This proposal is focused on studies to elucidate the mechanisms of radiation-induced cognitive dysfunction. This is an important problem because 30-50% of the patients who survive more than 18 months after whole-brain irradiation (WBI) suffer from severe cognitive deficits. We have characterized a rat model of radiation-induced cognitive dysfunction using a fractionated dose of WBI that is biologically equivalent doses typically given to brain tumor patients. During those studies, we made the novel finding that the density of the capillary bed decreased in three areas of the brain, including the hippocampus which is involved in learning and memory. This decrease occurred as early as 10 weeks post-irradiation. There was partial recovery of the capillary bed by 20 weeks, and thereafter a decline in capillary density in the irradiated rats paralleled that observed in the controls, out to one year post-irradiation. The capillary loss occurred much earlier than vascular damage previously reported for high single doses of WBI and much earlier than the appearance of cognitive deficits, which occurred 6-9 months post-irradiation, as measured in a radial-arm maze. These findings suggest that a cascade of events, beginning with capillary loss, leads eventually to cognitive dysfunction. However, the limited numbers of animals (2-6) per group and sampling times, the lack of a quantitative assessment of demyelination and glial cell damage, and the absence of dose-response data leave it uncertain whether there is a causal relationship between the capillary loss and the cognitive deficits.
The specific aims of the present grant proposal should strengthen the evidence. If early damage to the blood vessels can be correlated with the late onset of cognitive deficits, it will not only have important mechanistic implications, but it would also provide an early biomarker for testing therapeutic interventions designed to ameliorate radiation-induced brain dysfunction. Such therapeutic intervention studies could potentially be performed in as little as 10 weeks.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA113321-02
Application #
7073347
Study Section
Clinical Neuroscience and Disease Study Section (CND)
Program Officer
Stone, Helen B
Project Start
2005-06-03
Project End
2009-04-30
Budget Start
2006-06-01
Budget End
2007-04-30
Support Year
2
Fiscal Year
2006
Total Cost
$221,402
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
Brown, William R; Thore, Clara R (2011) Perivascular fibrosis in multiple sclerosis lesions. Brain Pathol 21:355
Brown, W R; Thore, C R (2011) Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol 37:56-74
Brown, William R (2010) A review of string vessels or collapsed, empty basement membrane tubes. J Alzheimers Dis 21:725-39
Robbins, Mike E; Payne, Valerie; Tommasi, Ellen et al. (2009) The AT1 receptor antagonist, L-158,809, prevents or ameliorates fractionated whole-brain irradiation-induced cognitive impairment. Int J Radiat Oncol Biol Phys 73:499-505
Mott, Ryan T; Thore, Clara R; Moody, Dixon M et al. (2009) Reduced ratio of afferent to total vascular density in mesial temporal sclerosis. J Neuropathol Exp Neurol 68:1147-54
Brown, William R; Moody, Dixon M; Thore, Clara R et al. (2009) Microvascular changes in the white mater in dementia. J Neurol Sci 283:28-31
Brown, William R (2009) Association of preterm birth with brain malformations. Pediatr Res 65:642-6
Atwood, Todd; Payne, Valerie S; Zhao, Weiling et al. (2007) Quantitative magnetic resonance spectroscopy reveals a potential relationship between radiation-induced changes in rat brain metabolites and cognitive impairment. Radiat Res 168:574-81
Brown, William R; Moody, Dixon M; Thore, Clara R et al. (2007) Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well. J Neurol Sci 257:62-6
Brown, William R; Blair, Robert M; Moody, Dixon M et al. (2007) Capillary loss precedes the cognitive impairment induced by fractionated whole-brain irradiation: a potential rat model of vascular dementia. J Neurol Sci 257:67-71

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