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New PET Tracer Visualizes Neuroinflammation and Response to Experimental Therapy in AD Mice



ARTICLE IN BRIEF

In two different studies, investigators described the potential of a new PET neuroimaging agent. In one, the PET tracer tracked the progression of neuroinflammation in mouse models of aging and Alzheimer's disease; in the other, it showed that inflammation in an Alzheimer's mouse model receded following treatment with an experimental oral drug.

WASHINGTON, DC—A new PET tracer for imaging of activated microglia tracks the progression of neuroinflammation in mouse models of aging and Alzheimer's disease (AD), according to a study that was presented here at the annual meeting of the Society for Neuroscience in November.

A second study demonstrated the ability of the same PET tracer to detect and monitor a reduction in neuroinflammation, and therefore visualize a therapeutic response in a mouse model of Alzheimer's disease following treatment with an experimental oral drug previously shown to reverse pathology in middle-stage AD mice.

Together, the studies demonstrate that a noninvasive biomarker for neurodegenerative disease progression and treatment response may finally be at hand, researchers said.

“A noninvasive tracer is hugely important,” said Margaret M. McCarthy, PhD, a professor and chair of pharmacology at the University of Maryland School of Medicine, who was not involved with the studies. “A biomarker of Alzheimer's disease would allow us to diagnose the disease in very early stages and monitor how treatment is working. You could increase or decrease the dose. It will let us test the effects of experimental therapeutics in real time instead of having to wait years. It's absolutely paradigm-shifting to be able to do this.”

The tracer, [18F]GE-180, is highly specific for imaging the translocator protein 18 kDa (TSPO), which is normally expressed at low levels in the brain but increases in response to brain injury and inflammation, in parallel with the extent of microglial activation. An older tracer, 11C-R-PK11195, has a lower affinity for TSPO and is limited by its poor signal-to-background.

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DR. CYNTHIA A. LEMERE: “It may be at least five years before a clinician in the United States could order this test. Until then, it will be most useful for clinical trials and staging of Alzheimers disease and other neurodegenerative diseases marked by inflammation.”

IMAGING INFLAMMATION IN AD MODELS

Investigators used the [18F]GE-180 tracer to image the brains of four young (four months old) wild-type mice, four old (26 months) wild-type mice, and four old transgenic mice with the amyloid precursor protein/presenilin 1 (APP/PS1) genes. In vivo PET imaging revealed an age-dependent elevation in whole brain uptake of the tracer in the wild-type mice, with an even higher uptake in the APP/PSI mice. The same pattern was seen in hippocampal-specific uptake; quantitative analysis of 1 mm brain slices by ex vivo PET and autoradiography, as well as immunohistochemical labeling of mouse brain sections for TSPO and microglia, confirmed the in vivo results.

“Taken together,” the researchers wrote in their abstract, “our studies indicate that [18F]GE-180 has potential as a novel PET tracer for neuroinflammation and may be useful as a biomarker for diagnosis, as well as for monitoring disease progression and treatment effects in human neurodegenerative diseases and animal models.”

The senior author of the study, Cynthia A. Lemere, PhD, an associate professor of neurology at Brigham and Women's Hospital and Harvard Medical School, said the maker of the new tracer, GE Healthcare, is already working with clinicians in the United Kingdom and Canada to image neuroinflammation in patients with Alzheimer's, traumatic brain injury, or multiple sclerosis.

To date, [18F]GE-180 has been administered to 50 patients outside the United States, according to Erin Bryant, a spokesperson for GE Healthcare. The company recently obtained approval for an investigational new drug application from the U.S. Food and Drug Administration (FDA), and expects results in 2015 and 2016 from several investigators in the U.S. working in several disease areas, Ms. Bryant said.

Among those investigators is Joseph C. Masdeu, MD, PhD, FAAN, chair of neurological sciences at Houston Methodist Institute for Academic Medicine and a professor of neurology at Weill Medical College of Cornell University.

“I will be using this compound to study inflammation in ALS,” Dr. Masdeu said. “We will conduct at least two sequential studies on people to see whether the changes in inflammation are restricted to where neurons are lost, and to correlate changes in the brain with changes in markers of inflammation in the blood.”

Even so, Dr. Lemere told Neurology Today, “it may be at least five years before a clinician in the United States could order this test. Until then, it will be most useful for clinical trials and staging of Alzheimer's disease and other neurodegenerative diseases marked by inflammation.”

TRACING TREATMENT EFFECTS

The second study presented at the Society for Neuroscience meeting used the GE-180 tracer to image the effects of treatment with an investigational oral compound, LM11A-31, known to target the p75 neurotrophin receptor. It was developed by the research team of Frank Longo, MD, PhD, currently in the Department of Neurology and Neurological Sciences at Stanford University, along with collaborator Stephen Massa, MD, PhD, at the University of California, San Francisco.

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DR. MICHELLE JAMES: “Back in the 70s, it was initially found in the kidney as an alternative binding site for diazepam. Later it was also found at very low levels in the healthy brain, but when Alzheimers develops, the levels of TSPO go through the roof. Thats why as an imaging biomarker, its beautiful.”

Compounds targeting p75 have previously been shown to reduce the degeneration of both synapses and neurons. Mouse studies published earlier this year found that LM11A-31 inhibited tau phosphorylation and misfolding and reversed late-stage pathology in two AD mouse models. Another study published in 2013 found that it also improved limb movement following a spinal cord injury. The drug has been licensed to PharmatrophiX and has successfully completed phase 1 safety studies; preparatory work is now underway for a phase 2a clinical trial of patients with early-stage AD.

In the paper presented at the meeting, the GE-180 tracer detected a drug effect in mice treated with LM11A-31, with lower levels of the tracer accumulating in the cortex and hippocampus of the eight treated mice compared with nine untreated mice (cortex/muscle: 1.89±0.11 versus 2.31±0.12, p<0.05; hippocampus/muscle: 1.78±0.09 versus 2.17±0.16, p<0.05). Autoradiography and PET results corresponded well with each other and with immunostaining for TSPO and for microglia.

The first study author, Michelle L. James, PhD, an instructor in the departments of radiology, neurology and neurological sciences at Stanford University, told Neurology Today that she has been studying TSPO radiotracers and PET imaging of neuroinflammation for over a decade, since before her PhD work in Sydney, Australia.

“It used to be called the peripheral benzodiazepine receptor,” she said. “Back in the 70s, it was initially found in the kidney as an alternative binding site for diazepam. Later it was also found at very low levels in the healthy brain, but when Alzheimer's develops, the levels of TSPO go through the roof. That's why as an imaging biomarker, it's beautiful.”

Toxicity studies have already shown the tracer to be safe, Dr. James said. “It's absolutely not dangerous. These radio tracers are injected at such low amounts, it would be unlikely for there to be any concerns about safety.”

Other so-called second generation tracers for TSPO, designed to have greater accuracy than the first one, have been developed in recent years. Results from human clinical trials of one, [11C]PBR28, were reported earlier this year. No head-to-head studies have yet been reported between the second generation tracers, but a recent comparison of [18F]GE-180 against the older tracer found that uptake of [18F]GE-180 was 24 percent higher in ischemic lesions and 18 percent lower in contralateral healthy tissue, demonstrating a better signal-to-noise ratio.

“The use of these new tracers is going to have a powerful impact on the understanding of inflammation in nearly all the neurodegenerative diseases — Alzheimer's, Parkinson's, ALS, you name it,” Dr. Masdeu told Neurology Today.

One drawback to the use of [18F]GE-180, he noted, is that about 25 percent of the population has a genotype for TSPO that does not bind to the tracer. “For them, the results are completely negative,” Dr. Masdeu said. “It can't be used in everyone.”

LINK UP FOR MORE INFORMATION:


•. Society for Neuroscience annual meeting abstract: Imaging neuroinflammation in mice using the 18F-GE180 TSPO PET tracer. Society for Neuroscience
    •. Society for Neuroscience annual meeting abstract: Positron emission tomography (PET) imaging using [18F]GE-180 detects reduced microglia activation after LM11A-31 therapy in a mouse model of Alzheimer's disease.
      •. Simmons DA, Knowles JK, Belichenko NP, et al. A small molecule p75NTR ligand, LM11A 3131, reverses cholinergic neurite dystrophy in Alzheimer's disease mouse models with mid- to late-stage disease progression. PLoS One 2014; 9(8):e102136.
      •. Boutin H, Murray K, Pradillo J, et al. 18F-GE-180: a novel TSPO radiotracer compared to 11C-R-PK11195 in a preclinical model of stroke. Eur J Nucl Med Mol Imaging 2014; Epub 2014 Oct 29.