bluuebunny/crossref_metadata_2025_split huggingface dataset:
Understanding sex‐specific molecular mechanisms in preclinical and Alzheimer’s disease through brain proteomics and transcriptomics
Authors: Sadeghi Iman , Rodríguez‐Fernández Blanca , Navarro Arcadi , Gispert Juan Domingo , Vilor‐Tejedor Natalia 
Published: December 2023

AbstractBackgroundSex‐specific molecular mechanisms active during the transition from the preclinical stage to clinically evident Alzheimer’s disease (AD) pathobiology are not yet fully understood. In this study, we used large‐scale multi‐omics data integration of brain proteomics, brain transcriptomics, and genomics to study sex‐specific co‐expression changes related to the AD continuum.MethodsThe study included postmortem brain proteomics samples from the dorsolateral prefrontal cortex (DLPFC) of cases with AD dementia (N = 200, 55% female), cognitively unimpaired individuals with amyloid‐beta pathology (CU A+, N = 206, 70% female), and without (CU A‐, N = 110, 50% female) from the ROSMAP and Banner studies [Figure 1]. Additionally, RNAseq data was obtained from cases with AD dementia (N = 203, 70% female), CU A+ (N = 204, 63% female), and Cu A‐ (N = 125, 56% female) from ROSMAP. We performed co‐expression network analysis to identify functional sex‐specific molecular modules that differentially behave in AD different stages along the AD continuum (AD dementia vs. CU A‐, CU A+ vs. CU A‐). We assessed the preservation of these modules in the brain transcriptome. Additionally, brain protein quantitative trait loci (pQTLs) enrichment analysis was performed to characterize significant modules enriched for AD risk variants. Finally, we assessed the association of sex‐specific modules with AD traits.ResultsProteomic network analysis showed modules significantly associated with pathological traits differentially by sex [Figure 2]. For instance, a module related to cellular localization showed upregulation in AD and CU A+ compared with CU A‐ [Figure 3A]. Association with pathological traits showed a positive correlation with global pathology and a negative correlation with global cognition only in female [Figure 3B]. In males, two modules related to ubiquitin proteolysis were changed in AD dementia and CU A+. Brain transcriptome showed preservation of the cellular localization module in female [Figure 3C]. This module was enriched for AD pQTLs in the brain, including variants from SYN3, FLOT2 and PACSIN2, which are involved in processing of amyloid and vesicle trafficking
[Figure 3D]
ConclusionsThis multi‐omics system network analysis reveals changes of a cellular localization‐related module, specifically in the females AD brain proteome and transcriptome, which could be used as potential therapeutic targets.
Recruitment and Retention Strategies Adopted in TATA Longitudinal Study of Aging Study: A prospective Cohort Study on Aging in Urban India
Authors: HS Sunitha , Lingegodwa Abhishek Mensegere , Arvind Prathima , Hameed Shafeeq K Shahul , Stezin Albert , Malo Palash Kumar , Velavarajan Goutham , Mallikarjun Divya N , Narayanasamy Rajitha , R Meghana , Singh Sadhana , Menon Meenakshi , Partha Ajith , M Amitha C , Diwakar Latha , Kommaddi Reddy Peera , Sundarakumar Jonas S. , Issac Thomas Gregor 
Published: December 2023

AbstractBackgroundRecruitment and retention of participants is a crucial step in any longitudinal study. The TATA Longitudinal Study for Aging (TLSA) is an urban cohort study to gather long term data to identify risk and protective factors for dementia in India.MethodWe have recruited more than 1000 individuals with age ≥ 45 years for the study. Our recruitment strategies centered around existing urban community centers in Bangalore, India, where we have conducted more than 50 awareness programs to inform the participants about the healthy aging and our study. We maintain the periodic contact with participants through telephone, in person visits and mental health awareness programs. Though we do not offer any treatment the clinical team provides brief feedback on participants blood test reports, ECG and MRI and makes appropriate referrals to the health system if necessary. To emphasize participant convenience and reduce burden, our study team has a mobile unit that conducts clinical and cognitive sessions at the participant’s location. Transportation is also offered for each participant to attend the sessions at the study center. During the COVID 19 pandemic period, all participants were given special attention in terms of enquiring about their well‐being and using standard methods to assess their anxiety and depression. To keep the participants engaged during COVID 19 pandemic, we had shared the links for virtual museums, materials to read and offered psychosocial support.ResultWe have approached 2225 individuals out of which 52% consented and able to complete the baseline assessment for them. It is been observed that good support and willingness to contribute to the study with the notion of potentially helping their future generations. Currently up to 50% of the participants completed first follow‐up sessions.ConclusionThe recruitment and retention of participants in the longitudinal clinical studies is a challenging task. However, TLSA study provides the unique insights on recruitment approaches that can be tailored and adopted for increasing the study enrolment and retaining in the urban cohorts of developing countries like India.
Supporting elderly people with cognitive impairment during and after hospital stays with Intersectoral Care Management – results of a randomized controlled trial
Authors: Boekholt Melanie , Nikelski Angela , Schumacher‐Schönert Fanny , Kracht Friederike , Chikhradze Nino , Vollmar Horst Christian , Hoffmann Wolfgang , Kreisel Stefan , Thyrian Jochen René 
Published: December 2023

AbstractBackgroundThere is a need to examine whether evidence based collaborative care management can be beneficial to people with cognitive impairment transitioning from hospital to primary care.MethodWe conducted a longitudinal multisite randomized controlled trial with two arms (care as usual and care as usual + intersectoral care management) and two follow‐ups 3 and 12 months after hospital discharge. The sample under analysis consists of n = 401 participants from 3 different hospitals in Germany who were at least 70 years old, cognitively impaired and community‐dwelling.A comprehensive assessment of medical, nursing and psychosocial data at time of admission was analyzed using pre‐specified algorithms to develop an individualized treatment and care plan. After discharge, care managers visited participants at home, aligned the plan and supported participants for up to 3 months afterwards.Primary outcomes were the rate of re‐admission to hospital, and physical and instrumental functionality (activities of daily living, ADL) after 3 months and rate of institutionalization and ADL after 12 months. Secondary outcomes of interest were: health related quality of life, depressive symptoms, cognitive status and frailty. Statistical analyses include regression models controlled for various factors.ResultThere was no statistically significant effect on the re‐admission rate after 3 months, the activities of daily living, or the institutionalization rate. However, analyses show a significant effect of collaborative care management on health related quality of life 3 as well as 12 months after hospital discharge. Furthermore, depressive symptoms were significantly less likely in the intervention group 3 months after discharge. No effects on cognition or frailty were shown.ConclusionDementia care management has a positive effect on cognitively impaired older people during and after their hospital stay. There is an effect on quality of life and mental wellbeing. It is arguable why there is none on ADL. There is a need to discuss whether it is an appropriate primary outcome measure for a complex care intervention, as the intervention is targeting the needs associated with impaired functionality rather than functionality directly. Further limitations are discussed in more detail.
Evaluation of APOE ε4 allele association with Depression and Anxiety among Elderly Individuals from India.
Authors: Arvind Prathima , Lingegodwa Abhishek Mensegere , Stezin Albert , Hameed Shafeeq K Shahul , Malo Palash Kumar , Mallikarjun Divya N , M Amitha C , Partha Ajith , R Meghana , Narayanasamy Rajitha , HS Sunitha , Menon Meenakshi , Singh Sadhana , Diwakar Latha , Sundarakumar Jonas S. , Issac Thomas Gregor , Kommaddi Reddy Peera 
Published: December 2023

AbstractBackgroundDepression and Anxiety are the most widespread forms of psychiatric disorders. Studies on families and twins indicate that genetic variations can be a risk factor. Apolipoprotein ε4 gene is one such gene (APOE ε4). Studies on both humans and animals indicate that APOE ε4 may be a susceptibility gene in depression and anxiety disorders mean while the contradictory observations also reported. The purpose of the study was to investigate the effects of APOE isoforms on depression and anxiety among two aging Indian cohorts.MethodThe study participants are from ongoing Srinivaspura Aging Neuro Senescence and COGnition (SANSCOG) (n = 4913) and TATA Longitudinal Study for Aging (TLSA) (n = 1089) study which are longitudinal, observational studies on aging from rural and urban India respectively. Depression and Anxiety were assessed using the Geriatric Depression Scale (GDS‐30) and Generalized Anxiety Disorder Assessment (GAD‐7). APOE gene polymorphism was determined by polymerase chain reaction (PCR). We performed the Chi‐square test to examine the relationship between prevalence of depression and anxiety in APOE ε4 homozygous, heterozygous and, non‐carriers.ResultThe basic socio demographic characteristics of both cohorts are escribed in Table 1. There was no significant association between APOE ε4 isoforms and prevalence of depression and anxiety in both cohorts as described in Table 2.ConclusionAPOE ε4 did not show any association with depression or anxiety in both cohorts. There may be other factors are predominant in modulating the depression and anxiety. Moreover, ethnicity plays a significant role in the prevalence of APOE ε4 gene and its modulation effects.
Quantification of encephalic transcripts of the APOE allele specific gene of European and African ancestry
Authors: Nascimento Santos Gabriel , Suemoto Claudia Kimie , Ferretti‐Rebustini Renata Eloah de Lucena , Rodriguez Roberta Diehl , Grinberg Lea T. , Pasqualucci Carlos Augusto , Brito Luciano Abreu , Scliar Marília Oliveira , Leite Renata Elaine Paraizo , Araujo Nathalia Matta , Borda Victor , Tarazona‐Santos Eduardo , Jacob‐Filho Wilson , Nitrini Ricardo , Yaffe Kristine , Zatz Mayana , Haddad Luciana Amaral , Naslavsky Michel S 
Published: December 2023

AbstractBackgroundThe APOE gene is identified as a major risk factor for late onset Alzheimer’s disease and has three alleles, ε2, ε3 and ε4, related to two non‐synonymous substitutions. The presence of the ε4 allele confers an increased risk for the disease in a dose dependent manner (odds ratio 12.9 for homozygous individuals and between 3.2 and 4.2 for heterozygous individuals). The most prevalent form of Alzheimer’s disease has a multifactorial etiology, where several genetic and environmental factors influence its pathology. Factors such as age and sex are relevant in determining the risk for APOE, recent studies point out that the ancestry around the APOE gene is also relevant to the risk for the disease. Individuals of African‐American ancestry have a reduced risk of developing the disease compared to European and Asian whites. These regions may act in a cis‐regulatory manner in modulating gene expression. The Brazilian population results from miscegenation between indigenous, African and European populations, offering an opportunity to study the effects of different ancestries on the risk of Alzheimer’s disease, fill the lack of genetic information about admixed groups and characterize the differential patterns of APOE’s expression in Brazilian population.MethodThis project aims to quantitatively characterize the role of different local ancestry in the different APOE genotypes using 36 post‐mortem brain tissue, with distinct genotypes and local ancestries combinations (33,34,44, European‐European, African‐African, European‐African, African‐European) and associating them with the expression of this gene through molecular marker genotyping and RT‐qPCR techniques. It is expected that the mRNA expression is differentially increased when European local ancestry is shown to be present, compared to non‐European ancestry and may explain, in part, the difference in risks observed in populations of different ancestries.Resultongoing researchConclusionongoing research
Lower blood levels of miR‐29b‐3p in healthy middle‐aged AD risk gene carriers
Authors: Dzianok Patrycja , Grabowska‐Pyrzewicz Wioleta , Staniak Karolina , Wojda Urszula , Kublik Ewa 
Published: December 2023

AbstractBackgroundA number of late‐onset Alzheimer’s disease (AD) risk genes have been discovered, among which the most studied but not fully explored is the apolipoprotein E gene (APOE). PICALM (coding Phosphatidylinositol Binding Clathrin Assembly Protein) is another well‐recognized risk‐gene, shown to interact with the APOE gene in conferring AD risk. MicroRNAs (miRNAs) are post‐transcriptional regulators of mRNAs, some of which are known to be involved in AD pathology. The purpose of this study was to investigate in middle‐aged, healthy participants the association between AD risk‐genes (APOE and PICALM) and circulating miRNAs that were previously identified as altered in AD patients.MethodBlood samples were collected from 76 healthy individuals (36 F, 36 M; age: 56.38±3.16), assigned to three groups: A+P+ (APOE/PICALM risk), A+P‐ (APOE risk, PICALM neutral alleles) and N group (APOE/PICALM neutral alleles). RT‐qPCR was used to compare the levels of 11 microRNA identified by us in previous studies as candidate early AD biomarkers in blood plasma (hsa‐miR‐29b‐3p, hsa‐miR‐34a‐5p, hsa‐miR‐125b, hsa‐miR‐146a, hsa‐miR‐135a, hsa‐miR‐30b‐5p, hsa‐miR‐142‐3p, hsa‐miR‐200a‐3p, hsa‐miR‐483‐5p, hsa‐miR‐486‐5p, hsa‐miR‐502‐3p) [1, 2]. We followed standard procedures of blood assays.ResultSingle gene risk (APOE) carriers had lower levels of miR‐29b‐3p than non‐carriers and double risk carriers (F(2,73) = 12.75, p < 0.001 with Welch homogeneity correction; post‐hoc with Tukey correction: p < 0.01 for A+P‐ versus N, p < 0.001 for A+P‐ versus A+P+). No other changes in miRNA panels were discovered.ConclusionDownregulation of miR‐29b‐3p in blood was detected repeatedly before in patients with AD, in 4 independent studies [1]. Here we show the same effect in a subpopulation of middle‐age, healthy individuals with APOE related genetic risk for AD. Further research is needed to understand the interaction reversing this effect in PICALM risk carriers. Longitudinal follow‐up may validate this blood‐based miRNA not only as an easy‐to‐access diagnostic biomarker, but also as a risk‐assessment biomarker for AD prevention.Funding: This work was funded by the Polish National Science Centre (NCN) grant no. 2018/31/N/HS6/03551, 2016/20/W/NZ4/00354 and 2018/29/B/NZ7/02757.[1], [2] https://doi.org/10.1016/j.arr.2018.10.008; 10.18632/oncotarget.15109.
RESTING‐STATE ELECTROENCEPHALOGRAPHIC RHYTHMS UNDERPINNING VIGILANCE ARE ABNORMAL IN POST COVID‐19 PATIENTS EXPERIENCING FATIGUE
Authors: Noce Giuseppe , Cacciola Elio Gentilini , Vassalini Paolo , Jakhar Dharmendra , Tucci Federico , Musat Andreea Maria , D'Ettorre Gabriella , Babiloni Claudio 
Published: December 2023

AbstractBackgroundPrevious evidence showed that persons experiencing post‐COVID‐19 with “brain fog” were characterized by abnormal resting‐state electroencephalographic (rsEEG) rhythms reflecting vigilance dysfunctions. In the present exploratory study, we tested the hypothesis that in post‐COVID persons with normal cognitive status, abnormalities in those rhythms (and vigilance function) may be related to fatigue.MethodWe enrolled post‐COVID participants about one year after their infection, which claimed “brain fog.” They underwent clinical/neuropsychological assessment and 61‐channel‐EEG recordings. Matched controls (never COVID‐19 affected) were included. Using eLORETA freeware, regional neural current densities were estimated in the rsEEG cortical sources at individual delta, theta, and alpha bands and at beta and gamma fixed bands. Clinical and instrumental data were evaluated in the long COVID‐19 patients as a function of fatigue symptoms over the controls.ResultThe post‐COVID patients had no cognitive deficits at the group level. Those patients showed lower posterior rsEEG alpha source activities than the controls. Notably, this effect was more significant with the long COVID‐19 patients experiencing fatigue symptoms than those without (Fig. 1).ConclusionIn post‐COVID patients with normal cognition, abnormal rsEEG alpha source activation may indicate a significant relationship between vigilance dysfunction and fatigue.
Novel Small‐Molecular Ligands for Prolyl Oligopeptidase to Combat Tauopathies
Authors: Eteläinen Tony , Pätsi Henri , Uhari‐Väänänen Johanna , Aikkila Hannes , Cui Hengjing , De Lorenzo Francesca , Kilpeläinen Tommi , Julku Ulrika , Wallén Erik A.A. , Myöhänen Timo T 
Published: December 2023

AbstractBackgroundTauopathies that include e.g. frontotemporal dementia and Alzheimer’s disease, are neurodegenerative diseases characterized by accumulation of hyperphosphorylated Tau in the brain. Tau is a tempting drug target for tauopathies but no Tau‐targeting therapies are in clinical use. We have recently shown that small‐molecular inhibitors of prolyl oligopeptidase (PREP) can activate protein phosphatase 2A (PP2A) by regulating PREP‐PP2A interaction. PP2A is the main phosphatase regulating Tau, and therefore, we decided to test the efficacy of a reference PREP inhibitor, KYP‐2047, and novel PREP ligands on cellular and animal models of tauopathies.MethodThe compounds, KYP‐2047 and HUP‐46, 55 and 59 (1, 5 and 10 μM), were first screened in the GFP‐2N4R‐Tau transfected HEK‐293 cells where the Tau aggregation was induced by small‐dose okadaic acid (OA; 10 nM), a PP2A inhibitor. The results were verified by using 2N4R‐Tau transfected HEK‐293 cells with 10 nM OA. After the treatment the cells were fractioned to RIPA soluble and SDS‐fractions, and total Tau and S262 phosphorylated Tau (pS262 Tau) levels were studied by Western blot (WB). Finally, KYP‐2047 and HUP‐46 were tested in PS19 Tau transgenic mouse. PS19 mice were treated with the ligands for 4 weeks (10 mg/kg/day, Alzet minipump i.p.) starting from 5.5 months old when the behavioral deficits were observed. After the treatment, the mice behavior was tested by Barnes Maze and locomotor activity assay, and total Tau, pS262 Tau and PP2A levels were studied.ResultIn the GFP‐Tau aggregation assay, all compounds decreased the GFP signal as an indicative of Tau aggregation with 10 mM concentration but HUP‐46 was the most effective (Fig. 1). WB that showed that PREP ligands had the most significant effect on total Tau and pS262 Tau in the SDS‐fraction. In the PS19 mice, KYP‐2047 restored normal behavior in Barnes maze and locomotor activity assay. HUP‐46 had similar effect but did not reach significance (Fig. 2). However, both compounds reduced significantly total Tau and pS262 Tau levels in mouse hippocampus and cortex, and activated PP2A (Fig. 3).ConclusionSmall‐molecular PREP ligands, such as KYP‐2047 and HUP‐46 have disease‐modifying effects on cellular and animal models of tauopathies.
India ENIGMA Initiative for Global Aging & Mental Health–A globally coordinated study of brain aging and Alzheimer’s Disease
Authors: John John P , Joshi Himanshu , Sinha Preeti , Harbishettar Vijaykumar , Tripathi Ravikesh , Cherian Anish V , Purushottam Meera , Viswanath Biju , Thennarasu Kandavel , Dhinagar Nikhil J , Chattopadhyay Tamoghna , Rajagopalan Priya , Jahanshad Neda , Benegal Vivek , YC Janardhana Reddy , Jain Sanjeev , Varghese Mathew , PT Sivakumar , Venkatasubramanian Ganesan , Thompson Paul M 
Published: December 2023

AbstractBackgroundThere is a “diversity” crisis in brain research, as most brain research is conducted in Caucasian populations. This lack of ethnic diversity means that we do not know if predictors of health (and disease) generalize to other ethnic groups.We have recently launched the India ENIGMA Initiative for Global Aging & Mental Health ‐ a globally coordinated study of brain aging and Alzheimer’s disease (AD), funded by the NIA/NIH, USA. Our overall goal is to identify predictive markers in the blood, genome, and epigenome that influence brain aging in India, to better understand prognosis, and to support personalized risk evaluations on each continent. To do this, we will leverage our global consortium, ENIGMA (http://enigma.ini.usc.edu), creating new links between international biobanks, and building research capacity.MethodAim 1. Create Lifespan Charts of brain aging Trajectories in India using MRI, DWI and Resting State Functional MRI. Aim 2. Identify Blood and Epigenetic Markers that Predict Brain Aging and AD in India. Aim 3. Using a combination of multimodal imaging, blood markers, and clinical data to predict clinical decline in India. We test structural equation models that hypothesize how brain aging depends on lifestyle and psychosocial factors (diet, family support, drug abuse, literacy, sleep, and depression), as well as sex, education, and AD genetic risk.ResultWe test structural equation models that hypothesize how brain aging depends on lifestyle and psychosocial factors (diet, family support, drug abuse, literacy, sleep, and depression), as well as sex, education, and AD genetic risk. With novel machine learning methods, we will analyze blood markers and plasma proteomic analytes, to define processes that are harmful to brain aging.ConclusionThe data emerging from this study is expected to help in personalized risk evaluations as well as identify etiological pathways to resilience across genetically and psychosocially diverse populations. This collaborative India‐US initiative will also enable future science initiatives, and equip the team from India with the necessary tools to train new scientists and independently conduct high impact research in the field of disorders of brain aging.