First-in-Humans Brain PET Imaging of the GluN2B-Containing N-methyl-d-aspartate Receptor with (R)-11C-Me-NB1.

The N-methyl-d-aspartate receptor (NMDAR) plays a crucial role in neurodegenerative diseases such as Alzheimer disease and in the treatment of major depression by fast-acting antidepressants such as ketamine. Given their broad implications, GluN2B-containing NMDARs have been of interest as diagnostic and therapeutic targets. Recently, (R)-11C-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 radioligand in a first-in-humans PET study. Methods: Six healthy male subjects were scanned twice on a fully integrated PET/MR scanner with (R)-11C-Me-NB1 for 120 min. Brain uptake and tracer distribution over time were investigated by SUVs. Test-retest reliability was assessed with the absolute percentage difference and the coefficient of variation. Exploratory total volumes of distribution (VT) were computed using an arterial input function and the Logan plot as well as a constrained 2-tissue-compartment model with the ratio of rate constants between plasma and tissue compartments (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 absolute percentage difference ranged from 6.9% to 8.5% and coefficient of variation from 4.9% to 6.0%, indicating a high test-retest reliability. A moderate correlation was found between SUV averaged from 70 to 90 min and VT using Logan plot (Spearman ρ = 0.44). Correlation between VT Logan and 2TCM was r = 0.76. Conclusion: The radioligand (R)-11C-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 NMDAR in the pathophysiology and treatment of neuropsychiatric disease such as Alzheimer disease and major depression. Additionally, it could help in the selection of appropriate doses of GluN2B-targeting drugs.

Making Sense of Patient-Derived iPSCs, Transdifferentiated Neurons, Olfactory Neuronal Cells, and Cerebral Organoids as Models for Psychiatric Disorders.

The improvement of experimental models for disorders requires a constant approximation towards the dysregulated tissue. In psychiatry, where an impairment of neuronal structure and function is assumed to play a major role in disease mechanisms and symptom development, this approximation is an ongoing process implicating various fields. These include genetic, animal, and post-mortem studies. To test hypotheses generated through these studies, in vitro models using non-neuronal cells such as fibroblasts and lymphocytes have been developed. For brain network disorders, cells with neuronal signatures would, however, represent a more adequate tissue. Considering the limited accessibility of brain tissue, research has thus turned towards neurons generated from induced pluripotent stem cells as well as directly induced neurons, cerebral organoids, and olfactory neuroepithelium. Regarding the increasing importance and amount of research using these neuronal cells, this review aims to provide an overview of all these models to make sense of the current literature. The development of each model system and its use as a model for the various psychiatric disorder categories will be laid out. Also, advantages and limitations of each model will be discussed, including a reflection on implications and future perspectives.

Seven day pre-analytical stability of serum and plasma neurofilament light chain.

Neurofilament light chain (NfL) has emerged as a biomarker of neuroaxonal damage in several neurologic conditions. With increasing availability of fourth-generation immunoassays detecting NfL in blood, aspects of pre-analytical stability of this biomarker remain unanswered. This study investigated NfL concentrations in serum and plasma samples of 32 patients with neurological diagnoses using state of the art Simoa technology. We tested the effect of delayed freezing of up to 7 days and statistically determined stability and validity of measured concentrations. We found concentrations of NfL in serum and plasma to remain stable at room temperature when processing of samples is delayed up to 7 days (serum: mean absolute difference 0.9 pg/mL, intraindividual variation 1.2%; plasma: mean absolute difference 0.5 pg/mL, intraindividual variation 1.3%). Consistency of these results was nearly perfect for serum and excellent for plasma (intraclass correlation coefficients 0.99 and 0.94, respectively). In conclusion, the soluble serum and plasma NfL concentration remains stable when unprocessed blood samples are stored up to 7 days at room temperature. This information is essential for ensuring reliable study protocols, for example, when shipment of fresh samples is needed.