Although cellular resolution has not yet been achieved, recent advances in functional and molecular neuroimaging have provided insights into brain structure and physiology, allowing for the study of specific proteins and protein aggregates in ways that are difficult or impossible to achieve at autopsy. Moreover, neuroimaging biomarker studies can immediately correlate data with structure and (dys)function.
The characteristic patterns of cortical and hippocampal volume loss in advanced AD are well known but difficult to quantify with precision at postmortem examination. Atrophy is particularly difficult to measure in the early stages of AD, when it superficially resembles the inconspicuous volume loss commonly observed among elderly individuals without neurodegeneration (so-called ‘healthy’ aging). Distinguishing such subtle differences is not a problem for high resolution quantitative magnetic resonance imaging (MRI). Applied longitudinally, this technique can distinguish the global atrophy rates of healthy aging vs. AD 14
, and predict progression from normal cognition to MCI15
and MCI to AD on the basis of regional volume losses and ventricular expansion over time ()16
. However, atrophy and cognitive decline occur in most neurodegenerative disorders, and while volume changes in certain brain regions may be suggestive of, or consistent with, AD, they do not reveal the underlying pathology.
Patterns of plaque and NFT formation in AD have been thoroughly studied. Until recently, however, antemortem examination of these pathological changes has been nearly impossible. Within the last decade, a number of radiological contrast compounds have been developed that specifically bind and highlight pathological structures in the CNS, including amyloid plaques, neurofibrillary tangles, activated microglia, and reactive astrocytes.
So far, five compounds ([18
C-PIB) have been reported as probes for imaging amyloid plaques in humans. One of these, [18
F] FDDNP, may be retained by neurofibrillary tangles 17
, but no agent that selectively binds to aggregates of tau has yet been described. Such a discovery would be a major advance for molecular imaging.
Of the amyloid-binding compounds, 11
C-PIB, short for “Pittsburgh Compound-B”, has been the most extensively studied and applied in AD research. Uptake of PIB can be measured by positron emission tomography (PET). In individuals with AD, increased retention of PIB shows a very specific pattern that is restricted to brain regions typically associated with amyloid deposition ()18
. Interestingly, an appreciable number of cognitively normal individuals over age 60 show a PIB signal pattern indistinguishable from that of AD subjects, suggesting that PIB PET can detect a preclinical stage of AD19
. When PIB PET and levels of CSF Aβ42
peptide were measured at the same time in individuals ranging from the cognitively normal to those with AD, it showed two discrete groups: PIB-‘negative’ individuals, and PIB-‘positive’ ones. Without exception, the ‘positive’ PIB group had low CSF Aβ42
. This finding is consistent with the idea that soluble Aβ42
is retained in the brain once plaques are formed. Larger longitudinal studies of cognitively normal subjects, comparing those with amyloid to those without amyloid, will be required to evaluate whether the presence of amyloid confers a greater risk of “conversion” to dementia.
Complementing these radiological studies of amyloid deposition, other PET labeling agents have been developed to image inflammation as reflected by activated microglia and reactive astrocytes that surround plaques. Among the changes that microglia undergo upon activation, increased expression of the peripheral benzodiazepine receptor has been exploited as a target for radiological compounds [11
C] (R)-PK11195. Only the third compound has been reported in human AD studies, in conjunction with PIB. In these studies of individuals with MCI or AD, PK11195 and PIB signals showed similar anatomic patterns, but their levels
did not show regional correlation23
; among AD subjects, there was an inverse correlation between PK11195 signal and cognitive performance. These findings suggest that microgliosis occurs concomitantly with amyloid deposition and may play a direct role in cognitive dysfunction. However, better imaging agents are needed to visualize microglial activation in AD. Like microglia, astrocytes show changes upon association with plaques, including elevation of monoamine oxidase B activity24
, but studies employing MAO-B inhibitors as radiotracers in AD are just emerging25
. Larger studies will be needed to understand whether imaging inflammation may inform subject selection for clinical trials, contribute to predictions of prognosis, and allow monitoring of response to therapy.