In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease
Introduction
Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder that presents clinically with asymmetrical bradykinesia, muscular rigidity and resting tremor and usually responds well to dopaminergic medication. Later postural instability, bulbar dysfunction and impaired autonomic reflexes may become features (Daniel and Lees, 1993). The condition is neuropathologically characterized by cell loss targeting the substantia nigra pars compacta and the presence of neuronal Lewy inclusion bodies (Gibb, 1992). Other brainstem nuclei, the cingulate and association cortical areas are also involved. Activated microglia were first reported in the substantia nigra of PD patients post-mortem (McGeer et al., 1988). More recently, microglial activation has also been described in the putamen, hippocampus, cingulate and temporal cortex of PD patients in post-mortem tissue (Imamura et al., 2003).
Detailed experimental and human post-mortem studies have shown that activation of microglia, the brain's resident tissue macrophages, has a particularly close association with active brain pathology. Microglia constitute 10–20% of glial cells and are ontogenetically related to cells of mononuclear–phagocyte lineage (Banati and Graeber, 1994). They are known to respond to a variety of pathological stimuli by de novo expression of numerous immunologically relevant molecules including HLA antigens, chemokines and cytokines (Kreutzberg, 1996). The transformation from a resting to an activated state is rapid and often takes place before any other sign of tissue damage or cell death can be seen. The presence of activated microglia is, therefore, a useful indicator of ongoing neuronal injury (Kreutzberg, 1996) and reflects disease activity rather than a specific etiology.
One of the molecules expressed de novo during the ‘activation’ of microglia is the ‘peripheral benzodiazepine binding site’ (PBBS), thought to be a mitochondrial protein that is distinct from the GABAA–receptor complex, the site of central benzodiazepine binding.
PK11195, [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide], is a selective ligand for the PBBS. In vivo and in the absence of invading blood-borne cells, the de novo expression of PBBS occurs primarily in activated microglia (Banati et al., 1997). Based on this relative cellular selectivity, [11C](R)-PK11195 PET has been used as a marker of in vivo microglial activation in inflammatory (Banati et al., 1999, Banati et al., 2000, Cagnin et al., 2001a, Cagnin et al., 2001b), ischemic (Gerhard et al., 2000, Gerhard et al., 2005, Pappata et al., 2000) and degenerative (Cagnin et al., 2001a, Cagnin et al., 2001b, Gerhard et al., 2003, Gerhard et al., 2004) brain lesions.
The contribution of microglial activation to the degenerative process in PD is presently not known, but it is likely to have a damaging rather than a beneficial role (Teismann et al., 2003). There is evidence from humans (Langston et al., 1999) and monkeys (McGeer et al., 2003) exposed to the nigral toxin MPTP that, after a discrete insult, progression of parkinsonian symptoms can occur, and this is accompanied by a prolonged neuroinflammatory response present years after the acute exposure.
A recent PET study using [11C](R)-PK11195 in early Parkinson's disease (Ouchi et al., 2005) reported increased binding potential values in the midbrain but did not address possible cortical involvement nor longitudinal aspects of microglial activation. The aim of our [11C](R)-PK11195 PET study was to determine in vivo the brain distribution of activated microglia in patients with PD, to correlate this with disease severity and duration and to assess changes in levels of activation longitudinally.
Section snippets
Patients and control subjects
Eighteen patients (13 men and 5 women; age range: 50 to 69 years, mean age 59 years and 2 months) were selected with a clinical diagnosis of idiopathic Parkinson's disease according to the UK Parkinson's Disease Society Brain Bank criteria (Daniel and Lees, 1993). None of the patients gave any evidence of cognitive decline nor a history of hallucinations. The patients had a wide range of disease severity (‘off’ UPDRS motor scores 6–70) and duration (1–20 years). Patient details are shown in
Age-matched healthy volunteers
[11C](R)-PK11195 mean BP values in normal control subjects were lowest in the striatum (mean 0.027 ± 0.075) and highest in the pons (mean 0.257 ± 0.085). Binding on the right and left sides of the brain was not significantly different for any of the regions of interest. Table 2 contains the averaged regional BP values for healthy volunteers.
Parkinson's disease patients
Group comparison (two-tailed t test) of findings for the 18 PD patients with those for the 11 healthy age-matched volunteers revealed significant increases
Discussion
In this study, using [11C ] (R)-PK11195 PET as an in vivo marker of peripheral benzodiazepine site expression, we have imaged the pattern of microglial activation associated with PD. Our patients showed a significant increase in subcortical mean [11C](R)-PK11195 binding involving the striatum, pallidum, thalamus and pons. Although first pathologically described in this location, increased substantia nigra microglial activation was only detected in some of our PD cases. Cortical regions
Conclusion
Activation of microglia is a non-specific response to the presence of brain pathology irrespective of the primary cause. [11C](R)-PK11195 PET, an in vivo marker of microglial activation, provides a potential means of localizing active brain disease (Banati et al., 1997, Banati et al., 2000, Cagnin et al., 2001a, Cagnin et al., 2001b). In our PD patients with [11C](R)-PK11195 PET, we observed widespread microglial activation in the brainstem, basal ganglia and frontal areas which did not
Acknowledgments
We thank the patients and volunteers who participated in this study. A. Blyth, H. McDevitt and L. Schnorr provided expert technical assistance with PET data acquisition. I. Trender-Gerhard has critically read the manuscript. N. Quinn and K. Bhatia, National Hospital for Neurology and Neurosurgery, London, kindly allowed us to examine two of their patients. The project has been supported by Action Research (SP 3615), the Parkinson's Disease Society UK (MAP 02/04) and the MRC and the
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