bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk factors and baseline cognition. Preliminary results from the LatAm‐FINGERS cohort
Authors: Corvalan Nicolas , Keller Greta , Surace Ezequiel Ignacio , Calandri Ismael Luis , Brucki Sonia Maria Dozzi , Salinas‐Contreras Rosa Maria , Suemoto Claudia Kimie , Velilla Lina M , Yassuda Monica Sanches , Allegri Ricardo , Caramelli Paulo , Lopera Francisco , Nitrini Ricardo , Sosa Ana Luisa , Sevlever Gustavo , Crivelli Lucia ,   LatAm‐FINGERS Consortium
Published: January 2025

AbstractBackgroundLatAm‐FINGERS ‐ the first non‐pharmacological multicenter randomized clinical trial in Latin America ‐ is a valuable opportunity to study lifestyle in a heterogeneous and multiethnic population exposed to a large number of cardiovascular risk factors. Our aims are to study the risk distribution in the LatAm‐FINGERS cohort and to explore the relationship between LIfestyle for BRAin Health (LIBRA) and cognition.MethodWe calculated the risk of dementia using the LIBRA score in the entire cohort (n = 1200). LIBRA consists of a weighted sum score (higher scores indicating greater dementia risk) of 12 modifiable risk and protective factors for cognitive decline. Cognition was assessed using the Latin America Neuropsychological Test Battery (LatAm‐NTB). We constructed mixed‐effects linear regression models to examine the relationship between the LIBRA and cognition as a fixed effect, with country as a random effect.ResultThe LIBRA ranged from ‐4.5 to 10, with a mean of 2.39 (±2.75). Men had significantly higher LIBRA scores than women (w = 125887, p = .003). Those with more education (>9 years) scored significantly lower in LIBRA compared to those with less education (w = 57458, p < .001), possibly due to the established association between education and health outcomes. No differences were found in LIBRA between individuals with and without APOE4 (w = 17475, p = 0.57). A significant relationship was observed between LIBRA and global cognition measured by LatAm‐NTB (β = ‐0.03, std. error = 0.004, t value = ‐9.28, p < .001). There was a relationship between LIBRA and memory (β = ‐0.05, std. error = 0.007, t value = ‐7.06, p < .001), executive functions (β = ‐0.02, std. error = 0.004, t value = ‐5.49, p < .001), and processing speed composites (β = ‐0.01, std. error = 0.005, t value = ‐3.30, p < .001).ConclusionOur results shed light on sex differences, revealing that men tend to exhibit higher LIBRA. The negative relationship between higher levels of education and LIBRA underscores the protective role of education on cognition. This highlights the significance of LIBRA as a useful risk composite for elucidating cognitive outcomes within the LatAm‐FINGERS cohort, characterized by its ethnic and cultural diversity.
Neuron‐derived small extracellular vesicles as a ‘liquid biopsy’ to assess brain insulin signaling deregulation in Alzheimer's disease pathogenesis
Authors: Cleary Jacob Alexander , Kumar Ashish , Su Yixin , Kim Susy , Singh Sangeeta , Harrison William , Hayden Kathleen M. , Lee Jingyun , Espeland Mark A. , Furdui Cristina M , Ding Jingzhong , Craft Suzanne , Deep Gagan 
Published: January 2025

AbstractBackgroundInsulin signaling deregulation in the brain is a critical risk factor for Alzheimer's disease (AD); however, molecular changes in this pathway during AD pathogenesis cannot be currently accessed in clinical setting due to lack of brain tissues. Here, we propose small extracellular vesicles (sEV) characterization as a non‐invasive approach to assess the status of insulin signaling in the AD brain.MethodIn postmortem brain tissues of cognitively normal (CN) and AD (n=5 each) subjects, expression of 84 genes, involved in insulin signaling and resistance was analyzed using pathway specific PCR array. Next, the level of key miRNAs (miR185‐5p, miR‐210‐3p, and miR342‐3p), that regulate the expression of insulin signaling genes, was assessed by TaqMan‐based qPCR in brain tissues and secreted sEV in their microenvironment. The expression of these miRNA was also analyzed in the neuron‐derived sEV (NDE) isolated from the plasma of 28 CN (18 female and 10 male) and 28 dementia (11 female and 17 male) subjects, all with type‐2 diabetes. These highly specific NDE were isolated by sequential immunoprecipitation using CD171 and synaptophysin surface markers, and the expression of studied miRNAs was correlated with corresponding clinical measures (MMSE score, Aβ1‐40 and Aβ1‐42 levels).ResultAD brain tissue revealed significant deregulation of genes involved in insulin signaling and resistance (e.g., AKT2, GSK3β, INSR, KRAS, PIK3R1, IGF1R, PTPN1, BRAF, GCK, UCP1, LDLR, NPY, and RRAS2). We also observed a significant increase in the expression of miRNAs (miR185‐5p, miR‐210‐3p, and miR342‐3p) involved in regulation of these genes. Interestingly, the expression of these miRNAs in the brain tissues as well as their secreted sEV showed a high degree of concordance. Most importantly, NDE in the plasma of individuals with dementia also showed a similar change in the expression of miRNAs regulating insulin signaling in the brain, suggesting suitability of sEV application as liquid biopsy for the brain tissue. Lastly, this increased expression of NDE miR‐185‐5p in dementia showed significant inverse correlation with MMSE Score.ConclusionNDE in plasma offer critical molecular information about insulin signaling and resistance in the brain, which could be valuable in making diagnostic and treatment decisions in AD.
Microglial‐targeted nSMase2 inhibitor fails to reduce tau spread in the animal model of Alzheimer’s disease
Authors: Huang Meixiang , Tallon Carolyn , Zhu Xiaolei , Huizar Kaitlyn , Piccirillo Silvia , Thomas Ajit G , Tenora Lukas , Liyanage Wathsala , Roda Francesca , Gualerzi Alice , Kannan Rangaramanujam M , Bedoni Marzia , Rais Rana , Slusher Barbara S 
Published: January 2025

AbstractBackgroundCognitive decline associated with Alzheimer’s disease (AD) correlates with hyperphosphorylated tau (pTau) propagating between neurons along networks connected by synapses. It has been hypothesized this transcellular transmission occurs partially by extracellular vesicles (EVs). Both genetic and pharmacological inhibition of nSMase2 has been found to inhibit EV biogenesis and pTau propagation. However, the lack of suitable nSMase2 inhibitors for clinical development has been a challenge. In our lab, a highly selective and nM potency nSMase2 inhibitor, termed DPTIP, was identified through a high‐throughput campaign. However, it has poor oral pharmacokinetics (PK), modest brain penetration, and rapid clearance, limiting its clinical translation. To improve its PK properties, we conjugated it to a hydroxyl‐PAMAM dendrimer delivery system, creating dendrimer‐DPTIP (D‐DPTIP), which selectively targets microglia. In previous studies, using a murine AAV‐hTau brain injection propagation model, we showed that administration of D‐DPTIP significantly inhibited tau spread. In this study we extended those studies to evaluate D‐DPTIP in Tau P301S (PS19) transgenic mice.MethodPS19 mice were chronically dosed for 20 weeks. Subsequently cognitive function was evaluated using the Y‐maze and Novel Object Recognition tests, and hippocampal volume was measured through MRI. Total tau and pTau levels were quantified by immunoblotting. Immunofluorescent staining and fluorescence‐activated cell sorting (FACS) were employed to identify cell types in the brain responsible for D‐DPTIP internalization. nSMase2 target engagement assays were conducted in both CD11b+ (microglial) and CD11b‐ (non‐microglial cells). Surface plasmon resonance imaging (SPRi) was used to characterize the origin of brain extracellular vesicles (EVs) released into plasma in PS19 mice ± D‐DPTIP treatment.ResultTotal tau, pTau, cognitive deficits, and hippocampal volume loss were not altered by D‐DPTIP treatment in the PS19 mice. D‐DPTIP was found to be co‐localized with microglia and selectively decreased nSMase2 activity in the CD11b+ cells. SPRi analysis showed a decrease in levels of activated microglia‐derived plasma EVs following treatment.ConclusionD‐DPTIP selectively targets and inhibits nSMase2 activity in microglia. Consequently, in the AAV‐hTau seeded model where microglial EVs play a central role, D‐DPTIP successfully inhibits tau propagation. However, its effectiveness is limited in PS19 mice, where neuronal‐mediated tau propagation is thought to be predominant.
Exploring the protective potential of bilobalide against amyloid beta peptide 1‐42‐induced toxicity in BE(2)‐M17 cells: insights via cell viability and cellular energetics
Authors: Chakraborty Manas , Dhiman Kunal , Gupta Veer 
Published: January 2025

AbstractBackgroundReliable treatment approaches for addressing early cognitive impairment and Alzheimer’s disease (AD) are currently lacking. Given the multifactorial nature of AD, therapeutic strategies need to focus on disease‐specific biochemical pathways. Given the significance of metabolic pathways in cognitive impairment, it is essential to investigate alternative disease modifiers capable of targeting multiple metabolic pathways, such as phytochemicals. This research project aims to identify alterations in bioenergetics and viability resulting from amyloid pathology in cell models. Additionally, it will assess the therapeutic potential of a of bilobalide a biologically active terpenoid extracted from Ginkgo biloba. in alleviating these changes.MethodThe Neuroblastoma cell line BE(2)‐M17 cells were utilized to establish an in vitro model of Alzheimer’s disease (AD). These cells underwent differentiation into mature human neurons through treatment with 10 µM retinoic acid. Prior to treatment with amyloid beta 1‐42 (20 µM) for 24 hours, the cells were pre‐treated with varying doses of bilobalide (1 µM, 5 µM, 10 µM, 15 µM, and 20 µM) for 24 hours. To assess the impact of bilobalide pretreatments on cell viability, a Cell Titer Glo assay was performed. The oxygen consumption rate, Total Reactive Oxygen Species (ROS), and 2',7'‐dichlorofluorescin diacetate (DCFDA) assays were conducted to evaluate cellular responses. Additionally, Seahorse analysis was employed to further investigate the oxygen consumption rate.ResultThe successful differentiation of the BE(2)‐M17 cells has been achieved and confirmed through morphological changes. The cell viability results indicate a substantial impact of bilobalide in mitigating the amylopathic changes induced by the amyloid beta insult. While the cell energetics evaluation is still underway, the preliminary results from the pilot study strongly suggest a significant impact of bilobalide in alleviating the amylopathic changes induced by the amyloid beta insultConclusionThe observed amelioration of amylopathic changes points towards the potential therapeutic effect of bilobalide in the context of Alzheimer’s disease. These initial findings provide promising indications of the potential effectiveness of bilobalide in influencing cellular energetics in the context of Alzheimer’s disease.
Counterfactual reasoning‐based intervention effect estimation for longitudinal cognitive decline
Authors: Kang Sohyun , Song Yeong‐Hun , Seong Joon‐Kyung 
Published: January 2025

AbstractBackgroundAfter the landmark approval of the Aβ‐lowering antibody for treatment of mild cognitive impairment and mild dementia due to Alzheimer’s disease (AD), it has intensified the need to stratify patients based on the likelihood that they will benefit from any amyloid‐lowering treatments currently in the pipeline. We therefore seek to identify individuals most likely to benefit from Aβ‐lowering drugs by estimating intervention effect based on counterfactual reasoning for longitudinal cognitive decline at the individual level.MethodWe utilized 3,542 T1‐weighted magnetic resonance images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), involving 3,103 Alzheimer’s patients and 439 cognitively normal individuals. Cortical thickness data, processed with FreeSurfer v7.0 and the Desikan‐Killiany atlas, underwent W‐score correction for age, sex, and education to address confounding effect. Amyloid positivity, determined by ADNIMERGE AV45 (>=1.11), was considered. Patients were stratified based on the clinical dementia rating sum of boxes (CDRSB) decline rate into fast or slow decliners. Our framework integrates counterfactual reasoning and intervention effect estimation through a deep explainable AI method rooted in causality. The framework comprises 1) amyloid‐neurodegeneration‐cognition encoding, 2) counterfactual map generation, and 3) intervention effect estimation, illustrated in Figure 1.ResultThe encoder achieved a 5‐fold cross‐validation accuracy of 0.9230 ± 0.0101, with corresponding F1 score and mAUC values of 0.8948 ± 0.0140 and 0.9454 ± 0.0108, respectively (Figure 2). Individual counterfactual neurodegeneration maps targeting slow decliners to fast decliners revealed positive amyloid changes and worsened cognitive outcomes (Figure 3). On the other hands, targeting fast decliners to slow decliners exhibited negative amyloid changes and improved cognitive outcomes. The correlation between cognitive deterioration probabilities (indicating fast decliner status) and amyloid intervention (counterfactual amyloid level) was positive and significant (r=0.2109, p<0.0001) (Figure 2).ConclusionAlthough this work focuses on the fundamental counterfactual reasoning for predicting the rate of longitudinal cognitive decline in the AD spectrum, it also has major potential clinical implications in the era of Aβ‐lowering therapies. By editing the patient‐tailored counterfactual reasoning process, we accurately estimate intervention effect at the baseline timepoint, so that maximize clinical benefit through optimized personalized treatment.
Locus Coeruleus Neuroimaging compared Voxel by Voxel to Histology‐ a postmortem human validation study
Authors: LaMore Tia , Huang Shuo , Marinho Pedro Burlacchini S. , Chen Yuheng , Li Song Hua , Lee Wing Hung , Carreira Luzia Lima , Rodriguez Roberta Diehl , Otaduy Maria Concepción Gracía , Shi Yonggang , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundNeuropathological studies indicate that locus coeruleus(LC) volume decreases in Alzheimer’s disease(AD) by 8% at each stage, (from Braak 0‐1), whereas in normal aging, the LC remains unchanged. These changes make LC volumetry by neuroimaging a promising way to track AD progression even before symptoms appear. However, LC’s small size and location make it prone to imaging artifacts. To assess the accuracy of neuroimaging sequences designed for LC volumetry, we used an in‐house histological computational method to compare histology and neuroimaging on a voxel‐by‐voxel basis.MethodWe investigated three cases (two Braak 1s, and a Braak 5). The whole brain underwent 7T MRI postmortem, pre‐autopsy, at the University of Sao Paulo. Upon autopsy, the brains were processed at UCSF and the histological LC was 3D reconstructed. In parallel, the GRE and TFL MRI sequence LCs were segmented (Figure 1). We applied affine& spline registration to match histology to MRI‐T1 volumes (voxel size=0.75mm)(Figure 1). To measure registration accuracy, we calculated DICE coefficients using T1 visible structures (Figure 2). Next, we analyzed the percentage overlap of voxels to investigate how accurately MRI sequences detected histology LC borders.ResultOverall, the DICE values for brainstem registration are high. Table 1 shows the overlapping percentages that are quite low, from 2.5%‐23%. For our Braak 1 cases, the least overlap of GRE MRI and histology LC borders is in rostral region, while in both TFL and GRE sequence for the Braak 5 case, the least LC overlap was in the caudal region (Table 1).ConclusionThese results suggest that accurately detecting LC borders using MRI remains a challenging task due to small size, imaging artifacts, and neuromelanin dependency, which is low at baseline in caudal LC. However, our overlap results did match previous findings on specific regional LC volume loss seen rostrally in early AD, despite no neuronal loss, and in later stages of AD, volume loss caudally. This points to the MRI LC signal being potentially clinically useful for disease monitoring. Our study will continue to examine the MRI signal picked up in the LC across Braak as regions of LC degeneration shift compared to the histology counterpart.
Association between hippocampal subfield volume estimated from ultra‐high field scans and cognitive and clinical symptoms in patients with late‐life depression and healthy controls
Authors: Hu Xiaochen , Zeyen Philip , Bischof Gérard N , Elmenhorst David , Andrassy Gregory , Aktas Beyza , Schruttke Neele , Lee You Na , Mokhtari Niloofar , Berron David , Giehl Kathrin , Onur Oezguer A. , Stirnberg Rüdiger , van Eimeren Thilo , Drzezga Alexander , Dafsari Forugh S , Stoecker Tony , Jessen Frank 
Published: January 2025

AbstractBackgroundLate‐life depression (LLD) is a risk factor for Alzheimer's disease (AD) dementia. Previous morphological studies have often associated LLD with atrophy within the medial temporal lobe (MTL), including the hippocampus. A number of previous studies have demonstrated the changes in several MTL subfields in LLD, such as the perirhinal cortex (PrC), cornu ammonis (CA), dentate gyrus (DG), subiculum and entorhinal cortex (EC), but with inconsistent results, which may be explained by the relatively low image resolution of the 3T scanner used in the previous studies.MethodA total of 93 individuals over the age of 60 were included in this study, of which 23 LLD patients and 29 normal controls without a history of depression underwent T1 and T2tse scans on a 7‐Tesla MRI scanner. Images were pre‐processed and roughly segmented into CA1‐3, DG, SUB, EC, and PrC (area 35, 36) using the Automated Segmentation Hippocampal Subfields (ASHS) and further separated into anterior and posterior (head and body). All segmented images were manually edited. Group comparisons of MTL subfield volumes were made, adjusting for age, sex, and years of education. Cognitive and clinical scores were correlated with the volume of each subfield.ResultLLD and controls did not differ in total hippocampal volume. LLD showed reduced volume in the head portion of the right DG (p=0.05) and a trend towards reduced ratio between left and right EC (p=0.07). No other group differences were observed. Correlational analyses revealed a significant association between bilateral hippocampal volume and TMT‐A speed, as well as the anxiety subscale of the Geriatric Depression Scale (GDS). Subfield analyses revealed significant associations between the anxiety subscale of the GDS and bilateral DG head volume (left: r=‐0.36, p=0.006; right: r=‐0.42, p=0.002) and between the left CA1 body and the cognition subscale of the GDS (r=0.29, p=0.03).ConclusionUsing ultra‐high field MRI, we demonstrated an anterior‐posterior differentiation along the hippocampal long axis in the involvement of cognitive and clinical symptoms in LLD. Future work should investigate the relationship between AD pathological changes and behavioral symptoms in LLD and whether MTL subfields may play a mediating role.
CSF profiling of impaired Blood‐brain barrier individuals: novel putative biomarkers discovery
Authors: Santis Giovanni De , Blennow Kaj , Zetterberg Henrik , Ashton Nicholas J. 
Published: January 2025

AbstractBackgroundBlood‐brain barrier (BBB) integrity is crucial for brain homeostasis and maintenance. This is a pilot study to investigate cerebrospinal fluid (CSF) levels of several proteins implicated in BBB integrity, such as aquaporin‐4 (AQP4), platelet‐derived growth factor (PDGFRβ), human major facilitator superfamily domain containing protein 2A (MFSD2A), matrix metalloproteinase (MMP)‐9, Matrix metalloproteinase (MMP)‐2, and Fibrinogen, for assessing BBB integrity.MethodCSF samples were collected from 100 participants (36 [36%] female and 64 males [64%]; mean [SD] age, 73,34 [9,05] years). Participants were stratified according to their CSF/serum albumin concentration ratio (Q‐Alb); intact BBB (Q‐Alb <9, n = 25), mild BBB damage (Q‐Alb 9‐14, n = 25), modest BBB damage (Q‐Alb 14‐30, n = 24), and severe BBB damage (Q‐Alb >30, n = 25). AD CSF biomarkers (p‐Tau181, total‐Tau, Aβ42/40 ratio) were assessed by LUMIPULSE G1200. Protein levels were quantified using ELISA Kits (CUSABIO, Thermofisher, Bioss Antibodies). Correlation analyses were conducted between protein levels and albumin CSF/serum ratios with R (Kruskal‐Wallis test with pairwise comparison, Bonferroni method, was performed).ResultCSF AQP4 and PDGFRβ levels were significantly higher in individuals with severe BBB damage (Figure 1). No significant differences are highlighted in the levels of MMP9, MMP2, MFSD2A and Fibrinogen; whereas, in both MFSD2A and Fibrinogen it is shown a notable difference in the levels of protein between the modest and intact groups, with a subsequent decline in the severe group. A positive correlation (Figure 2) between PDGFRB and AQP4 with Q‐Alb (PDGFRB, r = 0,273, P < 0,0001; AQP4, r = 038, P < 0,001) was found, where AQP4 seems to best reflect albumin stratification (Figure 3).ConclusionIn this pilot study, we show that CSF concentration of some blood‐brain barrier‐related proteins increases with severity of BBB damage. This highlights their potential as novel biomarkers for monitoring BBB integrity. Remarkably, the presence of high concentrations of Fibrinogen in the CSF could be an important feature to further investigate.
Are exercise classes for older people, including those with dementia, located in areas with the greatest need in the North East of England?
Authors: Ardle Ríona Mc , Foster Lucy , Long Annabelle , Alcock Lisa 
Published: January 2025

AbstractBackgroundApproximately 944,000 people are living with dementia in the UK (∼0.8% of the population). The World Health Organisation consider dementia a public health priority. Efforts to prevent dementia and to decelerate its progression to dependency/disability are vital.Promoting physical activity (e.g. exercise classes) can support dementia prevention and once diagnosed, support independence. Previous research indicates that most exercise classes for older adults in the East Midlands of England are in areas with small percentages of older inhabitants and only 2% are cited as suitable for dementia. As older adults in the North East (NE) of England have worse health outcomes, greater socioeconomic deprivation and lower life expectancy, we aimed to identify the geographical distribution and population characteristics of exercise classes in NE of England.MethodFor preliminary analysis, one county in NE of England was selected, Tyne and Wear, an area of 538km2 with an estimated population of 1,136,371 (19% aged ≥65 years) in 2021. The area is primarily urban (∼98%). Exercise classes were identified via a comprehensive Google search undertaken in December 2023 and geocoded. Data were input into a geographic information system (ArcGIS, Esri). Spatial analysis tools in ArcGIS calculated number and percentage of classes with respect to population age, socio‐economic status and population density.Result427 exercise classes were identified as suitable for older adults; <1% (n = 2) were advertised as appropriate for people with dementia. 5.4% were situated in areas where the predominant age group are aged ≥65years (Fig. 1), 20.6% in areas with the greatest socio‐economic deprivation (Fig. 2; based on Index of Multiple Deprivation) and 98% in urban areas (Fig. 3).ConclusionResults highlight that there are limited opportunities for people with dementia to participate in exercise classes in Tyne and Wear, England. Additionally, most exercise classes are in urban areas where a low percentage of the population are aged ≥65years, limiting their accessibility to older people. Addressing this issue may contribute to health equity and disability‐free life expectancy in NE, supporting both dementia prevention and dementia post‐diagnostic support. Further work will consider the rest of NE of England (Northumberland, Durham) for a more representative analysis.