bluuebunny/crossref_metadata_2025_split huggingface dataset:
Application of AT(N) classification using two CSF A‐markers and two CSF N‐markers to Alzheimer’s Clinical Syndrome (ACS) and non‐ACS
Authors: Kasuga Kensaku , Tsukie Tamao , Kikuchi Masataka , Ishiguro Takanobu , Tokutake Takayoshi , Shimizu Soichiro , Yoshizawa Hiroshi , Miyashita Akinori , Onodera Osamu , Iwatsubo Takeshi , Ikeuchi Takeshi ,   the Japanese Alzheimer’s Disease Neuroimaging Initiative
Published: December 2023

AbstractBackgroundCerebrospinal fluid (CSF) biomarkers reflect the pathological process underlying Alzheimer’s disease (AD) and improve the accuracy of AD diagnosis. AT(N) classification using these CSF biomarkers has been used within the research framework to identify points on AD continuum. However, there has been little research into the utility of AT(N) classification in clinical practice.MethodsWe measured the CSF levels of amyloid‐β (Aβ) 42, Aβ40, phosphorylated tau (Thr181), total tau (tTau), and neurofilament light chain (NfL) in samples from clinical cases, comprising 230 patients with Alzheimer’s clinical syndrome (ACS) and 328 patients with non‐ACS. The concordance between two A‐markers (i.e., Aβ42 alone and the Aβ42/Aβ40 ratio) and the two N‐markers (i.e., tTau and NfL) were analyzed. We evaluated the prevalence of biological AD (i.e., A+T+) and the percentage of each AT(N) category identified using the CSF biomarkers in the ACS and non‐ACS samples.ResultsThe concordance of A‐markers was not significantly different between the ACS (87.4%) and non‐ACS (74.1%) groups. However, the frequency of discordant cases with AAβ42‐alone+/AAβ‐ratio− was significantly higher in the non‐ACS (23.8%) than in the ACS group (7.4%). The concordance of two N‐markers was 40.4% in the ACS group and 24.4% in the non‐ACS group. In the ACS samples, the frequency of biological AD in Ntau+ cases was 95% and that in NNfL+ cases was 65%. When the Aβ42/Aβ40 ratio was used as the A‐marker, the proportion of biological AD was 64.3% in ACS samples and 24.4% in non‐ACS samples. Notably, the proportion of AD continuum in the non‐ACS group was substantially different when the A‐marker was Aβ42 alone than when it was the Aβ42/Aβ40.ConclusionsAlthough the AT(N) classification system was intended for use in research, it may also be also useful for clinical diagnosis. As an A‐marker, the Aβ42/Aβ40 ratio reflects Aβ deposition more accurately than Aβ42 alone. As an N‐marker, NfL reflects neurodegeneration more accurately than tTau, particularly in non‐ACS patients. Thus, we recommend the use of AT(N) classification in clinical practice that is defined by CSF levels of AAβ‐ratioTNNfL.
The rs‐gamma connectivity alterations related to the atrophy pattern and CSF p‐tau in early‐onset AD
Authors: Fide Ezgi , Yerlikaya Deniz , Ada Emel , Yener Görsev 
Published: December 2023

AbstractBackgroundAmong the other frequencies, the gamma frequency has received the least attention in the study of Alzheimer’s disease (AD). Previous studies point to association between amyloid accumulation and gamma alterations, suggesting that gamma activity may serve as a potential biomarker for the pathophysiology of AD. The goal of the current study is to examine changes in resting‐state (rs) gamma activity in patients with CSF‐proven early‐onset AD (EOAD) and their relationship to structural pathology associated with the disease.MethodDrug‐naive CSF‐proven EOAD patients [mean age: 57.92 (4.35) years] and age‐, gender, and education‐matched healthy controls (HC) [mean age: 57.58 (4.01) years] were included. Gamma imaginary part of coherency (ICoh) was measured in total gamma (30‐48 Hz), gamma‐1 (30‐35 Hz), gamma‐2 (35‐40 Hz), and gamma‐3 (40‐48 Hz) frequencies. Gray matter volumes compared between groups. The rsEEG gamma activity was used for discriminant analysis. The relationships between rsEEG, MRI, and CSF p‐tau measurements were investigated.ResultIn the EOAD group, gray matter volume in temporal, parietal, and occipital areas were decreased by over 20%. We discovered that the volume of frontal and neighboring regions, that were intact in this patient group, was negatively correlated with F8‐TP8 and F4‐C4 ICoh of sub‐gamma bands. On the contrary, the volume of temporal and parietal regions where the atrophy was prominent, was positively correlated with P8‐O2 and C3‐O1 ICoh of sub‐gamma bands. In the EOAD, executive function and F7‐TP7, P3‐O1 sub‐gamma bands were negatively correlated.Regarding CSF, p‐Tau and C3‐C4 gamma‐1 showed strong positive correlation (r = 0.615). Lastly, a set of gamma ICoh measurements displayed a correct classification rate of 83% between groups.ConclusionGamma coherence follows pair‐specific alterations related to atrophy pattern in EOAD. The gamma connectivity becomes greater where atrophy is increased and when CSF p‐tau is higher in EOAD. This study establishes the significance of sub‐gamma oscillations as a non‐invasive biomarker candidate with achieving an 83% correct classification rate between groups.
Modeling Aberrant Dynamic Causal Brain Circuits in Alzheimer’s Disease
Authors: Lee Byeongwook 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive and severely debilitating disease that negatively affects cognitive and memory function and is linked to increased disability in everyday functioning and risk of mortality. Neurodegeneration of focal brain areas in AD progressively impacts large‐scale brain circuits, leading to significant cognitive impairments. However, little is known regarding aberrant context‐dependent dynamic causal interactions between distributed brain regions, and their links to cognitive impairments and neuropathology, across AD clinical stages.MethodWe addressed critical gaps in our knowledge of functional circuit mechanisms underlying cognitive dysfunction in AD by leveraging innovative computational tools and state‐of‐the‐art clinical, phenotypic, cognitive, experimental, fMRI data from AD Human Connectome Project database.ResultTo this end, we identified that (1) dynamic causal interaction patterns between DMN‐MTL‐FPN‐SN nodes distinguish between clinical stages of AD in working memory task, (2) dynamic causal interactions between DMN‐MTL‐FPN‐SN nodes become progressively weaker along clinical AD disease stages in both memory tasks, and (3) dynamic causal interaction patterns between DMN‐MTL‐FPN‐SN nodes are significantly associated with task performance.ConclusionThese findings will identify aberrant dynamic causal circuits associated with episodic and working memory deficits across AD clinical stages.
Utility of Baseline Pathological, Neuroimaging and Clinical Markers for Progression Prognosis and Subtype Classification in Early Parkinson’s Disease: Implications for Cognitive Impairment
Authors: McNamara Angus , Ellul Benjamin , Baetu Irina , Lau Stephan , Jenkinson Mark , Collins‐Praino Lyndsey E 
Published: December 2023

AbstractBackgroundCognitive dysfunction is a well‐recognised PD symptom, but it is highly heterogenous and under‐assessed clinically. Interestingly, PD motor subtypes are associated with different risk of cognitive decline. However, subtype classification is currently reliant on subjective clinician assessment and may consequently be misdiagnosed. Therefore, objective biomarkers of PD progression are critically needed, but must be validated prior to clinical deployment. We assessed the utility of various clinical, neuroimaging and pathological measures as predictors of cognitive outcomes up to 5‐years follow‐up in early PD.MethodData was extracted from the Parkinson’s Progression Markers Initiative. Cognitive assessments were compiled into an overall cognition score via principal component analysis. Distinct subgroups were identified via Fuzzy C‐Means clustering on Year‐5 Unified Parkinson’s Disease Rating Scale (UPDRS) motor scores. Models predicting cluster membership were created via logistic regression and a stratified cross‐validation machine learning pipeline, comparing two predictor inputs: 1) baseline motor assessments; and 2) incorporating additional measures, including prodromal assessments (sleep, olfactory and autonomic function), neuroimaging (proxy SN volume, striatal DaT binding) and biofluid markers (CSF alpha‐syn, p‐tau, a‐beta, and serum IGF‐1) at baseline. Finally, cluster membership was used for retroactive assessment of baseline and follow‐up cognitive data.ResultsTwo clusters were identified, with cluster two (n = 117) demonstrating higher rigidity, lower DaT binding, worsened motor outcomes and increased mood dysfunction at follow‐up compared to tremor‐dominant cluster one (n = 183). Additionally, rigid‐dominant membership was predicted by male sex, higher p‐tau, along with lower a‐beta, predicting 40% of variance (n = 111). This was significantly higher (P<0.001) than baseline motor scores alone, only accounting for 18% of variance. This was supported by machine learning, whereby incorporating additional assessments corresponded to a classification accuracy of 62%, compared to 26% when omitted. Finally, higher probability of belonging to the rigid‐dominant cluster yielded significant negative correlations cognition at baseline and follow‐up.ConclusionIncreased likelihood of rigid‐dominance corresponded to more profound cognitive decline, which may in part result from neuropathological marker concentrations as highlighted by predictive models. Therefore, further tracking of this cohort, specifically conversion into MCI or dementia, could provide insight into pathological contribution to differences in cognitive decline between PD subtypes.
Identification of Necessary Plasma Biomarkers for Prediction of Alzheimer’s Disease Neuropathologic Change
Authors: Bermudez Camilo , Graff‐Radford Jonathan , Syrjanen Jeremy A. , Stricker Nikki H. , Algeciras‐Schimnich Alicia , Kouri Naomi , Kremers Walter K. , Petersen Ronald C. , Jack Clifford R. , Knopman David S. , Dickson Dennis W. , Nguyen Aivi T. , Reichard Ross R. , Murray Melissa E. , Mielke Michelle M. , Vemuri Prashanthi 
Published: December 2023

AbstractBackgroundPlasma biomarkers for Alzheimer’s disease (AD) such as phosphorylated tau protein 181 (p‐tau 181), neurofilament light chain (NfL), amyloid‐β 42/40 ratio (Aβ42/40), and glial fibrillary acidic protein (GFAP) have shown high performance in the discrimination of those with clinical mild cognitive impairment (MCI) or dementia from cognitively unimpaired individuals, but few population‐based autopsy studies have evaluated the neuropathological correlates of plasma biomarkers.MethodWe utilized a population‐based prospective study of 350 participants with autopsy and antemortem plasma biomarker data. Plasma biomarkers Aβ42/40 ratio, p‐tau181, GFAP, and NfL were measured using Quanterix Simoa assays. We predicted AD neuropathological change (ADNC), Braak staging, and neuritic plaque score using these plasma biomarkers and investigated the added utility of cognitive and demographic information. We utilized a variable selection procedure in cross‐validated (CV) logistic regression models by minimizing the Bayesian Information Criterion to identify the best set of predictors for a given outcome among plasma biomarkers, demographic variables, and neuropsychological tests included in the Mayo Clinic Preclinical Alzheimer Cognitive Composite (Mayo‐PACC).ResultADNC was best predicted with plasma GFAP, NfL, p‐tau181 biomarkers along with APOE ε4 carrier status and Mayo‐PACC cognitive score (CV AUC = 0.821). Braak staging was best predicted using plasma GFAP, p‐tau181, and cognitive scores (CV AUC = 0.788). Neuritic plaque score was best predicted using plasma Aβ42/40 ratio, p‐tau181, GFAP, and NfL biomarkers (CV AUC = 0.778). Inclusion of plasma biomarkers demonstrated significantly better prediction of Braak staging (p<0.01) and neuritic plaque score (p<0.01), but not ADNC (p = 0.13), when compared to models that included only cognitive and demographic information. Univariate models consistently underperformed in comparison to multivariate models.ConclusionPlasma biomarkers can provide valuable predictive information about the presence of AD pathology, which can facilitate earlier recognition and diagnosis of AD. Incorporation of demographic and cognitive variables along with plasma variables in multivariable models will improve prediction accuracy of AD pathology, specifically Braak staging and ADNC.
Vascular Risk Factors for Idiopathic Normal Pressure Hydrocephalus: A Systematic Review and Meta‐analysis
Authors: Cai Hanlin , Yang Feng , Gao Hui , Huang Keru , Qin Linyuan , Wang Ruihan , Liu Yi , Zhou Liangxue , Zhou Dong , Chen Qin 
Published: December 2023

AbstractBackgroundIdiopathic normal pressure hydrocephalus (iNPH) is a clinical syndrome characterized by cognitive decline, gait disturbance and urinary incontinence. Several observational studies have indicated that iNPH patients have a high occurrence of vascular comorbidities compared to normal populations. This study aims to identify the specific vascular risk factors for iNPH and review the possible pathogenesis between vascular risk factors and iNPH development.MethodWe searched PubMed, Web of Science, Embase, and the Cochrane Library for studies that reported possible risk factors for iNPH development. Meta‐analysis of the data obtained resulted in pooled odds ratios and 95% confidence intervals.ResultThirteen studies conducted in 7 countries comprising 1350 iNPH patients and 80043 controls were included in this meta‐analysis. Our data suggest that hypertension (Pooled OR = 2.42, 95% CI 1.82 to 3.22, I2 = 61.7%), diabetes mellitus (Pooled OR = 2.91, 95% CI 2.17 to 3.92, I2 = 50.1%), coronary heart disease (Pooled OR = 1.92, 95% CI 1.02 to 3.61, I2 = 90.3%),and peripheral vascular disease (Pooled OR = 2.77, 95% CI 1.50 to 5.13, I2 = 0.0%) are important risk factors for iNPH. Overweight was also considered a possible vascular risk factor (Pooled OR = 2.01, 95% CI 1.34 to 3.04, I2 = 0.0%), but the result was not stable as demonstrated by sensitivity analysis. Hyperlipidemia, smoking, and alcohol use were not significantly associated with iNPH development.ConclusionOur meta‐analysis identified that hypertension, diabetes mellitus, coronary heart disease, and peripheral vascular disease were important risk factors for iNPH. Overweight is also considered a possible vascular risk factor, but the evidence thus far has not been robust.
Outbreak of tauopathy in the olfactory system of PS19 mice: an early marker for Alzheimer’s disease diagnosis?
Authors: Dourte Marion , Kienlen‐Campard Pascal 
Published: December 2023

AbstractBackgroundClinical data indicate that impairment of olfactory function is an early indicator of neurodegenerative diseases, including Alzheimer’s disease (AD)(Attems et al., 2014). Our hypothesis is that typical AD lesions could appear in olfactory neurons from the olfactory epithelium (OE). The olfactory epithelium can be easily collected in human individuals (e.g., by nasal brushing), which provides an important tool to investigate the pathology in patients. Here, we address the question of the occurrence of tauopathy in the OE of transgenic mice and its correlation with pathology in the central nervous system (CNS). We use Tau P301S mice (PS19 mice), a tauopathy mouse model. These mice express human tau protein (1N4R) carrying the P301S mutation. They develop neurofibrillary tangle‐like inclusions in the cortex and hippocampus, leading to progressive neurodegeneration at eight months (Yoshiyama et al., 2007).MethodMouse samples were collected from heterozygous PS19 and wild‐type (WT) mice. Immunohistochemical staining (DAB) was used to demonstrate the presence of hyperphosphorylated human tau protein (hTau). We investigated regions of the olfactory system to correlate with data obtained in CNS regions (e.g., hippocampal formation, entorhinal cortex). Mouse heads decalcification was also implemented to preserve the olfactory epithelium structure. Western blots were performed to monitor tau levels and tau phosphorylation pattern.ResultThe hyperphosphorylated human tau protein (Ser202, Thr205) is only detected in PS19 mice sections while the endogenous murine tau protein is expressed both in WT and PS19 mice. The localization and expression of these proteins vary according to the region (OE or CNS subregions), the age (3, 6 or 9 months), and the genotype of the mice (WT or heterozygous PS19). It also seems that tau lesions may spread between brain regions that are directly connected, notably through the olfactory pathway.ConclusionIn PS19 mice, a pathological phosphorylation pattern peaked in the OE prior to vulnerable CNS regions or olfactory bulbs. We hypothesize that tau lesions appearing early in the OE may spread in the olfactory bulb and finally reach the entorhinal cortex and piriform cortex, highlighting the significance of the olfactory system investigation as an early diagnosis tool.
African initiatives on stroke and dementia to improve health outcomes and international trial participation
Authors: Akinyemi Rufus O. 
Published: December 2023

AbstractBackgroundGlobally, 1 out of every 3 persons alive has a risk of developing either a stroke or dementia. 68% of the 78 million individuals projected to have dementia by 2050 will be from LMICs where the burden of vascular risk factors is rising at an alarming rate, stroke occurrence is on the rise and infrastructure for stroke surveillance, prevention, care and rehabilitation are also lacking. There are global initiatives from the World Stroke Organization towards improving primary prevention globally and the recently launched Blueprint for Dementia Research by the World Health Organization has identified six themes and eight drivers for scaling up dementia research with accompanying strategies and timelines.MethodWe describe the development of two African ‐ led initiatives with similar goals of providing platforms for diverse African experts in the fields of stroke and dementia to work collaboratively to improve research, care, prevention, advocacy and build capacity to reduce the burden of stroke and dementia in Africa as well as improve African participation in global research efforts to improve health outcomes and participation in global trials.ResultThe African Stroke Organization (ASO) and the African Dementia Consortium (AfDC) were established in 2020 and 2022 respectively with clear visions and robust governance frameworks organized into steering committees and working groups. Both organizations are currently involved in regional programs and vital research collaborations with international partners.ConclusionIt is feasible to establish regional initiatives that can enhance diversity in global stroke and VCI research and international trial participation.
Memory Keepers Medical Discovery Team: addressing Indigenous dementia disparities through deep exploration of culture and community‐specific context
Authors: Jacklin Kristen , Blind Melissa J , Warry Wayne , Ketcher Dana , Lewis Jordan P. , Pederson Collette , Johnson January , Trudeau Rhonda , Pitawanakwat Karen , Strong Lois , Summers Marlene , Martin Wesley , Lambrou Nickolas H. , Zuelsdorff Megan , Gleason Carey E. 
Published: December 2023

AbstractBackgroundThe Memory Keepers Medical Discovery Team (MK‐MDT) was established in 2016 to address brain health equity for Indigenous and rural populations. Indigenous populations are under‐represented in Alzheimer’s disease and related dementias (ADRD) research studies and clinical trials, yet there is a dire need to address ADRD disparities in this population. In this paper we outline our research approach and studies underway at the MK‐MDT that are designed to address the ADRD disparity in Indigenous populations in the US and Canada. We highlight our flagship study “Indigenous Cultural Understandings of Alzheimer’s Disease and Dementia – Research and Engagement” (ICARE) as a key foundational ethnographic study necessary to advance the field.MethodThe MK‐MDT incorporates a community‐based participatory research (CBPR) approach with two‐eyed seeing. Two‐eyed seeing ensures the inclusion and valuing of Indigenous knowledge throughout the research process. In ICARE, we maintain a consistent focus on ethnographic research with Indigenous communities to ensure deep understanding of how culture and context shape the dementia experience. Interviews, sequential focus groups, participant observation and fieldnotes are used to populate an ethnographic database on the lived experience of dementia in Indigenous populations. We incorporate a diversity perspective by working with multiple Indigenous communities for each study. We invest in community engagement infrastructure such as community advisory committees, elder advisors, community‐based researchers and outreach workers to ensure our methods follow local ethical protocols, is culturally safe, and community controlled.ResultWe have successfully initiated NIH‐funded programs of research aimed at reducing dementia disparities. ICARE was launched in 2018 and included 54 interviews and 14 sequential focus group sessions (n = 17) in four diverse Indigenous communities, establishing the first stage of a robust ethnographic database. Findings support the existence of an Indigenous specific understanding of dementia that impacts the dementia care experience.ConclusionThe CBPR approach coupled with two‐eyed seeing has allowed for authentic engagement with multiple Indigenous communities and has supported the collection of ethnographic data that can be used to develop culturally appropriate health promotion materials and interventions. The community‐based infrastructure that has been established is currently supporting multiple projects, including clinical research.
Modern trial outcome measures increase trial participation and recruitment of representative peoples
Authors: Elahi Fanny M 
Published: December 2023

AbstractBackgroundClinical trials have been one size fits all, despite evidence that dementia ensues from a combination of pathologies with effects from environment, sex/gender, race/ethnicity and other factors influencing disease course. Cardiovascular diseases and cancer have measures (imaging and molecular biomarkers) that aid in capturing targetable biology. These biomarkers are used for risk stratification, precise diagnostic classification, in addition to inclusion as outcomes in trials. Clinical trials for brain degenerative disorders would benefit from a similar precision approaches.MethodWe performed proteomics analyses on banked plasma samples from longitudinal observational studies of vascular cognitive impairment and dementia (VCID) and a clinical trial (SPRINT‐MIND) targeting hypertension, a major VCID risk factor. Using multi‐modal analytical approaches we combined molecular measures with imaging and clinical outcomes to identify promising molecular markers for risk stratification for VCID clinical trials and maximizing benefit of interventions for VCID.ResultProteins related to angiogenesis as well as innate immune activation were found to be dysregulated in cases versus controls. With multivariate analyses, components with high loading from proteins involved in these multi‐cellular phenotypes were associated with cognitive outcomes. Using network analyses, key molecular nodes were validated via orthogonal methods.ConclusionA simple molecular panel with key proteins involved in dysregulated molecular networks mediating the effect of vascular disease on cognition could be developed and used for risk stratification in clinical trials of VCID. Greater precision in clinical trials would ensure higher benefit at lower cost, at all levels.