In vivo visualization of activated glia by [11C] (R)-PK11195-PET following herpes encephalitis reveals projected neuronal damage beyond the primary focal lesion

A major challenge in the assessment of brain injury and its relationship to the ensuing functional deficits is the accurate delineation of the areas of damage. Here, we test the hypothesis that the anatomical distribution pattern of activated microglia, a normally dormant population of resident brain macrophages, can be used as a surrogate marker of neuronal injury not only at the primary lesion site but also in the antero- and retrograde projection areas of the lesioned neurones. Two patients with asymmetrical herpes simplex encephalitis were serially scanned 6 and 12 months after the acute illness using PET with [C-11] (R)-PK11195, a marker of activated microglia/brain macrophages. The evolving structural changes in the brain were measured by volumetric MRI and compared with the pattern of [C-11](R)-PK11195 binding. Corresponding to the clinically observed cognitive deficits, quantitative [C-11](R)-PK11195-PET revealed highly significant signal increases within the affected limbic system and additionally in areas connected to the limbic system by neural pathways, including the lingual gyrus in the occipital lobe and the inferior parietal lobe, which had normal morphology on structural MRI. The increased [C-11](R)-PK11195 binding, signifying the presence of activated microglia, persisted many months (>12) after antiviral treatment. Cortical areas that showed early high [C-11](R)-PK11195 binding subsequently underwent atrophy. These observations demonstrate that in vivo imaging of activated microglia/brain macrophages provides a dynamic measure of active tissue changes following an acute focal lesion. Importantly, the glial tissue response in the wake of neuronal damage is protracted and widespread within the confines of the affected distributed neural system and can be related to the long-term functional deficits.