Histamine-3 Receptor Availability and Glutamate Levels in the Brain: A PET-1H-MRS Study of Patients With Schizophrenia and Healthy Controls.

BACKGROUND: The histamine-3 receptor (H3R) may have a role in cognitive processes through its action as a presynaptic heteroreceptor inhibiting the release of glutamate in the brain. To explore this, we examined anterior cingulate cortex (ACC) and striatum H3R availability in patients with schizophrenia and characterized their relationships with glutamate levels in corresponding brain regions. METHODS: We employed a cross-sectional study, recruiting 12 patients with schizophrenia and 12 healthy volunteers. Participants underwent positron emission tomography using the H3R-specific radio ligand [11C]MK-8278, followed by proton magnetic resonance spectroscopy to measure glutamate levels, recorded as Glu and Glx. Based on existing literature, the ACC and striatum were selected as regions of interest. RESULTS: We found significant inverse relationships between tracer uptake and Glu (r = -0.66, P = .02) and Glx (r = -0.62, P = .04) levels in the ACC of patients, which were absent in healthy volunteers (Glu: r = -0.19, P = .56, Glx: r = 0.10, P = .75). We also found a significant difference in striatal (F1,20 = 6.00, P = .02) and ACC (F1,19 = 4.75, P = .04) Glx levels between groups. CONCLUSIONS: These results provide evidence of a regionally specific relationship between H3Rs and glutamate levels, which builds on existing preclinical literature. Our findings add to a growing literature indicating H3Rs may be a promising treatment target in schizophrenia, particularly for cognitive impairment, which has been associated with altered glutamate signaling.

Striatal dopaminergic alterations in individuals with copy number variants at the 22q11.2 genetic locus and their implications for psychosis risk: a [18F]-DOPA PET study.

Dopaminergic dysregulation is one of the leading hypotheses for the pathoetiology underlying psychotic disorders such as schizophrenia. Molecular imaging studies have shown increased striatal dopamine synthesis capacity (DSC) in schizophrenia and people in the prodrome of psychosis. However, it is unclear if genetic risk for psychosis is associated with altered DSC. To investigate this, we recruited healthy controls and two antipsychotic naive groups of individuals with copy number variants, one with a genetic deletion at chromosome 22q11.2, and the other with a duplication at the same locus, who are at increased and decreased risk for psychosis, respectively. Fifty-nine individuals (21 with 22q11.2 deletion, 12 with the reciprocal duplication and 26 healthy controls) received clinical measures and [18F]-DOPA PET imaging to index striatal Kicer. There was an inverse linear effect of copy number variant number on striatal Kicer value (B = -1.2 × 10-3, SE = 2 × 10-4, p < 0.001), with controls showing levels intermediate between the two variant groups. Striatal Kicer was significantly higher in the 22q11.2 deletion group compared to the healthy control (p < 0.001, Cohen's d = 1.44) and 22q11.2 duplication (p < 0.001, Cohen's d = 2) groups. Moreover, Kicer was positively correlated with the severity of psychosis-risk symptoms (B = 730.5, SE = 310.2, p < 0.05) and increased over time in the subject who went on to develop psychosis, but was not associated with anxiety or depressive symptoms. Our findings suggest that genetic risk for psychosis is associated with dopaminergic dysfunction and identify dopamine synthesis as a potential target for treatment or prevention of psychosis in 22q11.2 deletion carriers.

Brain metabolic network covariance and aging in a mouse model of Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD), the leading cause of dementia worldwide, represents a human and financial impact for which few effective drugs exist to treat the disease. Advances in molecular imaging have enabled assessment of cerebral glycolytic metabolism, and network modeling of brain region have linked to alterations in metabolic activity to AD stage. METHODS: We performed 18 F-FDG positron emission tomography (PET) imaging in 4-, 6-, and 12-month-old 5XFAD and littermate controls (WT) of both sexes and analyzed region data via brain metabolic covariance analysis. RESULTS: The 5XFAD model mice showed age-related changes in glucose uptake relative to WT mice. Analysis of community structure of covariance networks was different across age and sex, with a disruption of metabolic coupling in the 5XFAD model. DISCUSSION: The current study replicates clinical AD findings and indicates that metabolic network covariance modeling provides a translational tool to assess disease progression in AD models.

Microglial activation, tau and amyloid deposition in TREM2 p.R47H carriers and mild cognitive impairment patients: a multi-modal/multi-tracer PET/MRI imaging study with influenza vaccine immune challenge.

BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer's disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer's disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile. METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype. RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores. CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer's disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer's disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer's disease should aim to enhance protective microglial actions.

Brain glucose metabolism in schizophrenia: a systematic review and meta-analysis of 18FDG-PET studies in schizophrenia.

BACKGROUND: Impaired brain metabolism may be central to schizophrenia pathophysiology, but the magnitude and consistency of metabolic dysfunction is unknown. METHODS: We searched MEDLINE, PsychINFO and EMBASE between 01/01/1980 and 13/05/2021 for studies comparing regional brain glucose metabolism using 18FDG-PET, in schizophrenia/first-episode psychosis v. controls. Effect sizes (Hedges g) were pooled using a random-effects model. Primary measures were regional absolute and relative CMRGlu in frontal, temporal, parietal and occipital lobes, basal ganglia and thalamus. RESULTS: Thirty-six studies (1335 subjects) were included. Frontal absolute glucose metabolism (Hedge's g = -0.74 ± 0.54, p = 0.01; I2 = 67%) and metabolism relative to whole brain (g = -0.44 ± 0.34, p = 0.01; I2 = 55%) were lower in schizophrenia v. controls with moderate heterogeneity. Absolute frontal metabolism was lower in chronic (g = -1.18 ± 0.73) v. first-episode patients (g = -0.09 ± 0.88) and controls. Medicated patients showed frontal hypometabolism relative to controls (-1.04 ± 0.26) while metabolism in drug-free patients did not differ significantly from controls. There were no differences in parietal, temporal or occipital lobe or thalamic metabolism in schizophrenia v. controls. Excluding outliers, absolute basal ganglia metabolism was lower in schizophrenia v. controls (-0.25 ± 0.24, p = 0.049; I2 = 5%). Studies identified reporting voxel-based morphometry measures of absolute 18FDG uptake (eight studies) were also analysed using signed differential mapping analysis, finding lower 18FDG uptake in the left anterior cingulate gyrus (Z = -4.143; p = 0.007) and the left inferior orbital frontal gyrus (Z = -4.239; p = 0.02) in schizophrenia. CONCLUSIONS: We report evidence for hypometabolism with large effect sizes in the frontal cortex in schizophrenia without consistent evidence for alterations in other brain regions. Our findings support the hypothesis of hypofrontality in schizophrenia.

Reduced cortical cerebral blood flow in antipsychotic-free first-episode psychosis and relationship to treatment response.

BACKGROUND: Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. METHODS: We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). RESULTS: There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected <0.05). No differences were found in relative-to-global CBF in the selected region of interests and in voxel-wise analysis. Relative-to-global frontal CBF was correlated with percentage change in total Positive and Negative Syndrome Scale after antipsychotic treatment (r = 0.67, p = 0.008). CONCLUSIONS: These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.

Sickness behaviour and depression: An updated model of peripheral-central immunity interactions.

Current research into mood disorders indicates that circulating immune mediators participating in the pathophysiology of chronic somatic disorders have potent influences on brain function. This paradigm has brought to the fore the use of anti-inflammatory therapies as adjunctive to standard antidepressant therapy to improve treatment efficacy, particularly in subjects that do not respond to standard medication. Such new practice requires biomarkers to tailor these new therapies to those most likely to benefit but also validated mechanisms of action describing the interaction between peripheral immunity and brain function to optimize target intervention. These mechanisms are generally studied in preclinical models that try to recapitulate the human disease, MDD, through peripherally induced sickness behaviour. In this proposal paper, after an appraisal of the data in rodent models and their adherence to the data in clinical cohorts, we put forward a modified model of periphery-brain interactions that goes beyond the currently established view of microglia cells as the drivers of depression. Instead, we suggest that, for most patients with mild levels of peripheral inflammation, brain barriers are the primary actors in the pathophysiology of the disease and in treatment resistance. We then highlight data gaps in this proposal and suggest novel lines of research.

The relationship between glutamate, dopamine, and cortical gray matter: A simultaneous PET-MR study.

Prefrontal cortex has been shown to regulate striatal dopaminergic function via glutamatergic mechanisms in preclinical studies. Concurrent disruption of these systems is also often seen in neuropsychiatric disease. The simultaneous measurement of striatal dopamine signaling, cortical gray matter, and glutamate levels is therefore of major interest, but has not been previously reported. In the current study, twenty-eight healthy subjects underwent 2 simultaneous [11C]-( + )-PHNO PET-MRI scans, once after placebo and once after amphetamine in a double-blind randomized cross-over design, to measure striatal dopamine release, striatal dopamine receptor (D2/3R) availability, anterior cingulate glutamate+glutamine (Glx) levels, and cortical gray matter volumes at the same time. Voxel-based morphometry was used to investigate associations between neurochemical measures and gray matter volumes. Whole striatum D2/3R availability was positively associated with prefrontal cortex gray matter volume (pFWE corrected = 0.048). This relationship was mainly driven by associative receptor availability (pFWE corrected = 0.023). In addition, an interaction effect was observed between sensorimotor striatum D2/3R availability and anterior cingulate Glx, such that in individuals with greater anterior cingulate Glx concentrations, D2/3R availability was negatively associated with right frontal cortex gray matter volumes, while a positive D2/3R-gray matter association was observed in individuals with lower anterior cingulate Glx levels (pFWE corrected = 0.047). These results are consistent with the hypothesis that the prefrontal cortex is involved in regulation of striatal dopamine function. Furthermore, the observed associations raise the possibility that this regulation may be modulated by anterior cingulate glutamate concentrations.

Evaluation of Intraperitoneal [18F]-FDOPA Administration for Micro-PET Imaging in Mice and Assessment of the Effect of Subchronic Ketamine Dosing on Dopamine Synthesis Capacity.

Positron emission tomography (PET) using the radiotracer [18F]-FDOPA provides a tool for studying brain dopamine synthesis capacity in animals and humans. We have previously standardised a micro-PET methodology in mice by intravenously administering [18F]-FDOPA via jugular vein cannulation and assessment of striatal dopamine synthesis capacity, indexed as the influx rate constant K i Mod of [18F]-FDOPA, using an extended graphical Patlak analysis with the cerebellum as a reference region. This enables a direct comparison between preclinical and clinical output values. However, chronic intravenous catheters are technically difficult to maintain for longitudinal studies. Hence, in this study, intraperitoneal administration of [18F]-FDOPA was evaluated as a less-invasive alternative that facilitates longitudinal imaging. Our experiments comprised the following assessments: (i) comparison of [18F]-FDOPA uptake between intravenous and intraperitoneal radiotracer administration and optimisation of the time window used for extended Patlak analysis, (ii) comparison of Ki Mod in a within-subject design of both administration routes, (iii) test-retest evaluation of Ki Mod in a within-subject design of intraperitoneal radiotracer administration, and (iv) validation of Ki Mod estimates by comparing the two administration routes in a mouse model of hyperdopaminergia induced by subchronic ketamine. Our results demonstrate that intraperitoneal [18F]-FDOPA administration resulted in good brain uptake, with no significant effect of administration route on Ki Mod estimates (intraperitoneal: 0.024 ± 0.0047 min-1, intravenous: 0.022 ± 0.0041 min-1, p = 0.42) and similar coefficient of variation (intraperitoneal: 19.6%; intravenous: 18.4%). The technique had a moderate test-retest validity (intraclass correlation coefficient (ICC) = 0.52, N = 6) and thus supports longitudinal studies. Following subchronic ketamine administration, elevated K i Mod as compared to control condition was measured with a large effect size for both methods (intraperitoneal: Cohen's d = 1.3; intravenous: Cohen's d = 0.9), providing further evidence that ketamine has lasting effects on the dopamine system, which could contribute to its therapeutic actions and/or abuse liability.

Neurotransmitter receptor densities are associated with changes in regional Cerebral blood flow during clinical ongoing pain.

Arterial spin labelling (ASL) plays an increasingly important role in neuroimaging pain research but does not provide molecular insights regarding how regional cerebral blood flow (rCBF) relates to underlying neurotransmission. Here, we integrate ASL with positron emission tomography (PET) and brain transcriptome data to investigate the molecular substrates of rCBF underlying clinically relevant pain states. Two data sets, representing acute and chronic ongoing pain respectively, were utilised to quantify changes in rCBF; one examining pre-surgical versus post-surgical pain, and the second comparing patients with painful hand Osteoarthritis to a group of matched controls. We implemented a whole-brain spatial correlation analysis to explore associations between change in rCBF (ΔCBF) and neurotransmitter receptor distributions derived from normative PET templates. Additionally, we utilised transcriptomic data from the Allen Brain Atlas to inform distributions of receptor expression. Both datasets presented significant correlations of ΔCBF with the µ-opioid and dopamine-D2 receptor expressions, which play fundamental roles in brain activity associated with pain experiences. ΔCBF also correlated with the gene expression distributions of several receptors involved in pain processing. Overall, this is the first study illustrating the molecular basis of ongoing pain ASL indices and emphasises the potential of rCBF as a biomarker in pain research.

The blood-CSF-brain route of neurological disease: The indirect pathway into the brain.

The brain is protected by the endothelial blood-brain barrier (BBB) that limits the access of micro-organisms, tumour cells, immune cells and autoantibodies to the parenchyma. However, the classic model of disease spread across a disrupted BBB does not explain the focal distribution of lesions seen in a variety of neurological diseases and why lesions are frequently adjacent to the cerebrospinal fluid (CSF) spaces. We have critically reviewed the possible role of a blood-CSF-brain route as a disease entry pathway into the brain parenchyma. The initial step of this pathway is the transfer of pathogens or immune components from the blood into the CSF at the choroid plexuses, where the blood-CSF barrier (BCSFB) is located. The flow of CSF results in disease dissemination throughout the CSF spaces. Access to the brain parenchyma from the CSF can then occur across the ependymal layer at the ventricular surface or across the pial-glial barrier of the subarachnoid space and the Virchow-Robin spaces. We have reviewed the anatomy and physiology of the blood-CSF-brain pathway and the brain barriers controlling this process. We then summarised the evidence supporting this brain entry route in a cross-section of neurological diseases including neuromyelitis optica, multiple sclerosis, neurosarcoidosis, neuropsychiatric lupus, cryptococcal infection and both solid and haematological tumours. This summary highlights the conditions that share the blood-CSF-brain pathway as a pathogenetic mechanism. These include the characteristic proximity of lesions to CSF, evidence of disruption of the brain barriers and the identification of significant pathology within the CSF. An improved understanding of pathological transfer through the CSF and across all brain barriers will inform on more effective and targeted treatments of primary and secondary diseases of the central nervous system.

The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic.

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

The neural and molecular basis of working memory function in psychosis: a multimodal PET-fMRI study.

Working memory (WM) deficits predict clinical and functional outcomes in schizophrenia but are poorly understood and unaddressed by existing treatments. WM encoding and WM retrieval have not been investigated in schizophrenia without the confounds of illness chronicity or the use of antipsychotics and illicit substances. Moreover, it is unclear if WM deficits may be linked to cannabinoid 1 receptor dysfunction in schizophrenia. Sixty-six volunteers (35 controls, 31 drug-free patients with diagnoses of schizophrenia or schizoaffective disorder) completed the Sternberg Item-Recognition paradigm during an fMRI scan. Neural activation during WM encoding and WM retrieval was indexed using the blood-oxygen-level-dependent hemodynamic response. A subset of volunteers (20 controls, 20 drug-free patients) underwent a dynamic PET scan to measure [11C] MePPEP distribution volume (ml/cm3) to index CB1R availability. In a whole-brain analysis, there was a significant main effect of group on task-related BOLD responses in the superior parietal lobule during WM encoding, and the bilateral hippocampus during WM retrieval. Region of interest analyses in volunteers who had PET/fMRI indicated that there was a significant main effect of group on task-related BOLD responses in the right hippocampus, left DLPFC, left ACC during encoding; and in the bilateral hippocampus, striatum, ACC and right DLPFC during retrieval. Striatal CB1R availability was positively associated with mean striatal activation during WM retrieval in male patients (R = 0.5, p = 0.02) but not male controls (R = -0.20, p = 0.53), and this was significantly different between groups, Z = -2.20, p = 0.02. Striatal CB1R may contribute to the pathophysiology of WM deficits in male patients and have implications for drug development in schizophrenia.

The relationship between grey matter volume and striatal dopamine function in psychosis: a multimodal 18F-DOPA PET and voxel-based morphometry study.

A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulation, the relationship between prefrontal structural volume and striatal dopamine function has not been tested in people with psychosis. We therefore investigated the in vivo relationship between striatal dopamine synthesis capacity and prefrontal grey matter volume in treatment-responsive patients with psychosis, and compared them to treatment non-responsive patients, where dopaminergic mechanisms are not thought to be central. Forty patients with psychosis across two independent cohorts underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer) and structural 3T MRI. The PET, but not MR, data have been reported previously. Structural images were processed using DARTEL-VBM. GLM analyses were performed in SPM12 to test the relationship between prefrontal grey matter volume and striatal Kicer. Treatment responders showed a negative correlation between prefrontal grey matter and striatal dopamine synthesis capacity, but this was not evident in treatment non-responders. Specifically, we found an interaction between treatment response, whole striatal dopamine synthesis capacity and grey matter volume in left (pFWE corr. = 0.017) and right (pFWE corr. = 0.042) prefrontal cortex. We replicated the finding in right prefrontal cortex in the independent sample (pFWE corr. = 0.031). The summary effect size was 0.82. Our findings are consistent with the long-standing hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology in schizophrenia, but critically also extend the hypothesis to indicate it can be applied to treatment-responsive schizophrenia only. This suggests that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia.

GABA-A receptor differences in schizophrenia: a positron emission tomography study using [11C]Ro154513.

A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case-control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p < 0.05; effect size = 1.4). There was also a significant positive correlation between [11C]Ro15-4513 VT and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.

Dopamine dysregulation in psychotic relapse after antipsychotic discontinuation: an [18F]DOPA and [11C]raclopride PET study in first-episode psychosis.

Although antipsychotic drugs are effective for relieving the psychotic symptoms of first-episode psychosis (FEP), psychotic relapse is common during the course of the illness. While some FEPs remain remitted even without medication, antipsychotic discontinuation is regarded as the most common risk factor for the relapse. Considering the actions of antipsychotic drugs on presynaptic and postsynaptic dopamine dysregulation, this study evaluated possible mechanisms underlying relapse after antipsychotic discontinuation. Twenty five FEPs who were clinically stable and 14 matched healthy controls were enrolled. Striatal dopamine activity was assessed as Kicer value using [18F]DOPA PET before and 6 weeks after antipsychotic discontinuation. The D2/3 receptor availability was measured as BPND using [11C]raclopride PET after antipsychotic discontinuation. Healthy controls also underwent PET scans according to the corresponding schedule of the patients. Patients were monitored for psychotic relapse during 12 weeks after antipsychotic discontinuation. 40% of the patients showed psychotic relapse after antipsychotic discontinuation. The change in Kicer value over time significantly differed between relapsed, non-relapsed patients and healthy controls (Week*Group: F = 4.827, df = 2,253.193, p = 0.009). In relapsed patients, a significant correlation was found between baseline striatal Kicer values and time to relapse after antipsychotic discontinuation (R2 = 0.518, p = 0.018). BPND were not significantly different between relapsed, non-relapsed patients and healthy controls (F = 1.402, df = 2,32.000, p = 0.261). These results suggest that dysfunctional dopamine autoregulation might precipitate psychotic relapse after antipsychotic discontinuation in FEP. This finding could be used for developing a strategy for the prevention of psychotic relapse related to antipsychotic discontinuation.

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine.

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen's d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in pre-limbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT1A receptors but no appreciable action at dopamine D2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schizophrenia and effects of ketamine relevant to its therapeutic use for  treating major depression.

Neuroinflammation is highest in areas of disease progression in semantic dementia.

Despite epidemiological and genetic data linking semantic dementia to inflammation, the topography of neuroinflammation in semantic dementia, also known as the semantic variant of primary progressive aphasia, remains unclear. The pathology starts at the tip of the left temporal lobe where, in addition to cortical atrophy, a strong signal appears with the tau PET tracer 18F-flortaucipir, even though the disease is not typically associated with tau but with TDP-43 protein aggregates. Here, we characterized the topography of inflammation in semantic variant primary progressive aphasia using high-resolution PET and the tracer 11C-PBR28 as a marker of microglial activation. We also tested the hypothesis that inflammation, by providing non-specific binding targets, could explain the 18F-flortaucipir signal in semantic variant primary progressive aphasia. Eight amyloid-PET-negative patients with semantic variant primary progressive aphasia underwent 11C-PBR28 and 18F-flortaucipir PET. Healthy controls underwent 11C-PBR28 PET (n = 12) or 18F-flortaucipir PET (n = 12). Inflammation in PET with 11C-PBR28 was analysed using Logan graphical analysis with a metabolite-corrected arterial input function. 18F-flortaucipir standardized uptake value ratios were calculated using the cerebellum as the reference region. Since monoamine oxidase B receptors are expressed by astrocytes in affected tissue, selegiline was administered to one patient with semantic variant primary progressive aphasia before repeating 18F-flortaucipir scanning to test whether monoamine oxidase B inhibition blocked flortaucipir binding, which it did not. While 11C-PBR28 uptake was mostly cortical, 18F-flortaucipir uptake was greatest in the white matter. The uptake of both tracers was increased in the left temporal lobe and in the right temporal pole, as well as in regions adjoining the left temporal pole such as insula and orbitofrontal cortex. However, peak uptake of 18F-flortaucipir localized to the left temporal pole, the epicentre of pathology, while the peak of inflammation 11C-PBR28 uptake localized to a more posterior, mid-temporal region and left insula and orbitofrontal cortex, in the periphery of the damage core. Neuroinflammation, greatest in the areas of progression of the pathological process in semantic variant primary progressive aphasia, should be further studied as a possible therapeutic target to slow disease progression.

Supervised clustering for TSPO PET imaging.

PURPOSE: This technical note seeks to act as a practical guide for implementing a supervised clustering algorithm (SVCA) reference region approach and to explain the main strengths and limitations of the technique in the context of 18-kilodalton translocator protein (TSPO) positron emission tomography (PET) studies in experimental medicine. BACKGROUND: TSPO PET is the most widely used imaging technique for studying neuroinflammation in vivo in humans. Quantifying neuroinflammation with PET can be a challenging and invasive procedure, especially in frail patients, because it often requires blood sampling from an arterial catheter. A widely used alternative to arterial sampling is SVCA, which identifies the voxels with minimal specific binding in the PET images, thus extracting a pseudo-reference region for non-invasive quantification. Unlike other reference region approaches, SVCA does not require specification of an anatomical reference region a priori, which alleviates the limitation of TSPO contamination in anatomically-defined reference regions in individuals with underlying inflammatory processes. Furthermore, SVCA can be applied to any TSPO PET tracer across different neurological and neuropsychiatric conditions, providing noninvasivequantification of TSPO expression. METHODS: We provide an overview of the development of SVCA as well as step-by-step instructions for implementing SVCA with suggestions for specific settings. We review the literature on SVCAapplications using first- and second- generation TSPO PET tracers and discuss potential clinically relevant limitations and applications. CONCLUSIONS: The correct implementation of SVCA can provide robust and reproducible estimates of brain TSPO expression. This review encourages the standardisation of SVCA methodology in TSPO PET analysis, ultimately aiming to improve replicability and comparability across study sites.

Specific and non-specific binding of a tracer for the translocator-specific protein in schizophrenia: an [11C]-PBR28 blocking study.

OBJECTIVE: The mitochondrial 18-kDa translocator protein (TSPO) is expressed by activated microglia and positron emission tomography enables the measurement of TSPO levels in the brain. Findings in schizophrenia have shown to vary depending on the outcome measure used and this discrepancy in TSPO results could be explained by lower non-displaceable binding (VND) in schizophrenia, which could obscure increases in specific binding. In this study, we have used the TSPO ligand XBD173 to block the TSPO radioligand [11C]-PBR28 and used an occupancy plot to quantify VND in patients with schizophrenia. METHODS: A total of 7 patients with a diagnosis of schizophrenia were recruited for this study. Each patient received two separate PET scans with [11C]PBR28, one at baseline and one after the administration of the TSPO ligand XBD173. All patients were high-affinity binders (HABs) for the TSPO gene. We used an occupancy plot to quantify the non-displaceable component (VND) using 2TCM kinetic estimates with and without vascular correction. Finally we computed the VND at a single subject level using the SIME method. RESULTS: All patients showed a global and generalized reduction in [11C]PBR28 uptake after the administration of XBD173. Constraining the VND to be equal for all patients, the population VND was estimated to be 1.99 mL/cm3 (95% CI 1.90 to 2.08). When we used vascular correction, the fractional TSPO occupancy remained similar. CONCLUSIONS: In schizophrenia patients, a substantial component of the [11C]PBR28 signal represents specific binding to TSPO. Furthermore, the VND in patients with schizophrenia is similar to that previously reported in healthy controls. These results suggest that changes in non-specific binding between schizophrenia patients and healthy controls do not account for discrepant PET findings in this disorder.