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Risk for Psychosis Marked by Overactive Microglia

16 Nov 2015

November 17, 2015. Elevated microglial activity marks the brains of those at risk of developing full-blown psychosis, according to a study published online October 16 in the American Journal of Psychiatry. Led by Oliver Howes of Imperial College London, UK, the study used positron emission tomography (PET) to screen brains for activity of microglia, non-neuronal cells that participate in immune responses. This revealed elevated microglial signals in people at risk for psychosis, as well as in those with schizophrenia.

The findings suggest that microglia may hold early signs of psychosis development, and may be an important avenue for new therapies that don't target neurotransmitters, as current antipsychotic medications do.

"This is a whole different type of biology to work with," said Peter Bloomfield, first author of the study. "A potential therapy might target a completely different subset of cells than current therapies do."

The new findings also push back the time at which signs of inflammation can be detected in the brains of people with schizophrenia. Postmortem studies have found increases in inflammatory molecules (see SRF related news report) and microglia density in people who had lived with schizophrenia for years (e.g., Radewicz et al., 2000). Two previous PET imaging studies also found enhanced microglial activity in schizophrenia (Doorduin et al., 2009), including recent-onset cases (van Berckel et al., 2008).

But the new study shows that neuroinflammation can precede psychosis onset, which means it is not just a consequence of living with a severe mental illness or taking medications. Bloomfield and colleagues screened people deemed at "ultra-high risk" (UHR) for psychosis: These people seek help for symptoms that do not cross the threshold for full-blown psychosis. Of UHR people, about a third develop psychosis within three years, usually with a diagnosis of schizophrenia (Fusar-Poli et al., 2012).

Researchers have converged on UHR cohorts to look for the earliest brain or biomarker signs of illness without medication complications. Blood tests have already detected signs of increased inflammation in this population (Perkins et al., 2015), and Howes' group has previously reported signs of increased dopamine synthesis capacity in a UHR group, particularly in those who eventually became psychotic (see SRF related news report). This raises questions about how the dopamine dysregulation is related to the microglial activity, said Anissa Abi-Dargham of Columbia University in New York City, who was not involved with the study.

"Is the inflammation a result of the dopamine dysregulation that they detect at the same stage, or are they both related to some other reason that sets them both in motion?" she asked in an interview with SRF.

Tracking translocator protein

Long considered mere support cells for neurons, microglia are increasingly recognized as key players in the brain. Microglia influence the environment around neurons by eating cellular debris, monitoring for foreign invaders, and promoting the release of inflammation-related molecules. Recent studies cast microglia in a more direct role in engineering neural connections (Stephan et al., 2012), with overactive microglia proposed to bring about a deficit in synaptic connectivity in schizophrenia.

Bloomfield and colleagues used a radioactive ligand called [11C]PBR28 to monitor microglial activity during the PET scan. PBR28 binds to a translocator protein found in mitochondria, particularly in those within microglia, and the protein is upregulated in inflammation. PBR28 produces a better signal than a radioligand used in previous studies, called PK11195. One caveat, however, is that people carrying a specific genetic polymorphism do not bind PBR28 very well, so the researchers genotyped each participant to take this into account.

With the new radioligand, the researchers picked up an elevated microglial signal in 14 UHR participants compared to 14 age-matched controls, whether measured over total gray matter, or in the frontal or temporal lobes. The size of the signal correlated with how severe the symptoms were (r = 0.730), suggesting a specific relationship to illness.

Consistent with this, the enhanced microglial activity did not seem a consequence of medication, as the results stood even if the two people who had taken medication were left out of the analysis.

While the study was being written up, the UHR participant with both the highest microglial signal and the most pronounced symptoms developed psychosis. The researchers will be following up with the rest of the UHR group to see if there is a relationship between neuroinflammation and psychosis onset, Bloomfield said.

This state of high microglial activity was maintained in schizophrenia: A slightly higher microglial signal emerged for 14 people with schizophrenia compared to 14 age-matched controls. Unlike the UHR group, however, the microglial signal did not correlate with symptoms. This might be expected, given that medication, chronicity, and aging effects could blur such a relationship, Abi-Dargham said.

What originally spurs the elevated microglial activity remains unclear. The researchers suggest that it may be a protective response to a more primary mishap, perhaps involving neurotransmitter dysfunction. Alternatively, the microglial activity might reflect an aberrant inflammatory response, which may be soothed by anti-inflammatory therapies. Clinical trials of anti-inflammatory agents have found mild success in schizophrenia (Sommer et al., 2014).

"There's an idea that, initially, microglial activity could be a helpful response that over time progresses to have a more detrimental impact," Bloomfield said. "But we don't really know at this stage."—Michele Solis.

Reference:

Bloomfield PS, Selvaraj S, Veronese M, Rizzo G, Bertoldo A, Owen DR, Bloomfield MA, Bonoldi I, Kalk N, Turkheimer F, McGuire P, de Paola V, Howes OD. Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study. Am J Psychiatry. 2015 Oct 16. Abstract