bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploration of novel biomarkers for neurodegenerative diseases using ligand‐binding assays
Authors: Kenzelmann Annalena , Boch Christina , Schulz Michael , Challagundla Malleswari , Just David , Klein Marco , Griesbeck Anne , Schroeder Christoph , Richter Mario 
Published: December 2023

AbstractBackgroundNeurodegeneration is a complex area involving multiple pathways and often has a long prodromal phase. Reliable biomarkers are needed to allow earlier diagnosis, monitoring of the disease progression, and studying the impact of therapeutic approaches.MethodTherefore, a screening was performed by Sciomics GmbH to identify potential protein biomarkers. The most promising analytes were selected, including cluster of differentiation 14 (CD14), osteopontin (OPN), vascular endothelial growth factor A (VEGF‐A), cancer antigen 15‐3 (CA15‐3) and carcinoembryonic antigen‐related cell adhesion molecule 1 (CEACAM‐1). Using quantitative ligand‐binding assays based on fluorescence or electrochemiluminescence these analytes were investigated regarding up‐ or downregulation in the presence of Alzheimer´s disease (AD), Parkinson´s disease (PD), Multiple Sclerosis (MS) or Amyotrophic Lateral Sclerosis (ALS) compared to healthy patients.ResultThe quantitative assays confirmed the screening in that CD14 levels were elevated in cerebrospinal fluid (CSF) of AD patients and that OPN levels were increased in CSF of PD patients. In addition, the following significant changes were observed: OPN was elevated in plasma of PD and MS patients, while it was decreased in CSF of MS patients. VEGF‐A levels were increased in the plasma of ALS patients and decreased in CSF of MS patients.ConclusionIncreased CD14 levels in AD CSF are in agreement with studies suggesting that CD14, a co‐receptor of toll like receptor 4 (TLR4) expressed on the surface of e.g. microglia, might mediate the interaction of fibrillar Aβ to TLR4 and thus induce inflammation. OPN has already been shown to be increased in CSF and blood of PD patients previously and it is suggested to be involved in PD pathogenesis due to its role in oxidative stress, apoptosis, mitochondrial dysfunction, and cytokine regulation. Other studies have shown increased levels of OPN in plasma of MS patients potentially due to its expression in activated T‐cells. However, some studies also show increased MS CSF levels in contrast to our findings, where OPN levels are lower in MS CSF. Literature data for VEGF‐A is more conflicting possibly due to different assays detecting different isoforms. To further solidify these findings, large‐scale analyses using well characterized samples should be done in the future.
Roles of HDAC6 in the pathogenesis of Alzheimer’s disease
Authors: Lee Yujeong , Lee Jeongmi , Jo Dong‐Gyu 
Published: December 2023

AbstractBackgroundIt has recently been demonstrated that HDAC6 depletion ameliorates the impairment of memory function and mitochondrial axonal transport induced by the accumulation of Aβ. However, very little is known about molecular mechanisms through which HDAC6 regulates APP processing. Also, it remains controversial whether HDAC6 induces inflammation or reduces it.MethodWe analyzed the expression of HDAC6 in AD patients and 5xFAD mice. We confirmed that HDAC6 regulates BACE1 in primary neurons and NLRP3 inflammasome in primary microglia. And we crossed HDAC6 knock‐out mice with 5xFAD mice and got 5xFAD/HDAC6 KO. We compared 5xFAD (n = 11) and 5xFAD/HDAC6 KO (n = 13). We did a nest building test, open field test, Morris water maze, Y‐maze, passive avoidance, and elevated plus maze. After finishing all these behaviour tests, we sacrificed the mouse and checked protein and mRNA. We did Immunohistochemistry using Aβ plaque, NLRP3 inflammasome and synapse‐related markers. We also did RNA‐seq analysis in these mice’s brains.ResultWe confirmed that the expression of HDAC6 was increased in the AD cortex compared to neuropathologically normal brains. The stability of BACE1 is regulated by its C‐terminal lysine, and HDAC6 deacetylates the C‐terminal lysine of BACE1 by direct binding. Also, HDAC6 deficiency reduced NLRP3 inflammasome activation‐, and subsequent inflammatory responses in microglia. By crossing HDAC6 knock‐out mice with 5xFAD mice, the role of HDAC6 was confirmed in an animal model of AD. HDAC6 deletion improved cognitive function and reduced the protein expression of BACE1 and inflammatory factors in 5xFAD mice. Also, HDAC6‐deficient 5xFAD mice developed fewer dense‐core plaques, IL‐1β, and ASC specks than 5xFAD mice. Furthermore, RNA‐sequencing was analyzed from the hippocampus of 5xFAD and 5xFAD/HDAC6 KO mice. Synapse and neuron development‐related genes were significantly up‐regulated, and type I interferon, immune response, and prion disease‐related genes were down‐regulated in HDAC6‐depleted mice. Finally, we confirmed that the ratio of PSD95 colocalized with C1q was significantly decreased in 5xFAD/HDAC6 KO compared to 5xFAD mice, which suggested that synapse loss was inhibited in AD mice.ConclusionThis study reveals distinct functions of HDAC6 and suggests HDAC6 as a significant regulator in the pathogenesis of AD that could be exploited therapeutically.
A proposed scheme for comprehensive and systematic evaluation of normal pressure hydrocephalus
Authors: Pitaksuteepong Pichaya , Supharatpariyakorn Thirawat , Wangsawatwong Piyanat , Thanprasertsuk Sekh , Chunamchai Sedthapong , Chunharas Chaipat , Pobpan Pea , Sringean Jirada , Paprad Tunchanok , Hemachudha Thiravat , Thanapornsangsuth Poosanu 
Published: December 2023

AbstractBackgroundAs ageing population continues to rise across the globe, age‐related conditions such as normal pressure hydrocephalus (NPH) are expected to become a prevalent health problem effecting gait and cognition in the elderly. Alas, the vague definition of NPH, coupled with the absence of standardized assessment protocols, can potentially result in unnecessary surgical interventions and complications. We aim to demonstrate the feasibility of our proposed objective scheme for a comprehensive and systematic evaluation of NPH, which we anticipate will be beneficial in guiding future management of this enigmatic disorder.MethodParticipants suspected of idiopathic NPH (iNPH) selected to undergo a trial of fluid diversion (i.e. large volume spinal tap) were enrolled to receive structured assessment with various biomarkers. This assessment includes pre‐fluid diversion evaluation of the following: iNPH grading scale (Kubo et al., 2008), voxel based morphometry analysis of the MRI, tablet‐based digitalized Montreal Cognitive Assessment, International Consultation on Incontinence Questionnaires, urodynamic studies. Tests that were conducted both pre‐ and post‐fluid diversion test included actigraphy, video gait analysis using Kinovea®, in‐house tablet‐based go/no‐go test and conjunction search test. During the fluid diversion trial, participants underwent an infusion test for objective quantification of cerebrospinal fluid dynamics. Cerebrospinal fluid was collected and analyzed for levels of Alzheimer’s disease biomarkers, specifically Aβ and tau species, using ELISA, as well as an α‐synuclein seeding assay. The decision to operate was made according to subjective improvement, which is the current standard of care, and subsequent assessments were repeated at 4‐month intervals for 1, 2, and 3 years postoperativelyResultBetween May 2022 and November 2022, six participants were recruited. Each test was completed by at least three out of the six participants. The participant who completed the most tests completed all but one of the tests. It is important to note that none of the participants recruited underwent shunt surgery.ConclusionThe proposed scheme for the assessment of NPH demonstrates feasibility, however, certain optimizations are necessary. Further research should be conducted to determine the correlation between these parameters and their performance in predicting long‐term responsiveness to shunt surgery.
Natural trimethoxyflavone improves memory in mice via cholinergic, oxidative, inflammatory and apoptotic pathways
Authors: Singh Varinder , Singh Manjinder , Singh Thakur Gurjeet , Shri Richa 
Published: December 2023

AbstractBackgroundDementia is a deliberating neurodegenerative disorder which causes impairment of intellectual functions. The USFDA approved drugs has limited efficacy and numerous side effects. Thus, finding newer drugs to manage dementia and cognitive disorders is certainly required. The present study explores the potential of a natural flavone, 5,7‐dihydroxy‐3',4',5'‐trimethoxyflavone (DHF), as memory enhancer drug against scopolamine‐induced cognitive deficit in mice.MethodsAnimals were treated with DHF (5‐10 mg/kg, p.o.) for 7 days after inducing cognitive impairment by scopolamine (1mg/kg,i.p.). Memory functions (passive shock avoidance task and Morris Water Maze), brain acetylcholinesterase (AChE) activity, inflammatory markers, oxidative stress, apoptotic biomarkers and histopathological studies (H&E and congo red staining for beta amyloid) were determined to measure memory improvement effects of DHF. In‐silico (molecular docking) studies were performed to understand the interactions of DHF with key pathological enzymes related to dementia.ResultsTreatment of scopolamine administered mice with DHF improved scopolamine‐induced cognitive impairment and restore brain biochemical parameters (inhibited acetylcholinesterase activity, enhanced glutathione levels, and reduced TBARS, TNF‐α, IL‐6, IL‐1β and caspase‐3 levels). Moreover, histopathological studies showed that DHF treatment reduced the neuronal cell death and amyloid depositions in mice brain. Further, molecular docking studies revealed string interactions of DHF with crucial amino acids of AChE and caspase‐3.ConclusionThese results suggest that DHF was effective in treating scopolamine induced cognitive deficit by improving cerebral cholinergic dysfunction and reducing brain oxidative stress, inflammation, apoptosis and beta‐amyloid depositions in mice. Thus, DHF could be developed as a potential alternative drug to treat memory disorders.
Multimodal retinal imaging in individuals with frontotemporal dementia compared to controls
Authors: Allen Ariana , Joseph Suzanna , Hemesath Angela , Kundu Anita , Robbins Cason B , Ma Justin , Haystead Alice , Winslow Lauren , Bozoki Andrea , Johnson Kim G , Stinnett Sandra , Grewal Dilraj S , Fekrat Sharon , Group MIND Study , School Duke University 
Published: December 2023

AbstractBackgroundA growing body of literature has shown a relationship between neurodegenerative diseases and ocular changes. Frontotemporal dementia (FTD) affects individuals under age 65. We use optical coherence tomography (OCT) and OCT angiography (OCTA) to characterize the retinal microvasculature and retinal and choroidal structure in patients with FTD vs normal cognition.MethodCross‐sectional comparison of patients with FTD to age‐ and sex‐matched controls with normal cognition. Exclusion criteria included diabetes, glaucoma, uncontrolled hypertension, and retinal or optic nerve pathology. Participants underwent OCT and OCTA imaging using the Zeiss Cirrus HD‐5000 Spectral‐Domain OCT with AngioPlex. Primary outcome measures included OCT parameters: subfoveal choroidal thickness, central subfield thickness, ganglion cell layer‐inner plexiform layer (GC‐IPL) thickness, and retinal nerve fiber layer (RNFL) thickness; and OCTA parameters: superficial capillary plexus foveal avascular zone area, 3×3mm and 6×6mm macular vessel density (VD) and perfusion density (PD), and 4.5×4.5mm peripapillary capillary perfusion density (CPD) and capillary flux index (CFI). Generalized estimating equations accounting for correlation between 2 eyes of the same subject were utilized for statistical analysis.ResultTwenty‐eight eyes of 17 participants with FTD and 85 eyes of 48 patients with normal cognition were analyzed. Individuals with FTD were matched to their normal cognition counterparts with regard to sex (64.7% vs 62.5% men, p = 0.871) and age (67.82 vs 68.98 years, p = 0.958). Compared to normal cognition participants, MMSE scores of FTD participants were significantly lower (p < 0.001). In FTD, average 4.5×4.5‐mm CFI was decreased compared to controls (p = 0.032). There was no difference in average 4.5×4.5mm CPD between FTD and controls (p = 0.172).ConclusionIndividuals with FTD exhibited significantly reduced average CFI compared to controls. Retinal microvasculature changes may be useful as a biomarker for FTD diagnosis.
Differences in metabolomic profiles of APOE4 carrier vs non‐carrier patients undergoing therapeutic plasma exchange with albumin replacement as a treatment for Alzheimer’s disease
Authors: Minguet Carla , Ortiz Ana Maria , Gonzalo Ricardo , Núñez Laura , Ruiz Agustin , Lopez Oscar L. , Boada Mercè , Páez Antonio , Bravo Isabel , Costa Montserrat 
Published: December 2023

AbstractBackgroundApolipoprotein E is the major apolipoprotein found in plasma, involved in lipid transport and metabolism. Carrying the ε4 allele of the APOE gene (ApoE4) is a risk factor for developing Alzheimer’s disease (AD) and is associated with altered plasma lipid levels and lipoprotein particle distribution. The AMBAR phase 2b/3 trial is a therapeutic approach for AD patients (MMSE:18‐26) based on a 14‐month program comprising 18 plasma‐exchange procedures with albumin replacement (PE‐Alb) to remove pathological substances from plasma, slowing AD progression. The aim of this study was to assess PE‐Alb differential effects on metabolites across the AMBAR trial between ApoE4 carriers and non‐carriers.Method442 metabolites were quantified in serum samples of 296 ApoE‐genotyped patients included in the AMBAR trial (225 PE‐Alb‐treated and 71 placebo), at 3 time‐points, using high‐throughput UHPLC‐MS (OWL‐Metabolomics, Spain). Data was stratified by ApoE4 carriers (n = 145) and non‐carriers (n = 151) and analyzed through a mixed model for repeated measures. Differences from placebo were assessed through month*treatment group interaction estimates. Reported p‐values were adjusted by Benjamini‐Hochberg procedure.ResultBaseline differences between ApoE4 carriers and non‐carriers were found according to what has been reported in the literature. In ApoE4 carriers, 29 metabolites significantly changed (Adjusted p‐value<0.05) in PE‐Alb‐treated patients compared to placebo at end of study (month 14). Eleven of them, which were in the free Fatty Acids (FA) class (6 monounsaturated‐FA, 3 polyunsaturated‐FA, 2 saturated‐FA), were down regulated. This would agree with the previously reported finding that free‐FA levels increase in blood from AD patients and participate in the pathogenesis of AD by multiple mechanisms. In Non‐carriers, 19 metabolites showed statistically significant change at month 14, 2 of them being downregulated. In both stratifications, most upregulated metabolites were in the Glycerophospholipid class (21/35) which has been reported to be decreased in AD. All other metabolites were in the Glycerolipids (4), Sphingolipids (4), Sterols (3), Bile acids (2) and Amino Acids (1) classes.ConclusionThese results demonstrate modulation of fatty acid metabolism in PE‐Alb‐treated patients from the AMBAR trial in relation to its ApoE genotype. Furthermore, treatment induced positive metabolite changes compared to placebo. These results deserve further investigation.
Sex impacts the association of plasma Glial Fibrillary Acidic Protein with neurodegeneration in Alzheimer’s disease
Authors: Abbas Sarah , Bellaver Bruna , Ferreira Pamela C.L. , Povala Guilherme , Ferrari‐Souza João Pedro , Lussier Firoza Z , Zalzale Hussein , Lemaire Peter Charles , Soares Carolina , Rohden Francieli , Aguzzoli Cristiano Schaffer , Cabrera Arlec , Leffa Douglas Teixeira , Therriault Joseph , Tissot Cécile , Servaes Stijn , Macedo Arthur C. , Chamoun Mira , Bezgin Gleb , Stevenson Jenna , Stevenson Alyssa , Rahmouni Nesrine , Pallen Vanessa , Karikari Thomas K , Ashton Nicholas J. , Benedet Andrea Lessa , Zetterberg Henrik , Blennow Kaj , Rosa‐Neto Pedro , Pascoal Tharick Ali 
Published: December 2023

AbstractBackgroundGrowing evidence suggests an increased prevalence of Alzheimer’s disease (AD) in females compared to males. Elucidating how disease biomarkers correlate in females and males is critical to understanding the basis of sex differences in AD. Our aim was to evaluate sex‐related differences in the association of plasma Glial fibrillary acidic protein (GFAP) levels, a biomarker of astrocyte reactivity, with downstream neurodegeneration in Alzheimer’s disease (AD) pathophysiology.MethodWe cross‐sectionally assessed participants from TRIAD cohorts. Unpaired t‐test compare the difference in plasma GFAP levels between females and males. We performed linear regression with an interaction term for sex to compare the association of plasma GFAP with neurodegeneration measured with hippocampal volume (HCV) between cognitively impaired females and males.ResultWe assessed 308 participants (MCI = 63, AD = 45 CN = 200, mean age = 69.8 (8)). Females showed significantly higher GFAP levels than males (Fig 1). We found a significant interaction term and strong correlation between plasma GFAP and neurodegeneration (HCV atrophy) (R‐squared = 0.13; P = 0.003) only in females. No association was found between GFAP and AD biomarkers in females or males without cognitive impairment (Fig 2).ConclusionOur results suggest astrocyte reactivity is highly associated with neurodegeneration, a process known to play a key role in AD pathophysiology, in females than males. This may have important implications for elucidating the basis of the higher prevalence of AD in females. Yet, these results were generated with a limited number of subjects and using a cross‐sectional design. Therefore, replication in larger, independent longitudinal datasets is needed to better understand the association of GFAP levels, sex, and AD pathophysiology.
Clinical validation of TAS Test automated hand motor analysis to discriminate subjective cognitive decline, mild cognitive impairment and dementia in a multidisciplinary cognitive clinic
Authors: Alty Jane E , Wang Xinyi , Li Renjie , Rudd Kaylee , Lawler Katherine , Salmon Katharine , McDonald Scott , Stuart Kimberley E , Bindoff Aidan D , Bai Quan , Vickers James C 
Published: December 2023

AbstractBackgroundGait analysis studies have shown that motor function declines across the Alzheimer’s disease (AD) continuum and may aid early detection of dementia risk. Hand movement analysis has been poorly investigated in comparison to gait but may be easier to assess using computer keyboards. TAS Test is a new automated online test of hand movements. The aim of this study was to evaluate TAS Test keyboard tapping tests compared to gold standard consensus diagnosis in a multidisciplinary team (MDT) cognitive clinic.MethodParticipants attending the ISLAND Cognitive Clinic in Tasmania, Australia underwent extensive neuropsychological, medical and MRI assessments before an MDT consensus diagnosis was formulated. They also completed 5 minutes of TAS Test keyboard tapping tests including single‐, alternate‐ and 3 step‐ key tapping tests. Motor features of frequency, rhythm, accuracy, and dwell time were extracted. Healthy controls (HC) with normal cognition also completed TAS Test. Accuracy to discriminate diagnostic groups using TAS Test motor features, adjusted for age, in ridge regression models was assessed using area under ROC curves (AUC) and compared to a null model which comprised only confounding variables.Result205 participants were recruited (mean [SD] age 69.0 [8.9] years): 91 from the Cognitive Clinic with Subjective Cognitive Decline (SCD, N = 16), Mild Cognitive Impairment (MCI, N = 40) or Dementia (N = 35) and 114 HCs. TAS Test discriminated better than null models with the following AUCs [95% CI]: SCD from HC: 0.82 [0.73‐0.91], MCI from HC: 0.78 [0.69‐0.86], Dementia from HC: 0.91 [0.86‐0.97], MCI from SCD: 0.7 [0.63‐ 0.92], Dementia from MCI: 0.82 [0.82‐0.97], all p <0.01. Hand tests were characterized by progressively slower, less rhythmic movements, with more pauses and less accuracy across the dementia continuum. Dominant hand features were more discriminatory than non‐dominant hand features.ConclusionA simple brief battery of keyboard tapping tests via the TAS Test website aids stratification of diagnostic groups. This novel hand motor approach is more accessible than gait analysis and opens new opportunities for objective motor measure in clinical and research applications. Longitudinal research is underway to assess if TAS Test can aid prediction of cognitive decline in cognitively healthy controls.
Neuroprotective potential of safinamide mesylate in streptozotocin induced sporadic Alzheimer’s disease in rats
Authors: Kajal Ms , Kumari Shamly , Deshmukh Rahul Renukadas 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is an age related progressive neurodegenerative disorder mainly characterized by cognitive decline, synaptic loss, and other mental functions. Extracellular amyloid beta (Aβ) deposits and intracellular accumulation of neurofibrillary tangles of tau protein are the two major hallmarks of AD. Multiple etiological factors have been linked with AD pathophysiology, oxidative stress, neuroinflammation, neurotransmitter deficit and foremost is the dysregulation of lipid metabolism, consistently involve in AD pathology and cognitive deficit. The present study was designed to investigate the neuroprotective potential of Safinamide mesylate in Streptozotocin induced sporadic Alzheimer’s disease in rats. STZ (3mg/kg) was administered bilaterally through the intracerebroventricular (i.c.v.) route on the 1st and 3rd days in rats.MethodIn the present study, we have explored the neuroprotective potential of Safinamide a potent MAO‐B inhibitor and a neuroprotective drug against STZ infused rats at dose levels of 15 and 30 mg/kg/i.p. for treating AD from day 15th to 28th. Spatial and non‐spatial memory was evaluated by using Morris Water Maze (MWM) and Object Recognition Test (ORT) while spontaneous locomotion is examined by Open field test . We further performed biochemical tests to check the levels of different oxidative stress markers & histopathological evaluation to analyze the neurodegeneration.ResultThe cognitive and memory deficits by the significant increase in oxidative stress markers produced by i.c.v. STZ was determined by biochemical analysis. The neurodegeneration in the hippocampus and cortex region was observed through histopathological analysis. Safinamide treatment significantly attenuated the STZ induced memory decline, neuroinflammation and prevented the neuronal loss. The observed cognitive improvement followed by safinamide administration may be due to its neuroprotective, anti‐inflammatory, and anti‐apoptotic activity.ConclusionBased on the outcomes of the current investigations it would be safe to conclude that safinamide mesylate has neuroprotective potential and the observed cognitive enhancement in STZ rats following safinamide mesylate treatment may be due to its antioxidant potential and its ability to protect or preserve neuronal cells.