Nonmotor and diagnostic findings in subjects with de novo Parkinson disease of the DeNoPa cohort
Abstract
Objective:
To determine nonmotor signs (NMS) and evaluate the utility of several diagnostic tools in patients with de novo Parkinson disease (PD).
Methods:
This is a large single-center study of the DeNoPa cohort, including frequency-matched healthy controls. This study covers motor signs, NMS, and a combination of diagnostic tests including olfactory testing, transcranial sonography of substantia nigra (TCS), and polysomnography (PSG). We report the frequency and characteristics of NMS and the outcomes of nonmotor tests at the time of diagnosis.
Results:
Cross-sectional analyses of baseline investigations identified significant differences in the NMS Questionnaire (NMSQuest) and the Scopa-AUT Gastrointestinal score in 159 drug-naïve PD patients vs 110 controls. In addition, patients with PD showed reduced olfactory function, hyperechogenicity on TCS, and higher frequency of REM sleep behavior disorder (RBD). In exploring predictive markers, we found that the combination of several investigations, i.e., the NMSQuest, Scopa-AUT Gastrointestinal score, and Smell Identification Test reached an area under the receiver operating characteristic curve (AUC) of 0.913 (95% confidence interval [CI] 0.878–0.948). With the addition of serum cholesterol and mean heart rate values, the AUC value reached 0.919 (95% CI 886–0.953); when TCS and PSG were added, the AUC increased to 0.963 (95% CI 0.943–0.982).
Conclusions:
We show feasibility and utility of standardized data acquisition in a large, single-center cohort of patients with de novo PD and matched healthy controls. The baseline results from our prospective investigations reached a value of >0.9 sensitivity and specificity for biological markers when we added routine laboratory investigations and quantified nonmotor features including sleep.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
REFERENCES
1.
Hughes AJ, Daniel SE, Blankson S, Lees AJ. A clinicopathologic study of 100 cases of Parkinson's disease. Arch Neurol 1993;50:140–148.
2.
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.
3.
Savica R, Carlin JM, Grossardt BR, et al. Medical records documentation of constipation preceding Parkinson disease: a case-control study. Neurology 2009;73:1752–1758.
4.
Morley JF, Duda JE. Olfaction as a biomarker in Parkinson's disease. Biomark Med 2010;4:661–670.
5.
van Rooden SM, Colas F, Martinez-Martin P, et al. Clinical subtypes of Parkinson's disease. Mov Disord 2011;26:51–58.
6.
Ray Chaudhuri K, Rojo JM, Schapira AV, et al. A proposal for a comprehensive gradation of Parkinson's disease severity combining motor and non motor assessments: meeting the unmet need. PLOS One 2013;8:e57221.
7.
Aarsland D, Bronnick K, Larsen JP, Tysnes OB, Alves G. Cognitive impairment in incident, untreated Parkinson disease: the Norwegian ParkWest study. Neurology 2009;72:1121–1126.
8.
Muller B, Larsen JP, Wentzel-Larsen T, Skeie GO, Tysnes OB. Autonomic and sensory symptoms and signs in incident, untreated Parkinson's disease: frequent but mild. Mov Disord 2011;26:65–72.
9.
Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197–211.
10.
Del Tredici K, Braak H. Lewy pathology and neurodegeneration in premotor Parkinson's disease. Mov Disord 2012;27:597–607.
11.
Chaudhuri KR, Martinez-Martin P. Quantitation of non-motor symptoms in Parkinson's disease. Eur J Neurol 2008;15(suppl 2):2–7.
12.
Hely MA, Reid WG, Adena MA, Halliday GM, Morris JG. The Sydney multicenter study of Parkinson's disease: the inevitability of dementia at 20 years. Mov Disord 2008;23:837–844.
13.
Gilman S, Low P, Quinn N, et al. Consensus statement on the diagnosis of multiple system atrophy: American Autonomic Society and American Academy of Neurology. Clin Auton Res 1998;8:359–362.
14.
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.
15.
Gordis L. Epidemiology, 3rd ed. Philadelphia: Elsevier Saunders; 2004.
16.
Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Mov Disord 2007;22:2314–2324.
17.
Emre M, Aarsland D, Brown R, et al. Clinical diagnostic criteria for dementia associated with Parkinson's disease. Mov Disord 2007;22:1689–1707.
18.
Chaudhuri KR, Martinez-Martin P, Brown RG, et al. The metric properties of a novel non-motor symptoms scale for Parkinson's disease: results from an international pilot study. Mov Disord 2007;22:1901–1911.
19.
Chaudhuri KR, Martinez-Martin P, Schapira AH, et al. International multicenter pilot study of the first comprehensive self-completed nonmotor symptoms questionnaire for Parkinson's disease: the NMSQuest study. Mov Disord 2006;21:916–923.
20.
Visser M, Marinus J, Stiggelbout AM, Van Hilten JJ. Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA-AUT. Mov Disord 2004;19:1306–1312.
21.
Trenkwalder C, Kohnen R, Hogl B, et al. Parkinson's Disease Sleep Scale: validation of the revised version PDSS-2. Mov Disord 2011;26:644–652.
22.
Stiasny-Kolster K, Mayer G, Schafer S, Moller JC, Heinzel-Gutenbrunner M, Oertel WH. The REM sleep behavior disorder screening questionnaire: a new diagnostic instrument. Mov Disord 2007;22:2386–2393.
23.
Damiano AM, McGrath MM, Willian MK, et al. Evaluation of a measurement strategy for Parkinson's disease: assessing patient health-related quality of life. Qual Life Res 2000;9:87–100.
24.
Kim HJ, Park SY, Cho YJ, et al. Nonmotor symptoms in de novo Parkinson disease before and after dopaminergic treatment. J Neurol Sci 2009;287:200–204.
25.
Chaudhuri KR, Healy DG, Schapira AV. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 2006;5:235–245.
26.
Tissingh G, Berendse HW, Bergmans P, et al. Loss of olfaction in de novo and treated Parkinson's disease: possible implications for early diagnosis. Mov Disord 2001;16:41–46.
27.
Doty RL. Olfaction in Parkinson's disease. Parkinsonism Relat Disord 2007;13(suppl 3):S225–S228.
28.
Ponsen MM, Stoffers D, Booij J, van Eck-Smit BL, Wolters E, Berendse HW. Idiopathic hyposmia as a preclinical sign of Parkinson's disease. Ann Neurol 2004;56:173–181.
29.
Buob A, Winter H, Kindermann M, et al. Parasympathetic but not sympathetic cardiac dysfunction at early stages of Parkinson's disease. Clin Res Cardiol 2010;99:701–706.
30.
Valappil RA, Black JE, Broderick MJ, et al. Exploring the electrocardiogram as a potential tool to screen for premotor Parkinson's disease. Mov Disord 2010;25:2296–2303.
31.
Ikeda K, Nakamura Y, Kiyozuka T, et al. Serological profiles of urate, paraoxonase-1, ferritin and lipid in Parkinson's disease: changes linked to disease progression. Neurodegener Dis 2011;8:252–258.
32.
Cereda E, Cassani E, Barichella M, et al. Low cardiometabolic risk in Parkinson's disease is independent of nutritional status, body composition and fat distribution. Clin Nutr 2012;31:699–704.
33.
Liu JP, Tang Y, Zhou S, Toh BH, McLean C, Li H. Cholesterol involvement in the pathogenesis of neurodegenerative diseases. Mol Cell Neurosci 2010;43:33–42.
34.
Gaenslen A, Unmuth B, Godau J, et al. The specificity and sensitivity of transcranial ultrasound in the differential diagnosis of Parkinson's disease: a prospective blinded study. Lancet Neurol 2008;7:417–424.
35.
Sixel-Döring F, Trautmann E, Mollenhauer B, Trenkwalder C. Rapid eye movement sleep behavioral events: a new marker for neurodegeneration in early Parkinson's disease? Sleep (in press 2013).
36.
American Academy of Sleep Medicine. REM Sleep Behavior Disorder. In: The International Classification of Sleep Disorders Diagnostic and Coding Manual, 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005:148–152.
37.
Schenck CH, Boeve BF, Mahowald MW. Delayed Emergence of a Parkinsonian disorder or dementia in 81% of older males initially diagnosed with idiopathic REM sleep behavior disorder (RBD): 16 year update on a previously reported series. Sleep Med (in press 2013).
38.
Iranzo A, Tolosa E, Gelpi E, et al. Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study. Lancet Neurol 2013;12:443–453.
39.
Braak H, Rub U, Gai WP, Del Tredici K. Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 2003;110:517–536.
40.
Jellinger KA. Synuclein deposition and non-motor symptoms in Parkinson disease. J Neurol Sci 2011;310:107–111.
Information & Authors
Information
Published In
Copyright
© 2013 American Academy of Neurology.
Publication History
Received: March 28, 2013
Accepted: July 1, 2013
Published online: August 30, 2013
Published in print: October 1, 2013
Disclosure
Dr. Mollenhauer has received speaker honoraria from Orion Corporation and GlaxoSmithKline; serves as an Associate Editor for the Journal of Alzheimer Disease; holds or has pending patents re: Method of differentially diagnosing dementias, Novel ELISA-based quantification of α-synuclein proteins in CSF and peripheral blood products using 384-well plates and MicroRNA expression profiling of CSF. She serves as a consultant for Bayer Schering Pharma AG and receives research support from Teva Pharmaceutical Industries Ltd., Desitin Pharmaceuticals, GmbH, Boehringer Ingelheim, GE Healthcare, the Michael J. Fox Foundation for Parkinson's Research, the American Parkinson's Disease Association, the Stifterverband für die Deutsche Wissenschaft (Dr. Werner Jackstädt-Stipend), and BMBF. Dr. Trautmann reports no disclosures. Dr. Sixel-Döring serves/has served on scientific advisory boards for Orion Corporation and Medtronic, Inc.; has received funding for travel from Boehringer Ingelheim; and has received speaker honoraria from Boehringer Ingelheim, Cephalon, Inc., Medtronic, Inc., Solvay Pharmaceuticals, Inc., UCB, and Orion Corporation. T. Wicke, Dr. Ebentheuer, M. Schaumburg, and E. Lang report no disclosures. Dr. Focke received funding from the Stifterverband für die Deutsche Wissenschaft (Dr. Werner Jackstädt-Stipend); served in an advisory board for GE Healthcare; and received honoraria from GlaxoSmithKline and travel support from UCB/Schwarz Pharma. Dr. Kumar has received a Movement Disorders Society Travel Grant (2012) and is a recipient of the National Health and Medical Research Council (NHMRC) of Australia Dora Lush Postgraduate Scholarship. Dr. Lohmann receives funding from the German Research Foundation. Dr. Klein is a member of the editorial board of Neurology® and has served as editor of the Continuum Issue Neurogenetics 2008 and as faculty at the annual meetings of the American Academy of Neurology since 2004. She has received consulting fees from Boehringer Ingelheim and Centogene and has received honoraria for speaking from Boehringer Ingelheim and Merz Pharma. She is the recipient of a career development award from the Hermann and Lilly Schilling Foundation. She is funded by the Volkswagen Foundation, the Deutsche Forschungsgemeinschaft, the Possehl Foundation, and received institutional support from the University of Luebeck for genetics research. Dr. Schlossmacher has received grants from the Michael J. Fox Foundation for Parkinson's Research, the Parkinson Research Consortium Ottawa, and the Government of Canada (CRC/CFI) and has served as an ad hoc, paid consultant for FoldRx, Genzyme Inc., Johnson & Johnson, Amicus Therapeutics, Elan Pharmaceuticals, Novartis Inc., and LINK Medicine. He has received lecture honoraria from Teva Neuroscience and has a scientific collaboration with Covance Inc, Epitomics Inc, and the Michael J. Fox Foundation. Dr. Kohnen has served on scientific advisory boards for UCB, Pfizer, and Mundipharma International Limited. T. Friede is an Associate Editor of Biometrical Journal and BMC Medical Research Methodology, a member of the Editorial Board of Therapeutic Innovation & Regulatory Science (formerly known as the Drug Information Journal), and an Academic Editor of PLOS One. He has acted or acts as a consultant to Novartis Pharma AG, Pharmalog Institut für Klinische Forschung GmbH, Biogen Idec, CSL Behring, Tibotec, and Schering Plough (Merck). He has received research funding from Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, and the Executive Agency for Health and Consumers. Dr. Trenkwalder serves on scientific advisory boards for Teva Pharma, Boehringer Ingelheim, UCB, Novartis, Mundipharma International Limited, and Britannia. She has received speaker honoraria from Boehringer Ingelheim, UCB, Novartis, and GlaxoSmithKline and serves on the editorial board and as guest editor of Sleep Medicine, CNS Drugs, and Movement Disorders. She receives research support from Teva Pharmaceutical Industries Ltd. and Mundipharma International Limited. Go to Neurology.org for full disclosures.
Study Funding
Supported by unrestricted research grants from the Paracelsus-Elena-Klinik, Kassel, Germany, and unrestricted research grants from TEVA Pharma/Lundbeck, GE Health care, and the Hermann und Lilly Schilling Foundation. The study sponsors provided support through an unrestricted grant and had no influence on the study design, collection and analysis of data, the writing of the paper, or the decision to submit the paper. The sponsors have been informed about the final manuscript and the submission for publication.
Authors
Author Contributions
B.M., F.S.D., and C.T. designed the study and were responsible for recruitment and data processing. E.T. and T.F. oversaw all statistical analyses. T.W., J.E., E.T., M.S., E.L., and N.K.F. were responsible for performing investigations and collecting and entering data. K.R.K., K.L., and C.K. performed genetic analyses and assisted in data interpretation. N.K. and M.G.S. were involved in sample analyses and data interpretation. C.T. oversaw patient recruitment and characterization and assisted in the interpretation of data. B.M., C.T., and E.T. wrote the manuscript. F.S.-D., M.G.S., T.F., C.K., R.K., and K.L. coedited the manuscript. B.M., C.T., and F.S.-D. had full access to the clinical primary data. B.M. and E.T. have full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors had access to the data generated in the study including the statistical analysis and decided to submit the paper for publication.
Metrics & Citations
Metrics
Citations
Download Citations
If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Select your manager software from the list below and click Download.
Cited By
- Krankheitsbedingte Zugangsbarrieren im Alter, E-Health für ältere Menschen: Deutsche Leichte Sprache als Türöffner, (75-99), (2024).https://doi.org/10.57088/978-3-7329-8888-4_5
- Cerebellar involvement in Parkinson’s disease: Pathophysiology and neuroimaging, Chinese Medical Journal, (2024).https://doi.org/10.1097/CM9.0000000000003248
- Lysosomal and synaptic dysfunction markers in longitudinal cerebrospinal fluid of de novo Parkinson’s disease, npj Parkinson's Disease, 10, 1, (2024).https://doi.org/10.1038/s41531-024-00714-1
- Progression subtypes in Parkinson’s disease identified by a data-driven multi cohort analysis, npj Parkinson's Disease, 10, 1, (2024).https://doi.org/10.1038/s41531-024-00712-3
- Genetic and phenotypic characterization of Parkinson’s disease at the clinic-wide level, npj Parkinson's Disease, 10, 1, (2024).https://doi.org/10.1038/s41531-024-00690-6
- Sleep disorders in Parkinson’s disease, an early and multiple problem, npj Parkinson's Disease, 10, 1, (2024).https://doi.org/10.1038/s41531-024-00642-0
- Plasma proteomics identify biomarkers predicting Parkinson’s disease up to 7 years before symptom onset, Nature Communications, 15, 1, (2024).https://doi.org/10.1038/s41467-024-48961-3
- The STRAT-PARK cohort: A personalized initiative to stratify Parkinson’s disease, Progress in Neurobiology, 236, (102603), (2024).https://doi.org/10.1016/j.pneurobio.2024.102603
- Parkinson's Disease, Diagnosis, Reference Module in Neuroscience and Biobehavioral Psychology, (2024).https://doi.org/10.1016/B978-0-323-95702-1.00196-2
- Clinical Evaluation of Sleep Disorders in Parkinson’s Disease, Brain Sciences, 13, 4, (609), (2023).https://doi.org/10.3390/brainsci13040609
- See more
Loading...
View Options
Get Access
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Personal login Institutional LoginPurchase Options
The neurology.org payment platform is currently offline. Our technical team is working as quickly as possible to restore service.
If you need immediate support or to place an order, please call or email customer service:
- 1-800-638-3030 for U.S. customers - 8:30 - 7 pm ET (M-F)
- 1-301-223-2300 for customers outside the U.S. - 8:30 - 7 pm ET (M-F)
- [email protected]
We appreciate your patience during this time and apologize for any inconvenience.