White Matter Hyperintensities (WMH) are areas of discrete high signal intensity on T2 and FLAIR brain MRI. They are associated with increasing age, vascular disease and other factors and cause cognitive decline, depression and gait impairment. Since accrual of WMH may diminish with treatment of vascular risk factors, there is a potential for therapeutic intervention Recent studies of mutant mice show that knockout of the Nrf2 (Nuclear factor erythroid-derived 2-like 2) gene results in loss of brain myelin with a vacuolar leukoencephalopathy that occurs with advancing age. Nrf2 activates antioxidant response elements (ARE) to modulate downstream anti-oxidant target genes. These findings, coupled with our preliminary data showing increased expression of Nrf2 target genes in the blood of patients with WMH, has led us to focus this study on Nrf2 and propose these aims.
Aim #1 a: Demonstrate that the number of OLIGOs and OPCs in WMH identified by post-mortem MRI are decreased in WMH compared to distant unaffected white matter.
Aim# 1b. Show that markers of oxidative stress, F2-isoprostane (myelin) and 8-OH-2dG (DNA), stain myelin sheaths and OLIGO nuclei in WMH compared to no staining in distant unaffected white matter.
Aim# 1c. Demonstrate increased nuclear Nrf2 protein and increased Nrf2 target gene expression in WMH and at the margins of WMH as compared to distant unaffected white matter.
Aim #2 a: Demonstrate that expression of Nrf2 target genes in blood using qRT-PCR is increased in subjects with large volume WMH compared to those with low volume WMH as measured using in vivo MRI.
Aim# 2b: Demonstrate that the expression of Nrf2 target genes using qRT-PCR is either persistently elevated or markedly increases in blood of subjects whose WMH volumes increase the most over 2 years compared to matched subjects who have the smallest changes in WMH volumes over 2 years.
Aim #3. Demonstrate that brain pathological changes and Nrf2 target gene expression changes in blood and WMH in Aims #1 and #2 are present in the blood and brain obtained from the same individual. In this study we will determine whether systemic and brain oxidative stress correlate with WMH damage, large WMH volumes and progression of WMH volumes over time. Systemic ROS damage brain endothelial cells allowing pro-oxidant molecules into brain that increase brain ROS that contribute to WMH. This study will begin to identify novel Nrf2 therapeutic targets for decreasing or preventing WMH. It will also begin to provide the rationale and preliminary data needed before antioxidant trials would be undertaken to reduce WMH with the goal of delaying or preventing cognitive decline.

Public Health Relevance

6. White Matter Hyperintensities (WMH) are associated with age, Alzheimer's Disease, hypertension and vascular risk factors and cause cognitive decline, depression and gait impairment. This study will determine whether systemic and brain oxidative stress correlate with loss of oligodendrocytes and their precursors in WMH, large WMH volumes and progression of WMH volumes over time which could lead to future treatment trials of WMH with antioxidants.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG042292-03
Application #
8826668
Study Section
Special Emphasis Panel (ZRG1-BDCN-L (02))
Program Officer
Wise, Bradley C
Project Start
2013-04-15
Project End
2018-03-31
Budget Start
2015-06-15
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
$594,055
Indirect Cost
$207,048
Name
University of California Davis
Department
Neurology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Sun, Ping; Liu, Da Zhi; Jickling, Glen C et al. (2018) MicroRNA-based therapeutics in central nervous system injuries. J Cereb Blood Flow Metab 38:1125-1148
Zhan, Xinhua; Stamova, Boryana; Sharp, Frank R (2018) Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer's Disease Brain: A Review. Front Aging Neurosci 10:42
Spartano, Nicole L; Himali, Jayandra J; Beiser, Alexa S et al. (2016) Midlife exercise blood pressure, heart rate, and fitness relate to brain volume 2 decades later. Neurology 86:1313-9
Tsao, Connie W; Himali, Jayandra J; Beiser, Alexa S et al. (2016) Association of arterial stiffness with progression of subclinical brain and cognitive disease. Neurology 86:619-26
Karakis, Ioannis; Pase, Matthew P; Beiser, Alexa et al. (2016) Association of Serum Vitamin D with the Risk of Incident Dementia and Subclinical Indices of Brain Aging: The Framingham Heart Study. J Alzheimers Dis 51:451-61
Fletcher, Evan; Villeneuve, Sylvia; Maillard, Pauline et al. (2016) ?-amyloid, hippocampal atrophy and their relation to longitudinal brain change in cognitively normal individuals. Neurobiol Aging 40:173-180
Pase, Matthew P; Himali, Jayandra J; Mitchell, Gary F et al. (2016) Association of Aortic Stiffness With Cognition and Brain Aging in Young and Middle-Aged Adults: The Framingham Third Generation Cohort Study. Hypertension 67:513-9
Miller, Joshua W; Green, Ralph; DeCarli, Charles (2016) 25-Hydroxyvitamin D in Patients With Cognitive Decline-Reply. JAMA Neurol 73:358
Scott, Julia A; Braskie, Meredith N; Tosun, Duygu et al. (2015) Cerebral Amyloid and Hypertension are Independently Associated with White Matter Lesions in Elderly. Front Aging Neurosci 7:221
Chen, Jason A; Wang, Qing; Davis-Turak, Jeremy et al. (2015) A multiancestral genome-wide exome array study of Alzheimer disease, frontotemporal dementia, and progressive supranuclear palsy. JAMA Neurol 72:414-22

Showing the most recent 10 out of 34 publications