The results of our study show that brain PK11195 uptake is low with the overall pattern of PK11195 brain distribution not changing with age. The PK11195 uptake was found to be lowest in the frontal-parietal-temporal cortex and highest in the pituitary gland, midbrain and thalamus. Intermediate tracer uptake was determined in the basal ganglia, occipital cortex, hippocampus and cerebellum, in descending order. We did not observe any hemispheric asymmetry in PK11195 uptake. However, overall PK11195 uptake increased with age, with the thalamus and midbrain showing relatively higher increases compared with other brain regions. Interestingly, we did not find similar significant age-related changes in BP values, except for the thalamus, which showed a trend. The differences in age-related changes between the SUV and BP may be because BP calculation depended on reference region uptake values, and a generalized whole-brain increase in PK11195 uptake, including the ‘reference region’ (See Figure 3), might have rendered BP values largely unchanged, except for the thalamus, where a relatively higher increase in PK11195 uptake resulted in a trend toward statistical significance.
Our findings indicate that, in the brain, there is a relatively low level of TSPO expression, which increases with age, probably due to an increase in TSPO number and/or expression, an increase in cells containing these receptors, or both. Moreover, TSPO expression is lowest in the cortex, particularly in the frontal, parietal and temporal cortices, and highest in the pituitary gland and midbrain, followed by thalamus, basal ganglia, hippocampus and cerebellum. Most importantly, the TSPO distribution pattern remains unchanged with increasing age, being largely similar in children and adults, and no hemispheric asymmetry is seen in the pattern or level of TSPO expression.
The observed PK11195 binding pattern in the present study is consistent with the normal brain TSPO distribution described in the literature [5, 6, 15]. Age-related increases in microglia and upregulation of TSPOs have been reported in several animal, human and postmortem studies [16–23]. It appears that aging may serve as a priming stimulus for microglia , and ontogenic changes in TSPOs, related to increase in glial cells, have been reported in rat and guinea pig brain [25–27]. Significantly greater numbers of microglia and astrocytes were reported in the hippocampus of aged female mice , and an age-related increase in the expression of a microglia-associated antigen was reported in rat and monkey brain [29, 30]. In a human postmortem study, an age-related increase in the number of enlarged and especially phagocytic microglia was found in the brain of neurologically normal individuals, aged 2 to 80 years . It appears that these age-related changes may be due to chronic and persistent neuronal damage over the years, shown to occur in the brains of experimental animals . Age-related oxidative damage to DNA, more for mitochondrial than for nuclear DNA , and accumulation of glycated proteins occurs in normal aging human brain . These changes lead to microglial activation, which is considered to be instrumental in the removal of such damage and routine ‘house-cleaning’. Therefore, an age-related increase in brain PK11195 uptake as seen in the present study is likely related to the age-related increase in activated microglia and increased TSPO expression.
We also found that the age-related increase in PK11195 uptake was higher in the thalamus and midbrain compared with other cortical and subcortical regions, which is consistent with a finding reported previously in an older adult group . In a study of normal adults aged 32 to 80 years, Cagnin et al. found that regional PK11195 BP did not significantly change with age, except in the thalamus, which showed an age-dependent increase . The thalamus is connected to widespread cortical regions. Similarly, the midbrain is reciprocally connected to several brain regions, primarily the thalamus and basal ganglia, and has one of the highest densities of microglia, particularly in the substantia nigra . Any subtle injury in various brain regions, as seen with normal aging, may induce a similar but cumulative and amplified microglial response in the thalamus and midbrain, leading to increased number of TSPOs and therefore increased PK11195 binding [37, 38]. This activation may facilitate remodeling, which is an adaptive process in long-term plasticity in response to progressive age-related neuronal loss. Further synaptic reorganization, most likely a compensatory response to the decline in age-related brain function associated with the reduction in functional integration across the distributed neuronal network (including the thalamus and midbrain), may induce progressively increased microglial activation and proliferation. It is interesting to note that enhanced age-related microglial activation in the midbrain, triggered by various insults and leading to inflammation-derived oxidative stress and cytokine-dependent toxicity, may contribute to nigrostriatal pathway degeneration and hasten progression of disease in idiopathic Parkinson’s disease . Indeed, markedly elevated neuroinflammation has been reported in the pons along with several other brain regions in patients with idiopathic Parkinson’s disease compared with age-matched healthy controls . Therefore, our findings of a higher age-related increase in PK11195 uptake in the midbrain may be reflective of an age-related increase in microglial activation that, beyond a threshold, depending upon the type and severity of noxious stimuli or insults, may result in some neurological impairment. However, there may be other possible explanations that need to be elucidated and explored in future studies.
A few adult studies have reported PK11195 BP values in several brain regions based on similar methodology, and our values are largely consistent with these studies [35, 41]. However, no study is available regarding the pediatric population, and detailed PK11195 brain PET kinetics and data about age-related changes is lacking. We believe that our study fills the existing knowledge gap and provides important information about PK11195 brain kinetics in the maturing brain and age-related changes in TSPO distribution. Our data will also assist in the interpretation and analysis of PK11195 PET scans in various neuroinflammatory conditions, especially in the pediatric population. The present study also suggests that SPM analysis can be useful for the evaluation of global cortical differences in PK11195 uptake.
One of the limitations of this work is the selection of a reference region for the calculation of BP, and as a result the calculated BP values may not be the true estimate of actual receptor ligand binding. Ideally, arterial sampling should be performed to obtain the true input function; however, it is not practical in routine clinical work, particularly in the pediatric population. A cluster analysis may be a reasonable compromise to obtain an estimate of a reference region as a substitute for the true input function, but this approach is only valid in the case where the whole brain is not expected to be uniformly involved in the neuroinflammatory process. Overall visual and SUV analysis may help in these cases.
Another limitation is the selection of children; although we recruited only those children in whom focal neuroinflammation was ruled out, they were not completely healthy children. It is difficult to recruit completely ‘normal’ children because of ethical constraints in exposing children to the radiation associated with PET studies. Further, allowing for the fact that a few of our children might have had subtle neuroinflammation or some other conditions which might have led to increased PK11195 uptake, completely normal children would be expected to have even lower PK11195 uptake values than observed here, and therefore will further enhance and strengthen our finding of age-related increases in brain PK11195 uptake. It is worth noting, however, that age-related changes observed in the pediatric age-range may not be completely representative due to possible differences in the level of neuroinflammation in these children, if any. It also infers that the normal pediatric PK11195 values should be equal to or less than the normal adult values and, as a result, pediatric PK11195 values that exceed adult values can be safely considered to be abnormal. This information has a practical implication for future studies using PK11195 PET in children, where only normal adult PK11195 data may be available for comparison purpose.