New Approach to Imaging Alzheimer Brain Amyloid

The diagnosis of Alzheimer’s disease (AD) is presently hampered by the lack of availability of a diagnostic test that is specific for this disease. A hallmark for the development of AD is the deposition of amyloid in brain. Indeed, the dementia of AD correlates with the deposition in brain of this amyloid, which is composed of an amino acid called Aß; Aß is generally comprised of 42-43 amino acids and this form is abbreviated Aß1-42/43. One possible diagnostic approach to AD is the development of a brain scan that would allow for semi-quantitation of the Aß amyloid burden in human brain. It is known that smaller forms of the Aß amyloid peptide comprised of the first 40 amino acids and designated Aß 1-40 binds to pre-existing amyloid plaques of AD brain. Therefore, the delivery to brain of Aß 1-40 binds to pre-existing amyloid plaques of AD brain. Therefore, the delivery to brain of Aß 1-40 that is radiolabeled to allow for detection by standard radiographic imaging techniques, such as single photon emission computed tomography (SPECT), may allow for not only the diagnosis of AD but also for the semi-quantitation of the Aß amyloid burden in AD brain. The latter would be beneficial in clinical trials that investigate the effects of new therapeutics in slowing the deposition of the amyloid in the brain of subjects with AD. Recent studies from the Principal Investigator’s laboratory indicate that radio labeled Aß1-40 undergoes negligible transport from blood to brain owing to the lack of transportability of this substance through the brain capillary endothelial wall, which makes up the blood-brain barrier (BBB) in vivo. The BBB selectively filters the brain uptake of molecules in the circulation and allows into the brain only those molecules that the brain needs for its metabolism. However, recent studies from this laboratory have shown that the conjugation of radiolabeled Aß1-40 to certain BBB drug delivery systems allows for the brain uptake of radiolabeled Aß1-40. Moreover, recent studies show that despite conjugation of the radiolabeled Aß1-40 to the blood-brain barrier drug delivery vector, the conjugate still binds to the ß-amyloid of AD brain. Further studies from this laboratory have discovered a novel and highly active brain drug delivery vector that is applicable not only for humans but for also Old World primates, such as rhesus monkeys. This is advantageous because aged rhesus monkeys (25-30 years) develop the same P-amyloid in their brains as that developed by patients with AD. Therefore, the necessary pre-clinical work that is required before studies in humans can be performed may now be done and is the subject of the present application. In these studies, Aß1-40 will be radiolabeled and conjugated to the BBB drug delivery system, which is comprised of a monoclonal antibody to the human insulin receptor. This conjugate will then be administered to aged rhesus monkeys and the brains of these animals will then be examined for Aß deposition at 6 to 48 hours after administration. The deposition in brain will be quantified using quantitative autoradiography, which is an experimental analog of SPECT scans performed in humans. The delivery system that will be used in the proposed studies may be modified using genetic engineering techniques so that the delivery system can be adapted to use in humans. Therefore, if the present studies in rhesus monkeys are successful then this work may be then extended to humans to test the feasibility of using this approach as a novel new way of diagnosing AD and estimating the ß-peptide amyloid burden in the brain of these patients.