scholarly journals M163. GLUTAMATE METABOLITES ARE ASSOCIATED WITH ALTERED HIPPOCAMPAL ACTIVATION BUT NOT HIPPOCAMPAL-STRIATAL CONNECTIVITY IN SUBJECTS WITH A CLINICAL HIGH RISK FOR PSYCHOSIS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S198-S198
Author(s):  
Emily Hird ◽  
Paul Allen ◽  
Natasza Orlov ◽  
Gemma Modinos ◽  
Matthijs Bossong ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Negative Relationship ◽  
Region Of Interest ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Hippocampal Activity ◽  
Potential Biomarker ◽  
Psychophysiological Interaction

Abstract Background We recently used Magnetic Resonance Spectroscopy (MRS) to show that transition to psychosis is associated with higher baseline hippocampal glutamate levels (1). We also used functional Magnetic Resonance Imaging (fMRI) in the same CHR subjects and showed that compared to healthy controls (HC), subjects at a clinical high-risk of psychosis (CHR) show decreased hippocampal activation to novel stimuli and increased novelty-modulated hippocampal-striatal connectivity (2). The aim of the present analysis was to explore the relationship between hippocampal glutamatergic metabolites, hippocampal activity, and hippocampal-striatal connectivity in these CHR subjects. Methods 75 CHR and 31 HC subjects participated in a novelty salience task whilst undergoing fMRI to measure hippocampal and striatal activation, and MRS to measure hippocampal glutamatergic metabolite levels. First, we tested for a three-way interaction between the hippocampal response to novel versus neutral stimuli, hippocampal glutamatergic metabolite levels, and group, using a Region of Interest approach in the bilateral hippocampus. Second, we carried out a Psychophysiological Interaction (PPI) analysis on the extracted hippocampal coordinates from the first analysis and tested for an interaction with hippocampal glutamatergic metabolite levels and group. Results The CHR group had higher clinical scores and lower GAF scores at baseline than HC. CHR subjects were younger, more were taking antipsychotic medication and they smoked more cigarettes than HC. At follow-up, 12 CHR subjects (16%) developed a first episode of psychosis (CHR-TR) and 63 (86%) did not (CHR-NTR). The CHR-TR subjects smoked fewer cigarettes than the CHR-NTR subjects. The first analysis revealed a significant interaction between group, fMRI activity and MRS Glx (a combined measure of glutamate and glutamine) in the right hippocampus (pFWE= 0.03; x y z = 28 -32 -4; t=3.61, z=3.49). This was driven by the CHR-TR group: contrast estimates indicated a positive relationship between fMRI activity and MRS Glx in the HC and CHR-NTR subjects, but a negative relationship between fMRI activity and glutamate in the CHR-TR subjects. The second analysis revealed that CHR-TR individuals exhibited greater connectivity between the hippocampus and the striatum (pFWE= 0.03; x y z = -6 6 -8; t=3.35, z=3.17), but that this was not associated with Glx. Discussion Whilst hippocampal glutamate metabolite levels are associated with altered hippocampal activity in CHR individuals - especially in those who later transition to psychosis - hippocampal glutamate metabolite levels do not modulate connectivity between the hippocampus and striatum. These findings are broadly consistent with previous work indicating a role for glutamate in hippocampal dysfunction and risk for psychosis, and indicate a potential biomarker for psychosis risk. References

scholarly journals Adverse clinical outcomes in people at clinical high-risk for psychosis related to altered interactions between hippocampal activity and glutamatergic function

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Paul Allen ◽  
Emily J. Hird ◽  
Natasza Orlov ◽  
Gemma Modinos ◽  
Matthijs Bossong ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Healthy Volunteers ◽  
Functional Outcome ◽  
Clinical Outcomes ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Hippocampal Activity ◽  
High Risk Cohort

AbstractPreclinical rodent models suggest that psychosis involves alterations in the activity and glutamatergic function in the hippocampus, driving dopamine activity through projections to the striatum. The extent to which this model applies to the onset of psychosis in clinical subjects is unclear. We assessed whether interactions between hippocampal glutamatergic function and activity/striatal connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis. We measured functional Magnetic Resonance Imaging of hippocampal activation/connectivity, and 1H-Magnetic Resonance Spectroscopy of hippocampal glutamatergic metabolites in 75 CHR participants and 31 healthy volunteers. At follow-up, 12 CHR participants had transitioned to psychosis and 63 had not. Within the clinical high-risk cohort, at follow-up, 35 and 17 participants had a poor or a good functional outcome, respectively. The onset of psychosis (ppeakFWE = 0.003, t = 4.4, z = 4.19) and a poor functional outcome (ppeakFWE < 0.001, t = 5.52, z = 4.81 and ppeakFWE < 0.001, t = 5.25, z = 4.62) were associated with a negative correlation between the hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (ppeakFWE = 0.016, t = 3.73, z = 3.39, ppeakFWE = 0.014, t = 3.78, z = 3.42, ppeakFWE = 0.011, t = 4.45, z = 3.91, ppeakFWE = 0.003, t = 4.92, z = 4.23) in the total CHR sample, not seen in healthy volunteers. As predicted by preclinical models, adverse clinical outcomes in people at risk for psychosis are associated with altered interactions between hippocampal activity and glutamatergic function.

scholarly journals Adverse clinical outcomes in people at clinical high-risk for psychosis related to activity and glutamate function in the hippocampus

2021 ◽  
Author(s):  
Paul Allen ◽  
Emily J. Hird ◽  
Natasza Orlov ◽  
Gemma Modinos ◽  
Matthijs Bossong ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Healthy Volunteers ◽  
Functional Outcome ◽  
Clinical Outcomes ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Preclinical Models ◽  
Hippocampal Activity

AbstractPreclinical models suggest that psychosis involves alterations in activity and glutamate function in the hippocampus, driving dopamine activity through projections to the striatum. The extent to which this model applies to the onset of psychosis in clinical subjects is unclear. We assessed whether interactions between hippocampal glutamatergic function and activity/striatal-connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis. We measured functional Magnetic Resonance Imaging of hippocampal activation/connectivity, and 1H-Magnetic Resonance Spectroscopy of hippocampal glutamatergic metabolites in 75 CHR participants and 31 healthy volunteers. At follow-up, 12 CHR participants had transitioned to psychosis and 63 had not. Within the clinical high-risk cohort, at follow-up, 35 and 17 participants had a poor or a good functional outcome, respectively. The onset of psychosis (ppeakFWE =.003, t=4.4, z=4.19) and a poor functional outcome (ppeakFWE <.001, t=5.52, z=4.81 and ppeakFWE <.001, t=5.25, z=4.62) were associated with a negative correlation between hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (ppeakFWE=.016, t=3.73, z=3.39, ppeakFWE=.014, t=3.78, z=3.42, ppeakFWE=.011, t=4.45, z=3.91, ppeakFWE=.003, t=4.92, z=4.23) in the total CHR sample, not seen in healthy volunteers. As predicted by preclinical models, adverse clinical outcomes in people at risk for psychosis are associated with altered interactions between hippocampal activity and glutamatergic function.

scholarly journals S163. GLUTAMATERGIC METABOLITES IN THE PSYCHOSIS SPECTRUM: FROM HIGH RISK SAMPLES TO FIRST EPISODE PSYCHOSIS

2020 ◽  
Vol 46 (Supplement_1) ◽  
pp. S98-S98
Author(s):  
Adriana Fortea ◽  
Mireia Masias ◽  
Jose Pariente ◽  
Daniel Ilzarbe ◽  
Francina Badia ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
High Risk ◽  
First Episode ◽  
Resonance Spectroscopy ◽  
Compensatory Mechanisms ◽  
Illness Onset ◽  
Recent Onset ◽  
Potential Biomarker ◽  
Siemens Scanner ◽  
Post Hoc

Abstract Background The N-methyl-D-aspartate receptor hypofunction model of schizophrenia suggests that dysfunction of these receptors leads to an excess release of glutamate and could explain the brain structural abnormalities characterizing these patients. However, glutamatergic pathways underlying transition to psychosis are yet unclear. Methods Youth with recent onset psychosis (FEP), within the first 5 years of disease, individuals with high risk for psychosis (HR) –including participants with psychosis risk syndrome meeting SIPS/SOPS criteria and offspring of parents with bipolar disorder or schizophrenia –, and healthy volunteers, were recruited and scanned with a 3T Siemens scanner. Magnetic resonance spectroscopy was performed using a 2x2x2 cm3 voxel (VOI) placed in the middle frontal region. Ratios of glutamate (Glu), and glutamate + glutamine (Glx) were quantified using LCModel. Results 18 adolescents with FEP, 33 HR and 32 healthy controls (HC) were included in the analysis. There were no significant differences between groups in mean age (16.4±2.1 vs 15.7±2.7 vs 16.8±1.9; F=2.0, p=.139), but there were trend-level differences in gender (%females: 33.3% vs 57.6% vs 68.8%; Х2=5.9, p=.052). Multivariate models controlling for gender showed a trend-level effect of group in Glu (F=2.9, p=.062), but not in Glx. Post-hoc pairwise contrasts for Glu revealed significantly higher Glu levels in HR individuals (1.38±0.16) compared to FEP (1.27±0.20) and HC (1.31±0.15). Discussion Our findings support that increased Glu in the prefrontal cortex may index risk of psychosis from the early stages of the disease, during adolescence. Our observations suggest a possible hyperglutamatergia in premorbid stages that may normalize –or even decrease – after illness onset, possibly related to treatment or compensatory mechanisms. While requiring replication in a larger sample and including follow-up through transition in HR individuals, our findings raise the possibility that abnormal glutamatergic metabolism in the prefrontal cortex could be used as a potential biomarker of illness and putative treatment target.

scholarly journals Glutathione as a molecular marker of functional impairment in patients with at-risk mental state: 7-Tesla 1H-MRS study

2020 ◽  
Author(s):  
Peter Jeon ◽  
Roberto Limongi ◽  
Sabrina D. Ford ◽  
Cassandra Branco ◽  
Michael Mackinley ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Functional Outcomes ◽  
Risk Group ◽  
High Risk Group ◽  
7 Tesla ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Healthy Control

AbstractA substantial number of individuals with clinical high-risk (CHR) mental state do not transition to psychosis. However, regardless of future diagnostic trajectories, many of these individuals develop poor social and occupational functional outcomes. The levels of glutathione, a crucial cortical antioxidant, may track variations in functional outcomes in early psychosis and prodromal states.Thirteen clinical high-risk and 30 healthy control volunteers were recruited for a 7-Tesla magnetic resonance spectroscopy scan with voxel positioned within the dorsal anterior cingulate cortex (ACC). Clinical assessment scores were collected to determine if any association was observable with glutathione levels.Bayesian Spearman test revealed a positive association between the Social and Occupational Functioning Assessment Scale (SOFAS) and the glutathione concentration in the clinical high-risk group but not in the healthy control group. After accounting for variations in SOFAS, CHR group had higher GSH levels than the healthy subjects.This study is the first to use 7-Tesla magnetic resonance spectroscopy to test whether ACC glutathione levels related to social and occupational functioning in a clinically high-risk group and offers preliminary support for glutathione levels as a clinically actionable marker of prognosis in emerging adults presenting with risk features for various severe mental illnesses.

scholarly journals Neural Autoantibodies in Cerebrospinal Fluid and Serum in Clinical High Risk for Psychosis, First-Episode Psychosis, and Healthy Volunteers

2021 ◽  
Vol 12 ◽  
Author(s):  
Christian G. Bien ◽  
Cathrin Rohleder ◽  
Juliane K. Mueller ◽  
Corinna I. Bien ◽  
Dagmar Koethe ◽  
...  
Keyword(s):  
Magnetic Resonance Imaging ◽  
High Risk ◽  
Magnetic Resonance ◽  
Healthy Volunteers ◽  
Serum Antibody ◽  
Mental Illnesses ◽  
First Episode ◽  
Clinical High Risk ◽  
Igg Antibodies ◽  
Resonance Imaging

The pathophysiological role of neural autoantibodies in acute psychotic disorders is receiving increased attention. However, there is still an ongoing debate, whether predominantly psychotic manifestations of autoimmune encephalitides exist that may remain undetected and, thus, untreated. Furthermore, it is discussed if such conditions can be diagnosed based on serum antibody results or if a reliable diagnosis requires additional cerebrospinal fluids (CSF) results. In this study, we screened pairs of serum and CSF samples from antipsychotic-naïve individuals with first-episode schizophrenic psychosis (FEP, n = 103), clinical high risk for psychosis (CHR, n = 47), and healthy volunteers (HV, n = 40) for eight different antibodies against various antigens that have been shown to be associated with autoimmune encephalitides: N-methyl-D-aspartate receptor (NMDAR, NR1 subunits only), glutamic acid decarboxylase (GAD65), leucine-rich glioma inactivated protein 1 (LGI1), contactin-associated protein-like 2 protein (CASPR2), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit 1, AMPAR subunit 2, γ-aminobutyric acid-B receptors (GABABR), and glycine receptors. All patients were within the norm with regards to a careful neurological examination, a magnetic resonance imaging (MRI) of the brain, an electroencephalogram (EEG), and routine blood pathology. All CSF samples were autoantibody-negative. In three serum samples of individuals with FEP, we detected low-titer CASPR2 immunoglobulin (Ig) G antibodies (≤1:160, n = 2) and non-IgG antibodies against NMDAR (n = 1) (overall serum-autoantibody prevalence in FEP: 2.91%). However, the IgG titers were below the laboratory cut-off defined for positivity, and non-IgG antibodies are of no clinical relevance. This suggests that there were no cases of autoimmune encephalitis in our cohort. Our results highlight the importance and the high specificity of CSF analysis to reliably detect autoantibodies. They confirm the hypothesis that pure psychotic manifestations of antibody-associated autoimmune encephalitides without any additional neuropsychiatric findings are very rare. However, special attention must be paid to those presenting with atypical mental illnesses with additional neurological symptoms, evidence of clinically-significant cognitive involvement, profound sleep-wake perturbations, seizures, electroencephalographic, or magnetic resonance imaging pathologies to be able to identify cases with autoimmune-mediated psychiatric syndromes.

scholarly journals Glutathione as a Molecular Marker of Functional Impairment in Patients with At-Risk Mental State: 7-Tesla 1H-MRS Study

2021 ◽  
Vol 11 (7) ◽  
pp. 941
Author(s):  
Peter Jeon ◽  
Roberto Limongi ◽  
Sabrina D. Ford ◽  
Cassandra Branco ◽  
Michael Mackinley ◽  
...  
Keyword(s):  
High Risk ◽  
Magnetic Resonance ◽  
Magnetic Resonance Spectroscopy ◽  
Functional Outcomes ◽  
Risk Group ◽  
High Risk Group ◽  
7 Tesla ◽  
Resonance Spectroscopy ◽  
Clinical High Risk ◽  
Healthy Control

A substantial number of individuals with clinical high-risk (CHR) mental state do not transition to psychosis. However, regardless of future diagnostic trajectories, many of these individuals develop poor social and occupational functional outcomes. The levels of glutathione, a crucial cortical antioxidant, may track variations in functional outcomes in early psychosis and prodromal states. Thirteen clinical high-risk and 30 healthy control volunteers were recruited for a 7-Tesla magnetic resonance spectroscopy scan with a voxel positioned within the dorsal anterior cingulate cortex (ACC). Clinical assessment scores were collected to determine if any association was observable with glutathione levels. The Bayesian Spearman’s test revealed a positive association between the Social and Occupational Functioning Assessment Scale (SOFAS) and the glutathione concentration in the clinical high-risk group but not in the healthy control group. After accounting for variations in the SOFAS scores, the CHR group had higher GSH levels than the healthy subjects. This study is the first to use 7-Tesla magnetic resonance spectroscopy to test whether ACC glutathione levels relate to social and occupational functioning in a clinically high-risk group and offers preliminary support for glutathione levels as a clinically actionable marker of prognosis in emerging adults presenting with risk features for various severe mental illnesses.

scholarly journals Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis

2021 ◽  
Author(s):  
Meike Heurich ◽  
Melanie Föcking ◽  
David Mongan ◽  
Gerard Cagney ◽  
David R. Cotter
Keyword(s):  
High Risk ◽  
Psychotic Disorder ◽  
Psychotic Disorders ◽  
Clinical Symptoms ◽  
First Episode Psychosis ◽  
Specific Protein ◽  
First Episode ◽  
Clinical High Risk ◽  
Blood Proteins ◽  
Episode Psychosis

AbstractEarly identification and treatment significantly improve clinical outcomes of psychotic disorders. Recent studies identified protein components of the complement and coagulation systems as key pathways implicated in psychosis. These specific protein alterations are integral to the inflammatory response and can begin years before the onset of clinical symptoms of psychotic disorder. Critically, they have recently been shown to predict the transition from clinical high risk to first-episode psychosis, enabling stratification of individuals who are most likely to transition to psychotic disorder from those who are not. This reinforces the concept that the psychosis spectrum is likely a central nervous system manifestation of systemic changes and highlights the need to investigate plasma proteins as diagnostic or prognostic biomarkers and pathophysiological mediators. In this review, we integrate evidence of alterations in proteins belonging to the complement and coagulation protein systems, including the coagulation, anticoagulation, and fibrinolytic pathways and their dysregulation in psychosis, into a consolidated mechanism that could be integral to the progression and manifestation of psychosis. We consolidate the findings of altered blood proteins relevant for progression to psychotic disorders, using data from longitudinal studies of the general population in addition to clinical high-risk (CHR) individuals transitioning to psychotic disorder. These are compared to markers identified from first-episode psychosis and schizophrenia as well as other psychosis spectrum disorders. We propose the novel hypothesis that altered complement and coagulation plasma levels enhance their pathways’ activating capacities, while low levels observed in key regulatory components contribute to excessive activation observed in patients. This hypothesis will require future testing through a range of experimental paradigms, and if upheld, complement and coagulation pathways or specific proteins could be useful diagnostic or prognostic tools and targets for early intervention and preventive strategies.

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