Cerebral amyloid angiopathy distribution in older people: A cautionary note.

INTRODUCTION: Radiolabeled ligands for fibrillar amyloid beta (Aß) peptides are used in positron emission tomography (PET) for dementia diagnosis. Current ligands do not discriminate parenchymal amyloid plaques from cerebral amyloid angiopathy (CAA). METHODS: We undertook neuropathological examination of 65 older people (81.6 ± 7.96 (mean ± SD) years, 27F/38M): 15 with neuropathological diagnosis of AD, 25 with neuropathological diagnosis of other neurodegenerative dementias (Lewy body dementia and Parkinson disease dementia), and 25 without significant neurodegenerative pathology. RESULTS: We observed CAA in non-Alzheimer's dementia (non-AD dementia) and control brains, of comparable extent to those with neuropathologically confirmed AD. Aß-positive vessel density did not differ significantly between non-AD dementia and control groups. Across all subjects there was a highly significant correlation between vessel Aß40 density and vessel Aß42 density (Spearman rho = 0.855, P < .001). CAA was absent or sparse in subcortical white matter across all patient groups. CONCLUSION: Our data indicate that CAA can be abundant in non-AD brains and raise a cautionary note regarding interpretation of amyloid PET imaging.

Tuning the pKa of Fluorescent Rhodamine pH Probes through Substituent Effects.

Rhodamine spirolactams (RSLs) have recently emerged as popular fluorescent pH probes due to their fluorescence turn-on capability and ease of functionalization at the spirolactam nitrogen. Design of RSLs is often driven by biological targeting or compatibility concerns, rather than the pH sensitivity of the probe, and the relationship between RSL structure and pKa is not well understood. To elucidate the relationship between pKa values and the properties of substituents attached to the spirolactam nitrogen, a series of 19 aniline-derived RSLs is presented. RSLs derived from di-ortho-substituted anilines exhibit pKa tunability across the moderately acidic region (ca. pH 4-6). Evaluation of pKa data using the Fujita-Nishioka model for ortho substituent effects reveals that both steric and electronic substituent properties influence RSL pH responsiveness, with pKa values increasing as substituent size and electron withdrawing character increase. These trends are attributed to changes in the RSL structure induced by large substituents, and to electronic influences on the protonated spirocyclic reaction intermediate. To demonstrate the practical applicability of these probes in completely aqueous environments, RSL-doped conjugated polymer nanoparticles that exhibit a ratiometric fluorescence response to changing pH levels are presented.