Chronic adult hydrocephalus is a leading cause of preventable neurological injury. Although its pathophysiology, diagnosis, and treatment are poorly understood it is likely that brain hypoxia, through vessel compression, plays a role in this injury. We first hypothesize that an initial mechanical cerebral blood flow (CBF) compromise is later temporized by adaptive angiogenesis, which evolves from hypoxia stimulated angiogenic factors. Our second general hypothesis states that cerebral spinal fluid (CSF) shunting partially restores CBF and oxygen level but in so doing reverses the adaptive angiogenesis. We have developed a canine model of chronic hydrocephalus, which allows measurement of ventricular size and pressure and their relationship to vascularity, cerebral blood flow, and oxygen delivery to the brain. Experimental and control animals will be studied for 12 weeks and in phase 2, will be shunted. Measurements include clinical status, ventricle size, CSF pressure, quantitative regional vessel morphology (density, size, area), immunohistochemistry (HIF-1, VEGF, GFAP), cerebral blood flow (multi-microsphere injections), and oxygen level (micro oxygen sensor). This study will be the first to identify the role and mechanism of chronic hypoxia in hydrocephalus. If the hypoxic state and proposed cerebrovascular response are demonstrated, strategies based on cerebrovascular manipulation or neuroprotection may be proposed as adjuncts to surgical shunting and shunting itself optimized. Secondary injury resulting from sudden shunt dysfunction may be minimized. With more physiological guided CSF drainage and adjunct treatments based on cerebral blood flow our treatment of adult chronic hydrocephalus would be greatly enhanced and its neurological morbidity reduced. Finally, the insights gained from these studies may have a broader application to other neuropathologies involving gradual compression or hypoxia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
7R01NS041553-03
Application #
6651041
Study Section
Special Emphasis Panel (ZRG1-BDCN-5 (01))
Program Officer
Jacobs, Tom P
Project Start
2001-09-30
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
3
Fiscal Year
2003
Total Cost
$344,250
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Surgery
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Yang, Jun; Dombrowski, Stephen M; Deshpande, Abhishek et al. (2010) VEGF/VEGFR-2 changes in frontal cortex, choroid plexus, and CSF after chronic obstructive hydrocephalus. J Neurol Sci 296:39-46
Deshpande, Abhishek; Dombrowski, Stephen M; Leichliter, Anna et al. (2009) Dissociation between vascular endothelial growth factor receptor-2 and blood vessel density in the caudate nucleus after chronic hydrocephalus. J Cereb Blood Flow Metab 29:1806-15
Dombrowski, S M; Deshpande, A; Dingwall, C et al. (2008) Chronic hydrocephalus-induced hypoxia: increased expression of VEGFR-2+ and blood vessel density in hippocampus. Neuroscience 152:346-59