Personalised Medicine and Parkinson's Disease: From Genes to Personality
Our concept of Parkinson’s disease (PD) has changed dramatically in the last 10 years and largely reverted to the original concept of the disorder as described by James Parkinson in his seminal essay of 1817. He described the “shaking palsy”, a condition associated with a multitude of motor and non-motor symptoms, which was named Parkinson’s disease (PD) by Charcot. (1) The visible and powerful response to levodopa treatment led research studies to focus on the dopaminergic aspects of PD for the last 50 years. As a result we have effective control of motor symptoms, however there is still no cure, no neuroprotection, and no effective medical treatment for troublesome dyskinesias and most non-motor symptoms. In some ways this therapeutic failure has been related to our lack of real understanding of the condition that James Parkinson described. We now know that PD is a multi-neurotransmitter dysfunction related disorder with multi-organ involvement resulting in a range of motor and non-motor symptoms. (1-3)
In addition, many external factors influence the treatment of PD and these include age, personality based preferences for treatment, cultural beliefs, lifestyle, pharmacogenetics, genetic susceptibility for development of PD and some non-motor symptoms as well as comorbidities.(4) Consideration of these factors is the basis of personalised medicine for PD and is the modern way forward.(4,5) These “enablers” constitute the true delivery of personalised medicine in PD and are shown in Figure 1. (Taken from Titova and Chaudhuri, 2017, Ref 4).
Figure 1. A circle of the various “enablers” of personalised medicine delivery. (Ref 4).
Table 1: The various different approaches that constitute delivery of personalised medicine in Parkinson’s disease. Taken from Titova et al (Ref 5)
Precision (Genomic) Medicine
For many, personalised medicine in PD means a genomic approach using precision based pathways.(6) For instance, there is increased frequency of PD in heterozygote carriers of the glucocerebrocidase gene (GBA) which constitutes the most common genetic mutation currently known in PD.(7) Carriers of the GBA mutation appear to be at increased risk for development of PD with cognitive decline. GBA mutation leads to abnormal glucocerebrocidase activity, which in turn may affect the accumulation of misfolded alpha-synuclein protein, thought to be the pathogenic source of PD. Chaperone proteins (heat shock protein (Hsp90)) are involved in this pathway and use of Hsp90 inhibitors is being investigated to examine whether misfolding of alpha-synuclein could be prevented. Related pharmacological agents such as ambroxol or isofagomine are currently in clinical trials as a precision medicine based approach to see if GBA positive cases could be prevented from progression to clinical PD.(8) The above example reflects a precision medicine based aspect of personalised medicine, which aims to address a specific genetic defect.
Pharmacogenetic Medicine
Pharmacogenetic aspects of personalised medicine in PD remains poorly explored. It is known that several genetic mutations and polymorphisms (the differences that naturally occur among human genes) may affect the pattern of response to dopamine replacement treatments in PD.(9) Some of the known links are shown in Table 2. Polymorphisms in several genes may affect how a patient responds to levodopa, whether they may develop dyskinesias or side effects such as daytime sleepiness or impulse control disorders. If this information were available, treatment could then be made specifically suited to the individual. For instance, the activity of the COMT gene that breaks down levodopa, has been shown to be different between Caucasian, African and South Asian subjects with PD. This phenomenon may explain racial differences in the effect of levodopa therapy and may in future dictate how levodopa doses needs to be adjusted. Low body weight has been considered a risk factor for development of levodopa induced dyskinesias and may also intertwine with racial phenotypes with lower body mass.10
However, the development and use of pharmacogenetic data requires much more exploration, and robust pharmacogenetic guidelines for the management of PD do not exist.(8)
Table 2: Pharmacogenetic principles that may underpin delivery of personalised medicine in Parkinson’s disease.
Subtype Specific Medicine
Non-motor subtyping of PD is a recent concept and a clinical realisation of the fact that many neurotransmitters are involved in PD and lead to clinical phenotypes not necessarily dominated by motor problems such as tremor, rigidity and bradykinesia. Recently work from the group of Chaudhuri et al has described the discrete non-motor symptoms dominant subtypes.(11.12) These subtypes (also known as endophenotypes) are likely to be related to significant non-dopaminergic dysfunction involving other chemicals in the brain such as acetylcholine, serotonin, and noradrenaline acting as neurotransmitters.(12,13)
Non-motor symptoms can be driven by cholinergic problems (associated with acetylcholine) clinically expressing as those who develop early memory and cognitive dysfunction, serotonergic problems where there may be considerable sleep disorder and fatigue or a noradrenergic syndrome when patients have predominantly autonomic sympotms.(4,5) In such patients recognition of the non-motor subtyping is important as a “one size fits all” dopamine replacement therapy paradigm for treatment will not be effective. Those with the sleep subtype may develop “sleep attacks” if given certain types of dopamine agonists and need to be recognised. Such patients, have a high risk of falling asleep while driving if prescribed dopamine agonists with a particular affinity for dopamine D3 receptor. Those with the cholinergic subtype would need early treatment with cholinesterase inhibitors. Thus, true individual delivery of treatment can be driven by non-motor subtyping in PD. However, the conventional treatment of PD still continues to be almost entirely reliant on dopamine replacement strategy and/or manipulation of brain dopaminergic pathways (such as with stereotactic surgery). This means that many non-dopaminergic symptoms remain largely untreated in spite of the enormous impact on the quality of life of PD patients and carers.(14)
Personality Driven Medicine
Another key area to consider is personality (Table 3) and clinical non-motor symptoms of PD. High anxiety states (neuroticism) may call for early management with continuous drug delivery so as to avoid non-motor fluctuations, which are usually associated with high anxiety states. On the other hand, many patients with levodopaphobia, an under-estimated problem, may need detailed counselling before any levodopa based treatment can be used. Such patients also need close monitoring regarding compliance once levodopa treatment is started. Other personality trends that lend to the risk of development of impulse control disorders have been described. In such patients dopamine agonists should either be avoided or need to be used with great caution and with regular clinical assessment.(15) Various personality based issues that will also need to be considered before PD treatment can be successfully initiated are shown in Table 3. These include non-acceptance of conventional treatment strategies for PD in those who believe only in complimentary or alternative medicine strategies, those who have had a past history of poor compliance with medicine, or those who have a history of substance abuse.
Table 3: Personality based aspects that may influence delivery of personalised medicine. Taken from Titova and Chaudhuri (Ref 4)
Lifestyle Specific Medicine
For the delivery of personalised medicine, other factors to consider are age and lifestyle. An active working person with PD may prefer a once daily non-oral medication to a three times a day oral drug (Figure 2). A working musician with PD on the other hand may prefer a “rescue” injection with apomporphine to enable him/her to perform on stage rather than take regular daily levodopa or other dopamine replacement therapies. Comorbidity (such as diabetes, osteoporosis, cardiovascular disease, helicobacter pylori related peptic ulcer) needs to be considered for effective and safe treatment with dopamine replacement therapies. As an example, diabetic PD patients maybe more prone to skin nodules from injection treatments, may suffer aggravation of postural hypotension when dopamine agonists are used and may have aggravation of diabetic poloyneuropathy with levodopa based treatments). Finally, the economic state of the country or health system is also important and can decide which treatments can actually be prescribed even though there may be expensive alternates.
Figure 2: Lifestyle based factors that may influence delivery of personalised medicine. Taken from Titova and Chaudhuri (Ref 8)
DRT = dopamine replacement therapy, LEDD = levodopa equivalent dose,
The creation of a personalised medicine checklist is long overdue and needs to be initiated so that treatment can be truly individualised in PD. This is essential as PD is a heterogeneous condition presenting with a complex medley of symptoms and signs, underpinned by a range of neurotransmitter dysfunction. Then there are genetic, personality based, ethnic and comorbid factors. Focusing purely on the dopaminergic system is misleading and PD management needs to address the non-dopaminergic aspects in conjunction with dopamine replacement therapy. Recognition of the non-motor subtypes of PD and its management remains a key unmet need. Personalising medicine, using the “enabling strands” as described in our circle of personalised medicine (Figure 1), should be an important way of delivering a holistic modern treatment of PD.
References:
1) Kalia LV, Lang AE. Parkinson's disease. Lancet 2015; 386(9996): 896-912.
2) Titova N, Padmakumar C, Lewis SJ, Chaudhuri KR. Parkinson's: a syndrome rather than a disease? J Neural Transm (Vienna) [published online ahead of print 2016 Dec 27]. doi: 10.1007/s00702-016-1667-6.
3) Jellinger KA. Neuropathobiology of non-motor symptoms in Parkinson disease. J Neural Transm (Vienna) 2015; 122(10): 1429-1440.
4) Titova N and Ray Chaudhuri K. Personalised medicine for Parkinson’s disease: time to be precise. Mov Disorders. 2017. DOI: 10.1002/mds.27027
5) Titova N, Jenner P, Ray Chaudhuri K. The future of Parkinson’s treatment: personalised and precision medicine. European Neurological Review 2017; 12(1).
6) American Medical Association. Genetics and personalised medicine. https://www.ama-assn.org/delivering-care/genetics-personalized-medicine. Accessed 10/04.17
7) Beavan MS, Schapira AH. Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. Ann Med 2013; 45(8): 511-521.
8) Beavan MS, Schapira AH. Glucocerebrosidase mutations and the pathogenesis of Parkinson disease. Ann Med 2013; 45(8): 511-521.
9) Lindpaintner K. Pharmacogenetics and the future of medical practice. Br J Clin Pharmacol 2002; 54(2): 221-230.
10) JC Sharma, M Vassallo. Prognostic significance of weight changes in Parkinson's disease: the Park–weight phenotype . Neurodegener Dis Manag. 4 (2014) 309-16.
11) Sauerbier A, Jenner P, Todorova A, Chaudhuri KR. Non motor subtypes and Parkinson's disease. Parkinsonism Relat Disord 2016; 22 Suppl 1: S41-46.
12) Marras C, Chaudhuri KR. Nonmotor features of Parkinson’s disease subtypes. Mov Disord 2016; 31(8): 1095-1102.
13) Sauerbier A, Qamar MA, Rajah T, Chaudhuri KR. New concepts in the pathogenesis and presentation of Parkinson's disease. Clin Med (Lond) 2016; 16(4): 365-370.
14) Martinez-Martin P, Rodriguez-Blazquez C, Kurtis MM, Chaudhuri KR; NMSS Validation Group. The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease. Mov Disord 2011;26(3):399-406. doi: 10.1002/mds.23462
15) Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol 2010; 67(5): 589-595.
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Nataliya Titova, MD, PhD is a senior researcher at the N.I. Pirogov Russian National Research Medical University in Moscow and also lead of the Personalised medicine programme as part of faculty of the National Parkinson Foundation Centre of Excellence at Kings College, London. She is also an active member of the Movement Disorders Society Parkinson’s disease nonmotor junior study group.
K Ray Chaudhuri, PhD is the Director of the National Parkinson Foundation Centre of Excellence at Kings College, London. and the Chairman of the MDS PD nonmotor study group. He served in the organising committee of the WPC meeting held in Portland in September 2016 and also was faculty speaker in past meetings at Montreal and Glasgow.
Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®.