Publications by authors named "Claudia Trenkwalder"

282 Publications

Clinically relevant copy-number variants in exome sequencing data of patients with dystonia.

Parkinsonism Relat Disord 2021 Feb 12;84:129-134. Epub 2021 Feb 12.

Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany; Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany.

Introduction: Next-generation sequencing is now used on a routine basis for molecular testing but studies on copy-number variant (CNV) detection from next-generation sequencing data are underrepresented. Utilizing an existing whole-exome sequencing (WES) dataset, we sought to investigate the contribution of rare CNVs to the genetic causality of dystonia.

Methods: The CNV read-depth analysis tool ExomeDepth was applied to the exome sequences of 953 unrelated patients with dystonia (600 with isolated dystonia and 353 with combined dystonia; 33% with additional neurological involvement). We prioritized rare CNVs that affected known disease genes and/or were known to be associated with defined microdeletion/microduplication syndromes. Pathogenicity assessment of CNVs was based on recently published standards of the American College of Medical Genetics and Genomics and the Clinical Genome Resource.

Results: We identified pathogenic or likely pathogenic CNVs in 14 of 953 patients (1.5%). Of the 14 different CNVs, 12 were deletions and 2 were duplications, ranging in predicted size from 124bp to 17 Mb. Within the deletion intervals, BRPF1, CHD8, DJ1, EFTUD2, FGF14, GCH1, PANK2, SGCE, UBE3A, VPS16, WARS2, and WDR45 were determined as the most clinically relevant genes. The duplications involved chromosomal regions 6q21-q22 and 15q11-q13. CNV analysis increased the diagnostic yield in the total cohort from 18.4% to 19.8%, as compared to the assessment of single-nucleotide variants and small insertions and deletions alone.

Conclusions: WES-based CNV analysis in dystonia is feasible, increases the diagnostic yield, and should be combined with the assessment of single-nucleotide variants and small insertions and deletions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2021.02.013DOI Listing
February 2021

Rotigotine Transdermal Patch for Motor and Non-motor Parkinson's Disease: A Review of 12 Years' Clinical Experience.

CNS Drugs 2021 Feb 9;35(2):215-231. Epub 2021 Feb 9.

Parkinson's Foundation Centre of Excellence, King's College Hospital, London, UK.

Motor and non-motor symptoms (NMS) have a substantial effect on the health-related quality of life (QoL) of patients with Parkinson's disease (PD). Transdermal therapy has emerged as a time-tested practical treatment option, and the rotigotine patch has been used worldwide as an alternative to conventional oral treatment for PD. The efficacy of rotigotine on motor aspects of PD, as well as its safety and tolerability profile, are well-established, whereas its effects on a wide range of NMS have been described and studied but are not widely appreciated. In this review, we present our overall experience with rotigotine and its tolerability and make recommendations for its use in PD and restless legs syndrome, with a specific focus on NMS, underpinned by level 1-4 evidence. We believe that the effective use of the rotigotine transdermal patch can address motor symptoms and a wide range of NMS, improving health-related QoL for patients with PD. More specifically, the positive effects of rotigotine on non-motor fluctuations are also relevant. We also discuss the additional advantages of the transdermal application of rotigotine when oral therapy cannot be used, for instance in acute medical emergencies or nil-by-mouth or pre/post-surgical scenarios. We highlight evidence to support the use of rotigotine in selected cases (in addition to general use for motor benefit) in the context of personalised medicine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40263-020-00788-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871129PMC
February 2021

COVID-19 Vaccination for Persons with Parkinson's Disease: Light at the End of the Tunnel?

J Parkinsons Dis 2021 ;11(1):3-8

Yerkes National Primate Research Center, Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.

Several COVID-19 vaccines have recently been approved for emergency use according to governmental immunization programs. The arrival of these vaccines has created hope for people with Parkinson's disease (PD), as this can help to mitigate their risk of becoming infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which can lead to serious, life-threatening disease, at least among those with more advanced PD. However, both persons with PD and physicians looking after these individuals have expressed concerns about the vaccine's efficacy and safety in the specific context of PD and its symptomatic treatment. Here, we discuss our perspective on these concerns, based on our interpretation of the literature plus the unfolding experience with widespread vaccination in the population at large. Because the benefits and risks of COVID-19 vaccines do not appear to be different than in the general population, we recommend COVID-19 vaccination with approved vaccines to persons with PD, unless there is a specific contraindication. Some caution seems warranted in very frail and terminally ill elderly persons with PD living in long-term care facilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JPD-212573DOI Listing
February 2021

Long-term safety and efficacy of apomorphine infusion in Parkinson's disease patients with persistent motor fluctuations: Results of the open-label phase of the TOLEDO study.

Parkinsonism Relat Disord 2021 Jan 12;83:79-85. Epub 2021 Jan 12.

University College London Institute of Neurology, Queen Square, London, UK. Electronic address:

Introduction: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP).

Methods: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO.

Results: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of -3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515).

Conclusions: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2020.12.024DOI Listing
January 2021

Novel Associations of and with Rapid Eye Movement Sleep Behavior Disorder.

Neurology 2021 Jan 4. Epub 2021 Jan 4.

Department of Human Genetics, McGill University, Montréal, QC, Canada.

Objective: To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).

Methods: We fully sequenced 25 genes previously identified in GWASs of PD, in a total of 1,039 iRBD patients and 1,852 controls. The role of rare heterozygous variants in these genes was examined using burden tests. The contribution of biallelic variants was further tested. To examine the potential impact of rare nonsynonymous variants on the protein structure, we performed structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex.

Results: We found an association between rare heterozygous nonsynonymous variants in and iRBD (=0.0003 at coverage >50X and 0.0004 at >30X), mainly driven by three nonsynonymous variants (p.V85M, p.I101V and p.V272M) found in 22 (1.2%) controls vs. two (0.2%) patients. All three variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare non-coding heterozygous variants in were also associated with iRBD (=0.0006 at >30X). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD.

Conclusion: Our results suggest that rare coding variants in and rare non-coding variants in are associated with iRBD. Additional studies are required to replicate these results and examine whether loss-of-function of could be a therapeutic target.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011464DOI Listing
January 2021

A geroscience approach for Parkinson's disease: Conceptual framework and design of PROPAG-AGEING project.

Mech Ageing Dev 2021 Mar 29;194:111426. Epub 2020 Dec 29.

IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; Laboratory of Systems Medicine of Healthy Aging and Department of Applied Mathematics, Lobachevsky University, Nizhny Novgorod, Russia.

Advanced age is the major risk factor for idiopathic Parkinson's disease (PD), but to date the biological relationship between PD and ageing remains elusive. Here we describe the rationale and the design of the H2020 funded project "PROPAG-AGEING", whose aim is to characterize the contribution of the ageing process to PD development. We summarize current evidences that support the existence of a continuum between ageing and PD and justify the use of a Geroscience approach to study PD. We focus in particular on the role of inflammaging, the chronic, low-grade inflammation characteristic of elderly physiology, which can propagate and transmit both locally and systemically. We then describe PROPAG-AGEING design, which is based on the multi-omic characterization of peripheral samples from clinically characterized drug-naïve and advanced PD, PD discordant twins, healthy controls and "super-controls", i.e. centenarians, who never showed clinical signs of motor disability, and their offspring. Omic results are then validated in a large number of samples, including in vitro models of dopaminergic neurons and healthy siblings of PD patients, who are at higher risk of developing PD, with the final aim of identifying the molecular perturbations that can deviate the trajectories of healthy ageing towards PD development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mad.2020.111426DOI Listing
March 2021

The role of intraoperative microelectrode recording and stimulation in subthalamic lead placement for Parkinson's disease.

PLoS One 2020 6;15(11):e0241752. Epub 2020 Nov 6.

Department of Neurosurgery, Göttingen University Medical Center, Göttingen, Germany.

Objective: Intraoperative microelectrode recording (MER) and test-stimulation are regarded as the gold standard for proper placement of subthalamic (STN) deep brain stimulation (DBS) electrodes in Parkinson's disease (PD), requiring the patient to be awake during the procedure. In accordance with good clinical practice, most attending neurologists will request the clinically most efficacious trajectory for definite lead placement. However, the necessity of microelectrode-test-stimulation is disputed, as it may limit the access to DBS therapy, excluding those not willing or incapable of undergoing awake surgery.

Methods: We retrospectively analyzed the MERs and microelectrode-test-stimulation results with regard to the decision on definite lead placement and clinical outcome in a cohort of 67 PD-patients with STN-DBS. All patients received bilateral quadripolar ring electrodes. To ascertain overall procedural efficacy, we calculated the surgical index (SI) by comparing preoperative motor improvement induced by levodopa to that induced by stimulation 7 to 18 months after surgery, measured as the relative difference between ON and OFF-states on the Unified Parkinson's Disease Rating Scale motor part (UPDRS-3). Additionally, a side-specific surgical index (SSSI) was calculated using the unilateral assessable items of the UPDRS-3. The SSSI where microelectrode-test-stimulation overruled MER were compared to those where the result of microelectrode-test-stimulation was congruent to MER results.

Results: A total of 134 electrodes were analyzed. For final lead placement, the central trajectory was chosen in 54% of patient hemispheres. The mean SI was 0.99 (± 0.24). SSSI averaged 1.04 (± 0.45). In 37 lead placements, microelectrode-test-stimulation overruled MER in the final trajectory selection, in 27 of these lead placements adverse effects during microelectrode-test-stimulation were decisive. Neither the number of test electrodes used nor the STN-signal length had an impact on the SSSI. The SSSI did not differ between lead placements with MER/microelectrode-test-stimulation congruency and those where the results of microelectrode-test-stimulation initiated lead placement in a trajectory with shorter STN signal.

Conclusion: Intraoperative testing is mandatory to ensure an optimal motor outcome of STN DBS in PD-patients when using quadripolar ring electrodes. However, we also demonstrated that neither the length of the STN-signal on MER nor the number of test electrodes influenced the motor outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241752PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7647091PMC
January 2021

Comprehensive Analysis of Familial Parkinsonism Genes in Rapid-Eye-Movement Sleep Behavior Disorder.

Mov Disord 2021 01 1;36(1):235-240. Epub 2020 Oct 1.

Department of Human Genetics, McGill University, Montréal, Québec, Canada.

Background: There is only partial overlap in the genetic background of isolated rapid-eye-movement sleep behavior disorder (iRBD) and Parkinson's disease (PD).

Objective: To examine the role of autosomal dominant and recessive PD or atypical parkinsonism genes in the risk of iRBD.

Methods: Ten genes, comprising the recessive genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7, and PLA2G6 and the dominant genes LRRK2, GCH1, and VPS35, were fully sequenced in 1039 iRBD patients and 1852 controls of European ancestry, followed by association tests.

Results: We found no association between rare heterozygous variants in the tested genes and risk of iRBD. Several homozygous and compound heterozygous carriers were identified, yet there was no overrepresentation in iRBD patients versus controls.

Conclusion: Our results do not support a major role for variants in these genes in the risk of iRBD. © 2020 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.28318DOI Listing
January 2021

[Update on restless legs syndrome].

Nervenarzt 2020 Oct;91(10):955-966

Zentrum für Parkinson-Syndrome und Bewegungsstörungen, Paracelsus-Elena Klinik, Klinikstr. 16, 34128, Kassel, Deutschland.

Restless legs syndrome (RLS), with a lifetime prevalence of up to 10%, is a frequent neurological disease and the most common movement disorder in sleep. A compulsive urge to move the legs with sensory symptoms and sleep disturbances can significantly impair the quality of life. Furthermore, RLS frequently occurs as a comorbidity to various internal and neurological diseases. It is diagnosed clinically based on the five essential diagnostic criteria. For treatment, an iron deficiency should first be excluded. Drugs approved for the treatment of RLS include dopaminergics (L-DOPA/benserazide) and dopamine agonists as well as oxycodone/naloxone, as a second-line treatment in severe cases. Augmentation as a deterioration of symptoms is a clinically defined complication of high-dose dopaminergic treatment, requiring special management strategies. Due to its high prevalence of up to 25%, RLS plays also an important role in the care of pregnant women.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00115-020-00997-8DOI Listing
October 2020

Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression.

Mov Disord 2020 11 15;35(11):1999-2008. Epub 2020 Aug 15.

Discovery and Early Development Biomarkers, Biogen, Cambridge, Massachusetts, USA.

Background: The objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker.

Methods: We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers.

Results: In the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 ± 7.2 pg/mL) than in controls (12 ± 6.7 pg/mL), P = 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P < 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association.

Conclusions: Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.28206DOI Listing
November 2020

A data-driven system to identify REM sleep behavior disorder and to predict its progression from the prodromal stage in Parkinson's disease.

Sleep Med 2021 Jan 23;77:238-248. Epub 2020 Apr 23.

Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Rigshospitalet, Glostrup, Denmark.

Objectives: To investigate electroencephalographic (EEG), electrooculographic (EOG) and micro-sleep abnormalities associated with rapid eye movement (REM) sleep behavior disorder (RBD) and REM behavioral events (RBEs) in Parkinson's disease (PD).

Methods: We developed an automated system using only EEG and EOG signals. First, automatic macro- (30-s epochs) and micro-sleep (5-s mini-epochs) staging was performed. Features describing micro-sleep structure, EEG spectral content, EEG coherence, EEG complexity, and EOG energy were derived. All features were input to an ensemble of random forests, giving as outputs the probabilities of having RBD or not (P (RBD) and P (nonRBD), respectively). A patient was classified as having RBD if P (RBD)≥P (nonRBD). The system was applied to 107 de novo PD patients: 54 had normal REM sleep (PDnonRBD), 26 had RBD (PD + RBD), and 27 had at least two RBEs without meeting electromyographic RBD cut-off (PD + RBE). Sleep diagnoses were made with video-polysomnography (v-PSG).

Results: Considering PDnonRBD and PD + RBD patients only, the system identified RBD with accuracy, sensitivity, and specificity over 80%. Among the features, micro-sleep instability had the highest importance for RBD identification. Considering PD + RBE patients, the ones who developed definite RBD after two years had significantly higher values of P (RBD) at baseline compared to the ones who did not. The former were distinguished from the latter with sensitivity and specificity over 75%.

Conclusions: Our method identifies RBD in PD patients using only EEG and EOG signals. Micro-sleep instability could be a biomarker for RBD and for proximity of conversion from RBEs, as prodromal RBD, to definite RBD in PD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sleep.2020.04.010DOI Listing
January 2021

World Brain Day 2020: move together to end Parkinson's disease.

Lancet Neurol 2020 08;19(8):643

Sir Charles Gairdner Hospital, Perth, WA, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(20)30215-5DOI Listing
August 2020

World Brain Day 2020: Move together to end Parkinson's disease.

J Neurol Sci 2020 09 24;416:116996. Epub 2020 Jun 24.

President, WFN, Department of Neurology, Sir Charles Gairdner Hospital, Nedlands, Perth, WA, Australia.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2020.116996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311342PMC
September 2020

variants in REM sleep behavior disorder: A multicenter study.

Neurology 2020 08 26;95(8):e1008-e1016. Epub 2020 Jun 26.

From the Department of Human Genetics (L.K., U.R., G.A.R., Z.G.-O.), Montreal Neurological Institute (L.K., J.A.R., U.R., E.L., F.A., R.B.P., G.A.R., Z.G.-O.), and Department of Neurology and Neurosurgery (J.A.R., F.A., R.B.P., G.A.R., Z.G.-O.), McGill University, Montréal; Oxford Parkinson's Disease Centre (M.T.M.H.) and Nuffield Department of Clinical Neurosciences (M.T.M.H.), University of Oxford, UK; Sleep Disorders Unit (I.A.), Pitié Salpêtrière Hospital, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière and Sorbonne Universities, Paris; National Reference Center for Narcolepsy, Sleep Unit (Y.D.), Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, France; Sleep Disorders Unit, Department of Neurology (B.H., A.S.), Medical University of Innsbruck, Austria; Department of Clinical Neurophysiology and Sleep Center (C.C.M.), University Lille North of France, CHU Lille; Sleep Disorder Unit (B.A.), Carémeau Hospital, University Hospital of Nîmes, France; Department of Biomedical and Neuromotor Sciences (DIBINEM) (G.P., E.A.), Alma Mater Studiorum, University of Bologna; IRCCS (G.P., E.A.), Istituto delle Scienze Neurologiche, Bologna; Department of Neurological Sciences (L.F.-S.), Università Vita-Salute San Raffaele, Milan, Italy; Department of Neurology with Institute of Translational Neurology (A.H.), University of Muenster, Germany; Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN; UC Gardner Neuroscience Institute and Gardner Family Center for Parkinson's Disease and Movement Disorders (A.J.E.), Cincinnati, OH; Sleep and Neurology Unit (V.C.D.C.), Beau Soleil Clinic, Montpellier; EuroMov (V.C.D.C.), University of Montpellier, France; Paracelsus-Elena-Klinik (B.M., F.S.-D., C.T.), Kassel; Department of Neurology (B.M., C.T.), University Medical Centre Goettingen; Department of Neurology (F.S.-D., W.O.), Philipps University, Marburg, Germany; Department of Neurology and Centre of Clinical Neuroscience (K.S., D.K.), Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic; Department of Medical Sciences and Public Health, Sleep Disorder Research Center (M.F., M.P.), University of Cagliari, Italy; Laboratory for Sleep Disorders (F.D., M.V.) and Department of Neurology (F.D., M.V.), St. Dimpna Regional Hospital, Geel, Belgium; Department of Medicine (DAME) (M.T., M.V.), University of Udine, Italy; Department of Clinical and Movement Neurosciences (M.T.), UCL Queen Square Institute of Neurology, London, UK; Clinical Neurology Unit (G.L.G., M.V.), Department of Neurosciences, University Hospital of Udine; DMIF (G.L.G.), University of Udine, Italy; Centre d'Études Avancées en Médecine du Sommeil (J.-F.G., A.D., J.Y.M., R.B.P.), Hôpital du Sacré-Cœur de Montréal; and Departments of Psychology (J.-F.G.), Neurosciences (A.D.), and Psychiatry (J.Y.M.), Université du Québec à Montréal, Canada.

Objective: To study the role of variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration.

Methods: A total of 4,147 individuals were included: 1,061 patients with iRBD and 3,086 controls. was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of variants on the risk of iRBD, age at onset (AAO), and conversion rates.

Results: variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87-3.22; = 1 × 10). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90-7.14; = 3.5 × 10), while for severe variant carriers it was 17.55 (95% CI, 2.11-145.9; = 0.0015). Carriers of severe variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or noncarriers ( = 0.029). Of the variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers ( = 0.011), with a trend for faster conversion among severe variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution.

Conclusions: variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of variants should be studied as a potential way to identify variant carriers who will develop a synucleinopathy in the future.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000010042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668554PMC
August 2020

A nanobody-based fluorescent reporter reveals human α-synuclein in the cell cytosol.

Nat Commun 2020 06 1;11(1):2729. Epub 2020 Jun 1.

Department of Neuro- and Sensory Physiology, University Medical Center Göttingen, D-37073, Göttingen, Germany.

Aggregation and spreading of α-Synuclein (αSyn) are hallmarks of several neurodegenerative diseases, thus monitoring human αSyn (hαSyn) in animal models or cell cultures is vital for the field. However, the detection of native hαSyn in such systems is challenging. We show that the nanobody NbSyn87, previously-described to bind hαSyn, also shows cross-reactivity for the proteasomal subunit Rpn10. As such, when the NbSyn87 is expressed in the absence of hαSyn, it is continuously degraded by the proteasome, while it is stabilized when it binds to hαSyn. Here, we exploit this feature to design a new Fluorescent Reporter for hαSyn (FluoReSyn) by fusing NbSyn87 to fluorescent proteins, which results in fluorescence signal fluctuations depending on the presence and amounts of intracellular hαSyn. We characterize this biosensor in cells and tissues to finally reveal the presence of transmittable αSyn in human cerebrospinal fluid, demonstrating the potential of FluoReSyn for clinical research and diagnostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-16575-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7264335PMC
June 2020

Neurogeriatrics-a vision for improved care and research for geriatric patients with predominating neurological disabilities.

Z Gerontol Geriatr 2020 Jul 19;53(4):340-346. Epub 2020 May 19.

Department of Neurology, University Hospital Schleswig-Holstein Campus Kiel, Kiel University, Arnold-Heller-Str. 3, House D, 24105, Kiel, Germany.

Geriatric medicine is a rapidly evolving field that addresses diagnostic, therapeutic and care aspects of older adults. Some disabilities and disorders affecting cognition (e.g. dementia), motor function (e.g. stroke, Parkinson's disease, neuropathies), mood (e.g. depression), behavior (e.g. delirium) and chronic pain disorders are particularly frequent in old subjects. As knowledge about these age-associated conditions and disabilities is steadily increasing, the integral implementation of neurogeriatric knowledge in geriatric medicine and specific neurogeriatric research is essential to develop the field. This article discusses how neurological know-how could be integrated in academic geriatric medicine to improve care of neurogeriatric patients, to foster neurogeriatric research and training concepts and to provide innovative care concepts for geriatric patients with predominant neurological conditions and disabilities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00391-020-01734-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311516PMC
July 2020

SMPD1 variants do not have a major role in rapid eye movement sleep behavior disorder.

Neurobiol Aging 2020 09 18;93:142.e5-142.e7. Epub 2020 Apr 18.

Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada; Department of Neurology and Neurosurgery, McGill University, Montréal, Quebec, Canada. Electronic address:

Mutations in the sphingomyelin phosphodiesterase 1 (SMPD1) gene were reported to be associated with Parkinson's disease and dementia with Lewy bodies. In the current study, we aimed to evaluate the role of SMPD1 variants in isolated rapid eye movement sleep behavior disorder (iRBD). SMPD1 and its untranslated regions were sequenced using targeted next-generation sequencing in 959 iRBD patients and 1287 controls from European descent. Our study reports no statistically significant association of SMPD1 variants and iRBD. It is hence unlikely that SMPD1 plays a major role in iRBD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.005DOI Listing
September 2020

Clinical trials in REM sleep behavioural disorder: challenges and opportunities.

J Neurol Neurosurg Psychiatry 2020 07 13;91(7):740-749. Epub 2020 May 13.

Paracelsus Elena Klinik, Kassel, Germany.

The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jnnp-2020-322875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735522PMC
July 2020

Impact of the COVID-19 Pandemic on Parkinson's Disease and Movement Disorders.

Mov Disord Clin Pract 2020 May 16;7(4):357-360. Epub 2020 Apr 16.

Paracelsus-Elena Klinik, Kassel, Department of Neurosurgery University Medical Center Goettingen Goettingen Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mdc3.12953DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197322PMC
May 2020

Rare Variants in Specific Lysosomal Genes Are Associated With Parkinson's Disease.

Mov Disord 2020 07 8;35(7):1245-1248. Epub 2020 Apr 8.

Department of Neurology, Universitätsklinikum Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.

Objective: Impaired lysosomal degradation of α-synuclein and other cellular constituents may play an important role in Parkinson's disease (PD). Rare genetic variants in the glucocerebrosidase (GBA) gene were consistently associated with PD. Here we examine the association between rare variants in lysosomal candidate genes and PD.

Methods: We investigated the association between PD and rare genetic variants in 23 lysosomal candidate genes in 4096 patients with PD and an equal number of controls using pooled targeted next-generation DNA sequencing. Genewise association of rare variants in cases or controls was analyzed using the optimized sequence kernel association test with Bonferroni correction for the 23 tested genes.

Results: We confirm the association of rare variants in GBA with PD and report novel associations for rare variants in ATP13A2, LAMP1, TMEM175, and VPS13C.

Conclusion: Rare variants in selected lysosomal genes, first and foremost GBA, are associated with PD. Rare variants in ATP13A2 and VPC13C previously linked to monogenic PD and more common variants in TMEM175 and VPS13C previously linked to sporadic PD in genome-wide association studies are associated with PD. © 2020 International Parkinson and Movement Disorder Society.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.28037DOI Listing
July 2020

Levodopa Equivalent Dose Conversion Factors: An Updated Proposal Including Opicapone and Safinamide.

Mov Disord Clin Pract 2020 Apr 16;7(3):343-345. Epub 2020 Mar 16.

Paracelsus-Elena-Klinik Klinikstr. 16, 34128 Kassel Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mdc3.12921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7111582PMC
April 2020

Impact of the COVID-19 Pandemic on Parkinson's Disease and Movement Disorders.

Mov Disord 2020 05 16;35(5):711-715. Epub 2020 Apr 16.

Paracelsus-Elena Klinik, Kassel, Department of Neurosurgery, University Medical Center, Goettingen, Goettingen, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.28067DOI Listing
May 2020

Mastering nocturnal jigsaws in Parkinson's disease: a dusk-to-dawn review of night-time symptoms.

J Neural Transm (Vienna) 2020 05 14;127(5):763-777. Epub 2020 Mar 14.

Department of Neurosurgery, University Medical Centre Goettingen, Paracelsus-Elena Hospital, Kassel, Germany.

Finding out about night-time symptoms from Parkinson's disease (PD) patients can be a challenge as many patients and their carers cannot recall many symptoms that occur during the night, resulting in an under-recognition or a large variability of responses from clinical interviews and scales. Moreover, technology-based assessments for most night-time symptoms are still not universally available for use in a patient's home environment. Therefore, most physicians rely on their clinical acumen to capture these night-time symptoms based on pieces of patients' history, bedpartner's reports, clinical features, associated symptoms or conditions. To capture more night-time symptoms, the authors identified common nocturnal symptoms based on how they manifest from dusk to dawn with selected features relevant to PD. While some symptoms occur in healthy individuals, in PD patients, they may impact differently. The authors intend this narrative review to provide a practical guide on how these common night-time symptoms manifest and highlight pertinent issues by focusing on prevalence, clinical symptomatology, and specific relationships to PD. It is also important to recognise that PD-specific sleep disturbances increase with advancing disease with additional contributions from ageing, comorbidities, and medication side effects. However, the relative contribution of each factor to individual symptom may be different in individual patient, necessitating clinical expertise for individual interpretation. While there are debatable issues in certain areas, they underlie the complexity of night-time symptoms. Understanding night-time symptoms in PD is like re-arranging jigsaw pieces of clinical information to create, but never complete, a picture for physicians to instigate appropriate management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-020-02170-6DOI Listing
May 2020

Delivering patient-centered care in Parkinson's disease: Challenges and consensus from an international panel.

Parkinsonism Relat Disord 2020 03 27;72:82-87. Epub 2020 Feb 27.

Center for Neurorestoration, Cleveland Clinic, Cleveland, OH, USA.

An international panel of movement disorders specialists explored the views and perceptions of people with Parkinson's disease (PD) about their condition and its treatment, including the potential mismatch between the clinician's view of the patient's condition and their own view of what aspects of the disease most affect their daily lives. The initiative was focused on Asian countries, so participants comprised experts in the management of PD from key centers in Asia, with additional insight provided by European and the North American movement disorders experts. Analysis of peer-reviewed publications on patient perceptions of PD and the factors that they consider important to their wellbeing identified several contributing factors to the mismatch of views, including gaps in knowledge of PD and its treatment, an understanding of the clinical heterogeneity of PD, and the importance of a multidisciplinary approach to patient care. The faculty proposed options to bridge these gaps to ensure that PD patients receive the personalized treatment they need to achieve the best possible outcomes. It was considered essential to improve patient knowledge about PD and its treatment, as well as increasing the awareness of clinicians of PD heterogeneity in presentation and treatment response. A multidisciplinary and shared-care approach to PD was needed alongside the use of patient-centered outcome measures in clinical trials and clinical practice to better capture the patient experience and improve the delivery of individualized therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2020.02.013DOI Listing
March 2020

Fine-Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies.

Ann Neurol 2020 04 12;87(4):584-598. Epub 2020 Feb 12.

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

Objective: Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in-depth analysis of the SNCA locus to identify RBD-specific risk variants.

Methods: Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta-analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan-Meier survival analysis.

Results: A 5'-region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E-08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5' risk variants across the different synucleinopathies. An independent iRBD-specific suggestive association (rs11732740) was detected at the 3' of SNCA (OR = 1.32, p = 4.7E-04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD-specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E-06). The known top PD-associated variant (3' variant rs356182) had an opposite direction of effect in iRBD compared to PD.

Interpretation: There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3' of SNCA. Several 5' SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584-598.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25687DOI Listing
April 2020

A Clinically Applicable Interactive Micro and Macro-Sleep Staging Algorithm for Elderly and Patients with Neurodegeneration.

Annu Int Conf IEEE Eng Med Biol Soc 2019 Jul;2019:3649-3652

Elderly and patients with neurodegenerative diseases (NDD) often complain about sleep problems and show altered sleep structure. Automated algorithms for efficient and specific sleep staging are needed. We propose a new algorithm using only one electroencephalographic and two electrooculographic channels to score wakefulness, rapid eye movement (REM) sleep and non-REM sleep in a cohort of elderly healthy controls (HC), patients with Parkinson's disease (PD), isolated REM sleep behavior disorder (iRBD), considered the prodromal stage of PD, and patients with PD and RBD (PD+RBD). The proposed method scores both standard 30-s epochs (macro-staging) and 5-s mini-epochs (micro-staging), whose evaluation may help to better understand sleep micro-structure. Moreover, the algorithm is interactive, as it labels the classified sleep epochs as either certain or uncertain, so that experts can manually review the uncertain ones. The algorithm performances were evaluated for macro-sleep staging, where it achieved overall accuracies of 0.87±0.05 in 41 HC, 0.86±0.10 in 57 PD, 0.76±0.10 in 31 iRBD and 0.77±0.10 in 30 PD+RBD patients when all 30-s epochs were considered. The accuracies increased to 0.91±0.05, 0.90±0.08, 0.85±0.09, 0.88±0.08 respectively when considering only the certain ones. The epochs labeled as uncertain were 9.95±4.15%, 11.13±7.86%, 18.39±7.38% and 18.90±8.00% in HC, PD, iRBD and PD+RBD respectively. The proposed interactive micro and macro sleep staging algorithm can be used in clinics to reduce the burden of manual sleep staging in elderly and patients with NDD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1109/EMBC.2019.8856705DOI Listing
July 2019

Movement disorders in 2019: from antibodies to lifestyle interventions.

Lancet Neurol 2020 01;19(1):10-12

Paracelsus-Elena-Klinik, Kassel, Germany; Department of Neurology, University Medical Center Goettingen, Goettingen, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1474-4422(19)30438-7DOI Listing
January 2020

Aberrant functional connectivity of resting state networks related to misperceptions and intra-individual variability in Parkinson's disease.

Neuroimage Clin 2020 5;25:102076. Epub 2019 Nov 5.

Department of Cognitive Neurology, University Medical Center Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany; German Primate Center, Leibniz Institute for Primate Research, Kellnerweg 4, Goettingen 37077, Germany; Leibniz Science Campus Primate Cognition, German Primate Center, Kellnerweg 4, Goettingen 37077, Germany. Electronic address:

Patients with Parkinson's disease (PD) frequently suffer from visual misperceptions and hallucinations, which are difficult to objectify and quantify. We aimed to develop an image recognition task to objectify misperceptions and to assess performance fluctuations in PD patients with and without self-reported hallucinations. Thirty-two non-demented patients with Parkinson's disease (16 with and 16 without self-reported visual hallucinations) and 25 age-matched healthy controls (HC) were tested. Participants performed a dynamic image recognition task with real and scrambled images. We assessed misperception scores and intra-individual variability in recognition times. To gain insight into possible neural mechanisms related to misperceptions and performance fluctuations we correlated resting state network connectivity to the behavioral outcomes in a subsample of Parkinson's disease patients (N = 16). We found that PD patients with self-reported hallucinations (PD-VH) exhibited higher perceptual error rates, due to decreased perceptual sensitivity and not due to changed decision criteria. In addition, PD-VH patients exhibited higher intra-individual variability in recognition times than HC or PD-nonVH patients. Both, misperceptions and intra-individual variability were negatively correlated with resting state functional connectivity involving frontal and parietal brain regions, albeit in partly different subregions. Consistent with previous research suggesting that hallucinations arise from dysfunction in attentional networks, misperception scores correlated with reduced functional connectivity between the dorsal attention and salience network. Intra-individual variability correlated with decreased connectivity between somatomotor and right fronto-parietal networks. We conclude that our task can detect visual misperceptions that are more prevalent in PD-VH patients. In addition, fluctuating visual performance appear to be a signature of PD-VH patients, which might assist further studies of the underlying pathophysiological mechanisms and cognitive processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nicl.2019.102076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906716PMC
January 2021

Identification of Restless Legs Syndrome Genes by Mutational Load Analysis.

Ann Neurol 2020 02 19;87(2):184-193. Epub 2019 Dec 19.

Helmholtz Zentrum München GmbH, German Research Center for Environmental Health, Institute of Neurogenomics, Neuherberg, Germany.

Objective: Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes.

Methods: We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth.

Results: Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes.

Interpretation: Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2020;87:184-193.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25658DOI Listing
February 2020