DOWN SYNDROME: AGE-DEPENDENCE OF PIB BINDING IN POSTMORTEM FRONTAL CORTEX ACROSS THE LIFESPAN

Abstract

Beta-amyloid (Aβ) deposition in brain accumulates as a function of age in people with Down syndrome (DS). By 40 years of age, virtually all people with DS have sufficient neuropathology for a diagnosis of Alzheimer disease (AD). In vivo imaging using the C-11-Pittsburgh Compound B (PiB) ligand has facilitated studies linking Aβ, cognition, and dementia in people with DS. However, there are no studies of PiB binding across the lifespan in DS. The current study describes in vitro 3H-PiB binding in the frontal cortex as a function of age and in comparison to sporadic AD. We used the highly fluorescent PiB derivative, 6-CN-PiB, which has similar binding properties as PiB in fixed tissue to visualize amyloid plaques and, if present, cerebral amyloid angiopathy (CAA) to determine what types of pathology PiB binding represents in vivo. In vitro 3H-PiB binding was measured in frozen frontal cortex of autopsy cases with DS in comparison to non-DS controls and sporadic AD cases. Non-specific binding was measured in the presence of 1 μM BTA-1. Tissue from 71 cases included young controls (YC, 1–39 years; N = 12), old controls (OC, 42–67 years; N = 13), DS (1–39 years; N = 8), DS with AD neuropathology (DSAD, 40–66 years; N = 31), and sporadic AD (67–88 years; N = 7). 6-CN-PiB binding in fixed frontal cortex was used to visualize binding to plaques and CAA. PiB binding was highest in DSAD and AD cases relative to controls. In DS, 3H-PiB binding was significantly associated with age. After age 40 years in DS, there was a dramatic rise in 3H-PiB binding along with increasing individual variability. 3H-PiB binding correlated with the amount of extracted Aβ42. Using fixed frontal tissue and fluorescent 6-CN-PiB, neuritic and cored plaques along with extensive CAA in vessels showed 6-CN-PiB binding. No binding for neurofibrillary tangles was observed. These results suggest that cortical 11C-PiB binding detected by positron emission tomography imaging reflects both plaques and extensive CAA binding in DS cortex. Funding: NIH/NICHD grant R01HD064993 (EH, FAS), NIH R21NS080576 (HL, HPS), BrightFocus A20140445 (HL) and NIH/National Institutes on Aging (NIA) P50AG16573, NIH/NIA R01AG21912 and NIH/NICHD R01HD065160 (ITL, ED).