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[11C]PBR28 is a positron emission tomography radioligand used to examine the expression of the 18 kDa translocator protein (TSPO). TSPO is located in glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (VT). Notably, VT reflects both specific binding and non-displaceable binding. Therefore, estimates of specific binding, such as binding potential (e.g. BPND) and specific distribution volume (VS) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these outcome measures are obtainable for [11C]PBR28. The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of the non-displaceable distribution volume (VND), which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME-derived VND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments, based on data from 54 unique [11C]PBR28 examinations, showed that VND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge (n = 5) showed that SIME provided VND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data (n = 11) showed that SIME-derived VS values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values. The results support the use of SIME for quantifying specific binding of [11C]PBR28, and suggest that VS can be used in complement to the conventional outcome measure VT. Additional studies in patient cohorts are warranted.

Fibromyalgia (FM) is a poorly understood chronic condition characterized by widespread musculoskeletal pain, fatigue, and cognitive difficulties. While mounting evidence suggests a role for neuroinflammation, no study has directly provided evidence of brain glial activation in FM. In this study, we conducted a Positron Emission Tomography (PET) study using [(11)C]PBR28, which binds to the translocator protein (TSPO), a protein upregulated in activated microglia and astrocytes. To enhance statistical power and generalizability, we combined datasets collected independently at two separate institutions (Massachusetts General Hospital [MGH] and Karolinska Institutet [KI]). In an attempt to disentangle the contributions of different glial cell types to FM, a smaller sample was scanned at KI with [(11)C]-(L)-deprenyl-D(2) PET, thought to primarily reflect astrocytic (but not microglial) signal. Thirty-one FM patients and 27 healthy controls (HC) were examined using [(11)C]PBR28 PET. 11 FM patients and 11 HC were scanned using [(11)C]-(L)-deprenyl-D(2) PET. Standardized uptake values normalized by occipital cortex signal (SUVR) and distribution volume (V(T)) were computed from the [(11)C]PBR28 data. [(11)C]-(L)-deprenyl-D(2) was quantified using λk(3). PET imaging metrics were compared across groups, and when differing across groups, against clinical variables. Compared to HC, FM patients demonstrated widespread cortical elevations, and no decreases, in [(11)C]PBR28 V(T) and SUVR, most pronounced in the medial and lateral walls of the frontal and parietal lobes. No regions showed significant group differences in [(11)C]-(L)-deprenyl-D(2) signal, including those demonstrating elevated [(11)C]PBR28 signal in patients (p’s≥0.53, uncorrected). The elevations in [(11)C]PBR28 V(T) and SUVR were correlated both spatially (i.e., were observed in overlapping regions) and, in several areas, also in terms of magnitude. In exploratory, uncorrected analyses, higher subjective ratings of fatigue in FM patients were associated with higher [(11)C]PBR28 SUVR in the anterior and posterior middle cingulate cortices (p’s

Microglia, the resident macrophages in the central nervous system, are thought to be maintained by a local self-renewal mechanism. Although preclinical and in vitro studies have suggested that the brain may contain immune cells also from peripheral origin, the functional association between immune cells in the periphery and brain at physiological conditions is poorly understood. We examined 32 healthy individuals using positron emission tomography (PET) and [(11)C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed both in brain microglia and blood immune cells. In 26 individuals, two measurements were performed with varying time intervals. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. All individuals were genotyped for TSPO polymorphism and categorized as high, mixed, and low affinity binders. We assessed TSPO binding expressed as total distribution volume of [(11)C]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells both at baseline and when analyzing change between two PET examinations. Furthermore, there was a significant correlation between change of leukocyte numbers and change in TSPO binding in brain, and a trend-level correlation to change in TSPO binding in blood cells. These in vivo findings indicate an association between immunological cells in blood and brain via intact BBB, suggesting a functional interaction between these two compartments, such as interchange of peripherally derived cells or a common regulatory mechanism. Measurement of radioligand binding in blood cells may be a way to control for peripheral immune function in PET studies using TSPO as a marker of brain immune activation.

Allergy is associated with non-specific symptoms such as fatigue and impaired cognition. Allergic patients also report worse sleep compared to healthy controls. As part of a study where we investigated seasonal changes in the glial cell marker translocator protein (TSPO), we studied fatigue, sleep and cognitive functions in allergic patients, in relation to seasonal changes in the glial cell marker translocator protein (TSPO) as measured using positron emission tomography (PET). We examined 18 patients with severe seasonal allergy and 13 healthy subjects in and out of pollen season, using TSPO PET, subjective ratings of fatigue and sleepiness, objective and subjective sleep measures and a test-battery of cognitive tests (CANTAB). Allergic subjects had shorter total sleep time, regardless of season, compared to healthy controls. Subjects with allergy also reported worse sleep quality during pollen season, but had a higher percentage of deep sleep. These effects were paralleled by increased fatigue and sleepiness, as well as increased levels of IL-5 and TNF-α during pollen season, but were unrelated to brain TSPO levels. Allergic patients showed lower scores on intra-extra dimensional set shift during pollen season, indicating lower capacity in set-shifting and flexibility of attention. We speculate that impaired sleep, together with neuroinflammatory mechanisms, contribute to a sickness-like state in allergy, characterized by fatigue, and dysregulated exteroceptive – and potentially increased interoceptive – attention.

Purpose Age-related changes in the serotonin system have been described, and proposed to be associated with behavioral changes observed particularly in the elderly population. The 5-HT 1B receptor is thought to have a regulatory role in a number of physiological functions, and has been implicated in several age-related diseases. The purpose of the present study was to examine if the availability of 5-HT 1B receptors is decreasing with age in healthy subjects. Methods Data from five previous studies were reanalyzed and pooled, generating data from fifty-one healthy subjects, age 20 to 70, that had been examined with positron emission tomography (PET) and the 5-HT 1B specific radioligand [ 11 C]AZ10419369 at baseline conditions. The binding potential ( BP ND ) in cortical and subcortical areas was calculated using the simplified reference tissue model (SRTM). After correction for partial volume effects (PVEc), the correlation between age and regional BP ND was examined. Results A statistically significant negative correlation between age and BP ND was obtained for neocortical regions and the ventral striatum (VST). The average reduction in BP ND per decade was 8% in cortex and 4% in VST. The BP ND in the caudate nucleus and the putamen was mainly unaffected by age. Conclusion The 5-HT 1B receptor availability decreases by age in cortical regions, whereas it remains stable in the caudate nucleus and putamen. By consequence, age-matching of control subjects will be necessary in future clinical studies.

Impairment of the central serotonin system in Parkinson's disease (PD) has been shown postmortem and in vivo with positron emission tomography (PET). The aim of this PET study was to examine and compare the availability of the 5-hydroxytryptamine (5-HT)(1B)-receptor subtype in patients with PD and age-matched control subjects. Twelve control subjects and 12 PD patients were examined with PET using the 5-HT(1B)-radioligand [(11)C]AZ10419369. In PD patients, 5-HT(1B)-receptor availability in the right orbitofrontal cortex was lower than in control subjects. A statistically significant negative correlation between 5-HT(1B)-receptor availability and age was obtained for the right temporal cortex in control subjects and for the right midbrain and left parahippocampal gyrus in PD patients. The lower regional 5-HT(1B)-receptor availability is in line with previous studies showing a decrease of serotonin imaging markers in PD and corroborates a role of the serotonin system in the pathophysiology of PD. The demonstrated age effect on 5-HT(1B) receptors suggest a physiologic and PD-related decline of serotonin function, indicating the importance of controlling for age in clinical studies.

We describe associations between sense of coherence (SOC) and sense of well-being, diseases, physical function and the predictive value of SOC on depression and mortality. The study included 190 participants, aged 85-103 years. Linear correlation analysis was used for relationships between SOC scores and continuous variables. The effects of SOC score on 1- and 4-year mortality, as well as on depression at the 5-year follow-up, were investigated using Cox regression models. The mean SOC score was 71.8±10.2 (±S.D.). SOC score was positively related to well-being (p≤0.001). Heart failure (p=0.009), chronic obstructive pulmonary disease (p=0.015), depression (p=0.015), and osteoarthritis (p=0.032) were significantly associated with low SOC scores, as were high scores on the Geriatric Depression Scale (GDS) (p=0.002). One-year mortality was significantly associated with the SOC score (OR=0.945, confidence interval (CI)=0.898-0.995, p=0.032), while the 4-year mortality was not (OR=0.995, CI=0.973-1.018, p=0.674). The SOC score did not predict depression at 5-year follow-up (OR=0.977, CI=0.937-1.018, p=0.267). Strong SOC was associated with well-being in this group of old people. Low SOC was found among those with diseases known to have a negative influence on daily life.

Seasonal allergy is associated with increased prevalence of psychiatric symptoms and disorders, as well as fatigue and cognitive difficulties that aggravate during pollen season. It is unclear if this results from the impact of peripheral allergic inflammation on the immune system in brain. We studied 15 allergic patients and 13 healthy controls in and out of pollen season in a balanced design. Positron emission tomography (PET) and the radioligand [11C]PBR28 was used to measure TSPO (translocator protein); a marker for immune cells (including microglia) in the brain. TSPO binding was quantified as total distribution volume of [11C]PBR28 in grey matter, controlled for polymorphisms in the TSPO gene that affect binding affinity. There were no differences between allergics and controls in TSPO levels, and no interaction with time of year. In peripheral blood, there was an increase in TNF-alpha (p = 0.04) but not IL-6 in allergics during pollen season. IL-5 was higher in allergics, and increased further during pollen season, with a corresponding pattern in the ratio between Th2 and Th1 cytokines (IL-5/IFN gamma; p’s

The interaction between immune cells in the periphery and brain in humans is poorly understood, partly due to the lack of in vivo studies. Here, we examined 32 healthy individuals using positron emission tomography (PET) and [11C]PBR28, a radioligand for the 18-kDa translocator protein (TSPO) which is expressed in immune cells both in brain and blood. In 26 individuals, two measurements were performed. In a subgroup of 19 individuals, of which 12 had repeat examinations, leukocyte numbers in blood was measured on each day of PET measurements. We assessed TSPO binding expressed as total distribution volume of [11C]PBR28 in brain and in blood cells. TSPO binding in brain was strongly and positively correlated to binding in blood cells at baseline (r = .85, p = 2.1 × 10−9, corrected for TSPO genotype). A correlation was also observed when analyzing change in TSPO levels in brain and blood between two PET examinations (r = .60, p = .002). Finally, there was a significant correlation between change of leukocyte numbers and change in brain TSPO binding, and a trend-level correlation to TSPO change in blood cells (r = .63, p = .038; r = .6, p = .052). These findings indicate a functional association between immunological cells in blood and brain at physiological conditions, such as interchange of peripherally derived cells or a common regulatory mechanism.

Methods: Twelve patients with idiopathic PD were implanted with a drug pump and an investigational catheter (Medtronic Inc) leading into the lateral ventricle. Patients were divided into 3 dose cohorts (0.2, 1.5 or 5 μg PDGF/day) and received either PDGF or placebo (buffer, 1 patient/cohort) for 12 days, after which all patients received buffer and were followed up to Day 85. Study objectives included continuous safety and tolerability assessments and UPDRS, MADRS, MMT, EQ5-D and DAT-binding (PET) assessments pre-treatment and at the end-of study.