Novel Biomarkers of Early Schizophrenia Identified

Fran Lowry

June 24, 2016

Two novel biomarkers, hypofrontality and posterior hyperactivity, identified by MRI, have been linked to early signs of schizophrenia, results of a new animal study show.

Being able to detect these early brain changes with MRI could potentially contribute to early diagnosis and new treatments of schizophrenia in humans, investigators, led by Fahmeed Hyder, PhD, professor, Yale University, New Haven, Connecticut, write.

Patients with schizophrenia often exhibit early signs of behavioral abnormalities. However, changes in the brain that underlie these behavioral signs have not been identified, Dr Hyder told Medscape Medical News.

The study was published online May 31 in Biological Psychiatry.

Translatable to Humans?

The investigators sought to characterize functional, metabolic, and anatomic changes in methylazoxymethanol acetate (MAM) rats, an animal model of early schizophrenia, and in saline-treated control (SHAM) rats.

"Prenatal exposure of methylazoxymethanol acetate, or MAM, mutates DNA and alters neuronal connections in a preclinical brain model," said Dr Hyder.

"This MAM model has behavioral impairments that are similar to schizophrenia patients. Past studies have examined the adult MAM rat as a model of schizophrenia patients. Since schizophrenia patients often exhibit early warning signs, such as underage drinking and drug abuse, we studied the MAM model in adolescence to see if there are specific imaging biomarkers," he added.

Using multimodal MRI methods, the researchers identified several biomarkers of anatomic, metabolic, and functional MRI abnormalities in their animal model of early schizophrenia.

"We used these magnetic resonance methods because they can be readily applied in people," Dr Hyder noted.

In the MAM rats, researchers detected functional and metabolic impairments in the orbitofrontal cortex (a part of the prefrontal cortex), which were associated with increased sensitivity to a sugar reward.

"Because the orbitofrontal cortex is involved in the evaluation of reward (for example, sugar, alcohol, and substance or drug), the prefrontal dysfunction may be a biomarker for vulnerability to such reward that is observed in schizophrenia patients in their early stages," Dr Hyder said.

The researchers also detected both functional and metabolic hyperactivity in posterior regions.

Hypofrontality and posterior hyperactivity observed in the MAM rats was supported by anatomic changes in the same regions.

In early adulthood, MAM rats had smaller brains than SHAM rats, especially in the primary visual areas in the posterior region of the brain.

The MAM rats also had larger lateral ventricles in the posterior region than SHAM rats.

"We would like to test these findings in schizophrenia patients who exhibit early warning signs," Dr Hyder said.

"Our findings can be used to diagnose schizophrenia patients at early stages, and then treated. This model recapitulates behavioral, anatomical, metabolic, and functional traits of schizophrenia, and the findings can be translated to humans," he said.

Far From the Clinic

Commenting on the findings for Medscape Medical News, Yvonne W. Lui, MD, from NYU Langone Medical Center, New York City, said the study adds to the growing body of research that is finding early brain alterations in schizophrenia.

"A 2016 consensus report from the World Federation of Societies of Biological Psychiatry states that clear neuroimaging biomarkers are lacking for the early detection of schizophrenia. However, there is a growing body of research using MRI that shows there are functional and structural alterations to the brain in schizophrenic patients," Dr Lui said.

"In addition, PET tracers are currently being developed that could more specifically target mechanisms of disease in disorders such as schizophrenia," she added.

"I think it's a very nice paper. The strength lies in the multimodal imaging that they've done. Most papers use single imaging, and this paper has used essentially four different imaging methods, and this allows us to compare abnormalities with one imaging technique to another imaging technique, from a research perspective," Paul Borghesani, MD, PhD, from the University of Washington, Seattle, told Medscape Medical News.

"From a clinical perspective, we are always seeking imaging correlates of schizophrenia. This is an animal model that is quite some distance from the clinic, so it's a very interesting model that may potentially help us understand schizophrenia, but there is considerable distance from the immediate clinic," he said.

The study was supported by the National Institutes of Health. Dr Hyder, Dr Lui, and Dr Borghesani report no relevant financial relationships.

Biol Psychiatry. Published online May 31, 2016. Abstract


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