bluuebunny/crossref_metadata_2025_split huggingface dataset:
[18F]AV45 standardized uptake value ratio harmonization using ComBat in multi‐center cross‐sectional Alzheimer’s studies
Authors: Nazneen Tahnia , Servaes Stijn , Hosseini Seyyed Ali , Tissot Cécile , Rahmouni Nesrine , Therriault Joseph , Macedo Arthur C. , Tudorascu Dana , Rosa‐Neto Pedro 
Published: December 2023

AbstractBackground[18F]AV45 (florbetapir) based Positron emission tomography (PET) imaging of brain amyloid load is one of the core biomarkers for Alzheimer’s disease (AD). However, with the rise in the trend of combining data from multicenter studies, the need to correct substantial technical variability associated with image intensity scale due to multi‐center effect continues to rise. While smoothing methods remove small variability, data‐driven feature harmonization methods can adjust for scanner settings and patient motion without over‐blurring the scans. Here we aimed to investigate the effect of ComBat harmonization on multi‐site florbetapir studies to reduce variance across diagnosis groups.MethodWe assessed 163 scans from the Alzheimer’s disease Neuroimaging Initiative (ADNI3) database. These scans were acquired from 14 different sites. T1‐weighted MRI images were processed using the ADNI pipeline. PET images had 20 min (4×5min frames) acquisition at 50‐70 min post‐injection of 370 MBq (10.0 mCi) ± 10% florbetapir. Raw PET images from all sites were downloaded for quality control at the University of Michigan where the rest of the preprocessing took place using ADNI guidelines. These preprocessed scans were then used to extract SUVR maps using the cerebellar gray matter as the reference region. Based on the literature, the global SUVR for each subject was estimated from the averaged frontal, parietal, temporal, and cingulate cortices. ComBat harmonization was then performed using multicenter data, preserving diagnosis group as the covariate. A paired t‐test and logistic regression were performed to analyze the effect of the harmonization method on the SUVR.ResultA paired t‐test confirms the significant difference between the pre‐and post‐ComBat SUVR, especially for AD samples. Although the variance only decreases by 7.1% for CN as opposed to 26.9% (MCI) and 55.4% (AD), this may be explained by the large variance in the age in the sample as well as the possibility of amyloid positive individuals in the CN population. The logistic regression shows an accuracy of 87.9% for AD.ConclusionEven though ComBat harmonization significantly reduces the variance in AD and MCI population, more studies need to be performed to check its use across all PET derived features.
Antagonistic Amyloid‐β and tau interactions with T1‐weighted/T2‐weighted magnetic resonance ratio in Alzheimer’s disesase continuum
Authors: Lim Hyeon‐Wu , Seong Joon‐Kyung , Lee Wha‐Jin 
Published: December 2023

AbstractBackgroundTau protein has been reported as a major cause of neurodegeneration in Alzheimer’s disease (AD) continuum. Decrease of T1‐weighted/T2‐weighted magnetic resonace (MR) ratio has been proposed as a measure of demyelination related to neurodegeneration, but some previous researches showed contradictory increase in several brain regions, which was considered as the effecs of other microstructures such as the amyloid‐related iron deposition. Therefore, amyloid β and tau proteins appear to affect the T1w/T2w ratio antagonistically, making their relationship need to be elucidated in order to unambiguously interpret the ratio.MethodWe obtained 221 individuals which include T1‐ and T2‐weighted MR images, and 18F‐florbetapir‐ and 18F‐flortaucipir‐PET images from ADNI. The subjects were then divided into four subgroups based on the status of global Aβ and tau accumulation amount: A‐T‐, A‐T+, A+T‐, and A+T+. We determined positive amyloid status(A+) as global Aβ PET SUVR > 1.11. When determining tau positivity, we used entorhinal cortex (EC) as the earliest tau accumulation region to selectively include tau‐negative individuals while amyloid is being presented. Group differences in regional T1w/T2w ratio values were evaluated.ResultWe found significant group differences in various cortical regions, but also observed distinct effects of Aβ and tau for the T1w/T2w difference. First of all, Aβ and tau affect the T1w/T2w ratio in an opposite direction. A+ individuals have greater T1w/T2w ratio values across wide cortical regions compared to A‐ individuals for both T‐ and T+ groups. However, A‐T+ groups have smaller T1w/T2w ratio values than A‐T‐ groups, while the significant group difference was observed across relatively few cortical regions. Second, Aβ has stronger effect on the T1w/T2w ratio than tau. Specifically, the group difference between A+T+ and A+T‐ shows that Aβ increase the ratio values more strongly than tau reduces the ratio values due to greater accumulation of Aβ in the A+T+ than A+T‐.ConclusionIn this work, we observed the antagonistic interaction of Aβ and tau with T1w/T2w ratio, while more interestingly, we also found that Aβ causes high T1w/T2w ratio, more than tau causes demyelination, followed by lowering T1w/T2w ratio.
In vivo Braak staing using 18F‐MK‐6240 PET in Alzheimer’s disease
Authors: Kang Jae Myeong , Park Kee Hyung , Noh Young 
Published: December 2023

AbstractBackgroundThis study aimed to identify the distribution of [18F]MK‐6240 PET retention and classified according to Braak staging in Alzheimer’s disease (AD). We also evaluated the relationship between [18F]MK‐6240 PET retention and cognitive functions and neurodegeneration.MethodWe enrolled 194 participants including 70 CU (cognitively unimpaired elderly participants older than 60 years old), 56 MCI, 60 probable AD, and 8 patients who had dementia other than AD (subcortical vascular dementia (n = 3), semantic variant primary progressive aphasia (n = 2), frontotemporal dementia (n = 2), corticobasal syndrome (n = 1)). All participants underwent 3T MRI, [18F]MK‐6240, and [18F]Flutemetamol (FLUTE) PET scans, APOE genotyping, and detailed neuropsychological tests. Braak staging was defined as the stages where regional SUVR of ROIs composing each Braak stage > = 1.3. We assessed the Braak staging in the subjects. Correlation analyses between global retention of MK‐6240 PET and neuropsychological test results or neurodegeneration were performed using linear regression.ResultThe proportion of amyloid positivity was 11.4% in CU, 45.5% in MCI, and 83.3% in probable AD. Among probable AD (n = 60), 12 patients were classified to other dementia after amyloid PET and tau PET confirmation. Main Braak stage was Braak 0 in CU, Braak III/IV in amyloid (+) MCI, Braak V/VI in AD dementia. In CU an patents with AD spectrum, global retention of MK‐6240 PET was significantly correlated with MMSE, CDR SOB, language, visuospatial function, memory and frontal/executive functions. In addition, global retention of MK‐6240 PET was correlated with the MRI markers for neurodegeneration, that is, mean cortical thickness and hippocampal volumes.Conclusion
[
18F]MK‐6240 PET successfully identified the Braak staging and associated with amyloid pathology and clinical phenotype in patients with AD. MK‐6240 PET also correlated with cognitive functions and neurodegeneration. MK6240 is a promising tau PET tracer with the potential to be sensitive surrogate markers of AD.
Neuronal SIRPα modulates disease pathology and progression in a mouse model of Alzheimer’s disease
Authors: Samuel Melanie , Iakova Polina , Abdulwahab Qudrat , Andrade Pilar , Jiang Danye 
Published: December 2023

AbstractBackgroundMicroglia are phagocytic cells that play multiple critical roles in Alzheimer’s disease susceptibility and progress. In parallel, they display remarkable diversity in their functional and molecular states in the context of disease. This suggests that a diverse portfolio of microglial subtypes modulates outcomes in AD, but the molecules that link microglia state to their function remain unknown. To address this question, we have probed whether microglia phagocytic states are regionally specified by brain neurons via a particular neuron‐derived receptor‐ligand pair – signal regulatory protein alpha (SIRPα) and CD47.MethodsTo investigate the role of SIRPα, we use cell‐specific loss‐ and gain‐of‐function genetic approaches together with murine AD models.ResultsOur data surprisingly show that neuron‐derived SIRPα is crucial for regulating microglial phagocytic function and phagocytic state in the context of AD. Neuronal SIRPα appears to achieve this by acting as a decoy receptor to prevent microglial CD47‐SIRPα signaling, thereby permitting microglia phagocytosis. In addition, we show that neuronal SIRPα alters microglia state by regulating microglia phagocytosis in a brain‐region specific manner. We have also identified AD pathology changes and cognitive dysfunction that are limited by neuronal SIRPα‐driven microglial phagocytosis.ConclusionWe show that neuronal SIRPα is a permissive cue for microglial phagocytosis in AD and is required to restrict AD progression and cognitive decline. Identification of a neuron‐derived mechanism that dictates microglia state plasticity is unexpected and changes the way we understand how neurons program microglia outcomes in the context of disease. Results from this study also help lay the groundwork for new therapeutic options to regionally modify brain microglia state and function.
Memory focused cognitive training for older people with MCI: A CogTale Meta‐Analysis
Authors: Bahar‐Fuchs Alex , Chesser Courtney , Hampstead Benjamin M. 
Published: December 2023

AbstractBackgroundCognition‐oriented treatments (COTs) such as cognitive training (CT) are effective for improving cognition in people with MCI. Although multi‐domain CT has positive effects on global cognition, the extent to which memory‐focused CT impacts memory functions more specifically, and how process‐based, strategy‐based, and group‐based CT studies compare remains unknown.MethodWe conducted a systematic review using CogTale (Sabates et al. 2021), a novel evidence synthesis tool which automates aspects of the meta‐analysis pipeline. Embase, Medline and PsycINFO databases were searched from inception to 19/10/2022. Studies reporting the results of a controlled, memory‐oriented CT intervention for people with MCI, and that reported at least one cognitive outcome were eligible. Multi‐domain CT, multicomponent interventions were excluded. Data from eligible studies was extracted into the CogTale platform, and methodological quality scores were computed for each study. Random effects inverse variance meta‐analysis was performed for all outcomes reported by a minimum of three studies, and confidence in the effect estimates was computed based on heterogeneity, precision, and risk of bias.ResultAfter removing duplicates, 653 studies were screened and 101 studies underwent full‐text review, of which 24 (17 reporting any strategy, 16 individually‐delivered) were eligible. Across studies, small to moderate effects were found for auditory‐verbal, visuospatial, and mixed memory outcomes, and for working memory. Findings were similar when only studies using any memory‐strategy were included (k = 17). However, when studies using only mnemonic strategy training (MST) were analysed (k = 8), effect estimates for the small number of outcomes that could be pooled did not reach significance, but the confidence in these findings was low.ConclusionMemory‐oriented CT studies are associated with gains in measures of memory and working memory but not on measures of global cognition in people with MCI. Although the analysis suggested that the use of any‐memory strategy (e.g., MST, errorless learning, spaced retrieval) were associated with similar effects, when examined in isolation, no evidence was found that MST‐based CT is associated with gains on any outcomes studied. More high‐quality studies of MST‐based CT are needed to determine whether this effortful approach to CT is beneficial relative to less effortful approaches such as rehearsal‐based CT.
A toolkit to study microglia states using stem cell‐derived models
Authors: Therrien Martine , Dolan Michael John , Jereb Sasa , Kamath Tushar , Meyer Daniel , Atkeson Trevor , Glass Christopher K. , Leinonen Ville , Blurton‐Jones Mathew , Macosko Evan , Stevens Beth 
Published: December 2023

AbstractBackgroundEmerging genetic studies of late‐onset Alzheimer’s Disease (LOAD) implicate microglia, the brain’s resident macrophages. More than half the risk genes associated with LOAD are expressed in microglia, yet we know little about the underlying biology or how myeloid cells contribute to LOAD pathogenesis. Single‐cell transcriptomic studies reveal diverse microglial states in patients and mouse models; however, we lack tools to track these states and understand the impact of environmental challenges or genetic susceptibility.MethodWe used human embryonic and induced pluripotent stem cell models to gain insights into microglia. These cells can be differentiated into microglia, enabling the broad characterization of cells in vitro and understanding their impact on the other cell types in xenograft models, allowing us to gain biological insight into disease pathogenesis.ResultOur lab has developed a novel human stem cell‐based platform1 which induces stem cell‐derived microglia (iMGLs) to take on diverse transcriptional signatures similar to those found in the human brain in response to exposure to brain‐relevant substrates. Moreover, we conceived a lentiviral protocol that allows for efficient genetic manipulation of microglia (>90% transduction). Building on these systems, we generated reporters of microglia state to track the expression of key microglial genes and adapted iPSC “villages”2, or pooled cultures, that combine iPSC cell lines in the same dish. Using these tools in vitro and in xenograft models3,4, we identified genetic regulators and functional changes of microglia states in LOAD.ConclusionTogether, these tools represent a broad toolset that will allow us to answer some of the most pressing questions, such as when and how in disease these states are formed, what is their impact on disease progression, and how plastic they are. These tools will be invaluable to understanding the role of microglia in AD and the brain in general.1. Dolan, M.‐J. et al. Biorxiv 2022.05.02.490100 (2022)2. Wells, M. F. et al. Biorxiv 2021.11.08.467815 (2021)3. Hasselmann, J. et al. Neuron
103, 1016‐1033.e10 (2019)4. Mancuso, R. et al. Nature Neuroscience
22, 2111‐2116 (2019)
Multiomics of iPSC‐derived ApoE3‐ and ApoE4 astrocytes and microglia uncovers cell type specific dysregulation of immunometabolism
Authors: van der Kant Rik , Blomberg Niek , Erlebach Lena , Feringa Femke M , Heijneman Jorin , Koppes Sascha , Kruijff Iris Daphne , McQuade Amanda , Miramontes Ricardo , Olivier‐Jimenez Damien , Robert Aiko , Thompson Leslie M. , Ori Alessandro , Kronenberg‐Versteeg Deborah , Mohammed Yassene , Kampmann Martin , Giera Martin 
Published: December 2023

AbstractBackgroundApoE4 is the major genetic risk factor for Alzheimer’s disease and the main lipid transporter in brain. How ApoE4 drives AD pathogenesis, and how this is related to changes in lipid metabolism, is not well understood. This lack of mechanistic insight has hampered the development of interventions that can reverse the pathological effects of ApoE4.MethodsHere we perform integrated multiomic analysis (lipidomics, metabolomics, transcriptomics and proteomics) on isogenic iPSC‐derived glia carrying an ApoE4/4, ApoE3/3 or ApoE‐knockout genotype. We employ pathway enrichment to identify candidate biological processes that contribute to AD pathogenesis and perform a number of biochemical‐ and intervention experiments to gain insight into the biological mechanism. We feed iPSC‐derived glia with different lipid species to better understand the interaction between lipids and immune dysfunction. Lastly, we generate a new open‐access resource (the Neurolipid atlas), to allow others in the field to interact with our lipid data.ResultsOur lipidomic analysis shows that ApoE4 has a major effect on lipid metabolism in human iPSC‐derived astrocytes and microglia. In both astrocytes and microglia, ApoE4 causes accumulation of cholesteryl esters (CE), triglycerides (TAG) as well changes in ceramide metabolism. Interestingly, transcriptomic and proteomic analysis in both cell types shows that ApoE4 glia have strongly upregulated cholesterol synthesis despite having already high levels of stored cholesterol (CE). Astrocytes and microglia show very distinct adaptations to ApoE4 in terms of energy production. Whereas ApoE4 astrocytes have higher levels of mitochondrial proteins, ApoE4 microglia downregulate mitochondrial proteins but have increased levels of key glycolytic proteins. Immune profiles, including DAM signatures in microglia, are changed in a similar direction in both ApoE4 astrocytes and microglia. Lipid feeding also directly affect these immune pathways.ConclusionOur data indicate that astrocytes and microglia display both common and distinct immunometabolic adaptations to the ApoE4 genotype. Interestingly, both ApoE4 microglia and astrocytes have increased stored cholesterol yet keep upregulating cholesterol synthesis, indicating a possibly pathogenic broken feedback loop. We also show that this altered lipid metabolism is tightly coupled to immune dysfunction and propose novel mechanisms and interventions that may normalize ApoE4 dysfunction in human glia in AD.
An agenda for addressing multimorbidity and racial and ethnic disparities
Authors: Quiñones Ana R. 
Published: December 2023

AbstractAdvancements in Alzheimer’s disease and related dementias (ADRD) research on the U.S. population acknowledge the importance of the high burden of ADRD on segments of the population and yet‐to‐be characterized risks attributable to the burden of multiple chronic diseases (multimorbidity). These realizations suggest successful strategies in caring for people with ADRD and their caregivers will rely not only on clinical treatments but also on more refined and comprehensive models of ADRD that take its broad effects on the whole‐person and the whole of society into consideration. To this end, it is critical to characterize and address the relationship between ADRD and multimorbidity combinations that complicate care and lead to poor outcomes, particularly with regard to racial and ethnic disparities in the occurrence, course, and effects of ADRD.
Observations on biomarkers in Roche Abeta‐targeting monoclonal antibody trials
Authors: Doody Rachelle S. 
Published: December 2023

AbstractBackgroundOne of the profound innovations in Alzheimer’s disease research has been the ability to image beta‐amyloid plaques in living patients with the use of amyloid PET imaging. This technology, coupled with advances in basic research that supported mechanisms of action targeting beta amyloid, and innovations in the clinical profiling of AD patients and in clinical trial designs have enabled the disease‐modification era for AD therapeutics.MethodWhile identifying amyloid plaques in living patients has greatly helped to stratify populations for study and treatment, measured changes in plaque burden during treatment with anti‐beta amyloid drugs has not proven to be a simple outcome measure that directly quantifies clinical benefit. Dissociations between amyloid reduction and downstream markers of AD pathology, such as those seen in the crenezumab and gantenerumab Autosomal Dominant AD studies (NCT01998841 and NCT05552157) suggest that the brain processes associated with AD can improve without causing concurrent measurable benefits in people at risk for or affected by genetic forms of AD, with or without lowering plaque burden.ResultBiomarker results in the phase III GRADUATE I and II (NCT03444870 and NCT03443973) trials with gantenerumab in early AD (sporadic) also suggest that even moderate reduction of beta‐amyloid plaques may not result in clinically meaningful benefits over a therapeutic time course that makes sense for patients, while the phase III CLARITY‐AD trial (NCT01767311) with lecanemab and phase III TRAILBLAZER‐ALZ 2 trial (NCT04437511) with donanemab suggest that enough reduction can cross the threshold for clinical efficacy. Taken together, these study data suggest that plaque depletion to a level near or below the amyloid PET positivity threshold may be necessary to see clinical benefit with this type of monotherapy.ConclusionThis observation, if confirmed, would not rule out the use of beta amyloid lowering therapies that do not completely clear beta amyloid when used in combination approaches.
Lecanemab: Amyloid Reduction and Evidence of Downstream Biomarker Modification
Authors: Irizarry Michael C. 
Published: December 2023

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils) which has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in a Phase 3 Study in early AD (Study 301). The objective of this analysis is to report biomarker results from Study 301.MethodsStudy 301 was a double‐blind, randomized, placebo‐controlled study of 1875 patients with early AD randomized to 10 mg/kg IV lecanemab or placebo for 18 months of treatment. Plasma, CSF, and imaging biomarkers of amyloid, tau, neurodegeneration, and gliosis were assessed.ResultsLecanemab met all primary and key secondary clinical endpoints with a high degree of statistical significance. Lecanemab improved markers of amyloid with reduction of brain amyloid by PET in as early as 3 months and improvement in CSF Aß42 and plasma Aß42/40. Biomarkers of tau showed improvement in CSF and plasma p‐tau181, and slowing of tau accumulation relative to placebo in the medial temporal regions by tau PET. For biomarkers of neurodegeneration and gliosis, there was improvement in CSF t‐tau, CSF neurogranin, and plasma GFAP. There were no significant differences in CSF or plasma Nf‐L between lecanemab and placebo. Volumetric MRI results were inconsistent, with reduced hippocampal atrophy on lecanemab, but greater cortical volume loss relative to placebo, possibly “pseudoatrophy” related to amyloid mobilization.ConclusionsLecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Improvements in biomarkers of amyloid, tau, neurodegeneration, and gliosis provide a biological basis for the treatment effects consistent with disease modification.
Uncovering the burden of Dementia in the Middle East and North Africa (MENA) Region: current situation, opportunities, and challenges
Authors: Chaaya Monique 
Published: December 2023

AbstractThe increase in the aging population in the Arab countries of MENA is consistent with the global trend. Yet, several countries in the region have no to little information about dementia burden. Projections are dire but preparedness is limited. Dementia studies from the Arab region remain scarce and available ones suggest that the disease incidence in an Arab population is higher than a population with similar literacy and educational profile. The only published study reporting on dementia incidence in the Arab region is from Egypt. Unpublished data from Lebanon reported a rate falling in the high range of incidence, lower than Venezuela, Mexico, and China and close to European and North American countries’ estimates. Using standardized and validated tools, in collaboration with Danish research experts in dementia, and with funding from Fogarty, Lebanese researchers were able to measure the burden of dementia among community based older adults. (crude prevalence 7.4% and standardized is 9). A more recent research activity supported by an NIA R01 grant and in collaboration with US‐based researchers, will establish a cohort study of 3000 older adults to assess ADRD burden, risk factors and dementia. Lebanon have benefited from two NIH funding opportunities to establish collaboration, train scientists, and build the infrastructure to study Dementia.