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Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis, but this has not been tested directly in vivo.  Here, we investigated synaptic vesicle glycoprotein 2A (SV2A) levels and their relationship to symptoms and structural brain measures using [ 11 C]UCB-J positron emission tomography in 18 patients with schizophrenia and 18 controls. We found significant group and group-by-region interaction effects on volume of distribution ( V T ). [ 11 C]UCB-J V T was significantly lower in the frontal and anterior cingulate cortices in schizophrenia with large effect sizes (Cohen’s d   =  0.8-0.9), but there was no significant difference in the hippocampus. We also investigated the effects of antipsychotic drug administration on SV2A levels in Sprague-Dawley rats using western blotting, [ 3 H]UCB-J autoradiography and immunostaining with confocal microscopy, finding no significant effects on any measure. These findings indicate that there are lower synaptic terminal protein levels in schizophrenia in vivo and that antipsychotic drug exposure is unlikely to account for them. Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis. Here, using [ 11 C]UCB-J PET, the authors show for the first time in vivo that levels of the synaptic marker protein SV2A are reduced in schizophrenia and unaffected by antipsychotic treatment in a rat model.

[11C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value = 3.1 times10−13). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.

Quantitative estimation of neuroreceptor occupancy by exogenous drugs using positron emission tomography is based on the reduction in the total volume of distribution (VT) of site-specific radioligands after drug administration. An estimate of the distribution volume of free and nonspecifically bound radioligand (VND) is also required to distinguish specific from total binding. However, a true reference region, devoid of specific binding, is often not available. We present a transformation of a graphical method, originally introduced by Lassen, using regional estimates of VT alone to determine occupancy, together with an extension that does not require baseline data.

Background Various plasma phosphorylated tau species have been shown to be associated with amyloid-β (Aβ) PET and Tau PET in Alzheimer’s disease (AD), but whether APOE ε4 affects the interaction between glial fibrillary acidic protein (GFAP) and phosphorylated tau (pTau), and whether a three-way interaction exists among APOE ε4, GFAP, and pTau that influences AD progression remain unclear. Methods The study included 563 participants from the Chinese Preclinical Alzheimer’s Disease Study (CPAS) and 243 from Alzheimer’s Disease Neuroimaging Initiative (ADNI), all of whom underwent Aβ PET, magnetic resonance imaging (MRI), neuropsychological assessments, and plasma biomarker analyses (GFAP, pTau181, pTau231, pTau217), with subsets undergoing Tau PET. The longitudinal data of 101 participants from ADNI were additionally included. We employed linear regression models with interaction terms to examine how APOE ε4 status and plasma GFAP levels modulate the relationships between plasma pTau biomarkers and AD pathology cross-sectionally and longitudinally. Results Plasma GFAP and pTau biomarkers (pTau181, pTau231, pTau217) are significantly elevated in Aβ-positive individuals, with stronger Aβ–pTau associations observed in APOE ε4 carriers (CPAS: β = 0.26, p  = 0.003 for pTau231; ADNI: β = 0.45, p  < 0.001 for pTau181). Across two cohorts, plasma GFAP levels significantly strengthened the associations between pTau biomarkers and Tau PET. Furthermore, subsequent analyses revealed that this modulatory effect of GFAP on the links between pTau and PET-derived pathological changes was more pronounced in APOE ε4 non-carriers, whereas in APOE ε4 carriers, a significant interaction between GFAP and pTau was only observed in specific Braak stage-specific regions within the CPAS cohort. In longitudinal analyses, we also observed stronger pTau181-associated longitudinal tau accumulation in individuals with high GFAP levels (Braak III-IV). Conclusion We demonstrate that APOE ε4 status critically modulates the relationship between pTau and Aβ pathology, whereas plasma GFAP primarily influences pTau–tau pathology associations, particularly in individuals without APOE ε4 allele. These findings underscore the role of reactive astrogliosis in tau propagation and support the utility of plasma biomarkers for AD diagnosis and prognosis.

Positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) is used to quantify neuroinflammation. Translocator protein is expressed throughout the brain, and therefore a classical reference region approach cannot be used to estimate binding potential (BPND). Here, we used blockade of the TSPO radioligand [11C]PBR28 with the TSPO ligand XBD173, to determine the non-displaceable volume of distribution (VND), and hence estimate the BPND. A total of 26 healthy volunteers, 16 high-affinity binders (HABs) and 10 mixed affinity binders (MABs) underwent a [11C]PBR28 PET scan with arterial sampling. Six of the HABs received oral XBD173 (10 to 90 mg), 2 hours before a repeat scan. In XBD173-dosed subjects, VND was estimated via the occupancy plot. Values of BPND for all subjects were calculated using this VND estimate. Total volume of distribution (VT) of MABs (2.94 ± 0.31) was lower than VT of HABs (4.33 ± 0.29) (P<0.005). There was dose-dependent occupancy of TSPO by XBD173 (ED50 = 0.34 ± 0.13 mg/kg). The occupancy plot provided a VND estimate of 1.98 (1.69, 2.26). Based on these VND estimates, BPND for HABs is approximately twice that of MABs, consistent with predictions from in vitro data. Our estimates of [11C]PBR28 VND and hence BPND in the healthy human brain are consistent with in vitro predictions. XBD173 blockade provides a practical means of estimating VND for TSPO targeting radioligands.

An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.An international group of experts in pharmacokinetic modeling recommends a consensus nomenclature to describe in vivo molecular imaging of reversibly binding radioligands.

Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.

Purpose PET can image neuroinflammation by targeting the translocator protein (TSPO), which is upregulated in activated microglia. The high nonspecific binding of the first-generation TSPO radioligand [ 11 C]PK-11195 limits accurate quantification. [ 18 F]GE-180, a novel TSPO ligand, displays superior binding to [ 11 C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [ 18 F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures. Methods Ten volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [ 18 F]GE-180. Kinetic modelling of time–activity curves with one-tissue and two-tissue compartment models and Logan graphical analysis was applied to the data. The primary outcome measure was the total volume of distribution ( V T ) across various regions of interest (ROIs). Secondary outcome measures were the standardized uptake values (SUV), the distribution volume and SUV ratios estimated using a pseudoreference region. Results The two-tissue compartment model was the best model. The average regional delivery rate constant ( K 1 ) was 0.01 mL cm −3  min −1 indicating low extraction across the blood–brain barrier (1 %). The estimated median V T across all ROIs was also low, ranging from 0.16 mL cm −3 in the striatum to 0.38 mL cm −3 in the thalamus. There were no significant differences in V T between HABs and MABs across all ROIs. Conclusion A reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low V T estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [ 18 F]GE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.

[11C]PBR28, a radioligand targeting the translocator protein (TSPO), does not produce a specific binding signal in approximately 14% of healthy volunteers. This phenomenon has not been reported for [11C]PK11195, another TSPO radioligand. We measured the specific binding signals with [3H]PK11195 and [3H]PBR28 in brain tissue from 22 donors. Overall, 23% of the samples did not generate a visually detectable specific autoradiographic signal with [3H]PBR28, although all samples showed [3H]PK11195 binding. There was a marked reduction in the affinity of [3H]PBR28 for TSPO in samples with no visible [3H]PBR28 autoradiographic signal (Ki=188±15.6 nmol/L), relative to those showing normal signal (Ki=3.4±0.5 nmol/L, P<0.001). Of this latter group, [3H]PBR28 bound with a two-site fit in 40% of cases, with affinities (Ki) of 4.0±2.4 nmol/L (high-affinity site) and 313±77 nmol/L (low-affinity site). There was no difference in Kd or Bmax for [3H]PK11195 in samples showing no [3H]PBR28 autoradiographic signal relative to those showing normal [3H]PBR28 autoradiographic signal. [3H]PK11195 bound with a single site for all samples. The existence of three different binding patterns with PBR28 (high-affinity binding (46%), low-affinity binding (23%), and two-site binding (31%)) suggests that a reduction in [11C]PBR28 binding may not be interpreted simply as a reduction in TSPO density. The functional significance of differences in binding characteristics warrants further investigation.

Loss of glutamatergic terminals is hypothesised to contribute to excitation-inhibition imbalance in schizophrenia, supported by evidence that the normal positive association between glutamate concentrations and synaptic terminal density is not found in patients with chronic schizophrenia. However, it is unknown whether the relationship between synaptic terminal density and glutamate levels is altered early in the course of illness. To address this, we investigated [ 11 C]UCB-J distribution volume ratio (DVR) and glutamatergic markers in healthy volunteers (HV) and in antipsychotic-naïve/free patients with schizophrenia (SCZ) recruited from first-episode psychosis services. Forty volunteers (HV n  = 19, SCZ n  = 21) underwent [ 11 C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy ( 1 H-MRS) imaging in the anterior cingulate cortex (ACC) and left hippocampus to index [ 11 C]UCB-J DVR and creatine-scaled glutamate (Glu/Cr) and glutamate in combination with glutamine (Glx/Cr). In the HV but not SCZ group, [ 11 C]UCB-J DVR was significantly positively associated with Glu/Cr (Spearman’s rho = 0.55, p  = 0.02) and Glx/Cr (Spearman’s rho = 0.73, p  = 0.0004) in the ACC, and with Glu/Cr in the left hippocampus (Spearman’s rho = 0.77, p  = 0.0001). DVR was significantly lower in the ACC in the SCZ group compared to the HV group (Kolmogorov-Smirnov Z = 1.44, p  = 0.03). Together, these findings indicate that the normal relationship between levels of a synaptic terminal density marker and levels of glutamate is disrupted early in the course of schizophrenia. This is consistent with the hypothesis that there is loss of glutamatergic terminals at illness onset.