bluuebunny/crossref_metadata_2025_split huggingface dataset:
Large‐scale proteomics to enable precision medicine for Alzheimer’s disease
Authors: Smets Bart , Emon Asif , Greene Jon , García‐González Pablo , Puerta Raquel , Socorro Alfredo Cabrera , Timmers Maarten , Ruiz Agustin , Whelan Christopher D 
Published: January 2025

AbstractBackgroundPrecision neuroscience is emerging as a transformative approach that aims to identify the right treatment for the right patient at the right time. To enable this, it is important to move beyond the categorization of patients based on clinical symptoms towards a biological definition of disease. For Alzheimer’s disease, significant progress has been made in this direction, with the development of the “A/T/N” biomarker framework that classifies patients based on underlying pathophysiology.MethodIt is essential to further characterize the molecular processes that drive disease progression within individual patients and to correctly stage those processes along the disease trajectory. Therefore, we are bringing together large biofluids proteomics datasets from different neurodegenerative disease cohorts. Analyses leverage Cox proportional‐hazards regressions to identify predictors of disease progression and, hypothesis‐driven (GSVA) and hypothesis‐free approaches (WGCNA, consensus clustering) to characterize pathological processes and disease subtypes.ResultHere, we present analyses of CSF proteomics data from the Spanish ACE Alzheimer’s disease cohort (n = 1321). MCI‐to‐dementia conversion analyses both replicate previous studies as well as identify novel biomarker candidates that might further augment the A/T/N framework (e.g. MMP10). We also provide an independent validation of work from Tijms et al. [1] that identified 3 different Alzheimer’s disease subtypes which are characterized by elevated levels of proteins associated with either (i) neuronal plasticity, (ii) innate immunity or (iii) blood‐brain barrier dysfunction. Extending upon these findings, we show that subtype 3 is characterized by an increase in CSF/plasma albumin ratio, further supporting the blood‐brain barrier dysfunction hypothesis. The subtypes stratify patients beyond the A/T/N categorization. The different subtypes might be valuable to increase precision.ConclusionLarge‐scale proteomics is a crucial tool to accelerate the development of novel precision treatments for Alzheimer’s disease, enabling the identification of novel fluid biomarkers for patient identification, stratification and disease progression, the characterization of molecularly defined disease subtypes, and the discovery of novel drug targets that are linked to specific patient populations.[1] Tijms et al. Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics. Brain 143, 3776–3792 (2020).
Comparative EEG biosignatures in Alzheimer’s disease and frontotemporal dementia: A pilot study
Authors: Meghdadi Amir H. , Verma Ajay , Mendez Mario F. , Berka Chris 
Published: January 2025

AbstractBackgroundAlzheimer's disease (AD) and frontotemporal dementia (FTD) are common causes of dementia, but differentiating between them can be challenging due to overlapping symptoms [1]. Quantitative electroencephalography (EEG) is emerging as a promising tool to identify potential biosignatures that can distinguish AD and FTD [2]–[5]. Prior EEG research has revealed slowing of the posterior dominant rhythm (PDR) in both AD and FTD patients compared to controls, reflecting underlying neurodegeneration. Our study aimed to compare quantitative EEG measures during resting‐state and attention tasks between bvFTD, PPAFTD, AD patients, and controls to determine if distinctive EEG/ERP profiles exist that can aid differential diagnosis.MethodsParticipants included individuals with behavioral‐variant Fronto‐temporal dementia (bvFTD, n=8, ages 42‐78), Primary Progressive Aphasia Frontotemporal dementia (PPAFTD, n=6, ages 53‐75), Alzheimer’s dementia (AD, n=20, ages 58‐79), and controls with normal cognition (HC, n=14, ages 47‐78). Twenty‐channel resting‐state EEG with eyes‐closed was collected during 5‐minutes of wakefulness (STAT X24). A subset of participants also completed a 3‐Choice‐vigilance‐task (3CVT) ERP attention task. Power spectral densities (PSD) during resting‐state and ERP waveforms elicited by the ERP task were computed and compared between groups.ResultsbvFTD on average exhibited a slowing of the posterior‐dominant rhythm (PDR) similar to the slowing observed in the AD group. However, unlike the AD group that showed a significant reduction in the power of the PDR (alpha power), both FTD groups had alpha power similar to HC. In the ERP attention task, FTD groups exhibited a delayed and reduced late positive potential (LPP) compared to controls.ConclusionsWe identified distinctive EEG biosignatures associated with Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD). Quantitative analysis of the posterior dominant rhythm (PDR) revealed that both AD and FTD patients exhibited slowing of the PDR frequency. However, the power of PDR was significantly reduced in the AD while relatively preserved in FTD. FTD subtypes may also demonstrate distinct EEG abnormalities such as more pronounced PDR slowing in bvFTD/ more delayed event‐related potential (ERP) components in PPAFTD. Additional research is still needed to validate the reliability and specificity of these EEG biosignatures in differentiating FTD subtypes from each other and from AD.
Unraveling the Early Trajectory of Cortical Tau Accumulation Using 18F‐MK6240
Authors: Dore Vincent , Krishnadas Natasha , Bourgeat Pierrick , Leuzy Antoine , Feizpour Azadeh , Cox Timothy , Huang Kun , Haeberlein Samantha Budd , Fripp Jurgen , Villemagne Victor L , Rowe Christopher C. 
Published: January 2025

AbstractBackgroundTau PET is instrumental in tracking the longitudinal progression of Alzheimer's disease (AD). 18F‐MK6240 is a high affinity tracer targeting the 3R/4R paired helical filaments of tau in AD. We aimed to evaluate the early phase of the natural progression of tau accumulation using 18F‐MK6240.Method231 participants: 100 cognitively unimpaired (CU) Aβ− (Centiloid<25CL), 58 CU Aβ+, 73 cognitively impaired Aβ+ (41 with mild cognitive impairment (MCI) and 32 with dementia) from the AIBL cohort were followed‐up with 18F‐MK6240 PET over one to four years (median 2.2years). Meta‐Temporal CenTauR (CTR) were generated using CapAIBL and CU CL<15, N=120 and AD (typical AD tau pattern, MMSE>24, CL>50 & age<75, N=39) as 0 and 100CTR anchored points. Abnormal level of tau was defined at 2 standard deviations above the CU Aβ‐ (13CTR). Linear ordinary differential equations (ODE) were employed to model the mean natural history of CTR based on tau accumulators (CTR>13 or CTR rate>0) only. Given the limited numbers of individuals with CTR>100, our analysis concentrated on the early phase of tau accumulation (CTR<100, N=204).ResultFigure 1A illustrates a linear relationship between the average and the rate of CTR, with a R of 0.72. Tau accumulation spanned from 0.5CTR/yr at 13CTR to 12.2CTR/yr at 100CTR, with a standard deviation of the residuals at 2.4CTR/yr. Figure 1B displays the individual’s trajectories projected on the ODE model. We estimated that, on average it takes 15.1 (CI:[12.6‐17.9]) years for an individual crossing 13CTR to reach 100CTR.ConclusionLongitudinal 18F‐MK6240 is a robust tool for estimating natural progression of tau accumulation. Our findings indicate that it typically takes around 15 years to reach the tau levels associated with mild AD once tau starts aggregating in the neocortex. These findings shed light into the initial stages of cortical tau accumulation, relevant for early diagnosis and therapeutic interventions in AD.
In vitro evaluation of neuroprotective effect of Anethum graveolens and its bioactives in H2O2‐induced oxidative stress model of SH‐SY5Y and biochemical studies
Authors: Sharma Himadri 
Published: January 2025

AbstractBackgroundAnethum graveolans commonly known as Dill is an herb from celery family displaying anti‐oxidant benefits. The present study focused on the potential of Anethum graveolans as a multifunctional curative remedy for AD treatment.MethodHexane (H) and ethyl acetate (EA) extracts of Dill were prepared and subjected to GC‐MS for identification of important bioactive components. H2O2 was used to induce oxidative stress in SH‐SY5Y cells and evaluation was done based on neuroprotection, reduced reactive oxygen species, and restoration of mitochondrial membrane potential (MMP). Additionally, anti‐Aβ fibrilization/ oligomerization activities were also analyzed along with anti‐acetylcholinesterase activity.ResultBased on GC‐MS results, 3 major components were identified apiole, carvone and dihydrocarvone (DHC). The extracts and pure compounds were assessed for their neuroprotective potential in which dose‐dependent increase in neuroprotection was observed in both extracts, apiole and carvone. Dill‐H displayed a dose‐dependent decrease in ROS levels which was more prominent than Dill‐EA extract. Pure compounds also exerted a decrease in ROS level with increasing concentration. Dill extracts (H/EA) exhibited dose‐dependent increase in mitochondrial membrane potential along with Carvone and DHC. Apiole showed less restoration of MMP compared to other pure compounds. For anti‐Aβ fibrilization activity, Dill‐EA, Carvone and Apiole show ≈40% inhibition followed by DHC (35%) and Dill‐H (30%). In MDS, maximum oligomerization inhibition was observed in DHC (26%) and apiole (14%). Dill extracts and compounds exhibit anti‐AChE activity and inhibited the enzyme through competitive inhibition except for DHC.ConclusionWe focused our research on small molecules from food to prevent AD. There is a need for a drug that is easily accessible, cost‐effective and has no/fewer side effects. In our study, Dill extracts and its identified bioactive compounds exhibited a multitargeted neuroprotection in the SH‐SY5Y cells making it a promising candidate for AD drug development.
Brain delivery of erythropoietin results in a significant reduction of brain Aβ and spatial memory deficits in the APP knock‐in mouse model
Authors: Chang Rudy Tieu , Chandrashekar Devaraj V. , Roules Grace‐Ann Chuli , Iwasaki Emi , Jagadeesan Nataraj , Sumbria Rachita K. 
Published: January 2025

AbstractBackgroundAlthough novel treatments for Alzheimer’s disease (AD) have begun to show modest therapeutic effects, agents that target hallmark AD pathology and offer neuroprotection are desired. Erythropoietin (EPO) is a glycoprotein hormone with neuroprotective effects but is faced with challenges including limited brain uptake and increased hematopoietic side effects with long‐term dosing. Therefore, EPO has been modified and bound to a chimeric transferrin receptor monoclonal antibody (cTfRMAb); the latter shuttles EPO past the blood‐brain barrier (BBB) into brain parenchyma and reduces its plasma exposure and potential for side effects. Our study sought to characterize the safety and pharmacokinetics (PK) of modified EPO following chronic dosing in healthy mice, and then utilize the optimized dose in mitigating hallmark AD pathologies in APP‐SAA knock‐in (KI) mice, a model that recapitulates Aβ pathology in the absence of APP overexpression, in vivo.MethodsFor the PK and safety study, a multidose design was employed with 10‐week‐old C57BL/6 male mice (n = 4‐5/dose) receiving doses ranging from 1‐ to 20‐mg/kg SQ for 4 weeks, aimed to evaluate the dose‐dependent plasma concentrations, and metabolic and hematologic safety of the modified EPO. The dose that resulted in the highest safety and sustained plasma exposure was dosed SQ to 5.5‐month‐old male APP‐SAA KI mice (n = 6) for 14 weeks. Control APP‐SAA KI mice (n = 5) received vehicle. The effect of modified EPO on Aβ load by immunoassays, and spatial memory via Y‐maze test, were assessed.ResultsThe 1mg/kg dose resulted in no adverse effects and sustained plasma exposure which are conducive to longitudinal dosing. APP‐SAA KI mice treated with the modified EPO had a remarkable (70‐80%, p<0.001) reduction in 6E10‐positive‐Aβ plaque area and number in the brain. Aggregated Aβ measured by ELISA was also significantly lower (p<0.05) with modified EPO treatment. Modified EPO increased the discrimination index for the novel arm (p<0.05), suggesting an improvement in spatial memory recall of the reinforced arm of the maze.ConclusionsThese findings provide essential data for dose optimization for longitudinal studies using cTfRMAb‐based therapeutics, and specifically modified EPO used herein, and illustrate the therapeutic potential of the brain‐penetrating cTfRMAb‐EPO in a novel AD mouse model devoid of APP overexpression.
Solving synaptic PET‐biomarker puzzle in Alzheimer's and other tauopathies with UCB‐J
Authors: Scarpa Miriam , Vallera Elisavet , Ausellé‐Bosch Sira , Rocha Filipa Monteiro , Mercan Buse Esra , Nordberg Agneta K , Kumar Amit 
Published: January 2025

AbstractBackgroundSynaptic loss is an eminent feature of tauopathies. The recently developed novel SV2A PET‐tracer UCB‐J has shown great promise in tracking synaptic loss in tauopathies. However, there have been discrepancies between the in vivo findings and a lack of mechanistic insight. Many of these studies indicated potential correlations between tau deposition, atrophy, cognitive‐impairment, and loss of UCB‐J binding. Hence, we found it of utmost relevance to perform extensive pre‐clinical validation of UCB‐J in tauopathic brains to gain a deeper understanding of synaptic loss for future PET‐biomarker validation.MethodWe applied an innovative multidimensional approach of postmortem brain imaging techniques (large and small frozen brain section autoradiography) and radioligand binding studies (saturation, competition, and regional distribution) alongside in‐depth biochemical analyses using a large repertoire of synaptic markers in Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), and control brains.ResultSaturation/competition studies showed one‐binding site (Kd: 3‐10 nM) for UCB‐J in the frontal cortex and globus pallidus (GP) of AD, PSP, and control brains. UCB‐J regional binding studies at the synaptosomal level clearly showed synaptic loss in different regions of AD and PSP brains as compared to control brains. In AD brains, the loss of UCB‐J binding showed the following order: Hippocampus > Frontal cortex > Temporal Cortex > Parietal Cortex > Cerebellum. Immunoblot analyses showed a positive‐correlation between UCB‐J binding and expression of synaptic proteins SV2A, synaptophysin, and synaptotagmin and demonstrated association with GABA/glutaminergic neurotransmitter machinery in GP of PSP brains. Interestingly, cortical and sub‐cortical 4R‐tau load distinctly affected synaptic marker protein levels in PSP brains. Large brain‐section autoradiography studies in AD brains indicated potential ‘off‐target’ interaction of UCB‐J with nuclear P‐tau. PSP brain's small brain‐section autoradiography also showed higher binding in cortical regions, specifically, in the parietal cortex where significantly (*p=0.034) higher 3H‐UCB‐J binding was observed compared to CN.ConclusionOur studies explicitly showed the high specificity of UCB‐J for SV2A and demonstrated synaptic deficits/loss in AD and PSP brain regions. Ongoing studies will shed more light on the interplay between different synaptic and pathological markers and help establish the reliability of UCB‐J as a definite marker of synaptic density/loss for tauopathies.
Exploring the role of telomere length in the efficacy of an exercise intervention for vascular cognitive impairment: a 12‐month randomised controlled trial substudy
Authors: Packer Amy , Barha Cindy K , Hsiung Ging‐Yuek Robin , Ambrose Caitlin E. , Pflueger Shannon , Tam Roger , Madden Kenneth , Field Thalia S , Davis Jennifer C , Wong Tsz Y. , Malanchini Margherita , Dima Danai , Powell Timothy R. , Liu‐Ambrose Teresa 
Published: January 2025

AbstractBackgroundSubcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Exercise is a potentially effective intervention for SIVCI. However, the mechanisms through which exercise promotes brain health and cognitive function are not well understood. Telomere length restoration and an increased capacity for cellular proliferation may provide a putative mechanism. Therefore, in this exploratory study we aimed to 1) assess the effect of a resistance training program on leukocyte telomere length; and 2) determine whether telomere length and/or change in telomere length is related to intervention response (i.e., change in cognitive function and/or brain structure).MethodThe sample consists of a subset of participants from a 12‐month single‐blinded, randomized controlled trial (ClinicalTrials.gov Identifier: NCT02669394). Participants (N = 91) were randomized to twice‐weekly resistance training (RT) or an active control group (balance and tone exercises; BAT). Study eligibility included: 1) age 55 years and older; 2) magnetic resonance imaging (MRI) evidence of cerebral small vessel disease; 3) mild cognitive impairment; and 4) the absence of dementia. We measured participants’ leukocyte (blood) telomere length at baseline, 6 months, and 12 months, using a qPCR‐based method. The intervention outcomes include cognitive function measured by the Alzheimer’s Disease Assessment Scale‐Cognitive‐Plus (ADAS‐Cog‐13 with additional cognitive tests) and structural brain magnetic resonance imaging (MRI) markers of SIVCI (e.g., white matter hyperintensities).ResultWe have generated telomere length data, demonstrating very good reproducibility with an intraclass correlation coefficient (ICC) of 0.853 [0.772, 0.907]. We will present findings that provide novel insights into the usefulness of telomere length as a predictive biomarker for intervention response. Furthermore, our work will contribute to the mechanistic understanding of exercise‐induced benefits for cognitive and brain health in SIVCI.ConclusionTo our knowledge, this is the first study to investigate the role of telomere length in the efficacy of an exercise intervention for vascular cognitive impairment. This could inform the development of personalised interventions and aid the discovery of novel therapeutic targets.
Cross‐cultural adaptation and validation of everyday functioning for traditional Chinese in Taiwan
Authors: Chen Poyu , Wu Chin‐Yi , Chuang I‐Ching , Huang Yu‐hua , Hsu Jung‐Lung , Sikkes Sietske A.M 
Published: January 2025

AbstractBackgroundDetecting functional performance decline from normal aging to dementia is critical for early detection and intervention. The informant‐based A‐IADL‐Q‐SV has been demonstrated with good psychometric properties. The aims of this study were to: (1) translate, culturally adapt, and validate the Traditional Chinese version of the A‐IADL‐Q‐SV‐TC for Taiwanese; (2) evaluate the psychometric properties.MethodsWe conducted the forward and backward translations with culture adaptation, followed by the consensus meeting with the original developer. The psychometric properties were investigated in both community and memory clinic settings. The Mini‐Mental State Examination (MMSE) and ICF‐based IADL scales were evaluated to test the construct validity and concurrent validity, respectively. Furthermore, diagnoses were established in a multidisciplinary consensus meeting, independent of the A‐IADL‐Q‐SV‐TC scores. The discriminate validity was examined by investigating the difference in A‐IADL‐Q‐SV‐TC between diagnostic groups across the dementia spectrum as well as the optimal cut‐off score to differentiate MCI from cognitively intact populations.Results146 informants of participants with normal cognition (NC), subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia participated this study. Results showed strong correlation between A‐IADL‐Q‐SV‐TC T‐score and both MMSE (r = .850, p <.001) and ICF‐based IADL scales (CDI, r = ‐.874, p <.001; DI, r = ‐.903, p <.001). As for the discriminate validity, participants diagnosed with cognitive impairment had lower A‐IADL‐SQ T‐scores (M= 45. 68, SD = 13.92) than participants without cognitive impairment (M = 65.03, SD = 4.53), t (85.521) = 11.227, p < .001. Furthermore, the overall diagnostic accuracy based on the AUC was 0.915 (95% CI: 0.87‐ 0.96) for the A‐IADL‐Q‐SV‐TC. The optimal cut‐off score for A‐IADL‐Q‐SV‐TC to differentiate MCI from cognitively intact populations was 54.58, resulting in a sensitivity of 0.72 and specificity of 0.98.ConclusionsWe demonstrated the A‐IADL‐SQ‐TC has sound psychometric properties as a valuable diagnostic tool.
COX‐2 as a potential blood based biomarker and a possible therapeutic target in Alzheimer’s Disease
Authors: Kumari Sakshi , Dey Sharmistha 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive brain disorder which leads to gradual decline in memory, thinking, behaviour and social skills. The current scenario for drug development is based on neuro‐inflammation and oxidative stress. Amyloid‐β (Aβ) deposition, a major hallmark of the disease activates microglia leading to neuro‐inflammation and neuro‐degeneration induced by activation of COX‐2 via NFkB p50 in glioblastoma cells.MethodThe level of proteins and their mRNA in blood of study groups were measured by surface plasmon resonance(SPR) and further validated by western blot and quantitative polymerase chain reaction (qPCR), respectively. The binding of designed peptide with COX‐2 was confirmed by SPR. Also, the rescue of neurotoxicity by peptide was checked by MTT assay on SH‐SY5Y cells (neuroblastoma cell line).ResultProteins and mRNA were found to be highly expressed in AD and MCI compared to GC. However, level of COX‐2 decreases with disease duration. The peptide showed binding affinity with COX‐2 with low dissociation constant in SPR and rescued the neurotoxicity of SH‐SY5Y cells by decreasing the level of Aβ, Tau and pTau proteins.ConclusionIt can be concluded that COX‐2 protein can serve as a potential blood‐based biomarker for early detection and can be a good platform for therapeutic intervention for AD.