Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation

doi:10.1016/j.msard.2017.04.008

Multiple Sclerosis and Related Disorders

Volume 15, July 2017, Pages 27-33

https://doi.org/10.1016/j.msard.2017.04.008 Get rights and content

Highlights

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Decreased PK11195 uptake was observed in enhancing MS lesions after the start of natalizumab.
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Decreased PK11195 uptake was observed in in chronic MS lesions after the start of natalizumab.
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PK11195-PET can be used as tool to assess longitudinal change in MS lesions.

Abstract

Objective

The objective of this study is to longitudinally analyze the uptake of [¹¹C]PK11195-PET in multiple sclerosis patients after 3 and 6 months of natalizumab treatment.

Methods

Eighteen MS patients, starting treatment with monocloncal anti-VLA-4, were enrolled in a longitudinal PK-PET study. PK uptake was quantified by volume of distribution (VT) calculation using image-derived input function at baseline, 3 and 6 months. Pharmacokinetic quantification was done using a segmented MRI, and selected areas included white matter, gadolinium enhancing lesions, non-enhancing lesions, cortical grey matter and thalamus. VTs of lesions were calculated in reference to each patient's white matter (VT ratio=VTr), to consider physiologic variability.

Results

Test–retest variability was stable for healthy control (HC). Quantification of PK uptake was completed in 18 patients, and baseline uptake was compared to 6-month uptake. After the start of natalizumab VTr significantly decreased in 13 individual enhancing lesions present within 5 patients (p=0.001). Moreover, VTr of the sum of non-enhancing lesions showed a moderate decrease (p=0.03). No longitudinal changes were detected in normal appearing white matter, the thalamus and cortical grey matter.

Conclusion

A reduction in PK11195 uptake was observed in both enhancing and chronic lesions after the start of natalizumab. PK11195 PET can be used as tool to assess the longitudinal change in MS lesions.

Introduction

PET imaging in combination with the ligand [¹¹C]PK11195 (PK) can be used to evaluate activated microglia and macrophages (MG/MΦ) in vivo (Banati, 2002). PK binds to the translocator protein (TSPO), which is expressed on the outer mitochondria membrane of activated MG/MΦ (Banati et al., 2000, Jucaite et al., 2012). Studies with PK confirmed the most prominent uptake within areas of increased inflammation, especially in enhancing lesions in multiple sclerosis (MS) patients (Debruyne et al., 2003), however most studies evaluating the binding of TSPO have been cross-sectional in design.

The innate immune system plays a pivotal role in the pathophysiology of MS, and important cell types involved in this process are resident microglia and blood-derived macrophages (Gandhi et al., 2010). In acute MS lesions, activated MG/MΦ are involved in demyelination and are the source of reactive nitrogen and oxygen species, which induces oxidative injury to mitochondria, oligodendrocytes and degenerating neurons (Fischer et al., 2012). Iron-containing pro-inflammatory MG/MΦ are present at the rim of chronic active MS lesions and at the site of ongoing demyelination (Mehta et al., 2013).

Natalizumab is a monoclonal antibody (AB) directed against VLA-4, an alpha-4 integrin expressed on leukocyte surfaces (Yednock et al., 1992). This protein interacts with its ligand, vascular cell adhesion molecule 1 (VCAM-1), which is located on endothelium, as well as on MG/MΦ and astrocytes (Chabot et al., 1997, Peterson et al., 2002). Blocking the VLA-4/VCAM-1 interaction decreases the influx of lymphocytes, reducing the effects of the adaptive immune response in the CNS, and subsequently the activation of microglia (del Pilar Martin et al., 2008, Waisman et al., 2015). In human studies, natalizumab therapy was shown to be highly effective for relapsing remitting MS (RRMS) with a significant reduction in relapse rates and MRI lesion activity (Miller et al., 2003, Johnson, 2007).

The current study aims to use PK11195-PET to evaluate the longitudinal uptake of PK11195 in a cohort of MS patients following the initiation of natalizumab treatment.

Section snippets

Human participants

This longitudinal study analyzed the degree of PK11195 uptake in natalizumab treated MS patients. The medication effect on PK11195 uptake was assessed over the period of 6 months (mo), using PK-PET imaging. Twenty-four patients with the diagnosis of RRMS or secondary progressive MS (SPMS) were enrolled in the study. However, the PET data from two participants had to be discarded because they were confounded by excessive motion, and four patients decided to withdraw consent. The eighteen

MS Patient cohort

This was a longitudinal, prospective study of PK11195 uptake in patients initiating natalizumab therapy. Patients were followed with MRI and PK-PET scans at baseline, 3mo and 6mo post natalizumab treatment. The eighteen patients utilized for this analysis are described in detail in Supplementary Table 1. Thirteen women and five men completed the study and mean age was 37.3 years. Mean disease duration, before starting natalizumab, was 8.2 years. The majority of patients were switching therapy

Discussion

We have shown a reduction in PK11195 uptake in MS patients following treatment with anti-VLA4 (natalizumab). We identify a longitudinal decrease of PK11195 uptake in EL, which was anticipated, however we also observe a decrease in this ligand's uptake in NEL. This study supports the potential utilization of PK-PET as an in vivo tool to assess the longitudinal effects of disease modifying agents in MS patients.

PK-PET imaging is a well-established method to assess CNS inflammation, and has been

Disclosures

Dr. Kaunzner received grant support from Biogen. Dr. Kang reports no disclosures. Ms. Monohan reports no disclosures. Dr. Kothari reports no disclosures. Dr. Nealon reports no disclosures. Dr. Perumal reports no disclosures. Dr. Vartanian is a speaker for Teva Neuroscience, has received honoraria for advising Genzyme, and has received grant support from the National MS society, Biogen, and Mallinckrodt. Dr. Kuceyeski reports no disclosures. Dr. Vallabhajosula reports no disclosures. Dr. Mozley

Study funding

Supported by Biogen.

Acknowledgements

We acknowledge Gulce Askin, MPH and Linda Gerber, Ph.D. for their support with the statistical analysis.

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¹: Same contributing author.

View full text

Reduction of PK11195 uptake observed in multiple sclerosis lesions after natalizumab initiation

Highlights

Abstract

Objective

Methods

Results

Conclusion

Introduction

Section snippets

Human participants

MS Patient cohort

Discussion

Disclosures

Study funding

Acknowledgements

J. Neuroimmunol.

NeuroImage

NeuroImage

Nucl. Med. Biol.

Visualising microglial activation in vivo

Glia

The peripheral benzodiazepine binding site in the brain in multiple sclerosis: quantitative in vivo imaging of microglia as a measure of disease activity

Brain

Kinetic analysis and test-retest variability of the radioligand [11C](R)-PK11195 binding to TSPO in the human brain - a PET study in control subjects

EJNMMI Res.

PET visualization of microglia in multiple sclerosis patients using [11C]PK11195

Eur. J. Neurol.

NADPH oxidase expression in active multiple sclerosis lesions in relation to oxidative tissue damage and mitochondrial injury

Brain: J. Neurol.

Iron is a sensitive biomarker for inflammation in multiple sclerosis lesions

PLoS One