bluuebunny/crossref_metadata_2025_split huggingface dataset:
CSF sTREM2 and YKL‐40 modify the balance between soluble and fibrillary β‐amyloid in non‐demented individuals
Authors: Cacciaglia Raffaele , Falcon Carles , Shekari Mahnaz , Salvadó Gemma , Milà‐Alomà Marta , Kollmorgen Gwendlyn , Carboni Margherita , Molinuevo Jose Luis , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   ALFA study
Published: December 2023

AbstractBackgroundCerebrospinal fluid (CSF) Aβ concentrations and Positron Emission Tomography (PET) imaging provide information of two different Aβ pools. Identifying the factors affecting the balance between soluble and deposited Aβ may inform on the mechanism of cerebral Aβ aggregation. Microglia and astroglia respond to Aβ pathology, yet their role in promoting the aggregation of Aβ plaques is unclear. We addressed whether CSF sTREM2 and YKL‐40 modulate the association between soluble and deposited Aβ in a cohort of middle‐aged cognitively unimpaired (CU) individuals.MethodThe first consecutive 320 CU individuals of the ALFA+ study with a [18F]flutemetamol (FTM) PET scan and CSF samples were included. CSF Aβ40, Aβ42, sTREM2, and YKL‐40 were measured with the Roche NeuroToolKit robust prototype immunoassays (Roche Diagnostics International Ltd). Standardized uptake value ratio images were calculated and a voxel‐wise regression was performed to predict FTM uptake. The interaction terms between CSF Aβ42/40 and either CSF sTREM2 or YKL‐40 served as predictors, while adjusting for age, sex, years of education, and APOE‐ε4. Statistical threshold was set to p<0.001 with a cluster extent correction of 100 voxels.ResultTable 1 describes the sample’s characteristics. As expected, CSF Aβ42/40 concentrations were negatively associated with Aβ PET uptake in widespread areas of the brain, but this association was modified by CSF sTREM2 and YKL‐40. Higher levels of CSF sTREM2 were associated with a reduced Aβ PET uptake for any level of CSF Aβ42/40 in the hippocampus bilaterally. Conversely, higher CSF YKL‐40 related to a higher Aβ PET uptake as a function of CSF Aβ42/40 in the precuneus, prefrontal cortex, and inferior parietal areas.ConclusionIn CU individuals, microglia and astroglia reactivity modify the association between soluble (CSF) and deposited (amyloid PET) Aβ. While TREM2‐mediated microglial response (as measured by CSF sTREM2) may prevent Aβ deposition in individuals with decreased soluble Aβ, astroglial reactivity (as measured by CSF YKL‐40) may have the opposite effect.
Prediction of continuous amyloid PET values by CSF tau measures
Authors: Wisch Julie K. , Gordon Brian A. , Barthélemy Nicolas R. , Horie Kanta , Henson Rachel L. , He Yingxin , Flores Shaney , Benzinger Tammie L.S. , Morris John C , Bateman Randall J. , Schindler Suzanne E. , Ances Beau 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) is a slowly progressive neurodegenerative disorder characterized by the presence of amyloid plaques that can be measured in vivo with positron emission tomography (PET). PET quantifies the lifetime accumulation of amyloid plaques, while cerebrospinal fluid (CSF) biomarkers reflect the production and clearance of Aβ and tau peptides at time of CSF collection. Previous work has demonstrated a relative plateau of CSF values at higher levels of amyloid burden. Our objective was to identify the range of amyloid PET values predicted by CSF measures of tau phosphorylation, which have been found to be strongly associated with amyloid PET burden.MethodCSF was collected within two years of an amyloid PET scan from 417 (63 cognitively impaired) participants enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (mean age 69.8 years, standard deviation 8.9 years). PET imaging was performed with Pittsburgh Compound B (PiB). CSF Aβ42, p‐tau181 and Aβ40 were measured with Lumipulse automated immunoassays. The CSF tau phosphorylation occupancies (percent of tau phosphorylated) at T111, T153, T175, T181, S199, S202, T205, S208, T217, and T231 were evaluated with an immunoprecipitation‐mass spectrometry (IPMS) assay. We applied a neural network to generate a simulated PET‐PiB scan and cortical summary estimates using the fluid biomarkers as modeled inputs. We used asymptotic regression to evaluate the range of amyloid PET values predicted by each CSF measure (Figure 1).ResultCombining fluid biomarkers generated a cortical amyloid burden estimate within 12.6% mean average percent error (MAPE). Four of the assessed fluid biomarkers individually generated estimates within 20% MAPE (Figure 2). Of these, CSF Lumipulse p‐tau181/Aβ42, pS208/S208 (%), and pT231/T231 (%) predicted amyloid PET burden up until a high level (3.08 SUVR/91.1 Centiloids; 3.01 SUVR/88.0 Centiloids; 2.79 SUVR/78.1 Centiloids, respectively) (Figure 3). CSF pT217/217 (%) also had high accuracy but a slightly lower prediction threshold (2.65 SUVR/71.8 Centiloids).ConclusionCSF measures including phosphorylated tau predict amyloid PET over different ranges. Combining different measures of CSF tau phosphorylation can generate estimates of cortical amyloid burden. Future work will evaluate the prediction of tau PET by CSF measures.
The gut microbiome as an early biomarker of preclinical Alzheimer disease
Authors: Ances Beau , Ferreiro Aura L. , Choi JooHee , Ryou Jian , Newcomer Erin , Stark Susan L. , Benzinger Tammie L.S. , Holtzman David M. , Fagan Anne M. , Schindler Suzanne E. , Cruchaga Carlos , Butt Omar Hameed , Morris John C , Tarr Philip , Dantas Gautam 
Published: December 2023

AbstractBackgroundThe current paradigm of Alzheimer disease (AD) pathology teaches that people progress from cognitive normality, to cognitive normality with biomarker evidence of disease (preclinical AD), and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiomes of symptomatic AD patients have distinct taxonomic compositions compared to healthy cognitively normal controls. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited.MethodIn this cross‐sectional study we compared the taxonomic composition, microbial functional potential, and metagenome‐assembled genomes (MAGs) abundances in a cohort of 93 cognitively normal individuals, 43 of whom had biomarker evidence of preclinical AD.ResultPreclinical AD individuals have distinct gut microbial taxonomic profiles compared to their healthy controls. Observed microbiome features correlated with amyloid, but not tau or neurodegeneration biomarkers, suggesting that the gut microbial community changes early in the disease process. We identified specific taxa and microbial pathways that were associated with preclinical AD; inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for preclinical AD status.ConclusionGut microbiome correlates of preclinical AD neuropathology have the potential to improve our understanding of AD etiology, enable the identification of gut‐derived biomarkers of AD or AD risk, and guide development of novel therapeutic interventions.
Mutation in presynaptic protein Bassoon induces tauopathy in vivo
Authors: Patel Henika , Martinez Pablo , You Yanwen , Kouri Naomi , Rothberg Darren M. , Yaguchi Hiroaki , Tanaka Shinya , Wakabayashi Koichi , Yabe Ichiro , Murray Melissa E. , Reeves Cristian A Lasagna 
Published: December 2023

AbstractBackgroundTau aggregation is the underlying cause of several neurodegenerative tauopathies. Formation of tau aggregates with seeding activity involves interactions with other proteins, but with unknown effects on tau‐seed properties. Our previous study found that Bassoon (BSN), a presynaptic protein, interacts with tau‐seed, exacerbating its toxicity in vivo. Bsn downregulation reduced tau spreading and overall pathology. A previous study also linked missense mutations in BSN to the aggregation of 3‐ and 4‐repeat tau in patients. However, it is unknown how genetic mutations in BSN influence tau pathology in vivo.MethodWe developed a knock‐in mouse model harboring a mutation in endogenous BSN (p.Pro3882Ala), equivalent to p.Pro3866Ala BSN mutation identified in patients. We evaluated the cognitive and motor abilities of aged heterozygous and homozygous BSNKI mice and also we analyzed BSN and tau patterns in the brains of these mice. Additionally, we examined BSN and tau patterns in the BSN mutation carrier.ResultAt 10 months, BSNKI mice did not exhibit anxiety‐related behavior and had similar activity as WT littermates. They also displayed similar cognitive abilities as the WT mice. Interestingly, the BSNKI mice displayed lower latency to fall off the rotarod and reduced grip strength compared to the WT mice. We also observed an increase in the accumulation of pathological tau and BSN deposits in the brains of the BSNKI mice. The BSN mutation carrier displayed inclusions of BSN and tau pathology.ConclusionWe developed a mouse model with a knock‐in mutation in the Bassoon gene, allowing us to evaluate the effects of this disease‐associated mutation in vivo. Our results have shown that the mice with Bsn mutation have impairments in motor coordination, and postural instability, similar to BSN mutation carriers and show pathological tau and BSN deposits in the brain. We found inclusions of BSN and tau pathology in BSN mutation the carrier that resembled certain pathological features of AD and PSP. These findings suggest that BSN plays a role in tau pathology and targeting it may represent a promising therapeutic strategy for tauopathies. Further research is needed to fully understand our findings' underlying mechanisms and potential therapeutic implications.
Plasma biomarkers as a diagnostic tool for amyloid status: factors affecting the frequency of false positive and false negative results
Authors: Rousset Rebecca Z. , Verberk Inge M.W. , van Harten Argonde C. , van der Flier Wiesje M. , Lemstra Afina W. , Pijnenburg Yolande A.L. , Wilson David , den Braber Anouk , Teunissen Charlotte E. 
Published: December 2023

AbstractBackgroundAmyloid Positron Emission Tomography (PET) and Cerebrospinal fluid (CSF) analysis are used to diagnose Alzheimer’s Disease (AD). Plasma biomarkers have been proposed as a cost‐effective and less invasive AD diagnostic tool. The main diagnostic markers of interest are Amyloid‐beta1‐42/1‐40 (Abeta1‐42/1‐40), phosphorylated Tau‐181 (pTau181), Glial Fibrillary Acidic Protein (GFAP), and Neurofilament Light chain (NfL). These markers have good predictive potential for AD diagnosis, but there is also disagreements between plasma analysis and amyloid status through PET/CSF analysis for a significant number of patients. We aim to identify factors that could account for discordancy of plasma and PET/CSF results.Method1183 participants were included from the Amsterdam Dementia Cohort (Table 1). Amyloid status was determined by Amyloid PET or CSF. Plasma Abeta1‐42/1‐40, pTau181, NfL and GFAP were measured and included of amyloid status in a multivariate logistic regression model. This logistic model was applied back in the cohort, returning a probability of amyloid positivity for each patient based on their plasma biomarkers concentrations. These probabilities were used to classify patients as plasma positive (≥ 0.5) or plasma negative (< 0.5). Analysis was carried out in 2 groups: patients with positive CSF/PET amyloid status and patients with negative CSF/PET amyloid status. Univariate logistic regression models were applied to identify demographic factors, comorbidities or medications associated with false negative (negative plasma status, positive CSF/PET amyloid status) and false positive (positive plasma status, negative CSF/PET amyloid status) cases.Result1183 patients had an amyloid status based on CSF or PET, of which 130 had false negative (10.99%), 106 had false positive (8.96%), 451 (38.12%) had true negative and 496 (41.93%) had true positive plasma results. Higher MMSE scores were associated with higher odds of having a false negative plasma status. Older age, having suffered a stroke, and impaired kidney function were associated with higher odds of false positive plasma results (Table 2).ConclusionWe identified MMSE score to be associated with false negative plasma results, and age, stroke, and kidney function to be associated with false positive plasma results. Adjusting for these factors may improve predictive ability of plasma biomarkers and AD diagnostic accuracy.
Discovery of high‐affinity amyloid ligands using a ligand‐based virtual screening pipeline
Authors: Chisholm Timothy Stewart , Mackey Mark , Hunter Christopher A 
Published: December 2023

AbstractBackgroundA ligand‐based virtual screening pipeline was developed to discover structurally novel ligands for Aβ(1‐42) fibrils.MethodA database of ligands that bind to Aβ(1‐42) fibrils was used to develop a two‐step ligand‐based virtual screening pipeline. The first step involved developing machine learnings models that use relatively simple chemical descriptors to predict ligand dissociation constants (Kd
). The second step involved constructing 3D models based on field points that describe the surface, shape, and electronic properties of ligands. The combined pipeline was then used to screen 63 million compounds from the ZINC15 database.1 The most promising compounds were experimentally evaluated using binding assays.ResultFor the first chemical descriptor model, a support vector machine model was found to predict the ‐log(Kd
/M) of Aβ(1‐42) fibril ligands with a mean absolute error of only 0.41. An ensemble of four 3D models were then developed that each predicted ‐log(Kd
/M) with a cross‐validation regression coefficient of 0.48–0.56. The ZINC15 database compounds were screened through the first chemical descriptor model, and the 10,000 compounds with the highest predicted affinities were then screened through the 3D models. The 46 highest‐ranked ligands were then evaluated using Thioflavin T competition assays, resulting in five new Aβ(1‐42) ligands with novel structures that exhibited nanomolar binding.ConclusionA ligand‐based virtual screening pipeline has been developed to discover new fibril‐binding ligands. Using Aβ(1‐42) fibrils as a target, five new structurally diverse ligands were found that exhibit nanomolar binding affinities.1. Sterling and J. J. Irwin, J. Chem. Inf. Model.
2015, 55, 2324‐2337.
Road to implementation: patient and healthcare professional’s perception of the blood test
Authors: Teunissen Charlotte E. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease blood‐based biomarkers show robust performance for discrimination of amyloid pathology and for monitoring disease progression, both on analytical and clinical level. Now it’s time to prepare for clinical implementation, beyond selected cohorts and in more diverse settings. We therefore started the CANTATE study, which aims to address clinical testing in academic and peripheral memory clinics and in primary care. We aim to elucidate differences between these settings, such as different a priori chances of being amyloid positive, and in test performances and requirements, for example exclusion versus inclusion. In addition, the context of use and perspectives on implementation in primary care are not yet known. We therefore aim to investigate and address attitudes and perspectives of patients and health care professionals on the current diagnostic process and blood‐based biomarker testing.MethodsWe surveyed perspectives of 111 people visiting the website of the Dutch Alzheimer’s association, which were mostly caregivers to persons with dementia, regarding blood‐based testing for a timely AD diagnosis.ResultsWhen presented with different scenarios, the majority of participants were interested in blood‐based testing for AD, independent of the severity of symptoms they might experience (71.2% if they would experience mild symptoms versus 64.0% if no symptoms). Trust in a negative outcome of a blood‐based test for AD, however, was influenced by symptom severity (78.4% would feel reassured if experiencing mild symptoms versus 48.6% upon severe symptoms). The availability of a treatment option increased interest in blood testing to 92.8%.ConclusionsThese results indicate that there is added value from a public perspective for blood‐based biomarker testing for AD.
Drug utilization among patients with mild cognitive impairment and Alzheimer’s disease in diverse populations: A large nationwide electronic health record cohort study
Authors: Sánchez‐Soliño Olga , Boroje Isabella , Yue Emma Xiaomeng , Vinikoor‐Imler Lisa C 
Published: December 2023

AbstractBackgroundCholinesterase inhibitors (ChE‐Is), such as donepezil, rivastigmine, and galantamine, and N‐methyl‐d‐aspartate receptor antagonists, such as memantine, are prescribed to decrease symptoms associated with cognitive impairment. Few studies have examined the initiation and utilization of these medications among diverse populations. This study’s objective was to characterize drug utilization among patients with mild cognitive impairment (MCI) and/or Alzheimer’s disease (AD) in the United States and stratify by gender, age and race/ethnicity.MethodThis retrospective cohort study was conducted using the Optum® Market Clarity database, which contains electronic health records and insurance claims. Cases of MCI and AD were identified utilizing the International Classification of Diseases, Ninth and Tenth Revisions diagnosis codes. Drug prescriptions were determined to occur before, on, or after the date of first diagnosis. All cases were required to have ≥12 months of enrollment in the database prior to first diagnosis. The study period was from January 2017 through September 2021. Descriptive statistics were calculated stratified by demographic groups.ResultA large number of cases were identified (197,346 MCI and 144,321 AD cases). Approximately 6% of individuals with MCI had prescriptions for ChE‐Is prior to diagnosis and 14% after diagnosis. For memantine, the proportions with prescriptions before and after MCI diagnosis were 2% and 5%, respectively. Among individuals with AD, prescriptions for ChE‐Is occurred in 22% prior to diagnosis and 32% after diagnosis. Memantine prescriptions increased from 10% prior to AD diagnosis to 18% after. The results did not differ by gender. The highest proportions with ChE‐Is and memantine prescriptions were older age groups <85 years. When examining race/ethnic groups, the proportion of MCI and AD cases with these prescriptions was generally lowest among African Americans.ConclusionAs expected, prescriptions for ChE‐Is and memantine increased after diagnosis. The proportion of MCI and/or AD cases with prescriptions were similar across genders. The proportion with prescriptions was generally lowest among African Americans. Future research into the discrepancy in the occurrence of prescriptions by race/ethnicity as well as the timing of certain prescriptions will be valuable in further understanding the patient population and their access to appropriate medications.
The Role of Alzheimer’s Disease Pathology in Cognition, Brain Volume, and Plasma Biomarker Concentrations in Traumatic Encephalopathy Syndrome
Authors: Asken Breton M. , Tanner Jeremy A. , VandeVrede Lawren , Mantyh William G , Casaletto Kaitlin B. , Staffaroni Adam M. , soleimani‐Meigooni David N. , Gaynor Leslie S , Fonseca Corrina S. , Shankar Ranjani , Grant Harli E. , Smith Karen , Lago Argentina Lario , Xu Haiyan , La Joie Renaud , Cobigo Yann , Rosen Howard J. , Perry David C. , Rojas Julio C. , Grinberg Lea T. , Miller Bruce L , Gardner Raquel C. , Wang Kevin K.W. , Kramer Joel H. , Rabinovici Gil D. 
Published: December 2023

AbstractBackgroundPatients with a history of repetitive head impacts (RHI) risk progressive memory loss and executive dysfunction consistent with traumatic encephalopathy syndrome (TES). TES is a clinical phenotype sensitive but non‐specific to underlying chronic traumatic encephalopathy (CTE). Cognitive symptoms overlap with Alzheimer’s disease (AD), and features of AD pathology like beta‐amyloid (Aβ) plaques often co‐occur with CTE. We investigated whether Alzheimer’s neuropathological changes influences cognition, brain volume, and plasma biomarkers in patients with RHI or TES.MethodsWe studied 154 patients who underwent Aβ‐PET, including 33 with RHI/TES (age 61.5±11.5, 100% male, 11/33 Aβ[+]), 62 with AD and no prior RHI (age 67.1±10.2, 48% male, 62/62 Aβ[+]), and 59 healthy controls without RHI (HC; age 73.0±6.2, 40% male, 0/59 Aβ[+]). Patients completed neuropsychological testing (memory, executive functioning, language, visuospatial) and structural MRI (regions of interest: frontal, temporal, parietal, occipital, hippocampus) and provided plasma samples analyzed for GFAP and NfL. Patients with RHI/TES were stratified as Aβ[+] or Aβ[‐] and compared to each other and with AD and HC groups (ANCOVA adjusting for age and sex).ResultsCognitively, Aβ[+] RHI/TES performed worse than Aβ[‐] RHI/TES on visuospatial (p = .04, d = 0.86) and memory testing (p = .07, d = 0.74). Comparing brain volume, Aβ[+] RHI/TES, but not Aβ[‐] RHI/TES, had lower parietal volume than HC (p = .003, d = 1.3). Conversely, Aβ[‐] RHI/TES had lower hippocampal volume than patients with AD (p = .03, d = 0.77). Comparing plasma biomarkers, Aβ[+] RHI/TES had higher plasma GFAP than HC (p = .01, d = 0.88) and similar GFAP levels to patients with AD (p = .26, d = 0.38). Conversely, Aβ[‐] RHI/TES had higher NfL than HC (p = .004, d = 0.93) and a trend towards higher plasma NfL than Aβ[+] RHI/TES (p = .11; d = 0.61).ConclusionsPatients with RHI/TES and positive Aβ‐PET have cognitive, brain volume, and plasma biomarker changes that more closely align to patients with AD than patients with Aβ[‐] RHI/TES. Visuospatial impairment and associated parietal atrophy may suggest the presence of AD pathology in participants with RHI. The suggestion of greater neuronal injury in patients with Aβ[‐] RHI/TES warrants further evaluation in supporting a diagnosis of TES due to suspected underlying CTE. Measuring these biomarkers in patients with RHI/TES could guide precise clinical management.