Abstract
Chronic active multiple sclerosis (MS) lesions have a rim of activated microglia/macrophages (m/M) leading to ongoing tissue damage, and thus represent a potential treatment target. Activation of this innate immune response in MS has been visualized and quantified using PET imaging with [11C]-(R)-PK11195 (PK). Accurate identification of m/M activation in chronic MS lesions requires the sensitivity to detect lower levels of activity within a small tissue volume. We assessed the ability of kinetic modeling of PK PET data to detect m/M activity in different central nervous system (CNS) tissue regions of varying sizes and in chronic MS lesions. Ten patients with MS underwent a single brain MRI and two PK PET scans 2 hours apart. Volume of interest (VOI) masks were generated for the white matter (WM), cortical gray matter (CGM), and thalamus (TH). The distribution volume (VT) was calculated with the Logan graphical method (LGM-VT) utilizing an image-derived input function (IDIF). The binding potential (BPND) was calculated with the reference Logan graphical method (RLGM) utilizing a supervised clustering algorithm (SuperPK) to determine the non-specific binding region. Masks of varying volume were created in the CNS to assess the impact of region size on the various metrics among high and low uptake regions. Chronic MS lesions were also evaluated and individual lesion masks were generated. The highest PK uptake occurred the TH and lowest within the WM, as demonstrated by the mean time activity curves. In the TH, both reference and IDIF based methods resulted in estimates that did not significantly depend on VOI size. However, in the WM, the test-retest reliability of BPND was significantly lower in the smallest VOI, compared to the estimates of LGM-VT. These observations were consistent for all chronic MS lesions examined. In this study, we demonstrate that BPND and LGM-VT are both reliable for quantifying m/M activation in regions of high uptake, however with blood input function LGM-VT is preferred to assess longitudinal m/M activation in regions of relatively low uptake, such as chronic MS lesions.
Highlights
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the Central Nervous System (CNS), eventually leading to neurodegeneration
Studies have demonstrated a high binding of PK in acute lesions,[15,16] which is consistent with histopathological studies demonstrating diffuse immune cell infiltration during the early stages of lesion development as compared to the lower levels found in chronic MS lesions.[17]
Time activity curves with Volume of interest (VOI) size
Summary
Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the Central Nervous System (CNS), eventually leading to neurodegeneration. A subset of chronic MS lesions, identified as chronic active or slowly expanding lesions have been described as having a hypocellular lesion center and a rim of activated pro-inflammatory microglia/macrophages (m/M).[1,2,3,4] These lesions demonstrate evidence of active demyelination and axonal destruction at their rim and are felt to contribute to long-term, ongoing tissue damage in MS.[1,3,5,6,7,8] Chronic active MS lesions have been found to be more prominent in progressive disease and their continued expansion may play an essential role in the pathogenesis of progressive MS.[2,9] Differentiating chronic MS lesion sub-types, especially chronic active lesions and recognizing ongoing biological activity, such as a high degree of inflammation, would provide a unique biomarker for disease activity and disability progression. The relatively low level of m/M activation in chronic MS lesions presents a challenge for longitudinal detection of change and requires a sensitive analytic method
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