Cerebral small vessel disease (CSVD) is the most prevalent neurological disorder in the elderly1. Broadly, CSVD comprises the gradual remodeling of brain microvessels due to hypertension, global hypoperfusion or other vascular risk factors2. In addition to increasing the risk of stroke and late life dementia, CSVD accelerates neurodegeneration in sporadic late onset Alzheimer's Disease (AD). However, the mechanism of the CSVD/AD interaction remains unclear and restoration of hypertension and other vascular risk factors, in longitudinal randomized clinical trials, lowers the risk for late-life dementia by only 5-20%.3 These data suggest that deleterious pathways initiated in mid-life CSVD are not fully rescued by treatments presently in clinical practice. Building upon our previous work, we will examine the spatiotemporal evolution of neuronal and microvascular network changes in CSVD alone and within an AD susceptible environment, so as to assess the long-term effects of the CSVD- induced injury. We will map the cognitive consequences of the changes in neurovascular function and use a multifaceted approach to identify the underlying neurobiological mechanisms leading to cognitive compromise. As less blood flow reaches the brain microcirculation from hemodynamic disturbances caused by CSVD, neurons associated with cognitive function will likely engage in suboptimal neurotransmission, thus negatively affecting cognitive behavior. We propose that treatment of vascular risk factors and endogenous neurovascular remodeling can achieve only partial functional recovery of CSVD. In an AD-susceptible environment, neurovascular remodeling will be further compromised; significant functional deficits persist in the chronic phase CSVD, and later-life disease is exacerbated. We will pursue the following objectives: 1. Identify short-term effects of CSVD on neurovascular function and cognition in AD susceptible environment vs. in healthy brain. 2. Identify long-term effects of CSVD on neurovascular function and cognition with AD progression vs. in healthy aging. 3. Downregulate ROCK signaling so as to ameliorate neurovascular dysfunction and stabilize cognitive decline. To effect significant neurovascular network injury on a slow temporal scale, we will gradually induce cerebral small vessel disease in non-transgenic and TgAD rats at the early-amyloid stage. We will bring to bear our expertise to conduct a battery of cognitive tests, in vivo MRI and two-photon fluorescence microscopy, in vivo electrophysiology, followed by post mortem pathological analyses. After pharmacological re-establishment of vascular risk factors and normalization of global brain blood flow, we will examine the brain microvascular network function, neuronal network function and pathological sequelae. These experiments will pinpoint the pathways still impaired after cessation of vascular insult, thus identifying potential targets for development of multi-drug therapeutic strategies. Using this strategy, our preliminary data in both CSVD alone and within an AD susceptible environment indicate up-regulation of the RhoA kinase pathway in the vasculature 30-days post-cessation of vascular insult in conjunction with compromised neurovascular function. Our approach to confirm the role of RhoA signaling and identify the downstream pathways contributing to late-life dementia will identify interventions to not only restore vascular function but prevent cognitive decline.

Public Health Relevance

Cerebral small vessel disease (CSVD), the most common neurological disease of the elderly, contributes to cognitive dysfunction and accelerates neurodegeneration in Alzheimer's Disease (AD). Current treatments to normalize vascular dysfunction in CSVD, such as high blood pressure, lower the risk of late-life dementia by only 5-20%. Therefore, understanding the link between cerebral small vessel disease and AD and developing more effective interventions is important for healthy aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG057665-01A1
Application #
9541804
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Mackiewicz, Miroslaw
Project Start
2018-07-15
Project End
2023-03-31
Budget Start
2018-07-15
Budget End
2019-03-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Sunnybrook Research Institute
Department
Type
DUNS #
246840065
City
Toronto
State
ON
Country
Canada
Zip Code
M4 3M5