scholarly journals Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Andre Altmann ◽  
David M Cash ◽  
Martina Bocchetta ◽  
Carolin Heller ◽  
Regina Reynolds ◽  
...  
Keyword(s):  
Gene Expression ◽  
Frontotemporal Dementia ◽  
Cell Function ◽  
Neurodegenerative Disorder ◽  
Positive Association ◽  
Negative Association ◽  
Marker Genes ◽  
Gene Set ◽  
Genetic Groups ◽  
Cortical Regions

Abstract Frontotemporal dementia is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of frontotemporal dementia, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work, we combined gene expression data for 16 772 genes from the Allen Institute for Brain Science atlas with brain maps of grey matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic Frontotemporal dementia Initiative study. No significant association was seen between C9orf72, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. After adjusting for spatial autocorrelation, between 1000 and 5000 genes showed a negative or positive association with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9Orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9Orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative association with genes involved in mitochondrial function, and a positive association with genes involved in vascular and glial cell function in each of the genetic groups. A set of 423 and 700 genes showed significant positive and negative association, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in frontotemporal dementia than previously assumed, and in the case of the positively associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood–brain barrier, respectively.

scholarly journals Analysis of brain atrophy and local gene expression in genetic frontotemporal dementia

2019 ◽  
Author(s):  
Andre Altmann ◽  
David M Cash ◽  
Martina Bocchetta ◽  
Carolin Heller ◽  
Regina Reynolds ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cell ◽  
Frontotemporal Dementia ◽  
Negative Correlation ◽  
Cell Types ◽  
Marker Genes ◽  
Positive Correlation ◽  
Gene Set ◽  
Genetic Groups ◽  
Cortical Regions

AbstractFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder characterized by neuronal loss in the frontal and temporal lobes. Despite progress in understanding which genes are associated with the aetiology of FTD, the biological basis of how mutations in these genes lead to cell loss in specific cortical regions remains unclear. In this work we combined gene expression data for 16,772 genes from the Allen Institute for Brain Science atlas with brain maps of gray matter atrophy in symptomatic C9orf72, GRN and MAPT mutation carriers obtained from the Genetic FTD Initiative study. No significant association was seen between (C9orf2, GRN and MAPT expression and the atrophy patterns in the respective genetic groups. Between 1,000 and 5,000 genes showed a negative or positive correlation with the atrophy pattern within each individual genetic group, with the most significantly associated genes being TREM2, SSBP3 and GPR158 (negative association in C9orf72, GRN and MAPT respectively) and RELN, MXRA8 and LPA (positive association in C9orf72, GRN and MAPT respectively). An overrepresentation analysis identified a negative correlation with genes involved in mitochondrial function, and a positive correlation with genes involved in vascular and glial cell function in each of the genetic groups. After adjusting for spatial autocorrelation, a set of 423 and 700 genes showed significant positive and negative correlation, respectively, with atrophy patterns in all three maps. The gene set with increased expression in spared cortical regions was enriched for neuronal and microglial genes, while the gene set with increased expression in atrophied regions was enriched for astrocyte and endothelial cell genes. Our analysis suggests that these cell types may play a more active role in the onset of neurodegeneration in FTD than previously assumed, and in the case of the positively-associated cell marker genes, potentially through emergence of neurotoxic astrocytes and alteration in the blood-brain barrier respectively.Abbreviated summaryAltmann et al. investigated the concordance between spatial cortical gene expression in healthy subjects and atrophy patterns in genetic frontotemporal dementia. They found that elevated gene expression of endothelial cell and astrocyte-related genes in regions with atrophy, suggesting a role of these cell types in the aetiology of frontotemporal dementia.

scholarly journals Plasma tau is increased in frontotemporal dementia

2018 ◽  
Vol 89 (8) ◽  
pp. 804-807 ◽  
Author(s):  
Martha S Foiani ◽  
Ione OC Woollacott ◽  
Carolin Heller ◽  
Martina Bocchetta ◽  
Amanda Heslegrave ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Single Molecule ◽  
Neurodegenerative Disorder ◽  
Primary Progressive Aphasia ◽  
Personality Change ◽  
Neurofilament Light Chain ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Brain Volumes ◽  
Genetic Groups

BackgroundFrontotemporal dementia (FTD) is a heterogeneous neurodegenerative disorder presenting clinically with personality change (behavioural variant FTD (bvFTD)) or language deficits (primary progressive aphasia (PPA)). About a third of FTD is familial with mutations in GRN, MAPT and C9orf72 being the major genetic causes. Robust biomarkers of the underlying pathology are still lacking in FTD with no markers currently being able to distinguish those with tau and TDP-43 inclusions during life.MethodsThis study used an ultrasensitive single molecule methodology to measure plasma tau concentrations in 176 participants: 71 with bvFTD, 83 with PPA and 22 healthy controls. The patient group included 36 with pathogenic mutations in either MAPT (n=12), GRN (n=9) or C9orf72 (n=15). Group comparisons were performed between clinical and genetic groups and controls using a linear regression model with bias-corrected bootstrap CIs. Correlative analyses were performed to investigate associations with measures of disease severity and progression.ResultsHigher plasma tau concentrations were seen in bvFTD (mean 1.96 (SD 1.07) pg/mL) and PPA (2.65 (2.15) pg/mL) compared with controls (1.67 (0.50) pg/mL). Investigating the PPA group further showed significantly higher levels compared with controls in each of the PPA subtypes (non-fluent, semantic and logopenic variants, as well as a fourth group not meeting criteria for one of the three main variants). In the genetic groups, only the MAPT group had significantly increased concentrations (2.62 (1.39) pg/mL) compared with controls. No significant correlations were seen with cross-sectional or longitudinal brain volumes, serum neurofilament light chain concentrations or disease duration.ConclusionPlasma tau levels are increased in FTD in all clinical groups, but in the genetic subtypes only in MAPT mutations, the group of patients who definitively have tau pathology at postmortem. Future studies will be required in pathologically confirmed cohorts to investigate this association further, and whether plasma tau will be helpful in differentiating patients with FTD with tau from those with other pathologies.

Perceived Overprotection and Its Association With Quality of Life in Dementia

GeroPsych ◽  
2019 ◽  
Vol 32 (3) ◽  
pp. 125-134
Author(s):  
Mechthild Niemann-Mirmehdi ◽  
Andreas Häusler ◽  
Paul Gellert ◽  
Johanna Nordheim
Keyword(s):  
Quality Of Life ◽  
Patient Autonomy ◽  
Positive Association ◽  
Well Being ◽  
Negative Association ◽  
Significant Positive Association ◽  
Cross Sectional ◽  
People With Dementia ◽  
Mental Well Being

Abstract. To date, few studies have focused on perceived overprotection from the perspective of people with dementia (PwD). In the present examination, the association of perceived overprotection in PwD is examined as an autonomy-restricting factor and thus negative for their mental well-being. Cross-sectional data from the prospective DYADEM study of 82 patient/partner dyads (mean age = 74.26) were used to investigate the association between overprotection, perceived stress, depression, and quality of life (QoL). The analyses show that an overprotective contact style with PwD has a significant positive association with stress and depression, and has a negative association with QoL. The results emphasize the importance of avoiding an overprotective care style and supporting patient autonomy.

Domestic Integration and Suicide in the Provinces of Canada

Crisis ◽  
1999 ◽  
Vol 20 (2) ◽  
pp. 59-63 ◽  
Author(s):  
Antoon A. Leenaars ◽  
David Lester
Keyword(s):  
Social Factors ◽  
Positive Association ◽  
Negative Association ◽  
Birth Rates ◽  
Marriage Rates ◽  
Suicide Rates ◽  
The Social ◽  
Divorce Rates ◽  
Low Levels ◽  
Over Time

Canada's rate of suicide varies from province to province. The classical theory of suicide, which attempts to explain the social suicide rate, stems from Durkheim, who argued that low levels of social integration and regulation are associated with high rates of suicide. The present study explored whether social factors (divorce, marriage, and birth rates) do in fact predict suicide rates over time for each province (period studied: 1950-1990). The results showed a positive association between divorce rates and suicide rates, and a negative association between birth rates and suicide rates. Marriage rates showed no consistent association, an anomaly as compared to research from other nations.

Autoimmunity and Frontotemporal Dementia

2018 ◽  
Vol 15 (7) ◽  
pp. 602-609 ◽  
Author(s):  
Antonella Alberici ◽  
Viviana Cristillo ◽  
Stefano Gazzina ◽  
Alberto Benussi ◽  
Alessandro Padovani ◽  
...  
Keyword(s):  
Frontotemporal Dementia ◽  
Language Impairment ◽  
Neurodegenerative Disorder ◽  
Chromosome 9 ◽  
Bibliographic Databases ◽  
Extensive Literature ◽  
Genetic Studies ◽  
Reading Frame ◽  
Current State ◽  
Extensive Evaluation

Background: Frontotemporal Dementia (FTD) is a neurodegenerative disorder which asymmetrically affects the frontotemporal lobe, characterized by behavioural abnormalities, language impairment, and deficits of executive functions. Genetic studies identified mutations causing the disease, namely Microtubule Associated Protein Tau (MAPT), Granulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) mutations, which contributed to elucidate the molecular pathways involved in brain depositions of either Tau or TAR DNA-binding protein 43 (TDP43) inclusions. However, in the majority of sporadic FTD patients, the mechanisms triggering Tau or TDP43 protein deposition are still to be uncovered. Objective: We aimed to present an extensive evaluation of literature data on immune homeostasis in FTD, in order to provide potentially evidence-based approaches for a disease still orphan of any treatment. Methods: A structured search of bibliographic databases from peer-reviewed literature was pursued focusing on autoimmunity in the brain and FTD. Results: One-hundred-fourteen papers were included in this review. The majority of studies (32) were represented by extensive literature revision on immunity, central nervous system (CNS) and autoimmunity; neuroimaging papers (11) in autoimmune diseases were evaluated, and immunomodulatory approaches (25) were revised. Six papers were found specifically related to FTD and autoimmune hypothesis, the other papers referring to current state of art on FTD. Conclusion: Overall this review contribute to expand the knowledge of a possible immune hypothesis in FTD, suggesting therapeutic perspectives in autoimmune related neurodegeneration, to reduce or revert the disease.

Utilizing Cancer - Functional Gene Set - Compound Networks to Identify Putative Drugs for Breast Cancer

2018 ◽  
Vol 21 (2) ◽  
pp. 74-83
Author(s):  
Tzu-Hung Hsiao ◽  
Yu-Chiao Chiu ◽  
Yu-Heng Chen ◽  
Yu-Ching Hsu ◽  
Hung-I Harry Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cancer Therapy ◽  
Cancer Treatment ◽  
Cancer Survival ◽  
Expression Profiles ◽  
Functional Gene ◽  
Gene Set Enrichment Analysis ◽  
Gene Set ◽  
Gene Sets

Aim and Objective: The number of anticancer drugs available currently is limited, and some of them have low treatment response rates. Moreover, developing a new drug for cancer therapy is labor intensive and sometimes cost prohibitive. Therefore, “repositioning” of known cancer treatment compounds can speed up the development time and potentially increase the response rate of cancer therapy. This study proposes a systems biology method for identifying new compound candidates for cancer treatment in two separate procedures. Materials and Methods: First, a “gene set–compound” network was constructed by conducting gene set enrichment analysis on the expression profile of responses to a compound. Second, survival analyses were applied to gene expression profiles derived from four breast cancer patient cohorts to identify gene sets that are associated with cancer survival. A “cancer–functional gene set– compound” network was constructed, and candidate anticancer compounds were identified. Through the use of breast cancer as an example, 162 breast cancer survival-associated gene sets and 172 putative compounds were obtained. Results: We demonstrated how to utilize the clinical relevance of previous studies through gene sets and then connect it to candidate compounds by using gene expression data from the Connectivity Map. Specifically, we chose a gene set derived from a stem cell study to demonstrate its association with breast cancer prognosis and discussed six new compounds that can increase the expression of the gene set after the treatment. Conclusion: Our method can effectively identify compounds with a potential to be “repositioned” for cancer treatment according to their active mechanisms and their association with patients’ survival time.

Gene Set Correlation Analysis and Visualization Using Gene Expression Data

2020 ◽  
Vol 15 ◽  
Author(s):  
Chen-An Tsai ◽  
James J. Chen
Keyword(s):  
Gene Expression ◽  
Correlation Analysis ◽  
Gene Expression Data ◽  
Differentially Expressed Gene ◽  
Differentially Expressed ◽  
Superior Performance ◽  
Expression Data ◽  
Gene Set ◽  
Gene Sets ◽  
Set Correlation

Background: Gene set enrichment analyses (GSEA) provide a useful and powerful approach to identify differentially expressed gene sets with prior biological knowledge. Several GSEA algorithms have been proposed to perform enrichment analyses on groups of genes. However, many of these algorithms have focused on identification of differentially expressed gene sets in a given phenotype. Objective: In this paper, we propose a gene set analytic framework, Gene Set Correlation Analysis (GSCoA), that simultaneously measures within and between gene sets variation to identify sets of genes enriched for differential expression and highly co-related pathways. Methods: We apply co-inertia analysis to the comparisons of cross-gene sets in gene expression data to measure the costructure of expression profiles in pairs of gene sets. Co-inertia analysis (CIA) is one multivariate method to identify trends or co-relationships in multiple datasets, which contain the same samples. The objective of CIA is to seek ordinations (dimension reduction diagrams) of two gene sets such that the square covariance between the projections of the gene sets on successive axes is maximized. Simulation studies illustrate that CIA offers superior performance in identifying corelationships between gene sets in all simulation settings when compared to correlation-based gene set methods. Result and Conclusion: We also combine between-gene set CIA and GSEA to discover the relationships between gene sets significantly associated with phenotypes. In addition, we provide a graphical technique for visualizing and simultaneously exploring the associations of between and within gene sets and their interaction and network. We then demonstrate integration of within and between gene sets variation using CIA and GSEA, applied to the p53 gene expression data using the c2 curated gene sets. Ultimately, the GSCoA approach provides an attractive tool for identification and visualization of novel associations between pairs of gene sets by integrating co-relationships between gene sets into gene set analysis.

scholarly journals Can Anhedonia Be Considered a Suicide Risk Factor? A Review of the Literature

Medicina ◽  
2019 ◽  
Vol 55 (8) ◽  
pp. 458 ◽  
Author(s):  
Bonanni ◽  
Gualtieri ◽  
Lester ◽  
Falcone ◽  
Nardella ◽  
...  
Keyword(s):  
Suicidal Behavior ◽  
Affective Disorders ◽  
Suicide Attempts ◽  
Positive Association ◽  
Negative Association ◽  
Schizophrenia Spectrum Disorders ◽  
Post Traumatic Stress ◽  
Significant Positive Association ◽  
Search Terms ◽  
Schizophrenia Spectrum

Background and Objectives: At present, data collected from the literature about suicide and anhedonia are controversial. Some studies have shown that low levels of anhedonia are associated with serious suicide attempts and death by suicide, while other studies have shown that high levels of anhedonia are associated with suicide. Materials and Methods: For this review, we searched PubMed, Medline, and ScienceDirect for clinical studies published from 1 January 1990 to 31 December 2018 with the following search terms used in the title or in the abstract: “anhedonia AND suicid*.” We obtained a total of 155 articles; 133 items were excluded using specific exclusion criteria, the remaining 22 articles included were divided into six groups based on the psychiatric diagnosis: mood disorders, schizophrenia spectrum disorders, post-traumatic stress disorder (PTSD), other diagnoses, attempted suicides, and others (healthy subjects). Results: The results of this review reveal inconsistencies. Some studies reported that high anhedonia scores were associated with suicidal behavior (regardless of the diagnosis), while other studies found that low anhedonia scores were associated with suicidal behavior, and a few studies reported no association. The most consistent association between anhedonia and suicidal behavior was found for affective disorders (7 of 7 studies reported a significant positive association) and for PTSD (3 of 3 studies reported a positive association). In the two studies of patients with schizophrenia, one found no association, and one found a negative association. For patients who attempted suicide (undiagnosed), one study found a positive association, one a positive association only for depressed attempters, and one a negative association. Conclusions: We found the most consistent positive association for patients with affective disorders and PTSD, indicating that the assessment of anhedonia may be useful in the evaluation of suicidal risk.

scholarly journals Multi-view feature selection for identifying gene markers: a diversified biological data driven approach

2020 ◽  
Vol 21 (S18) ◽  
Author(s):  
Sudipta Acharya ◽  
Laizhong Cui ◽  
Yi Pan
Keyword(s):  
Gene Expression ◽  
Feature Selection ◽  
Gene Selection ◽  
Marker Gene ◽  
Biological Data ◽  
Protein Interaction Data ◽  
Marker Genes ◽  
Data Sets ◽  
Gene Markers ◽  
Multi Objective

Abstract Background In recent years, to investigate challenging bioinformatics problems, the utilization of multiple genomic and proteomic sources has become immensely popular among researchers. One such issue is feature or gene selection and identifying relevant and non-redundant marker genes from high dimensional gene expression data sets. In that context, designing an efficient feature selection algorithm exploiting knowledge from multiple potential biological resources may be an effective way to understand the spectrum of cancer or other diseases with applications in specific epidemiology for a particular population. Results In the current article, we design the feature selection and marker gene detection as a multi-view multi-objective clustering problem. Regarding that, we propose an Unsupervised Multi-View Multi-Objective clustering-based gene selection approach called UMVMO-select. Three important resources of biological data (gene ontology, protein interaction data, protein sequence) along with gene expression values are collectively utilized to design two different views. UMVMO-select aims to reduce gene space without/minimally compromising the sample classification efficiency and determines relevant and non-redundant gene markers from three cancer gene expression benchmark data sets. Conclusion A thorough comparative analysis has been performed with five clustering and nine existing feature selection methods with respect to several internal and external validity metrics. Obtained results reveal the supremacy of the proposed method. Reported results are also validated through a proper biological significance test and heatmap plotting.

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