Amyloid PET Ligands for Dementia

The progressive nature of neurodegeneration suggests an age-dependent process that ultimately leads to synaptic failure and neuronal damage in cortical areas of the brain critical for memory and higher mental functions. The increasing age of the population in developed countries suggests that, if unchecked, these disorders will become increasingly prevalent. In the absence of specific biologic markers, direct pathologic examination of brain tissue still is the only definitive method for establishing a diagnosis of Alzheimer disease (AD) and other types of dementia. Pathologic hallmarks of AD are intracellular neurofibrillary tangles (NFT) and extracellular amyloid plaques. NFT are intraneuronal bundles of paired helical filaments mainly composed of the aggregates of an abnormally phosphorylated form of tau protein; neuritic plaques consist of dense extracellular aggregates of β-amyloid (Aβ), surrounded by reactive gliosis and dystrophic neurites. To date, all available evidence strongly supports the notion that an imbalance between the production and removal of Aβ leading to its progressive accumulation is central to the pathogenesis of AD. A growing understanding of the molecular mechanisms of Aβ formation, degradation, and neurotoxicity is being translated into new therapeutic approaches. Whereas AD is the most common cause of dementia in the elderly, postmortem studies have found dementia with Lewy Bodies and frontotemporal lobe degeneration each to account for about 20% of cases. Molecular neuroimaging techniques such as PET have been used for the in vivo assessment of molecular processes at their sites of action, permitting detection of subtle pathophysiological changes in the brain at asymptomatic stages The development of molecular imaging methods for noninvasively assessing disease-specific traits such as Aβ burden in AD is allowing early diagnosis at presymptomatic stages, more accurate differential diagnosis and, when available, the evaluation and monitoring of disease-modifying therapy.