In Vivo Imaging of Synaptic Density in Schizophrenia

PET tracer may demonstrate that schizophrenia is linked to decreased brain synapses

Patrick D. Skosnik, Ph.D., and Rajiv Radhakrishnan, M.D.

Yale University

Funded in September, 2016: $200000 for 3 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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PET tracer may demonstrate that schizophrenia is linked to decreased brain synapses

Investigators will use a newly developed positron emission  tomography (PET) tracer in individuals with schizophrenia to examine whether this disorder, and its symptoms and degrees of severity, are directly associated with decreases in brain synapses where transmission of electrochemical messages from one brain cell to another occur.  

When individuals first show signs of schizophrenia, usually in their early 20’s, magnetic resonance imaging (MRI) shows that the brain’s areas of grey matter (brain cells) and white matter (nerve fibers that connect brain regions) are reduced. Moreover, this reduction or “atrophy” progresses over the course of the disease. However, postmortem/autopsy studies have shown that it is not the brain cells themselves that atrophy. Rather, atrophy occurs in two essential structures that transmit brain cells’ electrochemical messages: “axons” and “dendrites.” Brain cell axons are fibers that send the cell’s electrochemical messages, while dendrites on neighboring cells receive those messages. This message exchange occurs at a junction called a “synapse.”

In schizophrenia, microscopic examination of autopsied brain tissue shows that dendrites receiving messages carried by the excitatory neurotransmitter glutamate are shorter and less dense. Further, the presynaptic terminals of axons (located at the ends of axon fibers) have also been shown to be atrophied. This finding corresponds to studies showing that schizophrenia is associated with decreased levels of glutamate, a neurotransmitter involved in several functions including mood, reward, attention, and learning. It is possible, therefore, that lower levels of these neurotransmitters in schizophrenia correspond to decreases or destruction of the synapses that facilitate their passage from one cell to another.

Now, for the first time, researchers will be able to measure the density of brain synapses in schizophrenia in vivo (i.e. in living patients). This is possible using a new PET tracer ([11C] UCB-J) that was recently developed at Yale. The tracer binds to specific proteins located on the ends of axon fibers, just prior to the synapse where the axon sends its message to awaiting dendrites. The binding of the tracer to this protein will serve as a proxy for measuring the density of synapses in living patients. Moreover, the investigators will be able to assess changes in the density of synapses over time (i.e. as the disease progresses).

The investigators hypothesize that people with schizophrenia will have decreased synaptic density. Moreover, they hypothesize that this decreased density will be correlated with worse symptoms and greater deficits in information processing as measured by electroencephalography (EEG).

In this preliminary study, they will use this Yale-developed PET tracer to see if there are differences in synaptic density between 12 patients with schizophrenia and 12 healthy adults. They will also examine whether decreases in synaptic density are correlated with symptom severity and cognitive performance. Lastly, they also will use EEG to measure alterations in information processing, and will attempt to determine whether such alterations relate to degree of synaptic loss.

Significance : This study may reveal that presynaptic dysfunction, which results in the loss of synapses, is a core feature of schizophrenia. If so, future research could be aimed at testing new therapies designed to increase synaptic function to treat schizophrenia.

ABSTRACT

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In Vivo Imaging of Synaptic Density in Schizophrenia

Background: Converging lines of evidence suggest presynaptic “microstructural” abnormalities in schizophrenia (SCZ). For example, post mortem (PM) studies have revealed reduced expression of region- specific presynaptic transcripts/proteins in SCZ, and genetic studies have reported alterations in genes related to synaptic integrity and function. Availability of an in vivo measure of synaptic density could provide a tool to test the hypothesis of altered synaptic density in SCZ while also addressing confounds that are inherent to PM studies (e.g., PM interval, storage, nature of death, etc.). Further, being able to measure synaptic density in vivo will permit the ability to relate synaptic density to concurrent measures of the phenomenology of SCZ in the same individual. Synaptic vesicle glycoproteins 2 (SV2) are integral proteins localized on the surface of synaptic vesicles and have an important role in synaptic vesicle exocytosis and neurotransmitter release. SV2A is one of three SV2 isoforms and is expressed in virtually all synapses. Thus, SV2A offers a unique target to image synaptic density in the human brain in vivo. UCB-J, an analog of levetiracetam (Keppra) binds to SV2A with high specificity and has been developed as a PET radioligand at Yale. The SV2A-specific signal measured using [11C]UCB-J is thus a proxy quantitative measure of synaptic density. The purpose of the current study is to examine synaptic density in SCZ in vivo utilizing [11C]UCB-J and to relate synaptic density to disease phenomena (see below) and electrophysiological (EEG) correlates of information processing. Hypotheses: Patients with schizophrenia (SCZ) will exhibit decreased synaptic density as estimated using the PET tracer [11C]UCB-J across brain regions. Further, [11C]UCB-J binding will be related to worse symptoms, and greater deficits in electrophysiological (EEG) measures of information processing. Aims: 1) To measure global and regional synaptic density in patients with SCZ (n=12) compared to healthy controls (n=12) using [11C]UCB-J, a novel PET tracer that binds to the synaptic vesicle protein SV2A utilizing High Resolution Research Tomography (HRRT), a PET scanner with the highest sensitivity and resolution available for human brain imaging. 2) To explore the relationship between [11C]UCB-J binding and disease phenomena including a) disease severity (total Positive and Negative Syndrome Scale [PANSS] scores; and b) electrophysiological indices of information processing and psychosis-related biomarkers (utilizing EEG). Methods: Using the validated PET SV2A radioligand [11C]UCB-J and the HRRT, [11C]UCB-J binding (VT) will be compared in patients with chronic SCZ and healthy controls. PET scanning will be performed using HRRT (Siemens/CTI, Knoxville, TN, USA). In addition to concurrent measures of phenomenology, EEG measures of information processing will be utilized (64 channel; Neuroscan SynAmps RT, Compumedics Neuroscan, Charlotte, NC, USA).

INVESTIGATOR BIOGRAPHIES

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Patrick D. Skosnik, Ph.D., and Rajiv Radhakrishnan, M.D.

Dr. Skosnik is an Assistant Professor in the Department of Psychiatry. He joined the faculty at Yale in 2010 (as research faculty), and was subsequently promoted to the rank of Assistant Professor in 2013. Dr. Skosnik has been interested in the neurobiology of psychosis since his early doctoral work at Northwestern University. Dr. Skosnik studied behavioral neuroscience under the mentorship of Dr. Sohee Park, one of the world leaders in schizophrenia  research. There he examined the cognitive, biochemical, and electrophysiological correlates of psychosis from the perspective  of the cannabinoid model of schizophrenia. During his postdoctoral study, he worked with two other pioneers in the schizophrenia research field (Dr. Brian O'Donnell and Dr. William Hetrick). During this time, he continued to examine the neural substrates of psychosis utilizing multiple imaging modalities (EEG, MRI, and PET). Since arriving at Yale, Dr. Skosnik has expanded his "multimodal imaging" approach, and has obtained additional grant support to study psychosis and drug abuse utilizing PET, EEG, and MRI. Currently, Dr. Skosnik is part of the Schizophrenia and Neuropharmacology Research Group at Yale (SNRGY) which is directed by Dr. Deepak C. D’Souza. He has been the recipient of two NARSAD Young Investigator Awards, was invited to participate in the NIH Early Career Reviewer (ECR) Program, was the 2016 Yale Nominee for the Charles A. Dana Foundation Neuroimaging Grant (awarded), and his work has been featured on the covers of Biological Psychiatry, Neuropsychopharmacology, and Clinical Neurophysiology.  

Dr. Radhakrishnan, MBBS, MD is a Clinical Instructor at Yale University School of Medicine. He graduated psychiatry residency from Yale and had also completed a postdoctoral fellowship in the Schizophrenia Research Clinic at Yale (under the mentorship of Dr. Deepak D'Souza). In his brief career, he has received a number of awards including the Seymour Lustman Research Award, the highest award for resident research achievement given by the Yale Department of Psychiatry and the Thomas P. Detre Fellowship Award in Translational Neuroscience Research in Psychiatry. Dr. Radhakrishnan's research has focused on examining the link between the cannabinoid system and schizophrenia and is currently invested in using PET imaging to further elucidate this relationship.

 

 

KEYWORDS


Anatomy: Synapses
Synaptic plasticity
Conditions: Schizophrenia
Function: Cognition
Memory

Technology: PET