The Temporal Dynamics of Poststroke Neuroinflammation: A Longitudinal Diffusion Tensor Imaging–Guided PET Study with ¹¹C-PK11195 in Acute Subcortical Stroke

Abstract

Animal experiments suggest that 2 different types of activated microglia (AMG) cells occur in the brain after a stroke: local AMG in the area of the infarct and remote AMG, which occurs along affected fiber tracts. We used 11 C-PK11195 PET to image AMG in vivo after stroke in humans in a prospective longitudinal study to investigate the temporal dynamics of AMG and relate local and remote AMG activity to pyramidal tract (PT) damage using diffusion tensor imaging (DTI). Methods: Eighteen patients underwent DTI-MRI, 11 C-PK11195 PET, and behavioral testing within 2 wk and 6 mo of acute subcortical stroke. In 12 patients, the PT was affected by the stroke (PT group), and in 6 patients it was not (non-PT group). Standardized volumes of interest (VOIs) were placed along the PT at the level of the brain stem, semioval center, and infarct. Tracer uptake ratios (ipsilateral to contralateral) were calculated for each VOI and related to tract damage (measured as fractional anisotropy ratio) and clinical outcome. Six controls underwent the same protocol but only once. Results: In both patient groups, local AMG activity in the infarct was increased initially and significantly decreased over the follow-up period. In contrast, remote AMG was detected only in the PT group in the brain stem along the affected tract and persisted during follow-up. No AMG was observed retrograde to the lesion at any time. Remote AMG activity along the affected PT in the brain stem correlated with initial PT damage as measured by DTI in the same tract portion. Local AMG activity in the infarct correlated with anterograde PT damage only at follow-up. After controlling for PT damage, initial AMG activity in the brain stem showed a positive correlation with clinical outcome, whereas persisting AMG activity in the infarct tended to be negatively correlated. Conclusion: DTIguided 11 C-PK11195 PET in acute subcortical stroke demonstrates differential temporal dynamics of local and remote AMG. Activity of both types related to anterograde PT damage as measured by DTI and might contribute differently to clinical outcome.

Amyloid Burden, Neuroinflammation, and Links to Cognitive Decline After Ischemic Stroke

“…A more promising pathophysiological process observed in conjunction with AD pathology as well as ischemic stroke is neuroinflammation and has thus been regarded as one possible link between the 2 pathologies. 40 Recent progress in brain imaging methods, especially the combination of microglia imaging using positron emission tomography and diffusion tensor imaging using MRI, 41 has demonstrated that persisting white matter inflammation after subcortical stroke can lead to the degeneration of fiber tracts over a 6-month observation period, 42,43 which can even occur trans-synaptically in callosal fibers not directly affected by the infarct. 44 Which factors are responsible for maintaining the inflammatory response over several months remains to be investigated with vascular risk factors (hypertension, dyslipidemia, or diabetes mellitus) or genetic factors being obvious candidates.…”

“…Two positron emission tomographic scans were performed between 5 and 7 months after the event to assess Aβ deposition with Pittsburg B compound ( 11 C-PIB) 47 and microglia activation with 11 C-[R]-PK11195. 48 Standardized uptake value ratios for 11 C-PIB (SUVR PIB ) in global gray and white matter relative to the cerebellum 49 and uptake ratios for 11 C-[R]-PK11195 (SUVR PK ) between the stroke-affected and -unaffected hemisphere gray and white matter were analyzed. 50 The cognitive performance at 5 to 7 months after stroke (MoCA2) was negatively correlated with gray matter Aβ deposition (SUVR PIB ; Figure 2).…”

Changes in Callosal Motor Fiber Integrity after Subcortical Stroke of the Pyramidal Tract

“…The PT delineation was based on a previously published method (Radlinska et al, 2009;Thiel et al, 2010), using the infarct region itself and cerebral peduncles as ROIs for fiber tracking. The FA ratio of the PT (rFA PT ) was calculated as a ratio of the affected and nonaffected hemisphere mean FA in the PT and NonPT groups, and as left/right hemisphere FA ratios in the TIA group.…”

PET imaging in ischemic cerebrovascular disease: current status and future directions

“…These anterograde regions of the tract undergo Wallerian degeneration in the weeks and months after the stroke. This relationship was further investigated in a similarly-designed but longitudinal study [64] , in which the extent of anterograde microglial activity in the brainstem was found to be linearly related to the extent of pyramidal tract damage (Fig. 6).…”