Relationships between Serotonin Transporter Binding in the Raphe Nuclei, Basal Ganglia, and Hippocampus with Clinical Symptoms in Cervical Dystonia:A [C]DASB Positron Emission Tomography Study

PurposeAlterations of the central serotonergic system have been implicated in the pathophysiology of dystonia. In this molecular imaging study, we assessed whether altered presynaptic serotonin transporter (SERT) binding contributes to the pathophysiology of cervical dystonia (CD), concerning both motor and non-motor symptoms (NMS).MethodsWe assessed the non-displaceable binding potential (BPND) using the selective SERT tracer [11C]DASB and positron emission tomography (PET) in 14 CD patients and 12 age- and gender-matched controls. Severity of motor symptoms was scored using the Toronto Western Spasmodic Torticollis Rating Scale and Clinical Global Impression jerks/tremor scale. NMS for depressive symptoms, anxiety, fatigue, and sleep disturbances were assessed with quantitative rating scales. The relationship between SERT binding and clinical patient characteristics was analyzed with the Spearman’s rho test and multiple regression.ResultsWhen comparing the CD patients with controls, no significant differences in BPND were found. Higher BPND in the dorsal raphe nucleus was statistically significantly correlated (p < 0.001) with motor symptom severity (rs = 0.65), pain (rs = 0.73), and sleep disturbances (rs = 0.73), with motor symptom severity being the most important predictor of SERT binding. Furthermore, fatigue was negatively associated with the BPND in the medial raphe nucleus (rs = −0.61, p = 0.045), and sleep disorders were positively associated with the BPND in the caudate nucleus (rs = 0.58, p = 0.03) and the hippocampus (rs = 0.56, p = 0.02).ConclusionMotor symptoms, as well as pain, sleep disturbances, and fatigue in CD showed a significant relationship with SERT binding in the raphe nuclei. Moreover, fatigue showed a significant relationship with the medial raphe nucleus and sleep disorders with the caudate nucleus and hippocampus. These findings suggest that an altered serotonergic signaling in different brain areas in CD is related to different motor as well as NMS, which will further stimulate research on the role of serotonin in the pathogenesis of dystonia

Myoclonus-dystonia : distinctive motor and non-motor phenotype from other dystonia syndromes

Background: myoclonus-dystonia (M-D) due to a pathogenic variant of SGCE is an autosomal dominant inherited movement disorder. Apart from motor symptoms, psychiatric disorders are highly prevalent in patients with MD. Previous studies suggest, but never tested directly, that the type of psychiatric disorder differs between dystonia syndromes, probably related to disease specific pathology. Little is known about other non-motor symptoms (NMS) in M.D. Here, we systematically study NMS in M-D in direct comparison to other types of dystonia and healthy controls. Methods: Standardized questionnaires were used to assess type and severity of psychiatric co-morbidity, sleep problems, fatigue and quality of life. Results of M-D patients with a pathogenic variant of SGCE were compared to results of idiopathic cervical dystonia (CD) patients, dopa-responsive dystonia (DRD) patients with a pathogenic variant of GCH1 and controls. Results: We included 164 participants: 41 M-D, 51 CD, 19 DRD patients, 53 controls. Dystonia patients (M-D, CD and DRD) had an increased prevalence of psychiatric disorders compared to controls (56-74% vs. 29%). In M-D we found a significantly increased prevalence of obsessive-compulsive disorder (OCD) and psychosis compared to CD and DRD. All dystonia patients had more sleep problems (49-68% vs. 36%) and fatigue (42-73% vs. 15%) than controls. Compared to other dystonia subtypes, M-D patients reported less excessive daytime sleepiness and fatigue. Conclusion: Psychiatric comorbidity is frequent in all dystonia types, but OCD and psychosis are more common in M-D patients. Further research is necessary to elucidate underlying pathways

Locally increased P-glycoprotein function in major depression: a PET study with [C-11]verapamil as a probe for P-glycoprotein function in the blood-brain barrier

The aetiology of depressive disorder remains unknown, although genetic susceptibility and exposure to neurotoxins are currently being discussed as possible contributors to this disorder. In normal circumstances, the brain is protected against bloodborne toxic influences by the blood-brain barrier, which includes the molecular efflux pump P-glycoprotein (P-gp) in the vessel wall of brain capillaries. We hypothesized that P-gp function in the blood-brain barrier is changed in patients with major depression. Positron emission tomography Was used to measure brain uptake of [C-11]verapamil, which is normally expelled from the brain by P-gp. Cerebral Volume of distribution (V-T) of [C-11]verapamil was used as a measure of P-gp function. Both region-of-interest (ROI) analysis and voxel analysis using statistical parametric mapping (SPM2) were performed to assess regional brain P-gp function. We found that patients with a major depressive episode, using antidepressants, compared to health), controls showed a significant decrease of [C-11]verapamil uptake in different areas throughout the brain, in particular in frontal and temporal regions. The decreased [C-11]verapamil uptake correlates with an increased function of the P-gp protein and may be related to chronic use of psychotropic drugs, Our results may explain why treatment-resistant depression can develop

Fatigue, Sleep Disturbances, and Their influence on Quality of Life In Cervical Dystonia Patients

Background Nonmotor symptoms (NMS) are highly prevalent in cervical dystonia (CD). In general, fatigue and sleep are important NMS that determine a decreased health-related quality of life (HR-QoL), but their influence in CD is unknown. The authors systematically investigated fatigue, excessive daytime sleepiness (EDS), and sleep quality in patients with CD and controls and assessed the influence of psychiatric comorbidity, pain, and dystonia motor severity. They also examined the predictors of HR-QoL.  Methods The study included 44 patients with CD and 43 matched controls. Fatigue, EDS, and sleep quality were assessed with quantitative questionnaires and corrected for depression and anxiety using analysis of covariance. The Toronto Western Spasmodic Torticollis Rating Scale and the Clinical Global Impression Scale-jerks/tremor subscale were used to score motor severity and to assess whether motor characteristics could explain an additional part of the variation in fatigue and sleep-related measures. HR-QoL was determined with the RAND-36 item Health Survey, and predictors of HR-QoL were assessed using multiple regression.  Results Fatigue scores were increased independently from psychiatric comorbidity (4.0 vs. 2.7; P<0.01), whereas EDS (7.3 vs. 7.4; P=0.95) and sleep quality (6.5 vs. 6.1; P=0.73) were highly associated with depression and anxiety. In patients with CD, motor severity did not explain the variations in fatigue (change in the correlation coefficient [R-2]=0.06; P=0.15), EDS (R-2=0.00; P=0.96), or sleep quality (R-2=0.04; P=0.38) scores. Fatigue, EDS, psychiatric comorbidity, and pain predicted a decreased QoL.  Conclusion Independent from psychiatric comorbidity and motor severity, fatigue appeared to be a primary NMS. Sleep-related measures were highly associated with psychiatric comorbidity, but not with motor severity. Only NMS predicted HR-QoL, which emphasizes the importance of attention to NMS in patients with CD

Sulfur K-Edge XAS Studies of the Effect of DNA Binding on the [Fe_4S_4] Site in EndoIII and MutY

S K-edge X-ray absorption spectroscopy (XAS) was used to study the [Fe_4S_4] clusters in the DNA repair glycosylases EndoIII and MutY to evaluate the effects of DNA binding and solvation on Fe–S bond covalencies (i.e., the amount of S 3p character mixed into the Fe 3d valence orbitals). Increased covalencies in both iron–thiolate and iron–sulfide bonds would stabilize the oxidized state of the [Fe_4S_4] clusters. The results are compared to those on previously studied [Fe_4S_4] model complexes, ferredoxin (Fd), and to new data on high-potential iron–sulfur protein (HiPIP). A limited decrease in covalency is observed upon removal of solvent water from EndoIII and MutY, opposite to the significant increase observed for Fd, where the [Fe_4S_4] cluster is solvent exposed. Importantly, in EndoIII and MutY, a large increase in covalency is observed upon DNA binding, which is due to the effect of its negative charge on the iron–sulfur bonds. In EndoIII, this change in covalency can be quantified and makes a significant contribution to the observed decrease in reduction potential found experimentally in DNA repair proteins, enabling their HiPIP-like redox behavior

Dose-response assessment of cerebral P-glycoprotein inhibition in vivo with [ 18 F]MC225 and PET

The Blood-Brain Barrier P-glycoprotein (P-gp) function can be altered in several neurodegenerative diseases and due to the administration of different drugs which may cause alterations in drug concentrations and consequently lead to a reduced effectiveness or increased side-effects. The novel PET radiotracer [18F]MC225 is a weak P-gp substrate that may show higher sensitivity to detect small changes in P-gp function than previously developed radiotracers. This study explores the sensitivity of [18F]MC225 to measure the dose-dependent effect of P-gp inhibitor tariquidar. Twenty-three rats were intravenously injected with different doses of tariquidar ranging from 0.75 to 12 mg/kg, 30-min before the dynamic [18F]MC225-PET acquisition with arterial sampling. Tissue and blood data were fitted to a 1-Tissue-Compartment-Model to obtain influx constant K1 and distribution volume VT, which allow the estimation of P-gp function. ANOVA and post-hoc analyses of K1 values showed significant differences between controls and groups with tariquidar doses >3 mg/kg; while applying VT the analyses showed significant differences between controls and groups with tariquidar doses >6 mg/kg. Dose-response curves were fitted using different models. The four-parameter logistic sigmoidal curve provided the best fit for K1 and VT data. Half-maximal inhibitory doses (ID50) were 2.23 mg/kg (95%CI: 1.669-2.783) and 2.93 mg/kg (95%CI: 1.135-3.651), calculated with K1 or VT values respectively. According to the dose-response fit, differences in [18F]MC225-K1 values could be detected at tariquidar doses ranging from 1.37 to 3.25 mg/kg. Our findings showed that small changes in the P-gp function, caused by low doses of tariquidar, could be detected by [18F]MC225-K1 values, which confirms the high sensitivity of the radiotracer. The results suggest that [18F]MC225 may allow the quantification of moderate P-gp impairments, which may allow the detection of P-gp dysfunctions at the early stages of a disease and potential transporter-mediated drug-drug interactions

Fluorodeoxyglucose and 11C-Choline positron emission tomography for distinction of metastatic plexopathy and neuritis: a case report

INTRODUCTION: Fluorodeoxyglucose positron emission tomography scanning has an established role in the diagnostic work-up of many malignant diseases and also in the evaluation of cancer treatment response. Fluorodeoxyglucose positron emission tomography may, however be non-specific as infectious processes are depicted as well. CASE PRESENTATION: We present a patient with longstanding leg pain and weakness due to plexopathy developed a few years after treatment for prostate cancer. Prostate-specific antigen was raised and magnetic resonance imaging showed contrast uptake in thickened sacral nerves, suspicious for metastasis. While fluorodeoxyglucose positron emission tomography showed increased uptake in the plexus region, (11)C-Choline- positron emission tomography did not show any uptake. It was concluded that the FDG uptake reflected plexus neuritis and no tumor. Treatment for pain relief was started. CONCLUSION: (11)C-Choline- positron emission tomography can be used to detect metastasis in patients with plexopathy suspicious for malignancy, while fluorodeoxyglucose positron emission tomography is more sensitive to inflammatory processes