Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The ...synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand
CUCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.
Chemical synapses are the predominant neuron-to-neuron contact in the central nervous system. Presynaptic boutons of neurons contain hundreds of vesicles filled with neurotransmitters, the diffusible ...signaling chemicals. Changes in the number of synapses are associated with numerous brain disorders, including Alzheimer's disease and epilepsy. However, all current approaches for measuring synaptic density in humans require brain tissue from autopsy or surgical resection. We report the use of the synaptic vesicle glycoprotein 2A (SV2A) radioligand (11)CUCB-J combined with positron emission tomography (PET) to quantify synaptic density in the living human brain. Validation studies in a baboon confirmed that SV2A is an alternative synaptic density marker to synaptophysin. First-in-human PET studies demonstrated that (11)CUCB-J had excellent imaging properties. Finally, we confirmed that PET imaging of SV2A was sensitive to synaptic loss in patients with temporal lobe epilepsy. Thus, (11)CUCB-J PET imaging is a promising approach for in vivo quantification of synaptic density with several potential applications in diagnosis and therapeutic monitoring of neurological and psychiatric disorders.
Neuroinflammation is associated with a broad spectrum of neurodegenerative and psychiatric diseases. The core process in neuroinflammation is activation of microglia, the innate immune cells of the ...brain. We measured the neuroinflammatory response produced by a systemic administration of theEscherichia colilipopolysaccharide (LPS; also called endotoxin) in humans with the positron emission tomography (PET) radiotracer 11CPBR28, which binds to translocator protein, a molecular marker that is up-regulated by microglial activation. In addition, inflammatory cytokines in serum and sickness behavior profiles were measured before and after LPS administration to relate brain microglial activation with systemic inflammation and behavior. Eight healthy male subjects each had two 120-min 11CPBR28 PET scans in 1 d, before and after an LPS challenge. LPS (1.0 ng/kg, i.v.) was administered 180 min before the second 11CPBR28 scan. LPS administration significantly increased 11CPBR28 binding 30–60%, demonstrating microglial activation throughout the brain. This increase was accompanied by an increase in blood levels of inflammatory cytokines, vital sign changes, and sickness symptoms, well-established consequences of LPS administration. To our knowledge, this is the first demonstration in humans that a systemic LPS challenge induces robust increases in microglial activation in the brain. This imaging paradigm to measure brain microglial activation with 11CPBR28 PET provides an approach to test new medications in humans for their putative antiinflammatory effects.
Converging evidence suggests that major depressive disorder (MDD) affects multiple large-scale brain networks. Analyses of the correlation or covariance of regional brain structure and function ...applied to structural and functional MRI data may provide insights into systems-level organization and structure-to-function correlations in the brain in MDD. This study applied tensor-based morphometry and intrinsic connectivity distribution to identify regions of altered volume and intrinsic functional connectivity in data from unmedicated individuals with MDD (n=17) and healthy comparison participants (HC, n=20). These regions were then used as seeds for exploratory anatomical covariance and connectivity analyses. Reduction in volume in the anterior cingulate cortex (ACC) and lower structural covariance between the ACC and the cerebellum were observed in the MDD group. Additionally, individuals with MDD had significantly lower whole-brain intrinsic functional connectivity in the medial prefrontal cortex (mPFC). This mPFC region showed altered connectivity to the ventral lateral PFC (vlPFC) and local circuitry in MDD. Global connectivity in the ACC was negatively correlated with reported depressive symptomatology. The mPFC-vlPFC connectivity was positively correlated with depressive symptoms. Finally, we observed increased structure-to-function correlation in the PFC/ACC in the MDD group. Although across all analysis methods and modalities alterations in the PFC/ACC were a common finding, each modality and method detected alterations in subregions belonging to distinct large-scale brain networks. These exploratory results support the hypothesis that MDD is a systems level disorder affecting multiple brain networks located in the PFC and provide new insights into the pathophysiology of this disorder.
Altered metabotropic glutamate receptor 5 markers in PTSD Holmes, Sophie E.; Girgenti, Matthew J.; Davis, Margaret T. ...
Proceedings of the National Academy of Sciences - PNAS,
08/2017, Letnik:
114, Številka:
31
Journal Article
Recenzirano
Odprti dostop
Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling disorder, but there is currently no targeted pharmacological treatment for it. Dysfunction of the glutamate system has been ...implicated in trauma and stress psychopathology, resulting in a growing interest in modulation of the glutamate system for the treatment of PTSD. Specifically, the metabotropic glutamate receptor 5 (mGluR5) represents a promising treatment target. We used 18FFPEB, a radioligand that binds to the mGluR5, and positron emission tomography (PET) to quantify in vivo mGluR5 availability in human PTSD vs. healthy control (HCs) subjects. In an independent sample of human postmortem tissue, we investigated expression of proteins that have a functional relationship with mGluR5 and glucocorticoids in PTSD. We observed significantly higher cortical mGluR5 availability in PTSD in vivo and positive correlations between mGluR5 availability and avoidance symptoms. In the postmortem sample, we observed up-regulation of SHANK1, a protein that anchors mGluR5 to the cell surface, as well as decreased expression of FKBP5, implicating aberrant glucocorticoid functioning in PTSD. Results of this study provide insight into molecular mechanisms underlying PTSD and suggest that mGluR5 may be a promising target for mechanism-based treatments aimed at mitigating this disorder.
Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD.
CPBR28 Positron Emission ...Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals-with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology.
•ICA identifies covarying source networks of synaptic density in 11C-UCB-J PET data.•Thirteen source networks were validated and identified across independent healthy control samples.•Several source ...networks showed age-related decline in subject loadings.
The human brain is inherently organized into distinct networks, as reported widely by resting-state functional magnetic resonance imaging (rs-fMRI), which are based on blood-oxygen-level-dependent (BOLD) signal fluctuations. 11C-UCB-J PET maps synaptic density via synaptic vesicle protein 2A, which is a more direct structural measure underlying brain networks than BOLD rs-fMRI.
The aim of this study was to identify maximally independent brain source networks, i.e., “spatial patterns with common covariance across subjects”, in 11C-UCB-J data using independent component analysis (ICA), a data-driven analysis method. Using a population of 80 healthy controls, we applied ICA to two 40-sample subsets and compared source network replication across samples. We examined the identified source networks at multiple model orders, as the ideal number of maximally independent components (IC) is unknown. In addition, we investigated the relationship between the strength of the loading weights for each source network and age and sex.
Thirteen source networks replicated across both samples. We determined that a model order of 18 components provided stable, replicable components, whereas estimations above 18 were not stable. Effects of sex were found in two ICs. Nine ICs showed age-related change, with 4 remaining significant after correction for multiple comparison.
This study provides the first evidence that human brain synaptic density can be characterized into organized covariance patterns. Furthermore, we demonstrated that multiple synaptic density source networks are associated with age, which supports the potential utility of ICA to identify biologically relevant synaptic density source networks.
The relatively modest spatial resolution of positron emission tomography (PET) increases the likelihood of partial volume effects such that binding potential (BPND) may be underestimated. Given ...structural grey matter losses across adulthood, partial volume effects may be even more problematic in older age leading to overestimation of adult age differences. Here we examined the effects of partial volume correction (PVC) in two studies from different sites using different high-affinity D2-like radioligands (18 F-Fallypride, 11C-FLB457) and different PET camera resolutions (∼5 mm, 2.5 mm). Results across both data sets revealed that PVC increased estimated BPND and reduced, though did not eliminate, age effects on BPND. As expected, the effects of PVC were smaller in higher compared to lower resolution data. Analyses using uncorrected data that controlled for grey matter volume in each region of interest approximated PVC corrected data for some but not all regions. Overall, the findings suggest that PVC increases estimated BPND in general and reduces adult age differences especially when using lower resolution cameras. The findings suggest that the past 30 years of research on dopamine receptor availability, for which very few studies use PVC, may overestimate effects of aging on dopamine receptor availability.
Metabotropic glutamate receptor subtype 5 (mGluR5) is integral to the brain glutamatergic system and cognitive function. This study investigated whether aging is associated with decreased brain ...mGluR5 availability.
Cognitively normal participants (n = 45), aged 18 to 84 years, underwent 18FFPEB positron emission tomography scans to quantify brain mGluR5. Distribution volume (VT) was computed using a venous or arterial input function and equilibrium modeling from 90 to 120 min. In the primary analysis, the association between age and VT in the hippocampus and association cortex was evaluated using a linear mixed model. Exploratory analyses assessed the association between age and VT in multiple brain regions. The contribution of gray matter tissue alterations and partial volume effects to associations with age was also examined.
In the primary analysis, older age was associated with lower 18FFPEB binding to mGluR5 (P = 0.026), whereas this association was not significant after gray matter masking or partial volume correction to account for age-related tissue loss. Post hoc analyses revealed an age-related decline in mGluR5 availability in the hippocampus of 4.5% per decade (P = 0.007) and a non-significant trend in the association cortex (P = 0.085). An exploratory analysis of multiple brain regions revealed broader inverse associations of age with mGluR5 availability, but not after partial volume correction.
Reductions in mGluR5 availability with age appear to be largely mediated by tissue loss. Quantification of 18FFPEB binding to mGluR5 may expand our understanding of age-related molecular changes and the relationship with brain tissue loss.
Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission ...tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18–55 years; 44 male; BMI=27.01±5.56), the largest cohort of subjects studied to date using the CB1R PET ligand 11COMAR. There was a significant decline in CB1R availability (VT) with age in the pallidum, cerebellum and posterior cingulate. Adjusting for BMI, age-related decline in VT remained significant in the posterior cingulate among males, and in the cerebellum among women. CB1R availability was higher in women compared to men in the thalamus, pallidum and posterior cingulate. Adjusting for age, CB1R availability negatively correlated with BMI in women but not men. These findings differ from those reported using 11COMAR and other radioligands such as 18FFMPEP-d2 and 18FMK-9470. Although reasons for these seemingly divergent findings are unclear, the choice of PET radioligand and range of BMI in the current dataset may contribute to the observed differences. This study highlights the need for cross-validation studies using both 11COMAR and 18FFMPEP-d2 within the same cohort of subjects.
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