ARTICLE IN BRIEF
Investigators used PET imaging to demonstrate that living patients with progressive multiple sclerosis show signs of extralesional inflammation, which could be used as a biomarker in the development of novel treatments.
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A positron emission tomography (PET) scan with a ligand that binds to a marker of inflammation has enabled scientists to differentiate active versus inactive chronic lesions in patients with secondary progressive multiple sclerosis (MS).
Magnetic resonance imaging (MRI) scans have only been able to localize chronic lesions but do not provide functional information about whether the lesion is surrounded by inflammation. The use of PET in MS remains experimental due to the insensitivity of ligands and the cost. But investigators say that it will someday have a place in the MS clinic to help clinicians identify active inflammation in patients with progressive MS and begin a targeted treatment with anti-inflammatory drugs.
The study findings were reported during the American Academy of Neurology Annual Meeting in Philadelphia and published in the April 7 online issue of the Journal of Nuclear Medicine.
“This tool gives us something new that MRI is not able to do,” said Laura Airas, MD, a neurologist/scientist at the University of Turku and lead author of the study. “PET gives us more information about what is going on in these lesions.”
Dr. Airas said that she and her colleagues set out to see whether PET could provide more useful information about the underlying neuropathology in patients with secondary progressive MS. They have been working with a PET ligand called 11C-PK11195 that binds to translocator protein (TSPO), a marker of inflammation. Their latest study found that the ligand-binding allows them to visualize inflammation in the area in and around the plaque and areas of normal-appearing white matter, that is, in areas that look normal in MRI. TSPO is only expressed in activated microglia.
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They scanned ten patients with secondary progressive MS and eight controls. They were able to co-localize the T1-hypointense lesions with TSPO-binding and determine which lesions were marked by inflammation and which were not. They conducted similar scans on postmortem human MS brain tissue sections.
According to Dr. Airas, the ligand-binding was also significantly increased in the periventricular and normal-appearing white matter [p<0.001] in patients with progressive MS compared to controls. The increased perilesional TSPO-uptake was seen in 57 percent of the chronic T1-lesions identified on an MRI scan. Autoradiography confirmed the ligand binding at the edge of the lesion, which was replete with activated microglia.
The study demonstrates for the first time in living patients, that those with progressive MS show signs of extralesional inflammation, which could be used as a biomarker in the development of novel treatments, Dr. Airas said. “We think PET holds promise as a research tool in understanding the central nervous system pathology of secondary progressive MS.”
She said it could also help identify potential therapeutics aimed at minimizing inflammation and even reducing neurodegeneration.
“If there is a lot of activation at the plaque edge, we would be more likely to prescribe anti-inflammatory agents to see if it would reduce the damage in the brain,” the neurologist said.
For now, the use of PET remains an experimental tool since the ligand used to detect microglial activation, 11C-PK11195, must be made in a cyclotron right before it is administered to a patient in the scanner. Scientists say it is also difficult to use because the signal-to-noise ratio is small. Most PET imaging sites do not have cyclotrons, and its use would be costly. Dr. Airas and others are working on more sensitive ligands that would also have a longer half-life.
They published an animal study using a new TSPO ligand, (18)F-GE-180, in March in the Journal of Nuclear Medicine. “The (18)F-GE-180 is able to reveal sites of activated microglia in both gray and white matter,” Dr. Airas and her colleagues wrote. “Therefore, (18)F-GE-180 is a promising new fluorinated longer-half-life tracer that reveals the presence of activated microglia in a manner that is superior to (11)C-(R)-PK11195 due to the higher binding potential observed for this ligand.”
Dr. Airas said that the findings from PET could ultimately lead to better treatments for progressive MS. In a recent study, they were able to test fingolimod in an inflammatory model in rats and showed it significantly reduced microglial activation.
The finding has led her to rethink what is going on in the brain in patients with progressive MS. It seems as though the nature of the inflammation changes in patients with progressive disease. “In the beginning, immune cells come from the periphery and cause axonal damage,” she explained. “But as the disease progresses, the inflammation becomes compartmentalized within the CNS, and the inflammatory changes and the microglial activation cause collateral damage and neurodegeneration. The traditional anti-inflammatory drugs don't work effectively on this aspect of MS. We need new ways of targeting microglial activation.”
MS patients enrolled in the current PET study were off medication during the scanning phase of the study.
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“With PET, we do see a different aspect of pathology than we do with MRI,” said Celia Oreja-Guevara, MD, PhD, chair of clinical neurological research in the neuroimaging and MS unit at the University Hospital San Carlos in Madrid. “In this current study, the scientists have demonstrated that we can find inflammation in normal-appearing white matter and in chronic plaques in progressive MS. This is an important finding. So far, we have not been able to differentiate between active and inactive lesions with MRI.”
Traditionally, she said, it was thought that secondary progressive MS is not marked by inflammation that can be seen in relapsing and remitting forms of the disease. “But this study tells us that they do have inflammation, which means that there are active lesions. It is important to classify patients and decide which ones might benefit from anti-inflammatory agents.”
David Leppert, MD, head of the neurosciences-neuro-inflammation group and group medical director at F. Hoffmann-La Roche in Basel, Switzerland, is also interested in exploring PET ligands to quantify the brain-diffuse (extralesional) inflammation in normal white matter in MS.
“What will be important is whether scientists can reliably detect brain diffuse inflammation based on activated microglia,” he said. “And then the question becomes: Can we demonstrate that novel MS therapies reduce the form of inflammation? And is this reduction correlated with less brain atrophy and ultimately with less disability?”
Dr. Leppert said that earlier research has linked activated microglia to increased loss of neurons in the brains of patients with secondary progressive MS. The dilemma in MS is that there are many drugs that suppress relapses but these drugs have limited impact on disease progression. “When you don't have a biomarker you can't develop reasonable treatment. PET imaging of TSPO upregulation may be a more immediate way to elucidate molecular mechanisms of neurodegeneration than structural imaging.”
The caveat with the study, he said, is that the ligand has a poor signal-to-noise ratio. “It limits the clinical application,” he added. Better ligands are needed for the use of PET in clinical trials, said Dr. Leppert. “This is extremely exciting work and it will drive attention to a gap in the diagnostic work-up in patients with progressive MS.”
This study was selected by members of the Neurology Today editorial advisory board as one of the noteworthy papers from the AAN Annual Meeting.
THE EXPERTS COMMENT ON PET FOR SECONDARY PROGRESSIVE MS
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•. AAN Meeting Abstract: In vivo PET imaging of activated microglial cells can be used to differentiate between inactive and active chronic lesions in progressive multiple sclerosis: http://bit.ly/1roAz7S
•. Rissanen E, Ruisku J, Rokka J, et al. In vivo detection of diffuse inflammation in secondary progressive multiple sclerosis using PET imaging and the radioligand 11C-PK11195. J Nucl Med 2014; E-pub 2014 Apr 7.
•. Dickens AM, Vainio S, Marjamäki P, et al. Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med