Levels of gene-expression-regulating enzyme altered in brains of people with schizophrenia

Levels of gene-expression-regulating enzyme altered in brains of people with schizophrenia
Using the PET scan tracer Martinostat, Mass. General Hospital investigators found that expression of HDAC epigenetic enzymes (red) is higher in a brain region (arrows) known to be important for executive functions in healthy control participants (left) than in participants with schizophrenia or schizoaffective disorder (right). Credit: Gilbert et. al., Journal of Clinical Investigation

A study using a PET scan tracer developed at the Martinos Center for Biomedical Imaging at Massachusetts General Hospital (MGH) has identified, for the first time, epigenetic differences between the brains of individuals with schizophrenia and those of unaffected study participants. In their report published online in the Journal of Clinical Investigation, the MGH team describes measuring differences in the expression of histone deacetylase (HDAC) enzymes, important regulators of gene transcription, in a brain structure known to be important for key cognitive functions. While reduced HDAC levels had previously been observed in postmortem brain samples from patients with schizophrenia, use of the tracer, named Martinostat, allows measurement of HDACs in the brains of living individuals.

"HDAC enzymes can profoundly influence gene expression in the and may alter cognition," says lead author Tonya Gilbert, Ph.D., formerly of the Martinos Center. "With Martinostat, instead of being confined to analyzing small tissue samples, as in earlier studies, we can now assay HDAC expression and distribution across the entire living brain in a single PET scan. Beyond comparisons between healthy and disease states, this will enable long-term studies exploring the relationship between HDAC levels and disease onset, progression and symptom severity."

Martinostat was developed by a Martinos Center team led by Jacob Hooker, Ph.D. , senior author of the current report, which is the first to use the tracer to compare HDAC levels in the brains of living individuals with and without a neuropsychiatric disorder. Previous animal studies had linked disruption of HDAC levels to cognitive issues, such as memory formation, and HDAC inhibitors have had beneficial effects in mouse models of several neuropsychiatric and neurodegenerative diseases.

For the current study the investigators focused on HDAC levels in the dorsolateral prefrontal cortex (DLPFC), a brain region known to be important for aspects of executive functions—such as working memory, planning and flexibility—that are impaired in people with schizophrenia. A previous study from the research team had observed lower expression of an important HDAC in DLFPC tissue from deceased patients with schizophrenia than in tissue from unaffected individuals.

The current study enrolled 14 individuals with schizophrenia or the related schizoaffective disorder, all receiving long-term treatment for moderately severe symptoms, and 17 healthy control volunteers. All participants completed a standard assessment of cognitive functions typically affected by schizophrenia, and those with schizophrenia had an interview to assess symptom severity prior to PET scanning with the Martinostat tracer.

As expected, the scans revealed that Martinostat uptake indicating binding to HDAC2—the enzyme that was reduced in the postmortem study—was significantly lower in the DLFPC of participants with schizophrenia than in the control group, with levels of reduction corresponding with worse cognitive performance scores. An analysis of Martinostat uptake across the whole brain indicated not only that HDAC expression was lower in some structures adjacent to the DLFPC but, unexpectedly, that it was higher in cerebral white matter and in the cerebellum, structures that also have been associated with .

"While we found preliminary correlations between the relative Martinostat signal in the cerebral white matter and multiple aspects of cognitive testing—such as processing speed and working memory—we don't yet know which types of cognitive factors HDAC is most closely correlated with," says Gilbert, who joined Eikonizo Therapeutics Inc. after completing a postdoctoral fellowship on Hooker's team, with whom she continues to collaborate. "Moving forward we hope to apply advanced cognitive measures to our studies to help better understand the relationship between HDAC levels and human cognition."

Hooker, an associate professor of Radiology at Harvard Medical School, adds, "We're very interested in understanding the role of HDACs across mental illness, as well as neurodevelopmental and neurodegenerative disease. Martinostat is being used by several teams at MGH to study Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, and several non-brain but HDAC-relevant diseases like heart failure and cancer. It's also being used at other academic medical centers to help learn how epigenetic alterations relate to disease processes."


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New PET scan tracer allows first imaging of the epigenetics of the human brain

More information: Tonya M. Gilbert et al, PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia, Journal of Clinical Investigation (2018). DOI: 10.1172/JCI123743
Provided by Massachusetts General Hospital
Citation: Levels of gene-expression-regulating enzyme altered in brains of people with schizophrenia (2018, December 14) retrieved 19 March 2019 from https://medicalxpress.com/news/2018-12-gene-expression-regulating-enzyme-brains-people-schizophrenia.html
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Dec 14, 2018
Not sure what this article is trying to say; however, this area of the brain is the "Lizard Brain", the cognitive behaviour is controlled up under the cerebral cortex?

Dec 14, 2018
Expression genetically? Allowance, switched, unswitched? You show results, not how, where, control, etc.. Your identification is questionable, i.e. causality, and mental state, along w/ pretty pics. I bring this up because Ancient Tribes cured schizophrenia with religion. This research does not appear Holistic or Concentrated.

Not sure what this article is trying to say; however, this area of the brain is the "Lizard Brain", the cognitive behaviour is controlled up under the cerebral cortex?


I'm not an expert at reading pet scans, but I'm pretty sure you're looking at the wrong part of the image. The "Lizard Brain" parts are deeper and maybe further back than the area indicated by the arrows. The part pointed to is part of the network used in higher cognitive functions. I assume it is of interest to researchers because current schizophrenia drugs don't do much to improve the kind of thinking that goes on in that network which must be frustrating to patients.

Dec 16, 2018
Not sure what this article is trying to say; however, this area of the brain is the "Lizard Brain", the cognitive behaviour is controlled up under the cerebral cortex?


I'm not an expert at reading pet scans, but I'm pretty sure you're looking at the wrong part of the image. The "Lizard Brain" parts are deeper and maybe further back than the area indicated by the arrows. The part pointed to is part of the network used in higher cognitive functions. I assume it is of interest to researchers because current schizophrenia drugs don't do much to improve the kind of thinking that goes on in that network which must be frustrating to patients.

The subjects have have a diagnosis, you're assuming, i.e. after the diagnosis; not causal

Dec 16, 2018
What causes the pic, i.e. the metabolic state of the entire brain? The response and the condition are separable. Known, Yung, Tribes, etc. may or may not be pertinent; therefore, this condition as What? A separate event, a suspicious event? Not definitive! Genes, yes; causality? As in Logic or Mindfulness? Teachable? Chemical Changes?

Dec 17, 2018
What are the thresholds for HDAC levels? The brain is thought so large for three reasons. Food surplus, noise reduction of limbs, and anticipating others.
Hyperactive anticipation of others has correlates with bipolar and schizophrenia, and yet that modality of cognition is irrefutably useful.
I also wonder if their can be connectionalist compensation, so that the localization of effects does not take into account neuroplastic adaptation. Not that the exception should make the rule, but in science it is sometimes the lack of something we use to inference, which does not always work if the whole is multiple realized or sheathed beyond distributions.
You cannot count bullet holes in airplanes to tell where to put the armor (holes in engines do not return), but you might use a split brain to explain ad hoc rationalization.
Who needs executive function in a fully autonomous universe? A fool choosing to be a participant!

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