Dataset Information

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study.

ABSTRACT: N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [¹⁸F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (V_T). Hippocampal DVR, but not V_T, was significantly lower in patients relative to controls (p = 0.02, Cohen's d = 0.81; p = 0.15, Cohen's d = 0.49), and negatively associated with total (rho = -0.47, p = 0.04), depressive (rho = -0.67, p = 0.002), and general symptom severity (rho = -0.74, p < 0.001). Exploratory analyses found no significant differences in other brain regions (anterior cingulate cortex, thalamus, striatum and temporal cortex). These findings are consistent with the NMDAR hypofunction hypothesis and identify the hippocampus as a key locus for relative NMDAR hypofunction, although further studies should test specificity and causality.

SUBMITTER: Beck K

PROVIDER: S-EPMC8361127 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study.

Beck Katherine K Arumuham Atheeshaan A Veronese Mattia M Santangelo Barbara B McGinnity Colm J CJ Dunn Joel J McCutcheon Robert A RA Kaar Stephen J SJ Singh Nisha N Pillinger Toby T Borgan Faith F Stone James J Jauhar Sameer S Sementa Teresa T Turkheimer Federico F Hammers Alexander A Howes Oliver D OD

Translational psychiatry 20210812 1

N-methyl-D-aspartate receptor (NMDAR) hypofunction is hypothesised to underlie psychosis but this has not been tested early in illness. To address this, we studied 40 volunteers (21 patients with first-episode psychosis and 19 matched healthy controls) using PET imaging with an NMDAR selective ligand, [18F]GE-179, that binds to the ketamine binding site to index its distribution volume ratio (DVR) and volume of distribution (VT). Hippocampal DVR, but not VT, was ...[more]

PMID: 34385418

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Project description:ImportanceExperimental and epidemiological studies implicate the cannabinoid 1 receptor (CB1R) in the pathophysiology of psychosis. However, whether CB1R levels are altered in the early stages of psychosis and whether they are linked to cognitive function or symptom severity remain unknown.ObjectiveTo investigate CB1R availability in first-episode psychosis (FEP) without the confounds of illness chronicity or the use of illicit substances or antipsychotics.Design, setting, and participantsThis cross-sectional, case-control study of 2 independent samples included participants receiving psychiatric early intervention services at 2 independent centers in Turku, Finland (study 1) and London, United Kingdom (study 2). Study 1 consisted of 18 volunteers, including 7 patients with affective or nonaffective psychoses taking antipsychotic medication and 11 matched controls; study 2, 40 volunteers, including 20 antipsychotic-naive or antipsychotic-free patients with schizophrenia or schizoaffective disorder and 20 matched controls. Data were collected from January 5, 2015, through September 26, 2018, and analyzed from June 20, 2016, through February 12, 2019.Main outcomes and measuresThe availability of CB1R was indexed using the distribution volume (VT, in milliliters per cubic centimeter) of 2 CB1R-selective positron emission tomography radiotracers: fluoride 18-labeled FMPEP-d2 (study 1) and carbon 11-labeled MePPEP (study 2). Cognitive function was measured using the Wechsler Digit Symbol Coding Test. Symptom severity was measured using the Brief Psychiatric Rating Scale for study 1 and the Positive and Negative Syndrome Scale for study 2.ResultsA total of 58 male individuals were included in the analyses (mean [SD] age of controls, 27.16 [5.93] years; mean [SD] age of patients, 26.96 [4.55] years). In study 1, 7 male patients with FEP (mean [SD] age, 26.80 [5.40] years) were compared with 11 matched controls (mean [SD] age, 27.18 [5.86] years); in study 2, 20 male patients with FEP (mean [SD] age, 27.00 [5.06] years) were compared with 20 matched controls (mean [SD] age, 27.15 [6.12] years). In study 1, a significant main effect of group on [18F]FMPEP-d2 VT was found in the anterior cingulate cortex (ACC) (t16 = -4.48; P < .001; Hedges g = 1.2), hippocampus (t16 = -2.98; P = .006; Hedges g = 1.4), striatum (t16 = -4.08; P = .001; Hedges g = 1.9), and thalamus (t16 = -4.67; P < .001; Hedges g = 1.4). In study 2, a significant main effect of group on [11C]MePPEP VT was found in the ACC (Hedges g = 0.8), hippocampus (Hedges g = 0.5), striatum (Hedges g = 0.4), and thalamus (Hedges g = 0.7). In patients, [11C]MePPEP VT in the ACC was positively associated with cognitive functioning (R = 0.60; P = .01), and [11C]MePPEP VT in the hippocampus was inversely associated with Positive and Negative Syndrome Scale total symptom severity (R = -0.50; P = .02).Conclusions and relevanceThe availability of CB1R was lower in antipsychotic-treated and untreated cohorts relative to matched controls. Exploratory analyses indicated that greater reductions in CB1R levels were associated with greater symptom severity and poorer cognitive functioning in male patients. These findings suggest that CB1R may be a potential target for the treatment of psychotic disorders.

Project description:Cholinergic dysfunction has been implicated in the pathophysiology of psychosis and psychiatric disorders such as schizophrenia, depression, and bipolar disorder. The basal forebrain (BF) cholinergic nuclei, defined as cholinergic cell groups Ch1-3 and Ch4 (Nucleus Basalis of Meynert; NBM), provide extensive cholinergic projections to the rest of the brain. Here, we examined microstructural neuroimaging measures of the cholinergic nuclei in patients with untreated psychosis (~31 weeks of psychosis, <2 defined daily dose of antipsychotics) and used magnetic resonance spectroscopy (MRS) and transcriptomic data to support our findings. We used a cytoarchitectonic atlas of the BF to map the nuclei and obtained measures of myelin (quantitative T1, or qT1 as myelin surrogate) and microstructure (axial diffusion; AxD). In a clinical sample (n = 85; 29 healthy controls, 56 first-episode psychosis), we found significant correlations between qT1 of Ch1-3, left NBM and MRS-based dorsal anterior cingulate choline in healthy controls while this relationship was disrupted in FEP (p > 0.05). Case-control differences in qT1 and AxD were observed in the Ch1-3, with increased qT1 (reflecting reduced myelin content) and AxD (reflecting reduced axonal integrity). We found clinical correlates between left NBM qT1 with manic symptom severity, and AxD with negative symptom burden in FEP. Intracortical and subcortical myelin maps were derived and correlated with BF myelin. BF-cortical and BF-subcortical myelin correlations demonstrate known projection patterns from the BF. Using data from the Allen Human Brain Atlas, cholinergic nuclei showed significant enrichment for schizophrenia and depression-related genes. Cell-type specific enrichment indicated enrichment for cholinergic neuron markers as expected. Further relating the neuroimaging correlations to transcriptomics demonstrated links with cholinergic receptor genes and cell type markers of oligodendrocytes and cholinergic neurons, providing biological validity to the measures. These results provide genetic, neuroimaging, and clinical evidence for cholinergic dysfunction in schizophrenia.

Dataset Information

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study.

Publications

N-methyl-D-aspartate receptor availability in first-episode psychosis: a PET-MR brain imaging study.

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