In this combined 11
C-PIB and 11
C-(R)-PK11195 PET study, we found that 7 (50%) of our 14 subjects with amnestic MCI had evidence of increased amyloid deposition. This is consistent with neuropathologic studies which report Aβ deposition in a significant proportion of subjects with MCI,29,30
and with the concept that amyloid deposition occurs early in the clinical evolution to AD. During a 2–3-year follow-up, three out of five of our PIB-positive but no PIB negative patients with MCI have converted to clinically probable AD. A longitudinal follow-up of the MCI cohort is ongoing.
Only one of 14 healthy controls showed increased PIB retention; this targeted the anterior cingulate and frontal and temporal cortices. Increased amyloid deposition has been reported in 10% of elderly healthy adults31
and its prevalence increases with age. Our relatively young control group (mean age 63.9 years; SD 5.3) might account for the low prevalence of significant PIB retention in our controls.
Compared to controls, our patients with MCI with increased PIB retention had significantly higher mean levels of cortical PK binding, although, after correction for multiple comparisons, only frontal PK uptake remained significantly raised, probably reflecting the low power of our small series. We detected regional increases in PK binding in our patients with MCI less frequently than raised PIB binding and there are a number of possible explanations for this. First, the specific signal associated with 11
C-(R)-PK11195 uptake is low compared with 11
C-PIB uptake, in part due to the lower density of activated microglia compared with amyloid plaques, as seen in AD,32
and also the higher background nonspecific signal seen with PK compared to that seen with 11
C-PIB. This may have resulted in false negative findings in some patients. When delineating ROIs, we used a probabilistic atlas that takes into account variations in individual brain structures and atrophy. However, a limitation of this study is that we did not formally perform partial volume correction. This also may have resulted in an underestimation of cortical PK binding and false negative findings. Against this, we detected increased binding in the anterior and posterior cingulate, relatively small structures compared to our other interrogated ROIs. Finally, evidence exists for multiple factors apart from Aβ that may influence reactivity of microglia within brain, for example ApoE4 status33
and region-specific differences in the reactivity of microglial populations.34
We did not perform apolipoprotein E genotyping in our subjects. Different ApoE alleles influence amyloid load and so future PET studies may allow the interaction between ApoE genotype, amyloid deposition, and microglial activation to be explored in vivo.
An early 11
C-PK11195 PET study in patients with AD with a lower sensitivity PET camera failed to detect increased binding compared to controls.35
However, there are a number of important methodologic differences between that and the present study. First, they used a cerebellar reference region where specific binding can be found. This may have led to apparent absent binding in other brain areas. Second, their control group consisted predominantly of patients with small cerebral gliomas which can bind PK. Third, they used racemic PK11195 whereas we used the active (R)-enantiomer of PK11195 which has been shown to bind PK binding sites with nanomolar affinity.36
More recently, SPECT15
studies in patients with AD demonstrated significant increases in cortical PK binding, confirming this tracer is capable of detecting microglial activation in vivo. The PET study14
included one patient with isolated memory impairment who demonstrated increased binding in subregions of the temporal lobe, although 18
F-FDG PET was normal at this time, suggesting that microglial activation can occur before metabolic deficits become evident, a viewpoint that is backed up by a histopathologic study in patients with AD.37
Here, microglial activation along with Aβ and congophilic deposits were found in the middle frontal gyrus in the absence of neurofibrillary tangles. These observations and our finding of comparable levels of PK binding in our PIB-positive MCI and AD group provide a rationale for assessing microglial activation in patients with MCI, a significant proportion of whom already have amyloid deposition at the time of clinical presentation.
We found no correlation between individual levels of amyloid deposition, as measured by 11
C-PIB PET, and microglial activation, as assessed by 11
C-(R)-PK11195 PET. This is in contrast to immunohistochemistry studies which have found activated microglial cells clustered at sites of neuritic plaques. However, it has also been demonstrated that not all amyloid plaques are associated with surrounding microglia,38
again implying that multiple factors may be involved in microglial activation as a response to amyloid pathology. Additionally, we found no correlation between MMSE scores or disease duration with PIB retention and PK binding in our PIB-positive subgroup. It is likely, however, that MMSE and other neuropsychometry measures in these patients are influenced by additional pathology such as the presence or absence of neurofibrillary tangles. The recent development of higher affinity PET radioligands which bind to the PBBS, such as 11
may provide greater sensitivity for assessing and quantifying microglial activation in cognitive impairment and allow one to further explore the relationship between microglial activation, fibrillar amyloid, and cognition. The follow-up of PIB-positive patients with MCI with in vivo PBBS markers will enable a better understanding of the time course of microglial activation and its significance as a predictor of clinical progression to AD, and provide the opportunity to monitor the pathophysiologic effects of anti-inflammatory agents in vivo.
Finally, two subjects with MCI with increased PK binding had normal PIB uptake. The first patient (MCI-5) was a 70-year-old woman who had small focal increases in PK binding in the frontal and parietal cortices. Since her symptoms began 5 years ago she has shown no progression in her symptoms, supported by annual clinical, neuropsychological, and neuroimaging assessments. While these do not suggest a neurodegenerative cause for her memory impairment, her diagnosis, and the cause for the PK findings, remains unclear. Continued follow-up will be important in assessing its significance. The second patient (MCI-3), who had increased PK binding in all cortical regions of interest, was a 74-year-old man with a history of memory impairment dating back at least 5 years. This was associated with ventricular enlargement on magnetic resonance neuroimaging but annual clinical and neuropsychological assessments showed no convincing progression over this time. Subsequently he suffered a subacute deterioration in his cognition associated with increasing ventricular enlargement. A ventriculoperitoneal shunt was inserted which led to an improvement in his symptoms. An underlying neurodegenerative condition, again, seems unlikely given the long period of stability in his symptoms. A more definitive diagnosis has not yet been made and it remains to be seen whether shunting remains beneficial over the long term.