In Vivo Cerebral Translocator Protein (TSPO) Binding and Its Relationship with Blood Adiponectin Levels in Treatment-Naïve Young Adults with Major Depression: A [11C]PK11195 PET Study

Adiponectin is an adipokine that mediates cellular cholesterol efflux and plays important roles in neuroinflammatory processes. In this study, we undertook positron emission tomography (PET) with the translocator protein (TSPO) ligand [11C]PK11195 and measured serum adiponectin levels in groups of treatment-naïve young adult patients with major depressive disorder (MDD) and matched healthy controls. Thirty treatment-naïve MDD patients (median age: 24 years) and twenty-three healthy controls underwent [11C]PK11195 PET. We quantified TSPO availability in brain as the [11C]PK11195 binding potential (BPND) using a reference tissue model in conjunction with the supervised cluster analysis (SVCA4) algorithm. Age, sex distribution, body mass index, and serum adiponectin levels did not differ between the groups. Between-group analysis using a region-of-interest approach showed significantly higher [11C]PK11195 BPND in the left anterior and right posterior cingulate cortices in MDD patients than in controls. Serum adiponectin levels had significant negative correlations with [11C]PK11195 BPND in the bilateral hippocampus in MDD patients, but significant positive correlations in the bilateral hippocampus in the control group. Our results indicate significantly higher TSPO binding in the anterior and posterior cingulate cortices in treatment-naïve young MDD patients, suggesting microglial activation in these limbic regions, which are involved in cognitive and emotional processing. The opposite correlations between [11C]PK11195 BPND in the hippocampus with serum adiponectin levels in MDD and control groups suggest that microglial activation in the hippocampus may respond differentially to adiponectin signaling in MDD and healthy subjects, possibly with respect to microglial phenotype.

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Insights into smouldering MS brain pathology with multimodal diffusion tensor and PET imaging

10.1101/2020.01.09.20017012 ◽

2020 ◽

Author(s):

Svetlana Bezukladova ◽

Jouni Tuisku ◽

Markus Matilainen ◽

Anna Vuorimaa ◽

Marjo Nylund ◽

...

Keyword(s):

White Matter ◽

Pet Imaging ◽

Microglial Activation ◽

Diffusion Tensor ◽

Volume Ratio ◽

Translocator Protein ◽

Control Group ◽

In Vivo Evaluation ◽

Conventional Mri

Objective: To evaluate in vivo the co-occurrence of microglial activation and microstructural white matter damage in multiple sclerosis (MS) brain, and to examine their association with clinical disability. Methods: 18-kDa translocator protein (TSPO) brain PET imaging was performed for evaluation of microglial activation by using the radioligand [11C](R)-PK11195. TSPO-binding was evaluated as the distribution volume ratio (DVR) from dynamic PET images. Diffusion tensor imaging (DTI) and conventional MRI were performed at the same time. Mean fractional anisotropy (FA) and mean (MD), axial (AD) and radial (RD) diffusivities were calculated within the whole normal appearing white matter (NAWM) and segmented NAWM regions appearing normal in conventional MRI. 55 MS patients and 15 healthy controls were examined. Results: Microstructural damage was observed in the NAWM of MS brain. DTI parameters of MS patients were significantly altered in the NAWM, when compared to an age- and sex-matched healthy control group: mean FA was decreased, and MD, AD and RD were increased. These structural abnormalities correlated with increased TSPO binding in the whole NAWM and in the temporal NAWM (p<0.05 for all correlations; p<0.01 for RD in the temporal NAWM). Both compromised WM integrity and increased microglial activation in the NAWM correlated significantly with higher clinical disability measured with expanded disability status scale (EDSS). Conclusions: Widespread structural disruption in the NAWM is linked to neuroinflammation, and both phenomena associate with clinical disability. Multimodal PET and DTI imaging allows in vivo evaluation of widespread MS pathology not visible using conventional MRI.

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Characteristics of Oral Microbiota in Patients with Esophageal Cancer in China

BioMed Research International ◽

10.1155/2021/2259093 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Hezi Li ◽

Zhilin Luo ◽

Hong Zhang ◽

Nali Huang ◽

Dong Li ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Group Analysis ◽

Control Group ◽

Oral Microbiota ◽

Healthy Controls ◽

Linear Discriminant ◽

Squamous Cell Carcinoma Group

Gut microbiota dysbiosis is closely associated with intestinal carcinogenesis, but the oral microbiota of patients with esophageal squamous cell carcinoma who live in high-risk regions in China has not been fully characterized. In the current study, oral microbial diversity was investigated in 33 patients with esophageal squamous cell carcinoma and 35 healthy controls in Chongqing, China, by sequencing 16S rRNA of V3-V4 gene regions. There were statistically significant differences in oral microbiota between esophageal squamous cell carcinoma patients and controls as determined via unweighted pair-group analysis with arithmetic means. At the phylum level, in esophageal squamous cell carcinoma patients, there were comparatively greater amounts of Firmicutes (34.0% vs. 31.1%) and Bacteroidetes (25.3% vs. 24.9%) and lower amounts of Proteobacteria (17.0% vs. 20.1%). At the genus level, esophageal squamous cell carcinoma patients exhibited comparatively greater amounts of Streptococcus (17.3% vs. 14.5%) and Prevotella_7 (8.6% vs. 8.5%) and lower amounts of Neisseria (8.1% vs. 10.7%). Using a linear discriminant analysis effect size method, Planctomycetes and Verrucomicrobia were identified in the esophageal squamous cell carcinoma group. 10 genera were higher abundances identified in the healthy control group, and different 10 genera were identified in the esophageal squamous cell carcinoma group. In the present study, there were significant differences in oral microbial compositions of esophageal squamous cell carcinoma patients and healthy controls. Further longitudinal and mechanistic studies are needed to further characterize relationships between oral microbiota and esophageal squamous cell carcinoma.

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Neuroinflammation in Children With Infantile Spasms: A Prospective Study Before and After Treatment With Acthar Gel (Repository Corticotropin Injection)

Journal of Child Neurology ◽

10.1177/0883073820932710 ◽

2020 ◽

Vol 35 (12) ◽

pp. 808-812

Author(s):

Harry T. Chugani ◽

Ajay Kumar

Keyword(s):

Infantile Spasms ◽

Translocator Protein ◽

Binding Potential ◽

Complete Disappearance ◽

Subcortical Structures ◽

Reference Tissue ◽

Positron Emission ◽

Before And After ◽

Gel Treatment ◽

A Prospective Study

The selective effectiveness of adrenocorticotropic hormone (ACTH) in treating infantile spasms suggests an underlying neuroinflammation. Because neuroinflammation is mediated by activated microglia, which express translocator protein (TSPO), we imaged neuroinflammation in children with infantile spasms using positron emission tomography (PET) with 11C-PK11195 (PK), which selectively binds to TSPO. Children were studied prospectively before and following treatment with Acthar Gel (repository corticotropin injection). We hypothesized that PK-PET would show neuroinflammation (increased PET uptake) in cortical and/or subcortical structures before treatment, and that this inflammation will be abolished/reduced following Acthar Gel treatment. Eight children with infantile spasms (5 males; mean age 1.8±1.1, range 0.9-4.1 years) were recruited. After clinical and video electroencephalograph (EEG) evaluation and dynamic PK-PET scan, children underwent treatment with Acthar Gel over 4 weeks, followed by repeat clinical evaluation/video-EEG 2 weeks after initiation of treatment and repeat PK-PET 2 weeks after treatment completion. Visual and quantitative analysis of PK-PET scans were performed. We calculated regional binding potential (measure of receptor-ligand binding) using a reference tissue model. Focal areas of increased PK-binding were found in the pretreatment PK-PET in 5 children. Following treatment, these increases were either reduced or normalized and were associated with cessation (n=4) or significant reduction (n=1) of spasms and complete disappearance of hypsarrhythmia. One child showed increased binding potential in basal ganglia and thalamus, despite normalization of cortical binding potential; however, these increases were likely associated with death-related causes. This study suggests Acthar Gel–responsive neuroinflammatory changes in children with infantile spasms, supporting a potential role of neuroinflammation in the pathogenesis of infantile spasms.

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2493

Journal of Clinical and Translational Science ◽

10.1017/cts.2017.236 ◽

2017 ◽

Vol 1 (S1) ◽

pp. 66-66 ◽

Cited By ~ 1

Author(s):

Brian Berman ◽

Erika Shelton ◽

Yubin Miao

Keyword(s):

Receptor Binding ◽

Rating Scale ◽

Focal Dystonia ◽

Binding Potential ◽

Pathophysiological Mechanism ◽

Healthy Controls ◽

Adult Onset ◽

Reference Tissue ◽

Gaba A ◽

Sensorimotor Network

OBJECTIVES/SPECIFIC AIMS: Determine whether GABA-A receptor binding is abnormal and linked to dystonia symptoms in cervical dystonia (CD). METHODS/STUDY POPULATION: There is increasing evidence that a key pathophysiological mechanism in adult-onset focal dystonia is a reduction in inhibitory control over the sensorimotor network. Results from a recent 11C-flumazenil PET imaging study suggest that abnormal inhibitory signaling in genetic and sporadic forms of dystonia may be due to reduced GABA-A binding. It remains unknown whether CD, the most common form of adult-onset focal dystonia, is associated with abnormal GABA-A binding. The goal of this research is to determine if GABA-A receptor binding is abnormal and linked to dystonia symptoms in CD. RESULTS/ANTICIPATED RESULTS: We investigated whole brain GABA-A binding in 15 CD patients (11F; 64±8 y) and 15 healthy controls (10F; 64±9 y) using 60-minute dynamic 11C-flumazenil PET scans. GABA-A receptor binding potential (BP) was estimated using a simplified reference tissue model. A 2-sample t-test was used to identify voxel-wise GABA-A BP differences between groups, and a regression analysis used to test for correlations between GABA-A BP and disease severity as measured with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS). A conventional region of interest analysis was also conducted to quantify BP changes within the sensorimotor network using the automated anatomical labeling atlas. DISCUSSION/SIGNIFICANCE OF IMPACT: CD patients have reduced GABA-A receptor binding compared with healthy controls, with the greatest reduction seen within the sensorimotor region of the thalamus. Furthermore, reductions in GABA-A binding in brain regions associated with coupling sensory and motor information predict motor severity. These findings support that reduced GABAergic signaling within sensorimotor integration regions is a key mechanism underlying dystonic symptoms in CD and could help inform the development of better, more targeted treatment options.

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Depiction of microglial activation in aging and dementia: Positron emission tomography with [11C]DPA713 versus [11C](R)PK11195

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x16646788 ◽

2016 ◽

Vol 37 (3) ◽

pp. 877-889 ◽

Cited By ~ 35

Author(s):

Masamichi Yokokura ◽

Tatsuhiro Terada ◽

Tomoyasu Bunai ◽

Kyoko Nakaizumi ◽

Kiyokazu Takebayashi ◽

...

Keyword(s):

Positron Emission Tomography ◽

Microglial Activation ◽

Second Generation ◽

Neuronal Degeneration ◽

Brain Regions ◽

Translocator Protein ◽

Emission Tomography ◽

Binding Potential ◽

Healthy Elderly ◽

Positron Emission

The presence of activated microglia in the brains of healthy elderly people is a matter of debate. We aimed to clarify the degree of microglial activation in aging and dementia as revealed by different tracers by comparing the binding potential (BPND) in various brain regions using a first-generation translocator protein (TSPO) tracer [11C]( R)PK11195 and a second-generation tracer [11C]DPA713. The BPND levels, estimated using simplified reference tissue models, were compared among healthy young and elderly individuals and patients with Alzheimer’s disease (AD) and were correlated with clinical scores. An analysis of variance showed category-dependent elevation in levels of [11C]DPA713 BPND in all brain regions and showed a significant increase in the AD group, whereas no significant changes among groups were found when [11C]( R)PK11195 BPND was used. Cognito-mnemonic scores were significantly correlated with [11C]DPA713 BPND levels in many brain regions, whereas [11C]( R)PK11195 BPND failed to correlate with the scores. As mentioned elsewhere, the present results confirmed that the second-generation TSPO tracer [11C]DPA713 has a greater sensitivity to TSPO in both aging and neuronal degeneration than [11C]( R)PK11195. Positron emission tomography with [11C]DPA713 is suitable for the delineation of in vivo microglial activation occurring globally over the cerebral cortex irrespective of aging and degeneration.

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Functional Analysis of Brain Imaging Suggests Changes in the Availability of mGluR5 and Altered Connectivity in the Cerebral Cortex of Long-Term Abstaining Males with Alcohol Dependence: A Preliminary Study

Life ◽

10.3390/life11060506 ◽

2021 ◽

Vol 11 (6) ◽

pp. 506

Author(s):

Yo-Han Joo ◽

Jeong-Hee Kim ◽

Hang-Keun Kim ◽

Young-Don Son ◽

Paul Cumming ◽

...

Keyword(s):

Functional Connectivity ◽

Alcohol Dependence ◽

Pet Imaging ◽

Metabotropic Glutamate Receptor ◽

Temporal Cortex ◽

Binding Potential ◽

Control Group ◽

Reference Tissue ◽

Significant Group

Direct in vivo evidence of altered metabotropic glutamate receptor-5 (mGluR5) availability in alcohol-related disorders is lacking. We performed [11C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in prolonged abstinent subjects with alcohol dependence to examine alterations of mGluR5 availability, and to investigate their functional significance relating to neural systems-level changes. Twelve prolonged abstinent male subjects with alcohol dependence (median abstinence duration: six months) and ten healthy male controls underwent [11C]ABP688 PET imaging and 3-Tesla MRI. For mGluR5 availability, binding potential (BPND) was calculated using the simplified reference tissue model with cerebellar gray matter as the reference region. The initial region-of-interest (ROI)-based analysis yielded no significant group differences in mGluR5 availability. The voxel-based analysis revealed significantly lower [11C]ABP688 BPND in the middle temporal and inferior parietal cortices, and higher BPND in the superior temporal cortex in the alcohol dependence group compared with controls. Functional connectivity analysis of the rs-fMRI data employed seed regions identified from the quantitative [11C]ABP688 PET analysis, which revealed significantly altered functional connectivity from the inferior parietal cortex seed to the occipital pole and dorsal visual cortex in the alcohol dependence group compared with the control group. To our knowledge, this is the first report on the combined analysis of mGluR5 PET imaging and rs-fMRI in subjects with alcohol dependence. These preliminary results suggest the possibility of region-specific alterations of mGluR5 availability in vivo and related functional connectivity perturbations in prolonged abstinent subjects.

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Neuroinflammation in schizophrenia: meta-analysis of in vivo microglial imaging studies

Psychological Medicine ◽

10.1017/s0033291718003057 ◽

2018 ◽

Vol 49 (13) ◽

pp. 2186-2196 ◽

Cited By ~ 35

Author(s):

Tiago Reis Marques ◽

Abhishekh H Ashok ◽

Toby Pillinger ◽

Mattia Veronese ◽

Federico E. Turkheimer ◽

...

Keyword(s):

Outcome Measure ◽

Meta Analysis ◽

Volume Of Distribution ◽

Axonal Guidance ◽

Translocator Protein ◽

Binding Potential ◽

Healthy Controls ◽

Imaging Studies ◽

The Difference

AbstractBackgroundConverging lines of evidence implicate an important role for the immune system in schizophrenia. Microglia are the resident immune cells of the central nervous system and have many functions including neuroinflammation, axonal guidance and neurotrophic support. We aimed to provide a quantitative review of in vivo PET imaging studies of microglia activation in patients with schizophrenia compared with healthy controls.MethodsDemographic, clinical and imaging measures were extracted from each study and meta-analysis was conducted using a random-effects model (Hedge's g). The difference in 18-kDa translocator protein (TSPO) binding between patients with schizophrenia and healthy controls, as quantified by either binding potential (BP) or volume of distribution (VT), was used as the main outcome. Sub-analysis and sensitivity analysis were carried out to investigate the effects of genotype, ligand and illness stage.ResultsIn total, 12 studies comprising 190 patients with schizophrenia and 200 healthy controls met inclusion criteria. There was a significant elevation in tracer binding in schizophrenia patients relative to controls when BP was used as an outcome measure, (Hedge's g = 0.31; p = 0.03) but no significant differences when VT was used (Hedge's g = −0.22; p = 0.29).ConclusionsIn conclusion, there is evidence for moderate elevations in TSPO tracer binding in grey matter relative to other brain tissue in schizophrenia when using BP as an outcome measure, but no difference when VT is the outcome measure. We discuss the relevance of these findings as well as the methodological issues that may underlie the contrasting difference between these outcomes.

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Quantification of [18F]DPA-714 Binding in the Human Brain: Initial Studies in Healthy Controls and Alzheimer'S Disease Patients

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2014.261 ◽

2015 ◽

Vol 35 (5) ◽

pp. 766-772 ◽

Cited By ~ 55

Author(s):

Sandeep SV Golla ◽

Ronald Boellaard ◽

Vesa Oikonen ◽

Anja Hoffmann ◽

Bart NM van Berckel ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Healthy Subjects ◽

Volume Ratio ◽

Information Criterion ◽

Volume Of Distribution ◽

Translocator Protein ◽

Binding Potential ◽

Reference Tissue ◽

Time Activity

Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([18F] DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [18F]DPA-714 binding in healthy subjects and Alzheimer's disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250 ± 10 MBq [18F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [18F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution ( VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [18F]DPA-714 cannot be used for separating individual AD patients from heathy subjects, but further studies including TSPO binding status are needed to substantiate these findings.

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A Common Thrombomodulin Amino Acid Dimorphism Is Associated with Myocardial Infarction

Thrombosis and Haemostasis ◽

10.1055/s-0038-1655947 ◽

1997 ◽

Vol 77 (02) ◽

pp. 248-251 ◽

Cited By ~ 62

Author(s):

Lena Norlund ◽

Johan Holm ◽

Bengt Zöller ◽

Ann-Kristin Öhlin

Keyword(s):

Myocardial Infarction ◽

Amino Acid ◽

Plasma Concentration ◽

Acute Coronary Syndromes ◽

Protein C ◽

Integral Membrane Protein ◽

Control Group ◽

Healthy Controls ◽

Coronary Syndromes ◽

Premature Myocardial Infarction

SummaryEndothelial dysfunction and haemostatic imbalance are believed to be important aetiological factors in the development of acute coronary syndromes. Thrombomodulin (TM) is an integral membrane protein crucial for normal endothelial function and activation of the protein C anticoagulant pathway. We have investigated the importance of a common C/T dimorphism in the TM gene (nucleotide 1418) for development of premature myocardial infarction (MI). The C/T dimorphism predicts an Ala455 to Val replacement in the sixth EGF-like domain of TM. The dimorphism was investigated in 97 MI survivors and 159 healthy controls. The C allele was significantly more frequent among patients than controls (p = 0.035). The allele frequency for the C allele was 0.82 in the patients and 0.72 in the control group. The plasma concentration of TM was investigated among healthy controls but was not related to the C/T dimorphism. In conclusion, the association of the C allele with premature MI, suggests that the TM gene and the C/T dimorphism may be aetiological factors involved in the pathogenesis of MI. Possibly, the Ala455 to Val replacement may affect the function of the TM molecule and the activation of the protein C anticoagulant pathway.

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Recovery of the decline in activities of daily living after hospitalization through an individualized exercise programme: Secondary Analysis of a Randomized Clinical Trial

The Journals of Gerontology Series A ◽

10.1093/gerona/glab032 ◽

2021 ◽

Author(s):

Nicolás Martínez-Velilla ◽

Mikel L Sáez de Asteasu ◽

Robinson Ramírez-Vélez ◽

Fabricio Zambom-Ferraresi ◽

Antonio García-Hermoso ◽

...

Keyword(s):

Exercise Training ◽

Daily Living ◽

Group Analysis ◽

Intervention Group ◽

Training Programme ◽

Control Group ◽

Bladder Control ◽

Patient Profile ◽

Climbing Stairs ◽

Exercise Training Programme

Abstract Background During the period of hospitalization patients can develop functional decline. The main aim of our study was to assess the natural trajectory of each Activity of Daily Living (ADL) and to assess how in-hospital exercise could influence short-term trajectory of ADLs. Methods Acutely hospitalized patients (n=297, 56.5% women) were randomly assigned to the intervention or control (usual care) group within the first 48 hours of admission. An exercise training programme was prescribed in two daily sessions (morning and evening) of 20 minutes duration during 5–7 consecutive days for the intervention group. The primary end-point was the change in every ADL (assessed with the Barthel Index) from 2 weeks before admission to hospital discharge. Results Acute hospitalization per se led to significant in-patient’s functional ability impairment in ADLs during hospitalization, whereas the exercise intervention reversed this trend (3.7 points; 95% CI, 0.5 to 6.8 points). After analyzing the trajectory of each one of the ADLs, patients in the control group significantly worsened all activities, but with a different degree of loss. For the between-group analysis, significant differences were obtained in many ADLs including bathing, dressing, grooming, bladder control, toilet use, transfers, mobility and climbing stairs (p<0.05). The control group had the greatest impairment in all domains analyzed (i.e., feeding, bathing, dressing, grooming, bowel control, bladder control, toilet use, transfers, mobility, and climbing stairs), p<0.05. Conclusions An individualized multicomponent exercise training programme in older adults is effective to reverse the loss of specific ADLs that frequently occurs during hospitalization. Each patient profile should receive an individualized prescription of exercise during hospitalizations.

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