Thanks to a compound that allows live imaging of astrocytes—those star-shaped glial cells in the brain—scientists find that the cells are highly activated early on in Alzheimer's disease (AD). A comparison of positron emission tomography (PET) scans between people with mild cognitive impairment (MCI) and AD revealed that the ligand, 11C-Deuterium-L-Deprenyl (C-DED), which binds preferentially to mitochondria in astrocytes, is most prominent in MCI patients who also test positive for amyloid plaques. The data are published in January's The Journal of Nuclear Medicine by researchers led by Agneta Nordberg of the Karolinska Institutet in Stockholm, Sweden. "It supports the theory that astrocytosis is a very early phenomenon in the development of Alzheimer's disease," Nordberg told ARF in an interview. "Astrocytes might increase in number very early to try to prevent deposition of amyloid."

Mystery shrouds the role of neuroinflammation in AD—is it a cause or consequence of the disease? If PET tracers can shine a light on when and where inflammation takes place in the pathological progression of AD, scientists may be able to figure out the answer. Previous studies that imaged activated microglia in AD did not resolve whether activation was related to amyloid deposits or not (see Edison et al., 2008 and Wiley et al., 2009). Postmortem studies on AD brains suggested that astrogliosis, shown by C-DED binding, is most pronounced early in AD, when a person is still cognitively normal (see Gulyás et al., 2011). Until now, however, no PET studies tried to use C-DED to investigate the relationship between astrocytes and amyloid in the living brains of AD and MCI patients. Nordberg and colleagues took that step using C-DED, an irreversible monoamine oxidase B (MAO-B) inhibitor, which binds to the enzyme that occurs abundantly on the astrocyte mitochondrial membranes. Since reactive astrocytes ramp up production of MAO-B, binding of C-DED is a good indicator of astrocytosis. Researchers have used C-DED to image astrocytes in patients with epilepsy, Creutzfeldt-Jakob disease, and amyotrophic lateral sclerosis, and those studies revealed that astrocytosis happens early in all of those diseases.

First author Stephen Carter and colleagues conducted C-DED PET scans on 14 healthy controls, seven AD patients, and eight people with MCI. The researchers scanned MCI and AD patients with PET for senile plaques using the amyloid ligand Pittsburgh Compound B (PIB), and for glucose metabolism by using fluorodeoxyglucose. MCI patients showed elevated C-DED binding in the frontal and parietal cortices relative to both controls and AD patients. That binding was most pronounced for MCI patients who were positive for plaques. However, the increased C-DED binding did not anatomically coincide with plaques. "What was surprising was that when amyloid was up [in the AD patients], the astrocytosis was down," said Nordberg. This hints that astrocytosis might be a very early event in the disease, waning as Aβ gets deposited. Or, it may be that a different kind of astrocyte becomes active later on in the disease, said Nordberg. "We can speculate that there are different types of astrocytes," she said, and those active at the endstage of the disease may not be detected by the C-DED binding.

There are several other possible reasons these astrocytosis appeared diminished in AD patients, said William Jagust, University of California at Berkeley. As the authors point out, this tracer is dependent on blood flow to the brain—which is known to be reduced in patients with AD—so impaired blood flow, not decreased astrocytes, may have caused lower C-DED binding in AD patients. Alternatively, there may be increased astrocytosis in the reference region of the brain, in this study the gray matter of the cerebellum, making it appear that binding in the cortices is going down. "I think between the technical questions and the small sample size, [the team has] still got a ways to go," Jagust said. But PET imaging using C-DED or similar ligands may prove to be useful to see if future anti-inflammatory drugs slow disease progression, he said.

"The findings are very consistent with the idea that neurodegeneration and inflammation go hand-in-hand," said Kerry O'Banion, University of Rochester Medical Center in New York. Since the C-DED binding was not correlated with amyloid binding, he said, "the work suggests a more global activation of astrocytes."

Several compounds are currently in development that may improve upon C-DED, said Keith Johnson, Massachusetts General Hospital, Boston. Such compounds may, for instance, bind reversibly, instead of irreversibly to MAO. "This should be seen as an early part of the evolution of something which could turn out to be quite useful," he said.

Nordberg's team is now working to image astrocytosis in a large number of subjects with familial AD mutations up to 30 years before they are expected to develop the disease. "The ultimate goal is to try to describe the time course of all stages of the disease," she said.—Gwyneth Dickey Zakaib

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References

Paper Citations

  1. . Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis. 2008 Dec;32(3):412-9. PubMed.
  2. . Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. Arch Neurol. 2009 Jan;66(1):60-7. PubMed.
  3. . Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography. Neurochem Int. 2011 Jan;58(1):60-8. PubMed.

Further Reading

Papers

  1. . Microglia, amyloid, and cognition in Alzheimer's disease: An [11C](R)PK11195-PET and [11C]PIB-PET study. Neurobiol Dis. 2008 Dec;32(3):412-9. PubMed.
  2. . Carbon 11-labeled Pittsburgh Compound B and carbon 11-labeled (R)-PK11195 positron emission tomographic imaging in Alzheimer disease. Arch Neurol. 2009 Jan;66(1):60-7. PubMed.

Primary Papers

  1. . Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med. 2012 Jan;53(1):37-46. PubMed.