bluuebunny/crossref_metadata_2025_split huggingface dataset:
External validity of trials on amyloid‐lowering therapy against Alzheimer’s disease: the population‐based Rotterdam Study
Authors: Claus Jacqueline Josephine , vom Hofe Ilse , Veenstra Annekee van Ijzinga , Licher Silvan , Seelaar Harro , De Jong Frank Jan , Neitzel Julia , Vernooij Meike W. , Ikram Arfan , Wolters Frank J. 
Published: January 2025

AbstractBackgroundTreatment with monoclonal antibodies against amyloid‐β slowed cognitive decline in recent randomized clinical trials in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimer’s disease (AD). However, trial eligibility criteria may affect generalizability to clinical practice.MethodsWe extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab from published reports, and applied these to participants with MCI and early clinical AD dementia from the population‐based Rotterdam Study. Participants underwent routine, standardized assessment from 2002‐2013, including questionnaires, blood sampling, brain MRI, cognitive testing, cardiovascular assessment, and –in a subset– amyloid‐PET. We determined trial eligibility for all participants, and assessed progression to dementia within 5 years among participants with MCI.ResultsOf 968 participants (mean age: 75 years, 56% women), 779 had MCI and 189 early clinical AD dementia. Around 40% of participants were ineligible because of amyloid negativity, similar across trials. Overall, at least one clinical exclusion criterion was present in 76.3% of participants for aducanumab, 75.8% for lecanemab, and 59.8% for donanemab. Criteria that most often led to exclusion were cardiovascular disease (35.2%), use of anticoagulants (31.2%), psychotropic or immunological medication (20.4%), psychiatric disease (15.9%), and lack of social support (15.6%). One‐third of participants were ineligible based on their brain MRI alone, which was similar across trials and due predominantly to various manifestations of cerebral small‐vessel disease. Combining amyloid, clinical, and imaging criteria, eligibility ranged from 8% for aducanumab and lecanemab to 15% for donanemab. Risk of progression to dementia tended to be higher for ineligible than for eligible participants for lecanemab (hazard ratio [95%CI]: 1.64 [0.92‐2.91]), but not aducanumab (HR: 1.17 [0.65‐2.12]) or donanemab (HR: 1.03 [0.67‐1.59]).ConclusionsLess than 15% of community‐dwelling individuals with MCI and early AD dementia would have been eligible for participation in recent RCTs of monoclonal antibodies against amyloid‐β, due in large part to comorbid vascular pathology. These findings underline that evidence for drug efficacy and safety is lacking for the vast majority of patients with AD in routine clinical practice.
Cerebrospinal fluid concentration of furin in patients with Alzheimer’s disease
Authors: Kulczynska‐Przybik Agnieszka , Mroczko Jan , Dulewicz Maciej , Zetterberg Henrik , Hanrieder Jörg , Blennow Kaj , Krawczuk Daria , Doroszkiewicz Julia , Borawska Renata , Slowik Agnieszka , Mroczko Barbara 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) is an uncurable, heterogeneous, and molecular complex neurodegenerative disease. Emerging evidence indicates that furin could play an essential role in the pathogenesis of neurodegenerative disorders. Furin participates in the proteolytic maturation and processing of large numbers of prohormones and proproteins, which among others play crucial roles in neuronal survival, axon growth, dendritic development, synaptogenesis, neurodegeneration, and inflammation. It is suggested that a stable activity of furin is crucial for maintaining of the central nervous system homeostasis. Some studies revealed reduced expression of mRNA of furin in the brains of Alzheimer's disease patients, which may suggest the implication of the protein in the pathophysiology of AD. However, little is known about changes of furin’s concentration in the cerebrospinal fluid (CSF) patients with AD. Therefore, we aimed to assess the usefulness of CSF furin’s measurement in patients with AD in relation to subjects without cognitive impairment. We also assessed associations between CSF concentrations of furin and neurochemical biomarkers of dementia.MethodThe study enrolled 39 participants, including patients with AD and subjects without cognitive decline. The concentrations of furin and classical biomarkers (amyloid beta 1‐42, amyloid beta 1‐40, Tau, as well as pTau181) were assessed in cerebrospinal fluid using a multiplexing method as well as enzyme‐linked immunosorbent assay.ResultA significantly higher CSF concentration of furin was noticed in AD patients as compared to subjects without cognitive impairment. Furthermore, in the whole study group of patients, the levels of furin correlated negatively with MMSE test and Aβ‐1‐42/ Aβ‐1‐40 ratio, as well as positively with total Tau and pTau181. Additionally, the CSF levels of furin significantly correlated with pTau181 protein in the AD group.ConclusionOur preliminary study indicates the potential role of furin in the pathology of AD and its potential usefulness as a candidate biomarker. However, further investigations on an independent larger group of patients are necessary.
Quantitative Analysis of Choroid Plexus Enlargement in Alzheimer's Dementia: A Study of Automated Volumetric Technique
Authors: Kim Dong‐Hee , Suh Chong Hyun , Jung Wooseok , Lee Seung Hyun , Kim Jinyoung , Cho Hyeonwoo , Lee Yeha , Kim Sang Joon , Moon Won‐Jin 
Published: January 2025

AbstractBackgroundChoroid plexus enlargement is implicated in the exacerbation of cognitive impairments characteristic of Alzheimer’s dementia (AD). Manual volumetric assessment by radiologists, while accurate, is impractical for large‐scale application due to its resource‐intensive nature. We examine the use of automated brain volumetry software as an efficient and cost‐effective alternative for quantifying choroid plexus volume.MethodWe collected 3D T1 brain MRI images from 293 patients aged between 44 and 91, with a median age of 73, at Konkuk University Hospital (n = 95), Asan Medical Center (n = 99), and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (n = 99). The study comprised 76 normal control (NC), 89 mild cognitive impairment (MCI), and 128 AD cases, with a female majority of 58.4%. Using VUNO‐Med DeepBrain software, we obtained choroid plexus segmentation masks and volumes from both radiologists and neural networks trained with deep learning. All choroid plexus volumes were normalized by intracranial volume (ICV) multiplied by 1000. Additionally, to assess DeepBrain's accuracy, we calculated the Intraclass Correlation Coefficient (ICC(2, k)) between the manually labeled volumes and those labeled by DeepBrain.ResultThe median choroid plexus volumes measured by radiologists were 1.328 for NC, 1.354 for MCI, and 1.495 for AD. In contrast, measurements by DeepBrain were 1.163 (NC), 1.284 (MCI), and 1.428 (AD). A one‐way ANOVA analysis (NC vs. MCI vs. AD) revealed that DeepBrain‐based measurements (p < 0.001) may be more significant than manual measurements (p = 0.17) in elucidating the relationship between choroid plexus enlargement and cognitive impairments in AD. Additionally, the Intraclass Correlation Coefficient (ICC(2, k)) between manual and DeepBrain volumes indicated a moderate correlation with a score of 0.69 (p < 0.001).ConclusionOur results suggest that automated brain volumetry is a reliable method for assessing choroid plexus volume, correlating with the cognitive impairment continuum in AD. Its implementation could significantly streamline the diagnostic process, offering a scalable and objective approach for clinicians and researchers.
Glutaric acid associates with early detection of cognitive impairment deciphering the association with depression
Authors: Chakraborty Manas , Dhiman Kunal , Sachdev Perminder S. , Brodaty Henry , Draper Brian , Trollor Julian N , Reppermund Simone , Kang Kristan , Mather Karen A , Poljak Anne , Wen Wei , Numbers Katya T. , Kochan Nicole A. , Catts Vibeke S. , Gupta Veer 
Published: January 2025

AbstractBackgroundThe initiation of cognitive impairment is triggered by a myriad of pathological events occurring decades before clinical symptoms manifest. Perturbed glucose and fatty acid metabolism notably contribute to the development of cognitive impairment, progressing further into clinical dementia. These metabolic alterations are evident in plasma through changes in specific metabolites. Notably, these changes are characteristic features in the pathophysiology of depression, a significant risk factor for cognitive impairment. This project aims to establish a blood‐based biomarker signature for early identification of cognitive changes in individuals with depression. Moreover, it aims to assist in diagnosing and understanding disease progression by quantifying plasma metabolite levels linked to fatty acid metabolism in samples obtained from participants in the Sydney Memory and Ageing Study.MethodPlasma samples underwent analysis to quantify fatty acids and carnitines using chemical derivatization through UPLC‐MRM/MS coupled with a 4000 QTRAP mass spectrometer which was equipped with an electrospray ion (ESI) source and operated in the multiple‐reaction monitoring (MRM) mode with negative‐ion (‐) detection.10‐μL aliquots of each of the resultant calibration solutions and each of the sample solutions were injected for analysis.ResultANCOVA, revealed significant changes in the levels of several biomarkers including glycolic acid (p‐value: 0.033), C181 carnitine (p‐value: 0.013), glutaric acid (p‐value: 0.08) levels in groups with Mild Cognitive Impairment (MCI) and MCI with comorbid depression compared to healthy groups. ROC curve analysis demonstrated that glutaric acid effectively distinguished between MCI and non‐MCI participants. The optimal threshold for classifying participants into MCI and non‐MCI groups was determined using the Youden Index to dichotomize them based on high and low biomarker levels. Logistic regression analysis, adjusting for age, sex, APOE ε4 genotype, and comorbid depression, revealed a significant association between glutaric acid levels and cognitive impairment in the context of depression, with a p‐value of <0.001 and an odds ratio of 2.49.ConclusionGlutaric acid proved to be a reliable discriminator between participants with MCI and those without MCI. The aforementioned findings revealed a strong correlation between glutaric acid and cognitive impairment associated with depression which could be used as biomarker for early detection of cognitice impairment.
Obstructive sleep apnea severity is associated with CSF biomarkers of synaptic dysfunction and neuroinflammation in a cohort at risk for AD
Authors: Edmunds Kyle J , Breidenbach Brianne M. , Glittenberg Matthew P , Johnson Sterling C. , Asthana Sanjay , Gallagher Catherine L. , Hermann Bruce P , Sager Mark A. , Carlsson Cynthia M. , Kollmorgen Gwendlyn , Quijano‐Rubio Clara , Blennow Kaj , Zetterberg Henrik , Bendlin Barbara B. , Peppard Paul E , Okonkwo Ozioma C 
Published: January 2025

AbstractBackgroundObstructive sleep apnea (OSA) is associated with hypoxia‐induced neuronal impairment and dysfunction—key risk factors for the pathogeneses of age‐related neurodegenerative diseases such as Alzheimer‘s disease (AD). This study examined longitudinal associations between OSA severity and CSF biomarkers associated with AD, synaptic dysfunction, and neuroinflammation in a sample of late‐middle‐aged adults with increased risk for AD.MethodN=25 cognitively unimpaired adults (64% female, mean age 65.8 ± 7.1 years, 42.3% APOE‐ε4 carriers) from the Wisconsin Alzheimer‘s Disease Research Center (ADRC) participated in overnight polysomnography, where the number of apneas, hypopneas, and respiratory effort related arousals (RERAs) per hour of sleep were recorded. OSA severity was estimated using the base 10 logarithm of the Respiratory Disturbance Index, or log10(RDI+1). Following sleep assessment, CSF samples were acquired via lumbar puncture over two subsequent study visits (mean 5.8 years between visits) and analyzed using the NeuroToolKit (NTK), a panel of robust prototype assays (Roche Diagnostics International Ltd), with measures including core AD biomakers—amyloid beta (Aβ)42, Aβ42:Aβ40, pTau181, pTau181:Aβ42, and tTau—as well as neurogranin, neurofilament light (NfL), α‐synuclein, glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), neuronal pentraxin II (NPTX2), and synaptosome associated protein 25 (SNAP25). Linear mixed effects models (with random intercept and random slope) were assembled to test longitudinal associations, adjusting for age, sex, and APOE‐ε4 carriage.ResultAD biomarker models indicated that RDI was associated with increased CSF levels of tTau (β=0.084, SE=0.013, p=0.014) and pTau181 (β=0.022, SE=0.003, p=0.023), but neither outcome remained robust after Bonferroni correction for multiple comparisons (adjusted α=0.0039). In contrast, models of synaptic dysfunction and neuroinflammation surpassed Bonferroni correction, showing a significant association between RDI and levels of α‐synuclein (β=0.09, SE=0.013, p=0.002) and neurogranin (β=0.13, SE=0.03, p=0.002).ConclusionThis work provides new evidence for the deleterious influence of OSA on biomarkers of synaptic dysfunction, neuroinflammation, and AD in a sample of late‐middle age to older adults enriched with risk for AD.
PLASMA BD‐TAU AS A SPECIFIC CORRELATE OF DISEASE SEVERITY AND DYNAMIC ACROSS THE ALZHEIMER'S DISEASE SPECTRUM
Authors: Piga Giuseppe , Gonzalez‐Ortiz Fernando , Yuksekel Idil , Houot Marion , Uribe Laura Gonzalez , Rametti‐Lacroux Armelle , Teichmann Marc , Bombois Stéphanie , Ber Isabelle Le , Dubois Bruno , Levy Richard , Lamari Foudil , Blennow Kaj , Villain Nicolas 
Published: January 2025

AbstractBackgroundThe identification of biomarkers for Alzheimer's disease (AD) remains a significant challenge, particularly for the clinical severity of the disease. Recent studies have shown that plasma brain‐derived‐tau (BD‐Tau) could be a promising biomarker for the identification of AD‐type neurodegeneration. This study aimed to investigate the potential of BD‐Tau in differentiating various clinical stages of AD, ranging from cognitively unimpaired AD to severe dementia AD. Additionally, the study intended to examine the association of BD‐Tau with clinical severity and elucidate its dynamic behavior throughout the natural course of AD.MethodCross‐sectional and longitudinal EDTA plasma data, along with clinical information, were utilized from the Pitié‐Salpêtrière hospital INSIGHT (cognitively unimpaired individuals with amyloid PET) and SOCRATES cohorts (AD and non‐AD symptomatic neurodegenerative disease according to up‐to‐date international criteria). Plasma BD‐Tau was analyzed using the Gothenburg University homebrew Quanterix Simoa immunoassay.ResultThe results revealed that BD‐Tau is only elevated in individuals with symptomatic AD, whether the primary or secondary neurodegenerative disease, and not in other neurodegenerative conditions. Additionally, BD‐Tau follows the clinical dynamics of AD, as it is only elevated in symptomatic AD patients, while individuals with AD biological changes but no symptoms have normal levels of BD‐Tau. BD‐Tau levels were also found to be significantly correlated with episodic memory scores and global cognitive performance across a wide range of AD severity. Longitudinal analyses further support BD‐Tau's potential as an AD‐type neurodegeneration biomarker, as it was found to increase over time only in the symptomatic AD group and not in other groups.ConclusionThese results support the notion that plasma BD‐Tau could be a promising specific biomarker for AD staging, as it follows the AD clinical severity spectrum and is not elevated in asymptomatic amyloidosis.
Proteomic dementia risk assessment in adults with diabetes
Authors: Wang Zhibo , Ning Yuye , Gao Pei‐Yang , Chen Meilin , Jia Jianping 
Published: January 2025

AbstractBackgroundThe prevalence of dementia among adults with diabetes represents a significant health challenge. Current dementia risk assessment tools are not tailored to the diabetic population. This study aims to develop more precise dementia risk predictive models for patients with diabetes using extensive blood proteomics.MethodThis prospective cohort study utilized UK Biobank data, encompassing baseline assessments from 2006 to 2010 and follow‐up until September 1, 2023. Excluding individuals with pre‐existing dementia, we included 3015 participants with diabetes and they had available Olink blood proteomics data (approximately 3000 proteins). Feature selection was conducted using a least absolute shrinkage and selection operator (LASSO) regression, and Generalized Linear Models (GLM) were applied to create a proteomic risk model. This model was trained on a tested cohort of 2111 diabetic adults and validated on an additional 904 individuals.ResultOur model, incorporating 48 proteins, outperformed conventional clinical dementia risk assessment tools, including demographic factors (age, sex, education year, APOE ε4 status) and cognitive assessments. In the validation cohort, the model's receiver operating characteristic area under the curve value was 0.83, significantly higher than the 0.56 to 0.73 range for clinical models (Figure 1). The protein models showed effective calibration in the validation cohort (Figure 2). Participants were divided into four groups based on predicted risk, and the results showed that the higher the level of predicted risk, the greater the risk of dementia (Figure 3). Mendelian randomization suggested a causal link between several proteins and dementia, like apolipoprotein E. Pathway analysis emphasized proteins related to the extracellular matrix, endopeptidase inhibition, and neuron projection.ConclusionOur proteomic risk model has high predictive accuracy in identifying dementia risk in adults with diabetes. Because this model uses only blood proteins, it is easier to generalize to the general population and thus easier to guide preventive care in patients with diabetes.
Identification of Chromone Hybrids as Interleukin‐6 and Acetylcholinesterase Inhibitor for treatment of Alzheimer’s Disease
Authors: Kaur Sukhvir , Bansal Yogita 
Published: January 2025

AbstractBackgroundNeuroinflammation plays an important role in progression of Alzheimer’s disease (AD). Interlukin‐6 (IL‐6) is well identified marker in initiating and regulating inflammation, and formation of senile plaques in brain. Therefore, simultaneous inhibition of both IL‐6 and acetylcholinesterase (AChE) may be an effective strategy for AD.MethodFour series of molecules are designed by coupling a chromone, and a N, N‐disubstituted amine as pharmacophore for IL‐6 and AChE inhibition, respectively through an alkyl linker of different lengths (1‐4 carbon atoms). Designed compounds were docked into AChE to identify the best fit compounds for calculating ADME, synthesis and evaluation of AChE inhibitory activity. The compounds showing >45% inhibition of EeAChE are selected for evaluation of IL‐6, AChE and butyrylcholinesterase (BuChE) inhibitory activities. The compound found to be most potent against was finally evaluated in vivo using STZ‐induced amnesia model in mice at three doses (0.2, 0.4 and 0.8 mg/kg).ResultDocking of all designed compounds in AChE pocket identify the 16 best fit compounds (Docking score > 8.3). The data suggests that a 2‐ or 3‐carbon atom linker is the most conducive to orient the pharmacophore for optimum binding with AChE active site. The predicted ADME properties of the 16 selected compounds suggest that these can cross the blood brain barrier (BBB) with good oral bioavailability. These compounds are synthesised and evaluated for anti‐AChE activity. Six compounds, showing >45% inhibition of AChE, are further evaluated for AChE, BuChE and IL‐6 inhibitory activities. Compound YS3g is found to be the most potent inhibitor of EeAChE (IC50 0.54 μM/ml) as well as IL‐6 (IC50 0.57 μM/ml). YS3g was evaluated in vivo at three different doses (0.2, 0.4 and 0.8 mg/kg) and show dose‐dependent effects. At higher dose (0.8 mg/kg), it reverses the STZ‐induced memory deficit in vivo and shows histopathology similar to that shown by normal‐control animal.ConclusionThe results implied hybrid compounds formed by combing chromone with piperazine ring through a three‐carbon atom chain might act as promising small‐molecule agent for further investigation against AD.
Associations between education attainment and brain‐predicted age difference: a population‐based study
Authors: Huang Huijie , Wang Jiao , Ma Jun , Xu Weili 
Published: January 2025

AbstractBackgroundEducation, as a proxy for cognitive reserves, has been linked to dementia; however, the association between education attainment and brain health remains unclear. We aim to investigate the association between education attainment and neuroimaging based brain‐predicted age difference (BPAD, the difference between brain age and chronological age).MethodThe study included 32,322 chronic neurological disease‐free participants (mean age 54.74 ± 7.49 years, 46.58% female) who underwent brain MRI scans 9+ years after baseline. Years of education were self‐reported and categorized as low (7 and 10 years), medium (13, 15, and 19 years), and high (20 years) according to the International Standard Classification of Education. BPAD was predicted based on 1,079 multimodal imaging‐derived phenotypes (including structural and functional MRI) by a LASSO machine learning model. Alzheimer's disease‐related polygenic risk score (PRSAD) was tertiled as low, moderate and high. Data were analyzed using linear regressions.ResultAt baseline, 6,332 (19.59%), 10,872 (33.64%), and 15,118 (46.77%) participants had low, medium, and high education, separately. Compared to low education, high education (β [95% CI]: ‐0.230 [‐0.392, ‐0.067]) was related to more negative BPAD. In joint‐effect analysis, the β (95% CI) of BPAD was ‐0.542 (‐0.796, ‐0.289) among participants with high education and low‐to‐moderate PRSAD, compared to those with low education and high PRSAD.ConclusionHigh education attainment was associated with more negative BPAD, particularly among people with a low‐to‐moderate genetic susceptibility for dementia.