€ T T E R - N E R G E R P O
E T
A L
2.
Zimprich A, Benet-Page`s A, Struhal W, et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes lateonset Parkinson disease. Am J Hum Genet 2011;89:168-175.
25.
Shi H, Rojas R, Bonifacino JS, Hurley JH. The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain. Nat Struct Mol Biol 2006;13:540-548.
3.
Ando M, Funayama M, Li Y, et al. VPS35 mutation in Japanese patients with typical Parkinson’s disease. Mov Disord 2012;27: 1413-1417.
26.
Hierro A, Rojas AL, Rojas R, et al. Functional architecture of the retromer cargo-recognition complex. Nature 2007;449:1063-1067.
27.
4.
Kumar KR, Weissbach A, Heldmann M, et al. Frequency of the D620N mutation in VPS35 in Parkinson disease. Arch Neurol 2012;69:1360-1364.
Struhal W, Presslauer S, Spielberger S, et al. VPS35 Parkinson’s disease phenotype resembles the sporadic disease. J Neural Transm 2014;121:755-759.
5.
Lesage S, Condroyer C, Klebe S, et al. Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology 2012;78:1449-1450.
Supporting Data
6.
Sharma M, Ioannidis JP, Aasly JO, et al. A multi-centre clinicogenetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. J Med Genet 2012;49:721-726.
Additional Supporting Information may be found in the online version of this article at the publisher’s web-site.
7.
Sheerin UM, Charlesworth G, Bras J, et al. Screening for VPS35 mutations in Parkinson’s disease. Neurobiol Aging 2012;33:838 e831-e835.
8.
Tsika E, Glauser L, Moser R, et al. Parkinson’s disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. Hum Mol Genet 2014;23:4621-4638.
9.
Zavodszky E, Seaman MN, Moreau K, et al. Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat Commun 2014;5:3828.
10.
McGough IJ, Steinberg F, Jia D, et al. Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. Curr Biol 2014;24:1670-1676.
11.
Anitei M, Wassmer T, Stange C, Hoflack B. Bidirectional transport between the trans-Golgi network and the endosomal system. Mol Membr Biol 2010;27:443-456.
12.
Bonifacino JS, Hurley JH. Retromer. Curr Opin Cell Biol 2008;20: 427-436.
13.
Rojas R, Kametaka S, Haft CR, Bonifacino JS. Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the trafficking of mannose 6-phosphate receptors. Mol Cell Biol 2007;27:1112-1124.
14.
Koschmidder E, Mollenhauer B, Kasten M, Klein C, Lohmann K. Mutations in VPS26A are not a frequent cause of Parkinson’s disease. Neurobiol Aging 2014;35:1512.e1-2.
15.
Shannon B, Soto-Ortolaza A, Rayaprolu S, et al. Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson’s disease. Neurobiol Aging 2014;35:1958.e1-2.
16.
Ropers F, Derivery E, Hu H, et al. Identification of a novel candidate gene for non-syndromic autosomal recessive intellectual disability: the WASH complex member SWIP. Hum Mol Genet 2011; 20:2585-2590.
17.
Valdmanis PN, Meijer IA, Reynolds A, et al. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am J Hum Genet 2007;80:152-161.
18.
Small SA, Kent K, Pierce A, et al. Model-guided microarray implicates the retromer complex in Alzheimer’s disease. Ann Neurol 2005;58:909-919.
19.
Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism—a prospective study. Can J Neurol Sci 1991;18: 275-278.
20.
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181184.
21.
Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:1-9.
22.
Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670-676.
23.
McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863-1872.
24.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164.
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Selective Changes of Ocular Vestibular Myogenic Potentials in Parkinson’s Disease €tter-Nerger, MD,1,2,3 Sendhil Govender,3 Monika Po €nther Deuschl, MD,1 Jens Volkmann, MD,4 Gu and J.G. Colebatch, DSc3* 1
Department of Neurology, Christian-Albrecht-University, Kiel, Germany 2Department of Neurology, University Hamburg-Eppendorf, Hamburg, Germany 3Prince of Wales Clinical School and Neuroscience Research Australia, University New South Wales, Sydney, NSW 2052, Australia 4Department of Neurology, Julius-Maximilian€rzburg, Germany University, Wu
ABSTRACT Background: Vestibular evoked myogenic potentials represent electrophysiological tools to measure vestibular reflex actions at different levels of the brainstem in Parkinson’s disease. Objective: To investigate cervical and ocular vestibular myogenic potentials in Parkinsonian patients with mild disability. Methods: In 13 Parkinsonian patients and 13 agematched healthy controls, cervical and ocular vestibular myogenic potentials were recorded after unilateral air-conducted tone bursts and bone-conducted stimuli delivered at the forehead or mastoids. Results: In contrast to relatively preserved cervical vestibular evoked myogenic potentials, ocular vestibular evoked myogenic potentials were significantly delayed and of reduced amplitude, particularly after impulsive stimulation in Parkinsonian patients. Levodopa had no significant effect on either type of response. Conclusion: In mild to moderate Parkinson’s disease, altered ocular vestibular myogenic potentials may indicate early functional involvement of the upper brainstem, in contrast to preserved lower brainstem function as reflected by normal cervical vestibular
V E S T I B U L A R C 2014 International Parkinson myogenic potentials. V and Movement Disorder Society Key Words: Parkinson’s disease; cervical vestibular evoked myogenic potentials; bone-conducted vibration; L-dopa
In the pathophysiological understanding of disease progression in Parkinson’s disease (PD), neuroanatomical observations by Braak1-3 have shed new light on the brainstem as a key structure affected in early stages of the disease. Postural instability is a defining feature of advanced PD,4 which is even present in earlier stages of the disease.5,6 One of the most important supraspinal postural control centers is the vestibular system,7,8 which is subdivided into different functional entities accessible to electrophysiological testing such as cervical vestibular evoked myogenic potential (cVEMP)9 in the lower and ocular vestibular evoked myogenic potential (oVEMP) in the upper brainstem.10 In late-stage PD, recent studies have reported reduced air conducted (AC)-evoked cVEMPs,11,12 a finding that was interpreted as evidence of decreased excitability of the vestibular nuclei within the brainstem. The aim of the current study was to determine the most sensitive diagnostic marker of brainstem excitability changes in earlier stages using cVEMPs or oVEMPs.
Patients and Methods Thirteen early-staged PD patients (9 men, 4 women; mean age, 68.2 6 2.1 years) and 13 age-matched healthy controls (5 men, 8 women; mean age, 67.0 6 1.5 years) without vestibular disorders or gaze palsy were investigated after giving written informed consent to the approved study. Thirteen PD patients were tested with medication (MED ON), a subgroup of seven PD patients without medication (MED OFF) on another day (Hoehn and Yahr 2.8 6 0.3). Detailed procedures and methodological issues of VEMP recordings and stimulation techniques have been outlined in detail previously.13 For cVEMP recordings, surface electromyogram (EMG) electrodes were applied
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*Correspondence to: Professor J. G. Colebatch, Department of Neurology, Prince of Wales Hospital, High Street, Randwick, Sydney NSW 2031, Australia, E-mail: [email protected] €tter-Nerger received funding from an educaFunding agencies: Dr Po tional grant of Glaxo-Smith-Kline and a grant from the German Association of Clinical Neurophysiology. Professor Colebatch’s research is supported by the National Health and Medical Research Council of Australia and the Garnett Passe and Rodney Williams Foundations.
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 30 June 2013; Revised: 15 October 2014; Accepted: 26 October 2014 Published online 27 December 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26114
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to symmetrical sites over the sternocleidomastoid (SCM) muscle and the upper sternum. The EMG was amplified (2,5003) (D150 amplifiers, Digitimer Ltd, Welwyn Garden City, UK), bandpass filtered (8 Hz-1.6 kHz), and digitized (Power1401, Cambridge Electronic Design, Cambridge, UK; sampling rate 5 kHz). Online averages of 256 EMG sweeps of 120 ms were performed (20 ms before the stimulus and 100 ms after the stimulus) at a rate of approximately 5 Hz using Signal software (version 2.15, Cambridge Electronic Design). The target contraction level corresponded to approximately 50 to 60 mV rectified EMG activity. A bipolar EMG electrode montage below the center of the eyes was used to record oVEMPs. The EMG was amplified (50,0003), bandpass filtered (5 Hz1 kHz), and sampled (10 kHz), 256 sweeps of 70 ms (10 ms before and 60 ms after the stimulus; repetition rate 5 Hz). The subjects were instructed to keep their facial muscles relaxed and to maintain the angle of up-gaze (20 degrees) during the measurements, because the angle of elevation influences oVEMP amplitudes.14 Acceleration was measured with two linear accelerometers placed above the ears, oriented in the interaural (y-axis) direction (model 751–100, Endevco, California, USA; frequency response up to 10 kHz). Acceleration amplitudes were measured at the largest initial peak. Three different stimuli were selected to evoke VEMPs: (1) AC stimulation (sine wave, 500 Hz, 2 ms, 140 dB peak sound pressure level (pSPL)) was delivered unilaterally using calibrated headphones (TDH 49, Telephonics Corp., Farmingdale, New York, USA) to the left and right ears; (2) BC vibration (sinusoidal waveform, 500 Hz, 6 ms, 40 Vpeak corresponding to approximately 24 N peak FL) was delivered at AFz (midway between Fpz and Fz, approximately at the hairline); (3) Impulsive stimuli (4 ms rise time, 5 V or 10 V peak, corresponding to approximately 3 and 6 N peak FL) applied to the left and right mastoids. Onset latencies, second peak latencies, and adjusted VEMP amplitudes were analyzed in relation to the clinically more affected (CMA) side and clinically less affected (CLA) side, whereas the side of the recorded cVEMP or oVEMP was related to the side of stimulation (ie, ipsilateral [i] or contralateral [c] to the stimulus). Mean and standard error of the ipsilateral cVEMPs and contralateral oVEMPs after AC and BC impulsive stimulation and both sides after BC 500 Hz stimulation were analyzed in SPSS (version 17, SPSS Inc., Chicago, IL, USA). Age, EMG levels, gait performance, and head acceleration were compared by independent t tests and found to be comparable between groups and conditions. VEMP differences were analyzed by calculating multifactorial generalized linear model (GLM) analyses of variance and post-hoc Bonferroni-corrected independent t tests.
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FIG. 1. Grand means of cVEMP recordings of 13 patients on medication (black traces; MED ON), seven patients without medication (gray traces; MED OFF), and 13 healthy controls (dashed traces) stimulated with AC sound (A), and BC vibration delivered at AFz (B) and impulses applied to the mastoid (C). CMA, clinically more affected side; CLA, clinically less affected side; iSCM and cSCM, ipsilateral and contralateral SCM with respect to the side of stimulation.
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FIG. 2. Grand means of oVEMP recordings of 13 patients on medication (black traces; MED ON), seven patients without medication (gray traces; MED OFF), and 13 healthy controls (dashed traces) stimulated with AC sound (A), and BC vibration delivered at AFz (B) and impulses to the mastoid (C). Note that the largest difference appears to be for impulsive stimulation applied to the more affected side. CMA, clinically more affected; CLA, clinically less affected; iEYE and cEYE, ipsilateral and contralateral eye with respect to the side of stimulation.
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Results The cVEMP first and second peak latencies were not significantly different between controls and medicated PD patients in the different stimulation conditions (Fig. 1). The cVEMP amplitudes were not generally different between controls and medicated patients in the ipsilateral SCM, although they appeared mildly, but not significantly, diminished on the clinically more affected side in the Parkinsonian group after AC stimulation compared with controls. No significant effect of levodopa (L-dopa) was seen on peak latencies or cVEMP amplitudes, nor were any significant interactions. In contrast to cVEMPs, oVEMP first (F 5 12.097, p 5 0.002) and second peak latencies (F 5 9.243, p 5 0.006) in the contralateral eye were significantly delayed in medicated PD patients compared with controls, particularly after impulsive stimulation of the clinically more affected side (controls vs. PD BC impulse CMA: 11.14 6 0.19 ms vs. 12.32 6 0.33 ms, t 5 -3.138, p 5 0.024; Fig. 2). Levodopa had no significant effect on first or second peak latencies. The oVEMP amplitudes were generally smaller in medicated PD patients compared with controls, particularly after BC impulsive stimulation on the clinically more affected side (controls vs. PD: stimulation CMA: 9.32 6 0.87 mV vs. 5.00 6 1.08 mV, t 5 3.122, p 5 0.03). If 5 mV were used as a cutoff for the effects of BC stimulation on the CMA side, then 8 of 13 PD patients’ results would fall below (61% sensitivity) and 12 of 13 controls’ above (92% specificity). Levodopa had no overall effect on oVEMP amplitudes.
Discussion The oVEMPs, particularly after impulsive BC stimulation, were the most sensitive measure for demonstrating vestibular abnormalities in mild to moderate PD. In our group of PD patients, AC and BC evoked cVEMPs showed only minor changes, such as slightly, but not significantly, reduced amplitudes in PD patients on the clinically more affected side. In contrast, oVEMPs were significantly delayed after AC and both BC stimuli and of reduced amplitude, particularly after BC impulsive stimulation. Three different stimuli were selected to evoke VEMPs, which are assumed to excite different parts of the vestibular system. For AC sounds, a differential effect of AC sounds occurs with possible activation of saccular afferents for cVEMPS15 and additional utricular afferents for oVEMP recordings.16,17 Similarly, 500 Hz BC vibration at Fz is assumed to excite mainly the saccule while recording cVEMPs and predominantly utricle during oVEMP measurements.18 The impulsive, smoothed “gamma-shaped” stimuli applied at the mastoids are assumed to mainly excite the utri-
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cle, which lies in the horizontal plane and contains a major portion of hair cells sensitive to medial acceleration.19,20 These ascending utricular-ocular projections seem to be particularly sensitive for detection of early PD-related vestibular changes. Previous studies investigating AC evoked cVEMPs in PD patients have shown normal cVEMP latencies, but reduced cVEMP incidence and amplitudes.11,12 The lack of cVEMP abnormality in this study compared with the earlier studies could be attributable to differences in experimental conditions (different duration of EMG recording with different precontraction levels; sound application of a different frequency, duration, and intensity; binaural vs. unilateral stimulation,21 which might be particularly critical in PD). However, the main factor is likely to be the different clinical characteristics of the PD patient groups with assessment of late-staged PD patients in the earlier study.12 Thus, cVEMPs might not be a sensitive marker in early PD. The lack of dopaminergic modulation of cVEMPs in the current study was surprising, because in a recent study cVEMP amplitudes were found to be increased by L-dopa.12 This might be attributable to the limited amount of abnormality in the present study, because cVEMP amplitudes were only slightly reduced in PD patients. The absence of a dopaminergic effect on the oVEMPs is in line with previous findings of differential effects of L-dopa on oculomotor abnormalities.22 We found affected oVEMPs within the upper brainstem compared with the relatively preserved cVEMPs, suggesting intact lower but impaired upper brainstem function in mild PD. This conclusion is surprising and opposite to the common concept of a temporally and anatomically ordered, ascending caudo-rostral propagation of the alpha-synuclein pathology in PD.1,2 The current VEMP findings reflect “functional” changes of neuronal excitability, which may not necessarily follow the “anatomical” neurodegeneration pattern. Conversely, recent observations have challenged Braak’s model, and the hypothesis of a more widely distributed neurodegeneration “network” model in PD has been proposed.23 The VEMP findings provide some support for that network-based hypothesis of propagation pattern in PD. In summary, our findings suggest selective vulnerability of specific otolith-ocular projections in the upper brainstem reflected by changed oVEMPs in early Parkinson’s disease.
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Effects of Rasagiline on the Progression of Nonmotor Scores of the MDS-UPDRS
body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord 2006;21:2042-2051. 2.
O N
Werner Poewe, MD,1* Robert A. Hauser, MD, MBA,2 and Anthony Lang, MD3 for the ADAGIO Investigators 1
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria 2Parkinson’s Disease and Movement Disorders Center, NPF Center of Excellence, University of South Florida, Tampa, Florida, USA 3Department of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada
ABSTRACT Background: A draft version of part 1 (Non-Motor Aspects of Experiences of Daily Living; nM-EDL) of the MDS-UPDRS scale was employed as a secondary outcome in the ADAGIO study, which assessed the effect of rasagiline in early Parkinson’s disease (PD) patients. Methods: This analysis includes 1,150 untreated PD patients randomized to placebo or rasagiline 1 or 2 mg/day for 36 weeks in the placebo-controlled phase of ADAGIO who had draft-nM-EDL assessments at baseline and week 36. Results: Over the 9-month placebo-controlled phase of the study, nM-EDL scores significantly deteriorated from baseline in the placebo group only (0.34 6 0.10 units; P < 0.001). Compared to the placebo group (n 5 583), there was significantly less deterioration in the 1-mg/day rasagiline group (n 5 280; treatment effect: 20.33 units; P < 0.05), whereas the treatment effect in the 2-mg/day rasagiline group (n 5 287) was not statistically significant (20.25 6 0.17 units; P 5 0.131). Conclusions: The nM-EDL subscale appears sensitive to change in very early PD, and treatment with rasagiline 1 mg/day was associated with significantly less decline in nonmotor experiences of daily living versus placebo. Given that score changes were numerically small, the clinical implications of this effect remain
-----------------------------------------------------------*Correspondence to: Prof. Dr. Werner Poewe, Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria; [email protected] Funding agencies: This study was funded by Teva Pharmaceutical Industries. Relevant conflicts of interest/financial disclosures: W.P., R.H., and A.L. have received consulting fees related to the ADAGIO study. They have not received any payments for the preparation of this article. Full financial disclosures and author roles may be found in the online version of this article. Received: 17 March 2014; Revised: 18 November 2014; Accepted: 23 November 2014 Published online 27 December 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26124
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E T
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2.
Zimprich A, Benet-Page`s A, Struhal W, et al. A mutation in VPS35, encoding a subunit of the retromer complex, causes lateonset Parkinson disease. Am J Hum Genet 2011;89:168-175.
25.
Shi H, Rojas R, Bonifacino JS, Hurley JH. The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain. Nat Struct Mol Biol 2006;13:540-548.
3.
Ando M, Funayama M, Li Y, et al. VPS35 mutation in Japanese patients with typical Parkinson’s disease. Mov Disord 2012;27: 1413-1417.
26.
Hierro A, Rojas AL, Rojas R, et al. Functional architecture of the retromer cargo-recognition complex. Nature 2007;449:1063-1067.
27.
4.
Kumar KR, Weissbach A, Heldmann M, et al. Frequency of the D620N mutation in VPS35 in Parkinson disease. Arch Neurol 2012;69:1360-1364.
Struhal W, Presslauer S, Spielberger S, et al. VPS35 Parkinson’s disease phenotype resembles the sporadic disease. J Neural Transm 2014;121:755-759.
5.
Lesage S, Condroyer C, Klebe S, et al. Identification of VPS35 mutations replicated in French families with Parkinson disease. Neurology 2012;78:1449-1450.
Supporting Data
6.
Sharma M, Ioannidis JP, Aasly JO, et al. A multi-centre clinicogenetic analysis of the VPS35 gene in Parkinson disease indicates reduced penetrance for disease-associated variants. J Med Genet 2012;49:721-726.
Additional Supporting Information may be found in the online version of this article at the publisher’s web-site.
7.
Sheerin UM, Charlesworth G, Bras J, et al. Screening for VPS35 mutations in Parkinson’s disease. Neurobiol Aging 2012;33:838 e831-e835.
8.
Tsika E, Glauser L, Moser R, et al. Parkinson’s disease-linked mutations in VPS35 induce dopaminergic neurodegeneration. Hum Mol Genet 2014;23:4621-4638.
9.
Zavodszky E, Seaman MN, Moreau K, et al. Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy. Nat Commun 2014;5:3828.
10.
McGough IJ, Steinberg F, Jia D, et al. Retromer binding to FAM21 and the WASH complex is perturbed by the Parkinson disease-linked VPS35(D620N) mutation. Curr Biol 2014;24:1670-1676.
11.
Anitei M, Wassmer T, Stange C, Hoflack B. Bidirectional transport between the trans-Golgi network and the endosomal system. Mol Membr Biol 2010;27:443-456.
12.
Bonifacino JS, Hurley JH. Retromer. Curr Opin Cell Biol 2008;20: 427-436.
13.
Rojas R, Kametaka S, Haft CR, Bonifacino JS. Interchangeable but essential functions of SNX1 and SNX2 in the association of retromer with endosomes and the trafficking of mannose 6-phosphate receptors. Mol Cell Biol 2007;27:1112-1124.
14.
Koschmidder E, Mollenhauer B, Kasten M, Klein C, Lohmann K. Mutations in VPS26A are not a frequent cause of Parkinson’s disease. Neurobiol Aging 2014;35:1512.e1-2.
15.
Shannon B, Soto-Ortolaza A, Rayaprolu S, et al. Genetic variation of the retromer subunits VPS26A/B-VPS29 in Parkinson’s disease. Neurobiol Aging 2014;35:1958.e1-2.
16.
Ropers F, Derivery E, Hu H, et al. Identification of a novel candidate gene for non-syndromic autosomal recessive intellectual disability: the WASH complex member SWIP. Hum Mol Genet 2011; 20:2585-2590.
17.
Valdmanis PN, Meijer IA, Reynolds A, et al. Mutations in the KIAA0196 gene at the SPG8 locus cause hereditary spastic paraplegia. Am J Hum Genet 2007;80:152-161.
18.
Small SA, Kent K, Pierce A, et al. Model-guided microarray implicates the retromer complex in Alzheimer’s disease. Ann Neurol 2005;58:909-919.
19.
Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism—a prospective study. Can J Neurol Sci 1991;18: 275-278.
20.
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181184.
21.
Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 1996;47:1-9.
22.
Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670-676.
23.
McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology 2005;65:1863-1872.
24.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164.
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Selective Changes of Ocular Vestibular Myogenic Potentials in Parkinson’s Disease €tter-Nerger, MD,1,2,3 Sendhil Govender,3 Monika Po €nther Deuschl, MD,1 Jens Volkmann, MD,4 Gu and J.G. Colebatch, DSc3* 1
Department of Neurology, Christian-Albrecht-University, Kiel, Germany 2Department of Neurology, University Hamburg-Eppendorf, Hamburg, Germany 3Prince of Wales Clinical School and Neuroscience Research Australia, University New South Wales, Sydney, NSW 2052, Australia 4Department of Neurology, Julius-Maximilian€rzburg, Germany University, Wu
ABSTRACT Background: Vestibular evoked myogenic potentials represent electrophysiological tools to measure vestibular reflex actions at different levels of the brainstem in Parkinson’s disease. Objective: To investigate cervical and ocular vestibular myogenic potentials in Parkinsonian patients with mild disability. Methods: In 13 Parkinsonian patients and 13 agematched healthy controls, cervical and ocular vestibular myogenic potentials were recorded after unilateral air-conducted tone bursts and bone-conducted stimuli delivered at the forehead or mastoids. Results: In contrast to relatively preserved cervical vestibular evoked myogenic potentials, ocular vestibular evoked myogenic potentials were significantly delayed and of reduced amplitude, particularly after impulsive stimulation in Parkinsonian patients. Levodopa had no significant effect on either type of response. Conclusion: In mild to moderate Parkinson’s disease, altered ocular vestibular myogenic potentials may indicate early functional involvement of the upper brainstem, in contrast to preserved lower brainstem function as reflected by normal cervical vestibular
V E S T I B U L A R C 2014 International Parkinson myogenic potentials. V and Movement Disorder Society Key Words: Parkinson’s disease; cervical vestibular evoked myogenic potentials; bone-conducted vibration; L-dopa
In the pathophysiological understanding of disease progression in Parkinson’s disease (PD), neuroanatomical observations by Braak1-3 have shed new light on the brainstem as a key structure affected in early stages of the disease. Postural instability is a defining feature of advanced PD,4 which is even present in earlier stages of the disease.5,6 One of the most important supraspinal postural control centers is the vestibular system,7,8 which is subdivided into different functional entities accessible to electrophysiological testing such as cervical vestibular evoked myogenic potential (cVEMP)9 in the lower and ocular vestibular evoked myogenic potential (oVEMP) in the upper brainstem.10 In late-stage PD, recent studies have reported reduced air conducted (AC)-evoked cVEMPs,11,12 a finding that was interpreted as evidence of decreased excitability of the vestibular nuclei within the brainstem. The aim of the current study was to determine the most sensitive diagnostic marker of brainstem excitability changes in earlier stages using cVEMPs or oVEMPs.
Patients and Methods Thirteen early-staged PD patients (9 men, 4 women; mean age, 68.2 6 2.1 years) and 13 age-matched healthy controls (5 men, 8 women; mean age, 67.0 6 1.5 years) without vestibular disorders or gaze palsy were investigated after giving written informed consent to the approved study. Thirteen PD patients were tested with medication (MED ON), a subgroup of seven PD patients without medication (MED OFF) on another day (Hoehn and Yahr 2.8 6 0.3). Detailed procedures and methodological issues of VEMP recordings and stimulation techniques have been outlined in detail previously.13 For cVEMP recordings, surface electromyogram (EMG) electrodes were applied
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*Correspondence to: Professor J. G. Colebatch, Department of Neurology, Prince of Wales Hospital, High Street, Randwick, Sydney NSW 2031, Australia, E-mail: [email protected] €tter-Nerger received funding from an educaFunding agencies: Dr Po tional grant of Glaxo-Smith-Kline and a grant from the German Association of Clinical Neurophysiology. Professor Colebatch’s research is supported by the National Health and Medical Research Council of Australia and the Garnett Passe and Rodney Williams Foundations.
Relevant conflicts of interest/financial disclosures: Nothing to report. Full financial disclosures and author roles may be found in the online version of this article. Received: 30 June 2013; Revised: 15 October 2014; Accepted: 26 October 2014 Published online 27 December 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26114
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to symmetrical sites over the sternocleidomastoid (SCM) muscle and the upper sternum. The EMG was amplified (2,5003) (D150 amplifiers, Digitimer Ltd, Welwyn Garden City, UK), bandpass filtered (8 Hz-1.6 kHz), and digitized (Power1401, Cambridge Electronic Design, Cambridge, UK; sampling rate 5 kHz). Online averages of 256 EMG sweeps of 120 ms were performed (20 ms before the stimulus and 100 ms after the stimulus) at a rate of approximately 5 Hz using Signal software (version 2.15, Cambridge Electronic Design). The target contraction level corresponded to approximately 50 to 60 mV rectified EMG activity. A bipolar EMG electrode montage below the center of the eyes was used to record oVEMPs. The EMG was amplified (50,0003), bandpass filtered (5 Hz1 kHz), and sampled (10 kHz), 256 sweeps of 70 ms (10 ms before and 60 ms after the stimulus; repetition rate 5 Hz). The subjects were instructed to keep their facial muscles relaxed and to maintain the angle of up-gaze (20 degrees) during the measurements, because the angle of elevation influences oVEMP amplitudes.14 Acceleration was measured with two linear accelerometers placed above the ears, oriented in the interaural (y-axis) direction (model 751–100, Endevco, California, USA; frequency response up to 10 kHz). Acceleration amplitudes were measured at the largest initial peak. Three different stimuli were selected to evoke VEMPs: (1) AC stimulation (sine wave, 500 Hz, 2 ms, 140 dB peak sound pressure level (pSPL)) was delivered unilaterally using calibrated headphones (TDH 49, Telephonics Corp., Farmingdale, New York, USA) to the left and right ears; (2) BC vibration (sinusoidal waveform, 500 Hz, 6 ms, 40 Vpeak corresponding to approximately 24 N peak FL) was delivered at AFz (midway between Fpz and Fz, approximately at the hairline); (3) Impulsive stimuli (4 ms rise time, 5 V or 10 V peak, corresponding to approximately 3 and 6 N peak FL) applied to the left and right mastoids. Onset latencies, second peak latencies, and adjusted VEMP amplitudes were analyzed in relation to the clinically more affected (CMA) side and clinically less affected (CLA) side, whereas the side of the recorded cVEMP or oVEMP was related to the side of stimulation (ie, ipsilateral [i] or contralateral [c] to the stimulus). Mean and standard error of the ipsilateral cVEMPs and contralateral oVEMPs after AC and BC impulsive stimulation and both sides after BC 500 Hz stimulation were analyzed in SPSS (version 17, SPSS Inc., Chicago, IL, USA). Age, EMG levels, gait performance, and head acceleration were compared by independent t tests and found to be comparable between groups and conditions. VEMP differences were analyzed by calculating multifactorial generalized linear model (GLM) analyses of variance and post-hoc Bonferroni-corrected independent t tests.
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FIG. 1. Grand means of cVEMP recordings of 13 patients on medication (black traces; MED ON), seven patients without medication (gray traces; MED OFF), and 13 healthy controls (dashed traces) stimulated with AC sound (A), and BC vibration delivered at AFz (B) and impulses applied to the mastoid (C). CMA, clinically more affected side; CLA, clinically less affected side; iSCM and cSCM, ipsilateral and contralateral SCM with respect to the side of stimulation.
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FIG. 2. Grand means of oVEMP recordings of 13 patients on medication (black traces; MED ON), seven patients without medication (gray traces; MED OFF), and 13 healthy controls (dashed traces) stimulated with AC sound (A), and BC vibration delivered at AFz (B) and impulses to the mastoid (C). Note that the largest difference appears to be for impulsive stimulation applied to the more affected side. CMA, clinically more affected; CLA, clinically less affected; iEYE and cEYE, ipsilateral and contralateral eye with respect to the side of stimulation.
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Results The cVEMP first and second peak latencies were not significantly different between controls and medicated PD patients in the different stimulation conditions (Fig. 1). The cVEMP amplitudes were not generally different between controls and medicated patients in the ipsilateral SCM, although they appeared mildly, but not significantly, diminished on the clinically more affected side in the Parkinsonian group after AC stimulation compared with controls. No significant effect of levodopa (L-dopa) was seen on peak latencies or cVEMP amplitudes, nor were any significant interactions. In contrast to cVEMPs, oVEMP first (F 5 12.097, p 5 0.002) and second peak latencies (F 5 9.243, p 5 0.006) in the contralateral eye were significantly delayed in medicated PD patients compared with controls, particularly after impulsive stimulation of the clinically more affected side (controls vs. PD BC impulse CMA: 11.14 6 0.19 ms vs. 12.32 6 0.33 ms, t 5 -3.138, p 5 0.024; Fig. 2). Levodopa had no significant effect on first or second peak latencies. The oVEMP amplitudes were generally smaller in medicated PD patients compared with controls, particularly after BC impulsive stimulation on the clinically more affected side (controls vs. PD: stimulation CMA: 9.32 6 0.87 mV vs. 5.00 6 1.08 mV, t 5 3.122, p 5 0.03). If 5 mV were used as a cutoff for the effects of BC stimulation on the CMA side, then 8 of 13 PD patients’ results would fall below (61% sensitivity) and 12 of 13 controls’ above (92% specificity). Levodopa had no overall effect on oVEMP amplitudes.
Discussion The oVEMPs, particularly after impulsive BC stimulation, were the most sensitive measure for demonstrating vestibular abnormalities in mild to moderate PD. In our group of PD patients, AC and BC evoked cVEMPs showed only minor changes, such as slightly, but not significantly, reduced amplitudes in PD patients on the clinically more affected side. In contrast, oVEMPs were significantly delayed after AC and both BC stimuli and of reduced amplitude, particularly after BC impulsive stimulation. Three different stimuli were selected to evoke VEMPs, which are assumed to excite different parts of the vestibular system. For AC sounds, a differential effect of AC sounds occurs with possible activation of saccular afferents for cVEMPS15 and additional utricular afferents for oVEMP recordings.16,17 Similarly, 500 Hz BC vibration at Fz is assumed to excite mainly the saccule while recording cVEMPs and predominantly utricle during oVEMP measurements.18 The impulsive, smoothed “gamma-shaped” stimuli applied at the mastoids are assumed to mainly excite the utri-
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cle, which lies in the horizontal plane and contains a major portion of hair cells sensitive to medial acceleration.19,20 These ascending utricular-ocular projections seem to be particularly sensitive for detection of early PD-related vestibular changes. Previous studies investigating AC evoked cVEMPs in PD patients have shown normal cVEMP latencies, but reduced cVEMP incidence and amplitudes.11,12 The lack of cVEMP abnormality in this study compared with the earlier studies could be attributable to differences in experimental conditions (different duration of EMG recording with different precontraction levels; sound application of a different frequency, duration, and intensity; binaural vs. unilateral stimulation,21 which might be particularly critical in PD). However, the main factor is likely to be the different clinical characteristics of the PD patient groups with assessment of late-staged PD patients in the earlier study.12 Thus, cVEMPs might not be a sensitive marker in early PD. The lack of dopaminergic modulation of cVEMPs in the current study was surprising, because in a recent study cVEMP amplitudes were found to be increased by L-dopa.12 This might be attributable to the limited amount of abnormality in the present study, because cVEMP amplitudes were only slightly reduced in PD patients. The absence of a dopaminergic effect on the oVEMPs is in line with previous findings of differential effects of L-dopa on oculomotor abnormalities.22 We found affected oVEMPs within the upper brainstem compared with the relatively preserved cVEMPs, suggesting intact lower but impaired upper brainstem function in mild PD. This conclusion is surprising and opposite to the common concept of a temporally and anatomically ordered, ascending caudo-rostral propagation of the alpha-synuclein pathology in PD.1,2 The current VEMP findings reflect “functional” changes of neuronal excitability, which may not necessarily follow the “anatomical” neurodegeneration pattern. Conversely, recent observations have challenged Braak’s model, and the hypothesis of a more widely distributed neurodegeneration “network” model in PD has been proposed.23 The VEMP findings provide some support for that network-based hypothesis of propagation pattern in PD. In summary, our findings suggest selective vulnerability of specific otolith-ocular projections in the upper brainstem reflected by changed oVEMPs in early Parkinson’s disease.
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Welgampola MS, Colebatch JG. Characteristics of tone burstevoked myogenic potentials in the sternocleidomastoid muscles. Otol Neurotol 2001;22:796-802.
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Effects of Rasagiline on the Progression of Nonmotor Scores of the MDS-UPDRS
body pathology associated with sporadic Parkinson’s disease reconsidered. Mov Disord 2006;21:2042-2051. 2.
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Werner Poewe, MD,1* Robert A. Hauser, MD, MBA,2 and Anthony Lang, MD3 for the ADAGIO Investigators 1
Department of Neurology, Innsbruck Medical University, Innsbruck, Austria 2Parkinson’s Disease and Movement Disorders Center, NPF Center of Excellence, University of South Florida, Tampa, Florida, USA 3Department of Neurology, Toronto Western Hospital, Toronto, Ontario, Canada
ABSTRACT Background: A draft version of part 1 (Non-Motor Aspects of Experiences of Daily Living; nM-EDL) of the MDS-UPDRS scale was employed as a secondary outcome in the ADAGIO study, which assessed the effect of rasagiline in early Parkinson’s disease (PD) patients. Methods: This analysis includes 1,150 untreated PD patients randomized to placebo or rasagiline 1 or 2 mg/day for 36 weeks in the placebo-controlled phase of ADAGIO who had draft-nM-EDL assessments at baseline and week 36. Results: Over the 9-month placebo-controlled phase of the study, nM-EDL scores significantly deteriorated from baseline in the placebo group only (0.34 6 0.10 units; P < 0.001). Compared to the placebo group (n 5 583), there was significantly less deterioration in the 1-mg/day rasagiline group (n 5 280; treatment effect: 20.33 units; P < 0.05), whereas the treatment effect in the 2-mg/day rasagiline group (n 5 287) was not statistically significant (20.25 6 0.17 units; P 5 0.131). Conclusions: The nM-EDL subscale appears sensitive to change in very early PD, and treatment with rasagiline 1 mg/day was associated with significantly less decline in nonmotor experiences of daily living versus placebo. Given that score changes were numerically small, the clinical implications of this effect remain
-----------------------------------------------------------*Correspondence to: Prof. Dr. Werner Poewe, Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria; [email protected] Funding agencies: This study was funded by Teva Pharmaceutical Industries. Relevant conflicts of interest/financial disclosures: W.P., R.H., and A.L. have received consulting fees related to the ADAGIO study. They have not received any payments for the preparation of this article. Full financial disclosures and author roles may be found in the online version of this article. Received: 17 March 2014; Revised: 18 November 2014; Accepted: 23 November 2014 Published online 27 December 2014 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.26124
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