bluuebunny/crossref_metadata_2025_split huggingface dataset:
TREM2 Agonism Affects Human Microglia Response in the Presence of Amyloid Pathology In Vivo
Authors: Geric Ivana , Jendresen Charlotte , Sans Laura , Afrang Negin , Misbaer Anke , Nair Arya , Dalby Maria , Balice‐Gordon Rita , Strooper Bart De , Plath Niels 
Published: December 2023

AbstractBackgroundPharmacological activation of TREM2 represents a novel therapeutic approach to slow Alzheimer´s disease (AD) progression. Mutations in microglial gene, TREM2, confers increased risk to developing late‐onset AD. Moreover, animal studies demonstrate the loss‐of‐of function variants or complete absence of Trem2 aggravates amyloid pathology. Genetic ablation of TREM2 function has been shown to lock microglia in a homeostatic state, preventing a switch to the disease‐associated state supporting the phagocytic clearance of misfolded proteins and cellular debris. Due to low gene sequence and protein structure homology between mouse and human TREM2, as well as phenotypical disparities between mouse and human microglia, monitoring the impact of TREM2 activation in vivo requires humanized animal models.MethodHere we studied the impact of TREM2 agonism on xenografted human microglia in a mouse model of amyloid pathology. We systematically treated 7‐month‐old transgenic AppNL‐G‐F mice transplanted with human embryonic‐stem‐cell‐derived microglia with TREM2 small molecule agonists. Human microglia were sorted from the brain and subsequently assessed using multi‐omics technologies.ResultThe activation of TREM2 lead to increased expression of cytokines and chemokines in xenografted human microglia in the presence of amyloid pathology in AppNL‐G‐F, but not in wild‐type mice. Other changes in the transcriptome profile indicated shifts in microglia populations in TREM2‐agonist‐treated AppNL‐G‐F mice. These effects were observed at exposures consistent with activation of TREM2 in vitro assessed by pSYK and sTREM2 levels.ConclusionAll together, we show the human microglia xenograft mouse model is a valuable tool to study the impact of pharmacological TREM2 activation in the presence of AD neuropathology.
Computerised cognitive testing and multi‐domain structural Magnetic Resonance Imaging in patients with idiopathic Normal Pressure Hydrocephalus and Alzheimer’s disease
Authors: Giovane Martina Del , Parker Thomas D , David Michael CB , Kolanko Magdalena A , Giunchiglia Valentina , Trender William , Carswell Christopher J , Malhotra Paresh A , Sharp David J , Hampshire Adam 
Published: December 2023

AbstractBackgroundIdiopathic normal pressure hydrocephalus (iNPH) is characterised by gait disturbance, urinary incontinence and cognitive impairment. Symptoms are potentially reversible via cerebrospinal fluid (CSF) diversion; thus early and accurate diagnosis is crucial. Symptoms and imaging features of iNPH often overlap with Alzheimer’s disease (AD) and other neurodegenerative conditions, which represent a major diagnostic challenge. We aimed to demonstrate the utility of computerised neuropsychology testing to aid iNPH diagnosis, as well as exploring the neuroanatomical correlates of cognitive dysfunction in iNPH.MethodiNPH (N = 11) and Alzheimer’s disease (N = 14) patients underwent online computerised cognitive testing (Figure 1) and MRI scanning. Raw cognitive scores were converted into ‘deviation from expected’ (DfE) scores using a novel normative approach, training linear models to N = ∼200,000 norms while accounting for demographics. T‐tests against 0 were conducted on the DfE scores to identify tasks sensitive to iNPH and/or AD. ANOVAs were used to identify differences in regional brain volumes and tract‐specific fractional anisotropy (FA) values in AD and iNPH relative to 10 age‐matched healthy controls (HC). General linear models were used to investigate whether cognitive tasks sensitive to iNPH and AD could predict the identified MRI abnormalities.ResultAD patients demonstrated significant impairments in all tasks, while iNPH patients scored significantly lower than controls in motor control, processing speed, visuospatial, and executive function tasks (Figure 2). One‐way multivariate ANOVA identified cognitive differences between groups (F(22,554) = 14.47, p<0.001), with iNPH performing significantly better on memory and language tests relative to AD. Compared to HC, iNPH patients had lower FA in the corpus callosum and skeleton, reduced cingulate cortex volume and higher total ventricular volume. AD patients, instead, had reduced FA in the inferior longitudinal fasciculus and skeleton, with lower temporal and parietal volumes relative to HC (Figure 3). For iNPH, target detection and words delayed recall predicted corpus callosum FA, while visuospatial tasks predicted ventricular and cingulate volumes. In the AD group, no statistically significant link was detected between task performance and structural changes following multiple comparisons correction.
ConclusionRemote computerised cognitive testing can discriminate between AD and iNPH and has the potential to predict disease‐related MRI abnormalities.
R953C Mutation in SORL1 Gene Causes Functional Abnormality of the Protein
Authors: Fazeli Elnaz , Young Jessica E. , Andersen Olav M. , Jayadev Suman 
Published: December 2023

AbstractBackgroundThe SORL1 (Sortilin Related Receptor 1) gene encodes for an endosomal sorting receptor, SORLA, and recent genetic studies have shown that it is the gene most frequently affected in patients with Alzheimer’s disease (AD). In the current study, we have identified a variant, R953C, (residing in the YWTD‐domain of SORLA) in a family where it segregates with early‐onset AD. We used cell biological assays to evaluate maturation and sorting defects of the mutant receptor.MethodTo investigate molecular consequences of R953C mutation, we transiently expressed SORLA‐WT and SORLA‐R953C in HEK293 and N2a cell lines. We analyzed the maturation and shedding of the receptor by Western blotting. Using flow cytometry, we determined the cell surface expression of the mutant compared to WT. Finally, the intracellular localization of the mutant was assessed by immunocytochemistry and confocal microscopy.ResultWe observed a significant decrease in the maturation and shedding of the mutant receptor, leading to an overall 80% reduction in soluble SORLA present in the culture media of cells transfected with R953C construct compared to WT. Our flow cytometry analysis demonstrated that in 80% of the cells expressing the mutant receptor, the SORLA protein is retrained intracellularly. In comparison, only 10‐15% of cells expressing the WT receptor showed intracellular retention. Within the cells, the R953C mutant receptor was primarily localized to the endoplasmic reticulum (ER) whereas the WT was mainly localized to the endosomes, suggesting the retention of the mutant in the ER and uncovering possible defects in entering the endosomal sorting pathway.ConclusionIn conclusion, we have elucidated some of the molecular mechanisms that appear to have a role in pathogenicity of R953C mutation.
T‐cell population and PD‐1 expression in Alzheimer’s disease patients do not follow the age trend of normal individuals
Authors: Chu Cheng‐I , Wu Ching‐Tse , Wang Feng‐Yu , Yang Hui‐Yu , Chang Chien‐Chung , Chang Chuang‐Rung 
Published: December 2023

AbstractBackgroundDestruction of cerebral neurons may relate to atypical immune responses. These intracerebral immune responses were induced by various antigens, such as viral DNA fragments or misfolded proteins. Aging is the major risk factor for Alzheimer’s disease (AD). Throughout the aging process, people experienced repetitive microbial infections and misfolded protein accumulation. But not every individual developed AD during aging. Immune regulation may contribute to determining whether the brain could clean unfavorable misfolded proteins and maintain homeostasis. T cell populations and programmed death 1 (PD‐1) are involved in immune pathology. In our study, we examined T cells and PD‐1 between normal aging and AD individuals to elucidate the role of immune regulation in aging‐related AD.MethodSixteen normal aging individuals (age range between 65‐91 years old) and 16 AD patients (age range 69‐88 years old) participated in this study. Peripheral blood mononuclear cells (PBMCs) were isolated from venous blood. Antibodies against T cells and PD‐1 molecules were used to classify PBMC with flow cytometry.Result(1) T cell population is different between normal and AD individualsThe normal aging group had significantly fewer adaptive immune T cells and fewer helper T cells (TH). However, these immune features were not present in AD patients.(2) PD‐1 pattern in PBMC is different between normal and AD individualsNatural killer T (NKT) cells with CD56 (neural cell adhesion molecule) had increased PD‐1 expression with normal aging. But AD patients did not show this trend of regulatory changes. These trends of suppressive phenotypic changes were absent in AD patients.ConclusionOur study demonstrated that the T‐cell population was shrinking progressively with normal aging. Nerve‐adherent NKT cells exhibited a higher inhibitory receptor (PD‐1). These findings suggested that T‐cell immune population tended to be suppressed with normal aging. However, these characteristic transitions of immune cells were not present in AD patients, suggesting that T cells were prone to activate in older AD patients. These distinctive immunomodulatory features of AD might be potential biomarkers of late‐onset AD, and predictive factors for developing AD in normal aging individuals.
Different astrocyte phenotypes mediate the pathological cascade early in the Alzheimer’s disease continuum
Authors: Pelkmans Wiesje , Shekari Mahnaz , Brugulat‐Serrat Anna , Sánchez‐Benavides Gonzalo , Minguillón Carolina , Fauria Karine , Molinuevo Jose Luis , Grau‐Rivera Oriol , González Escalante Armand , Kollmorgen Gwendlyn , Carboni Margherita , Ashton Nicholas J. , Zetterberg Henrik , Blennow Kaj , Suarez‐Calvet Marc , Gispert Juan Domingo ,   ALFA study
Published: December 2023

AbstractBackgroundGlial fibrillary acidic protein (GFAP) and chitinase‐3‐like protein 1 (YKL‐40) are biomarkers of different astrocyte phenotypes, both of which are elevated in the dementia phase of Alzheimer’s disease (AD). However, the specific contribution of these astrocyte phenotypes early in the AD continuum is not fully understood. Here, we studied how these two astrocyte phenotypes mediate the early pathogenic cascade in the preclinical stage of AD.MethodWe assessed 384 cognitively unimpaired individuals from the ALFA+ study with amyloid‐β (Aβ)42/40, phosphorylated tau (p‐tau181), neurofilament light (NfL) and YKL‐40 measured in cerebrospinal fluid (CSF) and GFAP measured in plasma, as well as [18F]flutemetamol positron emission tomography (PET) and neuropsychological testing (Annual change in the Preclinical Alzheimer’s Cognitive Composite [PACC]). Path analysis using structural equation modelling was used to quantify the relationships between biomarkers of reactive astrogliosis and Amyloid‐Tau‐Neurodegeneration biomarkers, while incorporating age, sex, and apolipoprotein E (APOE) ε4 effects. Direct effects with FDR‐corrected p‐values below .05 were considered significant.ResultCSF Aβ42/40 was associated with Aβ aggregation as measured by PET and with CSF p‐tau181, respectively. The latter was associated with CSF NfL, but no associations were found between any biomarkers and PACC changes in this early sample (Figure 1; Table 1). Plasma GFAP mediated the association between CSF Aβ42/40 and Aβ‐PET. Additionally, CSF YKL‐40 mediated the association between Aβ‐PET and p‐tau181 and between p‐tau181 and NfL. APOE ε4 had a direct association with CSF Aβ42/40 only, whereas age had independent associations with CSF Aβ42/40, NfL, GFAP and YKL‐40. Male sex was associated with higher CSF NfL levels, independently of other variables tested.ConclusionOur results suggest that astrocyte phenotypes that release GFAP into the blood influence the aggregation of soluble Aβ into fibrillary plaques. On the other hand, those releasing YKL‐40 into the CSF appear to play a role later in the pathological cascade, mediating downstream tau pathology and neuronal damage. These results indicate that different astrocyte phenotypes are specifically involved in distinct stages of the early pathological cascade in preclinical AD. Interventions targeting astrocyte dysfunction in preclinical stages may prevent or delay the onset of AD dementia.
PSP/DEGESCO: A Progressive Supranuclear Palsy Genome‐Wide Association Study in the Spanish Population
Authors: García‐González Pablo , de Rojas Itziar , Rabano Alberto , Bullido María J. , Puerta Raquel , Olivé Clàudia , Álvarez‐Martínez Victoria , Perez‐Tur Jordi , Mendioroz Maite , Fortuño Maria Antonia , Belbin Olivia , Compta Yaroslau , Sanchez‐Juan Pascual , Tárraga Lluís , Boada Mercè , Ruiz Agustin 
Published: December 2023

AbstractBackgroundProgressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy. We genotyped all the available histopatologically confirmed PSP cases from the Spanish National Biobank Network and patients with a probable PSP diagnosis recruited from research groups linked to the Dementia Genetics Spanish Consortium (DEGESCO). Here, we present the results of the genome‐wide association study (GWAS) performed after the first stage of this project.MethodDNA samples were genotyped by the Centro Nacional de Genotipado (Santiago de Compostela, Spain) using the Affymetrix Axiom 815K Spanish biobank array. After quality control, we kept 156 histopathological (discovery) and 197 clinical (validation) PSP samples. Then, we selected 650 and 800 sex‐matched controls from GR@ACE/DEGESCO for stratified genome‐wide association of the discovery and validation sets, respectively (Table 1). We ran PC1‐4 adjusted logistic regressions with plink v2.00 and meta‐analyzed the discovery and validation sets using METAL. Finally, we meta‐analyzed our results with 36 previously reported SNPs1 reaching the largest PSP sample size to date (N = 3053).ResultWe found a strong genome‐wide significant (GWS) signal associated to the MAPT H1/H2 haplotype (rs8070723 G: OR = 3.40; 95%CI = 2.64‐4.39; p = 2.60·10−20, Figure 1) and identified a previously unreported signal in chromosome 7p13 (rs76827509 T: OR = 0.45; 95%CI = 0.35‐0.58; p = 3.09·10−10). We replicated, with nominal significance, 5 GWS SNPs reported in previous GWAS (Table 2) and found significant effects for NFASC and TOMM40. Because APOE and TOMM40 are in strong linkage disequilibrium, we also checked the effect of APOE variants. We found a protective effect (OR = 0.66; 95%CI = 0.48‐0.90; p = 9.75·10−3) of the rs429358 C allele (APOE ε4) in our dataset.ConclusionThe strong GWS signal of the H1 haplotype confirms the validity of our GWAS results2. We were able to replicate several PSP loci (Table 1). The NFASC variant reached borderline GWS significance after meta‐analysis and is a good PSP risk factor candidate. Finally, the APOE ε4 allele was protective for PSP in our cohort. The second stage of PSP/DEGESCO genotyped 218 additional PSP samples.
1 Sanchez‐Contreras, M. Y. et al. Mol. Neurodegener. (2018)
2 Höglinger, G. U. et al. in Nature Genetics (2011)
The impact of amyloid‐PET and FDG‐PET on the progression from amnestic MCI to AD dementia in clinical practice
Authors: Echeveste Beatriz , Arbizu Javier , Guillén Fernando , Riverol Mario 
Published: December 2023

AbstractBackgroundAlzheimer disease (AD) is the most common cause of dementia worldwide. It is known that cerebral amyloid aggregation and neurodegeneration are first steps in the physiopathology of AD. In the prodromal phase, a clinical diagnosis of amnesic mild cognitive impairment (aMCI) can be stablished, but not all subjects with MCI have a prodromal AD. The objective of this study was to determinate the impact of amyloid and FDG PET on the progression from aMCI to AD dementia.MethodsFrom October 2013 to March 2021, we prospectively selected 145 patients with a diagnosis aMCI. We excluded subjects older than 85 and those with structural brain lesion on brain MRI. Participants went through an amyloid and an FDG‐PET scans and were classified as positive or negative for amyloid and neurodegeneration. Patients were followed to stablish progression to AD dementia, 118 patients were followed up more than 36 months. Statistical analyses were done with STATA with significance set at p<0.05. All analyses were adjusted by age, gender, and education.ResultsDemographics are shown on table 1. Sensibility, specificity, negative predictive value, and positive predictive value during the 4 years are shown on table 2. 88 patients were A+ and 74 patients were A‐. We divided the patients in 4 groups: A+/FDG+ (n:54), A+/FDG‐ (n:34), A‐/FDG‐ (40), A‐/FDG+(4). The mean of conversion were 39.95 months, this time depends on the result of the biomarkers. A‐ patients converted less and latter with a mean of 75.07 (IC 56.54→81) month, than A+ patients, that converted earlier (chi2 = 20.37 Pr>chi2 = 0.0000). A+/FDG+ converted with a mean of 27.79 (20.40‐33.21) months while A+/FDG‐ converted earlier with a mean of 37.38 (20.73‐48.26) month. (chi2 = 4.16 Pr>chi2 = 0.0415).ConclusionsAmyloid and FDG PET can help us to stablish prognosis in aMCI patients. We have observed that a positive amyloid PET is associated with an increased risk of progression to AD dementia. Even more, aMCI patients with both, amyloid PET and FDG, positive PETs progressed more often and earlier to AD dementia than those who have a positive amyloid PET but a negative FDG‐PET.
Functional connectivity in Alzheimer’s disease: A resting‐state EEG study
Authors: Kehm Christina S. , Fassbender Ronja V. , Onur Oezguer A. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is mainly associated with amnestic deficits. Imaging studies revealed a disruption of functional networks in AD, which plays a crucial role for the cognitive deficits. There is also evidence from resting‐state Electroencephalography (rsEEG) studies, which found altered functional connectivity measuring EEG coherence in AD (Babiloni et al., 2021; Wang et al., 2015). This was especially seen for the Alpha frequency band, which is known for its diagnostic potential in the disease. Furthermore, studies suggest that Alpha band marker correlate with cognitive decline in AD (Babiloni et al., 2010). The main aim of the current work is to gain a better understanding of the functional connectivity in Alzheimer’s disease based on EEG given a very high temporal resolution.MethodThe sample consisted of 15 patients (AD, 72.3 ± 8.28 years, 66.7% male) with mild cognitive impairment to mild dementia with a typical cerebrospinal fluid profile of Alzheimer’s disease or pathological Amyloid‐PET and 15 age‐matched healthy controls (HC, 72.93 ± 7.17 years, 53.3% male). All participants underwent a neuropsychological examination and rsEEG. The rsEEG was recorded with the Neurowerk Amplifier using an elastic cap with 19 electrodes (10‐20 system). Raw data were preprocessed and further analyzed with regard to functional connectivity focusing on the Alpha frequency band (Brainstorm, SPSS, EEGlab). Functional connectivity was calculated by the magnitude squared coherence. Coherence was further clustered in global coherence and coherence per electrode. Finally, coherence scores were evaluated in relation to neuropsychological scores.ResultsCenters of functional connectivity were found in frontal‐frontal and frontal‐parietal/occipital electrode pairs. Alpha frequency band (8 – 13 Hz), particularly Alpha1 frequency band (8 – 11 Hz), yielded the highest coherence scores. When comparing AD and HC, patients showed reduced coherence in Alpha2 (11 – 13 Hz) and Beta (13 – 20 Hz). Additionally, moderate correlations of global coherence and behavioral measures were found mainly for the Alpha1 frequency band.ConclusionAlzheimer’s disease can be associated with poorer functional connections of certain brain areas and rsEEG coherence might be a potential biomarker for AD.
Ex vivo identification of transcriptional regulation landscape and potential therapeutic targets against oxidative stress using Alzheimer’s disease patient‐derived dermal fibroblast: findings from BICWALZS cohort
Authors: Nam You Jin , Yoon Sunwoo , Kim Yeojin , Park Sunghong , Hong Sunhwa , Cho Yong Hyuk , Roh Hyun Woong , Son Sang Joon , Hong Chang Hyung 
Published: December 2023

AbstractBackgroundReactive oxygen species (ROS) is considered as a central pathophysiology for neurodegeneration in Alzheimer’s disease (AD). Many studies using in vitro cell line or in vivo mouse model have shown the possible association between ROS defense mechanisms and cellular damage. However, that connection was not elucidated well in AD patient‐derived cell or brain organoids. In this study, we aimed to identify transcriptional regulation landscape and potential therapeutic targets against oxidative stress using AD dementia patient‐derived dermal fibroblastMethodsFor the purposes of ex vivo research, we performed skin biopsy and stabilized dermal fibroblasts in vitro. Total of 20 AD dementia patients and 22 cognitively normal older adults were assessed. All of AD dementia patients were amyloid positive on PET imaging, APOE e4 carrier, and cognition was imparied. On the contrary, all of cognitively normal older adults were amyloid negative on PET imaging, and APOE e4 non‐carrier. We applied H2O2 (600 uM) to dermal fibroblast for 24 hours as an oxidant agent to promote oxidative stress. After that, to identify transcriptional regulation landscape against oxidative stress, RNA sequencing was performed.ResultsTotal of 406 transcripts (up = 61, down = 345) were commonly differentially expressed in both of AD dementia and cognitively normal older adults derived dermal fibroblast by ROS‐H2O2. These transcripts were enriched in GO categories related to cell division, cell cycle, and DNA repair. Interestingly, 133 transcripts (up = 41, down = 92) were only differentially expressed in AD dementia dermal fibroblast by ROS‐H2O2. These transcripts were enriched in GO categories related to DNA duplex unwinding, cell division, and DNA replication. Total of 147 transcripts (up = 67, down = 80) were only differentially expressed in cognitively normal older adults dermal fibroblast by ROS‐H2O2. These transcripts were enriched in GO categories related to negative regulation of cell proliferation, notch signaling pathway, and NMDA glutamate receptor signaling pathway.ConclusionWe identified transcriptional regulation landscape by ROS‐H2O2 in AD dementia and cognitively normal older adults dermal fibroblast. Further bioinformatic analysis with computational tools and validation experiments will be performed to find potential therapeutic targets against oxidative stress.