Small vessel ischemic disease in the elderly whose signature on Magnetic Resonance Imaging (MRI) is white matter hyperintensities (WMH) on T2 and FLAIR sequences is presumed to be caused by chronic hypoperfusion. WMH change is nearly ubiquitous, negatively impacts cognitive and motor processing in nondemented individuals, has synergistic effects on Alzheimer disease pathology, and increases the risk of functional decline and dementia. Cognitive decline that occurs as a result of small vessel cerebrovascular disease has been termed subcortical vascular cognitive impairment (VCI), a likely under- recognized cause of mild cognitive impairment in the elderly. Despite recent advances in our understanding of the impact of WMH changes on cognitive and motor health in the elderly, the underlying mechanisms and functional trajectory of these changes, as well as the attendant risks of subcortical VCI and dementia remain largely unknown. The goals of this study are to investigate the effects of changes in cerebral blood flow over time on WMH burden accumulation, determine whether WMH lesions are focal signs of a more diffuse pathological process, and identify anatomical and perfusion MRI markers that confer increased risk of cognitive and motor impairment.
Specific aims are to: 1) Identify the role of altered perfusion in the formation of WMH accumulation in the elderly, 2) Characterize WMH and perfusion-related microstructural white matter changes in normal appearing white matter (NAWM) and the corpus callosum, and 3) Determine MRI biomarkers of cognitive and motor decline. Non-demented seniors over age 65 will be asked to participate. In addition to annual conventional psychometric and neurologic testing, subjects will also be followed longitudinally with unobtrusive assessment of in-home gait and motor activity. Eighty subjects will undergo yearly high-field (3 and 7 Tesla) MRI. Longitudinal measures of grey and white matter perfusion will be obtained using arterial spin labeling, a non-invasive means of quantifying cerebral blood flow. Evidence of microstructural decline in white matter integrity will be evaluated in NAWM and the corpus callosum using diffusion tensor imaging and quantitative T1 relaxography. Volumetric quantification of WMH lesion burden will be obtained for all subjects. This study proposes to use high-field advanced imaging techniques to investigate the mechanisms behind WMH-related cognitive impairment and motor function decline in a well-characterized elderly cohort. This study would be one of the first to prospectively study the effects of cerebral hypoperfusion over time on cognitive and motor function in elderly at risk for cognitive impairment and dementia, and establish a causal relationship between CBF and commonly observed WMHs changes. In addition, this study will determine the extent and functional effects of widespread microstructual damage to the NAWM and corpus callosum in those with WMH lesions. Ultimately, the goal of this proposal is to determine the mechanisms behind VCI and identify elderly at risk for cognitive and motor impairment, so that early treatment and preventative measures can be instituted.

Public Health Relevance

White matter hyperintensity (WMH) change on MRI is observed in up to 92% of non-demented elderly, and is associated with subcortical vascular cognitive impairment and functional decline. Despite this, little is known about the etiology of this condition, or which MRI biomarkers can distinguish those who will progress to dementia from those who will remain stable or improve. This longitudinal study proposes to use high-field MRI measures of perfusion and white matter integrity to determine the mechanisms behind WMH-related cognitive and motor impairment and determine MRI biomarkers to help identify those at risk for cognitive and motor decline, so that prevention and treatment strategies can be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG036772-03
Application #
8431391
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Wagster, Molly V
Project Start
2011-03-01
Project End
2016-02-29
Budget Start
2013-04-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$298,337
Indirect Cost
$104,612
Name
Oregon Health and Science University
Department
Neurology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Dodge, Hiroko H; Zhu, Jian; Harvey, Danielle et al. (2014) Biomarker progressions explain higher variability in stage-specific cognitive decline than baseline values in Alzheimer disease. Alzheimers Dement 10:690-703
Erten-Lyons, Deniz; Woltjer, Randall; Kaye, Jeffrey et al. (2013) Neuropathologic basis of white matter hyperintensity accumulation with advanced age. Neurology 81:977-83