Thursday, April 18, 2024
4/18/2024
Alzheimer’s disease (AD) is the most common form of dementia among the elderly and affects over five million individuals in the U.S. The pathological hallmarks of AD include the accumulation in the brain of plaques of amyloid and Tau protein. We propose to irradiate the brain of a mouse model of AD with arrays of parallel, thin planes (~0.3 mm) of x-rays spaced about 1.0 mm on-center, called microbeams. These beams arrays are known from studies using synchrotron-generated microbeams to be tolerated by tissues, including the brain and spinal cord, at up to very high doses. Furthermore, other investigators have shown that the irradiation of the brains of a mouse model of AD with conventional, i.e., broad x-rays, ablates the amyloid plaques and improves their cognitive performance. Therefore, our reasoning behind the use of x-ray microbeams to treat AD is that it ablates plaques while sparing the brain. Also, we hypothesize that nearly the entire human brain, perhaps without the brain stem, can be irradiated with microbeams with no consequences. In that regard, for the clinical use the spacing between microbeams can be increased beyond 1.0 mm to prevent beam smearing caused by the cardiac-induced brain pulsation. Moreover, we expect amyloid ablation will be more effective with high-dose-rate microbeams compared to the convention low-dose-rate irradiations because the existing results indicate that higher dose and higher dose rate are more effective in ablating the plaques. Finally, the spacing between the microbeams should facilitate the clearance of the plaque debris, which is also a consideration. The mice will be subjected to cognitive tests and histological studies. Several mice and rats will also be imaged using PET/MRI to examine the reduction of amyloid plaques, and the rate of plaque ablation produced by both microbeams and conventional broad beams. The AD mice model will be purchased with the genetic mutation already affecting the animal. The entire AD mutated animals’ brains, excluding the brain stem, will be irradiated comparatively using microbeams and conventional broad beams. X-ray microbeams are produced by positioning a multislit collimator in the path of the incident beam. The animals will be irradiated and will be kept for at least three months after irradiations. The tests will be performed using a specific ligand that binds to amyloid plaques, giving us the ability to examine the reduction of amyloid plaques between all dose groups, and to examine the rate of the amyloid plaque ablation. The results will provide us the optimal irradiation parameters, i.e. microbeam thickness and spacing, as well as the minimum microbeam dose that produces effective plaque ablation. Confirmation that the necessary irradiations will not cause cognitive deficits would also be an important finding.
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