Pramipexole Extended Release: A Novel Treatment Option in Parkinson's Disease

Pramipexole, the most commonly prescribed dopamine agonist worldwide, meanwhile serves as a reference substance for evaluation of new drugs. Based on numerous clinical data and vast experiences, efficacy and safety profiles of this non-ergoline dopamine agonist are well characterized. Since October 2009, an extended-release formulation of pramipexole has been available for symptomatic treatment of Parkinson's disease. Pramipexole administration can be cut down from three times to once a day due to the newly developed extended-release formulation. This is considerable progress in regard to minimizing pill burden and enhancing compliance. Moreover, the 24 h continuous drug release of the once-daily extended-release formulation results in fewer fluctuations in plasma concentrations over time compared to immediate-release pramipexole, given three times daily. The present study summarizes pharmacokinetics and all essential pharmacological and clinical characteristics of the extended-release formulation. In addition, it provides all study data, available so far, with regard to transition and de-novo administration of extended-release formulation for patients with Parkinson's disease. It further compares efficacy and safety data of immediate-release pramipexole with the extended-release formulation of pramipexole

From a systems view to spotting a hidden island : A narrative review implicating insula function in alcoholism

Excessive use of alcohol promotes the development of alcohol addiction, but the understanding of how alcohol induced brain alterations lead to addiction remains limited. To further this understanding, we adopted an unbiased discovery strategy based on the principles of systems medicine. We used functional magnetic resonance imaging data from patients and animal models of alcohol addiction-like behaviors, and developed mathematical models of the 'relapse-prone' network states to identify brain sites and functional networks that can be selectively targeted by therapeutic interventions. Our systems level, non-local, and largely unbiased analyses converged on a few well-defined brain regions, with the insula emerging as one of the most consistent findings across studies. In proof-of-concept experiments we were able to demonstrate that it is possible to guide network dynamics towards increased resilience in animals but an initial translation into a clinical trial targeting the insula failed. Here, in a narrative review, we summarize the key experiments, methodological developments and knowledge gained from this complete round of a discovery cycle moving from identification of 'relapse-prone' network states in humans and animals to target validation and intervention trial. Future concerted efforts are necessary to gain a deeper understanding of insula function a in a state-dependent, circuit-specific and cell population perspective, and to develop the means for insula-directed interventions, before therapeutic targeting of this structure may become possible.Peer reviewe

Ga-68-PSMA ligand PET/CT in patients with prostate cancer: How we review and report

Recently, positron emission tomography (PET) imaging using PSMA-ligands has gained high attention as a promising new radiotracer in patients with prostate cancer (PC). Several studies promise accurate staging of primary prostate cancer and restaging after biochemical recurrence with Ga-68-PSMA ligand Positron emission tomography/computed tomography (PET/CT). However, prospective trials and clinical guidelines for this new technique are still missing. Therefore, we summarized our experience with Ga-68-PSMA ligand PET/CT examinations in patients with primary PC and biochemical recurrence. It focuses on the technical and logistical aspects of Ga-68-PSMA ligand PET/CT examination as well as on the specific background for image reading discussing also potential pitfalls. Further, it includes relevant issues on free-text as well as structured reporting used in daily clinical routine

Ga-68-PSMA ligand PET/CT in patients with prostate cancer: How we review and report

Recently, positron emission tomography (PET) imaging using PSMA-ligands has gained high attention as a promising new radiotracer in patients with prostate cancer (PC). Several studies promise accurate staging of primary prostate cancer and restaging after biochemical recurrence with Ga-68-PSMA ligand Positron emission tomography/computed tomography (PET/CT). However, prospective trials and clinical guidelines for this new technique are still missing. Therefore, we summarized our experience with Ga-68-PSMA ligand PET/CT examinations in patients with primary PC and biochemical recurrence. It focuses on the technical and logistical aspects of Ga-68-PSMA ligand PET/CT examination as well as on the specific background for image reading discussing also potential pitfalls. Further, it includes relevant issues on free-text as well as structured reporting used in daily clinical routine

Comparing Discounting of Potentially Real Rewards and Losses by Means of Functional Magnetic Resonance Imaging

AimDelay discounting (DD) has often been investigated in the context of decision making whereby individuals attribute decreasing value to rewards in the distant future. Less is known about DD in the context of negative consequences. The aim of this pilot study was to identify commonalities and differences between reward and loss discounting on the behavioral as well as the neural level by means of computational modeling and functional Magnetic Resonance Imaging (fMRI). We furthermore compared the neural activation between anticipation of rewards and losses.MethodWe conducted a study combining an intertemporal choice task for potentially real rewards and losses (decision-making) with a monetary incentive/loss delay task (reward/loss anticipation). Thirty healthy participants (age 18-35, 14 female) completed the study. In each trial, participants had to choose between a smaller immediate loss/win and a larger loss/win at a fixed delay of two weeks. Task-related brain activation was measured with fMRI.ResultsHyperbolic discounting parameters of loss and reward conditions were correlated (r = 0.56). During decision-making, BOLD activation was observed in the parietal and prefrontal cortex, with no differences between reward and loss conditions. During reward and loss anticipation, dissociable activation was observed in the striatum, the anterior insula and the anterior cingulate cortex.ConclusionWe observed behavior concurrent with DD in both the reward and loss condition, with evidence for similar behavioral and neural patterns in the two conditions. Intertemporal decision-making recruited the fronto-parietal network, whilst reward and loss anticipation were related to activation in the salience network. The interpretation of these findings may be limited to short delays and small monetary outcomes

The SyBil-AA real-time fMRI neurofeedback study: protocol of a single-blind randomized controlled trial in alcohol use disorder

Background: Alcohol Use Disorder is a highly prevalent mental disorder which puts a severe burden on individuals, families, and society. The treatment of Alcohol Use Disorder is challenging and novel and innovative treatment approaches are needed to expand treatment options. A promising neuroscience-based intervention method that allows targeting cortical as well as subcortical brain processes is real-time functional magnetic resonance imaging neurofeedback. However, the efficacy of this technique as an add-on treatment of Alcohol Use Disorder in a clinical setting is hitherto unclear and will be assessed in the Systems Biology of Alcohol Addiction (SyBil-AA) neurofeedback study. Methods: N = 100 patients with Alcohol Use Disorder will be randomized to 5 parallel groups in a single-blind fashion and receive real-time functional magnetic resonance imaging neurofeedback while they are presented pictures of alcoholic beverages. The groups will either downregulate the ventral striatum, upregulate the right inferior frontal gyrus, negatively modulate the connectivity between these regions, upregulate, or downregulate the auditory cortex as a control region. After receiving 3 sessions of neurofeedback training within a maximum of 2 weeks, participants will be followed up monthly for a period of 3 months and relapse rates will be assessed as the primary outcome measure. Discussion: The results of this study will provide insights into the efficacy of real-time functional magnetic resonance imaging neurofeedback training in the treatment of Alcohol Use Disorder as well as in the involved brain systems. This might help to identify predictors of successful neurofeedback treatment which could potentially be useful in developing personalized treatment approaches. Trial registration: The study was retrospectively registered in the German Clinical Trials Register (trial identifier: DRKS00010253 ; WHO Universal Trial Number (UTN): U1111–1181-4218) on May 10th, 2016

Anterior insula stimulation suppresses appetitive behavior while inducing forebrain activation in alcohol-preferring rats

The anterior insular cortex plays a key role in the representation of interoceptive effects of drug and natural rewards and their integration with attention, executive function, and emotions, making it a potential target region for intervention to control appetitive behaviors. Here, we investigated the effects of chemogenetic stimulation or inhibition of the anterior insula on alcohol and sucrose consumption. Excitatory or inhibitory designer receptors (DREADDs) were expressed in the anterior insula of alcohol-preferring rats by means of adenovirus-mediated gene transfer. Rats had access to either alcohol or sucrose solution during intermittent sessions. To characterize the brain network recruited by chemogenetic insula stimulation we measured brain-wide activation patterns using pharmacological magnetic resonance imaging (phMRI) and c-Fos immunohistochemistry. Anterior insula stimulation by the excitatory Gq-DREADDs significantly attenuated both alcohol and sucrose consumption, whereas the inhibitory Gi-DREADDs had no effects. In contrast, anterior insula stimulation failed to alter locomotor activity or deprivation-induced water drinking. phMRI and c-Fos immunohistochemistry revealed downstream activation of the posterior insula and medial prefrontal cortex, as well as of the mediodorsal thalamus and amygdala. Our results show the critical role of the anterior insula in regulating reward-directed behavior and delineate an insula-centered functional network associated with the effects of insula stimulation. From a translational perspective, our data demonstrate the therapeutic potential of circuit-based interventions and suggest that potentiation of insula excitability with neuromodulatory methods, such as repetitive transcranial magnetic stimulation (rTMS), could be useful in the treatment of alcohol use disorders.Peer reviewe

Brain Network Allostasis after Chronic Alcohol Drinking Is Characterized by Functional Dedifferentiation and Narrowing

Alcohol use disorder (AUD) causes complex alterations in the brain that are poorly understood. The heterogeneity of drinking patterns and the high incidence of comorbid factors compromise mechanistic investigations in AUD patients. Here we used male Marchigian Sardinian alcohol-preferring (msP) rats, a well established animal model of chronic alcohol drinking, and a combination of longitudinal resting-state fMRI and manganese-enhanced MRI to provide objective measurements of brain connectivity and activity, respectively. We found that 1 month of chronic alcohol drinking changed the correlation between resting-state networks. The change was not homogeneous, resulting in the reorganization of pairwise interactions and a shift in the equilibrium of functional connections. We identified two fundamentally different forms of network reorganization. First is functional dedifferentiation, which is defined as a regional increase in neuronal activity and overall correlation, with a concomitant decrease in preferential connectivity between specific networks. Through this mechanism, occipital cortical areas lost their specific interaction with sensory-insular cortex, striatal, and sensorimotor networks. Second is functional narrowing, which is defined as an increase in neuronal activity and preferential connectivity between specific brain networks. Functional narrowing strengthened the interaction between striatal and prefrontocortical networks, involving the anterior insular, cingulate, orbitofrontal, prelimbic, and infralimbic cortices. Importantly, these two types of alterations persisted after alcohol discontinuation, suggesting that dedifferentiation and functional narrowing rendered persistent network states. Our results support the idea that chronic alcohol drinking, albeit at moderate intoxicating levels, induces an allostatic change in the brain functional connectivity that propagates into early abstinence.Peer reviewe

Wavelet-Based Angiographic Reconstruction of Computed Tomography Perfusion Data Diagnostic Value in Cerebral Venous Sinus Thrombosis

Objective: The aim of this study was to test the diagnostic value of wavelet-based angiographic reconstruction of CT perfusion data (waveletCTA) to detect cerebral venous sinus thrombosis (CVST) in patients who underwent whole-brain CT perfusion imaging (WB-CTP). Materials and Methods: Datasets were retrospectively selected from an initial cohort of 2863 consecutive patients who had undergone multiparametric CT including WB-CTP. WaveletCTA was reconstructed from WB-CTP: the angiographic signal was generated by voxel-based wavelet transform of time attenuation curves (TACs) from WB-CTP raw data. In a preliminary clinical evaluation, waveletCTA was analyzed by 2 readers with respect to presence and location of CVST. Venous CT and MR angiography (venCTA/venMRA) served as reference standard. Diagnostic confidence for CVST detection and the quality of depiction for venous sections were evaluated on 5-point Likert scales. Thrombus extent was assessed by length measurements. The mean CT attenuation and waveletCTA signal of the thrombus and of flowing blood were quantified. Results: Sixteen patients were included: 10 patients with venCTA-/venMRAconfirmed CVST and 6 patients with arterial single-phase CT angiography (artCTA)-suspected but follow-up-excluded CVST. The reconstruction of waveletCTA was successful in all patients. Among the patients with confirmed CVST, waveletCTA correctly demonstrated presence, location, and extent of the thrombosis in 10/10 cases. In 6 patients with artCTA-suspected but follow-up-excluded CVST, waveletCTA correctly ruled out CVST in 5 patients. Reading waveletCTA in addition to artCTA significantly increased the diagnostic confidence concerning CVST compared with reading artCTA alone (4.4 vs 3.6, P = 0.044). The mean flowing blood-to-thrombus ratio was highest in waveletCTA, followed by venCTA and artCTA (146.2 vs 5.9 vs 2.6, each with P < 0.001). In waveletCTA, the venous sections were depicted better compared with artCTA (4.2 vs 2.6, P < 0.001), and equally well compared with venCTA/venMRA (4.2 vs 4.1, P = 0.374). Conclusions: WaveletCTA was technically feasible in CVST patients and reliably identified CVST in a preliminary clinical evaluation. WaveletCTA might serve as an additional reconstruction to rule out or incidentally detect CVST in patients who undergo WB-CTP

Dermal Phospho-Alpha-Synuclein Deposition in Patients With Parkinson's Disease and Mutation of the Glucocerebrosidase Gene

Heterozygous mutations in the glucocerebrosidase gene (GBA1) represent the most common genetic risk factor for Parkinson's disease (PD) and are histopathologically associated with a widespread load of alpha-synuclein in the brain. Therefore, PD patients with GBA1 mutations are a cohort of high interest for clinical trials on disease-modifying therapies targeting alpha-synuclein. There is evidence that detection of phospho-alpha-synuclein (p-syn) in dermal nerve fibers might be a biomarker for the histopathological identification of PD patients even at premotor or very early stages of disease. It is so far unknown whether dermal p-syn deposition can also be found in PD patients with GBA1 mutations and may serve as a biomarker for PD in these patients. Skin biopsies of 10 PD patients with different GBA1 mutations (six N370S, three E326K, one L444P) were analyzed by double-immunofluorescence labeling with anti-p-syn and anti-protein gene product 9.5 (PGP9.5, axonal marker) to detect intraaxonal p-syn deposition. Four biopsy sites (distal, proximal leg, paravertebral Th10, and C7) per patient were studied. P-syn was found in six patients (three N370S, three E326K). P-syn deposition was mainly detected in autonomic nerve fibers, but also in somatosensory fibers and was not restricted to a certain GBA1 mutation. In summary, dermal p-syn in PD patients with GBA1 mutations seems to offer a similar distribution and frequency as observed in patients without a known mutation. Skin biopsy may be suitable to study p-syn deposition in these patients or even to identify premotor patients with GBA1 mutations