bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disentangling neurodegeneration subtypes of Alzheimer’s disease using data‐driven methods
Authors: Grothe Michel J. , Levin Fedor , Teipel Stefan J. , Habes Mohamad 
Published: December 2020

AbstractBackgroundResearch on understanding heterogeneity in Alzheimer’s disease (AD) has traditionally relied on ‘a priori’ categorizations of recognized clinical or pathologic disease variants. More recently, application of clustering methods to high‐dimensional spatial features from neuroimaging data has allowed data‐driven discovery of AD subtypes based on differentiated regional patterns of neurodegeneration.MethodsWe provide an up‐to‐date review of structural MRI studies that leveraged data‐driven approaches to examine heterogeneity in regional neurodegeneration patterns among AD patients. Findings will be discussed in relation to different families of clustering methods employed across studies. We further present primary data from our ongoing studies characterizing AD neurodegeneration subtypes by means of FDG‐PET as a potentially more sensitive molecular imaging marker of neurodegenerative processes.ResultsData‐driven studies across multiple independent cohorts and employed methodologies provide converging evidence for the existence of distinct MRI atrophy subtypes that broadly resemble the differentiation into atypical medial temporal‐ vs neocortical‐predominant patterns characterizing established neuropathological subtypes. These studies not only allowed for a regionally more detailed characterization of the respective atrophy patterns, but also pointed to the existence of more differentiated atrophy profiles within these broad subtype categories. Concordantly, our cluster analyses of FDG‐PET data confirmed a broad distinction into AD subtypes characterized by medial temporal/limbic‐ vs neocortical‐predominant hypometabolism, and at a higher resolution further distinguished a rare frontal variant from the typical temporo‐parietal neocortical pattern (Fig‐1). In a pilot imaging‐pathologic association study based on ante‐mortem FDG‐PET of 34 pathologic AD cases, the neocortical‐predominant subtype was more likely to have neocortical tau Braak stage VI and to have higher CERAD ratings of cortical neuritic plaques, whereas Thal amyloid phase and diffuse plaque ratings did not differ from the limbic‐predominant subtype. The limbic‐predominant subtype had a higher burden of comorbid cerebrovascular disease, but TDP‐43 or Lewy body comorbidity did not differ significantly between subtypes.ConclusionsData‐driven approaches applied to neuroimaging data can give an unbiased and regionally detailed estimate of the distinct neurodegeneration subtypes present among AD dementia patients. Methodological consensus on the optimal clustering techniques and input features is needed to define the most robust subtype‐defining neurodegeneration patterns to be used for patient stratification.
Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics
Authors: Tijms Betty M. , Visser Pieter Jelle 
Published: December 2020

AbstractBackgroundAlzheimer’s disease (AD) is a biologically heterogeneous disorder. Cerebrospinal fluid (CSF) contains thousands of proteins, with concentrations reflecting ongoing (patho)physiological processes. This provides the opportunity to study many biological processes at the same time in patients. Using a dual clustering technique, non‐negative matrix factorization, we studied whether biological subtypes of AD can be detected in CSF proteomics in two independent cohorts, and we will provide an overview how subtypes differed on biological clinical characteristics.MethodWe selected individuals with AD (defined as abnormal ab42 in CSF) and controls (normal cognition and normal AD biomarkers) from ADNI and the EMIF‐AD biomarker multimodality biomarker discovery study (ADNI: 32 preclinical AD, 103 prodromal AD, 62 AD‐dementia, 45 controls; EMIF‐AD: 56 preclinical AD, 90 prodromal AD, 77 AD‐dementia, and 82 controls). In ADNI we studied 149 proteins measured with mass reaction monitoring spectrometry and a multiplex rules based medicine assay, and in EMIF‐AD 556 proteins measured with tandem‐mass tag spectrometry. Proteins were selected when concentrations differed between AD and controls, scaled to include only positive values and then clustered with non‐negative matrix factorisation. Subtypes were compared on demographical, clinical and protein CSF markers not used for clustering.ResultBoth cohorts showed three protein profiles, based on which we allocated individuals to three subtypes: In EMIF‐AD, subtype 1 included 80 individuals (36%), subtype 2 included 71 individuals (32%) and subtype 3included 72 individuals (32%). In ADNI, subtype 1 included 97 individuals (45%), subtype 2 included 69 individuals (35%) and subtype 3 included 39 individuals (20%). Gene Ontology (GO) pathway analysis showed that proteins specifically increased in subtype 1 were enriched for synapse functioning, in subtype 2 for innate immune system activation and in subtype 3 for blood‐brain barrier dysfunction (all pFDR <0.05). Compared to controls, subtypes showed overlapping and distinct regional atrophy patterns: subtype 1 atrophy showed most pronounced atrophy in temporal areas; subtype 2 showed more involvement of parietal areas, and subtype 3 of frontal areas.ConclusionBiological heterogeneity amongst individuals with AD can be robustly detected with CSF proteomics, and this provides new opportunities for development of patient tailored treatment approaches.
DNA Aβ42 immunotherapy induces epigenetic changes of the gene expression profile in brain in the 3XTG‐AD mouse model
Authors: Lambracht‐Washington Doris , Fu Min , Rosenberg Roger N. 
Published: December 2020

AbstractBackgroundAlzheimer's disease (AD) has been associated with deposition of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. We have used a DNA Aβ42 trimer construct for immunization of 3xTg‐AD mice and found significant reduction of amyloid and tau pathology. Our working hypothesis is that DNA Aβ42 immunotherapy affects the gene expression profiles in brains of the treated mice, and is thus changing the microenvironment for possible AD prevention.MethodsMice were immunized with DNA Aβ42 trimer in 6‐week intervals during the experimental time line (24 months). Amyloid and tau pathology was evaluated in brains by immunohistochemistry. FFPE sections from DNA Aβ42 immunized 3xTg‐AD mice, non‐treated 3xTg‐AD controls and age and gender matched wild‐type controls (n=4/group) were used for RNA isolation and gene expression analysis using a Neuroinflammation gene panel (Nanostring nCounter).ResultsThe analysis of differently expressed genes in brains from 24 months old mice showed significant changes in transcript levels between non‐immunized AD mice and wild‐type controls for genes involved in microglia (Trem2, Ccl3, Ccl4, Csf1, CD68, CD84, Apoe, Itax1, Irf8, Ctse, Ctss) and astrocyte function (Lnc2, CD14, CD109, CD72, Vim, S100a10), cytokine and inflammatory signaling (Mpec1, Btk, Ssp1, Il1r1, Il6a, Inpp5d, Ch25h, Lilrb4a, Syk, Tgb1), matrix remodeling (Ptprc, Ssp1, Mmp2, Tgfb1), apoptosis (Bcl2a1, Bax, Casp4, Casp8, Fas), the innate (C1qa, C1qb, C3ar1, C4a, Btk, Tyrobp, Ly6a, Syk) and adaptive immune response (CD74, Btk, Ctse, Ctss, Fcer1g, Fcr2b, Inpp5d, Lilrb4a), consistent with an inflammatory phenotype in AD. These genes were also changed in the DNA Aβ42 immunized 3xTg‐AD mice compared to the non‐immunized AD mice nudging into direction of the wild‐type controls indicative of downregulation of inflammation due to immunotherapy, respectively. Significant changes were found for the immediate early genes, Bdnf, Arc, Homer1, Egr1 and c‐fos, involved in neuronal and neurotransmission pathways which were higher expressed in DNA Aβ42 immunized 3xTg‐AD mice and wild‐type controls compared to non‐immunized 3xTg‐AD mice indicating effects of DNA Aβ42 immunotherapy on synapse plasticity and memory formation.ConclusionThe multitude of changes after DNA Aβ42 immunization shows that this intervention has high potential for disease prevention.
Novel modulators of mitochondrial complex I ROS production as potential AD therapeutics
Authors: Green Jakob , Jiang Yuqi , Chen Qun , Lesnefsky Edward , Zhang Shijun 
Published: December 2020

AbstractBackgroundAmong the indicated pathogenic factors of Alzheimer’s disease (AD), mitochondrial dysfunction has been recognized as an essential contributor, especially for the late onset AD (LOAD). That this observed dysfunction is the cause or consequences of other AD‐related injuries has been debated, results from both sides are in agreement that the roles of mitochondria in connection with other AD pathologies are convergent. This strongly advocates that targeting mitochondrial dysfunction represents a promising approach to develop more effective AD therapeutics.MethodChemical probes based on a novel lead structure that showed promising neuroprotective activities both in vitro and in vivo AD models were designed and synthesized to identify protein targets. Mouse brain mitochondria were purified from C57BL/6 mice and complex I was further isolated. OXPHOS studies were conducted in purified mitochondria upon treatment with our lead compound. Photo‐affinity labeling studies were conducted upon incubation of chemical probes with complex I. Colocalization was studied using neuronal MC65 cells and chemical probes.ResultOXPHOS studies established that the lead compound only modulated the state 3 respiratory of pyruvate, the complex I substrate, but not succinate, the complex II substrate. Enzymatic studies of ETC also confirmed its selective modulation of complex I. The immunocytochemistry studies in MC65 cells indicated that the designed chemical probe localized to mitochondria. Protein labeling studies confirmed the direct interaction of the chemical probe with mitochondria complex I. Further analysis suggested that our chemical probe binds to the FMN binding site of complex I. Competition studies using the lead compound and NADH supported the selective labeling of complex I sub‐units.ConclusionStudies from in vitro, ex vivo, and in vivo models established that the lead compound selectively modulates the production of mitochondria complex I ROS without interfering with mitochondria membrane potential and bioenergetics, representing a novel mechanism of action. Chemical biology studies employing photo‐affinity labeling probes also confirmed the interaction of the probes with complex I and suggested the FMN binding site as the interaction site. Collectively, the results strongly encourage developing mitochondria complex I ROS modulators based on this novel chemical scaffold as potential AD therapeutics.
Mechanistic insights of novel NLRP3 inhibitors as potential AD therapeutics
Authors: Green Jakob , Blevins Hallie , Xu Yiming , Zhang Shijun 
Published: December 2020

AbstractBackgroundNLRP3 inflammasome is an essential component of innate immunity and its activation leads to the production of interleukin (IL)‐1β and IL‐18, and promotes inflammatory cell death. Recent studies have indicated a critical role for the NLRP3 inflammasome in the pathogenesis of Alzheimer’s disease (AD), where neuroinflammation has been recognized as an essential player. Thus, novel NLRP3 inhibitors represent a novel approach to develop AD therapeutics.MethodChemical probes based on a novel lead NLRP3 inhibitor that exhibits promising neuroprotective activities in AD models were synthesized to understand mode of action. Recombinant human NLRP3 protein was produced with his‐tag attached on both N‐ and C‐terminus. Photo‐affinity labeling and pull‐down assays were conducted using cell lysates of J774A.1 cells, and analyzed by silver staining and western blotting. Binding studies were performed using the recombinant human NLRP3 protein by microscale thermophoresis (MST) technique. ATPase activity of NLRP3 protein was analyzed by ADP glow assay. Drug affinity responsive target stability (DARTS) studies were performed using J774A.1 cell lysates.ResultChemical probes exhibited comparable potency as the lead compound to inhibit the release of IL‐1β from J774A.1 cells. Protein labeling and pull‐down studies clearly indicated the selective recognition of NLRP3 protein from J774A.1 cell lysates by the chemical probe. Further competition studies revealed that our lead inhibitor bins to NLRP3 differently than MCC950, the known NLRP3 inhibitor. Binding studies also confirmed the direct interaction of our inhibitor with the NLRP3 protein. DARTS studies also showed that upon incubation with the lead inhibitor, the stability of NLRP3 by pronase digestion was increased. We also confirmed that our NLRP3 inhibitor does not inhibit the ATPase activity of NLRP3.ConclusionChemical biology studies employing molecular biology, biochemical and biophysical techniques established that small molecule NLRP3 inhibitors derived from a novel chemical scaffold directly bind to the NLRP3 protein without interfering its ATPase activity, thus representing a novel mode of action. The results also indicated a distinct mode of action compared to the known NLRP3 inhibitor MCC950. Collectively, the results strongly encourage developing new analogs based on this novel chemical scaffold as novel NLRP3 inhibitors and potential AD therapeutics.
Mnemonic strategic training increases functional connectivity in amnestic mild cognitive impairment: Results from a randomized controlled trial
Authors: Simon Sharon Sanz , Hampstead Benjamin M , Silva Mariana PN , Duran Fabio LS , Fonseca Luciana Mascarenhas , Martin Maria Da Graça M , Avila Renata , Porto Fabio Henrique de Gobbi , Brucki Sonia Maria Dozzi , Martins Camila B , Tascone Lyssandra dos Santos , Amaro Edson , Busatto Geraldo , Bottino Cassio Machado de Campos 
Published: December 2020

AbstractBackgroundPrevious research showed that mnemonic strategy training (MST) improves cognitive performance in people with MCI, and has been associated with increased brain activation consonant with the cognitive processes engaged by the training, such as, semantic memory, decision‐making, cognitive control, face processing and social cognition. Despite the growing body of literature on MST in MCI, we are not aware of any randomized controlled study that have examined the effect of MST on resting‐state functional connectivity (FC). Therefore, the aim of the present study was to investigate the effect of MST, focused on face‐name associations, on resting‐state FC in older adults with MCI.MethodTwenty‐six amnestic MCI participants were randomized to one of two interventions: MST (N=14) or an Education Program (EP) (N=12). Both interventions were face‐to‐face, and occurred twice a week over two consecutive weeks (i.e., four sessions). Open‐eyes resting‐state functional magnetic resonance imaging (fMRI) was collected at pre‐ and post‐intervention. Nine regions of interest (ROIs) were selected a priori, based on areas that showed activation changes in a face‐name fMRI paradigm after MST (considering the contrast post>pre within the MST group, and in the comparison MST > EP). Changes in FC (post > pre, and pre > post) were examined through ROI‐to‐ROI analysis in the contrasts MST > EP and EP > MST. Analyses were conducted with CONN toolbox 17.f, and significant results were corrected for multiple comparison using false discovery rate (FDR).ResultAt post‐intervention, the MST group showed increased FC relative to the EP. Specifically, there was FC increase between the right inferior frontal gyrus (pars triangularis) and three ROIs in the left hemisphere: fusiform gyrus, temporal pole and orbitofrontal cortex. Within group analysis showed that FC increased after intervention only in the MST group, whereas the EP group showed decreased FC.ConclusionOur findings indicate that MST enhance FC in functionally relevant regions for the training; effects that support a general change in the innate connectivity that are not limited to a task‐specific condition. Our results extent the knowledge on the underlying mechanisms of MST, and may provide neurophysiological evidence of transfer.
Effects of APOE4 on Alzheimer’s disease, Lewy body disease, cerebral amyloid deposition and cognitive dysfunction
Authors: Jung Jin Ho , Jeong Seong Ho , Jeon Seun , Baik Kyoungwon , Lee Yang Hyun , Chung Seok Jong , Yoo Han Soo , Sohn Young H. , Lee Phil Hyu , Ye Byoung Seok 
Published: December 2020

AbstractBackgroundWe investigated the effects of apolipoprotein E e4 allele (APOE4) on the risk of Alzheimer’s disease (AD) and/or Lewy body disease (LBD), cerebral amyloid deposition, and cognitive dysfunction.MethodWe consecutively recruited 131 control subjects and 208 (110 non‐demented and 98 demented) patients with AD and/or LBD. Patients were categorized into typical AD (pure AD and Lewy body variant of AD), typical LBD (pure LBD and LBD with amyloid deposition), and typical AD with LBD based on clinical features and biomarker evidence from 18F‐Florbetaben (FBB) positron emission tomography (PET) and dopamine transporter PET. Logistic regression analysis was performed to investigate whether APOE4 increased the risk for each disease. General linear models (GLMs) were performed to investigate the independent and interaction effects of APOE4, typical AD and typical LBD on cerebral FBB deposition, cross‐sectional cognition and the rate of longitudinal cognitive decline.Result
APOE4 increased the risk of pure AD, AD with DLB, Lewy body variant of AD, and DLB with amyloid deposition, but did not increase the risk of pure LBD. In overall participants, APOE4 increased the risk of typical AD, but not typical LBD. APOE4, typical AD and typical LBD were positively associated with occipital FBB deposition; typical LBD was associated with higher occipital FBB deposition in the absence of typical AD; and APOE4 was associated with higher occipital FBB deposition in the presence of typical LBD. In GLMs for cross‐sectional cognition, APOE4 was associated with lower scores in verbal memory tests and higher clinical dementia rating sum of boxes (CDR‐SOB); it was associated with higher CDR‐SOB in the presence of typical LBD and lower scores in verbal memory tests in the presence of typical AD. APOE4 had no significant effects on the rates of longitudinal cognitive changes.Conclusion
APOE4 is associated with increased risks of AD and amyloid deposition but not with LBD. APOE4 and typical LBD are independently and synergistically associated with occipital amyloid deposition. APOE4 interacts with typical AD on poor memory function and interacts with typical LBD on higher CDR‐SOB cross‐sectionally, but did not have significant effects on longitudinal cognitive decline.
From systems biology to precision medicine: Leveraging heterogeneity
Authors: Saykin Andrew J. 
Published: December 2020

AbstractBackgroundKnowledge regarding cognitive decline in older adults with Alzheimer’s disease and related disorders (AD/ADRD) has accumulated rapidly but has not yielded disease modifying therapies or prevention. Clinical and biological heterogeneity are key challenges for identification of viable therapeutic targets. Some degree of mixed pathology is typical and it seems increasingly unlikely that targeting amyloid beta or tau alone will arrest AD progression. A precision medicine approach leveraging heterogeneity to tailor therapeutic strategies to an individual’s biological and phenotypic profile may prove more effective.MethodData and analytic approaches are growing rapidly, e.g., the ADNI cohort includes over 2000 individuals at various stages along the AD continuum followed longitudinally with various combinations of cognitive assessment, multi‐modal MRI, PET (FDG, amyloid & tau) as well as biosample collection for genomics, proteomics and metabolomics assays. Other clinic‐ and community‐ based cohort studies are also collecting rich high dimensional data sets of various types. Genomic data is accumulating on an unprecedented scale with the NIA AD initiatives anticipating the availability of 50,000 complete human genomes for analysis in the coming years. In parallel, human brain bank derived neuropathology and –omics data and model systems for AD are being developed, validated and leveraged for therapeutic development. Multi‐scale analytic strategies are needed to identify informative and actionable features from such large and high‐dimensional data sets.ResultsEvidence demonstrating that AD is biologically “complex,” involving multiple risk genes and biological pathways, and lifestyle factors leading to gene by environment interactions will be reviewed. One promising approach to addressing biological complexity is development of polygenic risk scores (PRS), which aggregates small susceptibility and protective effects from various genes and pathways into a composite measure. Second generation PRS are endophenotype‐specific targeting genetic influences on A/T/N, vascular, inflammatory and other AD related pathways.ConclusionMapping between phenotypic and biological heterogeneity remains a work in progress. The current NIA‐AA research framework emphasizes biomarker‐based classification, which is important for properly targeted clinical trials. We hypothesize that a systems approach incorporating polygenic profiling across disease dimensions may provide a basis for tailored therapeutics during the earliest stages of disease.
Imaging genomics in the ENIGMA Consortium
Authors: Thompson Paul M 
Published: December 2020

AbstractBackgroundWe offer an update on recent work by the ENIGMA Consortium, CHARGE Consortium, and UK Biobank ‐ and a worldwide alliance of over 1,400 scientists ‐ to understand how human genetic and epigenetic variation affect biomarkers of brain aging and Alzheimer's disease (AD).MethodFor 10 years, ENIGMA, CHARGE, and (more recently) the UK Biobank have screened the genomes and neuroimaging data from over 50,000 persons worldwide, as well as epigenome‐wide methylation data, to ask: (1) which common and rare genetic variants affect the brain throughout life? (2) which variants affect brain aging and biomarkers of AD ‐ such as hippocampal volume, longitudinal brain atrophy rates over time, and white matter hyperintensities? (3) how do AD risk variants, in APOE and elsewhere, affect brain biomarkers from youth to old age? For 10 years, we harmonized analyses of worldwide anaotmical MRI, diffusion MRI, rsFMRI, and EEG markers across over 200 cohorts, to examine how genome‐wide genomic variation and epigenetic variants affect structural and functional biomarkers of aging and AD.ResultGWAS in over 51,662 persons revealed over 200 common genetic variants affecting cortical architecture; of 255 nominally significant loci (P ≤ 5 × 10−8); 199 survived multiple testing correction (P ≤ 8.3 × 10−10; 187 surface area; 12 thickness). Variation in cortical and hippocampal structure is genetically correlated with cognitive function, AD, Parkinson’s disease, insomnia, major depression and ADHD. ENIGMA's Plasticity Working Group analyzed longitudinal MRI data of 10,163 persons aged 4 to 99 years, and discovered 5 genome‐wide significant loci and 15 genes influencing brain change rates at different times throughout life, and an age‐dependent effect of the APOE haplotype on brain structure. These age‐dependent influences of common genetic variants implicate immunological and metabolic processes. Epigenome‐wide screens revealed additional loci where methylation levels robustly associate with hippocampal volume in cohorts worldwide.ConclusionCommon genetic variants affect rates of brain change, hippocampal and regional cortical measures, throughout life; coordinated analyses of harmonized data are revealing the timing of genetic and epigenetic drivers of brain aging, and the first catalogs of common variants that associate with longitudinal markers of brain aging.