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Immune System Involvement in Cerebral Amyloid Angiopathy

  • Author / Creator
    Munsterman, Danielle
  • Background:
    Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease featuring beta-amyloid deposits within the cerebral vasculature. It is a major cause of cognitive decline and intracerebral hemorrhage in the elderly. A gap in knowledge surrounding mechanisms underlying CAA pathogenesis has contributed to a lack of treatments and early diagnostic biomarkers for CAA. Expanding understanding of the mechanisms contributing to CAA pathophysiology may aid in diagnostic and risk stratification biomarker discovery and potential identification of novel therapeutic targets. This is of clinical interest, given the high prevalence of CAA amongst the elderly and a globally aging population. This thesis evaluated differences in blood gene expression in CAA and the relationship to CAA severity. Insight to changes in immune system that occur in CAA are identified which may have relevance to cerebrovascular disease in CAA and as biomarkers to aid in the diagnosis and severity assessment of CAA.
    Methods:
    In 27 patients with CAA blood cell gene expression was compared to 55 controls. RNA was isolated from PAXgene tubes and measured by RNA sequencing. Differentially expressed genes between CAA and controls were identified by ANOVA adjusting for age and sex. Functional pathway analysis identified pathways associated with CAA. A prediction model to distinguish CAA from controls was developed and evaluated. Differentially expressed genes based on CAA small vessel disease (CAA-SVD) score as a marker of CAA severity were identified using ANOVA and functional pathway analysis in patients with CAA.
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    Results:
    In patients with CAA compared to controls 686 differentially expressed genes were identified (p|1.2|), of interest ADAM15, CAMK1D, CAP1 and TGFB1. In CAA canonical pathway analysis identified cell movement of phagocytes, activation of phagocytes, CREB, degranulation of leukocytes, immune response of cells, inflammatory response, and IL-23 signaling. A 24 gene panel differentiated patients with CAA from controls with >95% sensitivity and specificity. The identified genes reveal differences in immune system regulation in patients with CAA compared to controls. Differences identified include a potential shift in beta-amyloid uptake by phagocytes (TGFB1, CREB, CAMK1D), an increase in vascular extracellular matrix disruption (ADAM15, CAP1), and a possible alteration in amyloid precursor processing (BRI3BP, SORCS3). ANOVA was used to identify genes associated with CAA-SVD score (p≤0.05, partial correlation coefficient ≥|0.5|). HDAC11, IL23A, TRAIL, TRAILR1, TRAILR2, and ICAM-1 were associated with CAA severity (CAA-SVD score). Canonical pathways analysis identified induction of T lymphocytes, binding of antigen presentation cells, IL-12 signaling in macrophages/monocytes, activation of phagocytes, and activation of antigen presenting cells to be associated with CAA severity (p≤0.05).
    Conclusions:
    Differences in blood gene expression are present in patients with CAA compared to control patients. These relate to differences in immune activation and signaling associated with CAA. The differences in blood cell gene expression shows promise to distinguish CAA from controls, though further evaluation in larger cohorts is required. An association between the peripheral immune system and CAA severity was also identified. Changes in neutrophil, monocyte, and Th17 cell gene expression in peripheral blood was associated with CAA severity.
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    Such gene expression changes were associated with cognitive measures including decreases in memory, executive functioning, and processing speed. This supports greater specificity of immune system changes contributing to CAA pathogenesis and cognitive decline, which may be of clinical value as future therapeutic targets or risk stratification markers in CAA. Although this data is preliminary and further evaluation in larger cohorts is required, differences in peripheral immune system responses were identified in CAA revealing gene targets with potential for providing diagnostic and risk stratification information.

  • Subjects / Keywords
  • Graduation date
    Fall 2022
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-c1wn-yd96
  • License
    This thesis is made available by the University of Alberta Library with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.