(Author's abstract): The goal of the research proposed in this application is to gain an objective clinico-pathological understanding of behavioral disorders seen in dementia of the Alzheimer type, in order to provide a framework for the assessment and treatment of these disturbances. Behavioral disorders are seen in approximately 60 percent of patients with a clinical diagnosis of probable Alzheimer's disease (AD), and are a major cause of disability and institutionalization. These disturbances lack objective clinical criteria, their neuropathological basis is unknown, and effective treatments for them are largely unavailable. Preliminary studies suggest that some behavioral disturbances commonly seen in dementia may be associated with abnormalities of circadian rhythms, and that degenerative changes in the neurological structures thought to be necessary for circadian rhythmicity may occur in AD. These findings may have important implications for diagnosis and treatment.
The specific aims of this research are to test whether abnormalities of specific circadian parameters will define specific subtypes of behavioral disorders in AD (pacing and sundowning), and to determine the pathologic alterations responsible for these syndromes. This will be accomplished with a detailed longitudinal clinical evaluation of AD patients being cared for in the same hospital environment, followed by post-mortem brain analysis. The clinical evaluations (75 patients studied once every 6 months for 3 years) will include objective measurement of the circadian cycles of rest-activity and core body temperature. The neuropathological examinations (approximately 15/yr) will focus on the suprachiasmatic nuclei (SCN) and the optic nerve, structures found to be altered in AD patients. Findings in the SCN and optic nerve will be correlated with clinical findings and also with pathologic changes elsewhere in the brain.
| Zipser, B D; Johanson, C E; Gonzalez, L et al. (2007) Microvascular injury and blood-brain barrier leakage in Alzheimer's disease. Neurobiol Aging 28:977-86 |
| Harper, David G; Volicer, Ladislav; Stopa, Edward G et al. (2005) Disturbance of endogenous circadian rhythm in aging and Alzheimer disease. Am J Geriatr Psychiatry 13:359-68 |
| Harper, David G; Stopa, Edward G; McKee, Ann C et al. (2004) Dementia severity and Lewy bodies affect circadian rhythms in Alzheimer disease. Neurobiol Aging 25:771-81 |
| Volicer, L; Harper, D G; Manning, B C et al. (2001) Sundowning and circadian rhythms in Alzheimer's disease. Am J Psychiatry 158:704-11 |
| Harper, D G; Stopa, E G; McKee, A C et al. (2001) Differential circadian rhythm disturbances in men with Alzheimer disease and frontotemporal degeneration. Arch Gen Psychiatry 58:353-60 |
| Greco, F A; Satlin, A; Solomon, A K (2000) Abnormal erythrocyte anion exchange in Alzheimer disease. Arch Pathol Lab Med 124:1141-6 |
| Khodeir, M; Conte, E E; Morris, J J et al. (2000) Effect of decreased mobility on body composition in patients with Alzheimer's disease. J Nutr Health Aging 4:19-24 |
| Stopa, E G; Volicer, L; Kuo-Leblanc, V et al. (1999) Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J Neuropathol Exp Neurol 58:29-39 |
| Volicer, L; Wells, J M; McKee, A C et al. (1999) Enhanced inhibition of free radical-induced deoxyribose breakdown by Alzheimer brain homogenates. Neurosci Lett 270:169-72 |
| Johnson, K A; Jones, K; Holman, B L et al. (1998) Preclinical prediction of Alzheimer's disease using SPECT. Neurology 50:1563-71 |
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