Extending our Understanding of the Dopaminergic Basis of Non-motor Symptoms in Parkinson’s Disease

European Neurological Review, 2015;10(1):23–7 DOI: http://doi.org/10.17925/ENR.2015.10.01.23

Abstract:

Parkinson’s disease (PD) is primarily considered as a motor disorder but there is increasing recognition of the wide range of non-motor symptoms (NMS), such as low mood, pain, apathy, fatigue and sleep problems, which may be experienced by PD patients across the spectrum of the disease. Notably, NMS often occur before motor symptoms develop and are known to place a significant burden on health-related quality of life (HRQoL) of the person with PD. Commonly, NMS go undiagnosed by the clinician and are therefore undertreated; however, to optimise patient outcomes, both motor and non-motor aspects of PD need to be recognised and managed effectively. The 10th International Congress on Non-Motor Dysfunctions in Parkinson’s Disease and Related Disorders held in Nice, France, in December 2014, offered the opportunity to look further into the dopaminergic basis of NMS and how this may affect clinical management. Britannia arranged an international faculty, chaired by Professor Amos Korczyn (Tel Aviv, Israel), to review the latest developments in our understanding of the underlying aetiology and clinical burden of non-motor features in PD that will ultimately help inform clinical practice. Surveys indicate that NMS have an extremely high prevalence among PD patients and evidence now suggests that it is the total ‘burden’ of NMS, combining frequency and severity, and not just the occurrence of individual NMS such as depression, which is the major determinant of a patient’s HRQoL. Recognising the significant contribution of NMS to the total clinical picture in PD, in order to provide a more comprehensive grading of PD severity, it is now proposed that the clinical assessment of PD patients needs a combined approach using for example the validated Non-motor Symptoms Scale (NMSS) to assess total NMS burden in addition to classic motor symptom scoring. Recent data from newly diagnosed PD patients also suggests there are different subtypes of PD that may have implications for both clinical trial design and the selection of therapy. Cognitive impairment often occurs in patients with PD, even in early disease, progressing to PD dementia in a substantial proportion of patients, which can limit therapeutic options. Posterior cortical dysfunction is a negative predictor of the progression of PD with mild cognitive impairment to PD dementia. Pronounced nigrostriatal denervation is characteristic of PD; however, cholinergic changes are also observed. Cholinergic depletion starts early in the disease process and by the time PD dementia develops patients will have a significant cholinergic deficit in various cortical regions. Current research is focused on the potential to reduce cognitive decline by decreasing beta-amyloid plaques.
Keywords: Parkinson’s disease (PD), non-motor symptoms, dopamine, cognitive impairment, apomorphine
Disclosure: Amos D Korczyn has received honoraria for sponsored symposia in educational meetings from Britannia. K Ray Chaudhuri has received honoraria for sponsored symposia in educational meetings from AbbVie, Britannia, Mundipharma, Otsuka, UCB and US WorldMeds. He has received educational grants from AbbVie, Britannia, Medtronic and UCB. Teus van Laar has received honoraria for sponsored symposia in educational meetings from AbbVie, Britannia, UCB and Medtronic.
Acknowledgments: Editorial assistance was provided by Dr Karen Wolstencroft, Helen Lawn Associates, supported by Britannia Pharmaceuticals Ltd.
Received: March 10, 2015 Accepted March 26, 2015
Correspondence: Amos D Korczyn, Department of Neurology, Tel Aviv University, Ramat Aviv 69978, Israel. E: amoskor@post.tau.ac.il

Support: The publication of this article was supported by Britannia Pharmaceuticals Ltd. The views and opinions expressed are those of the authors and not necessarily those of Britannia Pharmaceuticals Ltd.

Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.

Non-motor Symptoms in Parkinson’s Disease – Impact, Recognition and Management
K Ray Chaudhuri
Professor of Movement Disorders; Director, National Parkinson Foundation Centre of Excellence, Kings College, Denmark Hill Campus, London, UK


Professor Chaudhuri considered that non-motor symptoms (NMS) were an integral part of Parkinson’s disease (PD) and the leading cause of poor quality of life (QoL) in PD patients. The association of NMS with motor PD has been recognised since the disease was first identified – in his original essay on PD, James Parkinson described several non-motor issues, including sleepiness and autonomic dysfunction.1 NMS often pre-date motor symptoms by 10–15 years2–4 and research on this topic has revealed that late onset hyposmia and rapid eye movement sleep disorder are possible pre-motor markers of motor PD.5 In terms of the patient experience, evidence now suggests that it is the total ‘burden’ of NMS, not just the occurrence of individual NMS such as depression, that is the major determinant of health-related QoL (HRQoL) in PD patients.6 In the Sydney multicentre study, long-term follow-up of PD patients for 20 years found that they were often troubled to a greater extent by NMS than by motor symptoms.7 As a result, PD is now considered by some to be a neuropsychiatric disorder.

NMS are highly prevalent in PD patients and several studies have reported that almost all patients (>98 %) report some symptoms.3,8 Data accumulated from eight international studies including over 2,500 PD patients indicate that most PD patients will report at least eight different NMS when assessed using the validated Non-Motor Symptoms Questionnaire: NMSQuest.9

An evolving area of research in PD relates to different genetic forms of PD and how they relate to non-motor signs. At least 18 mutations in the synuclein alpha (SNCA) gene, one of the PARK family of genes known to be associated with PD, have been described. Analysis of SNCA missense mutations and multiplications, albeit in a relatively small number of PD patients, has suggested that dementia is a marker for this genetic form of PD.10 LRRK2 (leucine-rich repeat kinase 2, another of the PARK gene family) mutations on the other hand are commonly associated with sleep disorders. LRRK2 mutation carriers often have a marked degree of insomnia, including disturbed sleep patterns with repeated wakening, a troubling form of restless leg syndrome and a high frequency of early morning ‘off’ periods. Variations in the GBA (glucosidase beta acid) gene are commonly seen in PD and parkinsonism. GBA mutations seem to be associated with autonomic issues, dementia and hallucinations, and patients often have a high degree of anxiety and depression. These emerging data on the non-motor markers of genetic subtypes of PD may help refine treatment strategies in the future.

References:
  1. Parkinson J, Essay on the shaking palsy, London: Sherwood, Neely and Jones, 1817.
  2. Chaudhuri KR, Healy DG, Schapira AH, Non-motor symptoms of Parkinson’s disease: diagnosis and management, Lancet Neurol, 2006;5:235–45.
  3. Barone P, Antonini A, Colosimo C, et al., The PRIAMO study: A multicenter assessment of nonmotor symptoms and their impact on quality of life in Parkinson’s disease, Mov Disord, 2009;24:1641–9.
  4. Zis P, Rizos A, Martinez-Martin P, et al., Non-motor symptoms profile and burden in drug naive versus long-term Parkinson’s disease patients, J Parkinsons Dis, 2014;4:541–7.
  5. Chen H, Burton EA, Ross GW, et al., Research on the premotor symptoms of Parkinson’s disease: clinical and etiological implications, Environ Health Perspect, 2013;121:1245–52.
  6. Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR, The impact of non-motor symptoms on healthrelated quality of life of patients with Parkinson’s disease, Mov Disord, 2011;26:399–406.
  7. Hely MA, Reid WG, Adena MA, et al., The Sydney multicenter study of Parkinson’s disease: the inevitability of dementia at 20 years, Mov Disord, 2008;23:837–44.
  8. Ray Chaudhuri K, Rojo JM, Schapira AH, et al., A proposal for a comprehensive grading of Parkinson’s disease severity combining motor and non-motor assessments: meeting an unmet need, PloS One, 2013;8:e57221.
  9. Todorova A, Jenner P, Ray Chaudhuri K, Non-motor Parkinson’s: integral to motor Parkinson’s, yet often neglected, Pract Neurol, 2014;14:310–22.
  10. Kasten M, Klein C, Chapter 7. Non-motor signs in genetic forms of Parkinson’s disease. In: Chaudhuri KR, Tolosa E, Schapira AHV, Poewe W, editors, Non Motor Symptoms of Parkinson’s Disease, Second ed., Oxford: Oxford University Press, 2014.
  11. Berg D, Postuma RB, Bloem B, et al., Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson’s disease, Mov Disord, 2014;29:454–62.
  12. Stern MB, Lang A, Poewe W, Toward a redefinition of Parkinson’s disease, Mov Disord, 2012;27:54–60.
  13. Martinez-Martin P, Rodriguez-Blazquez C, Abe K, et al., International study on the psychometric attributes of the non-motor symptoms scale in Parkinson disease, Neurology, 2009;73:1584–91.
  14. Halliday GM, Leverenz JB, Schneider JS, Adler CH, The neurobiological basis of cognitive impairment in Parkinson’s disease, Mov Disord, 2014;29:634–50.
  15. Erro R, Vitale C, Amboni M, et al., The heterogeneity of early Parkinson’s disease: a cluster analysis on newly diagnosed untreated patients, PloS One, 2013;8:e70244.
  16. Halliday G, Lees A, Stern M, Milestones in Parkinson’s disease – clinical and pathologic features, Mov Disord, 2011;26:1015–21.
  17. Gasca-Salas C, Estanga A, Clavero P, et al., Longitudinal assessment of the pattern of cognitive decline in nondemented patients with advanced Parkinson’s disease, J Parkinsons Dis, 2014;4:677–86.
  18. Williams-Gray CH, Mason SL, Evans JR, et al., The CamPaIGN study of Parkinson’s disease: 10-year outlook in an incident population-based cohort, J Neurol Neurosurg Psychiatry, 2013;84:1258–64.
  19. Braak H, Ghebremedhin E, Rub U, et al., Stages in the development of Parkinson’s disease-related pathology, Cell Tissue Res, 2004;318:121–34.
  20. Petrou M, Bohnen NI, Muller ML, et al., Abeta-amyloid deposition in patients with Parkinson disease at risk for development of dementia, Neurology, 2012;79:1161–7.
  21. Muller ML, Frey KA, Petrou M, et al., beta-Amyloid and postural instability and gait difficulty in Parkinson’s disease at risk for dementia, Mov Disord, 2013;28:296–301.
  22. Hilker R, Thomas AV, Klein JC, et al., Dementia in Parkinson disease: functional imaging of cholinergic and dopaminergic pathways, Neurology, 2005;65:1716–22.
  23. Bohnen NI, Muller ML, Kotagal V, et al., Olfactory dysfunction, central cholinergic integrity and cognitive impairment in Parkinson’s disease, Brain, 2010;133(Pt 6):1747–54.
  24. Kotagal V, Albin RL, Muller ML, et al., Symptoms of rapid eye movement sleep behavior disorder are associated with cholinergic denervation in Parkinson disease, Ann Neurol, 2012;71:560–8.
  25. Alves G, Larsen JP, Emre M, et al., Changes in motor subtype and risk for incident dementia in Parkinson’s disease, Mov Disord, 2006;21:1123–30.
  26. Williams-Gray CH, Evans JR, Goris A, et al., The distinct cognitive syndromes of Parkinson’s disease: 5 year follow-up of the CamPaIGN cohort, Brain, 2009;132(Pt 11):2958–69.
  27. van Laar T, Postma AG, Drent M, Continuous subcutaneous infusion of apomorphine can be used safely in patients with Parkinson’s disease and pre-existing visual hallucinations, Parkinsonism Relat Disord, 2010;16:71–2.
  28. Yarnall AJ, Lashley T, Ling H, et al., Apomorphine: A potential modifier of amyloid deposition in Parkinson’s disease? 17th International Congress of Parkinson’s Disease and Movement Disorders. Sydney, Australia, 2013.
  29. Weintraub D, Doshi J, Koka D, et al., Neurodegeneration across stages of cognitive decline in Parkinson disease, Arch Neurol, 2011;68:1562–8.
  30. Melzer TR, Watts R, MacAskill MR et al. Grey matter atrophy in cognitively impaired Parkinson’s disease, J Neurol Neurosurg Psychiatry, 2012;83:188–94.
Keywords: Parkinson’s disease (PD), non-motor symptoms, dopamine, cognitive impairment, apomorphine