The Topography of Striatal Dopamine and Symptoms in Psychosis: An Integrative PET and MRI study

Background: Striatal dopamine dysfunction is thought to underlie symptoms in psychosis, yet it remains unclear how a single neurotransmitter could cause the diverse presentations that are observed clinically. One hypothesis is that the consequences of aberrant dopamine signalling vary depending on where within the striatum the dysfunction occurs. Positron emission tomography (PET) allows for the quantification of dopamine function across the striatum. In the current study we use a novel method to investigate the relationship between spatial variability in dopamine synthesis capacity and psychotic symptoms. Methods: We used a multimodal imaging approach combining 18F-DOPA PET and resting state MRI in 29 patients with first episode psychosis and 21 healthy controls. In each participant, resting state functional connectivity maps were used to quantify the functional connectivity of each striatal voxel to well-established cortical networks. Network-specific striatal dopamine synthesis capacity(Kicer) was then calculated for the resulting connectivity defined parcellations. Results: The connectivity defined parcellations generated Kicer values with equivalent reliability, and significantly greater orthogonality to standard anatomical parcellation methods. As a result, dopamine-symptom associations were significantly different from one another for different subdivisions, whereas no unique subdivision relationships were found when using an anatomical parcellation. In particular, dopamine function within striatal areas connected to the default mode network was strongly associated with negative symptoms(p<0.001). Conclusion: These findings suggest that individual differences in the topography of dopamine dysfunction within the striatum contribute to shaping psychotic symptomatology. Further validation of the novel approach in future studies is necessary

An automatic analysis framework for FDOPA PET neuroimaging

In this study we evaluate the performance of a fully automated analytical framework for FDOPA PET neuroimaging data, and its sensitivity to demographic and experimental variables and processing parameters. An instance of XNAT imaging platform was used to store the King's College London institutional brain FDOPA PET imaging archive, alongside individual demographics and clinical information. By re-engineering the historical Matlab-based scripts for FDOPA PET analysis, a fully automated analysis pipeline for imaging processing and data quantification was implemented in Python and integrated in XNAT. The final data repository includes 892 FDOPA PET scans organized from 23 different studies. We found good reproducibility of the data analysis by the automated pipeline (in the striatum for the Kicer: for the controls ICC = 0.71, for the psychotic patients ICC = 0.88). From the demographic and experimental variables assessed, gender was found to most influence striatal dopamine synthesis capacity (F = 10.7, p < 0.001), with women showing greater dopamine synthesis capacity than men. Our automated analysis pipeline represents a valid resourse for standardised and robust quantification of dopamine synthesis capacity using FDOPA PET data. Combining information from different neuroimaging studies has allowed us to test it comprehensively and to validate its replicability and reproducibility performances on a large sample size

Molecular imaging in Parkinson's disease

The present work explores brain functional changes in drug-naïve Parkinson's disease (PD) patients by means of molecular imaging techniques. Thirty-one consecutive drug-naïve PD patients from the Neurological Clinic of the University of Flor-ence underwent clinical assessment, neuropsychological assessment, MRI, [123I]FP-CIT SPECT, [18F]FDG PET. First, [18F]FDG-PET was employed to identify in drug-naïve PD patients brain metabolic alteration uniquely related to disease process and not modulated by anti-parkinsonian therapeutic intervention. Second, [18F]FDG-PET and [123I]FP-CIT SPECT were employed together to explore the early functional changes in brain function related to dopaminergic depletion in the putamen and in the caudate nucleus

Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study.

Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265Funder: Wellcome Trust (Wellcome); doi: https://doi.org/10.13039/100004440Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms. 1H-MRS was used to measure hippocampal glutamate concentrations, and 18F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p < 0.05), but not transition to a psychotic disorder (p = 0.22), and was not significantly related to hippocampal glutamate concentration (p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampal glutamate concentrations

The Effects of Antipsychotic Treatment on Presynaptic Dopamine Synthesis Capacity in First-Episode Psychosis: A Positron Emission Tomography Study

BACKGROUND: Elevated striatal dopamine synthesis capacity has been implicated in the etiology and antipsychotic response in psychotic illness. The effects of antipsychotic medication on dopamine synthesis capacity are poorly understood, and no prospective studies have examined this question in a solely first-episode psychosis sample. Furthermore, it is unknown whether antipsychotic efficacy is linked to reductions in dopamine synthesis capacity. We conducted a prospective [18F]-dihydroxyphenyl-L-alanine positron emission tomography study in antipsychotic naïve/free people with first-episode psychosis commencing antipsychotic treatment. METHODS: Dopamine synthesis capacity (indexed as influx rate constant) and clinical symptoms (measured using Positive and Negative Syndrome Scale) were measured before and after at least 5 weeks of antipsychotic treatment in people with first-episode psychosis. Data from a prior study indicated that a sample size of 13 would have >80% power to detect a statistically significant change in dopamine synthesis capacity at alpha = .05 (two tailed). RESULTS: A total of 20 people took part in the study, 17 of whom were concordant with antipsychotic medication at therapeutic doses. There was no significant effect of treatment on dopamine synthesis capacity in the whole striatum (p = .47), thalamus, or midbrain, nor was there any significant relationship between change in dopamine synthesis capacity and change in positive (ρ = .35, p = .13), negative, or total psychotic symptoms. CONCLUSIONS: Dopamine synthesis capacity is unaltered by antipsychotic treatment, and therapeutic effects are not mediated by changes in this aspect of dopaminergic function