bluuebunny/crossref_metadata_2025_split huggingface dataset:
Research diagnostic criteria for Alzheimer’s disease: Findings from the multinational LipiDiDiet Trial
Authors: Rosenberg Anna , Solomon Alina , Soininen Hilkka , Visser Pieter Jelle , Blennow Kaj , Hartmann Tobias , Kivipelto Miia ,   LipiDiDiet Clinical Study Group
Published: December 2020

AbstractBackgroundLipiDiDiet is a randomized controlled trial investigating the effects of a multinutrient medical food product on change in cognition among individuals with prodromal AD. This study aimed at investigating participants’ baseline AD biomarker profile, including classification according to the IWG‐2 and NIA‐AA 2011 & 2018 diagnostic criteria, and assessing the impact on 2‐year cognitive/functional decline and progression to dementia.MethodLipiDiDiet targeted 311 individuals aged 55–85 years at 11 sites in four countries. Prodromal AD was defined according to the IWG‐1 criteria: evidence for AD pathology (abnormality in any CSF or imaging biomarker) and episodic memory impairment. Key outcomes were e.g. change in cognition and function (Neuropsychological Test Battery NTB z‐scores, CDR‐SB) and progression to dementia. Linear mixed models were used to investigate change in NTB and CDR‐SB scores across different baseline biomarker profiles (biomarker profile x time interactions). Associations between biomarker profiles and risk of progression to dementia were analyzed with Cox proportional hazards models adjusted for randomization group, MMSE, and study site.ResultCSF Aβ, t‐tau, and p‐tau levels were abnormal in 88%, 86%, and 69% of participants with centrally assessed CSF (N=107). 64% had an A+/T+/N+ profile. While cognitive/functional decline tended to be more pronounced in the IWG‐2 prodromal AD, NIA‐AA 2011 high and intermediate AD likelihood, and NIA‐AA 2018 AD groups, few statistically significant differences were observed between diagnostic groups within each set of criteria. Hazard ratio (95% CI) for progression to dementia was 4.7 (1.6–13.7) among participants with IWG‐2 prodromal AD (compared with no prodromal AD); 7.5 (1.0–55.0) for NIA‐AA 2011 high AD likelihood group (compared with SNAP), and 9.4 (1.2–72.7) for NIA‐AA 2018 AD group (compared with non‐Alzheimer’s pathologic change).ConclusionDespite being less restrictive than the more recent diagnostic criteria, IWG‐1 criteria reliably identified individuals with AD pathology. Findings may have implications for future trial design, as these criteria may be preferred due to feasibility in trials conducted in diverse settings, e.g. clinical trials which do not directly target Aβ or tau pathology.
Short‐ and long‐term effects of glycaemic load on cognition, dementia risk and plasma Amyloid‐β levels
Authors: Gentreau Mélissa , Chuy Virginie , Féart Catherine , Samieri Cécilia , Raymond Michel , Berticat Claire , Artero Sylvaine 
Published: December 2020

AbstractBackgroundIn animal models, carbohydrates increase β‐amyloid aggregation, tau phosphorylation and hippocampal atrophy which lead to the development of Alzheimer’s disease (AD). In epidemiological studies, cross‐sectional analyses on the impact of carbohydrate consumption on cognition are inconsistent. Besides, the long‐term effects of high carbohydrate intake on the risk of dementia and AD are poorly described. Here, we investigated i) the association between glycaemic load (GL) and cognition ii) the longitudinal association between GL and the onset of dementias (AD and others dementias) and iii) the associations between GL and plasma β‐amyloid peptides (Aβ) (possible biomarkers of AD pathology).MethodNo less than 2,777 non‐demented participants from the Three‐City Study (Bordeaux and Montpellier centre), aged over 65, filled a complete semi‐quantitative Food Frequency Questionnaire which was used to estimate GL (GL assesses both the carbohydrate quantity and quality, and reflects glycaemic response). At baseline, participants underwent a battery of neuropsychological tests (global cognition, visual memory, executive function, verbal fluency). Clinical diagnosis of dementia was made at each follow‐up (every 2‐3 years during 12 years). In a sub‐sample of 378 participants, plasma Aβ was measured. Plasma levels of Aβ1–40, Aβ1–42, Aβn‐40, and Aβn‐42 were measured using an xMAP‐based assay technology. We used Cox proportional hazards models to test the association between GL and the onset of dementia and linear regressions to test the associations between GL and cognitive performance or plasma Aβ.ResultAfter adjustment for potential confounders (age, sex, education, APOE‐ε4, BMI, type 2 diabetes, hypertension, cardiovascular history, history of stroke, hypercholesterolemia, history of head trauma, good subjective health, tobacco, energy intake, Mediterranean diet, physical activity), high afternoon‐snack GL was associated with increased dementia risk in APOE‐ε4 carriers (HR = 1.27 [1.03‐1.56]). Unexpectedly, GL was associated with higher cognitive performance, particularly for global cognition and visual memory (p <.01). We found no significant association between GL and plasma Aβ.ConclusionHigh carbohydrate consumption was associated with a long‐term risk of dementia in APOE‐ε4 carriers. However, carbohydrate consumption seems to promote short‐term cognitive performance.
Bacteria isolated from the stools of Alzheimer’s disease patients exacerbate cognitive impairment in 3xTg AD mouse model
Authors: Marizzoni Moira , Tournier Benjamin , Pauis Arthur , Millet Philippe , Mirabelli Peppino , Salvatore Marco , Cattaneo Annamaria , Frisoni Giovanni B. 
Published: December 2020

AbstractBackgroundHuman microbiota‐associated (HMA) murine models are developed by gavaging mice with human bacteria or stools and are increasingly used to study the relation between the human microbiota and disease. The aim of this study is to evaluate the effect of gut bacteria isolated from donors with or without Alzheimer’s dementia on behavior in AD transgenic (Tg) mice.MethodSixty female, one‐year 3xTg mice (APPSWE, PS1M146V and TauP301L) received (1) antibiotic treatment (for 14 days before the first gavage), (2) stomach acid suppressant administration, (3) laxative administration (immediately before the first gavage) and, (4) microbiota transplantation (or saline, once every 2 weeks for 2 months). The transplanted microbiota consisted of bacteria isolated from stools of donors pertaining to four different profiles: i) amyloid positive AD patient, amyloid negative cognitively healthy subjects ii) with or iii) without protective APOE genotype and, iv) young healthy donor. As additional control, we included a group of mice that received bacteria isolated from stools of untreated 3xTg mice. Stools collection and behavioral assessment (open‐field test, Y‐maze test, radial maze test, elevated plus maze test) was performed before antibiotic treatment and at day 3, 30, 60 after the first gavage. All mice were sacrificed at day 60 for ex‐vivo assessments.ResultAfter 60 days from the first gavage, the bacteria from the AD patient induced AD‐like behavior in 3xTg mice, including impaired general activity in the open‐field test and exacerbated anxiety in the elevated plus maze test, compared with mice that received saline or bacteria from untreated 3xTg mice. The bacteria from the other human donors did not influence mouse behavior.ConclusionThe microbiota of AD patients induced an AD‐like phenotype in 3xTg mice. Brain and gut ex‐vivo assessments, 16S rRNA gene sequencing as well as behavioral longitudinal analysis are on‐going to evaluate the human microbiota transplantation efficiency and its effect on AD pathology and inflammation.
Identification of genomic biomarkers with machine learning for early and differential diagnosis of late‐onset Alzheimer’s disease (LOAD)
Authors: Erdoğan Onur , Esme Mert , Balci Cafer , Rafatov Sevda , Cankurtaran Mustafa , Yavuz Burcu Balam , İyigün Cem , Son Yeşim Aydın 
Published: December 2020

AbstractBackgroundThe complex genetic etiology of the LOAD is still unclear, which restrains the early and/or differential diagnosis of LOAD. Genome‐Wide Association Studies (GWAS) is designed to explore the statistical interactions of variants, but interactions between variants are overseen by the univariate analysis. The machine learning algorithms are able to capture hidden patterns for the understanding of complex genetic disorders.MethodsThe controlled accessed GWAS datasets provided by ADNI (210 controls and 344 cases), and GenADA (777 controls and 798 cases), and NCRAD (1310 controls and 1289 cases) initiatives. GWAS analysed with PLINK, following p‐value filtering for the initial dimension reduction. Random Forest (RF) implemented with 5‐fold cross‐validation (CV) using RANGER package in R. LOAD RF model variants mapped and consensus genes are selected.ResultsTest performances of LOAD‐RF models of ADNI, NCRAD and GenADA datasets were 72,9%, 68,8%, and 92,4% respectively. 390 variants from ADNI, 1740 from NCRAD, and 434 from GenADA datasets were included in the individual LOAD‐RF models.No consensus variants are observed, but when the genomic locations of the variants are mapped, 62 genes common to at least two datasets are identified. 5 out of 6 genes common in all three LOAD‐RF models were also found to be reported as differentially expressed in the AD vs control subclusters of astrocyte cells (LFC>0.5, FDR = 0.01) (Ref1). Enrichment analysis based on consensus genes revealed cell adhesion as the top GO term for biological processes.ConclusionThe meta‐analysis of GWAS datasets for LOAD is performed, and the variants common in three predictive models at the gene level are analyzed. In the next phase of this study, the predictive performance of 6 variants are selected will be evaluated from the saliva samples collected from Turkish AD patients and controls. The outcomes of this study and know‐how acquired will allow us to offer an early/differential diagnostic tool based on the genotyping of the consensus variants for the early and differential diagnosis of the LOAD. Reference: (1) Grubman, A., et al. Nat Neurosci 22, 2087–2097 (2019).
Methylomic variation induced by LPS exposure in a microglial cell line
Authors: Imm Jennifer L. 
Published: December 2020

AbstractBackgroundDespite extensive research, it is still unknown how AD pathogenesis occurs and how this links into the development of the pathological Aβ and Tau aggregates in the brain. More recent evidence has indicated that microglia may play a key role in AD risk and pathogenesis. This comes from large cohort studies identifying genetic variants associated with late onset Alzheimer’s disease with immune related functions. Chronic activation of microglia is thought to cause them to exist in a pre‐activated or “primed” state resulting in them having a heightened response to immune stimuli such as lipopolysaccharide. Despite increasing investigation into the role of microglia in Alzheimer’s disease onset and progression there are few studies focussed on the epigenomic consequences of chronic immune stimulation. However, in order to study this it is first important to understand the epigenomic consequences of acute immune stimulation.MethodAn immortalized primary microglial cell line (SV40; Accegen) were plated and underwent one of three treatments; 24 hour exposure to 1 µg/mL LPS, 24 hour exposure to 1 µg/mL LPS followed by a 24 hour recovery period, or no treatment (control). DNA was collected from cells and DNA methylation was assessed using the IlluminaEPIC array. Using median absolute derivation, linear modelling and pathway analysis we identified loci undergoing dynamic methylation changes upon LPS challenge and the cellular pathways these loci are associated with.ResultThis study has identified methylomic variation associated with microglial exposure to LPS and recovery. We identified 173 significant loci with these loci being associated with pathways such as extracellular matrix organisation, enzyme activity and organelle membranes. We have also shown there are no changes to epigenetic or mitotic age upon immune stimulation.ConclusionWe have shown that there are epigenetic changes occurring upon acute microglial stimulation with LPS. These are changes occurring within pathways that are key to cellular function and response to response to infection. Finally we have shown that LPS exposure does not affect epigenetic or mitotic age. In the future it will be of interest to study DNA methylation changes in this microglia cell line after chronic exposure to LPS.
A novel proteomics assay allows parallel quantitation of a panel of synaptic proteins in human cerebrospinal fluid
Authors: Nilsson Johanna , Gobom Johan , Brinkmalm Gunnar , Zetterberg Henrik , Brinkmalm Ann , Blennow Kaj 
Published: December 2020

AbstractBackgroundA reduction of synaptic activity is one of the earliest events in neurodegenerative diseases such as Alzheimer’s disease (AD)[1‐4]. A 35% loss in the number of synapses have also been found in AD, by using synaptic proteins as markers[3‐4]. Detection and quantification of synaptic markers is therefore a hot topic due to the significant role of synapses in the disease pathology and progression of neurodegenerative diseases. In this study, we developed a novel proteomics assay approach to quantify a panel of 17 synaptic proteins in cerebrospinal fluid. The synaptic panel includes but are not limited to: synucleins, neuronal pentraxins, SNARE proteins and neurogranin.MethodStable isotope labeled peptide standards were added during digestion of 100 µL CSF samples, followed by purification with solid‐phase extraction. Quantification was performed by micro‐high‐performance liquid chromatography (Ultimate 3000 standard liquid chromatography system, Thermo Fisher Scientific Inc,) parallel reaction monitoring mass spectrometry (Q Exactive, Thermo Fisher Scientific Inc.).ResultWe show a novel strategy to quantify 17 synaptic proteins in CSF in parallel to study several properties of synaptic pathology simultaneously. In a CSF pilot study of 20 AD and 20 healthy controls, several synaptic proteins were found to be increased (p‐value≤0.001) such as neurogranin, complexin‐2, VAMP2 and beta‐synuclein. Interestingly, the neuronal pentraxins (NPTX1, NPTX2 and NPTXR) showed no significant difference between AD and control.ConclusionWe have successfully established a method that can measure and compare levels of a panel of synaptic proteins in individual patient CSF samples. The pilot study shows very promising results where several synaptic proteins potentially could be used as biomarkers for synaptic pathology in Alzheimer’s disease. References: (1) Bagetta, V., et al., Synaptic dysfunction in Parkinson's disease. Biochem Soc Trans, 2010. 38(2): p. 493‐7. (2) Schneider, J.A., et al., The neuropathology of probable Alzheimer disease and mild cognitive impairment. Ann Neurol, 2009. 66(2): p. 200‐8. (3) Schulz‐Schaeffer, W.J., The synaptic pathology of alpha‐synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia. Acta Neuropathol, 2010. 120(2): p. 131‐43. (4) Clare, R., et al., Synapse loss in dementias. J Neurosci Res, 2010. 88(10): p. 2083‐90.
Practice variation in diagnosing dementia: A nationwide overview of diagnostic work‐ups in Dutch hospitals
Authors: Hafdi Melanie , Richard Edo , van Gool Willem A 
Published: December 2020

AbstractBackgroundTo date, there is no gold standard for diagnosing dementia and diagnostic strategies vary widely between specialists and hospitals. More insight into diagnostic practice variation can be used to improve quality of diagnostics. Aim: To determine variation in diagnostic strategies between Dutch hospitals.MethodIn the Netherlands, all health insurance claim data are centrally registered. Information on diagnostic ancillary services carried out from 2015 to 2018 was collected via national‐level insurance claims for patients that received a (new) diagnose‐coding for dementia in 2018. Hospitals were included in the analysis if they diagnosed >50 patients with dementia and were divided in academic medical centres (AMC), non‐academic training hospitals (TH) and general hospitals (GH).Result71 of 98 (72%) Dutch hospitals fulfilled the inclusion criterion, accounting for a total of 20.073 new dementia diagnoses in 2018. Nearly all patients underwent some form of ancillary diagnostic services (n=20.068) in the preceding 3‐4 years, however frequencies and diagnostic modalities differed widely between hospitals. The range of percentages between hospitals that performed MRI/CT‐imaging ranged from 37 to 99% (median 76.7%) of all patients that were diagnosed with dementia, neuropsychological assessment from 0‐89% (median 31.8%), cerebrospinal fluid examination from 0‐14% (median 2.4%), PET/SPECT‐imaging from 0‐16% (median 6.2%) and electroencephalography from 1‐20% (median 5.8%). The percentage of patients subjected to ancillary diagnostic investigations decreased sharply with increasing age (approximately 2 times for patients >90 years when compared to patients of 70‐80 years old). There were no distinct differences according to gender, or number of patients that were diagnosed, whereas PET/SPECT‐imaging was slightly more frequently used in academic centres (8% in AMCs versus 5% in GHs, p=0.003).ConclusionIn the Netherlands, diagnostic ancillary methods used vary widely between hospitals both in frequency and modality. This variation may be driven by the flexibility in national guidelines due to limited evidence of diagnostic accuracy and added value of different diagnostic tests, varying doctor and patient preferences and differences in available diagnostic techniques per hospital. Future research could explore this heterogeneity further and help to identify a practice strategy that combines the most benefit with the least burden for patients.
Intensive measurement of cognition to support early detection of cognitive change in individuals at risk of dementia
Authors: Brewster Paul , Rush Jonathan , Ozen Lana , Jacobs Diane M , Kaye Jeffrey , Nygaard Haakon B , Feldman Howard H , Hofer Scott M ,   Canadian Thumbs Up Study Group
Published: December 2020

AbstractBackgroundCognitive changes in nondemented older adults are best measured longitudinally and relative to individual baselines. Effect sizes of early changes in cognition are small with most traditional measures, and so there is a need for alternative measurement approaches that can improve statistical power to detect change. Remotely administered mobile assessments can address this need by permitting much more frequent repeated measurements, which then permits statistical delineation of early slopes of decline from performance variation associated with extraneous factors (e.g., mood, practice). MyCogHealth is an iOS/Android app for self‐administered cognitive assessments and customizable surveys. Inclusion of MyCogHealth in the Canadian Thumbs Up program (CTU) will permit evaluation of feasibility and utility of intensive measurement designs for capturing early cognitive changes in older adults identified to be at increased risk of dementia.MethodThe CTU Platform Trial Cohort will complete five intensive measurement “bursts” in three‐month intervals using MyCogHealth. Each burst involves brief self‐administered assessments completed twice daily across seven consecutive days. Each assessment includes the Symbol Match test (processing speed), Dot Memory (visual short‐term memory), a digital Trailmaking Test analogue, and surveys assessing state factors that can affect cognition. A pilot cohort (N=17; Mean age=74; Mean MoCA score=28) was followed for 12 months using this protocol to evaluate feasibility and psychometric integrity of the Symbol Match and Dot Memory tests in this design.ResultIn the pilot cohort Symbol Match correlated with Digit Span Forward and the Trailmaking Test (r=.51‐.66). Dot Memory correlated with Backward Digit Span (r=.49), Trailmaking Test (r=‐.59), object naming (r=.64), and visual episodic memory (r=.58). Retest reliability was .80 for Dot Memory and .87 for Symbol Search. Intraclass correlation was .77 for Symbol Search and .42 for Dot Memory. Participant retention was 100% and compliance with burst testing was 94%.ConclusionPreliminary results support the feasibility, validity, and reliability of self‐administered burst testing deployed longitudinally. Inclusion of MyCogHealth in CTU should be informative in capturing early slopes of decline in the study cohort. Such early detection of decline will inform more powerful, personalized trials where those at the highest predicted risk would be included and those at lower risk excluded.
The Brain Health Support Program: A web‐based interactive platform to increase dementia literacy and awareness regarding lifestyle factors in at‐risk individuals
Authors: Belleville Sylvie , Nygaard Haakon B , Bherer Louis , Camicioli Richard , Carrier Julie , Anderson Nicole D , Dang‐Vu Thien Thanh , Dwosh Emily , Ferland Guylaine , Harris Elaine , Laurin Danielle , Liu‐Ambrose Teresa , Madlensky Lisa , Miller Lesley , Montero‐Odasso Manuel , Phillips Natalie , Pichora‐Fuller M Kathleen , Robillard Julie , Smith Eric E , Speechley Mark R , Wittich Walter , Chertkow Howard , Feldman Howard H ,   CCNA
Published: December 2020

AbstractBackgroundPrior studies have reported that older adults can benefit from formal educational programs about dementia. Participating in an online educational program focusing on risk and protective factors could potentially increase participants’ dementia literacy, empowerment, and engagement in brain health promotion, which in turn could reduce their dementia risk. The goal is to develop a comprehensive, compelling, and evidence‐based online educational program on risk and protective factors for dementia.MethodThe Brain Health Support Program is being developed as part of the Canadian Consortium on Neurodegeneration in Aging CAN‐Thumbs‐Up initiative. The program is designed to improve dementia literacy, promote lifestyle changes in at‐risk individuals who are cognitively intact or have mild cognitive impairment, and evaluate its effectiveness.ResultsThe content is based on the epidemiological literature on risk and protective factors for dementia. The format is determined from a review of web‐based educational programs for older adults and is co‐created with experts, stakeholders and citizen advisors. The program contains eight interactive modules with new content provided weekly over a 12‐month period. The modules contain general information and tips on modifiable risk factors including diet, physical activity, cognitively stimulating activity, sleep, vascular health, social and psychological factors, vision and hearing, as well as information on dementia, stigma, and stereotypes. Participants have access to an individualized risk profile to determine personal goals and are given feedback on lifestyle changes. Content is available in French and English. Changes in dementia literacy, self‐efficacy, attitudes toward dementia and modifiable risk factors will be collected from the platform.ConclusionProviding access to scientifically validated education through an interactive web‐based platform is expected to have a positive effect on participants’ attitude, engagement in brain health behaviours and dementia literacy. It might also increase readiness to change and maintain positive lifestyle changes. The content and format are co‐created with users and stakeholders, which should increase its relevance and facilitate future implementation.