Brain clearance of Alzheimer's amyloid-β40 in the squirrel monkey:: A SPECT study in a primate model of cerebral amyloid angiopathy

Squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Previous studies suggested that circulating amyloid-beta40 peptide (Abeta40) crosses the blood-brain barrier (BBB) and may therefore enhance cerebrovascular amyloidosis in aged squirrel monkeys. In the present study, we used single photon emission computed tomography (SPECT) to determine elimination of I-123-Abeta40 and Tc-99m-DTPA. an extracellular marker, from the brain in squirrel monkeys at different age. Following intracerebral microinfusions, the time-activity brain clearance curves indicated bi-exponential removal of I-123-Abeta40 with an initial rapid washout (1.1 less than or equal tot(1/2) 2.7 h). This, plus the observed appearance of 123 I-radioactivity in plasma suggest significant brain-to-blood transport, In contrast, Tc-99m-DTPA was removed slowly by brain interstitial fluid bulk flow (monoexponential decay with 6.8 less than or equal to t(1/2) less than or equal to 16.8 h). A comparison of three middle aged (11 - 16 years old) vs. two old (22 yrs old) monkeys was consistent with an age-related decline in the BBB capacity to remove I-123-Abeta from the brain. This correlated with an age-dependent increase in Abeta40/42 cerebrovascular immunoreactivity and amyloid deposition. Thus. vascular clearance plays an important role in reducing Abeta levels in the squirrel monkey brain and impaired Abeta40 elimination across the BBB may contribute to the development of CAA.