Objective Parkinson disease is characterized by motor and nonmotor symptoms, reduced striatal dopamine signaling, and loss of dopamine neurons in the substantia nigra. It is now known that the pathological process in Parkinson disease may begin decades before the clinical diagnosis and include a variety of neuronal alterations in addition to the dopamine system. Methods This study examined the density of all synapses with synaptic vesicle glycoprotein 2A (SV2A) in Parkinson disease subjects with mild bilateral disease (n = 12) and matched normal controls (n = 12) using in vivo high‐resolution positron emission tomographic imaging as well as postmortem autoradiography in an independent sample with Parkinson disease (n = 15) and normal controls (n = 13) in the substantia nigra and putamen. Results A group‐by‐brain region interaction effect (F10, 22 = 3.52, p = 0.007) was observed in the primary brain areas with in vivo SV2A binding. Post hoc analyses revealed that the Parkinson disease group exhibited lower SV2A in the substantia nigra (−45%; p < 0.001), red nucleus (−31%; p = 0.03), and locus coeruleus (−17%; p = 0.03). Exploratory analyses also revealed lower SV2A binding in clinically relevant cortical areas. Using autoradiography, we confirmed lower SV2A in the substantia nigra (−17%; p < 0.005) and nonsignificant findings in the putamen (−4%; p = 0.06). Interpretation This work provides the first evidence of synaptic loss in brainstem nuclei involved in the pathogenesis of Parkinson disease in living patients. SV2A imaging holds promise for understanding synaptic changes central to the disease. Ann Neurol 2020;87:329–338

Background Arterial blood sampling is the gold standard method to obtain the arterial input function (AIF) for quantification of whole body (WB) dynamic 18F-FDG PET imaging. However, this procedure is invasive and not typically available in clinical environments. As an alternative, we compared AIFs to population-based input functions (PBIFs) using two normalization methods: area under the curve (AUC) and extrapolated initial plasma concentration (CP*(0)). To scale the PBIFs, we tested two methods: (1) the AUC of the image-derived input function (IDIF) and (2) the estimated CP*(0). The aim of this study was to validate IDIF and PBIF for FDG oncological WB PET studies by comparing to the gold standard arterial blood sampling. Methods The Feng 18F-FDG plasma concentration model was applied to estimate AIF parameters (n = 23). AIF normalization used either AUC(0–60 min) or CP*(0), estimated from an exponential fit. CP*(0) is also described as the ratio of the injected dose (ID) to initial distribution volume (iDV). iDV was modeled using the subject height and weight, with coefficients that were estimated in 23 subjects. In 12 oncological patients, we computed IDIF (from the aorta) and PBIFs with scaling by the AUC of the IDIF from 4 time windows (15–45, 30–60, 45–75, 60–90 min) (PBIFAUC) and estimated CP*(0) (PBIFiDV). The IDIF and PBIFs were compared with the gold standard AIF, using AUC values and Patlak Ki values. Results The IDIF underestimated the AIF at early times and overestimated it at later times. Thus, based on the AUC and Ki comparison, 30–60 min was the most accurate time window for PBIFAUC; later time windows for scaling underestimated Ki (− 6 ± 8 to − 13 ± 9%). Correlations of AUC between AIF and IDIF, PBIFAUC(30–60), and PBIFiDV were 0.91, 0.94, and 0.90, respectively. The bias of Ki was − 9 ± 10%, − 1 ± 8%, and 3 ± 9%, respectively. Conclusions Both PBIF scaling methods provided good mean performance with moderate variation. Improved performance can be obtained by refining IDIF methods and by evaluating PBIFs with test-retest data.

In this positron emission tomography (PET) study with [ 11 C]UCB-J, we evaluated synaptic vesicle glycoprotein 2A (SV2A) binding, which is decreased in resected brain tissues from epilepsy patients, in subjects with temporal lobe epilepsy (TLE) and compared the regional binding pattern to [ 18 F]fluorodeoxyglucose (FDG) uptake. Methods: Twelve TLE subjects and 12 control subjects were examined. Regional [ 11 C]UCB-J binding potential (BP ND) values were estimated using the centrum semiovale as a reference region. [ 18 F]FDG uptake in TLE subjects was quantified using mean radioactivity values. Asymmetry in outcome measures was assessed by comparison of ipsilateral and contralateral regions. Partial volume correction (PVC) with the iterative Yang algorithm was applied based on the FreeSurfer segmentation. Results: In 11 TLE subjects with medial temporal lobe sclerosis (MTS), the hippocampal volumetric asymmetry was 25 ± 11%. After PVC, [ 11 C]UCB-J BP ND asymmetry indices were 37 ± 19% in the hippocampus, with very limited asymmetry in other brain regions. Reductions in [ 11 C]UCB-J BP ND values were restricted to the sclerotic hippocampus when compared to control subjects. The corresponding asymmetry in hippocampal [ 18 F]FDG uptake was 22 ± 7% and correlated with that of [ 11 C]UCB-J BP ND across subjects (R 2 = .38). Hippocampal asymmetries in [ 11 C] UCB-J binding were 1.7-fold larger than those of [ 18 F]FDG uptake. Significance: [ 11 C]UCB-J binding is reduced in the seizure onset zone of TLE subjects with MTS. PET imaging of SV2A may be a promising biomarker approach in the presurgical selection and evaluation of TLE patients and may improve the sensitivity of molecular imaging for seizure focus detection.

SummaryBradykinin and substance P are involved in inflammation and act through Gq-protein-coupled receptors. Local anaesthetics inhibit the signalling of these receptors and have potent antiinflammatory actions. The aim of this study was to investigate the effects of local anaesthetics on the cutaneous flare responses to bradykinin and substance P. Skin blood flow responses to intradermal injections of bradykinin and substance P were assessed in the absence and presence of anaesthetic and analgesic concentrations of lidocaine, levobupivacaine and ropivacaine. All local anaesthetics significantly attenuated the vascular responses to bradykinin (p = 0.001) and substance P (p < 0.001). There were no differences in this effect between the different agents, but anaesthetic concentrations had a greater attenuating effect than analgesic concentrations on the substance P response (p < 0.001). Local anaesthetics may therefore be useful in the suppression of inflammation and the prevention of postoperative hyperalgesia. Bradykinin and substance P are chemical mediators involved in the inflammatory response, which act predominantly through the Gq-protein-coupled B2 and NK1 receptors, respectively [12,13]. Their intradermal administration elicits pain and a cutaneous flare and wheal response, reflecting vasodilation and increased vascular permeability [14]. As local anaesthetics are known to inhibit Gq protein function, and have been shown to affect B2 and NK1 receptor signalling in vitro [15,16], we hypothesised that they would attenuate the flare responses to exogenous bradykinin and substance P in human skin.The aim of this study was to investigate the effects of lidocaine, levobupivacaine and ropivacaine on the flare responses to bradykinin and substance P in the peripheral skin of healthy humans.