SPECT Brain Imaging in Neuropsychiatric Disorders
Clinical Brain Disorders Branch, NIMH
Summary
Single photon emission computed tomography, SPECT, allows the measurement of the 3-d distribution of radioactive tracers in brain. Tracers in use fall into two main classes. In the first class, the tracer is taken up in brain in proportion to blood flow and thus can be utilized as a marker of neural activity. The second class of tracers binds to sites in brain such that the activity then reflects the distribution of the related neurochemistry. Previous work focused on the use of radio-Xenon for absolute flow measurements during cognitive activation tasks. This work was extended to perfusion related tracers using Tc-99m to determine their ability for rCBF measurements using dose normalization and split dose activation paradigms. While this work was largely successful, other more sensitive means exist for CBF measurements leaving us to concentrate on the use of SPECT for neurochemistry
Our main area of interest is the dopamine system where we are able to examine postsynaptic receptor density using IBZM and to also measure the presynaptic side with beta-CIT, a marker for the dopamine reuptake transporter. IBZM studies in normal volunteers, Parkinson’s Disease patients with clinical asymmetrical presentation, and identical twins with Tourette’s syndrome have established that this technique is able to provide a sensitive measure of clinically meaningful dopamine function. Studies in schizophrenic patients, both drug free and treated with various neuroleptics have shown a curvilinear relation between blood level and estimated D2 receptor occupancy as well as showing a relation between dopaminergic measures and clinical symtomatology.
Other neurochemistry studies involve IQNB, a muscarinic receptor antagonist. SPECT IQNB scans demonstrated focal areas of reduced uptake in patients with dementia. Current studies involve using IQNB to determine if receptor up-regulation is possible in a clinical population. We have compared normal controls with Alzheimer patients on both perfusion scans and IQNB after chronic low dose scopolamine. The difference in groups was marked when comparing the ratio I-QNB to HMPAO uptake, indicating a double dissociation and suggesting a differential sensitivity to chronic cholinergic blockade.
Research Highlights:
- SPECT imaging of D2 receptors in Mz twins discordant for severity of Tourette’s syndrome: significant correlation of increased IBZM uptake in caudate with degree of discordance for tic severity. (Ms accepted to Science) Current study in ongoing to examine dopamine transporter with beta-CIT in TS singletons.
- Individual variation in D2 occupancy in clozapine treated subjects: dose reduction associated with increased IBZM binding (ms is now under review, Amer J Psych)
- Extrapyramidal side effects with risperidone and haloperidol at comparable D2 occupancy levels: In typical and atypical neuroleptics drug induced parkinsonism was seen in similar frequency for comparable occupancy levels above 60%. (Ms submitted, study continuing to examine titration of individual dose levels)
- Within-subject changes in striatal D2 receptor binding potential are related to changes in schizophrenic symptoms: In subjects studied at two time points during drug free washout, changes in peak BP was significantly correlated with negative symptoms. ( study continuing, Neurosci. Abst, 1995)
- Beta-CIT SPECT studies of dopamine and serotonin transport in neuropsychiatric patients: project begun with NIAAA examining alcoholic patients. A related project is to examine serotonin transport in monkeys bred for serotonin depletion.
- Analysis of metabolites of beta-CIT in plasma human and non-human primates: comparison of protein extraction and organic extraction methods have shown a species specific difference and suggest that the hydrophilic nature of the metabolites would not interfere with quantitative SPECT analysis. (ms under review)
- Beta-CIT and IBZM SPECT of primates with neonatal and adult hippocampal lesions: Effect on striatal dopaminergic neurons: Preliminary results suggest that striatal dopamine binding was decreased in monkeys with neonatal lesion as compared to adult lesions, whereas dopamine transporter binding was either reduced or not different in adult lesions compared to neonatal and controls.
- In vivo uptake of IQNB stereoisomers in human brain: all four isomers have been imaged in two normal controls, results show that the RS and RR isomers have different affinities at M1 and M2 receptor subtypes and that there may be an age related increase in number of unoccupied muscarinic receptors.
- Cholinergic regulation in Alzheimer’s patients following chronic scopolamine: Our previous low dose study has been repeated with a higher dose scop and is currently being analyzed.
- Prospective study of subjects at risk for Alzheimer’s disease: to be examined with IQNB, study in planning stages.
- Muscarinic receptor occupancy related to clozapine treatment and cognitive deficits in schizophrenia: study beginning.
Significance to Biomedical Research and to the Program of the Institute:
In vivo measurement of brain neurochemistry is of considerable importance not only for understanding the possible underlying physiological imbalance or deficit in neuropsychiatric disorders but also for its ability in developing and monitoring potential pharmacological interventions. SPECT is readily available in many Nuclear Medicine Departments giving the possibility of wide utilization once appropriate single photon tracers and quantification methods have been established. Our results have demonstrated that SPECT IBZM provides measures sensitive to clinically meaningful dopamine function thus showing considerable potential for the study of dopamine activity in schizophrenia.
Recent Publications:
Coppola, R, Knable, MB, Jones, DW, Gorey, JG, Lee, KS, Weinberger, DR: In vivo uptake of I-123 QNB stereo isomers in human brain, Soc for Neurosci, 21:2041,1995
Knable, MB, Coppola, R, Jones, DW, Gorey, J, Lee, KS, Weinberger, DR: Within-subject changes in striatal D2 receptor binding potential are related to changes in schizophrenic symptoms, Soc for Neurosci, 21:2125, 1995
Heinz, A, Jones, DW, Gorey, JG, Lee, KS, Saunders, RC, Knable, MB, Weinberger, DR: [I-123]Beta-CIT and [I-123]IBZM SPECT of rhesus monkeys with neonatal and adult lesions of the amygdala-hippocampus: Effect on striatal dopaminergic neurons, J Nuc Med, 37:281P, 1996
Knable, MB, Jones, DW, Coppola, R, Hyde, TM, Lee, KS, Gorey, J, Weinberger, DR: Lateralized differences in Iodine-123-IBZM uptake in the basal ganglia in asymmetric Parkinson’s disease, J Nuc Med, 36:1216-1225, 1995
Lee, KS, He, XS, Coppola, R, Gorey, J, Jones, DW, Knable, deCosta, BR, Rice, KC, Weinberger, DR: A novel method for rapid and efficient radioiodination of I-123-IQNB, J Nuc Med, in press
Lee, KS, Jones, DW, Gorey, J, Coppola, R, Knable, MB, Heinz, A, He, XS, deCosta, BR, Rice, KC, Weinberger, DR: Determination of the optimum pH for high radioiodination yields from stannylated precursors, J Nuc Med, 37:187P, 1996
Lee, KS, Jones, DW, Gorey, J, Coppola, R, Knable, MB, Heinz, A, Porter, K, He, XS, deCosta, BR, Rice, KC, Weinberger, DR: A kit formulation to prepare (R,S)-[I-123]IQNB for SPECT imaging of muscarinic receptors, J Nuc Med, 37:143P, 1996
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Dr. Richard Coppola. Thank you!
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Updated June 16, 1997