bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cognitive and functional progression along the continuum from mild cognitive impairment (MCI) to Alzheimer’s disease (AD): A latent class analysis using the U.S. National Alzheimer’s Coordinating Center (NACC) data set
Authors: Mouchet Julie , Betts Keith A. , Ionescu‐Ittu Raluca , Butler Lesley M. , Delmar Paul , Georgieva Mihaela V. , Kulalert Thomas , Desai Urvi 
Published: December 2020

AbstractBackgroundThe trajectory of AD progression is heterogeneous between individuals, and the predictors of cognitive and functional decline associated with rapid progression remain poorly understood. Better understanding of the cognitive and functional trajectories and predictors of decline is critical for articulating the natural history of the disease, identifying subgroups of individuals with MCI at higher risk of developing dementia, and contextualizing clinical trial data for AD treatments.MethodSubjects newly diagnosed with MCI in the NACC uniform data set from September 2005 to February 2019 were identified. Cognition and function were measured by the Clinical Dementia Rating‐Sum of Boxes (CDR‐SB). CDR‐SB score trajectories were fitted using a linear multi‐step growth mixture model, which was then used to identify three latent classes of subjects based on the similarity of progression patterns. Multivariate multinomial logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for baseline predictors across the latent classes.ResultOf 830 subjects included in the study sample, 42% were male, and the median age was 79.0 years. Median CDR‐SB at the time of MCI diagnosis was 0.5 (interquartile range=0.5–1.0; Table). Average follow‐up after initial MCI diagnosis was 3.6 years (standard deviation=2.5). Subjects were classified in three latent classes with differing CDR‐SB trajectories: fast progressors (21% of sample; average CDR‐SB increase=1.87 points/year), slow progressors (22%; average CDR‐SB increase=0.51 points/year), and non‐progressors (57%; no CDR‐SB increase) (Figure). Independent factors at MCI diagnosis associated with fast progressors vs non‐progressors were: older age (OR 1.04, 95% CI 1.01–1.07), female sex (2.00, 1.23–3.23), one copy of apo ε4 (1.89, 1.18–3.02), higher baseline CDR‐SB score (3.20, 2.25–4.54), and lower baseline Mini Mental State Examination (MMSE) score (0.89, 0.81–0.98).ConclusionIn this NACC‐based study, three latent classes of subjects were identified based on CDR‐SB progression trajectories. Older age, female sex, one copy of apo ε4, and worse baseline cognitive scores (CDR‐SB and MMSE) were associated with faster progression on CDR‐SB.
Modelling the cascade of biomarker changes in progranulin‐related frontotemporal dementia
Authors: Venkatraghavan Vikram , Panman Jessica L. , van der Ende Emma Louise , Steketee Rebecca , Jiskoot Lize C. , Poos Jackie M. , Dopper Elise G.P. , Meeter Lieke H.H. , Kaat Laura Donker , Rombouts Serge A.R.B. , Vernooij Meike W. , Kievit Anneke J.A. , Premi Enrico , Cosseddu Maura , Bonomi Elise , Olives Jaume , Rohrer Jonathan D. , Sanchez‐Valle Raquel , Borroni Barbara , Bron Esther E. , van Swieten John C. , Papma Janne M. , Klein Stefan ,   GENFI Consortium investigators
Published: December 2020

AbstractBackgroundProgranulin related frontotemporal dementia (FTD‐GRN) is a fast progressive disorder, in which pathophysiological changes precede overt clinical symptoms in only a short time period. Modelling the cascade of multimodal biomarker changes aids in understanding the etiology of this disease, enables monitoring of individual mutation carriers, and would give input for disease‐modifying treatments. In this cross‐sectional study, we estimated the temporal cascade of biomarker changes for FTD‐GRN, in a data‐driven way.MethodWe included 56 presymptomatic and 35 symptomatic GRN mutation carriers, and 35 healthy non‐carriers. Of the symptomatic subjects, 17 had behavioural variant FTD (bvFTD), 16 presented as non‐fluent variant primary progressive aphasia (nfvPPA). The selected biomarkers for establishing the cascade of changes were neurofilament light chain, regional grey matter volumes, fractional anisotropy of white matter tracts, and cognitive domains. We used a data‐driven analysis called discriminative event‐based modelling (Venkatraghavan, NeuroImage, 2019) with a novel modification to its Gaussian Mixture Model (GMM) called Siamese GMM, to estimate the cascade of biomarker changes for FTD‐GRN. Using cross‐validation, we estimated disease severities of individual mutation carriers in the test set based on their progression along the biomarker cascade established on the training set.ResultNeurofilament light chain and white matter tracts were the earliest biomarkers to become abnormal in FTD‐GRN mutation carriers. Attention and executive functioning were also affected early on in the disease process. Based on the estimated individual disease severities, presymptomatic mutation carriers could be distinguished from symptomatic mutation carriers with a sensitivity of 95% and specificity of 100% in the cross‐validation experiment. There was a high correlation (r=0.94, p<0.001) between estimated disease severity and years since symptom onset in nfvPPA, but not in bvFTD (r=0.33, p=0.46).ConclusionIn this study, we unravelled the temporal cascade of multimodal biomarker changes for FTD‐GRN. Our results suggest that axonal degeneration is one of the first disease events in FTD‐GRN, which calls for designing disease modifying treatments that strengthens the axons. We also demonstrated a good delineation between symptomatic and presymptomatic carriers using the estimated disease severities, which suggest that our model could enable monitoring of individual mutation carriers.
NLRP3 inflammasome activation regulates microglial migration
Authors: McManus Roisin M. , Griep Angelika , Gomez‐Cabrero David , Tegner Jesper , Heneka Michael T. 
Published: December 2020

AbstractBackgroundThis laboratory has demonstrated an important role for the NLRP3 inflammasome in the progression of Alzheimer’s disease (AD) with activation found in post‐mortem tissue from individuals with AD (Heneka et al., 2013) and in transgenic mouse models of AD expressing amyloid precursor protein (APP) and presenilin 1 (PS1; APP/PS1 mice). However, APP/PS1 mice deficient for NLRP3 were protected from AD‐pathology, with a significant reduction in cleaved‐caspase‐1 and IL‐1β. We wanted to examine the wider implications of NLRP3 inflammasome deficiency beyond IL‐1β, and uncover other pathways and signaling mechanisms employed by microglia to protect the brain from the build up of Aβ.MethodRNA sequencing was performed on CD11b+ cells from the brains of 4, 6 and 12 month old wildtype, APP/PS1, NLRP3‐/‐ and APP/PS1.NLRP3‐/‐ mice. Microglia were prepared from the brains of 1‐day old wildtype and NLRP3‐/‐ mice for live cell imaging, migratory assays and flow cytometric analysis. In a separate series of experiments CD11b+ cells were isolated from the brains of wildtype, APP/PS1, NLRP3‐/‐ and APP/PS1.NLRP3‐/‐ mice and myeloid cells were also prepared from the blood of humans with and without AD to replicate all findings in these models.ResultThe RNA sequencing analysis found a significant increase in pathways related to chemokine signaling in NLRP3‐/‐ and APP/PS1. NLRP3‐/‐ mice. Wildtype microglia significantly migrated to Aβ, however NLRP3‐/‐ microglia or cells treated with NLRP3 inhibitors had increased migration to Aβ and greater Aβ phagocytosis, which was associated with CCL2 release and mediated via the receptors CCR2 and CCR4. Importantly, we were able to replicate these findings using monocyte‐derived microglia‐like cells from humans and in NLRP3‐/‐ and APP/PS1/NLRP3‐/‐ mice ex vivo.ConclusionWe have identified a new mechanism where microglia release CCL2 to migrate to Aβ and phagocytose this peptide. Critically, this activity is increased in NLRP3‐/‐ cells or those treated with NLRP3‐specific inhibitors, together demonstrating a previously unknown role for the NLRP3 inflammasome in regulating cellular migratory and phagocytic behavior. These findings provide insights into the pathogenesis of AD and importantly highlight the NLRP3 inflammasome as a serious target for prevention and early treatment of AD.
The effect of educational intervention by tele‐nursing on caregiver burden in family caregivers of elderly with Alzheimer's disease
Authors: Sadeghmoghadam Leila , Shahriyan Fariba , Delshad Ali , Deluee Masoume Amiri 
Published: December 2020

AbstractBackgroundIt is estimated that 90% of people with Alzheimer's disease live in their homes. And in 80% of the cases, the burden of caring for these people falls on family members. Therefore, it is necessary to develop and evaluate intervention programs for home caregivers to prevent and relieve their caregiver burden. The aim of this study was to determine the effect of educational intervention by tele‐nursing on caregiver burden in family caregivers of elderly with Alzheimer's disease.MethodThis quasi‐experimental study was performed on 44 home caregivers of elderly people with Alzheimer's disease in Neyshabur during In the first six months of 2019. The participants in the first stage were selected based on inclusion criteria and purposeful sampling method. In the second stage, they were randomly divided into intervention and control groups by by permutation blocks. For the intervention group, 6 weeks educational intervention was conducted through tele‐nursing. The control group received routine care. Data collection tools included demographic information form and standard Copenhagen Burnout Inventory questionnaire (CBI). Data were analyzed by SPSS version 22 and independent t‐test, paired t‐test and chi‐square tests.ResultThe mean score of total caregiver burden before intervention was not significantly different between the two groups (P = 0.425). After the intervention, a significant decrease was observed in the intervention group compared to the control group (P <0.0001). The control and intervention groups had a significant difference in the caregiver burden rating after the intervention (P <0.0001).ConclusionThe findings of the present study indicate that training through telenursing is an effective and cost effective method of reducing the care burden of caregivers of older people with Alzheimer's disease. Since the issue of family care for Alzheimer's sufferers is a very sensitive and important issue for Alzheimer's policy makers and social service providers. And while this requires a great deal of cost and human resources, it can be suggested as a low‐cost and effective method of reducing the burden of care for caregivers of patients with Alzheimer's disease.
Is machine learning prediction of Aβ positivity consistent? An assessment of multiple datasets
Authors: Grecchi Elisabetta , Grisan Enrico , Buckley Christopher , Wolber Jan 
Published: December 2020

AbstractBackgroundRecent applications of machine learning methodologies in AD suggest that synergistic utilisation of imaging and non‐imaging biomarkers may improve the ability to predict subject’s likelihood to present with amyloid pathology prior to performing a PET scan. In this work we developed an algorithm for prediction of patient amyloid positivity that shows robust performance across different databases, thus being more likely to be suitable for real‐world application.MethodMachine learning (ML) algorithms that combine imaging (MRI volumes), genetic (ApoE status), psychometric (MMSE and CDR), and demographic (age/gender) data were developed to predict a patient’s probability of being Aβ positive. The patient’s [18F]flutemetamol PET scan served as the standard of truth (SoT). Two ML methodologies (LASSO and RUS‐BOOST) were tested to tackle both the unbalance between Aβ positive/negative patients and selection of volumetric brain regions. The algorithms were trained and tested using combination of 5 different databases, excluding all healthy controls: MCI Progression Phase III trial (204 MCI), AIBL (52 MCI, 16 pAD), Biofinder (117 SCD, 147 AD), and a subset of ADNI data selected for the ADNI evolution prediction data (564 MCI, 147 AD).ResultThe cross‐validation results and the performance of the algorithms with different test sets are reported in Tables 1 and 2. We report AUC, accuracy, sensitivity, specificity, PPV and NPV for a probability threshold of 0.5 (Table1). PPV and NPV are also reported for threshold optimized and selected by the algorithm to provide a sensitivity of approximately 0.75 (Table 2), which results in a lower rate of misclassified amyloid positive.ConclusionWe show that the developed algorithms can be confidently used across several independently acquired datasets. Our results suggest that for optimal usage as screening tool in a specific clinical trial, ML techniques should be adjusted for the characteristic of the specific population under analysis. Despite fairly consistent performance of the two methods within cross validation, results can vary when applying the learned models to different datasets, suggesting that cohort selection criteria, composition, and geographical origin may additionally influence outcomes.
Relationships of time‐varying resting state network stability and cognitive function along the Alzheimer’s disease spectrum
Authors: Chumin Evgeny J. , Risacher Shannon L. , West John D. , Apostolova Liana G. , Farlow Martin R. , McDonald Brenna C. , Saykin Andrew J. , Sporns Olaf 
Published: December 2020

AbstractBackgroundResting‐state functional connectivity (rsFC) neuroimaging studies of Alzheimer’s Disease (AD) have reported alterations in network community structure and time‐varying rsFC (tvFC). However, the temporal stability of community organization in tvFC has not been investigated. Therefore, the purpose of this work was to characterize the relationship of tvFC and cognitive function (CF) along the spectrum of AD progression.MethodsData were part of the Indiana Alzheimer Disease Center and Indiana Memory and Aging study cohorts, randomly split into discovery and validation samples (Table1). After standard preprocessing, rsFC (10min acquisition) and tvFC (∼60sec tapered, partially overlapping windows) were estimated for two cortical brain region parcellations (200 and 300 nodes). Modularity was estimated for rsFC and for all tvFC windows, across a range of community scales, with final network stability metric calculated as area under the curve of the mean temporal agreement across scales, within and between seven canonical resting‐state networks (RSNs). The Montreal Cognitive Assessment score was used as an index of overall CF. Spearman partial correlation (adjusted for age, education, and sex) was used to investigate relationships of tvFC stability with CF.ResultsNo significant relationships were identified between CF and rsFC or tvFC community structure metrics (quality and number of communities). For tvFC, temporal stability of two network blocks, between visual‐frontoparietal and within ventral attention, showed significant associations with CF across both samples and both parcellations. Additionally, in the 300‐node parcellation, visual network metrics correlated with CF (Figure1). CF was negatively associated with tvFC community stability of regions belonging to different RSNs (Figure1A) and positively with regions within RSNs (Figure1B,C).ConclusionOverall, these findings demonstrate a loss in the stability of RSNs in tvFC with decreasing CF. The networks identified here are generally implicated in cognitive control as well as orientation and attention to salient stimuli. These findings demonstrate that tvFC stability (independent of community and parcellation size) is related to CF along a spectrum of AD risk. Temporal dynamics at rest have potential as a biomarker to characterize progression in prodromal AD. Longitudinal studies are needed to assess the predictive validity of RSN dynamics.
CSF 7‐ketocholesterol is related to β‐amyloid and white matter microstructure in healthy adults
Authors: Iriondo Ane , Garcia‐Sebastian Maite , Arrospide Arantzazu , Arriba Maria , Aurtenetxe Sara , Barandiaran Myriam , Clerigue Montserrat , Ecay Mirian , Estanga Ainara , Gabilondo Alazne , Izagirre Andrea , Saldias Jon , Tainta Mikel , Villanua Jorge A , Blennow Kaj , Zetterberg Henrik , Mar Javier , Abad‐García Beatriz , Dias Irundika , Goñi Félix María , Martinez‐Lage Pablo 
Published: December 2020

AbstractBackgroundAbnormal cholesterol metabolism changes the neuronal membrane and interferes with amyloidogenesis. Oxysterols in CSF are related to Alzheimer’s disease (AD) biomarkers in mild cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance. We aim to demonstrate that the association of oxysterols, biomarkers and WM microstructure occurs early in asymptomatic individuals.MethodWe studied the association of inter‐individual variability of CSF 24‐hydroxycholesterol (24‐OHC), 27‐hydroxycholesterol (27‐OHC), 7‐ketocholesterol (7‐KC), 7β‐hydroxycholesterol (7β‐OHC), β‐amyloid1‐42 (Aβ42), total‐tau (t‐tau), phosphorylated‐tau (p‐tau), neurofilament (NfL) and WM microstructure in cognitive regions, using diffusion tensor imaging (DTI), generalized lineal models and moderation/mediation analyses in 153 healthy adults.Result7‐KC levels were related to Aβ42 (B = ‐1.41; p = 0.041). Higher 7‐KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD) and radial (RD) diffusivity in cognitive regions. 7‐KC modulated the association between AxD and NfL in the corpus callosum splenium (B = 39.39, p = 0.017) and genu (B = 68.64, p = 0.000) and fornix (B = 10.97, p = 0.000). Lower Aβ42 levels were associated to lower FA and higher MD, AxD and RD in the fornix, corpus callosum, inferior longitudinal fasciculus and hippocampus. The association between AxD and Aβ42 was moderated by 7K‐C (p= 0.048).ConclusionThis study adds clinical evidence to support the role of 7K‐C on axonal integrity and the involvement of cholesterol metabolism in the Aβ42 generation process.
STAT3 inhibition reverses neuroinflammation and Aβ metabolism induced by systemic inflammation
Authors: Millot Perine , San Carine , Bennana Evangeline , Hugon Jacques , Paquet Claire , Hosten Benoit , Mouton‐Liger Francois 
Published: December 2020

AbstractBackgroundSTAT3 is a transcriptional factor involved in various physiological processes, including immune reaction. Abnormal activation of the, STAT3, has been recently associated with Alzheimer Disease (AD). Phosphorylation of STAT3 is dramatically increased in the hippocampus of AD mouse model and in AD post‐mortem brain. STAT3 phosphorylation is critical for cytokines secretion known to be involved in neuroinflammation, such as Il‐1β, IL‐6 or TNF‐α. Moreover, STAT3 may act as a transcriptional regulator of BACE1, the key enzyme in amyloïd β (Aβ) production. Our group have previously shown that neuroinflammation and increased brain Aβ production induced by systemic inflammation in wild‐type (WT) mice is associated with an excessive activation of STAT3 (Rebillat et al., 2015). Inhibitors of STAT3 have already shown beneficial effects in several pathology, such as cancer. The main objective of this research project was to investigate if STAT3 inhibitors could reverse neuroinflammation and abnormal BACE1 regulation in vivo and be considered as potential drug candidates for treatment in AD.MethodC57BL/6 wild type mice were injected intraperitoneally with LPS (1mk/kg) versus saline once a day for 3 days to induce neuroinflammation and STAT3 activation. Inhibition of STAT3 activation is mediated by intraperitoneal injection of STATTIC, a small molecule which selectively inhibits dimerization and nuclear translocation of STAT3. Brains were collected and dissected; immunohistochemistry and western blotting were performed for neuroinflammation, STAT3 activation and Aβ metabolism (as BACE1 level).ResultSTATTIC injection significantly decreases LPS‐induced microglial activation in the hippocampus. In addition, STAT3 inhibition reduces production of cytokines IL‐6, IL‐10 and TNF‐α triggered by LPS administration. We also observed a significative reduction of BACE1 level in the hippocampus of mice treated with LPS and STATTIC compared to those exposed to LPS alone.ConclusionTaking together, our results show that STATTIC can reverse neuroinflammation and BACE1‐Aβ signaling deregulation induced by systemic inflammation, and pave the way for further explorations of the therapeutic potential of STAT3 inhibition in AD.
An Alzheimer’s linked loss‐of‐function CLN5 variant impairs Cathepsin D maturation consistent with a retromer trafficking defect
Authors: Reitz Christiane 
Published: December 2020

AbstractBackgroundWhile lysosomal storage diseases (LSDs) typically have been regarded as causing neurodegeneration early in life, recent observations showed that genetic variants that cause one type of LSD, Gaucher’s disease, can also cause Parkinson’s disease, strongly suggesting that genes causing LSDs might also act as risk factors for other late‐onset neurodegenerative disorders, notably Alzheimer’s disease (AD).MethodCapitalizing on data from a whole exome sequencing study of 31 multiplex Alzheimer’s disease (AD) families, we examined a select group of genes (CLN3, CLN5, CTSD) that cause another LSD, Neuronal ceroid lipofuscinosis (NCL), because they have been directly or indirectly associated with retromer trafficking, a key pathological mechanism in AD. To validate variant(s) identified in these analyses, we turned to cell culture to determine whether they have deleterious effects on normal function. Finally, because all three genes converge on Cathepsin D, we tested whether the abnormal function caused by identified variant(s) would affect the normal processing of this protein.ResultWe identified a missense variant in CLN5 c.A959G (p.Asn320Ser) that segregated with AD in multiplex families. We demonstrated that this variant causes glycosylation defects in the expressed protein, which causes it to be retained in the endoplasmic reticulum with reduced delivery to the endolysosomal compartment, CLN5’s normal cellular location. We showed that this variant reduces the normal processing of Cathepsin D and decreases levels of full‐length APP, in line with a defect in retromer‐dependent trafficking.ConclusionCLN5 is highly expressed in the brain, in particular in microglia. Retromer deficiency has been found in microglia of AD brains, but the mechanisms underlying this deficiency are unclear. While future studies expressing the identified CLN5 variant are required to further characterize its functional consequences, we postulate that it mediates its AD‐associated toxicity by affecting retromer function in microglia. Notably, independent supporting evidence for an etiologic overlap between NCL and AD comes from recent studies reporting a novel PSEN1 mutation in a family diagnosed with adult‐onset NCL (Dolzhanskaya et al. J Alzheimers Dis. 2014), and a recent whole‐exome sequencing study reporting a CLN13 (CTSF; Cathepsin F) mutation in a kindred with early‐onset Alzheimer’s disease (Bras et al., Neurobiol Aging. 2016).