Cutting Edge Science for Parkinson’s Clinicians is a partnership educational meeting sponsored by Bial Pharma UK Ltd, and designed and delivered by the Parkinson’s Academy. The theme of this two day meeting was to ‘Question everything’, to review what we already know, and to think about how clinical observations and crossteam collaborations can drive us forward.
Taking a tongue in cheek approach, the Coventry & Warwickshire team reviewed how Parkinson’s treatment has changed over time. Ancient texts show that Ayurvedic, Chinese and Greek practitioners clearly understood the clinical presentations of tremor, rigidity, slowness, gait disturbance, dementia and depression as a symptom complex. They often already used plant-medicines, including mucuna pruriens, which contains levodopa,1 and is still used today by patients seeking ‘alternative’ treatments. Skipping forward, the team reviewed how leading luminaries such as Charcot used astute observations to start to define Parkinson’s for the modern day. The observations of Oliver Sacks of using levodopa for post-encephalitic parkinsonism have been made famous by the book Awakenings, but it is less appreciated that Oliver Sacks was also one of the first neurologists to warn about high doses of levodopa and the development of dyskinesia.2
The importance of collaboration was underscored by Professor Bastiaan Bloem who noted that while the importance of the multidisciplinary team (MDT) in the management of PD is something often bandied about, it generally refers to a neurologist, together with a nurse specialist and perhaps some physical and/or occupational therapy. However, Professor Bloem argued that the definition of the MDT should be expanded to reflect the modern understanding of Parkinson’s as a multi-system disease. For example, dependent on need, relevant clinicians should include a gastroenterologist, pulmonologist, neuro-ophthalmologist, dentist etc.3 In his comprehensive review of the effectiveness of physical therapies, Professor Bloem noted that the effectiveness of a number of different physical therapy approaches in PD has been established,4 and there is now Level II evidence for occupational therapy.5
Understanding Parkinson’s as a multifactorial disease not only affects how it should be treated, but also provides a smorgasbord of mechanisms which can be tested for their efficacy. Dr Simon Stott reviewed the current approaches to targeting disease mechanisms in Parkinson’s including immunotherapy, immunomodulation, LRRK2 inhibition, GLP1 agonists, neurotrophic factors and cell replacement. Dr Stott advocated for a field which understands Parkinson’s as a syndrome and suggested that understanding of the prodrome should help subtype the syndrome and open the door to developing tailored ‘precision’ medicine.6
Research into prodromal Parkinson’s is indeed rapidly growing, as many believe this period will be the main target for disease-modifying medications. Dr Alistair Noyce reviewed the wealth of evidence now supporting the idea of constipation, REM behavioural disorder, urinary dysfunction, as well as anxiety and depression as key features of this ‘pre-diagnostic’ phase.7 Individually they do not allow a diagnosis of PD, but when considered together, they reflect the gradual development of the clinical syndrome. He described the ongoing PREDICT-HD study which uses an algorithm to identify indicators of PD risk.8 The study is actively recruiting, looking for healthy people aged 60–80 years, who have access to the Internet, and do not have a current diagnosis of PD.
Taking on the theme of precision medicine based on genomic subtypes, Dr Camille Carroll described research into the role of homocysteine. Epidemiological evidence has clearly linked homocysteine elevation to an increased risk of coronary artery disease, stroke, and dementia. In Parkinson’s, administration of levodopa drives up homocysteine levels via the COMT pathway,9 and is associated with worse outcomes in terms of mood and cognition.10 Studies in Parkinson’s patients have shown that gene polymorphisms are related to plasma homocysteine concentration, with one genotype having much higher plasma levels than others.11 Dr Carroll discussed that while an early study showed that vitamin B supplementation, but not the COMT inhibitor entacapone, reduced homocysteine levels compared to placebo,12 the study was not enriched for the higher-risk genotypes and was too short to be able to show any impacts on cognition or mood. She proposed that it may be time to revisit the homocysteine story and evaluate how it may play into the ideas of precision medicine in PD. For example, should patients with the higher-risk polymorphism be proactively treated with Vitamin B and perhaps the new COMT inhibitor opicapone? Controlled trials would be needed to address this question.
Dr Alan Whone opened his presentation of the pioneering Bristol GDNF study by noting that, while the study did not meet its primary endpoint,13 many interesting findings can be realised in the data, and it would be wrong to view this study as a failure. This was the first trial to use the specially developed delivery system direct to the putamen. The system was shown to be safe over 80 weeks, and is now being used in two new trials; one evaluating cerebral dopamine neurotrophic factor, and one for children with brain tumours. Dr Whone also highlighted the issue of subgroups. While the differences in clinical outcome between the GDNF and placebo groups were statistically indistinguishable, there was a relatively large variation in response. Of note, nine patients in the GDNF group, but none in the placebo group improved by more than 35%, although some did not improve at all. Understanding which patients responded best will be an important step forward.
In her presentation, Professor Iracema Leroi highlighted that neuropsychiatric symptoms (dementia, psychosis, depression, anxiety, apathy and impulse control disorders etc) in Parkinson’s are so common, the disease is more accurately described as a neuropsychiatric disorder.14 Psychosis and dementia frequently co-exist, and the development of one often heralds the advent of the other.15 Together, they are associated with poorer quality of life, increased morbidity and mortality, and increased caregiver burden and nursing home placement.16 Cognitive stimulation therapy (CST) is an evidence-based psychosocial intervention that involves engaging and cognitively stimulating activities and discussions based on principles of errorless learning and validation. PD-CST is an individualised form of this treatment specifically for people with parkinsonian syndromes to be delivered by their care partners at home.17
“Increasing age is the main non-modifiable risk for Parkinson’s. It is also the main risk factor for frailty” said Professor Richard Walker as he started his presentation. Hospital admission data shows that patients with PD are almost twice as likely to stay in hospital for more than 3 months, and even more likely to die in hospital, than other patients.18 The main reasons for admission include pneumonia, motor decline, urinary tract infection and hip fractures. One way to assess frailty is the frailty phenotype19, where frailty is defined as a clinical syndrome in which ≥3 of the following five criteria are present: unintentional weight loss (10lb in past year), self-reported exhaustion, weakness (grip strength), slow walking speed and/or low physical activity. As Professor Walker observed, some of these are manageable, or even preventable, with good care.
For more information about future Cutting Edge Science for Parkinson’s Clinicians events, see neurologyacademy.org
- Manyam BV. Paralysis agitans and levodopa in “Ayurveda”: ancient Indian medical treatise. Mov Disord 1990;5(1):47-48.
- Santos-Lobato BL, Tumas V. Harbinger of storm: influence of Oliver Sacks on levodopa therapy in early 1970s. Arq Neuropsiquiatr 2016;74(8):687- 689.
- Radder DLM, de Vries NM, Riksen NP, et al. Multidisciplinary care for people with Parkinson’s disease: the new kids on the block! Expert Rev Neurother 2019;19(2):145-157.
- Bloem BR, de Vries NM, Ebersbach G. Nonpharmacological treatments for patients with Parkinson’s disease. Mov Disord 2015;30(11):1504-1520.
- Sturkenboom IH, Graff MJ, Hendriks JC, et al. Efficacy of occupational therapy for patients with Parkinson’s disease: a randomised controlled trial. Lancet Neurol 2014;13(6):557-566.
- Titova N, Chaudhuri KR. Personalized medicine in Parkinson’s disease: Time to be precise. Mov Disord 2017;32(8):1147-1154.
- Schrag A, Horsfall L, Walters K, Noyce A, Petersen I. Prediagnostic presentations of Parkinson’s disease in primary care: a case-control study. Lancet Neurol 2015;14(1):57-64.
- Noyce AJ, R’Bibo L, Peress L, et al. PREDICT-PD: An online approach to prospectively identify risk indicators of Parkinson’s disease. Mov Disord 2017;32(2):219-226.
- Hu XW, Qin SM, Li D, Hu LF, Liu CF. Elevated homocysteine levels in levodopa-treated idiopathic Parkinson’s disease: a meta-analysis. Acta Neurol Scand 2013;128(2):73-82.
- Christine CW, Auinger P, Joslin A, Yelpaala Y, Green R, Parkinson Study Group DI. Vitamin B12 and Homocysteine Levels Predict Different Outcomes in Early Parkinson’s Disease. Mov Disord 2018;33(5):762-770.
- Yasui K, Nakaso K, Kowa H, Takeshima T, Nakashima K. Levodopa-induced hyperhomocysteinaemia in Parkinson’s disease. Acta Neurol Scand 2003;108(1):66-67.
- Postuma RB, Espay AJ, Zadikoff C, et al. Vitamins and entacapone in levodopa-induced hyperhomocysteinemia: a randomized controlled study. Neurology 2006;66(12):1941-1943.
- Whone A, Luz M, Boca M, et al. Randomized trial of intermittent intraputamenal glial cell line-derived neurotrophic factor in Parkinson’s disease. Brain 2019;142(3):512-525.
- Weintraub D, Burn DJ. Parkinson’s disease: the quintessential neuropsychiatric disorder. Mov Disord 2011;26(6):1022-1031.
- Ffytche DH, Pereira JB, Ballard C, Chaudhuri KR, Weintraub D, Aarsland D. Risk factors for early psychosis in PD: insights from the Parkinson’s Progression Markers Initiative. J Neurol Neurosurg Psychiatry 2017;88(4):325-331.
- Goldman JG, Holden S. Treatment of psychosis and dementia in Parkinson’s disease. Curr Treat Options Neurol 2014;16(3):281.
- McCormick SA, Vatter S, Carter LA, et al. Parkinson’s-adapted cognitive stimulation therapy: feasibility and acceptability in Lewy body spectrum disorders. J Neurol 2019;266(7):1756-1770.
- Low V, Ben-Shlomo Y, Coward E, Fletcher S, Walker R, Clarke CE. Measuring the burden and mortality of hospitalisation in Parkinson’s disease: A cross-sectional analysis of the English Hospital Episodes Statistics database 2009-2013. Parkinsonism Relat Disord 2015;21(5):449-454.
- Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001;56(3):M146-156.