Ten percent of humans lack specific binding of [11C]PBR28 to 18 kDa translocator protein (TSPO), a biomarker for inflammation. “Non-binders” have not been reported using another TSPO radioligand, [11C]-(R)-PK 11195, despite its use for more than two decades. This study asked two questions: 1) What is the cause of non-binding to PBR28? 2) Why has this phenomenon not been reported using [11C]-(R)-PK 11195? Methods Five binders and five non-binders received whole-body imaging with both [11C]-(R)-PK 11195 and [11C]PBR28. In vitro binding was performed using leukocyte membranes from binders and non-binders and the tritiated versions of the ligand. Rhesus monkeys were imaged with [11C]-(R)-PK 11195 at baseline and after blockade of TSPOs. Results Using [11C]PBR28, uptake in all five organs with high densities of TSPO (lung, heart, brain, kidney, and spleen) was 50% to 75% lower in non-binders than in binders. In contrast, [11C]-(R)-PK 11195 distinguished binders and non-binders in only heart and lung. For the in vitro assay, [3H]PBR28 had more than ten-fold lower affinity to TSPO in non-binders than in binders. The in vivo specific binding of [11C]-(R)-PK 11195 in monkey brain was ∼80-fold lower than that reported for [11C]PBR28. Conclusions Based on binding of [3H]PK 11195 to leukocyte membranes, both binders and non-binders express TSPO. Non-binding to PBR28 is caused by its low affinity for TSPO in non-binders. Non-binding may be differentially expressed in organs of the body. The relatively low in vivo specific binding of [11C]-(R)-PK 11195 may have obscured its detection of non-binding in peripheral organs.

Purpose To explore whether the ‘hikikomori’ syndrome (social withdrawal) described in Japan exists in other countries, and if so, how patients with the syndrome are diagnosed and treated. Methods Two hikikomori case vignettes were sent to psychiatrists in Australia, Bangladesh, India, Iran, Japan, Korea, Taiwan, Thailand and the USA. Participants rated the syndrome's prevalence in their country, etiology, diagnosis, suicide risk, and treatment. Results Out of 247 responses to the questionnaire (123 from Japan and 124 from other countries), 239 were enrolled in the analysis. Respondents’ felt the hikikomori syndrome is seen in all countries examined and especially in urban areas. Biopsychosocial, cultural, and environmental factors were all listed as probable causes of hikikomori, and differences among countries were not significant. Japanese psychiatrists suggested treatment in outpatient wards and some did not think that psychiatric treatment is necessary. Psychiatrists in other countries opted for more active treatment such as hospitalization. Conclusions Patients with the hikikomori syndrome are perceived as occurring across a variety of cultures by psychiatrists in multiple countries. Our results provide a rational basis for study of the existence and epidemiology of hikikomori in clinical or community populations in international settings.

The peripheral benzodiazepine receptor (PBR) is upregulated on activated microglia and macrophages and thereby is a useful biomarker of inflammation. We developed a novel PET radioligand, [ 11 C]PBR28, that was able to image and quantify PBRs in healthy monkeys and in a rat model of stroke. The objective of this study was to evaluate the ability of [ 11 C]PBR28 to quantify PBRs in brain of healthy human subjects. Twelve subjects had PET scans of 120 to 180 min duration as well as serial sampling of arterial plasma to measure the concentration of unchanged parent radioligand. One-and two-tissue compartmental analyses were performed. To obtain stable estimates of distribution volume, which is a summation of B max /K D and nondisplaceable activity, 90 min of brain imaging was required. Distribution volumes in human were only ∼5% of those in monkey. This comparatively low amount of receptor binding required a two-rather than a one-compartment model, suggesting that nonspecific binding was a sizeable percentage compared to specific binding. The time-activity curves in two of the twelve subjects appeared as if they had no PBR binding -i.e., rapid peak of uptake and fast washout from brain. The cause(s) of these unusual findings are unknown, but both subjects were also found to lack binding to PBRs in peripheral organs such as lung and kidney. In conclusion, with the exception of those subjects who appeared to have no PBR binding, [ 11 C]PBR28 is a promising ligand to quantify PBRs and localize inflammation associated with increased densities of PBRs.

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Objectives-Peripheral benzodiazepine receptors (PBRs) are upregulated on activated microglia and are thereby biomarkers of neuroinflammation. We developed a PET ligand with an aryloxyanilide structure, [O-methyl-11 C]N-acetyl-N-(2-methoxybenzyl)-2-phenoxy-5-pyridinamine ([ 11 C] PBR28), to image PBRs. The objectives of the current study were to evaluate kinetics of brain uptake, and the influence of the peripheral binding on the arterial input function in rhesus monkey.Methods-Brain (baseline: n=6, blocking: n=1) and whole-body PET imaging (baseline: n=3, blocking: n=1) of [ 11 C]PBR28 were performed with the measurement of radiometabolite-corrected arterial input function in all brain and two whole body scans.Results-Saturating doses of nonradioactive PBR ligands markedly increased [ 11 C]PBR28 in plasma (∼400% increase) and brain (∼200%) at 2 min by displacing radioligand from PBRs in peripheral organs. Brain uptake of radioactivity peaked in baseline scans at ∼40 min after injection of [ 11 C]PBR28 and was high (∼300% standardized uptake value). The images showed no receptorfree region that could be used for reference tissue analysis. Thus, quantitation of receptor density required measurement of parent radioligand in arterial plasma. Nondisplaceable uptake was estimated from the blocked scans and was only ∼5% of total distribution volume measured under baseline conditions. Distribution volume of [ 11 C]PBR28 was stably determined within 110 min of scanning.Conclusions-Regional brain uptake of [ 11 C]PBR28 in monkey could be quantified as a value proportional to the density of receptors -namely, as equilibrium distribution volume. [ 11 C]PBR28 had high levels of specific binding in brain and should provide a sensitive measure of changes in PBRs.

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PurposeTo examine the relationship between depressive symptoms, subjective cognitive function, and quality of life in Japanese adults using the Cognitive Complaints in Bipolar Disorder Rating Assessment (COBRA).Patients and methodsWe evaluated 585 adult community volunteers using the Patient Health Questionnaire-9 (PHQ-9) for evaluation of depressive symptoms and the COBRA for evaluation of subjective cognitive function. We additionally used the 8-item Short-Form Health Survey and the Sheehan Disability Scale to evaluate the quality of life (QoL).ResultsMeasures of subjective cognitive function were significantly correlated with depressive symptoms and QoL. Structural equation modeling demonstrated that depressive symptoms directly and indirectly decreased QoL via their effects on subjective cognitive dysfunction. Measures of depressive symptoms were more closely related to QoL than were measures of subjective cognitive function.LimitationsStudy participants were general adult population community volunteers and included healthy people; thus, these results may not be generalizable to patients with depression or bipolar disorder. In addition, the cross-sectional design of this study prevented the identification of causal relationships among the parameters.ConclusionChanges in subjective cognitive function may affect QoL via depressive symptoms. Evaluations of subjective cognitive function may help identify factors that reduce QoL.