Gait and balance disorders are among the most common causes of falls in older adults. Recent clinical studies identify a novel microvascular etiology that contributes to gait abnormalities in the elderly: cerebral micro- hemorrhages (CMHs). In the elderly hypertension is the major risk factor for CMHs, which are associated with rupture of small intracerebral vessels and progressively impair neuronal function. Although CMHs affect one third of older individuals, their pathogenesis remains completely obscure and there are no therapeutic interven- tions available for prevention. The central hypothesis of this application that hypertension exacerbates mito- chondrial oxidative stress in aged cerebral vessels, which results in activation of MMPs, collagen degradation and remodeling of the extracellular matrix, promoting microvascular fragility. The resulting CMHs impair fine motor coor- dination, promoting gait and balance abnormalities. Our prediction based on this hypothesis is that attenuation of mitochondrial oxidative stress or inhibition of MMP activation will protect the structural integrity of cerebral vessels preventing the development of CMHs and preserving normal gait and balance function in aging. Based on our ex- tensive experience in this field and our preliminary data, we are well positioned to test our hypotheses using innova- tive mouse models of CMHs and advanced methods of gait analysis in mice.
Specific Aims : 1) Determine how the number, size and localization of CMHs impact gait and balance function in aged mice. The proposed studies will use novel, sensitive and translationally highly relevant methods to characterize CMH-related abnormalities of fractal properties of gait cycle and establish the link between the severity, number and localization of the CMHs and gait abnormalities in aged mice. The predictive power of gait abnormalities to CMH-related cognitive impairment will al- so be determined. 2) Determine how age-related changes in extracellular matrix composition, MMP activation and CMHs relate. Our hypothesis is that aging exacerbates activation of MMPs, collagen degradation and remodeling of the extracellular matrix, promoting microvascular fragility and CMHs. 3) Determine the role of mitochondrial oxi- dative stress in increased susceptibility to CMHs in aging. Our hypothesis is that overexpression of catalase tar- geted to the mitochondria or treatment with the mitochondria-targeted antioxidant on structural integrity of cerebral vessels. Together, the proposed studies will identify a fundamental mechanism responsible for age-related ex- acerbation of CMHs, and thus vascular-induced neurological deficits ?increased mitochondria-derived ROS production and consequential degradation of cerebrovascular structural integrity. These outcomes will have an important positive impact, since they will enable us to develop novel, translationally relevant interventional strategies for prevention of CMHs, protecting gait and balance function in the elderly.

Public Health Relevance

The proposed research is relevant to public health because gait abnormalities, which are present in over 30% of older adults, increase risk of falls with often tragic consequences. The present application focuses on an important and potentially preventable (yet under-studied) cause of age-related gait and balance abnormalities: cerebral microbleeds caused by hypertension-induced rupture of small cerebral vessels. The discovery of the cellular mechanisms responsible for increased vulnerability to cerebral microhemorrhage in the elderly is ultimately expected to increase understanding of the pathogenesis of gait and balance abnormalities and will lead to the development of novel therapeutic interventions for the prevention; thus, the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of disability in the elderly.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
St Hillaire-Clarke, Coryse
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Oklahoma Health Sciences Center
Other Health Professions
Schools of Medicine
Oklahoma City
United States
Zip Code
Ungvari, Zoltan; Tarantini, Stefano; Donato, Anthony J et al. (2018) Mechanisms of Vascular Aging. Circ Res 123:849-867
Toth, Peter; Tarantini, Stefano; Rutkai, Ibolya et al. (2018) Assessment of endothelial function in leptomeningeal arterioles derived from patients with Alzheimer's disease and vascular cognitive impairment. Am J Physiol Heart Circ Physiol 315:H790-H793
Valcarcel-Ares, Marta Noa; Tucsek, Zsuzsanna; Kiss, Tamas et al. (2018) Obesity in Aging Exacerbates Neuroinflammation, Dysregulating Synaptic Function-related Genes and Altering Eicosanoid Synthesis in the Mouse Hippocampus: Potential Role in Impaired Synaptic Plasticity and Cognitive Decline. J Gerontol A Biol Sci Med Sci :
Csipo, Tamas; Fulop, Gabor A; Lipecz, Agnes et al. (2018) Short-term weight loss reverses obesity-induced microvascular endothelial dysfunction. Geroscience :
Ungvari, Zoltan; Yabluchanskiy, Andriy; Tarantini, Stefano et al. (2018) Repeated Valsalva maneuvers promote symptomatic manifestations of cerebral microhemorrhages: implications for the pathogenesis of vascular cognitive impairment in older adults. Geroscience 40:485-496
Van Skike, Candice E; Jahrling, Jordan B; Olson, Angela B et al. (2018) Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer's disease and vascular cognitive impairment. Am J Physiol Heart Circ Physiol 314:H693-H703
Dohare, Preeti; Cheng, Bokun; Ahmed, Ehsan et al. (2018) Glycogen synthase kinase-3? inhibition enhances myelination in preterm newborns with intraventricular hemorrhage, but not recombinant Wnt3A. Neurobiol Dis 118:22-39
Ungvari, Zoltan I; Yabluchanskiy, Andriy; Hasko, Gyorgy et al. (2018) Age-dependent cardiovascular effects of sepsis in a murine model of cecal ligation and puncture: implications for the design of interventional studies. Am J Physiol Heart Circ Physiol :
Fulop, Gabor A; Ramirez-Perez, Francisco I; Kiss, Tamas et al. (2018) IGF-1 deficiency Promotes Pathological Remodeling of Cerebral Arteries: A Potential Mechanism Contributing to the Pathogenesis of Intracerebral Hemorrhages in Aging. J Gerontol A Biol Sci Med Sci :
Reagan, Alaina M; Gu, Xiaowu; Paudel, Sijalu et al. (2018) Age-related focal loss of contractile vascular smooth muscle cells in retinal arterioles is accelerated by caveolin-1 deficiency. Neurobiol Aging 71:1-12

Showing the most recent 10 out of 18 publications