The vascular endothelium in the brain is an essential part of the blood-brain-barrier (BBB) because of its very tight structure to secure a functional and molecular separation of the brain from the rest of the body and to protect neurons from pathogens and toxins. Impaired transport of metabolites across the BBB due to its increasing dysfunction affects brain health and cognitive functioning, thus providing a starting point of neurodegenerative diseases. The term "cerebral metabolic syndrome" is proposed to highlight the importance of lifestyle factors in neurodegeneration and to describe the impact of increasing BBB dysfunction on neurodegeneration and dementia, especially in elderly patients. If untreated, the cerebral metabolic syndrome may evolve into dementia. Due to the high energy demand of the brain, impaired glucose transport across the BBB via glucose transporters as GLUT1 renders the brain increasingly susceptible to neurodegeneration. Apoptotic processes are further supported by the lack of essential metabolites of the phosphocholine synthesis. In Alzheimer's disease (AD), inflammatory and infectious processes at the BBB increase the dysfunction and might be pace-making events. At this point, the potentially highly relevant role of the thrombocytic amyloid precursor protein (APP) in endothelial inflammation of the BBB is discussed. Chronic inflammatory processes of the BBB transmitted to an increasing number of brain areas might cause a lasting build-up of spreading, pore-forming β-amyloid fragments explaining the dramatic progression of the disease. In the view of the essential requirement of an early diagnosis to investigate and implement causal therapeutic strategies against dementia, brain imaging methods are of great importance. Therefore, status and opportunities in the field of diagnostic imaging of the living human brain will be portrayed, comprising diverse techniques such as positron emissions tomography (PET) and functional magnetic resonance imaging (fMRI) to uncover the patterns of atrophy, protein deposits, hypometabolism, and molecular as well as functional alterations in AD.

Furthermore, no statistically significant associations between changes in any of the neurotransmitter ratios and plasma levels of ketamine, norketamine, or dehydronorketamine were observed (p corr > 0.05). Conclusion: This study provides evidence for decreased hippocampal GABA+/tCr ratio 2 h following ketamine administration. As MRS methodology measures total levels of intraand extracellular GABA, results might indicate drug induced alterations in GABA turnover. Our study in healthy humans suggests that changes in GABA levels, particularly in the hippocampus, should be further assessed for their relevance to ketamine´s antidepressant effects.

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The N-methyl-D-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer's disease and in the treatment of major depression by new fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of large interest as diagnostic and therapeutic targets. Recently, (R)-11 C-Me-NB1 was investigated preclinically and shown to be a promising radioligand for imaging GluN2B subunits.Here, we report on the performance characteristics of this novel radioligand in a first-in-human PET study. Methods: Six healthy male subjects were scanned twice on a fully-integrated PET/MR scanner with (R)-11 C-Me-NB1 for 120 min. Brain uptake and tracer distribution over time were investigated by standardized uptake values (SUV). Test-retest reliability was assessed with the absolute percentage difference (APD) and the coefficient of variation (COV).Exploratory total volumes of distribution (VT) were computed using an arterial input function and the Logan plot as well as a constrained two-tissue compartment model with K1/k2 coupled (2TCM). SUV was correlated with VT to investigate its potential as a surrogate marker of GluN2B expression. Results: High and heterogeneous radioligand uptake was observed across the entire gray matter with reversible kinetics within the scan time. SUV APD ranged from 6.8 -8.5% and COV from 4.9 -6.0%, indicating a high test-retest reliability. A moderate correlation was found between SUV averaged from 70-90 min and VT using Logan plot (Spearman's rho = 0.44).Correlation between VT Logan and 2TCM was r= 0.76. Conclusion: The novel radioligand, (R)-11 C-Me-NB1, was highly effective in mapping GluN2B-enriched NMDARs in the human brain.With a heterogeneous uptake and a high test-retest reliability, this radioligand offers promise to deepen our understanding of the GluN2B-containing NMDA receptor in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer's disease and major depression.Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs.

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Background Selective serotonin reuptake inhibitors (SSRIs) are predominantly prescribed for people suffering from major depressive disorder. These antidepressants exert their effects by blocking the serotonin transporter (SERT), leading to increased levels of serotonin in the synaptic cleft and subsequently to an attenuation of depressive symptoms and elevation in mood. Although long-term studies investigating white matter (WM) alterations after exposure to antidepressant treatment exist, results on the acute effects on the brain’s WM microstructure are lacking. Methods In this interventional longitudinal study, 81 participants were included (33 patients and 48 healthy controls). All participants underwent diffusion weighted imaging on 2 separate days, receiving either citalopram or placebo using a randomized, double-blind, cross-over design. Fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were calculated within the FMRIB software library and analyzed using tract-based spatial statistics. Results The repeated-measures ANOVA model revealed significant decreases after SSRI administration in mean diffusivity, axial diffusivity, and radial diffusivity regardless of the group (P < .05, family-wise error [FWE] corrected). Results were predominantly evident in frontal WM regions comprising the anterior corona radiata, corpus callosum, and external capsule and in distinct areas of the frontal blade. No increases in diffusivity were found, and no changes in fractional anisotropy were present. Conclusions Our investigation provides the first evidence, to our knowledge, that fast WM microstructure adaptations within 1 hour after i.v. SSRI administration precede elevations in mood due to SSRI treatment. These results add a new facet to the complex mode of action of antidepressant therapy. This study was registered at clinicaltrials.gov with the identifier NCT02711215.

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