Novel Strategies to Enhance MRI Detection of Ultra-Small Brain Lesions in Vascular Dementia

Andy Shih, Ph.D.

Medical University of South Carolina

Funded in September, 2013: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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MRI innovations may advance early diagnosis and aid prevention of vascular dementia

Through studies in mice, researchers will seek to improve MRI detection of tiny blockages in the brain’s small blood vessels that can lead to vascular dementia. Their findings may help clinicians identify at-risk patients and implement early prevention strategies. Research shows a strong link between dementia and the presence of miniscule microscopic lesions (microinfarcts) that obstruct blood flow in tiny blood vessels in the brain. The impact of accumulated microinfarcts on vascular cognitive impairment, though, is not known. While powerful 7T MRI imaging can detect relatively large microinfarcts, scientists do not know whether 7T MRI has sufficient resolution to identify lesions that are smaller, or those that may have occurred long ago. Clinicians need this information to determine whether a patient is at risk for vascular cognitive impairment based on how many microinfarcts the patient has experienced. To address this problem, the investigators will seek to answer three questions. 1) What are the smallest lesions that can be detected with the currently used 7T MRI? 2) What cellular and structural features account for their visibility and for how long are they visible? 3) Will advanced MRI methods and new molecular probes (molecules that attach specifically to areas of brain damage) enhance detection of currently invisible microinfarcts? The investigators hypothesize that 7T MRI detects only large and relatively new microinfarcts, but that certain improvements and innovations will expand the population of microinfarcts that can be identified. They will test this hypothesis in three studies in mice. To start, they will use a fine, focused laser to create microinfarcts in the brains of mice that differ in size, location and age (newer and older). Then they will determine the minimal lesion size that can be detected with the currently used diagnostic 7T MRI scans, and see whether performance can be improved by using higher resolutions achieved by extending the scanning times. They will compare the MRI data to the autopsied mouse brain tissue to confirm lesion sizes detected. Second, they will assess MRI’s capacity to detect old as well as new microinfarcts. This will include using two-photon imaging in parallel with MRI to identify inflammation and scar tissue that might underlie the MRI signals of older microinfarcts. Third, they will begin to test the abilities of a new MRI method (called diffusion kurtosis imaging) and a new microinfarct-specific contrast-enhancing imaging probe to improve detection. Significance: Both the immediate results and the longer-term development of new technology will help physicians better interpret MRI findings so that they can determine whether their patients are at risk for developing vascular dementia and to manage their preventive care more effectively.

ABSTRACT

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Novel Strategies to Enhance MRI Detection of Ultra-Small Brain Lesions in Vascular Dementia

Vascular cognitive impairment (VCI) is an insidious disease that progressively destroys memory and cognitive function with age. With a growing elderly population in the United States, VCI will become a significant healthcare burden within the coming decades. It is thus essential to develop methods to detect and treat VCI before the onset of cognitive decline. Cerebral microinfarcts are microscopic brain lesions caused by blockade of small blood vessels that have recently emerged as a potential determinant of cognitive decline. Microinfarcts represent the single most widespread form of tissue infarction in VCI, and their prevalence is greatly underestimated in MRI scans and post-mortem histopathology. Microinfarcts are strongly associated with VCI even after controlling for other disease factors such as sub-cortical lacunes and amyloid plaque deposition. Recent advances have demonstrated the feasibility of detecting microinfarcts with 7-tesla magnetic resonance imaging (7T MRI), supporting their potential as imaging biomarkers of VCI. A critical barrier for current progress, however, is that the spatiotemporal features of microinfarct growth are not understood. This gap in knowledge limits our ability to classify visible microinfarcts as lesions of a specific age (new versus old lesions), size, and cellular pathology. This information is necessary to gauge the extent of the disease progression. MRI techniques must therefore be refined to improve detection and interpretation of small anomalous signals seen in the human brain. In this regard, controlled mouse models of microinfarction can provide timely information. Our overarching hypothesis is that current MRI scans detect only large, acute microinfarcts in the human brain, but improvements in imaging resolution and utilization of specific imaging sequences will enable detection of a larger population of microinfarcts. Thus, our primary goal is to understand how factors including lesion size, age, and the MRI method used can affect the ability to detect microinfarcts in the mouse brain. Our findings are expected to provide clinicians with detailed information on how to interpret small anomalous MRI signals and better identify patients at-risk for VCI.

INVESTIGATOR BIOGRAPHIES

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Andy Shih, Ph.D.

Andy Y. Shih, PhD, is an Assistant Professor in Neuroscience at the Medical University of South Carolina. He received his Ph.D. from the University of British Columbia, with a focus on molecular mechanisms of brain protection during stroke. He then continued as a post-doctoral fellowship at the University of California, San Diego, to study stroke injury in the intact brain using in vivo two-photon microscopy. During this time, he developed a novel rodent model of ultra-small brain lesions that are common in the aging human population and strongly linked to cognitive decline. The goal of his current research is to understand how the breakdown of cerebral vasculature during dementia, stroke, and neurodegeneration contribute to cognitive dysfunction, and how optimization of MRI may be used to detect of vascular damage in humans. To perform this research, his laboratory makes use of multimodal brain imaging techniques and rodent genetic targeting strategies to visualize and manipulate small blood vessels of the brain.