The corticotrophin-releasing factor/urocortin system regulates white fat browning in mice through paracrine mechanisms

Objectives: The corticotrophin-releasing factor (CRF)/urocortin system is expressed in the adipose tissue of mammals, but its functional role in this tissue remains unknown. Methods: Pharmacological manipulation of the activity of CRF receptors, CRF1 and CRF2, was performed in 3T3L1 white pre-adipocytes and T37i brown pre-adipocytes during in vitro differentiation. The expression of genes of the CRF/urocortin system and of markers of white and brown adipocytes was evaluated along with mitochondrial biogenesis and cellular oxygen consumption. Metabolic evaluation of corticosterone-deficient or supplemented Crhr1-null (Crhr1−/−) mice and their wild-type controls was performed along with gene expression analysis carried out in white (WAT) and brown (BAT) adipose tissues. Results: Peptides of the CRF/urocortin system and their cognate receptors were expressed in both pre-adipocyte cell lines. In vitro pharmacological studies showed an inhibition of the expression of the CRF2 pathway by the constitutive activity of the CRF1 pathway. Pharmacological activation of CRF2 and, to a lesser extent, inhibition of CRF1 signaling induced molecular and functional changes indicating transdifferentiation of white pre-adipocytes and differentiation of brown pre-adipocytes. Crhr1−/− mice showed increased expression of CRF2 and its agonist Urocortin 2 in adipocytes that was associated to brown conversion of WAT and activation of BAT. Crhr1−/− mice were resistant to diet-induced obesity and glucose intolerance. Restoring physiological circulating corticosterone levels abrogated molecular changes in adipocytes and the favorable phenotype of Crhr1−/− mice. Conclusions: Our findings suggest the importance of the CRF2 pathway in the control of adipocyte plasticity. Increased CRF2 activity in adipocytes induces browning of WAT, differentiation of BAT and is associated with a favorable metabolic phenotype in mice lacking CRF1. Circulating corticosterone represses CRF2 activity in adipocytes and may thus regulate adipocyte physiology through the modulation of the local CRF/urocortin system. Targeting CRF receptor signaling specifically in the adipose tissue may represent a novel approach to tackle obesity

Deep Brain Stimulation of the Pallidum is Effective and Might Stabilize Striatal D2 Receptor Binding in Myoclonus–Dystonia

Purpose: To assess clinical efficacy of deep brain stimulation (DBS) of the pallidum in Myoclonus–Dystonia (M–D) patients, and to compare pre- and post-operative striatal dopamine D2 receptor availability. Methods: Clinical parameters were scored using validated rating scales for myoclonus and dystonia. Dopamine D2 receptor binding of three patients was studied before surgery and approximately 2 years post-operatively using 123-I-iodobenzamide Single Photon Emission Computed Tomography. Two patients who did not undergo surgery served as controls. Results: Clinically, the three M–D patients improved 83, 17, and 100%, respectively on the myoclonus rating scale and 78, 23, and 65% on the dystonia rating scale after DBS. Dopamine D2 receptor binding did not change after surgery. In the two control subjects, binding has lowered further. Conclusion: These findings confirm that DBS of the pallidum has beneficial effects on motor symptoms in M–D and suggest this procedure might stabilize dopamine D2 receptor binding

Distribution and coexistence of myoclonus and dystonia as clinical predictors of SGCE mutation status: a pilot study

Introduction: Myoclonus-dystonia (M-D) is a young onset movement disorder typically involving myoclonus and dystonia of the upper body. A proportion of the cases are caused by mutations to the autosomal dominantly inherited, maternally imprinted, epsilon-sarcoglycan gene (SGCE). Despite several sets of diagnostic criteria, identification of patients most likely to have an SGCE mutation remains difficult. Methods: Forty consecutive patients meeting pre-existing diagnostic clinical criteria for M-D underwent a standardized clinical examination (20 SGCE mutation positive and 20 negative). Each video was reviewed and systematically scored by two assessors blinded to mutation status. In addition, the presence and coexistence of myoclonus and dystonia was recorded in four body regions (neck, arms, legs, and trunk) at rest and with action. Results: Thirty-nine patients were included in the study (one case was excluded owing to insufficient video footage). Based on previously proposed diagnostic criteria, patients were subdivided into 24 "definite," 5 "probable," and 10 "possible" M-D. Motor symptom severity was higher in the SGCE mutation-negative group. Myoclonus and dystonia were most commonly observed in the neck and upper limbs of both groups. Truncal dystonia with action was significantly seen more in the mutation-negative group (p <0.05). Coexistence of myoclonus and dystonia in the same body part with action was more commonly seen in the mutation-negative cohort (p <0.05). Conclusion: Truncal action dystonia and coexistence of myoclonus and dystonia in the same body part with action might suggest the presence of an alternative mutation in patients with M-D

Prediction of the Levodopa Challenge Test in Parkinson's Disease Using Data from a Wrist-Worn Sensor.

The response to levodopa (LR) is important for managing Parkinson's Disease and is measured with clinical scales prior to (OFF) and after (ON) levodopa. The aim of this study was to ascertain whether an ambulatory wearable device could predict the LR from the response to the first morning dose. The ON and OFF scores were sorted into six categories of severity so that separating Parkinson's Kinetigraph (PKG) features corresponding to the ON and OFF scores became a multi-class classification problem according to whether they fell below or above the threshold for each class. Candidate features were extracted from the PKG data and matched to the class labels. Several linear and non-linear candidate statistical models were examined and compared to classify the six categories of severity. The resulting model predicted a clinically significant LR with an area under the receiver operator curve of 0.92. This study shows that ambulatory data could be used to identify a clinically significant response to levodopa. This study has also identified practical steps that would enhance the reliability of this test in future studies

Rare inborn errors of metabolism with movement disorders:a case study to evaluate the impact upon quality of life and adaptive functioning

Background: Inborn errors of metabolism (IEM) form an important cause of movement disorders in children. The impact of metabolic diseases and concordant movement disorders upon children's health-related quality of life (HRQOL) and its physical and psychosocial domains of functioning has never been investigated. We therefore conducted a case study on the HRQOL and development of adaptive functioning in children with an IEM and a movement disorder. Methods: Children with co-existent IEM and movement disorders were recruited from paediatric outpatient clinics. We systematically collected clinical data and videotaped examinations. The movement disorders were diagnosed by a panel of specialists. The Pediatric Quality of Life Inventory 4.0 and the Vineland Adaptive Behavior Scale were used to assess the HRQOL and adaptive functioning, respectively. Results: We recruited 24 children (10 boys, mean age 7y 5 m). Six types of movement disorders were recognised by the expert panel, most frequently dystonia (16/24), myoclonus (7/24) and ataxia (6/24). Mean HRQOL (49.63, SD 21.78) was significantly lower than for other chronic disorders in childhood (e.g. malignancy, diabetes mellitus, rheumatic disease, psychiatric disorders; p Conclusions: A broad spectrum of movement disorders was seen in patients with IEM, although only five were receiving treatment. The overall HRQOL in this population is significantly reduced. Delay in adaptive functioning, most frequently seen in relation to activities of daily living, and the severity of the movement disorder contribute to this lower HRQOL. We plead for a greater awareness of movement disorders and that specialists should be asked to diagnose and treat these wherever possible

Long-term experience with intraoperative microrecording during DBS neurosurgery in STN and GPi

Intraoperative microelectrode recording (MER) for targeting during deep brain stimulation (DBS) procedures has been evaluated over a period of 4 years, in 57 consecutive patients with Parkinson's disease, who received DBS in the subthalamic nucleus (STN-DBS), and 28 consecutive patients with either dystonia (23) or Parkinson's disease (five), in whom the internal segment of the globus pallidus (GPi-DBS) was targeted. The procedure for DBS was a one-stage bilateral stereotactic approach using a combined electrode for both MER and macrostimulation. Up to five micro/macro-electrodes were used in an array with a central, lateral, medial, anterior, and posterior position. Final target location was based on intraoperative test stimulation. For the STN, the central trajectory was chosen for implantation in 50% of the cases and for the globus pallidus internus (GPi) in 57% of the cases. Furthermore, in 64% of the cases, the channel selected for the permanent electrode corresponded with the trajectory having the longest segment of STN MER activity. For the GPi, this was the case in 61%. The mean and standard deviation of the deepest contact point with respect to the magnetic resonance imaging (MRI)-based target for the STN was 2.1 +/- 1.5 mm and for the GPi was -0.5 +/- 1.2 mm. MER facilitates the selection of the final electrode location in STN-DBS and GPi-DBS, and based on the observed MER activity, a pre-selection could be made as to which channel would be the best candidate for macro-test stimulation and at which depth should be stimulated. The choice of the final location is based on intraoperative test stimulation, and it is demonstrated that regularly it is not the central channel that is chosen for implantation. On average, the target as defined by MER activity intensity was in accordance with the MRI-based targets both for the STN and GPi. However, the position of the best MER activity did not necessarily correlate with the locus that produced the most beneficial clinical response on macroelectrode testing intraoperativel

The actual use of directional steering and shorter pulse width in selected patients undergoing deep brain stimulation

Introduction: Directional deep brain stimulation (DBS) and pulse with <60 mu s increase side-effects threshold, enlarging the therapeutic window. However, new systems allowing these advanced features are more expensive and often available only for a limited number of patients in some centers. It is unknown how many and which DBS patients actually need the advanced features because of an insufficient improvement with standard parameters. Methods: We included in the analysis all patients with Parkinson's disease, dystonia and tremor who were selected to receive implantation of advanced DBS systems based on specific preoperative or intraoperative clinical features. Results: After a median follow-up of 15 months, 54.9% of the 51 patients implanted with directional leads were using the advanced features in one or both leads (n = 42 leads, 42%), meaning these leads were programmed either with directional stimulation (n = 9, 9%), a shorter pw (n = 20, 20%) or both (n = 13, 13%). This included 92% of patients implanted in the Vim, 44% of those implanted in the STN, and 40% of those implanted in the GPi. Conclusions: DBS systems with advanced features may be particularly indicated for selected patients based on some clinical characteristics and the chosen target. This data may help clinicians allocate resources in a more informed way.Scientific Assessment and Innovation in Neurosurgical Treatment Strategie

Hemodynamic and EEG Time-Courses During Unilateral Hand Movement in Patients with Cortical Myoclonus. An EEG-fMRI and EEG-TD-fNIRS Study.

Multimodal human brain mapping has been proposed as an integrated approach capable of improving the recognition of the cortical correlates of specific neurological functions. We used simultaneous EEG-fMRI (functional magnetic resonance imaging) and EEG-TD-fNIRS (time domain functional near-infrared spectroscopy) recordings to compare different hemodynamic methods with changes in EEG in ten patients with progressive myoclonic epilepsy and 12 healthy controls. We evaluated O(2)Hb, HHb and Blood oxygen level-dependent (BOLD) changes and event-related desynchronization/synchronization (ERD/ERS) in the alpha and beta bands of all of the subjects while they performed a simple motor task. The general linear model was used to obtain comparable fMRI and TD-fNIRS activation maps. We also analyzed cortical thickness in order to evaluate any structural changes. In the patients, the TD-NIRS and fMRI data significantly correlated and showed a significant lessening of the increase in O(2)Hb and the decrease in BOLD. The post-movement beta rebound was minimal or absent in patients. Cortical thickness was moderately reduced in the motor area of the patients and correlated with the reduction in the hemodynamic signals. The fMRI and TD-NIRS results were consistent, significantly correlated and showed smaller hemodynamic changes in the patients. This finding may be partially attributable to mild cortical thickening. However, cortical hyperexcitability, which is known to generate myoclonic jerks and probably accounts for the lack of EEG beta-ERS, did not reflect any increased energy requirement. We hypothesize that this is due to a loss of inhibitory neuronal components that typically fire at high frequencies

Simultaneous PET-MRI Studies of the Concordance of Atrophy and Hypometabolism in Syndromic Variants of Alzheimer's Disease and Frontotemporal Dementia: An Extended Case Series

Background: Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. Objectives: The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimer’s disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. Method: PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n = 4 per group). Atrophy was rated visually and also quantified with measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohen’s kappa. Results: Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0–0.25 for PCA to 0.29–0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. Conclusion: The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practic