Traditionally, multiple sclerosis (MS) has been considered a white matter disease with focal inflammatory lesions. It is, however, becoming clear that significant pathology, such as microglial ...activation, also takes place outside the plaque areas, that is, in areas of normal-appearing white matter (NAWM) and gray matter (GM). Microglial activation can be detected in vivo using 18-kDa translocator protein (TSPO)-binding radioligands and PET. It is unknown whether fingolimod affects microglial activation in MS. The aim of this study was to investigate whether serial PET can be used to evaluate the effect of fingolimod treatment on microglial activation.
Ten relapsing-remitting MS patients were studied using the TSPO radioligand
C-(
)-PK11195. Imaging was performed at baseline and after 8 and 24 wk of fingolimod treatment. Eight healthy individuals were imaged for comparison. Microglial activation was evaluated as distribution volume ratio of
C-(
)-PK11195.
The patients had MS for an average of 7.9 ± 4.3 y (mean ± SD), their total relapses averaged 4 ± 2.4, and their Expanded Disability Status Scale was 2.7 ± 0.5. The patients were switched to fingolimod because of safety reasons or therapy escalation. The mean washout period before the initiation of fingolimod was 2.3 ± 1.1 mo. The patients were clinically stable on fingolimod. At baseline, microglial activation was significantly higher in the combined NAWM and GM areas of MS patients than in healthy controls (
0.021).
C-(
)-PK11195 binding was reduced (-12.31%) within the combined T2 lesion area after 6 mo of fingolimod treatment (
0.040) but not in the areas of NAWM or GM.
Fingolimod treatment reduced microglial/macrophage activation at the site of focal inflammatory lesions, presumably by preventing leukocyte trafficking from the periphery. It did not affect the widespread, diffuse microglial activation in the NAWM and GM. The study opens new vistas for designing future therapeutic studies in MS that use the evaluation of microglial activation as an imaging outcome measure.
Alterations in the brain’s μ-opioid receptor (MOR) system have been associated with several neuropsychiatric disorders. Central MOR availability also varies considerably in healthy individuals. ...Multiple epidemiological factors have been proposed to influence the MOR system, but due to small sample sizes the magnitude of their influence remains inconclusive. We compiled 11Ccarfentanil positron emission tomography scans from 204 individuals with no neurologic or psychiatric disorders, and estimated the effects of sex, age, body mass index (BMI) and smoking on 11Ccarfentanil binding potential using between-subject regression analysis. We also examined hemispheric differences in MOR availability. Older age was associated with increase in MOR availability in frontotemporal areas but decrease in amygdala, thalamus, and nucleus accumbens. The age-dependent increase was stronger in males. MOR availability was globally lowered in smokers but independent of BMI. Finally, MOR availability was higher in the right versus the left hemisphere. The presently observed variation in MOR availability may explain why some individuals are prone to develop MOR-linked pathological states, such as chronic pain or psychiatric disorders. Lateralized MOR system may reflect hemispheric work specialization in central emotion and pain processes.
•Sex, age and smoking have regionally specific influence on human μ-opioid receptor (MOR) availability in the brain.•MOR availabilities have regional asymmetries between the two hemispheres, right hemisphere being more abundant in MORs.•Variability in MOR system may explain why some individuals are vulnerable to chronic pain and neuropsychiatric disorders.
Major depressive disorder is associated with lowered mood, anxiety, anhedonia, sleep problems, and cognitive impairments. Many of these functions are regulated by μ-opioid receptor (MOR) system. ...Preclinical, in vivo, and post-mortem studies have however yielded inconclusive results regarding the role of the MOR in depression and anxiety. Moreover, it is not known whether alterations in MOR are already present in subclinical depression and anxiety. In a large-scale retrospective cross-sectional study we pooled data from 135 (113 males and 22 females) healthy subjects whose brain's MOR availability was measured with positron emission tomography (PET) using an agonist radioligand
Ccarfentanil that has high affinity for MORs. Depressive and anxious symptomology was addressed with BDI-II and STAI-X questionnaires, respectively. Both anxiety and depression scores in the subclinical range were negatively associated with MOR availability in cortical and subcortical areas, notably in amygdala, hippocampus, ventral striatum, and orbitofrontal and cingulate cortices. We conclude that dysregulated MOR availability is involved in altered mood and pathophysiology of depression and anxiety disorders.
We studied if midlife insulin resistance (IR) and APOE genotype would predict brain beta-amyloid (Aβ) accumulation and Aβ change in late-life in 5-year follow-up
CPIB-PET study. 43 dementia-free ...participants were scanned twice with
CPIB-PET in their late-life (mean age at follow-up 75.4 years). Participants were recruited from the Finnish Health2000 study according to their HOMA-IR values measured in midlife (mean age at midlife 55.4 years; IR+ group, HOMA-IR > 2.17; IR- group, HOMA-IR <1.25), and their APOEε4 genotype. At late-life follow-up,
CPIB-PET composite SUVr was significantly higher in IR+ group than IR- group (median 2.3 (interquartile range 1.7-3.3) vs. 1.7 (1.5-2.4), p = 0.03). There was no difference between IR- and IR+ groups in
CPIB-PET SUVr 5-year change, but the change was significantly higher in IR+/APOEε4+ group (median change 0.8 (0.60-1.0)) than in IR-/APOEε4- (0.28 (0.14-0.47), p = 0.02) and in IR+/APOEε4- group (0.24 (0.06-0.40), p = 0.046). These results suggest that APOEε4 carriers with midlife IR are at increased risk for late-life Aβ accumulation.
•Psychopathy is characterized by antisocial behavior and poor behavioral control.•Molecular brain basis of psychopathy remains poorly characterized.•We studied D2R and MOR availability in violent ...offenders with high psychopathic traits.•Psychopathic subjects had lowered D2R availability in striatum.•D2R signaling could be the putative macromolecular pathway for psychopathy.•Evidence for the aberrant MOR system is more limited.
Psychopathy is characterized by antisocial behavior, poor behavioral control and lacking empathy, and structural alterations in the corresponding neural circuits. Molecular brain basis of psychopathy remains poorly characterized. Here we studied type 2 dopamine receptor (D2R) and mu-opioid receptor (MOR) availability in convicted violent offenders with high psychopathic traits (n = 11) and healthy matched controls (n = 17) using positron emission tomography (PET). D2R were measured with radioligand 11Craclopride and MORs with radioligand 11Ccarfentanil. Psychopathic subjects had lowered D2R availability in caudate and putamen, and striatal D2R availability was also associated with degree of psychopathic traits in this prisoner sample. No group differences were found in MOR availability, although in the prisoner sample, psychopathic traits were negatively correlated with MOR availability in the amygdala and nucleus accumbens. We conclude that D2R signaling could be the putative neuromolecular pathway for psychopathy, whereas evidence for alterations in the MOR system is more limited.
Purpose
The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission ...tomography (PET) and the radioligand
11
CPBR28.
Methods
11
CPBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19–80 years; BMI range 17.6–36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (V
T
) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts.
Results
There were significant positive correlations between age and V
T
in the frontal and temporal cortex. BMI showed a significant negative correlation with V
T
in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher V
T
. A subgroup analysis revealed a positive correlation between V
T
and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects.
Conclusion
These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.
Nasal spray formulations of naloxone, a mu-opioid receptor (MOR) antagonist, are currently used for the treatment of opioid overdose. They may have additional therapeutic utility also in the absence ...of opioid agonist drugs, but the onset and duration of action at brain MORs have been inadequately characterized to allow such projections. This study provides initial characterization of brain MOR availability at high temporal resolution following intranasal (IN) naloxone administration to healthy volunteers in the absence of a competing opioid agonist. Fourteen participants were scanned twice using positron emission tomography (PET) and
Ccarfentanil, a selective MOR agonist radioligand. Concentrations of naloxone in plasma and MOR availability (relative to placebo) were monitored from 0 to 60 min and at 300-360 min post naloxone. Naloxone plasma concentrations peaked at ~20 min post naloxone, associated with slightly delayed development of brain MOR occupancy (half of peak occupancy reached at ~10 min). Estimated peak occupancies were 67 and 85% following 2 and 4 mg IN doses, respectively. The estimated half-life of occupancy disappearance was ~100 min. The rapid onset of brain MOR occupancy by IN naloxone, evidenced by the rapid onset of its action in opioid overdose victims, was directly documented in humans for the first time. The employed high temporal-resolution PET method establishes a model that can be used to predict brain MOR occupancy from plasma naloxone concentrations. IN naloxone may have therapeutic utility in various addictions where brain opioid receptors are implicated, such as gambling disorder and alcohol use disorder.
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