Cerebrovascular disease is a major risk factor for dementia. All-cause dementia, (vascular dementia, Alzheimer's disease, and mixed disorders) is diagnosed in up to 48% of stroke survivors, with about 20% incidence in the first year after stroke. Several stroke risk factors, including hypertension, high cholesterol, diabetes, and age, also independently increase the risk of dementia. But multiple studies demonstrate that even after controlling for risk factors, stroke alone still doubles the risk of new onset dementia. We propose to model how stroke increases the risk of developing dementia by developing a new mouse model where stroke causes delayed cognitive dysfunction. In our model mice undergo DH stroke as a result of distal middle cerebral artery occlusion followed by hypoxia. This confers a primarily cortical infarct. Mice display normal working memory 8 days after stroke but by 6-7 weeks later they develop deficits in working and spatial memory, accompanied by a prolonged inflammatory response. A part of this inflammatory response is the appearance of B cells in the stroke core, in follicle-like structures. Such structures in the CNS have recently been linked to several neurodegenerative diseases. We propose here to develop our model and test whether B cells are pathogenic in our model.
In Aim 1 we will use a panel of cognitive tests at key timepoints to assess which areas of cognition are affected in this model, and also carefully phenotype the delayed inflammatory response to stroke. We hypothesize that pathogenic features of neuroinflammation will precede or coincide with cognitive impairment.
In Aim 2 we will use a B cell-depleting antibody and B cell knockout mice to ask whether B cells are required for cognitive dysfunction to occur. This work has high potential to produce significant impact because there are currently no well-accepted models and little is known about the genesis of this common and debilitating disorder. At the conclusion of these experiments we will have characterized the cognitive deficit and inflammatory responses in our model and will know whether B cells are causative. This information will allow us to pursue critical future studies on the mechanisms that underlie post-stroke dementia, and in addition will provide a way to test potential therapies.

Public Health Relevance

Stroke is a major risk factor for dementia, but there are no established animal models to study how stroke causes memory impairment. In this application we propose to develop such an animal model, and use it to understand how stroke increases the risk of dementia. We hope to discover mechanisms that will lead to treatments that can prevent dementia in stroke survivors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS078571-02
Application #
8539106
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Bosetti, Francesca
Project Start
2012-09-01
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$190,397
Indirect Cost
$69,772
Name
Stanford University
Department
Neurology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Doyle, Kristian P; Buckwalter, Marion S (2014) A mouse model of permanent focal ischemia: distal middle cerebral artery occlusion. Methods Mol Biol 1135:103-10