bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between plasma neurofilament light chain levels and cognition in early Parkinson's disease
Authors: Yong Alisa C.W. , Tan Yi Jayne , Ng Ebonne YL , Lu Zhonghao , Ng Samuel YE , Chia Nicole SY , Choi Xinyi , Heng Dede , Neo Shermyn XM , Xu Zheyu , Tay Kay Yaw , Au Wing Lok , Tan Eng King , Tan Louis C.S. , Ng Adeline Su Lyn 
Published: December 2020

AbstractBackgroundPlasma neurofilament light chain (NfL) levels reflect large calibre myelinated axonal loss; and has been proposed as a blood‐based biomarker for neurodegeneration in dementia and parkinsonian disorders. Recent studies have suggested an association between increased plasma NfL levels and worse global cognition in Parkinson’s Disease (PD) patients. However, its relationship with specific cognitive domains remain unclear. This study thus aims to investigate the association between plasma NfL and cognitive domains in early PD.MethodPlasma NfL was measured using Quanterix’s Single Molecule Array (Simoa) technology in a total of 197 subjects (175 early PD patients and 22 healthy controls). Cognitive function was assessed using a standard battery of neuropsychological tests. This included the Mini‐Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) as tests of global cognition, as well as two tests for each of five relevant cognitive domains, namely episodic memory, language, working memory, visuospatial, and executive function.ResultPD patients had higher plasma NfL levels (mean=16.3 pg/ml, SD=8.59) compared to healthy controls (mean=12.2 pg/ml, SD=4.18) (p=.023). Amongst PD patients, increased NfL levels associated significantly with worse global cognition scores (MMSE: b=‐1.11 p=.009; MoCA: b=‐1.27, p=.026). In particular, higher levels of plasma NfL significantly correlated with poorer episodic memory (b=‐.541, p=.003) and executive function scores (b=‐.427, p=.002). No significant associations were found between plasma NfL and cognitive measures in healthy controls.ConclusionHigher plasma NfL levels were found in PD patients compared to healthy controls and associated significantly with poorer global cognitive function in PD. Interestingly, higher NfL levels correlated with worse episodic memory and executive function. These results implicate plasma NfL’s role as a potential biomarker for cognition in PD. Further studies are required to validate these findings.
CSF biomarkers in neuropathological Alzheimer's disease
Authors: Leroy Melanie , Maurage Claude Alain , Pasquier Florence , Deramecourt Vincent , Lebouvier Thibaud 
Published: December 2020

AbstractBackgroundSince the new ATN classification system positing a biological definition of Alzheimer’s disease (AD), cerebrospinal fluid (CSF) biomarkers are the keystone of AD diagnosis in countries where amyloid and tau positron emission tomography (PET) are not available. However, data confronting CSF biomarkers with pathology are still scarce.MethodAmong the 242 patients within Lille Brain bank, 23 patients had both CSF biomarkers and a neuropathologically confirmed AD. CSF collection was performed during follow up at the Lille Memory Clinic. CSF Ab42, Tau and pTau were measured and classified as pathological or normal regarding the cutoff at the time. The ATN profile (where A+ stands for pathological Ab42, T+ for pathological pTau and N+ for pathological Tau) was then determined.Result21/23 patients had early onset AD, the age at first symptoms, the delay between the first symptoms and the lumbar puncture (LP) as well as the the delay between the autopsy and the LP were not different between groups. The MMSE at LP was above 15 in the A+T+N‐ (23.8 ± 4.5), the A‐T‐N+ (22) and the A+T+N+ group, and was statistically different between A+T+N‐ vs A‐T‐N+ (p = 0.03) and A+T+N‐ vs A‐T+N+ (P = 0.01) groups. Among our pathologically proved AD cases, 14/23 were A+T+N+, while 7 patients had 2 pathological biomarkers (4 were A+T+N‐ and 3 were A‐T+N+) and 2 patients had one (one was A+T‐N‐ and one was A‐T‐N+). AD was the main neuropathological diagnosis in all cases except for the A‐T+N‐ case where progressive supranuclear palsy was the main diagnosis (Figure 1).ConclusionDespite neuropathological evidence of amyloid deposition, neuronal death and neurodegeneration at autopsy, only 60% of our AD patients had a full A+T+N+ CSF profile. CSF Ab42/40 ratio may improve correlations between biomarkers and pathology by reincorporating some of our A‐T+ patients into the A+T+ group. We are currently confirming these data by repeating the measures using modern fully‐automated assays, including CSF Ab42/40 ratio.
Process evaluation of the FindMyApps program trial: A tablet computer‐based intervention for self‐management and meaningful activities for people with dementia
Authors: Beentjes Kim Maria , Kerkhof Yvonne JF , Neal David Peter , Ettema Teake P , Koppelle Mylène Anouk , Meiland Franka , Graff Maud , Dröes Rose‐Marie 
Published: December 2020

AbstractBackgroundIt has been demonstrated that people with dementia’s wellbeing can improve by using touchscreen technology. The FindMyApps program is a training and web‐based selection‐tool to help people with dementia and their caregivers find suitable apps that can improve their self‐management and engagement in meaningful activities. As part of an exploratory RCT into FindMyApps a process evaluation was conducted according to the MRC Framework for process evaluation. Contextual, implementation and mechanisms of impact factors which may influence trial outcomes were evaluated.MethodA mixed methods design was used, in which quantitative and qualitative data were collected by semi‐structured interviews (SSI) with stakeholders The SSI comprised closed and open questions, designed specifically for this study. Twenty people with mild dementia (MMSE >17; GDS 3‐4) or Mild Cognitive Impairment (MCI) and twenty informal caregivers in both experimental and control groups, as well as 3 other stakeholders (researchers, technical helpdesk person) involved in the implementation of the intervention, were interviewed. Participants were recruited in the Netherlands. Exclusion criteria: moderate to severe dementia or severe sight problems. All participant dyads were provided a tablet computer for the three months intervention period. In the experimental group, people with dementia and caregivers were trained to use the tablet and FindMyApps after which the caregivers guided the persons with dementia to learn to use FindMyApps and find, and use, suitable apps for self‐management and meaningful activities. In the control group, dyads only received general instruction in tablet use and a list of websites where to find potentially useful apps.ResultRegarding contextual factors, it was found that some technical problems might have influenced the intervention. Regarding implementation, participants noted that the training in the use of FindMyApps was of variable quality. Regarding mechanisms of impact it was found that dyads usually used the apps they found through FindMyApps regularly and enjoyed them, but they did not use FindMyApps itself regularly.ConclusionFindMyApps was experienced as a useful tool by most people with dementia/MCI and informal caregivers. Several adaptations to the trial protocol are recommended, to ensure robust outcomes in a definitive trial into its effectiveness.
ABCA7 mutations are major contributors to Alzheimer’s disease in Belgian patients
Authors: Bossaerts Liene , Hens Elisabeth , Van den Bossche Tobi , De Roeck Arne , Engelborghs Sebastiaan , Peeters Karin , De Deyn Peter Paul , Sleegers Kristel , Van Broeckhoven Christine 
Published: December 2020

AbstractBackground
ABCA7 was initially associated with Alzheimer’s disease (AD) in genome‐wide association studies. Recent genetic studies suggest a role for rare premature termination codon (PTC) mutations in ABCA7. While we observed loss of ABCA7 protein for PTC mutations, there was a high variability between mutations due to transcript rescue. Apart from PTC mutations there are missense mutations with unknown effect on ABCA7 protein. Segregation patterns and pathogenicity of ABCA7 mutations are still poorly understood. We aimed at investigating the genetic contribution of ABCA7 in Belgian AD and control cohorts.MethodTargeted resequencing of ABCA7 coding region or whole exome sequencing were used in Belgian AD patient (n = 1478) and control (n = 757) cohorts. Genetic variants were validated by Sanger sequencing. Haplotype analysis was done using STRs flanking ABCA7. Clinicopathological characteristics of carriers were retrospectively reviewed. Mean onset age was 69.3 ± 7.3 years for AD patients and 73.9 ± 8.0 years for controls.ResultIn 69 patient carriers we identified 15 different ABCA7 PTC mutations (69/1478, 4.67%) and 15 PTC in controls (OR = 2.46 (95% CI [1.40–4.33], p = 0.001). The AD PTC carriers had a mean onset age of 69.5 ± 9.7 years (range 48‐90). Also 114 missense mutations were observed in patients (114/1478, 7.71%) and 35 in controls (OR = 1.72 (95% CI [1.17‐2.55], p = 0.006)). The p.G1820S mutation was carried by a familial AD patient aged 65 years and was absent in controls. Genetic screening of family members showed an autosomal dominant inheritance pattern with co‐segregation of p.G1820S on a shared haplotype of at least 2.63 Mb. p.G1820S is located in the second nucleotide binding domain of ABCA7. Whole exome sequencing of family members excluded co‐segregation of variants in other genes associated with AD.ConclusionMutations in ABCA7 are relatively frequent in the Belgian population and particularly in familial AD. Continued identification and characterization of ABCA7 mutations is needed in case clinical genetic testing of ABCA7 is considered. ABCA7 patients might represent an important subtype of AD and new knowledge about their clinical and genetic profile might contribute to diagnosis, risk prediction and development of targeted therapeutics.
Does cerebral hemodynamic compromise contribute to cerebral cortical microinfarcts: A proof of concept study in patients with internal carotid artery occlusion
Authors: van den Brink Hilde , Ferro Doeschka A , de Bresser Jeroen , Bron Esther E , Onkenhout Laurien P , Kappelle Jaap , Biessels Geert Jan ,   the Heart Brain Connection Consortium
Published: December 2020

AbstractBackgroundCerebral cortical microinfarcts (CMI) are small ischemic lesions that are associated with cognitive impairment and are often detected in patients with dementia, also in patients with a clinical diagnosis of Alzheimer’s disease (AD). CMI probably have multiple etiologies. Cerebral hypoperfusion has also been proposed as a causal factor. We studied CMI in patients with internal carotid artery (ICA) occlusion, as a model for cerebral hemodynamic compromise, addressing CMI presence and spatial distribution, also in relation to the condition of the remaining arterial supply.MethodsWe included 95 patients with a complete ICA occlusion (age 66.2±8.3, 22% female) and a reference group of 125 participants (age 65.5±7.4, 47% female) from the Heart‐Brain Study. Participants underwent an extensive evaluation including clinical and neuropsychological assessment, and 3T brain MR, on which CMI were rated according to standardized criteria.ResultsCMI were more common in patients with an ICA occlusion (54%, median 2, range 1‐33) than in the reference group (6%, median 0; range 1‐7) (OR 14.3; 95% CI 6.2‐33.1; p<.001). Among patients with a unilateral ICA occlusion, CMI were more common ipsilateral to the occlusion than in the contralateral hemisphere (median 2 and 0 respectively; p<.001). In patients with CMI the number of (other) occluded or stenosed cervical arteries was higher (p=.038), and cerebral blood flow tended to be lower (B ‐6.2 ml/min/100ml; 95% CI ‐12.4‐0.02; p=.05) than in patients without CMI.ConclusionCMI are very common in patients with an ICA occlusion, preferably in the hemisphere of the occluded ICA and CMI burden was related to the severity of cervical arterial compromise. Supporting the etiological role of hemodynamics in the occurrence of CMI. Given the common occurrence of CMI in patients with AD and known effects of AD on cerebral perfusion, further studies on the interplay between AD pathologies, cerebral perfusion and CMIs in relation to clinical outcomes, in particular cognitive decline, are warranted.
Diffusion structural network metrics as a predictor for Alzheimer’s disease diagnosis in Down syndrome using support vector machine classification
Authors: Brown Stephanie SG , Mak Elijah , Grigorova Monika , Beresford‐Webb Jessica , Walpert Madeleine Jane , Jones Elizabeth , Hong Young T , Fryer Tim D , Coles Jonathan P , Aigbirhio Franklin I , Handen Benjamin L , Christian Brad T , Klunk William E , Menon David K , Nestor Peter J , Holland Anthony J , Zaman Shahid 
Published: December 2020

AbstractBackgroundAlzheimer’s Disease (AD) is known to pathologically develop in Downs Syndrome in almost one hundred percent of cases, although at present structural changes to the brain are minimally utilized for diagnoses of neurodegeneration due to limited understanding of which white matter alterations are directly relevant to clinical presentation. By novel application of machine learning to metrics of the structural connectome in Downs Syndrome, this project aims to identify specific white matter networks that significantly impact classification of cases into AD positive or negative.MethodA pilot sample of 21 healthy Down’s syndrome participants and 4 Down’s syndrome participants with a diagnostic consensus of either mild cognitive impairment (MCI) or dementia underwent diffusion‐weighted and T1‐weighted MRI scanning at 3T. These data form part of a consortium, which will be utilised to increase sample size for future iterations of this analysis. Whole brain structural connectomes were produced for each participant, utilizing fibre orientation distributions and spherical deconvolution informed filtering of the tractograms. For accurate localisation of nodes to brain regions, the T1‐weighted scan was pre‐processed, segmented, parcellated and co‐registered to diffusion space. Networks were created by examining connection density between T1‐delineated structural nodes. Connection density matrices were used to train and test a support vector machine (SVM) classifier.ResultsPreliminary results show widespread reduction in network structural connectivity in the Down’s syndrome participants diagnosed with dementia or mild cognitive impairment (Fig. 1). The parietal, occipital and to a lesser extent the temporal areas of the network exhibit the most marked decreases in connection density, and no edges of the network displayed increased connection density in dementia or MCI patients compared to healthy Downs syndrome. Multivariate analyses indicate that although SVM classification of the networks has a >80% accuracy, false‐negative classifications were common due to the low number of Down’s syndrome dementia participants.ConclusionsThis pilot application of SVM to diffusion‐derived brain networks in Down’s syndrome demonstrates utility and feasibility as a diagnostic classifier. We expect that increased sample size should yield a more robust trained model.
Can OMICS data help us to understand the mechanisms of APOE?
Authors: Sáez María Eugenia , Moreno‐Grau Sonia , Madrid Laura , Ramirez Alfredo , Ried Janina S. , González‐Pérez Antonio , Ruiz Agustín ,   GR@ACE/DEGESCO Consortium, CHARGE Consortium, GERAD Consortium
Published: December 2020

AbstractBackgroundWhile being the most prominent genetic risk factor for Alzheimer’s disease (AD), the effects of APOE variants on the biology and development of AD are still poorly understood. The IMI ADAPTED consortium strives to illuminate the mechanisms underlying the effects of APOE following a holistic approach. In this presentation we describe how the integration of a systematic APOE‐stratified re‐analysis of publicly available GWAS, transcriptomics and proteomics for AD led to new insights in APOE mediated effects in AD.MethodWe re‐analysed AD relevant data including 39,186 human genomes, 2,338 transcriptomes, and 2,365 proteomes along with snRNAseq brain data from diverse AD cohorts. Data were obtained from diverse public repositories and AD research consortia (AddNeuroMed,ADGC,ADNI,AMP‐AD,CHARGE,GERAD,GR@ACE,Mount Sinai,NIA‐GENADA,MAYO,ROSMAP and TGEN). Genes showing differences between cases and controls stratified by APOE genotype were identified as well as those showing differences between the APOE genotype carriers. Results of the different OMICS were integrated using the robust rank aggregation (RRA) method to identify effects which are consistent across multiple layers of OMICS data followed by pathway analysis.ResultsThe stratified GWAS analysis identified genome‐wide significant loci for AD in the APOE ε3 and APOE ε4 genotype strata. After integration with plasma and brain expression profiles, the pathway analysis found enrichment for several processes related to the immune system and glia function among other relevant pathways, of which those differing between APOE strata are of particular interest.ConclusionThe systematic APOE genotype‐stratified analysis of human GWAS, transcriptomics, and proteomics data revealed promising candidate genes and pathways that help to elucidate the mechanisms by which APOE affects the AD risk. OMICS data in APOE relevant cell models will refine these findings. Disclosure: This project has received funding from the Innovative Medicines Initiative 2 JU under grant agreement No 115975. This Joint Undertaking receives support from the EU’s Horizon2020 research and innovation programme and EFPIA. This study was sponsored by AbbVie Deutschland GmbH & Co KG. AbbVie contributed to the study design, research, and interpretation of data, writing, reviewing, and approving the abstract. Some authors are currently employed by AbbVie and may own AbbVie stock.
Modelling AD‐relevant pathophysiology in neurons, astrocytes and microglia from two complete sets of isogenic iPSC lines generated by the ADAPTED project
Authors: Socorro Alfredo Cabrera , Schmid Benjamin , Clausen Christian , Holst Bjørn , Peitz Michael , Grezella Clara , Brustle Oliver , Bahnassawy Lamiaa , Bennett Keiryn , Ried Janina S. , Sáez María Eugenia , Ramaswamy Gayathri , Ruiz Agustin , Bakker Margot H.M. , Vicario Carlos , Lourenco Teresa Silva , Reinhardt Peter 
Published: December 2020

AbstractBackgroundApolipoprotein E (APOE) genotype is the main genetic risk factor for Alzheimer’s disease (AD). APOE ε2 haplotype is protective, APOE ε3 is neutral, and APOE Ɛ4 is associated with the highest risk to develop the disease. APOE highly is conserved in vertebrates, but homology between human and mouse sequence is low (73.4% for peptide and 78.7% for the genetic sequences). To better understand the contribution of each APOE allele to the pathophysiology of AD it is necessary to generate preclinical models that recapitulate the molecular and biochemical properties of this complex gene. Within ADAPTED (Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development) project we have generated and characterized human iPSC‐derived brain cells to fill this important gap.MethodAll ADAPTED isogenic iPSC‐lines were differentiated into clinically relevant cell types (neurons, astrocytes and microglia) that were characterized using unbiased methodologies (transcriptomics, metabolomics and proteomics) and functional assays such as neuronal activity, cytokine release and phagocytosis. We performed all possible comparisons across genotypes, and mostly focused on results that were replicated across the two sets.ResultWe prioritized the study of iPSC‐derived glial cells based on expression levels of apoE and their critical role in brain function and AD pathophysiology. Our strategy led to the identification of APOE allele‐specific molecular signatures and pathways that partially replicates clinical findings (e.g. inflammatory response and metabolic properties). Functional assays revealed genotype differences that were also replicated in different genetic backgrounds.ConclusionSystematic comparison of relevant cells types stratified by APOE genotypes revealed key signatures and mechanisms that have been associated to AD. Data generated from iPSC‐derived cells proves this model as a reliable tool to further study the human biology of APOE, providing one step further in our understanding of AD and the potential identification of more effective therapies. iPSC lines generated within ADAPTED are globally available to the scientific community via EBiSC repository.
Characterization of transcriptional and proteomics changes in brain cells derived from isogenic hiPSCs reveals cell type–and genotype‐specific mechanisms modified by APOE
Authors: Ried Janina S. , Curado Marco Rocha , Sáez María Eugenia , Bahnassawy Lamiaa , Lee Heyne , Reinhardt Peter , Mohler Eric G. , Madrid Laura , Socorro Alfredo Cabrera , Grezella Clara , Nicolas Armel , Rao Francesco , Ramaswamy Gayathri , Bakker Margot H.M. 
Published: December 2020

AbstractBackgroundWhile being the most prominent genetic risk factor for AD, the effects of APOE variants on biology and the development of AD is still poorly understood. The IMI ADAPTED consortium strives to illuminate the mechanisms underlying the effect of APOE with several approaches. Complementing the reanalysis of the publicly available human data, hiPSC lines with different APOE genotypes (ε3/ε3, ε4/ε4, ε3/ε4, ε2/ε2), differentiated into distinct brain cell types provide a tool to study cell‐type level effects of the APOE genotype. Further, OMICS data of human APOE modified mouse model (ε2/ε2, ε3/ε3, ε4/ε4) allowed cross species comparison and model validation.MethodFor multiple brain cell types differentiated from the APOE modified isogenic hiPSC (neurons, astrocytes, microglia and macrophages) and mice transcriptomics and proteomics data were generated. Differential gene expression (DGE) and protein expression (DPE) was calculated, followed by gene set enrichment. Clustering approaches were used to identify shared and differing gene signatures across genotypes. We further applied upstream regulator and network analysis on the individual cell‐type results and integrated these results across cell types. The results were compared with DGE and DPE results from the humanized APOE mouse model. Finally, the identified genes and mechanisms were combined with the results of the integrated analysis of data from postmortem human brain samples of AD cases and controls.ResultsThe observed transcriptional changes confirmed and extended the phenotypic observations and refined the insight of genes identified in the integrated analysis of APOE genotype stratified human OMICS data. Several genes/proteins and pathways were consistently identified on transcriptome and proteome level. Further, shared patterns of expressions of genes across genotypes and potential mechanisms involved in this were detected.ConclusionsIn depth transcriptomics and proteomics analysis of APOE modified hiPSCs‐derived cells enabled to study cell type and genotype specific effects and contributed with this to the understanding of mechanisms affected by different APOE genotypes. The findings in hiPSC we be compared with human blood and CSF OMICS analysis to be potentially used as biomarker for AD and AD progression.