The Personalized Parkinson Project: examining disease progression through broad biomarkers in early Parkinson's disease

B R Bloem, W J Marks Jr, A L Silva de Lima, M L Kuijf, T van Laar, B P F Jacobs, M M Verbeek, R C Helmich, B P van de Warrenburg, L J W Evers, J intHout, T van de Zande, T M Snyder, R Kapur, M J Meinders, B R Bloem, W J Marks Jr, A L Silva de Lima, M L Kuijf, T van Laar, B P F Jacobs, M M Verbeek, R C Helmich, B P van de Warrenburg, L J W Evers, J intHout, T van de Zande, T M Snyder, R Kapur, M J Meinders

Abstract

Background: Our understanding of the etiology, pathophysiology, phenotypic diversity, and progression of Parkinson's disease has stagnated. Consequently, patients do not receive the best care, leading to unnecessary disability, and to mounting costs for society. The Personalized Parkinson Project (PPP) proposes an unbiased approach to biomarker development with multiple biomarkers measured longitudinally. Our main aims are: (a) to perform a set of hypothesis-driven analyses on the comprehensive dataset, correlating established and novel biomarkers to the rate of disease progression and to treatment response; and (b) to create a widely accessible dataset for discovery of novel biomarkers and new targets for therapeutic interventions in Parkinson's disease.

Methods/design: This is a prospective, longitudinal, single-center cohort study. The cohort will comprise 650 persons with Parkinson's disease. The inclusion criteria are purposely broad: age ≥ 18 years; and disease duration ≤5 years. Participants are followed for 2 years, with three annual assessments at the study center. Outcomes include a clinical assessment (including motor and neuro-psychological tests), collection of biospecimens (stool, whole blood, and cerebrospinal fluid), magnetic resonance imaging (both structural and functional), and ECG recordings (both 12-lead and Holter). Additionally, collection of physiological and environmental data in daily life over 2 years will be enabled through the Verily Study Watch. All data are stored with polymorphic encryptions and pseudonyms, to guarantee the participants' privacy on the one hand, and to enable data sharing on the other. The data and biospecimens will become available for scientists to address Parkinson's disease-related research questions.

Discussion: The PPP has several distinguishing elements: all assessments are done in a single center; inclusion of "real life" subjects; deep and repeated multi-dimensional phenotyping; and continuous monitoring with a wearable device for 2 years. Also, the PPP is powered by privacy and security by design, allowing for data sharing with scientists worldwide respecting participants' privacy. The data are expected to open the way for important new insights, including identification of biomarkers to predict differences in prognosis and treatment response between patients. Our long-term aim is to improve existing treatments, develop new therapeutic approaches, and offer Parkinson's disease patients a more personalized disease management approach.

Trial registration: Clinical Trials NCT03364894 . Registered December 6, 2017 (retrospectively registered).

Keywords: Biomarkers; Cohort studies; Disease progression; Parkinson’s disease; Wearable device.

Conflict of interest statement

BRB, ALSdL, MLK, TvL, BPFJ, MMV, RCH, BPvdW, LJWE, JiH, TvdZ and MJM declare to have no competing interest.

WJM, TMS and RK are employees of, and equity holder in, Verily Life Sciences LLC.

For the sake of transparency, a full list of disclosures of the first author, Bastiaan R Bloem, is provided: BR Bloem currently serves as Associate Editor for the Journal of Parkinson’s disease, has received honoraria from serving on the scientific advisory board for Zambon and Kyowa Kirin, has received fees for speaking at conferences from AbbVie, Zambon and Bial, and has received research support from the Netherlands Organization for Scientific Research (NWO), the Michael J Fox Foundation for Parkinson’s Research, UCB, the Stichting Parkinson Fonds, the Hersenstichting Nederland, the Parkinson’s Foundation, Verily Life Sciences, Topsector Life Sciences and Health, and the Parkinson Vereniging.

Figures

Fig. 1
Fig. 1
The Verily Study Watch (an Investigational Device), along with syncing/charging cradle and Study Hub. The photographs are owned by Verily and have a copyright. Verily kindly granted written permission to use and adopt if for this publication

References

    1. De Lau LM, Breteler MM. Epidemiology of Parkinson's disease. Lancet Neurol. 2006;5(6):525–535. doi: 10.1016/S1474-4422(06)70471-9.
    1. Dorsey ER, Bloem BR. The Parkinson pandemic-a call to action. JAMA Neurol. 2018;75(1):9–10. doi: 10.1001/jamaneurol.2017.3299.
    1. Caligiore D, Helmich RC, Hallett M, Moustafa AA, Timmermann L, Toni I, Baldassarre G. Parkinson's disease as a system-level disorder. NPJ Parkinson’s Disease. 2016;2:16025. doi: 10.1038/npjparkd.2016.25.
    1. Kalia LV, Kalia SK, Lang AE. Disease-modifying strategies for Parkinson's disease. Mov Disord. 2015;30(11):1442–1450. doi: 10.1002/mds.26354.
    1. Marek K, Jennings D, Lasch S, Siderowf A, Tanner C, Simuni T, Coffey C, Kieburtz K, Flagg E, Chowdhury S. The parkinson progression marker initiative (PPMI) Prog Neurobiol. 2011;95(4):629–635. doi: 10.1016/j.pneurobio.2011.09.005.
    1. Stoeklé H-C, Mamzer-Bruneel M-F, Vogt G, Hervé C. 23andMe: a new two-sided data-banking market model. BMC medical ethics. 2016;17(1):19. doi: 10.1186/s12910-016-0101-9.
    1. Ding H, Sarokhan AK, Roderick SS, Bakshi R, Maher NE, Ashourian P, Kan CG, Chang S, Santarlasci A, Swords KE. Association of snca with parkinson: replication in the Harvard neurodiscovery center biomarker study. Mov Disord. 2011;26(12):2283–2286. doi: 10.1002/mds.23934.
    1. Okun MS, Siderowf A, Nutt JG, O’Conner GT, Bloem BR, Olmstead EM, Guttman M, Simuni T, Cheng E, Cohen EV. Piloting the NPF data-driven quality improvement initiative. Parkinsonism Relat Disord. 2010;16(8):517–521. doi: 10.1016/j.parkreldis.2010.06.005.
    1. Yarnall AJ, Breen DP, Duncan GW, Khoo TK, Coleman SY, Firbank MJ, Nombela C, Winder-Rhodes S, Evans JR, Rowe JB, et al. Characterizing mild cognitive impairment in incident Parkinson disease: the ICICLE-PD study. Neurology. 2014;82(4):308–316. doi: 10.1212/WNL.0000000000000066.
    1. Gaenslen A, Wurster I, Brockmann K, Huber H, Godau J, Faust B, Lerche S, Eschweiler GW, Maetzler W, Berg D. Prodromal features for Parkinson's disease--baseline data from the TREND study. Eur J Neurol. 2014;21(5):766–772. doi: 10.1111/ene.12382.
    1. Hipp G, Vaillant M, Diederich NJ, Roomp K, Satagopam VP, Banda P, Sandt E, Mommaerts K, Schmitz SK, Longhino L, et al. The Luxembourg Parkinson's study: a comprehensive approach for stratification and early diagnosis. Front Aging Neurosci. 2018;10:326. doi: 10.3389/fnagi.2018.00326.
    1. Lawton M, Baig F, Rolinski M, Ruffman C, Nithi K, May MT, Ben-Shlomo Y, Hu MT. Parkinson's disease subtypes in the Oxford Parkinson disease Centre (OPDC) discovery cohort. J Park Dis. 2015;5(2):269–279.
    1. Silva de Lima AL, Hahn T, LJW E, de Vries NM, Cohen E, Afek M, Bataille L, Daeschler M, Claes K, Boroojerdi B, et al. Feasibility of large-scale deployment of multiple wearable sensors in Parkinson's disease. PLoS One. 2017;12(12):e0189161. doi: 10.1371/journal.pone.0189161.
    1. Sturkenboom IH, Graff MJ, Hendriks JC, Veenhuizen Y, Munneke M, Bloem BR. Nijhuis-van der Sanden MW, group OTs: efficacy of occupational therapy for patients with Parkinson's disease: a randomised controlled trial. Lancet Neurol. 2014;13(6):557–566. doi: 10.1016/S1474-4422(14)70055-9.
    1. van der Marck MA, Munneke M, Mulleners W, Hoogerwaard EM, Borm GF, Overeem S. Bloem BR, group is: integrated multidisciplinary care in Parkinson's disease: a non-randomised, controlled trial (IMPACT) Lancet Neurol. 2013;12(10):947–956. doi: 10.1016/S1474-4422(13)70196-0.
    1. van Nimwegen M, Speelman AD, Overeem S, van de Warrenburg BP, Smulders K, Dontje ML, Borm GF, Backx FJ, Bloem BR, Munneke M, et al. Promotion of physical activity and fitness in sedentary patients with Parkinson's disease: randomised controlled trial. BMJ. 2013;346:f576. doi: 10.1136/bmj.f576.
    1. Bloem BR, Munneke M. Revolutionising management of chronic disease: the ParkinsonNet approach. BMJ. 2014;348:g1838. doi: 10.1136/bmj.g1838.
    1. Bloem BR, Rompen L, de Vries NM, Klink A, Munneke M, Jeurissen P. ParkinsonNet: a low-cost health care innovation with a systems approach from the Netherlands. Health Aff (Millwood) 2017;36(11):1987–1996. doi: 10.1377/hlthaff.2017.0832.
    1. Nijkrake MJ, Keus SH, Overeem S, Oostendorp RA, Vlieland TP, Mulleners W, Hoogerwaard EM, Bloem BR, Munneke M. The ParkinsonNet concept: development, implementation and initial experience. Mov Disord. 2010;25(7):823–829. doi: 10.1002/mds.22813.
    1. Alfaro-Almagro F, Jenkinson M, Bangerter NK, Andersson JLR, Griffanti L, Douaud G, Sotiropoulos SN, Jbabdi S, Hernandez-Fernandez M, Vallee E, et al. Image processing and quality control for the first 10,000 brain imaging datasets from UK biobank. Neuroimage. 2018;166:400–424. doi: 10.1016/j.neuroimage.2017.10.034.
    1. Miller KL, Alfaro-Almagro F, Bangerter NK, Thomas DL, Yacoub E, Xu J, Bartsch AJ, Jbabdi S, Sotiropoulos SN, Andersson JL, et al. Multimodal population brain imaging in the UK biobank prospective epidemiological study. Nat Neurosci. 2016;19(11):1523–1536. doi: 10.1038/nn.4393.
    1. Helmich RC, Janssen MJ, Oyen WJ, Bloem BR, Toni I. Pallidal dysfunction drives a cerebellothalamic circuit into Parkinson tremor. Ann Neurol. 2011;69(2):269–281. doi: 10.1002/ana.22361.
    1. Beck AT, Steer RA, Carbin MG. Psychometric properties of the Beck depression inventory: twenty-five years of evaluation. Clin Psychol Rev. 1988;8(1):77–100. doi: 10.1016/0272-7358(88)90050-5.
    1. Weintraub D, Mamikonyan E, Papay K, Shea JA, Xie SX, Siderowf A. Questionnaire for impulsive-compulsive disorders in Parkinson's disease–rating scale. Mov Disord. 2012;27(2):242–247. doi: 10.1002/mds.24023.
    1. Starkstein SE, Mayberg HS, Preziosi T, Andrezejewski P, Leiguarda R, Robinson R. Reliability, validity, and clinical correlates of apathy in Parkinson’s disease. J Neuropsychiatry Clin Neurosci. 1992;4(2):134–139. doi: 10.1176/jnp.4.2.134.
    1. Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacobs GA. Manual for the state-trait anxiety inventory. Palo Alto: Consulting Psychologists Press; 1983.
    1. Visser M, Marinus J, Stiggelbout AM, Van Hilten JJ. Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA-AUT. Mov Disord. 2004;19(11):1306–1312. doi: 10.1002/mds.20153.
    1. Marinus J, Visser M, van Hilten JJ, Lammers GJ, Stiggelbout AM. Assessment of sleep and sleepiness in Parkinson disease. Sleep. 2003;26(8):1049–1054. doi: 10.1093/sleep/26.8.1049.
    1. Stiasny-Kolster K, Mayer G, Schäfer S, Möller JC, Heinzel-Gutenbrunner M, Oertel WH. The REM sleep behavior disorder screening questionnaire—a new diagnostic instrument. Mov Disord. 2007;22(16):2386–2393. doi: 10.1002/mds.21740.
    1. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep. 1991;14(6):540–545. doi: 10.1093/sleep/14.6.540.
    1. Ware JE, Jr, Kosinski M, Keller SD. A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity. Med Care. 1996;34(3):220–233. doi: 10.1097/00005650-199603000-00003.
    1. Antonini A, Martinez-Martin P, Chaudhuri RK, Merello M, Hauser R, Katzenschlager R, Odin P, Stacy M, Stocchi F, Poewe W. Wearing-off scales in Parkinson's disease: critique and recommendations. Mov Disord. 2011;26(12):2169–2175. doi: 10.1002/mds.23875.
    1. Kalf JG, Borm GF, de Swart BJ, Bloem BR, Zwarts MJ, Munneke M. Reproducibility and validity of patient-rated assessment of speech, swallowing, and saliva control in Parkinson's disease. Arch Phys Med Rehabil. 2011;92(7):1152–1158. doi: 10.1016/j.apmr.2011.02.011.
    1. Project Baseline. . Accessed 23 May 2019.
    1. Verheul ER, Jacobs B, Meijer C, Hildebrandt M, de Ruiter J. Polymorphic encryption and Pseudonymisation for personalised healthcare. IACR Cryptology ePrint Archive. 2016;2016:411.
    1. Manders P, Siezen A, Gazzoli S, Smit C, Swinkels D, Zielhuis G. The Radboud biobank: a central facility for prospective clinical biobanking in the radboud university medical center, Nijmegen. Open Journal of Bioresour. 2014;5:2. doi: 10.5334/ojb.36.
    1. Goetz CG, Tilley BC, Shaftman SR, Stebbins GT, Fahn S, Martinez-Martin P, Poewe W, Sampaio C, Stern MB, Dodel R. Movement Disorder Society-sponsored revision of the unified Parkinson's disease rating scale (MDS-UPDRS): scale presentation and clinimetric testing results. Mov Disord. 2008;23(15):2129–2170. doi: 10.1002/mds.22340.
    1. Hoops S, Nazem S, Siderowf AD, Duda JE, Xie SX, Stern MB, Weintraub D. Validity of the MoCA and MMSE in the detection of MCI and dementia in Parkinson disease. Neurology. 2009;73(21):1738–1745. doi: 10.1212/WNL.0b013e3181c34b47.
    1. Hauser RA, Gordon MF, Mizuno Y, Poewe W, Barone P, Schapira AH, Rascol O, Debieuvre C, Frassdorf M. Minimal clinically important difference in Parkinson's disease as assessed in pivotal trials of pramipexole extended release. Parkinsons Dis. 2014;2014:467131.
    1. Horvath K, Aschermann Z, Acs P, Deli G, Janszky J, Komoly S, Balazs E, Takacs K, Karadi K, Kovacs N. Minimal clinically important difference on the motor examination part of MDS-UPDRS. Parkinsonism Relat Disord. 2015;21(12):1421–1426. doi: 10.1016/j.parkreldis.2015.10.006.
    1. Lucza T, Karadi K, Kallai J, Weintraut R, Janszky J, Makkos A, Komoly S, Kovacs N. Screening mild and major neurocognitive disorders in Parkinson's disease. Behav Neurol. 2015;2015:983606. doi: 10.1155/2015/983606.
    1. Pavlou M, Ambler G, Seaman SR, Guttmann O, Elliott P, King M, Omar RZ. How to develop a more accurate risk prediction model when there are few events. BMJ. 2015;351:h3868. doi: 10.1136/bmj.h3868.
    1. Litvan I, Goldman JG, Troster AI, Schmand BA, Weintraub D, Petersen RC, Mollenhauer B, Adler CH, Marder K, Williams-Gray CH, et al. Diagnostic criteria for mild cognitive impairment in Parkinson's disease: Movement Disorder Society task force guidelines. Mov Disord. 2012;27(3):349–356. doi: 10.1002/mds.24893.
    1. Wood K-L, Myall DJ, Livingston L, Melzer TR, Pitcher TL, MacAskill MR, Geurtsen GJ, Anderson TJ, Dalrymple-Alford JC. Different PD-MCI criteria and risk of dementia in Parkinson’s disease: 4-year longitudinal study. Npj Parkinson’s Disease. 2016;2:15027. doi: 10.1038/npjparkd.2015.27.
    1. Simuni T, Caspell-Garcia C, Coffey C, Lasch S, Tanner C, Marek K, Investigators P. How stable are Parkinson's disease subtypes in de novo patients: analysis of the PPMI cohort? Parkinsonism Relat Disord. 2016;28:62–67. doi: 10.1016/j.parkreldis.2016.04.027.
    1. Nalls MA, Keller MF, Hernandez DG, Chen L, Stone DJ, Singleton AB. Baseline genetic associations in the Parkinson's progression markers initiative (PPMI) Mov Disord. 2016;31(1):79–85. doi: 10.1002/mds.26374.
    1. Schrag A, Siddiqui UF, Anastasiou Z, Weintraub D, Schott JM. Clinical variables and biomarkers in prediction of cognitive impairment in patients with newly diagnosed Parkinson's disease: a cohort study. The Lancet Neurology. 2017;16(1):66–75. doi: 10.1016/S1474-4422(16)30328-3.
    1. Lerche S, Heinzel S, Alves G, Barone P, Behnke S, Ben-Shlomo Y, Berendse H, Bloem BR, Burn D, Dodel R, et al. Aiming for study comparability in Parkinson's disease: proposal for a modular set of biomarker assessments to be used in longitudinal studies. Front Aging Neurosci. 2016;8:121. doi: 10.3389/fnagi.2016.00121.

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