TY - JOUR A1 - Odin, Per A1 - Chaudhuri, K. Ray A1 - Volkmann, Jens A1 - Antonini, Angelo A1 - Storch, Alexander A1 - Dietrichs, Espen A1 - Pirtošek, Zvezdan A1 - Henriksen, Tove A1 - Horne, Malcolm A1 - Devos, David A1 - Bergquist, Filip T1 - Viewpoint and practical recommendations from a movement disorder specialist panel on objective measurement in the clinical management of Parkinson’s disease JF - npj Parkinson's Disease N2 - Motor aspects of Parkinson’s disease, such as fluctuations and dyskinesia, can be reliably evaluated using a variety of “wearable” technologies, but practical guidance on objective measurement (OM) and the optimum use of these devices is lacking. Therefore, as a first step, a panel of movement disorder specialists met to provide guidance on how OM could be assessed and incorporated into clinical guidelines. A key aspect of the incorporation of OM into the management of Parkinson’s disease (PD) is defining cutoff values that separate “controlled” from “uncontrolled” symptoms that can be modified by therapy and that relate to an outcome that is relevant to the person with PD (such as quality of life). Defining cutoffs by consensus, which can be subsequently tested and refined, is the first step to optimizing OM in the management of PD. OM should be used by all clinicians that treat people with PD but the least experienced may find the most value, but this requires guidance from experts to allow non-experts to apply guidelines. While evidence is gained for devices that produce OM, expert opinion is needed to supplement the evidence base. KW - Parkinson's disease Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-234435 VL - 4 ER - TY - JOUR A1 - Sulzer, David A1 - Cassidy, Clifford A1 - Horga, Guillermo A1 - Kang, Un Jung A1 - Fahn, Stanley A1 - Casella, Luigi A1 - Pezzoli, Gianni A1 - Langley, Jason A1 - Hu, Xiaoping P. A1 - Zucca, Fabio A. A1 - Isaias, Ioannis U. A1 - Zecca, Luigi T1 - Neuromelanin detection by magnetic resonance imaging (MRI) and its promise as a biomarker for Parkinson’s disease JF - npj Parkinson's Disease N2 - The diagnosis of Parkinson’s disease (PD) occurs after pathogenesis is advanced and many substantia nigra (SN) dopamine neurons have already died. Now that therapies to block this neuronal loss are under development, it is imperative that the disease be diagnosed at earlier stages and that the response to therapies is monitored. Recent studies suggest this can be accomplished by magnetic resonance imaging (MRI) detection of neuromelanin (NM), the characteristic pigment of SN dopaminergic, and locus coeruleus (LC) noradrenergic neurons. NM is an autophagic product synthesized via oxidation of catecholamines and subsequent reactions, and in the SN and LC it increases linearly during normal aging. In PD, however, the pigment is lost when SN and LC neurons die. As shown nearly 25 years ago by Zecca and colleagues, NM’s avid binding of iron provides a paramagnetic source to enable electron and nuclear magnetic resonance detection, and thus a means for safe and noninvasive measure in living human brain. Recent technical improvements now provide a means for MRI to differentiate between PD patients and age-matched healthy controls, and should be able to identify changes in SN NM with age in individuals. We discuss how MRI detects NM and how this approach might be improved. We suggest that MRI of NM can be used to confirm PD diagnosis and monitor disease progression. We recommend that for subjects at risk for PD, and perhaps generally for older people, that MRI sequences performed at regular intervals can provide a pre-clinical means to detect presymptomatic PD. Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-240207 VL - 4 ER - TY - JOUR A1 - Ullrich, M A1 - Weber, M A1 - Post, A M A1 - Popp, S A1 - Grein, J A1 - Zechner, M A1 - González, H Guerrero A1 - Kreis, A A1 - Schmitt, A G A1 - Üҫeyler, N A1 - Lesch, K-P A1 - Schuh, K T1 - OCD-like behavior is caused by dysfunction of thalamo-amygdala circuits and upregulated TrkB/ERK-MAPK signaling as a result of SPRED2 deficiency JF - Molecular Psychiatry N2 - Obsessive-compulsive disorder (OCD) is a common neuropsychiatric disease affecting about 2% of the general population. It is characterized by persistent intrusive thoughts and repetitive ritualized behaviors. While gene variations, malfunction of cortico-striato-thalamo-cortical (CSTC) circuits, and dysregulated synaptic transmission have been implicated in the pathogenesis of OCD, the underlying mechanisms remain largely unknown. Here we show that OCD-like behavior in mice is caused by deficiency of SPRED2, a protein expressed in various brain regions and a potent inhibitor of Ras/ERK-MAPK signaling. Excessive self-grooming, reflecting OCD-like behavior in rodents, resulted in facial skin lesions in SPRED2 knockout (KO) mice. This was alleviated by treatment with the selective serotonin reuptake inhibitor fluoxetine. In addition to the previously suggested involvement of cortico-striatal circuits, electrophysiological measurements revealed altered transmission at thalamo-amygdala synapses and morphological differences in lateral amygdala neurons of SPRED2 KO mice. Changes in synaptic function were accompanied by dysregulated expression of various pre- and postsynaptic proteins in the amygdala. This was a result of altered gene transcription and triggered upstream by upregulated tropomyosin receptor kinase B (TrkB)/ERK-MAPK signaling in the amygdala of SPRED2 KO mice. Pathway overactivation was mediated by increased activity of TrkB, Ras, and ERK as a specific result of SPRED2 deficiency and not elicited by elevated brain-derived neurotrophic factor levels. Using the MEK inhibitor selumetinib, we suppressed TrkB/ERK-MAPK pathway activity in vivo and reduced OCD-like grooming in SPRED2 KO mice. Altogether, this study identifies SPRED2 as a promising new regulator, TrkB/ERK-MAPK signaling as a novel mediating mechanism, and thalamo-amygdala synapses as critical circuitry involved in the pathogenesis of OCD. KW - molecular biology KW - neuroscience KW - physiology KW - psychiatric disorders Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-232096 VL - 23 ER - TY - JOUR A1 - Langhauser, Friederike A1 - Casas, Ana I. A1 - Dao, Vu-Thao-Vi A1 - Guney, Emre A1 - Menche, Jörg A1 - Geuss, Eva A1 - Kleikers, Pamela W. M. A1 - López, Manuela G. A1 - Barabási, Albert-L. A1 - Kleinschnitz, Christoph A1 - Schmidt, Harald H. H. W. T1 - A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection JF - npj Systems Biology and Applications N2 - Network medicine utilizes common genetic origins, markers and co-morbidities to uncover mechanistic links between diseases. These links can be summarized in the diseasome, a comprehensive network of disease–disease relationships and clusters. The diseasome has been influential during the past decade, although most of its links are not followed up experimentally. Here, we investigate a high prevalence unmet medical need cluster of disease phenotypes linked to cyclic GMP. Hitherto, the central cGMP-forming enzyme, soluble guanylate cyclase (sGC), has been targeted pharmacologically exclusively for smooth muscle modulation in cardiology and pulmonology. Here, we examine the disease associations of sGC in a non-hypothesis based manner in order to identify possibly previously unrecognized clinical indications. Surprisingly, we find that sGC, is closest linked to neurological disorders, an application that has so far not been explored clinically. Indeed, when investigating the neurological indication of this cluster with the highest unmet medical need, ischemic stroke, pre-clinically we find that sGC activity is virtually absent post-stroke. Conversely, a heme-free form of sGC, apo-sGC, was now the predominant isoform suggesting it may be a mechanism-based target in stroke. Indeed, this repurposing hypothesis could be validated experimentally in vivo as specific activators of apo-sGC were directly neuroprotective, reduced infarct size and increased survival. Thus, common mechanism clusters of the diseasome allow direct drug repurposing across previously unrelated disease phenotypes redefining them in a mechanism-based manner. Specifically, our example of repurposing apo-sGC activators for ischemic stroke should be urgently validated clinically as a possible first-in-class neuroprotective therapy. KW - neurology KW - pharmacology KW - systems biology Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-236381 VL - 4 ER - TY - JOUR A1 - Kirsch, Anna Dalal A1 - Hassin-Baer, Sharon A1 - Matthies, Cordula A1 - Volkmann, Jens A1 - Steigerwald, Frank T1 - Anodic versus cathodic neurostimulation of the subthalamic nucleus: A randomized-controlled study of acute clinical effects JF - Parkinsonism and Related Disorders N2 - Introduction Stimulation settings of deep brain stimulation (DBS) have evolved empirically within a limited parameter space dictated by first generation devices. There is a need for controlled clinical studies, which evaluate efficacy and safety of established programming practice against novel programming options provided by modern neurostimulation devices. Methods Here, we tested a polarity reversal from conventional monopolar cathodic to anodic stimulation in an acute double-blind, randomized, cross-over study in patients with PD implanted with bilateral STN DBS. The primary outcome measure was the difference between efficacy and side-effect thresholds (current amplitude, mA) in a monopolar review and the severity of motor symptoms (as assessed by MDS-UPDRS III ratings) after 30 min of continuous stimulation in the medication off-state. Results Effect and side effect thresholds were significantly higher with anodic compared to cathodic stimulation (3.36 ± 1.58 mA vs. 1.99 ± 1.37 mA; 6.05 ± 1.52 mA vs. 4.15 ± 1.13 mA; both p < 0.0001). However, using a predefined amplitude of 0.5 mA below the respective adverse effect threshold, blinded MDS-UPDRS-III-ratings were significantly lower with anodic stimulation (anodic: median 17 [min: 12, max: 25]; cathodic: 23 [12, 37]; p < 0.005). Conclusion Effective anodic stimulation requires a higher charge injection into the tissue, but may provide a better reduction of off-period motor symptoms within the individual therapeutic window. Therefore, a programming change to anodic stimulation may be considered in patients suffering from residual off-period motor symptoms of PD despite reaching the adverse effect threshold of cathodic stimulation in the subthalamic nucleus. KW - deep brain stimulation KW - subthalamic nucleus KW - Parkinson's disease KW - anodic stimulation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-325820 VL - 55 ER -