total 2,535 journal entries from 51 primary care partners (75% female, mean age = 60 years old, 55% children of care recipient, 40% spouses) and their care network were analyzed.Journal entries: We identified four categories of communication and coordination activities: 1) information acquisition in which care network members sought updates; 2) information sharing including tracking behaviors, symptoms, and daily activities; 3) strategy development in which care network members used two‐way communication to co‐create care solutions; and 4) feedback including affirmation, empathy, gratitude, confirmation, and information exchange.Interviews: We identified three journal usefulness themes: individual level usefulness including tracking information and therapeutic benefits; network level usefulness including facilitating collaboration; and relational usefulness including increased situational awareness and feeling seen as a care partner.ConclusionThe CareVirtue journal facilitated communication across the care network and also enabled self‐exploration, heightened awareness, and collaborative strategy development among the care network.
A systematic review of the neuroanatomical correlates and predictors of psychosis in Alzheimer’s disease
Authors: Scarfo Sara , Grigoriadou Loulouda , Marsella Antonella M.A. , Moshfeghi Yashar , McGeown William J 
Published: June 2023

AbstractBackgroundPsychotic symptoms (delusions or hallucinations) are a particularly prevalent form of neuropsychiatric symptom in people with Alzheimer’s disease (AD) and Mild Cognitive Impairment (MCI). Notably, their presence has been associated with an aggravation of the clinical picture of AD, with features including more rapid cognitive and functional decline, increased distress for the individuals and their caregivers (resulting in a higher rate of hospitalisation), and increased mortality. A growing number of studies detailing the relationship between neuroanatomy and these symptoms have been published in the last three decades in an attempt to clarify the underlying mechanisms. The aim of this systematic review is to capture all of the studies on AD that report links between psychotic symptoms and neuroanatomy, and to synthesise and evaluate these. Differences in the neuroimaging techniques employed, psychosis assessment tools, and brain areas investigated, as well as the sample size of the studies and disease stage of the patients, are likely to produce heterogeneous results, and these factors will be investigated during the review process.MethodThe protocol for this systematic review has been pre‐registered using the Open Science Foundation (DOI 10.17605/OSF.IO/TG8XP). Searches were performed using the databases PubMed, Web of Science and PsycInfo. These were followed by screening titles and abstracts and then full texts. These steps were performed by two independent reviewers, and recorded in a PRISMA flowchart. Inclusion of the studies was determined according to the following eligibility criteria: studies were either cross‐sectional or longitudinal to investigate the brain regions/networks that predict the future manifestation of psychotic symptoms; they contained samples of people with AD and/or MCI; they had a focus on delusions and/or hallucinations; they were limited to publications in English and peer‐reviewed publications; they had no restriction on publication date.ResultData extraction on full texts is currently underway. Once extraction is complete, data will be synthesised through summary tables and narrative descriptions.ConclusionThis systematic review intends to provide a comprehensive summary and synthesis of the brain regions and networks that are associated with psychosis and will capture key elements of the studies that are likely to impact their findings.
Pathologic TDP43 Associated Tri‐Glial Dysfunction in Amnestic and Non‐amnestic Clinical Dementia Syndromes: A Multiplexed Immunofluorescence Study
Authors: Lilek Jaclyn N , Ajroud Kaouther , Spencer Callen , Matos Arleen , Liu Xueyan , Bonakdarpour Borna , Mesulam M.‐Marsel , Bambakadis Eva , Shapiro Rachel , Feldman Alexander , Castellani Rudolph J , McCord Matthew , Jamshidi Pouya , Gefen Tamar , Weintraub Sandra , Flanagan Margaret E ,   Mesulam Center for Cognitive Neurology & Alzheimer’s Disease
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a substantial cause of death and disability. In addition to the plaques and tangles classically observed in AD, other co‐existing brain lesions also contribute to the development of cognitive impairment, such as pathologic trans‐active response DNA‐binding protein 43 (pTDP43). TDP43 is ubiquitously expressed in the brain and mechanistic studies suggest potential roles for TDP43 in maintaining normal physiologic conditions in glia (astrocytes, microglia, oligodendrocytes) (Bulgiani, 2022). Effective glial functioning and signaling are crucial to maintaining functional connectivity and pTDP43 is strongly associated with lower cognitive performance (Flanagan, 2018). However, pTDP43’s role in tri‐glial dysfunction remains unclear. We hypothesize that nuclear astrocytic TDP43 loss alters astrocyte‐to‐microglial signaling, and results in tri‐glial dysfunction. Here we examine glial pTDP43 subtypes in amnestic and non‐amnestic clinical dementia syndromes with matched AD pathology.MethodParaffin embedded autopsy samples (hippocampus and middle frontal cortex) were stained using multiplexed immunofluorescence (Pu.1: microglia, GLUL: astrocytes, total TDP43), and imaged. Indica Labs Halo software was used to perform quantitative analyses on whole slide images. Cases were matched for AD pathology (low and high) (Montine, 2012). Students’ t‐tests were performed to compare cell counts between groups. Kolmogorov–Smirnov test was performed to check approximate normality before applying t‐test and all measurements passed it. Clinical phenotypes (AD dementia vs. behavioral variant frontotemporal dementia (bvFTD)) and pTDP43 status were compared (n = 50). Spatial localization plots, NSInC colocalization indices, and Box plot comparisons were used to assess the impact of glial pTDP43 on the microenvironment.ResultHippocampal astrocyte counts are lowest in the AD dementia setting with the highest AD pathology burden, and presence of co‐existing pTDP43. Cases with high AD pathology had lower astrocyte counts when co‐existing pTDP43 was present when comparing both AD dementia with pTDP43 vs. AD dementia without pTDP43 (p = 0.03), and AD dementia with pTDP43 vs. bvFTD without pTDP43 (p = 0.05).ConclusionContradictory to studies showing increased GFAP in mutant TDP43 mice (Yan, 2014), the lowest astrocyte counts were found in individuals with AD dementia, highest burden of AD pathology, and presence of pTDP43. Results support the role of astroglial heterogeneity contributing to white matter dysfunction via selective vulnerability.