Previous feasibility analysis demonstrated the possibility of brain receptor imaging with PET (Small et al., 2006a
). Using receptor-binding concepts, the feasibility of imaging Aβ (and tau) aggregates (SPs and NFTs, respectively) in the living brain of AD patients can be established by analogous analysis. This assumes that the molecular imaging probe binds to the aggregate site(s) in a saturable and specific manner, similar to neuroreceptor binding.
A feature of the pathogenesis of AD is the pathological aggregation of the β-amyloid peptide into fibrillary SPs and the hyperphosphorylation of the tau protein into NFTs. The prospect of in vivo
visualization of these neuropathological lesions has driven several groups [e.g. Pittsburgh (Klunk et al., 2003b
), UCLA (Shoghi-Jadid et al., 2002
), University of Pennsylvania (Kung et al., 2003
)] to search for imaging biomarkers of these pathologies. The ideal AD imaging biomarker should be specific for the intended molecular targets (e.g. amyloid and tau aggregates or both), clear well from non-specific binding areas (i.e. have low general lipid binding, like white matter), and yield a reliable signal to noise ratio for amyloid/tau to non-specific sites. All this assumes that the probe binds to the aggregate site(s) in a saturable and specific manner, similar to neuroreceptor binding, although it is now apparent that amyloid and tau aggregates are complex conglomerates that contain multiple binding sites with different affinities for probes (e.g. [18F]FDDNP binds at sites different from thioflavin probes in general). Similar to receptor binding, binding of Aβ (and tau) aggregates should be displaceable in vivo (Kepe et al., 2006
Two ligands emerged as primary candidates for imaging protein aggregates in the living brain. These are 1,1-dicyano-2-[6-(dimethylamino)-2-naphthalenyl]-propene ([18F]FDDNP) and N-methyl-[11C]2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (Pittsburgh compound B or PIB). PET studies using both ligands are able to discriminate between AD patients and controls, potentially track conversion from mild cognitive impairment to dementia (see ) and discriminate patients diagnosed with AD from Prion dementia (Small et al., 2006b
; Mintun et al., 2006
; Boxer et al., 2007
; Rabinovici et al., 2007
Figure 1 Provides representative examples of PET images (FDDNP) binding and glucose metabolism in subjects diagnosed with MCI (mild cognitive impairment), AD (Alzheimer disease), and Healthy Control. Bright areas show increased glucose utilization and FDDNP binding. (more ...)
Results in living patients with [18F]FDDNP confirm the in vitro
analysis of feasibility about in vivo
detection of brain pathologies in dementia patients. Analysis of binding data in all neocortical areas of AD patients offers an understanding of the progressive nature of the disease in agreement with the Braak model of brain neuropathological changes (Braskie et al.
, unpublished observation). Excellent correlations with glucose metabolic rates (FDG-PET) in the same subjects are also observed. Initial neuropathological processes occur in the medial temporal lobe, expanding later to the rest of the temporal lobe, the parietal lobe and finally engulfing the whole neocortex. Brain pathology accumulation in the medial/lateral temporal lobe, and not the average Logan standard uptake volume (SUV) throughout the cortex, is emerging as a key tool to identify early brain pathology in agreement with earlier reports (Shoghi-Jadid et al., 2002
). The sensitivity of [18F]FDDNP to both NFTs and SPs offers an opportunity to follow the neuropathological evolution of the disease, initiated by intraneuronal NFT formation in the transentorhinal cortex, entorhinal cortex and hippocampus. [18F]FDDNP also has permitted the visualization of tauopathies in living patients. Frontal lobe dementia patients present prominent frontal and temporal signals compared with controls, suggesting [18F]FDDNP utility in differentiating FTD from AD (Small et al., 2002
; Boxer et al., 2007
PIB retention also differentiates AD patients from controls (Klunk et al., 2003a
). Healthy control subjects show little PIB retention in cortical areas, while patients diagnosed with AD show PIB retention in frontal, temporal and parietal regions. In the cerebellum and the white matter, areas without known amyloid distribution, retention in controls and AD patients were comparable with PIB. However, the pattern is somewhat distinct from the pattern of distribution of protein aggregates in the brain that typically begins in the entorhinal areas and progress to involve the other limbic and neocortical areas.
The early success with the use of [18F]FDDNP (Shoghi-Jadid et al., 2002
) and PIB (Klunk et al., 2004
) offers an unprecedented opportunity to follow the neuropathological evolution of AD in living subjects. These in vivo
probes can also be applied to examine the biology of related disorders such as depression where there is considerable overlap in neurobiological substrates. Post mortem studies in patients with late-life depression are limited and point to focal pathological changes that may contribute to the pathophysiology of the disorder (Rajkowska, 2000
). Post mortem tissue from well characterized samples will help better elucidate the pathways to depression, especially if the post mortem data can be integrated with antemortem neuroimaging findings.