Brain pathology and neuronal losses in the living brain of Alzheimer's patients

2-(1-{6-[(2-[F-18]Fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP)–the first molecular imaging probe reported to be effective in the visualization of neuropathology in the living brain of Alzheimer's disease (AD) patients–labels amyloid-like aggregates (Aβ plaques and neurofibrillary tangles (NFTs)) both in vitro and in vivo. [F-18]FDDNP has proven useful in following reliably the neuropathological progression of the disease in the living brain, more specifically: (a) the distribution of [F-18]FDDNP accumulation follows known patterns of pathology deposition established from pathological determinations by Braak and Braak; (b) the degree of [F-18]FDDNP brain deposition correlates well with behavioral measures in these patients (e.g., MMSE); and (c) conversion of controls to MCI, and MCI to AD have also been reliably followed with high precision and sensitivity. These results in humans are logically paralleled with transgenic rodents, e.g., the triple Aβ transgenic rat model, recently developed by Cephalon Inc. and Xenogen Biosciences. We have also established that quantification of the resulting decreases in 5-HT1A receptor densities with PET is excellent in vivo marker of neuronal damage, particularly the vulnerable glutamatergic pyramidal neurons in hippocampus. Using 4-[F-18]fluoro-N-{2-[1-(2-methoxyphenyl)piperazinyl]ethyl}-N-(2-pyridinyl)benzamide ([F-18]MPPF) with PET imaging we found that AD patients had receptor densities significantly decreased in both hippocampi and in dorsal raphe nucleus. A strong correlation of 5-HT1A receptor decreases in hippocampus with worsening of clinical symptoms (MMSE scores) was also found. Decreases in 5-HT1A receptor measures correlate with decreased glucose utilization ([F-18]FDG PET) and with increased neuropathological loads ([F-18]FDDNP PET) in several neocortical regions in the same AD subjects.