The Inflammatory and Pathological Profile of Ischemic Infarcts in Humans with Post-Stroke Dementia
Vivian Nguyen, Ph.D.
Tuesday, November 3, 2015
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Chapters
Introduction
Research goal
Stroke pathophysiology
The cascade of damaging events after stroke
Could inflammation continue for longer than previously thought
The evidence
Hypothesis I
Is there a chronic immune response in the stroke lesion of humans with vascular dementia?
Characterizing the inflammatory response in human stroke lesions
Staging of human stroke lesions
Cells of the immune system
CD20+ B cells were present in 45% of non-acute stroke-dementia patients
Antibodies present in non-acute stroke-dementia patients
CD3+ T cells were present in 100% of non-acute stroke-dementia patients
41% of helper CD4+ and 59% of cytotoxic CD8+ T cells present in non-acute stroke-dementia patients
Using Luminex MAGPIX® and Milliplex® immunoassays to determine the cytokine/chemokine profile of stroke-dementia patients
How are cytokine/chemokine levels impacted by autolysis time in human post-mortem tissue?
Cytokine/chemokine expression in normal control patients
Cytokine/chemokine expression in stroke patients with acute lesions
Cytokine/chemokine expression in stroke patients with non-acute lesions
Hypothesis II
We began by screening existing stroke models
Developing our mouse model of delayed cognitive dysfunction after stroke
Our DH Stroke model
DH Stroke causes delayed cognitive dysfunction together with motor recovery
Immune cell infiltration into the brain after stroke
How long does inflammation last after stroke in mice
CD68+ macrophages/microglia: 1 week post stroke
CD68+ macrophages/microglia: 7 and 12 weeks post stroke
CD3e+ T cells: 1 week post stroke
CD3+ T cells: 7 and 12 weeks post stroke (Diagram 1)
CD3+ T cells: 7 and 12 weeks post stroke (Diagram 2)
Mouse SEM
Human SEM
Introduction
MHCII+ antigen presentation: 1 week post stroke
MHCII+ antigen presentation: 7 and 12 weeks post stroke
B220+ B cells: 1 week post stroke
B220+ B cells: 7 and 12 weeks post stroke
Plasma cells are present in the stroke lesion
Anti-mouse IgG
Does antibody infiltration impact hippocampal function and contribute to delayed memory deficits?
A deficit in LTP appears in the weeks after stroke
Does the ablation of B lymphocytes prevent delayed cognitive dysfunction?
What about Rituxan®?
Ablation of B cells with mouse Rituxan (anti-CD20)
Does ablation of B cells and a decrease in antibodies with mouse Rituxan (anti-CD20) prevent delayed cognitive dysfunction?
Treatment with Rituxan prevents a delayed cognitive decline after stroke
Working model
Future direction: How much diversity is there in inflammation after stroke?
Patient A has substantially less inflammation in the brain 7 weeks after stroke
Summary
Thank You
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