bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevention of dementia using mobile phone applications (PRODEMOS): A randomized controlled trial in progress
Authors: Eggink Esmé , van Charante Eric P Moll , Hoevenaar‐Blom Marieke P , Andrieu Sandrine , Hafdi Melanie , Coley Nicola , Sadhwani Shan , Wimo Anders , Barnes Linda , Handels Ron , Kivipelto Miia , Song Manshu , Georges Jean , van Der Groep Bram , van der Meijden Mark , Wang Youxin , Wang Wei , van Gool Willem A , van Marwijk Harm , Brayne Carol , Richard Edo 
Published: December 2020

AbstractBackgroundThe rising prevalence of dementia will largely occur in low‐ and middle‐income countries. Up to 30% of all dementia cases may be attributable to potentially modifiable risk factors. Therefore, lifestyle interventions targeting these risk factors can potentially prevent or delay the onset of dementia. Mobile Health (mHealth) may be a suitable way to improve accessibility to such prevention strategies in vulnerable and hard to reach populations. We will investigate the implementation and effectiveness of an interactive, coach‐supported mHealth intervention to reduce the risk of dementia by targeting dementia risk factors.MethodDesign and participants: Our prospective open‐label blinded endpoint (PROBE) RCT is ongoing in the United Kingdom (UK) and in China. Following a pilot study, enrollment of 2400 participants (1200 in UK and 1200 in China) takes place over 2020. People are eligible if they are 55‐75 years, are of low socio‐economic status (for those in the UK) or from the general population (China), have ≥ 2 dementia risk factors, and have a smartphone. Intervention: Participants will be randomized to a coach‐supported, interactive mHealth platform, facilitating self‐management of dementia risk factors (including hypertension, diabetes, dyslipidemia, overweight, physical inactivity, smoking, and poor diet) or to a control platform with static health information only. The intervention and follow‐up will be 18 months. Outcomes: The primary effectiveness outcome is dementia risk, as measured by the CAIDE dementia risk score. The main secondary outcomes are improvement of individual risk factors and cost‐effectiveness. Implementation outcomes include acceptability, adoption, feasibility, fidelity and sustainability of the intervention. Implementation outcomes will be evaluated using both qualitative and quantitative methods.ResultThe mHealth platform has been developed and is being tested in a pilot study. Qualitative studies in China and UK have yielded valuable insights to optimize the dementia prevention intervention tailored to the target population.ConclusionThe current study, targeting populations with a high dementia risk and poor access to preventive care, may provide proof of principle for the implementation potential and effectiveness of a coach‐supported mHealth intervention to reduce the risk of dementia.
Assessing the landscape of Alzheimer’s disease cohort data
Authors: Birkenbihl Colin , Salimi Yasamin , Domingo‐Fernández Daniel , Fröhlich Holger , Hofmann‐Apitius Martin 
Published: December 2020

AbstractBackgroundData collected in cohort studies lay the groundwork for a plethora of Alzheimer’s disease (AD) research endeavours. While there exist numerous cohort datasets in our field, few dedicated efforts have focused on comparing these datasets to each other. In recent years, large research consortia, such as EMIF and ROADMAP, were formed to investigate and evaluate the AD data landscape. To the best of our knowledge, such previous approaches have solely investigated cohorts at the metadata level without considering the cohort dataset itself. In this work, we explored eight major AD cohort datasets with the aim of 1) characterizing their underlying data, 2) assessing the quantity and availability of data, 3) evaluating the interoperability across distinct cohort datasets, and 4) presenting our findings in an interactive web application. Thus, we allow researchers to investigate the AD data landscape and find the most suited datasets for their research.MethodWe collected data from multiple major AD cohort studies. Through intensive manual curation of these datasets, we identified which data modalities can be found in the shared data. Using descriptive statistics and visualizations, we highlighted differences and similarities between cohorts focusing on key demographic characteristics and AD biomarkers. Finally, we assessed and compared the longitudinal follow‐up data for each study.ResultWe show that demographics can vary substantially across cohorts (Table 1). The overlap between datasets is limited with regard to assessed measurements (Figure 1). Additionally, distributions of the same variables often differ across cohorts due to differences in processing and normalization; thus, hampering dataset interoperability. By investigating longitudinal follow‐up data, we demonstrate that although there is reasonable longitudinal coverage on cognitive assessments, important biomarkers were only collected for a small fraction of study participants over time (Figure 2). All results can be explored at: https://adata.scai.fraunhofer.deConclusionOur investigation shows that while multiple major AD cohort studies willingly share their data, there is still a severe lack of interoperability within the AD data landscape. To address these issues, it is necessary to define a common AD data model powered by a semantic layer that maps and aligns measurements across datasets.
Association of plasma neurofilament light chain (pNfL) with neuroimaging markers of neurodegeneration and cerebrovascular disease
Authors: Chong Joyce R , Blennow Kaj , Zetterberg Henrik , Schöll Michael , Ashton Nicholas J , Karikari Thomas K. , Saridin Francis , Tanaka Tomotaka , Hilal Saima , Lai Mitchell Kim Peng , Chen Christopher 
Published: December 2020

AbstractBackgroundCerebrospinal fluid (CSF) concentrations of neurofilament light chain (NfL) have previously been reported to be associated with severity of white matter hyperintensity (WMH) (Bjerke, M. et al. 2014; Jonsson, M. et al. 2010; Sjogren, M. et al. 2001). CSF NfL level has also been reported to be significantly increased in vascular dementia (VaD) patients compared with cognitively normal controls (NCI) (Zhao, Xin et al. 2019). However, plasma NfL (pNfL) in VaD subjects and its association with WMH or other magnetic resonance imaging (MRI) markers of cerebrovascular disease (CeVD) have yet to be investigated. The objectives of this study were to (1) examine whether pNfL levels differ between diagnostic groups (NCI, cognitive impairment no dementia [CIND], Alzheimer’s disease [AD] and VaD, and (2) assess the association between pNfL with neuroimaging markers (amyloid PET, MRI) and cognition (Mini‐Mental State Examination [MMSE] scores).MethodThis study included participants who were clinically diagnosed as NCI (n=43), CIND (n=99), VaD (n=22) or AD (n=44). Presence of significant CeVD burden (CeVD+) was defined as occurrence of cortical infarcts and/or ≥2 lacunes, and/or confluent white matter lesions on MRI. Presence of neurodegeneration (N+) was determined by medial temporal atrophy scores. Presence of elevated brain amyloid (A+) was determined by visual assessment of amyloid PET, performed with either PiB (n=178) or NAV (n=30) ligand. pNfL was measured on the Simoa‐HD 1 platform.ResultpNfL level was significantly increased in VaD and AD patients compared with NCI. Across all participants, pNfL was higher in CeVD+ or N+ groups. pNfL was associated with WMH (rho=0.304, p<0.001) and lacunes (rho=0.221, p<0.001), but not cortical infarcts. There was no difference in pNfL level between the A+ and A‐ groups. Similarly, pNfL did not correlate with SUVR measured by PiB or NAV amyloid PET tracer. Correlation between pNfL and MMSE was moderate but significant (rho=‐0.340, p<0.001). pNfL was independently associated with WMH and worse performance in MMSE.ConclusionpNfL level was increased in both VaD and AD. pNfL was associated with cognitive decline and WMH.
The Caribbean‐Hispanic Alzheimer’s brain transcriptome reveals ancestry‐specific disease mechanisms
Authors: Felsky Daniel , Sariya Sanjeev , Schneider Julie A. , Bennett David A. , Mayeux Richard , De Jager Philip L. , Tosto Giuseppe 
Published: December 2020

AbstractBackgroundEthnicity substantially impacts risk for Alzheimer’s disease, with elevated risk in Caribbean‐Hispanics (CH). However, the mechanisms of this population‐specific risk are unknown. Here we report the first transcriptomic analysis of brain tissue from a population of CH Alzheimer's disease (AD) patients.MethodRNA sequencing was performed on postmortem dorsolateral prefrontal cortex tissue from A) 38 genetically‐confirmed CH subjects (nAD = 20, nnon‐AD = 18), and B) 596 non‐Hispanic Caucasians (nAD = 359, nnon‐AD = 238). Robust regression was used to identify AD‐associated genes in both samples and transcriptome‐wide results were compared to identify genes with concordant vs. discordant associations.ResultIn CH, 893/17 301 genes were associated with AD status. Of these 893 genes, 107 were also significantly associated with AD in Caucasians after correction (all but 2 with the same direction of effect). Genome‐wide, association t‐statistics were positively correlated between samples (rho = 0.37). Rank‐based gene ontology enrichment analysis revealed several processes discordantly (signal recognition particle (SRP)‐dependent protein targeting and cell killing) and concordantly (neurotransmitter secretion) associated with AD between populations.ConclusionThe CH‐specific upregulation of SRP‐related genes in AD suggests unique etiopathogenic mechanisms in this population and links to the P.gingivalis hypothesis of AD. This is the first step toward identifying AD‐related disease mechanisms in CH as we have identified target genes and pathways for further investigation.
Two distinct molecular patterns of TDP‐43 pathology in cases with Alzheimer’s disease pathology
Authors: Tomé Sandra , Vandenberghe Rik , Ospitalieri Simona , Van Schoor Evelien , Tousseyn Thomas , Otto Markus , von Arnim Christine , Thal Dietmar Rudolf 
Published: December 2020

AbstractBackgroundTDP43 is a nuclear protein involved in transcription regulation, which is cleaved, phosphorylated and mislocated to the cytoplasm in pathological conditions. TDP43‐positive neuronal inclusions define frontotemporal lobar degeneration (FTLD‐TDP) and limbic predominant age‐related TDP43 encephalopathy (LATE). Neuronal TDP43 inclusions are also seen in Alzheimer’s disease (AD) brain, in ca. 70% of AD patients. We aimed to investigate the role of TDP43 in the development of AD and whether this role differs from that seen in FTLD‐TDP.MethodWe selected non‐diseased (n=20), preclinical AD (n=16), neuropathologically‐confirmed AD (n=45), and FTLD‐TDP (n=10) cases. Paraffin‐embedded human brain tissue of the hippocampal formation, amygdala, frontal and occipital cortices was immunohistochemically analyzed with antibodies against pathological phosphorylated TDP43 (pTDP43409/410, pTDP43409 and pTDP43403/404) and the N‐ and C‐terminus of TDP43 (N‐t or C‐t‐TDP43).ResultWe found that the majority of p‐preAD (n=11) and AD cases (n=34) presented neuronal cytoplasmic inclusions (NCIs) and neurofibrillary tangle‐like material (NFTs) positive for pTDP43, phosphorylated at serines 409/410 but not 403/404. Non‐phosphorylated TDP43 epitopes were absent in these cases, except for single lesions positive for C‐terminal TDP43 epitopes. The remaining AD cases (with full‐blown AD neuropathology) presented a molecular pattern similar to that observed in FTLD‐TDP: NCI, dystrophic neurites or NFTs positive for all TDP43 markers used in this study. We referred to these cases as AD/FTLD. These cases presented either typical AD symptoms, a mix of AD and FTD symptoms, or an FTD clinical picture. The majority of AD cases presented a classical AD clinical phenotype.ConclusionTDP‐43 presents two distinct molecular patterns: one AD‐related pattern, which was associated to clinical AD symptoms; and a second AD/FTLD pattern molecularly similar with FTLD‐TDP lesions, that was associated to an FTD clinical picture.
Regional brain glucose metabolism and gray matter volumetry for the evaluation of chronic traumatic encephalopathy in retired male soccer players: An [18F]FDG‐PET/MRI study
Authors: Aranha Mateus Rozalem , Coutinho Artur M , Carneiro Camila de Godoi , Neto Adalberto Studart , Tsunemi Miriam , Moreira Everton Luis Santos , Ianof Jessica N , Anghinah Renato , Nitrini Ricardo , Cerri Giovanni Guido , Fortea Juan , Buchpiguel Carlos A , Leite Claudia da Costa 
Published: December 2020

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a progressive tauopathy mostly described in military personnel, boxers and American football players. Soccer / European football players are also exposed to long‐term repetitive mild traumatic brain injuries (mTBI), which can lead to CTE. We hypothesized that retired soccer players may present with brain damage, as measured by regional brain glucose metabolism (rBGM) and gray matter (GM) volume in comparison to individuals without exposure to traumatic brain injury. We aim to evaluate rBGM measured with [18F]FDG‐PET, GM volume and the load of white matter lesions (WML) measured with MRI in a group of retired soccer players.MethodsThis prospective study included 19 retired male soccer players (mean = 57,6 years old) and 20 controls matched by age (mean = 60,6 years old), submitted to brain MRI and [18F]FDG‐PET in a 3 Tesla SIGNA PET/MRI scanner (GE Healthcare) from January 2017 to September 2019. Assessment of rBGM, GM volume and load of WML were performed with the SPM8 software. Both groups were compared using the appropriate statistical tests available at SPM8 and R. The p‐value used for significance was 0.001, and correction for multiple comparisons was applied to the SPM analyses (pFWE/FDR< 0.05).ResultsRetired soccer players presented with reduced rBGM in both temporal lobes, reaching statistical significance in left temporal pole and anterior aspect of left inferior temporal gyrus (pFWE/FDR<0.05). Reduction of grey matter volume were observed in similar regions, however with a lower extension, and without surviving correction for multiple comparisons (puncorrected<0.001). There were no differences between groups regarding WML.ConclusionOur study shows a significant reduction in rGBM and less evident reduction in GM volume in the lateral and medial temporal lobes of retired soccer players in comparison to controls, which may be attributable to repetitive mTBI.
Alzheimer‐like pathology in trisomy 21 cerebral organoids amenable to pharmacological inhibition reveals BACE2 as a gene‐dose‐sensitive AD‐suppressor in human brain
Authors: Alic Ivan , Goh Pollyanna , Murray Aoife , Portelius Erik , Gough Gillian , Gkanatsiou Eleni , Wallon David , Rovelet‐Lecrux Anne , Rostagno Agueda , Ghiso Jorge , Francis Paul T. , Strydom Andre , Hardy John , Zetterberg Henrik , Nizetic Dean 
Published: December 2020

AbstractBackgroundA population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β‐amyloid‐(Aβ)‐precursor‐protein gene (APP). This is in contrast to non‐DS patients who inherit just the duplication of the APP gene (DupAPP), who develop EOAD with 100% penetrance, raising hypotheses of potential other AD‐suppressing genes on chromosome 21.MethodCerebral organoids were grown in vitro from isogenic T21 and normal induced‐pluripotent‐stem‐cells (iPSCs), as well as a DupAPP patient. Trisomy of chromosome‐21 gene BACE2 was corrected to disomy by CRISPR/Cas9 editing. Organoids were analysed histologically and organoid pools profiled for β‐amyloid secretion by immunoprecipitation‐mass spectrometry (IP‐MS). Tissue‐quantity‐independent peptide ratios were compared between organoid conditioned media (CM) and cerebrospinal fluid (CSF) from DS and age‐matched euploid individuals.ResultWe found that T21, but not DupAPP, organoids secrete increased proportions of putative BACE2‐θ‐secretase (Aβ1‐19) and BACE2‐Aβ‐degrading protease (AβDP or Aβ‐clearance) products (Aβ1‐20 and Aβ1‐34) compared to isogenic normal controls. Increased ratios of BACE2‐related to BACE2‐unrelated anti‐amyloidogenic cleavages were reproduced in CSF of people with DS, mirroring organoid secretions. Finally, CRISPR/SpCas9‐HF1‐reduction of BACE2 (3 to 2 copies) in T21‐iPSC significantly decreased AβDP/amyloidogenic ratio and triggered early and accelerated AD‐like pathology in T21 organoids. The pathology consisted of insoluble amyloid plaque‐like deposits, fibrillar aggregates, pathologically altered Tau, and premature neuronal loss, and was preventable by an early application of a combination of β‐secretase and γ‐secretase inhibitors.ConclusionOur combined data demonstrate the role of BACE2 as a genetic‐dose‐dependent AD‐suppressor in human brain, and organoid technology as a potential assay for screening for other protective genes and disease‐preventive drugs.
Neighborhood disadvantage is associated with accelerated cortical thinning and cognitive decline in cognitively unimpaired adults
Authors: Hunt Jack FV , Vogt Nicholas M , Jonaitis Erin M , Buckingham William R , Koscik Rebecca L , Zuelsdorff Megan , Okonkwo Ozioma C , Clark Lindsay R , Johnson Sterling C , Asthana Sanjay , Bendlin Barbara B , Kind Amy J 
Published: December 2020

AbstractBackgroundSocial and economic conditions of an individual’s living environment constitute an important social determinant of health. Exposure to high neighborhood‐level socioeconomic disadvantage is associated with negative health outcomes. Recent cross‐sectional studies demonstrated that living in the most highly disadvantaged areas was associated with lower hippocampal volume, total brain volume1 and cognitive performance2 in an unimpaired older cohort. Using longitudinal data from a subset of the same cohort, we tested associations between high neighborhood‐level disadvantage, longitudinal cortical thickness and cognitive function.MethodCognitively unimpaired participants from the Wisconsin Registry for Alzheimer’s Prevention and Wisconsin Alzheimer’s Disease Research Center Clinical Core cohorts who had completed >=2 MRI scans were included (N=645, mean[s.d] baseline age=60.6[7.3], 66.2% female). Cortical thickness was estimated in Alzheimer’s disease (AD) signature regions3 using the CAT12 toolbox and annualized change rates between baseline and follow‐up scans were calculated. Neighborhood‐level disadvantage was indicated by Area Deprivation Index (ADI)4,5 and relative quintiles were determined based on state of residence. Cognitive outcomes included a Preclinical Alzheimer’s Cognitive Composite (PACC3)6 and its component sub‐tests (Trails Making Test‐B (TMTB, executive function), Rey Auditory Verbal Learning Test Trials 1‐5 and one of two delayed logical memory tests). Parameters of linear fixed‐effect models (cortical thickness) or mixed‐effects models (cognitive testing), including age, sex, race and years of education were estimated in R. Cognitive test models additionally controlled for practice effects and age2 to account for non‐linear age‐related decline.ResultLiving in the most disadvantaged neighborhoods (top 20% ADI vs all others) was associated with decreasing cortical thickness over time within AD‐signature region (b[95%CI]=‐0.02mm/year[‐0.03,‐0.005], p=0.01) and sub‐regions (Fig.1). Additionally, rates of decline in PACC3 and TMTB were steeper for those in the most disadvantaged neighborhoods (Fig.2, Table).ConclusionIn cognitively unimpaired adults, exposure to the highest relative levels of neighborhood‐level disadvantage was associated with increased rates of cortical thinning and declining cognitive test performance, particularly in the executive function domain. Using longitudinal data, this work extends previous cross‐sectional studies, providing additional evidence that living in highly disadvantaged neighborhoods may be associated with accelerated neurodegeneration and cognitive decline with implications for AD and related dementia risk assessment.
Assessment of vitamin B12 and erythrocyte levels in Alzheimer's disease
Authors: Santos Gustavo AA , Fazan Valeria Paula Sassoli , Pardi Paulo Celso 
Published: December 2020

AbstractBackgroundThe reduction in serum levels of erythrocytes and vitamin B12 may be related to the cognitive decline in elderly people with Alzheimer's.MethodA case control study was carried out in healthy patients (n = 39) and diagnosed with Alzheimer's Disease (n = 44). Inclusion and exclusion criteria were established. We performed a complete blood count and B12 and folic acid evaluation. The collections, material processing and sample analysis took place according to the recommendations of the Brazilian Society of Clinical Pathology.Resultin patients with Alzheimer's disease, vitamin B12 levels were 267.72 pgml, while in healthy subjects, 388.52 pg / ml. Red blood cells in patients with Alzheimer's, 4.39; and in the healthy 4.75.Conclusionthe early diagnosis of Alzheimer's disease represents a primary goal, and the role of biomarkers appears to be crucial to the routine of the clinical environment. Our studies have demonstrated low levels of B12, being compatible with literature that associates low concentrations of B12 with cognitive decline.
The pathological role of Pb in AD through impairing functions of blood‐brain barrier system
Authors: Du Yansheng , Territo Paul R. , Zheng Wei 
Published: December 2020

AbstractBackgroundLead (Pb) is an environmental factor has been suspected of contributing to Alzheimer’s disease (AD) and other dementia. Our previous study has shown that chronic Pb exposure increased brain levels of beta‐amyloid (Aβ) and amyloid plaques, a pathological hallmark for AD, in APP transgenic mice possibly by inhibiting Aβ clearance. However, it remains unclear how different levels of Pb affect Aβ clearance and the blood‐brain system (BBBS) in the blood‐brain barrier system.MethodTg‐APP mice were administrated with Pb‐acetate at three different doses by oral gavage for 4 weeks. Dynamic contrast‐enhanced CT (DCE‐CT) imaging method was used to quantify the real‐time brain regional blood flow, blood volume, and BBBS permeability.ResultChronic Pb exposures significantly increased permeability surface area product (PS) and brain perfusion, indicating that Pb disrupted the mouse blood‐brain barrier system was possibly mediated by inflammation.ConclusionChronic Pb exposure at toxic and even subtoxic levels would damage the BBBS and induce dementia by allowing blood contents to escape into the brain parenchyma.