Objective During the natural course of multiple sclerosis (MS), the brain is exposed to aging as well as disease effects. Brain aging can be modeled statistically; the so‐called “brain‐age” paradigm. Here, we evaluated whether brain‐predicted age difference (brain‐PAD) was sensitive to the presence of MS, clinical progression, and future outcomes. Methods In a longitudinal, multicenter sample of 3,565 magnetic resonance imaging (MRI) scans, in 1,204 patients with MS and clinically isolated syndrome (CIS) and 150 healthy controls (mean follow‐up time: patients 3.41 years, healthy controls 1.97 years), we measured “brain‐predicted age” using T1‐weighted MRI. We compared brain‐PAD among patients with MS and patients with CIS and healthy controls, and between disease subtypes. Relationships between brain‐PAD and Expanded Disability Status Scale (EDSS) were explored. Results Patients with MS had markedly higher brain‐PAD than healthy controls (mean brain‐PAD +10.3 years; 95% confidence interval [CI] = 8.5–12.1] versus 4.3 years; 95% CI = 2.1 to 6.4; p < 0.001). The highest brain‐PADs were in secondary‐progressive MS (+13.3 years; 95% CI = 11.3–15.3). Brain‐PAD at study entry predicted time‐to‐disability progression (hazard ratio 1.02; 95% CI = 1.01–1.03; p < 0.001); although normalized brain volume was a stronger predictor. Greater annualized brain‐PAD increases were associated with greater annualized EDSS score (r = 0.26; p < 0.001). Interpretation The brain‐age paradigm is sensitive to MS‐related atrophy and clinical progression. A higher brain‐PAD at baseline was associated with more rapid disability progression and the rate of change in brain‐PAD related to worsening disability. Potentially, “brain‐age” could be used as a prognostic biomarker in early‐stage MS, to track disease progression or stratify patients for clinical trial enrollment. ANN NEUROL 2020 ANN NEUROL 2020;88:93–105

PurposePET 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 [11C]PK-11195 limits accurate quantification. [18F]GE-180, a novel TSPO ligand, displays superior binding to [11C]PK-11195 in vitro. Our objectives were to: (1) evaluate tracer characteristics of [18F]GE-180 in the brains of healthy human subjects; and (2) investigate whether the TSPO Ala147Thr polymorphism influences outcome measures.MethodsTen volunteers (five high-affinity binders, HABs, and five mixed-affinity binders, MABs) underwent a dynamic PET scan with arterial sampling after injection of [18F]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 (VT) 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.ResultsThe two-tissue compartment model was the best model. The average regional delivery rate constant (K1) was 0.01 mL cm−3 min−1 indicating low extraction across the blood–brain barrier (1 %). The estimated median VT 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 VT between HABs and MABs across all ROIs.ConclusionA reversible two-tissue compartment model fitted the data well and determined that the tracer has a low first-pass extraction (approximately 1 %) and low VT estimates in healthy individuals. There was no observable dependency on the rs6971 polymorphism as compared to other second-generation TSPO PET tracers. Investigation of [18F]GE-180 in populations with neuroinflammatory disease is needed to determine its suitability for quantitative assessment of TSPO expression.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3444-z) contains supplementary material, which is available to authorized users.

Long-term potentiation (LTP) at hippocampal CA3-CA1 synapses is thought to be mediated, at least in part, by an increase in the postsynaptic surface expression of a-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors induced by N-methyld-aspartate (NMDA) receptor activation. While this process was originally attributed to the regulated synaptic insertion of GluA1 (GluR-A) subunit-containing AMPA receptors, recent evidence suggests that regulated synaptic trafficking of GluA2 subunits might also contribute to one or several phases of potentiation. However, it has so far been difficult to separate these two mechanisms experimentally. Here we used genetically modified mice lacking the GluA1 subunit (Gria1 ) ⁄ ) mice) to investigate GluA1-independent mechanisms of LTP at CA3-CA1 synapses in transverse hippocampal slices. An extracellular, paired theta-burst stimulation paradigm induced a robust GluA1-independent form of LTP lacking the early, rapidly decaying component characteristic of LTP in wild-type mice. This GluA1-independent form of LTP was attenuated by inhibitors of neuronal nitric oxide synthase and protein kinase C (PKC), two enzymes known to regulate GluA2 surface expression. Furthermore, the induction of GluA1-independent potentiation required the activation of GluN2B (NR2B) subunit-containing NMDA receptors. Our findings support and extend the evidence that LTP at hippocampal CA3-CA1 synapses comprises a rapidly decaying, GluA1-dependent component and a more sustained, GluA1-independent component, induced and expressed via a separate mechanism involving GluN2B-containing NMDA receptors, neuronal nitric oxide synthase and PKC.

Purpose: Measurements of non-displaceable binding (V ND ) of positron emission tomography (PET) ligands are not often made in vivo in humans because they require ligands to displace binding to target receptors and there are few readily available, safe ones to use. A technique to measure V ND for ligands for the 18-kDa translocator protein (TSPO) has recently been developed which compares the total volume of distribution (V T ) before and after administration of the TSPO ligand XBD173. Here, we used XBD173 with an occupancy plot to quantify V ND for two TSPO radiotracers, [ 18 F]GE-180 and [ 11 C]PBR28, in cohorts of people with multiple sclerosis (MS). Additionally, we compared plots of subjects carrying high (HAB) or mixed binding (MAB) affinity polymorphisms of TSPO to estimate V ND without receptor blockade. Procedures: Twelve people with MS underwent baseline MRI and 90-min dynamic [ 18 F]GE-180 PET or [ 11 C]PBR28 PET (n = 6; three HAB, three MAB each). Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model. V ND was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173) and the polymorphism plot (by modelling the differences in signal across presence and absence of rs6971 genotypes). Results: Whole brain V T (mean ± standard deviation) was 0.29 ± 0.17 ml/cm 3 for [ 18 F]GE-180 and 5.01 ± 1.88 ml/cm 3 for [ 11 C]PBR28. Using the occupancy and polymorphism plots respectively, V ND for [ 18 F]GE-180 was 0.11 ml/cm 3 (95 % CI = 0.02, 0.16) and 0.20 ml/cm 3 (0.16, 0.34), accounting for, on average, 55 % of V T in the whole brain. For [ 11 C]PBR28, these values were 3.81 ml/cm 3 (3.02, 4.21) and 3.49 ml/cm 3 (1.38, 4.27), accounting for 67 % of average whole brain V T .Sujata Sridharan and Joel Raffel are joint first authors. Conclusions:Although V T for [ 18 F]GE-180 is low, indicating low brain penetration, half the signal shown by MS subjects reflected specific TSPO binding. V T for [ 11 C]PBR28 was higher and two thirds of the binding was non-specific. No brain ROIs were devoid of specific signal, further confirming that true reference tissue approaches are potentially problematic for estimating TSPO levels.