Treatment principles

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Treatment principles

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Treatment principles
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Current treatments and medications
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Levodopa
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Once swallowed, orally-administered levodopa moves down the gastrointestinal tract – a process sometimes delayed in PD due to impaired gastric motility – until it is absorbed into the blood via the duodenum.[van Gerpen, 2014] From the circulation, levodopa eventually makes its way to the brain, crosses the blood–brain barrier,a and is taken into nigrostriatal nerve terminals that convert it into biologically active dopamine.[van Gerpen, 2014]

The role of dopamine is not confined to the brain, however; it is also a key component of the peripheral nervous system, and helps to regulate the immune system and the function of several organs.[Arreola et al., 2016] It is important, therefore, to prevent conversion of levodopa to dopamine outside the brain, both to conserve the drug for use by the brain, and to prevent unpleasant side effects.[DeMaagd & Philip, 2015; van Gerpen, 2014] To this end, a dopa decarboxylase  enzyme inhibitor is added to the formulation that preserves levodopa in its biologically-inert form until it reaches the brain.[van Gerpen, 2014]

 aThe blood–brain barrier is an active tissue that protects the brain from potentially harmful external substances.[Loch-Neckel & Koepp, 2010]

Arreola R, Alvarez-Herrera S, Pérez-Sánchez G, et al. Immunomodulatory effects mediated by dopamine. J Immunol Res 2016; 2016: 3160486.

DeMaagd G, Philip A. Parkinson’s disease and its management. Pharmacol Therapeut 2015; 40 (9): 590–600.

Loch-Neckel G, Koepp J. The blood-brain barrier and drug delivery in the central nervous system. Rev Neurol 2010; 51 (3): 165–174.

van Gerpen. Conventional oral treatment in Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Other references used on slide
Hornykiewicz O. A brief history of levodopa. J Neurol 2010; 257 (Suppl 2): S249–S252.

Jankovic J, Aguilar GL. Current approaches to the treatment of Parkinson’s disease. Neuropsychiatr Dis Treat 2008; 4 (4): 743–757.

Trenkwalder C, Kuoppamäki M, Vahteristo M, et al.  Increased dose of carbidopa with levodopa and entacapone improves “off” time in a randomized trial. Neurology 2019; 92 (13): e1487–e1496.

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Mechanism of action of levodopa plus a peripheral dopa decarboxylase inhibitor
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The slide shows the mechanism of action of levodopa, when taken in combination with a dopa decarboxylase inhibitor.

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Strengths and limitations of levodopa
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Although levodopa has been a major success story for the management of PD, it does have some limitations, such as the development of dopa-related response fluctuations (both motor and non-motor) and drug-induced dyskinesias.[Hametner et al., 2010]

In a patient experiencing response fluctuations, a single dose of levodopa/decarboxylase inhibitor relieves symptoms for several hours.[Sinemet PI, 2008; Hametner et al., 2010] Once absorbed into the bloodstream, the concentration of levodopa halves (half-life) in approximately 50 minutes, although the addition of a decarboxylase inhibitor extends the half-life to approximately 90 minutes.[Sinemet PI, 2008] Therefore, patients with fluctuations typically need to take their levodopa several times during the day to control their symptoms.[Sinemet PI, 2008]

The duration of therapeutic effect of levodopa doses often decreases over time, as the patient begins to experience greater periods of motor fluctuations and/or drug-induced dyskinesias.[Chapuis et al., 2005] From this point onwards, the patient experiences shorter periods of relief from motor symptoms, and greater periods of time with levodopa-induced complications, all of which can substantially impair the patient’s quality of life.[Chapuis et al., 2005

Chapuis S, Ouchchane L, Metz O, et al. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 2005; 20 (2): 224–230.

Ferreira JJ, Katzenschlager R, Bloem BR, et al. Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson’s disease. Eur J Neurol 2013; 20 (1): 5–15.

Hametner E, Seppi K, Poewe W. The clinical spectrum of levodopa-induced motor complications. J Neurol 2010; 257 (Suppl 2): S268–S275.

Sinemet® (carbidopa–levodopa). Prescribing information. Merck & Co, 2014.

Other references used on slide
Freitas ME, Hess CW, Fox SH. Motor complications of dopaminergic medications in Parkinson’s disease. Semin Neurol 2017; 37 (2): 147–157.

Nutt JG, Fellman JH. Pharmacokinetics of levodopa. Clin Neuropharmacol 1984; 7 (1): 35–49.

Sethi KD. The impact of levodopa on quality of life in patients with Parkinson disease. Neurologist 2010; 16 (2): 76–83.

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Change in levodopa response over time – ‘wearing-off’
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Levodopa is the major symptomatic therapy for PD and provides benefit to virtually all patients.[Obeso et al., 2000] During the so-called ‘honeymoon’ period, the effects of levodopa tend to be long-lasting and side effects are tolerable.[Obeso et al., 2000] Beyond this ‘honeymoon’ period, however, patients may struggle to maintain good symptom control as the duration of response to levodopa therapy becomes progressively shorter.[Obeso et al., 2000] This problem is known as ‘wearing-off’.

‘Wearing-off’ is a predictable recurrence of PD symptoms that precedes a scheduled dose of levodopa and usually improves with medication.[Bhidayasiri et al., 2015] By contrast, the less predictable fluctuations – sometimes called ‘yo‑yoing’ – are associated with more advanced stages of PD.[Thanvi & Lo, 2004]

However, it has been argued that there is no reason to delay the initiation of levodopa therapy in patients with PD, because the onset of motor fluctuations and dyskinesias are associated with the duration of the disease, rather than exposure to levodopa.[Cilia et al., 2014]

Bhidayasiri R, Hattori N, Jeon B, et al. Asian perspectives on the recognition and management of levodopa ‘wearing-off’ in Parkinson’s disease. Expert Rev Neurother 2015; 15 (11): 1285–1297.

Cilia R, Akpalu A, Sarfo FS, et al. The modern pre-levodopa era of Parkinson’s disease: insights into motor complications from sub-Saharan Africa. Brain 2014; 137 (Pt 10): 2731–2742.

Obeso JA, Rodriguez-Oroz MC, Chana P. The evolution and origin of motor complications in Parkinson’s disease. Neurology 2000; 55 (11 Suppl 4): S13–S20.

Thanvi BR, Lo TC. Long term motor complications of levodopa: clinical features, mechanisms, and management strategies. Postgrad Med J 2004; 80 (946): 452–458.

Other reference used on slide
Schapira AH, Emre M, Jenner P, Poewe W. Levodopa in the treatment of Parkinson’s disease. Eur J Neurol 2009; 16 (9): 982–989.

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Dyskinesia and motor fluctuations
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Motor complications, such dyskinesia and motor fluctuations, can greatly worsen the quality of life of patients, particularly during mid to late PD.[Chapuis et al., 2005] One of the priorities for the management of PD during this time is to optimise the administration of dopaminergic medication, minimising time spent in ‘OFF’ states (e.g., akinesia) or experiencing dyskinesias.[Connolly & Lang, 2014]

Since a patient may lack the ability to store dopamine during more advanced PD, the maintenance of dopamine levels requires multiple doses of dopaminergic medication each day, typically orally, which results in an oscillating, pulsatile form of therapy.[Tambasco et al., 2012; Chapuis et al., 2005; Stacy, 2009] This pattern of administration increases the likelihood of levodopa-induced dyskinesia.[Tambasco et al., 2012; Chapuis et al., 2005; Stacy, 2009] ‘OFF’ states can be particularly severe during the night and early morning (see slide).[Chapuis et al., 2005; Stacy, 2009]

Various strategies may be employed to keep ‘OFF’ states to a minimum.[Connolly & Lang, 2014] The dosage of dopaminergic medication can be increased, or divided into smaller but more frequent doses (‘dose fractionation’).[Connolly & Lang, 2014] Additional treatments may be prescribed, which conserve levodopa or dopamine, or increase their potency.[Connolly & Lang, 2014; Stacy, 2009] The continuous delivery of intravenous levodopa may reduce the occurrence of motor fluctuations.[Aquilonius & Nyholm, 2017]

Aquilonius SM, Nyholm D. Development of new levodopa treatment strategies in Parkinson’s disease – from bedside to bench to bedside. Ups J Med Sci 2017; 122 (2): 71–77.

Chapuis S, Ouchchane L, Metz O, et al. Impact of the motor complications of Parkinson’s disease on the quality of life. Mov Disord 2005; 20 (2): 224–230.

Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311 (16): 1670–1683.

Stacy M. Medical treatment of Parkinson disease. Neurol Clin 2009; 27 (3): 605–631.

Tambasco N, Simoni S, Marsili E, et al.  Clinical aspects and management of levodopa-induced dyskinesia. Parkinson’s Disease 2012; 745947.

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Other medications used in the treatment of Parkinson’s disease (I)
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Dopamine agonists play a major role in the treatment of PD.[Factor, 2008] They act by directly stimulating intact postsynaptic receptors in the brain linked to motor control.[Müller, 2012] Although they tend to be less potent than levodopa in reducing parkinsonian motor symptoms, dopamine agonists are much less likely to cause dyskinesias.[Factor, 2008] This characteristic can make dopamine agonists a useful tool for the management of early and fluctuating PD.[Factor, 2008]

Dopamine agonists have several key advantages over levodopa: they tend to have a longer half-life, which allows for a more prolonged action; their absorption in the gut is not inhibited by dietary protein; and they are easily absorbed across the blood–brain barrier.[Factor, 2008] Dopamine agonists may therefore allow the patient to reduce their levodopa usage without worsening their parkinsonian symptoms.[Stochi, 2014]

 

Factor SA. Current status of symptomatic medical therapy in Parkinson’s disease. Neurotherapeutics 2008; 5 (2): 164–180.

Müller T. Drug therapy in patients with Parkinson’s disease. Transl Neurodegener 2012; 1 (1): 10.

Stochi F. Conventional treatment-related motor complications: their prevention and treatment. In:  Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Other references used on slide
APO-go AMPOULES (apomorphine). Summary of product characteristics. Britannia Pharmaceuticals Limited, February 2018.

Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and movement disorder society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord 2018; 33 (8): 1248–1266.

Lundbeck Institute Campus. https://institute.progress.im/en/image-bank. Accessed 11 January 2019.

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Other medications used in the treatment of Parkinson’s disease (II)
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References

Patients who are experiencing ‘wearing-off’ may benefit from taking a monoamine oxidase type B inhibitor (MAO-B inhibitor).[Factor, 2008; Stochi, 2014] MAO-B inhibitors inhibit the breakdown of either dopamine or levodopa in the body, thus prolonging their therapeutic effect and time spent in ‘ON’ states.[Connolly & Lang, 2014] MAO-B inhibitors may be used during early PD, before the patient moves on to more potent treatments, such as dopamine agonists or levodopa.[Connolly & Lang, 2014]

Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311 (16): 1670–1683.

Factor SA. Current status of symptomatic medical therapy in Parkinson’s disease. Neurotherapeutics 2008; 5 (2): 164–180.

Stochi F. Conventional treatment-related motor complications: their prevention and treatment. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Other references used on slide
Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and movement disorder society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord 2018; 33 (8): 1248–1266.

Lundbeck Institute Campus. https://institute.progress.im/en/image-bank. Accessed 11 January 2019.

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Other medications used in the treatment of Parkinson’s disease (III)
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Patients who are experiencing ‘wearing-off’ may benefit from taking a catechol-O-methyltransferase inhibitor (COMT inhibitor).[Factor, 2008; Stochi, 2014] COMT inhibitors inhibit the breakdown of dopamine and of levodopa in the body, thus prolonging their therapeutic effect and time spent in ‘ON’ states.[Connolly & Lang, 2014]

Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014; 311 (16): 1670–1683.

Factor SA. Current status of symptomatic medical therapy in Parkinson’s disease. Neurotherapeutics 2008; 5 (2): 164–180.

Stochi F. Conventional treatment-related motor complications: their prevention and treatment. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Other reference used on slide
Lundbeck Institute Campus. https://institute.progress.im/en/image-bank. Accessed 11 January 2019.

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Other medications used in the treatment of Parkinson’s disease (IV)
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References

Certain non-dopaminergic agents help to reduce dyskinesias through an indirect mechanism,[Factor, 2008] but have the limitation of worsening side effects, such as hallucinations and psychosis, in some individuals.[Müller, 2012] A newer non-dopaminergic agent has been recently licensed for patients with mid to late PD experiencing motor fluctuations,[Xadago SPC, 2016] with both dopaminergic and non-dopaminergic properties.[Stocchi & Torti, 2016]

Factor SA. Current status of symptomatic medical therapy in Parkinson’s disease. Neurotherapeutics 2008; 5 (2): 164–180.

Stocchi F, Torti M. Adjuvant therapies for Parkinson’s disease: critical evaluation of safinamide. Drug Des Devel Ther 2016; 10: 609–618.

Xadago®. Summary of Product Characteristics. Zambon S.p.A, June 2016.

Other references used on slide
Stayte S, Vissel B. Advances in non-dopaminergic treatments for Parkinson’s disease. Front Neurosci 2014; 8: 113.

Stochi F. Conventional treatment-related motor complications: their prevention and treatment. In:  Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

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Holistic medicine and the multi-disciplinary approach
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The primary emphasis of the care of patients with PD should focus on maximising their quality of life and reducing disability.[Prizer & Browner, 2012] Conventional medical and surgical therapies are still limited to providing only partial and temporary relief.[Prizer & Browner, 2012] Research has shown that the incorporation of allied healthcare clinicians, such as specialist nurses, physiotherapists and speech therapists, is essential to provide the best quality of care for patients with PD.[Lim et al., 2017; Prizer & Browner, 2012; Ypinga et al., 2018] Ideally, this should be organised using an integrative and interdisciplinary model, which promotes open and continuing communication between the patient and all of the clinicians and other practitioners involved in care.[Lim et al., 2017; Prizer & Browner, 2012] The integrated, holistic approach allows patient preferences and goals to be incorporated into treatment.[Prizer & Browner, 2012; Lim et al., 2017]

Lim SY, Tan AH, Fox SH, et al. Integrating patient concerns into Parkinson’s disease management. Curr Neurol Neurosci Rep 2017; 17 (1): 3.

Prizer LP, Browner N. The integrative care of Parkinson’s disease: a systematic review. J Parkinsons Dis 2012; 2 (2): 79–86.

Ypinga JHL, de Vries NM, Boonen LHHM, et al. Effectiveness and costs of specialised physiotherapy given via ParkinsonNet: a retrospective analysis of medical claims data. Lancet Neurol 2018; 17 (2): 153–161.

Other reference used on slide
National Collaborating Centre for Chronic Conditions. Parkinson’s disease: national clinical guideline for diagnosis and management in primary and secondary care. London: Royal College of Physicians, 2006.

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Exercise and Parkinson’s disease
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With the exception of tremor symptoms, tailored exercise and physical activity therapies have been shown to improve all the prominent motor symptoms experienced by individuals with PD.[Borrione et al., 2014] In order to increase adherence rates, the patients themselves should choose a program of exercise they would find most enjoyable.[Borrione et al., 2014] Indeed, patient education about the benefits of an active lifestyle is important.[Borrione et al., 2014] The exercise sessions should last 60–75 minutes, and be undertaken at least three times a week.[Borrione et al., 2014]

Borrione P, Tranchita E, Sansone P, Parisi A. Effects of physical activity in Parkinson’s disease: a new tool for rehabilitation. World J Methodol 2014; 4 (3): 133–143.

Other references used on slide
Mak MK, Wong-Yu IS, Shen X, Chung CL. Long-term effects of exercise and physical therapy in people with Parkinson disease. Nat Rev Neurol 2017; 13 (11): 689–703.

Oliveira de Carvalho A, Filho ASS, Murillo-Rodriguez E, et al. Physical exercise for Parkinson’s disease: clinical and experimental evidence. Clin Pract Epidemiol Ment Health 2018; 14: 89–98.

Tomlinson CL, Patel S, Meek C, et al. Physiotherapy intervention in Parkinson’s disease: systematic review and meta-analysis. BMJ 2012; 345: e5004.

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Treatment principles in the advanced stages of Parkinson’s disease
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References

Although levodopa and dopamine agonists are initially able to control motor symptoms effectively, eventually most patients will start to develop motor complications, which comprise ON– OFF motor fluctuations and dyskinesia.[Stochi, 2014]

‘Wearing-off’ is one of the more troublesome problems associated with long-term dopaminergic therapy.[Jenner, 2015] It is characterised by an increasingly short duration of effect of individual doses of levodopa or dopamine agonists, which results in a faster reversion to uncontrolled motor symptoms.[Jenner, 2015]

Current treatment of ‘wearing-off’ attempts to provide a more sustained and continuous delivery of dopaminergic medication by (a) increasing the frequency or dosage of medication, (b) splitting a single, large dose over several, smaller administrations (‘fractionation’), or (c) using a modified release form of medication, which remains effective over a longer duration.[Jenner, 2015]

During late-stage PD, oral administration of dopaminergic medication becomes less effective as patients experience more fluctuations and motor complications,[Jenner, 2015] and may also have difficulty swallowing.[Miller et al., 2006] Several non-oral alternatives have been developed, including transdermal (e.g., patches), pulmonary (e.g., inhalers or nebulisers), nasal (e.g., intranasal sprays), buccal (e.g., absorbed under the tongue), and intraduodenal (intestinal infusion) medications.[Jenner, 2015]

Jenner P. Treatment of the later stages of Parkinson’s disease – pharmacological approaches now and in the future. Transl Neurodegener 2015; 4: 3.

Miller N, Noble E, Jones D, Burn D. Hard to swallow: dysphagia in Parkinson’s disease. Age Ageing 2006; 35 (6): 614–618.

Stochi F. Conventional treatment-related motor complications: their prevention and treatment. In:  Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Other reference used on slide
Chaudhuri KR, Bhidayasiri R, van Laar T. Unmet needs in Parkinson’s disease: new horizons in a changing landscape. Parkinsonism Relat Disord 2016; 33 (Suppl 1): S2–S8.

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Deep brain stimulation – the surgical approach
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Deep brain stimulation
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In the 1980s and 1990s, a surgical intervention was trialled for the treatment of PD.[Huys et al., 2014; Moldovan et al., 2015] Deep brain stimulation (DBS) involves the implantation of one or more electrodes into specific regions of the brain.[Hickey & Stacy, 2016; Huys et al., 2014] The electrodes deliver electrical stimuli to change or disrupt abnormal patterns of neural signalling.[Hickey & Stacy, 2016; Huys et al., 2014] The process often results in improvements in motor function, as well as reduced motor complications.[Hickey & Stacy, 2016] The treatment is now well established worldwide, and more than 100,000 patients have benefited from DBS.[Huys et al., 2014]

Moldovan AS, Groiss SJ, Elben S, et al. The treatment of Parkinson’s disease with deep brain stimulation: current issues. Neural Regen Res 2015; 10 (7): 1018–1022.

Hickey P, Stacy M. Deep brain stimulation: a paradigm shifting approach to treat Parkinson’s disease. Front Neurosci 2016; 10: 173.

Huys AML, Bally FB, Pollak P. Deep brain stimulation in Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Other reference used on slide
Haubenberger D, Hallett M. Essential tremor. N Engl J Med 2018; 378 (19): 1802–1810.

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Where to target – the globus pallidus pars interna (GPi) versus the subthalamic nucleus (STN)
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The most common targets for DBS are the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN).[Pouratian et al., 2012] However, the optimal choice of target is still unclear since, when looking at the evidence, there do not appear to be unequivocal, clinically significant differences that make one target obviously superior to the other.[Tan et al., 2016]

Some researchers have expressed concerns that STN DBS may have more significant adverse effects on cognition, as compared with GPi DBS.[Tagliati, 2012] However, a recent high-quality trial showed no difference between the two methods in a combined score of cognition, mood, and behaviour.[Odekerken et al., 2016]

Pouratian N, Thakkar S, Kim W, Bronstein JM. Deep brain stimulation for the treatment of Parkinson’s disease: efficacy and safety. Degener Neurol Neuromuscul Dis 2012; 2012 (2).

Odekerken VJJ, Boel JA, Schmand BA, et al.; NSTAPS study group. GPi vs STN deep brain stimulation for Parkinson disease: three-year follow-up. Neurology 2016; 86 (8): 755–761.

Tagliati M. Turning tables: should GPi become the preferred DBS target for Parkinson disease? Neurology 2012; 79 (1): 19–20.

Tan ZG, Zhou Q, Huang T, Jiang Y. Efficacies of globus pallidus stimulation and subthalamic nucleus stimulation for advanced Parkinson’s disease: a meta-analysis of randomized controlled trials. Clin Interv Aging 2016; 11: 777–786.

Other reference used on slide
Castrioto A, Moro E. New targets for deep brain stimulation treatment of Parkinson’s disease. Expert Rev Neurother 2013; 13 (12): 1319–1328.

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The clinical efficacy of deep brain stimulation
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The PD SURG trial was designed to assess the impact of DBS on patient quality of life.[Williams et al., 2010] A total of 366 patients with advanced PD were randomised to either undergo DBS or receive non-surgical therapy.[Williams et al., 2010] There were clear advantages for surgery compared with medical therapy alone after one year, both in terms of patient-assessed quality of life, and clinical assessment of symptoms.[Williams et al., 2010] These benefits were likely to be meaningful to patients, although DBS would only be expected to affect some symptoms, such as mobility and activities of daily living, but not others (e.g., social support, cognition, and communication).[Williams et al., 2010] The results of the PD SURG trial also showed substantial benefits of DBS in the time and severity of dyskinesia, and ‘OFF’ periods.[Williams et al., 2010]

Williams A, Gill S, Varma T, et al.; PD SURG Collaborative Group. Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson’s disease (PD SURG trial): a randomised, open-label trial. Lancet Neurol 2010; 9 (6): 581–591.

Other references used on slide
Anderson D, Beecher G, Ba F. Deep brain stimulation in Parkinson’s disease: new and emerging targets for refractory motor and nonmotor symptoms. Parkinsons Dis 2017; 2017: 5124328.

Huys AML, Bally FB, Pollak P. Deep brain stimulation in Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Pouratian N, Thakkar S, Kim W, Bronstein JM. Deep brain stimulation for the treatment of Parkinson’s disease: efficacy and safety. Degener Neurol Neuromuscul Dis 2012; 2012 (2).

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Disease modification
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The ‘holy grail’ – a disease-modifying drug
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Despite decades of research dedicated to researching disease-modifying therapies for PD, most drug candidates have failed and none has been consistently shown to alter the trajectory of disease progression.[Kalia et al., 2015] Many early attempts at translating preclinical findings to positive outcomes in clinical trials were based on animal models, which are not able to fully reflect the full range of complexities of ‘real-life’ PD.[Athauda & Foltynie, 2015; Kalia et al., 2015]

Ideally, disease-modifying therapies would intervene early to preserve motor function for as long as possible, and delay or even prevent the onset of overt disease in patients at high risk (e.g., non-manifesting gene mutation carriers) or people in the prodromal PD phase.[Kalia et al., 2015] It is unlikely that any single intervention will be sufficient to achieve this, however, and so several therapies will need to be discovered and developed before the underlying disease process of PD can be effectively delayed.[Kalia et al., 2015]

Athauda D, Foltynie T. The ongoing pursuit of neuroprotective therapies in Parkinson disease. Nat Rev Neurol 2015; 11 (1): 25–40.

Kalia LV, Kalia SK, Lang AE. Disease-modifying strategies for Parkinson’s disease. Mov Disord 2015; 30 (11): 1442–1450.

Other references used on slide
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Lang AE, Espay AJ. Disease modification in Parkinson’s disease: current approaches, challenges, and future considerations. Mov Disord 2018; 33 (5): 660–677.

Van Dam D, De Deyn PP. Drug discovery in dementia: the role of rodent models. Nat Rev Drug Discov 2006; 5 (11): 956–970.

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Immunotherapeutic approaches targeting α-synuclein
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In recent years, immunotherapy has emerged as a promising approach for targeting and clearing accumulated proteins involved in neurodegenerative diseases, such as PD.[Lee & Lee, 2016; Sardi et al., 2018] The efficacy of passive immunotherapy has been demonstrated in several preclinical animal models.[Tran et al., 2014] For example, a recent study using a mouse model of PD showed that antibodies, specifically designed to target misfolded α-synuclein, were able to block the entry and propagation of α-synuclein in nerve cells, and thus prevent the development and spread of neuropathological abnormalities in the brain.[Tran et al., 2014]  

However, researchers face a number of potential problems in developing immunotherapy for PD.[Lee & Lee, 2016; Sardi et al., 2018] First, the intervention should not interfere with the normal, physiological function of α-synuclein.[Lee & Lee, 2016] To achieve this, highly-specific antibodies that attach only to pathogenic forms of α-synuclein need to be developed.[Lee & Lee, 2016] Effective methods need to be established to deliver these therapeutic antibodies into the central nervous system, ideally through the blood–brain barrier.[Lee & Lee, 2016] So, while this potential therapeutic approach appears to be a promising one, substantial hurdles need to be overcome before a safe and effective therapy is available for human use.[Lee & Lee, 2016]

Lee JS, Lee SJ. Mechanism of anti-α-synuclein immunotherapy. J Mov Disord 2016; 9 (1): 14–19.

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Tran HT, Chung CH, Iba M, et al. α-synuclein immunotherapy blocks uptake and templated propagation of misfolded α-synuclein and neurodegeneration. Cell Rep 2014; 7 (6): 2054–2065.

Other references used on slide
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Dehay B, Bourdenx M, Gorry P, et al. Targeting α-synuclein for treatment of Parkinson’s disease: mechanistic and therapeutic considerations. Lancet Neurol 2015; 14 (8): 855–866.

Harikrishna Reddy D, Misra S, Medhi B. Advances in drug development for Parkinson’s disease: present status. Pharmacology 2014; 93 (5–6): 260–271.

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Other targets for disease modification
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Leucine-rich repeat kinase 2 (LRRK2) and glucagon-like peptide 1 (GLP-1)
The discovery of key genes that increase the risk of developing PD has helped researchers to understand much of the molecular pathways involved in the disease.[Kalia et al., 2015] One of these genes, LRRK2, has provided a novel mechanism for a potential therapy.[Kalia et al., 2015] An abnormal form of this gene, which increases PD risk, is known to enhance the function of this kinase enzyme, so researchers are actively developing agents that will do the opposite and inhibit its function.[Kalia et al., 2015]

The gut peptide GLP-1 has been investigated as a potential therapeutic target as it has been shown to promote synapse preservation, reduce protein aggregation, and reduce inflammation.[Brundin et al., 2015] Further, placebo-controlled trials are being conducted to explore this target using a slow-release, weekly injection of a GLP-1 agonist.[Brundin et al., 2015]

The GBA gene
Individuals with mutations in the GBA gene can suffer from the lysosomal storage disorder ‘Gaucher disease’.[Balestrino & Schapira, 2018] The GBA gene encodes a protein that converts glucosylceramide into ceramide and glucose; deficiency in the GBA protein leads to a build-up of undegraded substrates.[Sardi et al., 2018] However, mutations in the GBA gene can also confer an increased risk of developing PD, and those who do develop PD are clinically indistinguishable from individuals with idiopathic PD, although a more rapid disease progression (including cognitive decline) has been reported.[Balestrino & Schapira, 2018; Cilia et al., 2016] Although the molecular mechanism underlying this connection is unknown, GBA is being explored as a potential therapeutic target in the treatment of PD.[Balestrino & Schapira, 2018] Also, novel glucosylceramide inhibitors have shown some potential as a therapy for PD in mouse models, with at least one such inhibitor – as of the time of writing – in clinical development.[Sardi et al., 2018; Sardi et al., 2017; ClinicalTrials.gov]

Caffeine and nicotine receptors
Both caffeine and nicotine are common substances found in plant-based stimulants, such as tea, coffee and tobacco. Coffee drinking is associated with a reduced risk of PD and caffeine itself may provide some symptomatic relief to patients with the disease.[Ascherio & Schwarzschild, 2016; Kalia et al., 2015] Caffeine binds to α-synuclein, inducing conformational changes that prevent its aggregation.[Negida et al., 2017] Caffeine may act as an antioxidant, reducing oxidative stress and therefore slowing the progression of PD.[Negida et al., 2017] It also increases dopamine release and the number of dopamine receptors in the striatum, and is an adenosine antagonist.[Negida et al., 2017] For all of these reasons, the therapeutic effects of caffeine are being tested in clinical trials.[Kalia et al., 2015]

Epidemiological studies have shown that smokers are considerably less likely to develop PD.[Kalia et al., 2015; Noyce et al., 2012] A history of smoking reduces the risk of PD by approximately 36%, compared with non-smokers.[Noyce et al., 2012] Clinical trials are therefore currently underway to determine whether or not nicotine is the main cause of this protective effect.[Kalia et al., 2015]

Ascherio A, Schwarzschild MA. The epidemiology of Parkinson’s disease: risk factors and prevention. Lancet Neurol 2016; 15 (12): 1257–1272.

Balestrino R, Schapira AHV. Glucocerebrosidase and Parkinson disease: molecular, clinical, and therapeutic implications. Neuroscientist 2018; 24 (5): 540–559.

Brundin P, Atkin G, Lamberts JT. Basic science breaks through: new therapeutic advances in Parkinson’s disease. Mov Disord 2015; 30 (11): 1521–1527.

Cilia R, Tunesi S, Marotta G, et al. Survival and dementia in GBA-associated Parkinson’s disease: the mutation matters. Ann Neurol 2016; 80 (5): 662–673.

ClinicalTrials.gov. A global study to assess the drug dynamics, efficacy, and safety of GZ/SAR402671 in Parkinson’s disease patients carrying a glucocerebrosidase (GBA) gene mutation (MOVES-PD). NCT02906020.

Kalia LV, Kalia SK, Lang AE. Disease-modifying strategies for Parkinson’s disease. Mov Disord 2015; 30 (11): 1442–1450.

Negida A, Elfil M, Attia A. Caffeine; the forgotten potential for Parkinson’s disease. CNS Neurol Disord Drug Targets 2017; 16 (6): 652–657.

Noyce AJ, Bestwick JP, Silveira-Moriyama L, et al. Meta-analysis of early nonmotor features and risk factors for Parkinson disease. Ann Neurol 2012; 72 (6): 893–901.

Sardi SP, Cedarbaum JM, Brundin P. Targeted therapies for Parkinson’s disease: from genetics to the clinic. Mov Disord 2018; 33 (5): 684–696.

Sardi SP, Viel C, Clarke J, et al. Glucosylceramide synthase inhibition alleviates aberrations in synucleinopathy models. Proc Natl Acad Sci USA 2017; 114 (10): 2699–2704.

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Gene- and cell-based therapies
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Gene therapy
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References

Over the last 10 years, there have been major advances in gene therapy approaches for the treatment of PD, several of which have entered human clinical trials.[Allen & Feigin, 2014; Coune et al., 2012] These trials have produced some promising results, albeit not consistently.[Allen & Feigin, 2014]

Evidence accumulated thus far indicates that gene therapy that targets multiple brain regions – including the striatum, the subthalamic nucleus, and the substantia nigra – can be both safe and well-tolerated in patients with PD.[Allen & Feigin, 2014]

Several key challenges remain in order to develop a safe and effective gene therapy.[Allen & Feigin, 2014] These include, how best to control gene expression, how to determine the optimal target, the optimal dose, and the ideal patient population for future gene therapy trials.[Allen & Feigin, 2014]

Allen PJ, Feigin A. Gene-based therapies in Parkinson’s disease. Neurotherapeutics 2014; 11 (1): 60–67.

Coune PG, Schneider BL, Aebischer P. Parkinson’s disease: gene therapies. Cold Spring Harb Perspect Med 2012; 2 (4): a009431.

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The potential of stem cell therapies
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References

A great deal of research effort is now being invested in stem cell transplantation therapies, to restore neurological function.[Pen & Jensen, 2017] In related fields, such as spinal cord injury research, important progress has been made using stem cells to treat patients with neurological injuries.[Pen & Jensen, 2017]

However, serious ethical and methodological issues remain, such as whether or not to use embryonic stem cells; how to prevent Lewy pathology from developing in transplanted cells; how best to deliver the cell-based therapies; and how to prevent rejection of transplanted cells by the patient’s immune system.[Barker et al., 2015; Pen & Jensen, 2017; Zhu et al., 2016] Recently, it has become possible to work with ‘induced pluripotent stem cells’ (iPSCs), which can subsequently become neurons.[Pen & Jensen, 2017] Hopefully, iPSCs will provide an easily accessible source of neurons for future cell transplantation.[Pen & Jensen, 2017]

Barker RA, Drouin-Ouellet J, Parmar M. Cell-based therapies for Parkinson disease – past insights and future potential. Nat Rev Neurol 2015; 11 (9): 492–503.

Pen AE, Jensen UB. Current status of treating neurodegenerative disease with induced pluripotent stem cells. Acta Neurol Scand 2017; 135 (1): 57–72.

Zhu B, Caldwell M, Song B. Development of stem cell-based therapies for Parkinson’s disease. Int J Neurosci 2016; 126 (11): 955–962.

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The future of treatment for Parkinson’s disease
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References

Unlike some other diseases, PD can be managed with a range of safe and effective pharmacological and non-pharmacological treatments that allow patients to live with their disease for several years after diagnosis.[Fox et al., 2018; Stochi, 2014; Wolters et al., 2014] However, a therapy that can delay or prevent the underlying disease process remains elusive.[Wolters et al., 2014; Kalia et al., 2015]

Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and movement disorder society evidence-based medicine review: update on treatments for the motor symptoms of Parkinson’s disease. Mov Disord 2018; 33 (8): 1248–1266.

Kalia LV, Kalia SK, Lang AE. Disease-modifying strategies for Parkinson’s disease. Mov Disord 2015; 30 (11): 1442–1450.

Stochi F. Conventional treatment-related motor complications: their prevention and treatment. In:  Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

Wolters E, de Munter H, Steinbusch H. Parkinson’s disease. In: Wolters & Baumann (eds). Parkinson Disease and Other Movement Disorders. VU University Press, 2014.

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