Nationwide Retrospective Analysis of Combinations of Advanced Therapies in Patients With Parkinson Disease.

BACKGROUND AND OBJECTIVES: Advanced therapies (ATs; deep brain stimulation [DBS] or pump therapies: continuous subcutaneous apomorphine infusion [CSAI], levodopa/carbidopa intestinal gel [LCIG]) are used in later stages of Parkinson disease (PD). However, decreasing efficacy over time and/or side effects may require an AT change or combination in individual patients. Current knowledge about changing or combining ATs is limited to mostly retrospective and small-scale studies. The nationwide case collection Combinations of Advanced Therapies in PD assessed simultaneous or sequential AT combinations in Germany since 2005 to analyze their clinical outcome, their side effects, and the reasons for AT modifications. METHODS: Data were acquired retrospectively by modular questionnaires in 22 PD centers throughout Germany based on clinical records and comprised general information about the centers/patients, clinical (Mini-Mental Status Test/Montréal Cognitive Assessment, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale [MDS-UPDRS], side effects, reasons for AT modification), and therapeutical (ATs with specifications, oral medication) data. Data assessment started with initiation of the second AT. RESULTS: A total of 148 AT modifications in 116 patients were associated with significantly improved objective (median decrease of MDS-UPDRS Part III 4.0 points [p < 0.001], of MDS-UPDRS Part IV 6.0 points [p < 0.001], of MDS-UPDRS Part IV-off-time item 1.0 points [p < 0.001]) and subjective clinical outcome and decreasing side effect rates. Main reasons for an AT modification were insufficient symptom control and side effects of the previous therapy. Subgroup analyses suggest addition of DBS in AT patients with leading dyskinesia, addition of LCIG for leading other cardinal motor symptoms, and addition of LCIG or CSAI for dominant off-time. The most long-lasting therapy-until requiring a modification-was DBS. DISCUSSION: Changing or combining ATs may be beneficial when 1 AT is insufficient in efficacy or side effects. The outcome of an AT combination is comparable with the clinical benefit by introducing the first AT. The added AT should be chosen dependent on dominant clinical symptoms and adverse effects. Furthermore, prospective trials are needed to confirm the results of this exploratory case collection. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with PD, changing or combining ATs is associated with an improvement in the MDS-UPDRS or subjective symptom reporting.

Differential expression of gut miRNAs in idiopathic Parkinson's disease.

OBJECTIVE: In the present work, we aimed to investigate the expression of microRNAs (miRNAs) in routine colonic biopsies obtained from patients with idiopathic Parkinson's disease (PD) and to address their value as a diagnostic biomarker for PD and their mechanistic contribution to PD onset and progression. METHODS: Patients with PD (n = 13) and healthy controls (n = 17) were prospectively recruited to undergo routine colonic biopsies for cancer screening. Total RNA was extracted from the biopsy material and the expression of miRNAs was quantified by Illumina High-Throughput Sequencing. RESULTS: Statistical analysis revealed a significant submucosal enrichment of the miRNA hsa-miR-486-5p in colonic biopsies from PD patients compared to the control subjects. The expression of miR-486-5p correlated with age and disease severity as measured by the UPDRS and Hoehn & Yahr scale. miRNA gene target analysis identified 301 gene targets that are affected by miR-486-5p. A follow-up associated target identification and pathway enrichment analysis further determined their role in distinct biological processes in the enteric nervous system (ENS). INTERPRETATION: Our work demonstrates an enrichment of submucosal miR-486-5p in routine colonic biopsies from PD patients. Our results will support the examination of miR-486-5p as a PD biomarker and help to understand the significance of the miR-486-5p gene targets for PD onset and progression. In addition, our data will support the investigation of the molecular and cellular mechanisms of GI dysfunction in PD.

Analyzing the co-localization of substantia nigra hyper-echogenicities and iron accumulation in Parkinson's disease: A multi-modal atlas study with transcranial ultrasound and MRI.

BACKGROUND: Transcranial B-mode sonography (TCS) can detect hyperechogenic speckles in the area of the substantia nigra (SN) in Parkinson's disease (PD). These speckles correlate with iron accumulation in the SN tissue, but an exact volumetric localization in and around the SN is still unknown. Areas of increased iron content in brain tissue can be detected in vivo with magnetic resonance imaging, using quantitative susceptibility mapping (QSM). METHODS: In this work, we i) acquire, co-register and transform TCS and QSM imaging from a cohort of 23 PD patients and 27 healthy control subjects into a normalized atlas template space and ii) analyze and compare the 3D spatial distributions of iron accumulation in the midbrain, as detected by a signal increase (TCS+ and QSM+) in both modalities. RESULTS: We achieved sufficiently accurate intra-modal target registration errors (TRE<1 mm) for all MRI volumes and multi-modal TCS-MRI co-localization (TRE<4 mm) for 66.7% of TCS scans. In the caudal part of the midbrain, enlarged TCS+ and QSM+ areas were located within the SN pars compacta in PD patients in comparison to healthy controls. More cranially, overlapping TCS+ and QSM+ areas in PD subjects were found in the area of the ventral tegmental area (VTA). CONCLUSION: Our findings are concordant with several QSM-based studies on iron-related alterations in the area SN pars compacta. They substantiate that TCS+ is an indicator of iron accumulation in Parkinson's disease within and in the vicinity of the SN. Furthermore, they are in favor of an involvement of the VTA and thereby the mesolimbic system in Parkinson's disease.

The Dopamine Receptor Antagonism of Opipramol: Relevance to Parkinsonism?

Drug-induced Parkinsonism (DIP) represents the second most-frequent etiology of Parkinson syndromes after neurodegenerative disorders. It has been described mainly for antipsychotics, Ca-channel blockers, antiemetics, and gastrointestinal prokinetics. In this article, we present a clinical case series of 10 patients, retrieved within our movement disorders hospital, with DIP under intake of opipramol. Symptoms completely resolved after drug withdrawal, and associated risk factors were old age, high doses, and presence of cortical atrophy. This frequently prescribed anxiolytic drug has so far not been associated with DIP. Our objective is to raise awareness of DIP as an adverse effect of opipramol.

A test-retest study on Parkinson's PPMI dataset yields statistically significant white matter fascicles.

In this work, we propose a diffusion MRI protocol for mining Parkinson's disease diffusion MRI datasets and recover robust disease-specific biomarkers. Using advanced high angular resolution diffusion imaging (HARDI) crossing fiber modeling and tractography robust to partial volume effects, we automatically dissected 50 white matter (WM) fascicles. These fascicles connect deep nuclei (thalamus, putamen, pallidum) to different cortical functional areas (associative, motor, sensorimotor, limbic), basal forebrain and substantia nigra. Then, among these 50 candidate WM fascicles, only the ones that passed a test-retest reproducibility procedure qualified for further tractometry analysis. Leveraging the unique 2-timepoints test-retest Parkinson's Progression Markers Initiative (PPMI) dataset of over 600 subjects, we found statistically significant differences in tract profiles along the subcortico-cortical pathways between Parkinson's disease patients and healthy controls. In particular, significant increases in FA, apparent fiber density, tract-density and generalized FA were detected in some locations of the nigro-subthalamo-putaminal-thalamo-cortical pathway. This connection is one of the major motor circuits balancing the coordination of motor output. Detailed and quantifiable knowledge on WM fascicles in these areas is thus essential to improve the quality and outcome of Deep Brain Stimulation, and to target new WM locations for investigation.

The role of the pallidothalamic fibre tracts in deep brain stimulation for dystonia: A diffusion MRI tractography study.

BACKGROUND: Deep Brain Stimulation (DBS) of the Globus pallidus internus (GPi) is gold standard treatment in medically refractory dystonia. Recent evidence indicates that stimulation effects are also due to axonal modulation and affection of a fibre network. For the GPi, the pallidothalamic tracts are known to be the major motor efferent pathways. The aim of this study is to explore the anatomic vicinity of these tracts and DBS electrodes in dystonia applying diffusion tractography. METHODS: Diffusion MRI was acquired in ten patients presenting for DBS for dystonia. We applied both a conventionally used probabilistic tractography algorithm (FSL) as well as a probabilistic streamline tracking approach, based on constrained spherical deconvolution and particle filtering with anatomic priors, to the datasets. DBS electrodes were coregistered to the diffusion datasets. RESULTS: We were able to delineate the pallidothalamic tracts in all patients. Using the streamline approach, we were able to distinguish between the two sub-components of the tracts, the ansa lenticularis and the fasciculus lenticularis. Clinically efficient DBS electrodes displayed a close anatomic vicinity pathway of the pallidothalamic tracts, and their course was consistent with previous tracer labelling studies. Although we present only anatomic data, we interpret these findings as evidence of the possible involvement of fibre tracts to the clinical effect in DBS. Electrophysiological intraoperative recordings would be needed to complement our findings. In the future, a clear and individual delineation of the pallidothalamic tracts could optimize the stereotactic process of optimal electrode localization. Hum Brain Mapp 38:1224-1232, 2017. © 2016 Wiley Periodicals, Inc.

A diffusion-based connectivity map of the GPi for optimised stereotactic targeting in DBS.

BACKGROUND: The GPi (globus pallidus internus) is an important target nucleus for Deep Brain Stimulation (DBS) in medically refractory movement disorders, in particular dystonia and Parkinson's disease. Beneficial clinical outcome critically depends on precise electrode localization. Recent evidence indicates that not only neurons, but also axonal fibre tracts contribute to promoting the clinical effect. Thus, stereotactic planning should, in the future, also take the individual course of fibre tracts into account. OBJECTIVE: The aim of this project is to explore the GPi connectivity profile and provide a connectivity-based parcellation of the GPi. METHODS: Diffusion MRI sequences were performed in sixteen healthy, right-handed subjects. Connectivity-based parcellation of the GPi was performed applying two independent methods: 1) a hypothesis-driven, seed-to-target approach based on anatomic priors set as connectivity targets and 2) a purely data-driven approach based on k-means clustering of the GPi. RESULTS: Applying the hypothesis-driven approach, we obtained five major parcellation clusters, displaying connectivity to the prefrontal cortex, the brainstem, the GPe (globus pallidus externus), the putamen and the thalamus. Parcellation clusters obtained by both methods were similar in their connectivity profile. With the data-driven approach, we obtained three major parcellation clusters. Inter-individual variability was comparable with results obtained in thalamic parcellation. CONCLUSION: The three parcellation clusters obtained by the purely data-driven method might reflect GPi subdivision into a sensorimotor, associative and limbic portion. Clinical and physiological studies indicate greatest clinical DBS benefit for electrodes placed in the postero-ventro-lateral GPi, the region displaying connectivity to the thalamus in our study and generally attributed to the sensorimotor system. Clinical studies relating DBS electrode positions to our GPi connectivity map would be needed to complement our findings.

Automated volumetry for unilateral hippocampal sclerosis detection in patients with temporal lobe epilepsy.

Hippocampal sclerosis (HS) is the most common cause of temporal lobe epilepsy (TLE) and can be identified in magnetic resonance imaging as hippocampal atrophy and subsequent volume loss. Detecting this kind of abnormalities through simple radiological assessment could be difficult, even for experienced radiologists. For that reason, hippocampal volumetry is generally used to support this kind of diagnosis. Manual volumetry is the traditional approach but it is time consuming and requires the physician to be familiar with neuroimaging software tools. In this paper, we propose an automated method, written as a script that uses FSL-FIRST, to perform hippocampal segmentation and compute an index to quantify hippocampi asymmetry (HAI). We compared the automated detection of HS (left or right) based on the HAI with the agreement of two experts in a group of 19 patients and 15 controls, achieving 84.2% sensitivity, 86.7% specificity and a Cohen's kappa coefficient of 0.704. The proposed method is integrated in the "Advanced Brain Imaging Lab" (ABrIL) cloud neurocomputing platform. The automated procedure is 77% (on average) faster to compute vs. the manual volumetry segmentation performed by an experienced physician.

Anomia produced by direct cortical stimulation of the pre-supplementary motor area in a patient undergoing preoperative language mapping.

There is sparse data on the analysis of supplementary motor area in language function using direct cortical stimulation of the supplementary motor area. Here, we report a patient who experienced isolated anomia during stimulation of the anterior supplementary motor area and discuss the role of the supplementary motor area in speech production. The role of the pre-supplementary motor· area in word selection, observed in fMRI studies, can be confirmed by direct cortical stimulation.

Task-Specific Dystonia in Professional Musicians. A Systematic Review of the Importance of Intensive Playing as a Risk Factor.

BACKGROUND: Focal dystonia in professional musicians is a movement disorder that manifests itself during playing. It is a multifactorial condition in which a genetic predisposition and exogenous factors both play a role. Evidence suggests that intensive playing is a risk factor for the development of task-specific dystonia in professional musicians. METHODS: This review is based on pertinent publications (1950-2013) retrieved by a systematic search in medical and musicological databases. The references of the retrieved publications were also considered in the search. RESULTS: 16 articles with clinical information on a total of 1144 affected musicians were reviewed systematically. Their overall quality was intermediate to poor, and a meta-analysis was therefore not possible. The Bradford Hill criteria were applied to study a possible causative link between intensive playing and musician's dystonia. Musician's dystonia generally arises after at least ten years of intensive playing (corresponding to roughly 10 000 hours of practice). An association was found between the affected limb and the type of instrument: the limb that is subject to the greatest fine motor demands is the one most commonly affected. The average age of onset is 28 to 44 years. CONCLUSION: The Bradford Hill causality criteria indicate that intensive playing is related to the development of musician's dystonia. In particular, the association of the type of instrument with the site of dystonia supports this thesis. The findings imply that task-specific dystonia in professional musicians should be included in the list of occupational diseases in Germany.

Connectivity patterns of pallidal DBS electrodes in focal dystonia: a diffusion tensor tractography study.

Deep brain stimulation (DBS) of the internal pallidal segment (GPi: globus pallidus internus) is gold standard treatment for medically intractable dystonia, but detailed knowledge of mechanisms of action is still not available. There is evidence that stimulation of ventral and dorsal GPi produces opposite motor effects. The aim of this study was to analyse connectivity profiles of ventral and dorsal GPi. Probabilistic tractography was initiated from DBS electrode contacts in 8 patients with focal dystonia and connectivity patterns compared. We found a considerable difference in anterior-posterior distribution of fibres along the mesial cortical sensorimotor areas between the ventral and dorsal GPi connectivity. This finding of distinct GPi connectivity profiles further confirms the clinical evidence that the ventral and dorsal GPi belong to different functional and anatomic motor subsystems. Their involvement could play an important role in promoting clinical DBS effects in dystonia.

ABrIL - Advanced Brain Imaging Lab : a cloud based computation environment for cooperative neuroimaging projects.

Neuroscience is an increasingly multidisciplinary and highly cooperative field where neuroimaging plays an important role. Neuroimaging rapid evolution is demanding for a growing number of computing resources and skills that need to be put in place at every lab. Typically each group tries to setup their own servers and workstations to support their neuroimaging needs, having to learn from Operating System management to specific neuroscience software tools details before any results can be obtained from each setup. This setup and learning process is replicated in every lab, even if a strong collaboration among several groups is going on. In this paper we present a new cloud service model - Brain Imaging Application as a Service (BiAaaS) - and one of its implementation - Advanced Brain Imaging Lab (ABrIL) - in the form of an ubiquitous virtual desktop remote infrastructure that offers a set of neuroimaging computational services in an interactive neuroscientist-friendly graphical user interface (GUI). This remote desktop has been used for several multi-institution cooperative projects with different neuroscience objectives that already achieved important results, such as the contribution to a high impact paper published in the January issue of the Neuroimage journal. The ABrIL system has shown its applicability in several neuroscience projects with a relatively low-cost, promoting truly collaborative actions and speeding up project results and their clinical applicability.

Evidence of a non-motor microlesion effect following deep brain surgery: a case report.

We report the case of a patient who developed acute transient psychosis after implantation, but not activation of pallidal deep brain electrodes for generalised dystonia. Psychotic symptoms coincided temporally with postoperative motor improvement induced by the microlesion effect after electode implantation. This finding suggests that the microlesion effect may not be confined to motor improvement, but also comprises non-motor symptoms. In our case, affection of adjacent dopaminergic fibres of passages has to be assumed.

Dopamine regulates the expression of the glutamate transporter GLT1 but not GLAST in developing striatal astrocytes.

Dopamine and L: -glutamate are important signals which guide the development of functional neural circuits within the striatal complex. Disequilibrium of these neurotransmitter systems is believed to be etiological for the genesis of neurological and psychiatric diseases. Since dopamine plays a crucial role for the early transmitter-regulated differentiation of striatal GABAergic neurons, we emphasized that dopaminergic transmission may also be involved in the fine tuning of intra-striatal glutamate action. In this study, we report that dopamine decreases the expression of the glutamate transporter GLT1 but not GLAST in striatal astrocytes by measuring gene and protein expression. Using glutamate-uptake approaches, we demonstrate an increase in glutamate clearance of externally added glutamate in dopamine-treated cultures compared to controls. Our findings imply that dopamine regulates the availability of L: -glutamate in the developing striatum. It is also suggested that the application of dopaminergic drugs can interfere with ontogenetic processes within the striatal complex.