The hypofrontality theory of the pathogenesis of schizophrenia predicts that cortical lesions cause psychosis. During a search for abnormalities of catecholaminergic neurotransmission in patients with complex partial seizures of the mesial temporal lobe, we discovered an increase of the rate of metabolism of an exogenous dopa tracer (6-[18F]fluoro-L-dopa) in the neostriatum of a subgroup of patients with a history of psychosis. When specifically assayed for this abnormality, patients with schizophrenia revealed the same significant increase of the rate of metabolism in the striatum. The finding is consistent with the theory that a state of psychosis arises when episodic dopamine excess is superimposed on a trait of basic dopamine deficiency in the striatum. The finding is explained by the hypothesis that cortical insufficiency, a proposed pathogenetic mechanism of both disorders, causes an up-regulation of the enzymes responsible for dopa turnover in the neostriatum as well as the receptors mediating dopaminergic neurotransmission.

The success of serotonin-selective reuptake inhibitors has lent support to the monoamine theory of major depressive disorder (MDD). This issue has been addressed in a number of molecular imaging studies by positron emission tomography or single-photon emission computed tomography of serotonin reuptake sites (5-HTT) in the brain of patients with MDD, with strikingly disparate conclusions. Our meta-analysis of the 18 such studies, totaling 364 MDD patients free from significant comorbidities or medication and 372 control subjects, revealed reductions in midbrain 5-HTT (Hedges' g = −0.49; 95% CI: (−0.84, −0.14)) and amygdala (Hedges' g = −0.50; 95% CI: (−0.78, −0.22)), which no individual study possessed sufficient power to detect. Only small effect sizes were found in other regions with high binding (thalamus: g = −0.24, striatum: g = −0.32, and brainstem g = −0.22), and no difference in the frontal or cingulate cortex. Age emerged as an important moderator of 5-HTT availability in MDD, with more severe reductions in striatal 5-HTT evident with greater age of the study populations ( P<0.01). There was a strong relationship between severity of depression and 5-HTT reductions in the amygdala ( P = 0.01). Thus, molecular imaging findings indeed reveal widespread reductions of ˜10% in 5-HTT availability in MDD, which may predict altered spatial-temporal dynamics of serotonergic neurotransmission.

We aimed to evaluate ⁶⁸Ga-DOTATATE PET/CT for the early prediction of time to progression and clinical outcome after a first cycle of peptide receptor radionuclide treatment (PRRT) in a cohort of patients with well-differentiated neuroendocrine tumors. Methods: Thirty-three consecutive patients (22 men and 11 women; mean age ± SD, 57.8 ± 12.1 y) were investigated at baseline and again 3 mo after initiation of the first cycle of PRRT. ⁶⁸Ga-DOTATATE receptor expression was assessed using 2 measures of standardized uptake value (SUV): maximum SUV (SUV_max) and tumor-to-spleen SUV ratio (SUV_T/S). Percentage change in SUV scores after PRRT relative to baseline (ΔSUV) was calculated. After completing 1–3 cycles of PRRT, patients entered the follow-up study, for estimation of time to progression. According to the Response Evaluation Criteria in Solid Tumors, progression was defined on the basis of contrast-enhanced CT. Clinical symptoms, as well as the tumor markers chromogranin A and neuron-specific enolase, were also recorded during regular follow-up visits. Results: The 23 of 31 patients with decreased SUV_T/S after the first PRRT cycle had longer progression-free survival than did the 8 of 31 patients with stable or increased scores (median survival not reached vs. 6 mo, P = 0.002). For the 18 of 33 patients showing a reduction in SUV_max, there was no significant difference in progression-free survival (median survival not reached vs. 14 mo, P = 0.22). Multivariate regression analysis identified SUV_T/S as the only independent predictor for tumor progression during follow-up. In the 17 of 33 patients with clinical symptoms before PRRT, ΔSUV_T/S correlated with clinical improvement (r = 0.52, P < 0.05), whereas ΔSUV_max did not (r = 0.42, P = 0.10). Changes in the tumor markers (chromogranin A and neuron-specific enolase) did not predict ΔSUV scores, clinical improvement, or time to progression. Conclusion: Decreased ⁶⁸Ga-DOTATATE uptake in tumors after the first cycle of PRRT predicted time to progression and correlated with an improvement in clinical symptoms among patients with well-differentiated neuroendocrine tumors; ΔSUV_T/S was superior to ΔSUV_max for prediction of outcome.

The dynamic and multicellular processes of neuroinflammation are mediated by the nonneuronal cells of the central nervous system, which include astrocytes and the brain’s resident macrophages, microglia. Although initiation of an inflammatory response may be beneficial in response to injury of the nervous system, chronic or maladaptive neuroinflammation can have harmful outcomes in many neurological diseases. An acute neuroinflammatory response is protective when activated neuroglia facilitate tissue repair by releasing anti-inflammatory cytokines and neurotrophic factors. On the other hand, chronic neuroglial activation is a major pathological mechanism in neurodegenerative diseases, likely contributing to neuronal dysfunction, injury, and disease progression. Therefore, the development of specific and sensitive probes for positron emission tomography (PET) studies of neuroinflammation is attracting immense scientific and clinical interest. An early phase of this research emphasized PET studies of the prototypical imaging biomarker of glial activation, translocator protein-18 kDa (TSPO), which presents difficulties for quantitation and lacks absolute cellular specificity. Many alternate molecular targets present themselves for PET imaging of neuroinflammation in vivo, including enzymes, intracellular signaling molecules as well as ionotropic, G-protein coupled, and immunoglobulin receptors. We now review the lead structures in radiotracer development for PET studies of neuroinflammation targets for neurodegenerative diseases extending beyond TSPO, including glycogen synthase kinase 3, monoamine oxidase-B, reactive oxygen species, imidazoline-2 binding sites, cyclooxygenase, the phospholipase A2/arachidonic acid pathway, sphingosine-1-phosphate receptor-1, cannabinoid-2 receptor, the chemokine receptor CX3CR1, purinergic receptors: P2X₇ and P2Y₁₂, the receptor for advanced glycation end products, Mer tyrosine kinase, and triggering receptor expressed on myeloid cells-1. We provide a brief overview of the cellular expression and function of these targets, noting their selectivity for astrocytes and/or microglia, and highlight the classes of PET radiotracers that have been investigated in early-stage preclinical or clinical research studies of neuroinflammation.