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  • 1
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    Online Resource
    Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration
    Springer Science and Business Media LLC ; 2020
    In:  Journal of Neuroinflammation Vol. 17, No. 1 ( 2020-12)
    Details
    In: Journal of Neuroinflammation, Springer Science and Business Media LLC, Vol. 17, No. 1 ( 2020-12)
    Abstract: Neuronal damage in acute CNS injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction in both mice and humans. However, whether and how the nature of the CNS insult—acute versus chronic—influences the astrocyte response, and whether astrocyte transcriptomic changes in these mouse models faithfully recapitulate the astrocyte reaction in human diseases remains to be elucidated. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, besides a shared “pan-injury” signature common to both types of conditions, and investigated the presence of these mouse astrocyte signatures in transcriptomic studies from human neurodegenerative diseases. Methods We performed a meta-analysis of 15 published astrocyte transcriptomic datasets from mouse models of acute injury ( n = 6) and chronic neurodegeneration ( n = 9) and identified pan-injury, acute, and chronic signatures, with both upregulated (UP) and downregulated (DOWN) genes. Next, we investigated these signatures in 7 transcriptomic datasets from various human neurodegenerative diseases. Results In mouse models, the number of UP/DOWN genes per signature was 64/21 for pan-injury and 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan-injury-UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction ( Gfap and Vim ), plus extracellular matrix (i.e., Cd44 , Lgals1, Lgals3, Timp1 ), and immune response (i.e., C3, Serping1, Fas, Stat1, Stat2, Stat3 ). The acute injury-UP signature was enriched in protein synthesis and degradation (both ubiquitin-proteasome and autophagy systems), intracellular trafficking, and anti-oxidant defense genes, whereas the acute injury-DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which are transcriptional repressors. The chronic neurodegeneration-UP signature was further enriched in astrocyte-secreted extracellular matrix proteins ( Lama4 , Cyr61 , Thbs4 ), while the DOWN signature included relevant genes such as Agl (glycogenolysis), S1pr1 (immune modulation), and Sod2 (anti-oxidant). Only the pan-injury-UP mouse signature was clearly present in some human neurodegenerative transcriptomic datasets. Conclusions Acute and chronic CNS injuries lead to distinct astrocyte gene expression programs beyond their common astrocyte reaction signature. However, caution should be taken when extrapolating astrocyte transcriptomic findings from mouse models to human diseases.
    Type of Medium: Online Resource
    ISSN: 1742-2094
    URL: Article
    DOI: 10.1186/s12974-020-01898-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2156455-3
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  • 2
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    Meta‐analysis of mouse transcriptomic studies supports a context‐dependent astrocyte reaction in acute CNS injury versus neurodegeneration : Molecular and cell biology/neuroinflammation
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. S2 ( 2020-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S2 ( 2020-12)
    Abstract: Neuronal damage in both acute central nervous system (CNS) injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction, which has traditionally been depicted with GFAP immunohistochemistry. However, whether and how the nature of the CNS insult —acute versus chronic — influences the astrocyte response is unknown. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, in addition to a shared “pan‐reactive” signature common to both types of conditions. Method We performed a meta‐analysis of 15 publicly available astrocyte transcriptomic datasets from acute injury (n=6) and chronic neurodegeneration (n=9) mouse models. We identified a pan‐reactive, acute injury‐ and chronic neurodegeneration‐specific signatures, with both up‐regulated (UP) and down‐regulated (DOWN) genes. Result The number of UP/DOWN genes for each signature was: 67/21 for pan‐reactive, 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan‐reactive‐UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction (i.e. Gfap, Vim ), plus extracellular matrix (i.e. Cd44, Lgals1, Lgals3, Timp1) , and immune response genes (i.e . C3, Serping1, Fas, Stat1, Stat2, Stat3 ). The acute injury‐UP signature was enriched in protein synthesis and degradation (both ubiquitin‐proteasome and autophagy systems), and anti‐oxidant defense genes, whereas the acute injury‐DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which were transcriptional repressors. The chronic neurodegeneration‐UP signature was further enriched in astrocyte‐secreted extracellular matrix proteins ( Lama4, Cyr61, Thbs4 ), while the DOWN set included genes such as Agl (glycogenolysis) , S1pr1 (immune modulation) and Sod2 (antioxidant). Conclusion We conclude that acute and chronic injuries to the CNS are associated with distinct astrocyte gene expression programs beyond their common astrocyte reaction signature.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S2
    DOI: 10.1002/alz.040699
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2201940-6
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  • 3
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    APOE and Alzheimer's disease: advances in genetics, pathophysiology, and therapeutic approaches
    Elsevier BV ; 2021
    In:  The Lancet Neurology Vol. 20, No. 1 ( 2021-01), p. 68-80
    Details
    In: The Lancet Neurology, Elsevier BV, Vol. 20, No. 1 ( 2021-01), p. 68-80
    Type of Medium: Online Resource
    ISSN: 1474-4422
    URL: Article
    DOI: 10.1016/S1474-4422(20)30412-9
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
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  • 4
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    Plasma biomarkers for prognosis of cognitive decline in patients with mild cognitive impairment
    Oxford University Press (OUP) ; 2022
    In:  Brain Communications Vol. 4, No. 4 ( 2022-07-04)
    Details
    In: Brain Communications, Oxford University Press (OUP), Vol. 4, No. 4 ( 2022-07-04)
    Abstract: Plasma-based biomarkers present a promising approach in the research and clinical practice of Alzheimer's disease as they are inexpensive, accessible and minimally invasive. In particular, prognostic biomarkers of cognitive decline may aid in planning and management of clinical care. Although recent studies have demonstrated the prognostic utility of plasma biomarkers of Alzheimer pathology or neurodegeneration, such as pTau-181 and NF-L, whether other plasma biomarkers can further improve prediction of cognitive decline is undetermined. We conducted an observational cohort study to determine the prognostic utility of plasma biomarkers in predicting progression to dementia for individuals presenting with mild cognitive impairment due to probable Alzheimer's disease. We used the Olink™ Proximity Extension Assay technology to measure the level of 460 circulating proteins in banked plasma samples of all participants. We used a discovery data set comprised 60 individuals with mild cognitive impairment (30 progressors and 30 stable) and a validation data set consisting of 21 stable and 21 progressors. We developed a machine learning model to distinguish progressors from stable and used 44 proteins with significantly different plasma levels in progressors versus stable along with age, sex, education and baseline cognition as candidate features. A model with age, education, APOE genotype, baseline cognition, plasma pTau-181 and 12 plasma Olink protein biomarker levels was able to distinguish progressors from stable with 86.7% accuracy (mean area under the curve = 0.88). In the validation data set, the model accuracy was 78.6%. The Olink proteins selected by the model included those associated with vascular injury and neuroinflammation (e.g. IL-8, IL-17A, TIMP-4, MMP7). In addition, to compare these prognostic biomarkers to those that are altered in Alzheimer's disease or other types of dementia relative to controls, we analyzed samples from 20 individuals with Alzheimer, 30 with non-Alzheimer dementias and 34 with normal cognition. The proteins NF-L and PTP-1B were significantly higher in both Alzheimer and non-Alzheimer dementias compared with cognitively normal individuals. Interestingly, the prognostic markers of decline at the mild cognitive impairment stage did not overlap with those that differed between dementia and control cases. In summary, our findings suggest that plasma biomarkers of inflammation and vascular injury are associated with cognitive decline. Developing a plasma biomarker profile could aid in prognostic deliberations and identify individuals at higher risk of dementia in clinical practice.
    Type of Medium: Online Resource
    ISSN: 2632-1297
    URL: Article
    DOI: 10.1093/braincomms/fcac155
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 3020013-1
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  • 5
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    Plasma biomarkers of neuroinflammation and vascular injury predict cognitive decline in patients with mild cognitive impairment : Biomarkers (non‐neuroimaging)/Plasma/Serum/Urine biomarkers
    Wiley ; 2020
    In:  Alzheimer's & Dementia Vol. 16, No. S5 ( 2020-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 16, No. S5 ( 2020-12)
    Abstract: The development of robust blood‐based biomarkers for pathological and clinical characterization of Alzheimer’s disease (AD) is necessary, particularly as therapeutic approaches shift towards early intervention. Novel, ultra‐sensitive Olink TM technology allows for high‐throughput quantification of protein signatures in biofluids. In this study, we examined the utility of this technology to identify plasma biomarkers associated with longitudinal cognitive performance in individuals presenting with mild cognitive impairment (MCI). Methods 60 participants from the Massachusetts ADRC Longitudinal Cohort with a clinical diagnosis of MCI, baseline global CDR of 0.5, and at least five annual follow‐up evaluations were classified into two groups based on their global CDR trajectory: MCI‐decline (an increase in global CDR from 0.5 to 1) and MCI‐stable (no change in global CDR). Five Olink TM Proximity Extension Assay (PEA) panels were assessed for technical reliability and used to quantify 460 plasma proteins at baseline visit. We built statistical models to identify proteins whose plasma levels were predictive of future cognitive decline, and used machine‐learning to evaluate the utility of these proteins for predicting conversion from MCI to dementia, relative to clinical and demographic predictors. Result Olink TM panels exhibited excellent technical precision and plate‐to‐plate replication. Of the 460 proteins measured, 60 did not pass quality control thresholds. A final model adjusting for age and sex identified 14 proteins with a significant fold‐change in MCI‐decline compared to MCI‐stable (p 〈 0.05), including NfL, CX3CL1, M‐CSF, VEGF‐A, IL‐8, NOS3, TNFRSF12A, and PHOSPHO1. An additional 10 proteins approached significance (p 〈 0.1), primarily representative of inflammatory and vascular processes. Addition of these proteins to a supervised classification model informed by baseline cognitive measured substantially improved the overall accuracy from 63% to 83.3% (AUC: 0.88, sensitivity: 0.76, specificity: 0.87). Conclusion Our findings suggest that plasma biomarkers of neuroinflammation and vascular injury have value as predictors of MCI‐to‐dementia progression. These circulating biomarkers may reflect CNS processes, blood‐brain barrier dysfunction, and/or systemic inflammation that drive AD associated pathophysiologies, or represent comorbid vascular pathologies. Developing a plasma biomarker panel could aid in prognostic deliberations by identifying MCI individuals at higher risk of progressing to dementia in clinical practice.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v16.S5
    DOI: 10.1002/alz.046134
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2201940-6
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  • 6
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    Characterization of glial responses in Alzheimer’s disease with cyclic multiplex fluorescent immunohistochemistry and machine learning
    Wiley ; 2021
    In:  Alzheimer's & Dementia Vol. 17, No. S3 ( 2021-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 17, No. S3 ( 2021-12)
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v17.S3
    DOI: 10.1002/alz.050902
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 7
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    Transcriptomic Differences in Endothelial Cells Across Five Brain Regions in Normal Aging and Alzheimer's Disease
    Wiley ; 2022
    In:  Alzheimer's & Dementia Vol. 18, No. S3 ( 2022-12)
    Details
    In: Alzheimer's & Dementia, Wiley, Vol. 18, No. S3 ( 2022-12)
    Abstract: Altered cerebral vasculature is recognized as a key feature of Alzheimer’s disease (AD) neuropathology, with current evidence suggesting a diverse collection of changes including aberrant angiogenesis, vascular pruning, inflammation, senescence, and other remodeling events. Previous studies examining the endothelial cell transcriptome in AD have been limited to 1‐2 brain regions and hampered by low numbers of isolated endothelial cell nuclei, potentially missing relevant regional heterogeneity. We hypothesized that such regional heterogeneity in endothelial cell gene expression in the normal aging brain may contribute to the varied vascular responses to AD neuropathology. Method Nuclei were isolated from five brain areas in subjects with increasing AD pathology (n=32 donors). The five brain areas chosen represent the hierarchical accumulation of tau pathology in AD: entorhinal cortex 〉 inferior temporal gyrus 〉 prefrontal cortex 〉 secondary visual cortex 〉 primary visual cortex. All subjects had detailed p‐tau, in vitro tau seeding, and amyloid‐beta plaque measurements available. Nuclei were FACS sorted to exclude NeuN+ and Olig2+ cells, and the resulting neuron‐ and oligodendrocyte‐depleted fraction was subject to single‐nucleus RNAseq. Endothelial cell nuclei were identified based on high von Willebrand factor expression and filtered to exclude contaminating glia, yielding a dataset comprised of 51,586 total nuclei. Result Transcriptomic analysis confirmed that endothelial cells share a core set of commonly upregulated genes across the five brain regions compared to other cell types. However, there is also regional heterogeneity with 193‐311 differentially upregulated genes expressed in endothelial cells within each brain area relative to all other areas. Compared to normal aging brain, endothelial cells from AD donors downregulated 962 genes and upregulated 936 genes that are enriched in vasculogenesis, blood‐brain barrier maintenance, senescence, and leukocyte interactions. Further analysis indicates regional differences in upregulation of these pathways and highlights the relationship to disease burden. Conclusion This dataset demonstrates a previously unrecognized regional heterogeneity in endothelial cell transcriptome in the normal aging human brain. These regional differences may impact the endothelial cell response to the local AD pathology. This dataset will inform ongoing research efforts to unravel the molecular underpinnings of AD‐induced endothelial cell dysfunction.
    Type of Medium: Online Resource
    ISSN: 1552-5260 , 1552-5279
    URL: Issue
    URL: Article
    DOI: 10.1002/alz.v18.S3
    DOI: 10.1002/alz.059018
    Language: English
    Publisher: Wiley
    Publication Date: 2022
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  • 8
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    Systematic review of human post‐mortem immunohistochemical studies and bioinformatics analyses unveil the complexity of astrocyte reaction in Alzheimer's disease
    Wiley ; 2022
    In:  Neuropathology and Applied Neurobiology Vol. 48, No. 1 ( 2022-02)
    Details
    In: Neuropathology and Applied Neurobiology, Wiley, Vol. 48, No. 1 ( 2022-02)
    Abstract: Reactive astrocytes in Alzheimer's disease (AD) have traditionally been demonstrated by increased glial fibrillary acidic protein (GFAP) immunoreactivity; however, astrocyte reaction is a complex and heterogeneous phenomenon involving multiple astrocyte functions beyond cytoskeletal remodelling. To better understand astrocyte reaction in AD, we conducted a systematic review of astrocyte immunohistochemical studies in post‐mortem AD brains followed by bioinformatics analyses on the extracted reactive astrocyte markers. Methods NCBI PubMed, APA PsycInfo and WoS‐SCIE databases were interrogated for original English research articles with the search terms ‘Alzheimer's disease’ AND ‘astrocytes.’ Bioinformatics analyses included protein–protein interaction network analysis, pathway enrichment, and transcription factor enrichment, as well as comparison with public human ‐omics datasets. Results A total of 306 articles meeting eligibility criteria rendered 196 proteins, most of which were reported to be upregulated in AD vs control brains. Besides cytoskeletal remodelling (e.g., GFAP), bioinformatics analyses revealed a wide range of functional alterations including neuroinflammation (e.g., IL6, MAPK1/3/8 and TNF), oxidative stress and antioxidant defence (e.g., MT1A/2A, NFE2L2, NOS1/2/3, PRDX6 and SOD1/2), lipid metabolism (e.g., APOE, CLU and LRP1), proteostasis (e.g., cathepsins, CRYAB and HSPB1/2/6/8), extracellular matrix organisation (e.g., CD44, MMP1/3 and SERPINA3), and neurotransmission (e.g., CHRNA7, GABA, GLUL, GRM5, MAOB and SLC1A2), among others. CTCF and ESR1 emerged as potential transcription factors driving these changes. Comparison with published ‐omics datasets validated our results, demonstrating a significant overlap with reported transcriptomic and proteomic changes in AD brains and/or CSF. Conclusions Our systematic review of the neuropathological literature reveals the complexity of AD reactive astrogliosis. We have shared these findings as an online resource available at www.astrocyteatlas.org .
    Type of Medium: Online Resource
    ISSN: 0305-1846 , 1365-2990
    URL: Issue
    URL: Article
    DOI: 10.1111/nan.v48.1
    DOI: 10.1111/nan.12753
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2008293-9
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  • 9
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    Development and Evaluation of a Natural Language Processing Annotation Tool to Facilitate Phenotyping of Cognitive Status in Electronic Health Records: Diagnostic Study
    JMIR Publications Inc. ; 2022
    In:  Journal of Medical Internet Research Vol. 24, No. 8 ( 2022-8-30), p. e40384-
    Details
    In: Journal of Medical Internet Research, JMIR Publications Inc., Vol. 24, No. 8 ( 2022-8-30), p. e40384-
    Abstract: Electronic health records (EHRs) with large sample sizes and rich information offer great potential for dementia research, but current methods of phenotyping cognitive status are not scalable. Objective The aim of this study was to evaluate whether natural language processing (NLP)–powered semiautomated annotation can improve the speed and interrater reliability of chart reviews for phenotyping cognitive status. Methods In this diagnostic study, we developed and evaluated a semiautomated NLP-powered annotation tool (NAT) to facilitate phenotyping of cognitive status. Clinical experts adjudicated the cognitive status of 627 patients at Mass General Brigham (MGB) health care, using NAT or traditional chart reviews. Patient charts contained EHR data from two data sets: (1) records from January 1, 2017, to December 31, 2018, for 100 Medicare beneficiaries from the MGB Accountable Care Organization and (2) records from 2 years prior to COVID-19 diagnosis to the date of COVID-19 diagnosis for 527 MGB patients. All EHR data from the relevant period were extracted; diagnosis codes, medications, and laboratory test values were processed and summarized; clinical notes were processed through an NLP pipeline; and a web tool was developed to present an integrated view of all data. Cognitive status was rated as cognitively normal, cognitively impaired, or undetermined. Assessment time and interrater agreement of NAT compared to manual chart reviews for cognitive status phenotyping was evaluated. Results NAT adjudication provided higher interrater agreement (Cohen κ=0.89 vs κ=0.80) and significant speed up (time difference mean 1.4, SD 1.3 minutes; P 〈 .001; ratio median 2.2, min-max 0.4-20) over manual chart reviews. There was moderate agreement with manual chart reviews (Cohen κ=0.67). In the cases that exhibited disagreement with manual chart reviews, NAT adjudication was able to produce assessments that had broader clinical consensus due to its integrated view of highlighted relevant information and semiautomated NLP features. Conclusions NAT adjudication improves the speed and interrater reliability for phenotyping cognitive status compared to manual chart reviews. This study underscores the potential of an NLP-based clinically adjudicated method to build large-scale dementia research cohorts from EHRs.
    Type of Medium: Online Resource
    ISSN: 1438-8871
    URL: Article
    DOI: 10.2196/40384
    Language: English
    Publisher: JMIR Publications Inc.
    Publication Date: 2022
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  • 10
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    Effect of APOE alleles on the glial transcriptome in normal aging and Alzheimer’s disease
    Springer Science and Business Media LLC ; 2021
    In:  Nature Aging Vol. 1, No. 10 ( 2021-10-11), p. 919-931
    Details
    In: Nature Aging, Springer Science and Business Media LLC, Vol. 1, No. 10 ( 2021-10-11), p. 919-931
    Type of Medium: Online Resource
    ISSN: 2662-8465
    URL: Article
    DOI: 10.1038/s43587-021-00123-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 3029419-8
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