bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome‐Wide Association Study of Dementia in a Community‐Based Sample of Older Subjects
Authors: Harper Jordan D. , Fan Kang‐Hsien , Aslam Muhammad Muaaz , Snitz Beth E , DeKosky Steven T , Lopez Oscar L. , Feingold Eleanor , Kamboh M. Ilyas 
Published: June 2023

AbstractBackgroundDementia broadly describes conditions that affect a person’s memory, cognition, and behavior with Alzheimer’s disease (AD) being the most common cause. AD affects millions of people in the U.S. and around the world causing a significant financial burden and placing significant stress on caretakers. AD is a complex disease influenced by both the environment and genetics, however, much of the genetic component remains unaccounted for. The purpose of this work was to use genome‐wide association analyses to detect genetic associations with incident AD in a sample of older adults age 75 and above.MethodWe performed a genome‐wide association study (GWAS) on the genome‐wide genotyped and imputed data (14,113,004 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia cases (mean age ± sd = 84.64±3.95) and 2,206 non‐demented subjects (mean age ± sd = 84.55±3.23).ResultThe established association of APOE*4 with AD was confirmed in this community‐based sample of older subjects (OR = 2.22; P = 9.36E‐14). In addition, a genome‐wide significant novel locus on chromosome 12 was observed near FAR2 and CCDC91 genes (OR = 3.31; P = 1.66E‐08). Sex‐stratified analyses showed a stronger association of APOE*4 with AD in females (P = 1.74E‐10) than in males (P = 2.43E‐05). In males, a novel SNP on chromosome 1 near LOC729987 and SNX7 genes reached genome‐wide significance (OR = 4.51; P = 3.72E‐08). Of the known AD genes, SNPs near or at TREM2, NME8/EPDR1, MS4A6A/MS4A4E, PICALM, APH1B, and PLCG2 showed nominal significance.ConclusionThe use of community‐based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case‐control studies. Replication of these signals and further study of these regions and genes will help to provide a clearer picture for their role in AD.
Differential expression and differential coexpression analyses revealed altered gene expressions and pathways in atypical Alzheimer’s Disease sub‐cohort brains
Authors: Huang Xiaoqing , Garfe Nur Jury , Reeves Cristian A Lasagna , Zhang Jie 
Published: June 2023

AbstractBackgroundIn the Alzheimer’s disease (AD) brain, the hyperphosphorylated tau protein forms neurofibrillary tangles (NFTs), which extent usually matches the dementia severity. However, for some patients, this is not the case. which we name them as asymptomatic AD (AsymAD, heavy NFTs but relatively normal cognition) and Low‐NFT AD (light NFT but severe dementia). We aim to characterize these two subtypes’ transcriptome and proteome, to understand the role of tauopathy in the AD etiology and identify resilient/vulnerable factors contributing to the cognitive decline as well as the potential drug targets for the precision treatment of AD.MethodWe performed differential analyses on both RNA and protein expression data from the atypical groups of two separate datasets ROSMAP and MSBB, using typical AD sub‐cohort as reference. In addition, highly correlated gene/protein co‐expression network modules were mined for each of the four datasets. Enrichment analysis identified biological processes and functions associated with the differentially expressed genes (DEGs) and co‐expressed modules.ResultFive DEG targets were tested in human AsymAD samples and compared with age‐matched controls and typical AD. Using western blot and qRT‐PCR, we confirmed the altered gene expressions in PSCK1 which is related to vesicle trafficking and neuron secretory pathway. Moreover, oppositely regulated pathways were identified for the two subtypes, such as oxidative phosphorylation pathway, neuron CREB signaling, necroptosis signaling pathway. Coexpression analysis also revealed that several coexpressed modules have significant altered expressions in the atypical AD subtypes as compared to typical AD group and are correlated with the disease severeness. For example, the protein modules from both ROSMAP and MSBB, which are enriched with mitochondrial functions and negatively correlated with disease severeness, are significantly elevated in Asym AD group than that of the typical AD or Low‐tau AD group.ConclusionWe have identified several altered pathways and genes that potentially render neuron protection or vulnerability. Identifying key factors in such uncoupling between tauopathy and cognitive impairment will not only improve precision medicine in AD, but also provide insights to prevent or slow down cognitive decline during AD progression. Further validations in Drosophila will elucidate their roles in the pathology or disease progression.
Mechanisms linking hearing loss with risk for dementia depends on age
Authors: van ’t Hooft Jochum J. , Pelkmans Wiesje , Tomassen Jori , Smits Cas , Legdeur Nienke , den Braber Anouk , Barkhof Frederik , van Berckel Bart N.M. , Yaqub Maqsood , Scheltens Philip , Pijnenburg Yolande A.L. , Visser Pieter Jelle , Tijms Betty M. 
Published: June 2023

AbstractBackgroundAge related hearing loss has been associated with increased prevalence and incidence of dementia. Underlying mechanisms that connect hearing loss with dementia remain largely unclear.MethodsWe studied the association of hearing loss and other risk markers for dementia in two cohorts with normal cognition and different age: 65 participants from the EMIF‐AD 90+ study (mean age 92.7 years, 56.9% female) and 60 participants from the EMIF‐AD PreclinAD study (mean age 74.4, 43.3% female). Individuals were selected when they had hearing function (‘digits‐in‐noise test’) and neuropsychological testing available. Amyloid binding potential (BPND) was derived from dynamic PET scans. We used linear regression analysis and generalized estimating equations to test the association of hearing loss and BPND. We used linear mixed models to test the association of hearing function and cognition over time. In the oldest‐to‐old individuals, magnetic resonance imaging was available at the time of hearing function testing, and we performed mediation analyses to study whether cognitive decline is mediated through regional brain regions. All models included age, sex, and amyloid status as covariates, and longitudinal analyses were corrected for education years.ResultsOldest‐to‐old individuals showed worse hearing functioning than the younger cohort (p< .001). In oldest‐to‐old hearing loss was not associated with BPND (p = .70), whereas younger individuals showed an association of hearing loss with higher BPND (p = .003, figure 1). Oldest‐to‐old individuals showed associations of worse hearing with a steeper decline in memory (β ± SE = ‐0.018 ± 0.007), global cognition (β ± SE = ‐0.017 ± 0.007) and language (β ± SE = ‐0.014 ± 0.007), while in the younger cohort worse hearing was associated with steeper decline in language only (β ± SE = ‐0.086 ± 0.02, figure 2). Mediation analyses demonstrated that the hippocampus and nucleus accumbens fully mediate the effects of hearing loss on memory and global cognition in the older individuals (figure 3‐4).ConclusionsHearing loss was associated with amyloid burden in younger individuals only, and with cognitive decline in both age groups. These results suggest that mechanisms linking hearing loss with risk for dementia depends on age.
Aggregation and antibody‐based inhibition of TDP‐43
Authors: Arias Carlos Quintero , Esposto Josephine C , Martic Sanela 
Published: June 2023

AbstractBackgroundTAR DNA‐binding protein 43 (TDP‐43) is a highly conserved nuclear protein, predominantly associated with RNA metabolism. Aberrant TDP‐43 inclusions are present in over 95% of post‐mortem brain tissue samples from Amyotrophic Lateral Sclerosis (ALS) patients. The highly disordered TDP‐43 C‐Terminal Domain (CTD) is associated with the greatest amount of disease‐related mutations and phosphorylation sites. The exact mechanism of TDP‐43 aggregation and formation into a pathological state has yet to be elucidated but is an important therapeutic target to consider.MethodFull‐length phosphorylated TDP‐43 (pS410) protein was treated with 6 hours of daily agitation over 9 days in vitro. Agitation and aging took place with and without the presence of TDP‐43 RRM2‐CTD specific antibodies. Dot‐blot analysis was performed to confirm the binding of antibodies to TDP‐43. Aggregation was monitored and characterized using biophysical analysis; methods included Thioflavin T (ThT), turbidity, and transmission electron microscopy (TEM).ResultPhospho‐TDP‐43 that had undergone agitation and extensive aging formed insoluble aggregates and ThT positive fibrils. The incubation with antibodies specific to the RRM2‐CTD inhibited aggregation and fibril formation in a concentration‐dependent manner.ConclusionSimilar immunotherapies exist for other neurodegenerative disease‐related proteins; inhibition of TDP‐43 aggregation and fibril formation using antibodies demonstrates the potential for the epitope‐specific treatment of TDP‐43 proteinopathies.1) Esposto, J., & Martic‐Milne, S. (2021). Biochimica et Biophysica Acta (BBA) ‐ Molecular Basis of Disease, 1867, https://doi.org/10.1016/j.bbadis.2021.166234.
MR‐template‐based volumes‐of‐interest generation in individual brain PET of mouse Alzheimer model not only without MR but also without spatial normalization
Authors: Seo Seung Yeon , Oh Jungsu S , Kim Jae Seung 
Published: June 2023

AbstractBackgroundThe spatial normalization (SN) of individual mouse brain PET or MRI onto template brain space is one of prerequisites for precise quantitative analysis of positron emission tomography (PET) of mouse brains. This has recently been exploited by deep learning‐based approaches, but is still challenging. Moreover, most of them are based on SN using MR templates, which is not always available in both clinical and preclinical studies.MethodIn this study, we propose a new only PET‐based deep learning‐based image generation approach to resolve MR‐less PET SN problem. We generated individual‐brain‐specific cortical volumes‐of‐interest (VOI) based on inverse‐spatial‐normalization (iSN) and deep convolutional neural network (deep CNN) models with input of PET images instead of MR images. We applied the proposed methods to the mutated amyloid precursor protein and presenilin‐1 mouse model of Alzheimer’s disease. Eighteen mice underwent T2‐weighted MRI and F‐18 FDG PET scans twice, before and after the administration of human immunoglobulin or antibody‐based treatments. Specifically, skull‐stripped PET images were used as the model inputs and iSN‐based cortical (target) and cerebellar (reference) VOIs were used as the labels. We compared our CNN‐based VOI with conventional (template‐based) VOI by both qualitative (visual) assessment and quantitative correlation analysis of mean cortical SUVR (i.e., cortical uptake normalized by cerebellar uptake) estimated by both methods.ResultIn qualitative visual assessment, there was no visible difference between CNN‐based VOI and template‐based VOI. The mean count obtained by CNN‐based VOI and template‐based VOI were highly significantly (P<0.001) correlated in target VOI (i.e., cortex).ConclusionSince our deep CNN‐based method successfully generated target VOI, showing concordant results with that of conventional VOI methods in mean count correlation analysis, we believe we have established methods of template‐based VOI not only without spatial normalization but also without MR.
8‐year safety and compliance to a multinutrient intervention in mild cognitive impairment/prodromal Alzheimer’s disease: Data from the placebo‐controlled LipiDiDiet trial
Authors: Hartmann Tobias , Solomon Alina , Visser Pieter Jelle , Blennow Kaj , Kivipelto Miia , Soininen Hilkka 
Published: June 2023

AbstractBackgroundLifestyle factors such as nutrition and diet are increasingly recognized as modifiable risk factors for the progression of mild cognitive impairment (MCI) to Alzheimer’s disease (AD). Previous studies with the multinutrient combination Fortasyn Connect (Souvenaid) have shown benefits in mild AD dementia. The LipiDiDiet1‐3 study was designed to investigate the effects of Fortasyn Connect in individuals with prodromal AD. With up to 6 years of randomised, double‐blind, placebo‐controlled (RCT) intervention and an additional 2 years of open‐label intervention, LipiDiDiet is a unique long‐running RCT with a nutritional intervention in prodromal AD/MCIAD.MethodIndividuals with prodromal AD (IWG‐1) were recruited from 11 sites across Finland, Sweden, Germany, and the Netherlands between 2009 and 2013 and randomized to the active product (125ml once‐a‐day drink; Fortasyn Connect) or a calorie‐matched placebo control. Following the first 2 years of intervention, participants could opt in for annual extensions up to a maximum of 6‐year double‐blind and 2‐year open‐label intervention. Main efficacy outcomes included measures of cognition, function, brain atrophy, and disease progression. Inherent to long‐term follow‐up studies like LipiDiDiet, interpretability of the safety data is limited by several factors like decreasing sample size, treatment switching, and potential non‐compliance, differential attrition, and gradual underreporting of events. We will report preliminary results on long‐term safety to the intervention over the full 8‐year intervention period.ResultFrom the 311 participants randomized at baseline, n = 245, 162, 84, 49, 29, 17, 8 participants completed respectively the 24‐, 36‐, 48‐, 60‐, 72‐, 84‐, and 96‐month intervention periods. The frequency, severity and types of recorded adverse events (AEs) were consistent with the studied population and none of the serious AEs was assessed by the investigators as related to the study product. The overall incidences of (serious)AEs were comparable between groups, both while on double‐blind treatment over the first 6 years and while on open‐label treatment from dementia diagnosis or start open‐label intervention onwards.ConclusionPreliminary results on safety suggest that there are no health concerns related to the use of Fortasyn Connect for up to 8 years in a prodromal AD/MCIAD population.
1Lancet Neurol. 2017;16:965‐975.
2Alz Dementia. 2021;17:29‐40.
3
Funding includes EU‐JPND.
Sex Differences in Regional Gray Matter Volume in Middle‐aged Adults
Authors: Kimura Kana , Blujus Jenna K , Driscoll Ira 
Published: June 2023

AbstractBackgroundMRI–based measures of structural brain integrity are used to aid in the diagnosis of Alzheimer’s disease (AD) and as surrogate markers of disease progression. Alterations in structural brain integrity become evident years to decades prior to the onset of clinical symptoms. Differentiating structural alterations related to normal vs. pathological aging remains a significant challenge however, especially in the absence of overt disease processes. While age‐related differences in structural brain integrity have been studied extensively, middle age is often omitted despite representing potentially a key period for intervention prior to substantial disease‐related damage. Moreover, sex differences in regional structural integrity are still largely understudied, and the literature remains equivocal, partly due to differences in sampling (size, age range, exclusion criteria) and analytical methods. The purpose of the current study is to aid in establishing normative sex‐related structural differences by characterizing regional gray matter (GM) volume in middle‐aged adults.MethodT1‐weighted images were acquired on a GE Signa 3T scanner (Waukesha, WI). Voxel‐based morphometry (VBM) (FSL v5.0.10) was applied to examine region‐specific GM sex‐differences while controlling for age, education, APOE, depressive symptoms and cognitive performance (N = 131; age range 40‐60; M/F = 52/79).ResultIn females, we observed higher GM volumes in the right frontal pole, right precentral gyrus, right superior occipital and left frontal orbital cortices, as well as the middle temporal and anterior cingulate gyrus bilaterally (P’s < 0.01). There were no regional GM differences favoring males.ConclusionWe report sex‐related dimorphism in regional GM in cognitively healthy, middle‐aged adults. We employed a well‐established technique that provides an unbiased regional GM assessment throughout the brain, while controlling for potential confounding factors in a well‐screened sample of community‐dwelling, middle‐aged individuals. Our results are largely in accordance with the existing literature, regardless of the age‐range sampled, with the exception of the frontal pole finding which has not been previously reported to the best of our knowledge. Establishing sex‐related differences in regional volumes, especially in middle age when the prevention and treatment efforts might be more fruitful, may aid in distinguishing pathological alterations early and inform more efficacious interventions.
Investigation of SLC6A9 and SLC5A1 as a promising therapeutic target for obesity and diabetes using in silico characterization, 3D structure prediction and molecular docking analysis
Authors: Sinha Jitendra Kumar , Durgvanshi Shantanu , Verma Manish , GHOSH SHAMPA 
Published: June 2023

AbstractBackgroundObesity is a multi‐factorial clinical condition resulting from energy dyshomeostasis. Obesity is known to be linked with the development of Type‐1 and Type‐2 diabetes due to abnormal glucose regulation. Additionally, it is associated with the onset of insulin resistance as well as atypical nutrient and hormonal sensing in the CNS. The role of GLYT1 has been implicated in the Dorsal Vagal Complex (DVC) which forms the brain‐liver axis for glucose release into the bloodstream. On the other hand, SGLT1 is majorly responsible for glucose absorption in the intestinal lumen.MethodThe current work focuses on in silico approaches to characterize the transporter proteins: Glycine Transporter‐1 (GLYT1) and Sodium‐Glucose Linked Transporter‐1 (SGLT1) as a potential target for the treatment of obesity and diabetes in an insulin independent manner. The sequence of the two proteins were obtained from the UniProt database which was used to calculate various physicochemical parameters giving detailed insight into its molecular weight, amino acid composition, theoretical PI, extinction coefficients and GRAVY index.ResultPrimary sequence analysis using ProtParam revealed the stability of SLC6A9 and SLC5A1 in test‐tube classifying it as stable and unstable respectively while secondary structure analysis using SOPMA shed light on its alpha helix and beta sheet composition as well as random coils. Three‐dimensional (3D) protein structures were generated using SWISS‐MODEL, an integrated web‐based homology modeling server, which were then verified using the SAVES server. Docking studies were performed using AutoDock4 which yielded potential drug candidates. The validated models of SLC6A9 and SLC5A1 were successfully submitted to PMDB ‐Protein Model Database with PMDB ID: PM0082326 and PM0082333 respectively which could be utilized for further Docking analysis and spectroscopy experiments.ConclusionA thorough explication of these results can aid the future research in development of a novel therapeutic strategy to battle this enigmatic rising epidemic of obesity and diabetes.
Sex‐specific accumulation and therapeutic effect of the histone variant H2A.Z in Alzheimer’s disease
Authors: Creighton Samantha D , Stefanelli Gilda , Brimble Mark A , Hategan Luca , Collins Emily , Zakaria Jacqueline , Vislavski Stefan , Reda Anas , McLean Timothy AB , Walters Brandon J , Fahnestock Margaret , Orouji Elias , Zovkic Iva 
Published: June 2023

AbstractBackgroundThere is growing evidence that dysregulation of gene expression plays a role in cognitive deficits and neuropathology in Alzheimer’s disease (AD), thus prompting interest in epigenetic factors as mechanisms of neurodegeneration and memory loss. Here, we assess the therapeutic potential of the histone variant H2A.Z. H2A.Z is a memory suppressor that is actively removed from DNA during learning to promote gene expression and memory formation. The memory‐suppressive effects of H2A.Z are further supported by our finding that H2A.Z levels increase in the aged brain and may act as a prelude to age‐related memory decline. We hypothesize that H2A.Z also accumulates in AD and that targeted depletion of H2A.Z is an effective therapy for memory impairment.MethodsTo characterize H2A.Z levels in the AD brain, we assessed genome wide (ChIP‐seq) and site‐specific (ChIP‐qPCR) binding of H2A.Z to DNA as well as mRNA expression of genes encoding H2A.Z in both the human post‐mortem and 5xFAD mouse hippocampus. To directly test the therapeutic potential of H2A.Z depletion, adeno‐associated virus (AAV) vector containing short hairpin RNA against H2A.Z was delivered in the hippocampus of 5xFAD mice and memory was assessed using object location and contextual fear conditioning tasks.ResultsConsistent with the hypothesis that H2A.Z accumulates in the AD brain, binding of H2A.Z increased at several memory and AD‐related genes in the human and 5xFAD female hippocampus. Interestingly, this effect was sex specific, as H2A.Z binding decreased in the male hippocampus across species. Similarly, mRNA expression of genes encoding H2A.Z increased in the human and 5xFAD female hippocampus. This female‐specific increase in H2A.Z was paralleled by the remediation of memory impairment following H2A.Z depletion in 5xFAD females but not males.ConclusionOur data are the first demonstration of histone variants as regulators of AD‐related memory impairment. The sex‐specific changes in H2A.Z generalize across species and provide promising support for H2A.Z depletion as a therapeutic strategy for AD in females.
Impact of APOE ε4 allele on familial aggregation and cerebrovascular disease in Alzheimer’s Dementia: A cross‐sectional pilot study from India
Authors: Thatikonda Navya Spurthi , Balachander Srinivas , Kumar Pramod , Kannampuzha Anand Jose , Dayal Pavithra , Viswanath Biju , Jain Sanjeev , Sivakumar Palanimuthu Thangaraju , Varghese Mathew , Sen Somdatta , Purushottam Meera 
Published: June 2023

AbstractBackgroundThe ε4 variant of the apolipoprotein E gene (APOE4) is associated with the risk of Alzheimer’s dementia (AD). Previous studies have reported APOE4 status association with familial loading and vascular changes in AD. With a diverse ethnic population, and high rates of metabolic syndromes, the consequences of being a carrier of the APOE4 polymorphism needs further exploration in Indian context.MethodPatients (N = 452) diagnosed to have AD, including 75 with a family history of AD in first‐degree relatives [‘familial’ AD (FAD)] and others without a significant family history [‘sporadic’ AD (SAD)], under evaluation at a tertiary hospital in India are described. All patients were assessed using Clinical Dementia Rating scale (CDR), Hindi Mental Status Examination (HMSE), Everyday Abilities Scale for India (EASI), Neuropsychiatric Inventory (NPI), and the Hachinski Ischemic Scale (HIS), along with detailed clinical evaluation. Blood samples were collected from AD patients, and 456 matched healthy controls for APOE genotyping using Polymerase Chain Reaction restriction fragment length polymorphism.ResultsThe ε4 allele frequency was 22.57% and 9.65% among AD patients and healthy controls. APOE4 carrier status was noted in 52% of FAD, 38.46% of SAD patients, and was a significant risk factor for FAD with an odd’s ratio (OR) of 1.73 (95% confidence interval (CI):1.04‐2.9, p = 0.03). The presence of APOE4 did not have a significant association with metabolic comorbidities (p = 0.54). Furthermore, APOE4 status was a negative predictor for cerebrovascular disease among all AD patients (OR: 0.32, 95% CI: 0.12‐0.71, p = 0.008).ConclusionAPOE4 allele has a positive association with familial aggregation and a negative association with cerebrovascular adversities in AD. The effect of APOE4 polymorphism on the clinical manifestation of AD in Indian population is unclear and needs further evaluation.