Transcriptomes in Peripheral Blood Mononuclear Cells of Dementia and Alzheimer Patients
ABSTRACT: With the aging population, there is a growing focus on dementia, especially Alzheimer’s disease (AD). The molecular basis underlying the pathogenesis of AD is gradually being elucidated. Increasing evidence has shown that the immunological function of leukocytes plays a crucial role in the development of neurodegenerative disorders. However, there have been few studies among the Taiwanese population. The aim of this study was to investigate potential biomarkers for early diagnosis of Alzheimer’s disease from blood leukocytes. Overall design: The peripheral blood mononuclear cells (PBMC) transcriptomes from 5 patients with mild cognitive impairment (MCI), 4 AD, as well as 4 normal controls (NC), were analyzed by microarray analysis.
Project description:With the aging population, there is a growing focus on dementia, especially Alzheimer’s disease (AD). The molecular basis underlying the pathogenesis of AD is gradually being elucidated. Increasing evidence has shown that the immunological function of leukocytes plays a crucial role in the development of neurodegenerative disorders. However, there have been few studies among the Taiwanese population. The aim of this study was to investigate potential biomarkers for early diagnosis of Alzheimer’s disease from blood leukocytes. Experiment Overall Design: The peripheral blood mononuclear cells (PBMC) transcriptomes from 5 patients with mild cognitive impairment (MCI), 4 AD, as well as 4 normal controls (NC), were analyzed by microarray analysis.
Project description:Due to an increasingly aging population, the incidence of dementias such as Alzheimer’s disease are steadily rising, with recent estimates predicting >115million dementia sufferers by 2050. The ability to identify early markers in blood, which appear before the onset of clinical symptoms is of considerable interest to allow early intervention, particularly in “high risk” groups such as those with Type 2 Diabetes (T2D). Here we present longitudinal genome-wide DNA methylation data comparing 18 elderly individuals with T2D who developed pre-symptomatic dementia within an 18 month period following baseline assessment to 18 age, sex and education matched controls who maintained normal cognitive function. We identified a highly significant overlap in the effect size of the top-ranked methylation sites at baseline and follow-up, and identified 8 robust loci, some of which have been previously related to neurodegenerative processes, which were consistently differentially methylated prior to symptoms at baseline, and at 18 month follow up, when a diagnosis of pre-symptomatic dementia had been provided. Finally we show a significant overlap in the effect size of the top-ranked methylation sites in converters, only after they develop symptoms of pre-symptomatic dementia, with changes at the same loci in blood samples from patients with clinically-diagnosed Alzheimer’s disease. Overall design: 18 elderly individuals with T2D who developed pre-symptomatic dementia within 18 months following baseline assessment and 18 age, sex and education matched controls who maintained normal cognitive function
Project description:Background: Mild cognitive impairment (MCI) is an intermediate state between normal aging, and Alzheimer’s disease, and other dementias. Early detection of dementia, and MCI, is a crucial issue in terms of secondary prevention. Blood biomarker detection is a possible way for early detection of MCI. Although disease biomarkers are detected by, in general, using single molecular analysis such as t-test, another possible approach is based on interaction between molecules. Results: Differential correlation analysis, which detects difference on correlation of two variables in case/control study, was carried out to the dataset with 745 microRNAs (miRNAs) from plasma samples of 30 age-matched controls and 23 MCI patients in Japan. The 20 pairs of miRNAs, which consist of 20 miRNAs, were selected as MCI markers. Two pairs of miRNAs (hsa-miR-191 and hsa-miR-101, and hsa-miR-103 and hsa-miR-222) out of 20 attained the highest area under the curve (AUC) value of 0.962 for MCI detection. Other two miRNA pairs that include hsa-miR-191 and hsa-miR-125b also attained high AUC value of ≥ 0.95. Pathway analysis was performed to the MCI markers for further understanding of biological implications. As a result, collapsed correlation on hsa-miR-191 and emerged correlation on hsa-miR-125b may have key role in MCI, and dementia progression. Conclusion: Differential correlation analysis, a bioinformatics tool to elucidate complicated and interdependent biological systems behind diseases, detects effective MCI markers that cannot be found by single molecule analysis such as t-test. Overall design: To detect plasma miRNA biomarker for MCI, the blood samples were collected from 30 age-matched controls (Normal, 12 males and 18 females, mean age of 70.4) and 23 MCI patients (11 males and 12 females, mean age of 72.8).Total RNA was extracted from plasma using the miRNeasy Mini Kit (Qiagen). Then, the miRCURY LNA™ Universal RT microRNA PCR System, Ready-to-Use Human panel I and panel II, V2. were performed to profile miRNAs differential expression in these plasma samples. Processed data were compared between control and MCI groups.
Project description:Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) are the two most common forms of dementia that occur during aging. Both AD and FTD are associated with the pathological aggregation of proteins. Nevertheless, it remains unclear how these protein aggregates lead to neuronal cell death in these dementias. Here we show that the histone demethylase LSD1 is mislocalized with cytoplasmic aggregates in human cases of AD and FTD. In addition, loss of LSD1 systemically in adult mice is sufficient to recapitulate many aspects of these diseases. From these data, we propose that the aggregation of Tau and TDP-43 lead to neuronal cell death in AD and FTD by interfering with the continuous requirement for LSD1 to repress inappropriate transcription. Furthermore, we observe the inappropriate reactivation of stem cell loci in the hippocampal neurons of LSD1 mutant mice. This suggests that LSD1 may function to maintain the fate of differentiated neurons by repressing stem cell transcription. Overall design: Hippocampus tissue was compared between Lsd1-sufficient (Lsd1(fl/fl)) and Lsd1-deficient mice (Cre-ER(TM)Lsd1(fl/fl))
Project description:Age-associated memory decline is due to variable combinations of genetic and environmental risk factors. How these risk factors interact to drive disease onset is currently unknown. Here we begin to elucidate the mechanisms by which post-traumatic stress disorder (PTSD) at a young age contributes to an increased risk to develop dementia at old age. We show that the actin nucleator Formin 2 (Fmn2) is deregulated in PTSD and in Alzheimer’s disease (AD) patients. Young mice lacking the Fmn2 gene exhibit PTSD-like phenotypes and corresponding impairments of synaptic plasticity while the consolidation of new memories is unaffected. However, Fmn2 mutant mice develop accelerated age-associated memory decline that is further increased in the presence of additional risk factors and is mechanistically linked to a loss of transcriptional homeostasis. In conclusion, our data present a new approach to explore the connection between AD risk factors across life span and provide mechanistic insight to the processes by which neuropsychiatric diseases at a young age affect the risk for developing dementia. Overall design: Role of Fmn2 gene for PTSD like phenotypes and impairments of synaptic plasticity.
Project description:Background: In aging and Alzheimer’s disease there are striking changes in CSF composition that may relate to altered choroid plexus function. Studying CP tissue gene expression at the BCSFB provides further insight into epithelial and stromal responses to aging and diseased states. Results: Highly significant differences in gene expression occurred in CP of advanced AD patients vs. normal controls. Immune-related pathways including acute phase response, cytokine/JAK/STAT signaling and cell adhesion were the most significantly enriched among the genes upregulated in AD patients, while methionine degradation, and protein translation genes were most notably downregulated. While the majority of gene expression changes in AD patients was also observed in FTD and HuD, there were significant differences among the disease groups. AD had the most unique expression findings, these genes being enriched in upregulated VEGF signaling and immune response proteins, e.g., interleukins. HuD/FTD patients uniquely displayed upregulated cadherin-mediated adhesion. Conclusions: This unique database of changes in CP tissue gene expression provides mechanistic insight into the effects of neurodegenerative diseases on CSF dynamics and hydrocephalus, particularly in regards to choroidal immune activation, metabolic homeostasis and resiliency of the CP. Overall design: Methods: Transcriptome-wide Affymetrix microarrays were used to determine disease-related changes in gene expression within human choroid plexus. Post-mortem tissue samples of the entire lateral ventricular choroid plexus were from 6 healthy controls and 7 patients with advanced (Braak & Braak stage III-VI) Alzheimer’s disease (AD), 4 with Frontotemporal dementia (FTD) and 3 with Huntington’s disease (HuD).
Project description:Winter2017 - Brain Energy Metabolism with PPP
This model is described in the article:
Mathematical analysis of the
influence of brain metabolism on the BOLD signal in Alzheimer's
Felix Winter1,2, Catrin
Bludszuweit-Philipp1 and Olaf Wolkenhauer2,3
Journal of Cerebral Blood Flow &
Blood oxygen level-dependent functional magnetic resonance
imaging (BOLD-fMRI) is a standard clinical tool for the
detection of brain activation. In Alzheimer’s disease
(AD), task-related and resting state fMRI have been used to
detect brain dysfunction. It has been shown that the shape of
the BOLD response is affected in early AD. To correctly
interpret these changes, the mechanisms responsible for the
observed behaviour need to be known. The parameters of the
canonical hemodynamic response function (HRF) commonly used in
the analysis of fMRI data have no direct biological
interpretation and cannot be used to answer this question. We
here present a model that allows relating AD-specific changes
in the BOLD shape to changes in the underlying energy
metabolism. According to our findings, the classic view that
differences in the BOLD shape are only attributed to changes in
strength and duration of the stimulus does not hold. Instead,
peak height, peak timing and full width at half maximum are
sensitive to changes in the reaction rate of several metabolic
reactions. Our systems-theoretic approach allows the use of
patient-specific clinical data to predict dementia- driven
changes in the HRF, which can be used to improve the results of
fMRI analyses in AD patients.
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Project description:MicroRNAs (miRNAs) are small (20-22 nucleotides) regulatory non-coding RNAs that strongly influence gene expression. Most prior studies addressing the role of miRNAs in neurodegenerative diseases (NDs) have focused on individual controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes. All cases had short postmortem intervals, relatively high-quality RNA, and state-of-the-art neuropathological diagnoses. The resulting data (over 113 million reads in total, averaging 5.6 million reads per sample) and secondary expression analyses constitute an unprecedented look into the human cerebral cortical miRNome at single nucleotide resolution. While we find no apparent changes in isomiR or miRNA editing patterns in correlation with ND pathology, our results validate and extend previous miRNA profiling studies with regard to quantitative changes in NDs. In agreement with this idea, we provide independent cohort validation for changes in miR-132 expression levels in AD (n = 8) and FTLD (n = 14) cases when compared to controls (n = 8). The identification of common and ND-specific putative novel brain miRNAs and/or short-hairpin molecules is also presented. The challenge now is to better understand the impact of these and other alterations on neuronal gene expression networks and neuropathologies. Using RNA deep sequencing, we sought to analyze in detail the small RNAs (including miRNAs) in the temporal neocortex gray matter from non-demented controls (n = 2), AD (n = 5), dementia with Lewy bodies (n = 4), hippocampal sclerosis of aging (n = 4), and frontotemporal lobar dementia (FTLD) (n = 5) cases, together accounting for the most prevalent ND subtypes.
Project description:We aimed at identification of variations of genome expression in white blood cells, which could serve as blood markers of early dementia in adults with Down syndrome Whole genome expression analysis was compared between groups of younger and older patients with or without severe cognitive disability
Project description:To date, little is known regarding the etiology and disease mechanisms of alzheimer’s disease (AD). There is a general urgency for novel approaches to advance AD research. In this study, we analyzed blood RNA from female patients with advanced AD and matched healthy controls using genome-wide gene expression microarrays. Our data showed significant alterations in 3,944 genes (≥2-fold, FDR≤1%) in AD whole blood, including 2,932 genes that are involved in broad biological functions. Importantly, we observed abnormal transcripts of numerous tissue-specific genes in AD blood involving virtually all tissues, especially the brain. Of altered genes, 157 are known to be essential in neurological functions, such as neuronal plasticity, synaptic transmission and neurogenesis. More importantly, 205 dysregulated genes in AD blood have been linked to neurological disease, including AD/dementia and Parkinson’s disease, and 43 are known to be the causative genes of 42 inherited mental retardation and neurodegenerative diseases. The detected transcriptional abnormalities also support robust inflammation, profound ECM impairments, broad metabolic dysfunction, aberrant oxidative stress, DNA damage and cell death. While the mechanisms are currently unclear, this study demonstrates strong blood-brain correlations in AD. The blood transcriptional profiles reflect the complex neuropathological status in AD, including neuropathological changes and broad somatic impairments. The majority of genes altered in AD blood have not previously been linked to AD. We believe that blood genome-wide transcriptional profiling may provide a powerful and minimally invasive tool for the identification of novel targets beyond Aβ and tauopathy for AD research. Overall design: Study subjects were all female, including patients with advanced AD (n=9, age 79.3±12.3 years) and age–matched female healthy controls (n=10, age 72.1±13.1 years). Peripheral blood from each study subjects were processed to isolate RNA. The isolated blood RNAs were assayed byt geneome-wide gene expression microarrays using the Sureprint G3 Human Gene Expression 8x60k v2 microarrays (Agilent Technologies, CA)