Brain Wise
Spring 2015

Much like other stealth diseases—think pancreatic and liver cancers, for example—schizophrenia is notorious for seeming to arrive only in full-blown severity.

And just as oncology researchers have been seeking biomarkers that signal the presence of neoplasms at a stage when they’re most easily halted, Johns Hopkins psychiatrist Koko Ishizuka and colleagues are on the trail of clues to the earliest workings of the pathology of major mental disorders—long before patients become captives of their symptoms.

The challenge has been to find a true window into the brain in action. Although several lines of evidence indicate that disturbances during neurodevelopment play a role in the etiology of schizophrenia and other major mental disorders, it hasn’t been possible to “see” brain-associated molecular activity as it’s occurring. Just as a publicity photo for a film can’t capture the experience of viewing the actual movie, neither blood cells, induced pluripotent stem cells nor autopsied brains provide a useful way to correlate neuronal changes with dynamic changes in patients’ mood, drive and cognition. What does offer that capability, says Ishizuka, is the nose.

The olfactory epithelium, she explains, is not only a unique part of the central nervous system that regenerates continuously throughout life, it’s a source of easily accessible neurons that originate from the two olfactory bulbs just above the nasal septum.

Using cultured olfactory cells, her research group is able to measure molecular changes that may reflect those in the brain. “We are looking in these neuronal cells,” says Ishizuka, “for molecular markers of phosphorylation of a protein called DISC1.” Her team originally reported that the phosphorylation is a key switch for neuronal maturation and have since found that the phosphorylation level was altered in cells from patients with schizophrenia and some mood disorders. Furthermore, the phosphorylation level was correlated with brain structure and cognitive function, indicating that the phosphorylation may be used as a predictive marker for such clinical phenotypes, after its validation with a larger cohort.

Ishizuka’s team is also looking for potential biomarkers to detect the effects of drug treatment in patients with bipolar disorder. Combining the nasal biopsy with a sophisticated microscopy technique called laser-capture microdissection, which they used to extract olfactory neurons from a larger biopsy sample, they are comparing results from a nasal biopsy before and six weeks after lithium treatment in patients, and results from nasal biopsies between similar time points in control subjects who received no lithium. “In the control subjects, the biomarker should be virtually unchanged from the first to the second biopsy,” says Ishizuka. “However, in lithium-treated patients, the changes in biomarker expression should differ markedly, a likely indication of drug efficacy.”

Results of these studies, says Akira Sawa, director of the Johns Hopkins Schizophrenia Center, could be applied clinically in as little as five years for making timely diagnoses of major mental disorders and for studying treatment responses with existing therapies—drug and behavioral—and perhaps even for testing new ones.

“We believe that by combining a biomarker with imaging studies and clinical evaluation,” says Ishizuka, “we’ll have a powerful set of tools for making an accurate, early diagnosis of schizophrenia and other mood disorders.”