Background: Parkinsonism is defined by motor features (tremor, bradykinesia, rigidity, and postural instability). Accompanying non-motor features (e.g. cognitive, autonomic, sleep disturbances) are underrecognized and undertreated. We hypothesized that clinical patterns occurring in early, medication-naïve Parkinsonism are distinguished by features such as tremor, sleep, autonomic, and cognitive dysfunction. Methods: Clinical and neuroimaging data were obtained in the Parkinson's Progression Marker Initiative. Group comparisons of Parkinsonism with dopaminergic deficits (PDD) (n = 388), controls (n = 196), and Parkinsonism with scans without evidence of dopaminergic deficits (n = 64) were done with ANOVA, chi-square, and post-hoc pairwise tests. To examine clinical patterns within the PDD group, k-means clustering was performed with non-motor or motor features, or both. Results: Among PDD, 4 non-motor patterns (% of PDD) (impulsive (14.9%), sleep-autonomic (22.9%), cognitive-olfactory (18.0%), and mild (44.1%)), 4 motor patterns (tremor plus bradykinesia (56.2%), tremor without bradykinesia (16.2%), postural instability (6.7%) and no tremor (20.9%)) and 5 combined motor/non-motor patterns (tremor with bradykinesia (42.3%), tremor without bradykinesia (15.5%), no tremor and mild non-motor features (17.0%), postural instability with sleep-autonomic disturbances (6.7%) and oldest onset cognitive-olfactory (18.6%)) were observed. Conclusions: To our knowledge, this is the first description of non-motor clinical patterns in early, medication-naïve Parkinsonism, suggesting that such features are intrinsic to Parkinsonian disorders.

1.
Aerts MB, Esselink RA, Post B, van de Warrenburg BP, Bloem BR: Improving the diagnostic accuracy in Parkinsonism: a three-pronged approach. Pract Neurol 2012;12:77-87.
2.
Jellinger KA: Formation and development of Lewy pathology: a critical update. J Neurol 2009;256(suppl 3):270-279.
3.
Jellinger KA: Neuropathobiology of non-motor symptoms in Parkinson disease. J Neural Transm 2015, Epub ahead of print.
4.
Chaudhuri KR, Healy DG, Schapira AH: Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 2006;5:235-245.
5.
Müller B, Assmus J, Herlofson K, Larsen JP, Tysnes OB: Importance of motor vs. non-motor symptoms for health-related quality of life in early Parkinson's disease. Parkinsonism Relat Disord 2013;19:1027-1032.
6.
Parkinson Progression Marker Initiative: The Parkinson progression marker initiative (PPMI). Prog Neurobiol 2011;95:629-635.
7.
Lewis SJ, Foltynie T, Blackwell AD, Robbins TW, Owen AM, Barker RA: Heterogeneity of Parkinson's disease in the early clinical stages using a data driven approach. J Neurol Neurosurg Psychiatry 2005;76:343-348.
8.
Zetusky WJ, Jankovic J, Pirozzolo FJ: The heterogeneity of Parkinson's disease: clinical and prognostic implications. Neurology 1985;35:522-526.
9.
Benamer TS, Patterson J, Grosset DG, Booij J, de Bruin K, van Royen E, et al: Accurate differentiation of Parkinsonism and essential tremor using visual assessment of [123I]-FP-CIT SPECT imaging: the [123I]-FP-CIT study group. Mov Disord 2000;15:503-510.
10.
Peeples M: R Script for K-Means Cluster Analysis. 2011. http://wwwmattpeeplesnet/kmeanshtml (accessed January 7, 2015).
11.
Tibshirani R, Walther G, Hastie T: Estimating the number of clusters in a dataset via the gap statistic. J R Stat Soc Series B 2000;63:411-423.
12.
What's New in SAS 9.3. Cary, NC, SAS Institute, Inc., 2012.
13.
Team RC: R: A language and environment for statistical computing Vienna, Austria, R Foundation for Statistical Computing, 2013.
14.
Marek K, Jennings D, Seibyl J, et al: Long-term follow-up of patients with scans without evidence of dopaminergic deficit (SWEDD) in the ELLDOPA study. Neurology 2005;64(suppl 1):A274.
15.
Peall K, Morris H, Bajaj N: SWEDD-UK meeting report. Adv Clin Neurosci Rehabil 2010;10:32-37.
16.
Batla A, Erro R, Stamelou M, Schneider SA, Schwingenschuh P, Ganos C, et al: Patients with scans without evidence of dopaminergic deficit: a long-term follow-up study. Mov Disord 2014;29:1820-1825.
17.
Bajaj N: SWEDD for the general neurologist. Adv Clin Neurosci Rehabil 2010;10:30-31.
18.
Silveira-Moriyama L, Schwingenschuh P, O'Donnell A, Schneider SA, Mir P, Carrillo F, et al: Olfaction in patients with suspected parkinsonism and scans without evidence of dopaminergic deficit (SWEDDs). J Neurol Neurosurg Psychiatry 2009;80:744-748.
19.
Jang WAJ, Kim HT: Non-motor symptoms in PD patients with SWEDDs (abstract). Mov Disord 2013;28(suppl 1):299.
20.
Erro R, Vitale C, Amboni M, Picillo M, Moccia M, Longo K, et al: The heterogeneity of early Parkinson's disease: a cluster analysis on newly diagnosed untreated patients. PLoS One 2013;8:e70244.
21.
Yang HJ, Kim YE, Yun JY, Kim HJ, Jeon BS: Identifying the clusters within nonmotor manifestations in early Parkinson's disease by using unsupervised cluster analysis. PLoS One 2014;9:e91906.
22.
van Rooden SM, Colas F, Martínez-Martín P, Visser M, Verbaan D, Marinus J, et al: Clinical subtypes of Parkinson's disease. Mov Disord 2011;26:51-58.
23.
Thenganatt MA, Jankovic J: Parkinson disease subtypes. JAMA Neurol 2014;71:499-504.
24.
Connolly BS, Lang AE: Pharmacological treatment of Parkinson disease: a review. JAMA 2014;311:1670-1683.
25.
Weintraub D: Impulse control disorders in Parkinson's disease: prevalence and possible risk factors. Parkinsonism Relat Disord 2009;15(suppl 3):S110-S113.
26.
Weintraub D, Nirenberg MJ: Impulse control and related disorders in Parkinson's disease. Neurodegener Dis 2013;11:63-71.
27.
Jain S, Waters CH: Controversies of dopamine agonists: somnolence, cardiac valvulopathy and repetitive behaviors. Current Drug Therapy 2007;2:17-20.
28.
Postuma RB, Gagnon JF, Montplaisir JY: REM sleep behavior disorder: from dreams to neurodegeneration. Neurobiol Dis 2012;46:553-558.
29.
Postuma RB, Lang AE, Massicotte-Marquez J, Montplaisir J: Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder. Neurology 2006;66:845-851.
30.
Schenck CH, Boeve BF, Mahowald MW: Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. Sleep Med 2013;14:744-748.
31.
Doty RL: Olfaction in Parkinson's disease and related disorders. Neurobiol Dis 2012;46:527-552.
32.
Stern Y: Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurol 2012;11:1006-1012.
33.
Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, et al: Variable expression of Parkinson's disease: a base-line analysis of the DATATOP cohort. The Parkinson study group. Neurology 1990;40:1529-1534.
34.
van de Berg WD, Hepp DH, Dijkstra AA, Rozemuller JA, Berendse HW, Foncke E: Patterns of α-synuclein pathology in incidental cases and clinical subtypes of Parkinson's disease. Parkinsonism Relat Disord 2012;18(suppl 1):S28-S30.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.