Clinical Therapeutics/Volume 35, Number 10, 2013
New Pharmacological Options for Treating Advanced Parkinson’s Disease David Devos, MD, PhD1; Caroline Moreau, MD, PhD2; Kathy Dujardin, PhD2; Ioav Cabantchik3; Luc Defebvre, MD, PhD2; and Regis Bordet, MD, PhD1 1
Department of Medical Pharmacology, EA 1046, Lille Nord de France University, Lille, France; Department of Neurology and Movement Disorders, EA 1046, Lille Nord de France University, Lille, France; and 3Adelina and Massimo DellaPergola Chair, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel
2
ABSTRACT Background: Parkinson’s disease (PD) affects about 1% of the over 60 population and is characterized by a combination of motor symptoms (rest tremor, bradykinesia, rigidity, postural instability, stooped posture and freezing of gait [FoG]) and non-motor symptoms (including psychiatric and cognitive disorders). Given that the loss of dopamine in the striatum is the main pathochemical hallmark of PD, pharmacological treatment of the disease has focused on restoring dopaminergic neurotransmission and thus improving motor symptoms. However, the currently licensed medications have several major limitations. Firstly, dopaminergic medications modulate all the key steps in dopamine transmission other than the most powerful determinant of extracellular dopamine levels: the activity of the presynaptic dopamine transporter. Secondly, other monoaminergic neurotransmission systems (ie noradrenergic, cholinergic and glutamatergic systems are altered in PD and may be involved in a variety of motor and non-motor symptoms. Thirdly, today’s randomized clinical trials are primarily designed to assess the efficacy and safety of treatments for motor fluctuations and dyskinesia. Fourthly, there is a need for disease- modifying treatments (DMTs) that slow disease progression and reduce the occurrence of the very disabling disorders seen in late-stage PD. Objective: To systematically review a number of putative pharmacological options for treating the main impairments in late-stage PD (ie gait disorders, cognitive disorders and behavioural disorders such as apathy). Methods: We searched the PubMed database up until July 2013 with logical combinations of the
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following search terms: “Parkinson’s disease”, “gait”, “cognition”, “apathy”, “advanced stage”, “modulation”, “noradrenergic”, “cholinergic”, “glutamatergic” and “neurotransmission”. Results: In patients undergoing subthalamic nucleus stimulation, the potentiation of noradrenergic and dopaminergic transmission by methylphenidate improves gait and FoG and may relieve apathy. However, the drug failed to improve cognition in this population. Potentiation of the cholinergic system by acetylcholinesterase inhibitors (which are licensed for use in dementia) may reduce pre-dementia apathy and falls. Modulation of the glutamatergic system by an N-methyl-D-aspartate receptor antagonist did not improve gait and dementia but may have reduced axial rigidity. A number of putative DMTs have been reported. Discussion: Novel therapeutic strategies should seek to reduce the appearance of the very disabling disorders observed in late-stage PD. Dopamine and/or noradrenaline transporter inhibitors, anticholinesterase inhibitors, Peroxisome-proliferator-activated-receptor-agonists and iron chelators should at least be investigated as putative DMTs by applying a delayedstart clinical trial paradigm to a large population Conclusions: There is a need for more randomized clinical trials of treatments for late-stage PD. (Clin Ther. 2013;35:1640–1652) & 2013 Elsevier HS Journals, Inc. All rights reserved.
Accepted for publication August 22, 2013. http://dx.doi.org/10.1016/j.clinthera.2013.08.011 0149-2918/$ - see front matter & 2013 Elsevier HS Journals, Inc. All rights reserved.
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D. Devos et al. Key words: gait, dementia, cognition, apathy, nondopaminergic treatment, disease-modifying treatment.
INTRODUCTION Parkinson’s disease (PD) is the second most frequent neurodegenerative disorder worldwide and affects about 1% of the over 60s.1 The disease is characterized by a combination of rest tremor, bradykinesia, rigidity and gait disorders. However, the clinical spectrum also encompasses non-motor symptoms, including behavioural disorders (such as apathy) and cognitive disorders.2 The core neuropathological features of PD are the loss of dopaminergic neurons in the substantia nigra and the deposition of iron and cytoplasmic protein aggregates (Lewy bodies) inside neurons. Given that the loss of dopamine in the striatum is the main pathochemical hallmark of PD, pharmacological treatment of the disease has been focused on restoring dopaminergic neurotransmission.3 The dopamine precursor levodopa remains the “gold standard” treatment for PD; it improves the patient’s motor functions, activities of daily living and quality of life. However, levodopa also has several pharmacokinetic drawbacks (notably its short halflife). Hence, the chronic administration of levodopa required for advanced PD is frequently associated with the development of levodopa-related motor fluctuations and dyskinesia. The prevalence of these motor complications ranges from 40% to 50% after 4 to 6 years of treatment.4,5 Inhibitors of the dopaminemetabolizing enzymes catechol-O-methyltransferase and monoamine oxidase-B (MAO-B) have been developed with a view to prolonging the half-life of levodopa and thus limiting motor fluctuations. Dopamine agonists directly stimulate postsynaptic dopamine receptors in the striatum, in order to decrease the need for levodopa and limit the appearance of motor complications.4,6,7 However, the dopamine agonists’ safety profile provides cause for concern, since these medications may variously induce impulse control disorders (ICDs), confusion, hallucinations, psychosis, excessive daytime sleepiness and sleep attacks.4,8 Deep brain stimulation of the subthalamic nucleus (STN) (or, to a lesser extent, the internal globus pallidus) is a proven, very effective means of controlling motor complications.9 However, the contraindications for this treatment limit its application to just a small proportion of PD patients. Continuous, subcutaneous
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apomorphine infusion is an effective treatment option for motor fluctuations but again is also only used with a small proportion of PD patients - probably because apomorphine is a dopaminergic agonist and the infusion pump is an external device. Earlier introduction of this treatment should nevertheless be considered.10 Duodenal levodopa infusion* appears to be a very effective therapy for motor complications. However, poor user-friendliness (a heavy, external pump and the need for gastrostomy) restricts Duodopas to use as a last-line therapy.11 Lastly, a number of licensed and unlicensed drugs have also been proposed (often with a low level of scientific evidence) for the treatment of non-motor symptoms (for a review, see 12). The beneficial, long-term effects of currently licensed medications are often countered by the appearance of gait, cognitive and behavioural disorders as the disease progresses. This may prompt institutionalization and constitutes a public health issue.13,14 The associated gait disorders are mainly characterized by impaired stride length regulation and thus a slower walking speed (ie gait hypokinesia).15 Furthermore, freezing of gait (FoG, ie a brief, involuntary, episodic absence of (or a marked reduction in) forward progression of the foot) can also be prominent.16 Although the disease mechanism underlying for FoG is not fully understood, several different factors are clearly involved. Gait disorders associated with FoG appear to be mainly related to disease severity and a hypodopaminergic state.17 Optimization of levodopa treatment is the main therapeutic option under these circumstances.16,17 However, the option of increasing the levodopa dose may be significantly restricted by (i) the worsening of levodoparelated motor complications, (ii) induction of confusion or sleepiness and (iii) progressive loss of efficacy as the disease worsens. Patients with PD have an almost sixfold greater risk of developing dementia than agematched, healthy controls do.18 In cross-sectional studies, 30% to 40% of PD patients meet the criteria for dementia.14 Moreover, a number of longitudinal studies have revealed that the cumulative incidence of dementia in patients with PD increases with age and disease duration and can even reach 80% to 90%.19–21 The cognitive profile in PD dementia (PDD) differs from that in Alzheimer’s disease (AD) and is dominated by severe impairments in attention and in executive and visuospatial functions; in contrast, memory encoding, *Duodopas (Solvay Pharmaceuticals, Pymble, Australia).
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Clinical Therapeutics language, and orientation in time and space are relatively unaffected.22–25 Early diagnosis of PDD is important because cholinesterase inhibitors are efficacious in this context.26,27 In terms of behavioural disorders, apathy is characterized by lack of interest, loss of initiative, diminished motivation, greater effort in performing everyday activities and indifference or flattening of affect. Apathy is frequently considered to be a symptom of depression but sometimes occurs in the absence of a mood disorder.28 Indeed, apathy is frequent in PD and has an estimated prevalence of between 13.9% and 60%,29,30 depending on the diagnostic criteria applied and whether demented and/or depressed patients are included. In fact, apathy is more frequent in late-stage PD and thus the prevalence has been estimated to be 15% in patients with stable disease, 30% in fluctuating patients and 56% in demented patients.31 Schematically, one can consider at least two different forms of apathy: dopaminergic apathy (with mesolimbic denervation)32 and late-stage apathy. The latter is not markedly improved by dopaminergic medications and may be predictive of the occurrence of dementia.33 At present, we lack specific treatments for these very disabling disorders of late-stage PD. However, changes in other monoaminergic neurotransmission systems (such as the noradrenergic, cholinergic and glutamatergic systems) occur in PD as a result of disease progression and the extension of neurodegeneration.3,34,35 However, most of today’s on-going or planned randomized clinical trials of non-dopaminergic drugs have been designed to assess efficacy in the treatment of motor fluctuations and dyskinesia.3,36 Here, we review a number of novel symptomatic treatment options for late-stage disorders: (1) potentiation of noradrenergic and dopaminergic transmission via inhibition of the norepinephrine transporter (NeT) and the dopamine transporter (DaT) , (2) potentiation of the cholinergic system by inhibition of acetylcholinesterase, (3) modulation of the glutamatergic system and (4) a number of putative disease-modifying treatments (DMTs) for reducing the occurrence of these disorders.
SYMPTOMATIC TREATMENT OPTIONS FOR LATE-STAGE DISORDERS Norepinephrine and Dopamine Transporter Inhibition Neuronal loss in the locus coeruleus (which can be as high as 70%) leads to a dramatic decrease in the
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norepinephrine content of the brain - second only to the loss of dopamine production.34 It has been reported that administration of an alpha-2 adrenergic antagonist decreased motor handicap in the unilateral 6-hydroxydopamine mouse model of PD.37 The relationship between norepinephrine depletion and the symptoms of PD remains to be characterized. However, norepinephrine is thought to be involved in FoG,38 since the synthetic precursor L-threo-DOPS (droxidopa) has particularly beneficial effects.39–41 Methylphenidate (MPD) is a central nervous system stimulant that is licensed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy in Europe and the USA. The compound blocks norepinephrine and dopamine reuptake by inhibiting the presynaptic NeT and DaT 42–44 (the most powerful determinant of extracellular dopamine levels)45 particularly in the striatum and the prefrontal cortex.46 Methylphenidate was first tested in a very small cohort of PD patients in 1961. A dose of between 0.5 and 1 mg/kg/d was associated with an improvement in voluntary movements and less rigidity.47 However, MPD ’s effects were mostly attributed to its impact on mood (ie its euphoriant action), which was associated with increased restless and insomnia in some patients. This might explain (at least in part) why MPD has not been further developed in PD. In fact, MPD has always been considered as a treatment for attention disorders, with potentially valuable effects on cognition and behaviour but not (at least directly) motor symptoms. The renewed interest in MPD was prompted by a suggestion that gait disorders in PD are profoundly influenced by attention disorders.
Gait and Axial Disorders Four open-label studies have assessed the efficacy of MPD in gait hypokinesia. The first study (by Auriel et al) assessed the effect of acute administration of MPD (20 mg) in 21 non-demented, non-stimulated PD patients who were free of major postural or gait disorders and had stable dopaminergic regimens.48 The researchers observed significant improvements in all gait parameters. The second study (by Nutt et al) found that 0.2 or 0.4 mg/kg MPD had effects on gait or on the performance of a tapping task when administered two hours after the infusion of levodopa but when not administered alone.44 The third open-label study (by Pollak et al)49 examined the
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D. Devos et al. effect of low-dose (10 mg) MPD on FoG in five patients with severe PD during the "off" state. Lowdose MPD was associated with improvements in all gait parameters and FoG. Lastly, Devos et al50 decided to test the effect of high-dose (1 mg/kg) MPD on gait disorders because low doses of the drug ( 0.25 mg/ kg) may only occupy half the striatal DaTs in humans.43 Over a three-month period, MPD was administered to 17 advanced PD patients undergoing STN stimulation. Acute administration of MPD (in both the presence and absence of levodopa) was associated with a lower number of steps and a lower test completion time (relative to the “off-drug, onstim” condition). Methylphenidate and levodopa reduced the parameters to a similar extent and had additive effects in this population. Twelve of the 17 patients displayed FoG episodes in either the “off drugs, on-stim” or the “off-stim, on-levodopa” condition. There was a non-significant trend towards a lower number of FoG episodes in the “on-levodopa, on-MPD” condition. In contrast to previous studies, chronic administration of high-dose MPD (in both the presence and absence of dopaminergic medications) clearly had an effect on gait disorders in advanced PD. Furthermore, two randomized clinical trials have been recently performed.51,52 The first (performed by Espay et al) was a six-month, double-blind, placebo-controlled, randomized, single-centre crossover study in 27 PD patients.51 The second (performed by Moreau et al) was a double-blind, placebo-controlled, randomized, multicentre trial in 69 PD patients.52 The two studies had similar objectives and provided complementary information, even though the respective effects of MPD on gait impairments differed. Espay et al recruited advanced-stage PD patients with gait impairments (Hoehn & Yahr stage III and a score of 1 or more for item 29 of the Unified Parkinson’s Disease Rating Scale (UPDRS) part III). Demented individuals or those undergoing STN stimulation were excluded. The included patients were randomized to 12 weeks of treatment with either placebo or 1 mg/kg MPD. Relative to placebo, MPD was associated with only a slight improvement in the composite gait score in the “off- levodopa” condition and did not improve the FoG questionnaire (FoGQ) score, the freezing diary score or kinematic variables. The UPDRS motor score was not improved (relative to placebo) by MPD. In the study by Moreau et al, 69 patients suffering from severe PD (despite the
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optimization of drug treatments and STN stimulation parameters) and FoG (subscores Z2 for item 14 of FoGQ, UPDRS part II item 15 for gait in the “on” condition and UPDRS part III item 30 for gait in the “on levodopa” condition) were randomized 1:1 to MPD or placebo for three months. As in Espay’s study, improved gait (the number of steps in the SWS test) was only observed in the “off-dopaminergic drug” condition. However, FoG was less frequent in the MPD group (relative to the placebo group) under both “off-” and “on-dopaminergic drug” conditions. The FoGQ score was lower in the MPD group than in the placebo group. Interestingly, global motor function (ie the UPDRS III motor score) was slightly better in the MPD group. The disparities between the results obtained respectively by Espay et al and Moreau et al. may be due to differences in the study design (ie six months of followup in Espay et al’s study, which increased the potential for faster progression of axial signs than during the three-month follow-up period in Moreau et al’s study),51,52 the study population (the patients in Moreau et al’s study were undergoing STN stimulation)52 and the FoG assessment method (questionnaires and an objective assessment in Moreau et al’s study vs questionnaires and an electronic walkway (which might not have elicited FoG sufficiently in Espay et al’s study).51 In summary, administration of MPD in PD was associated with improved gait in the open-label studies and in the second (larger) double-blind, placebocontrolled study.52 There were fewer motor symptoms in the absence of levodopa and fewer FoG episodes before and after an acute levodopa challenge. These clinical benefits had a positive impact on activities of daily living and quality of life.52 Thus, MPD may be a new therapeutic option for alleviating gait disorders with FoG in PD patients undergoing. However, the long-term risk/benefit balance (especially in terms of the worsening of axial signs and the potential cardiovascular risk in the elderly) remains to be characterized.
Apathy Dopaminergic apathy notably occurs in PD patients undergoing STN stimulation after the tapering of dopaminergic medications. The symptoms can be relieved by the administration of dopamine agonists.53,54 Chronic administration of high-dose MPD (for three months) was associated with a significant
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Clinical Therapeutics reduction in apathy (as measured on the Lille Apathy Rating Scale (LARS)) in a subgroup of seven advanced-stage PD patients undergoing STN stimulation.52 However, the study was not specifically designed to assess apathy. Methylphenidate (5 mg, twice a day) also sharply reduced severe apathy in a non-stimulated patient at an earlier stage of PD.55 In conclusion, there are still too few data to draw firm conclusions as to the value of MPD in apathy in PD although a beneficial effect is plausible.
Attention and Cognitive Disorders The various studies of MPD and cognitive function have yielded conflicting results. Two open-label studies showed a slight improvement in attention performance. A reduction in simple reaction time was noted after administration of a single, 20 mg dose of MPD to 21 patients.48 Memory and visuospatial performance levels were unchanged.48 An improvement in sustained attention was observed after three-month course of MPD (1 mg/kg/d) in 10 non-demented patients but not in 7 demented patients.50 However, these results have not been confirmed in randomized, double-blind studies. In a study of five PD patients after the withdrawal of antiparkinsonian medications, Camicioli et al administered 0.2 mg/kg oral MPD or placebo and (30 minutes later) a one-hour, intravenous infusion of levodopa (2 mg/kg per hour) or placebo. The researchers observed a lower choice reaction time with MPD (relative to placebo) but failed to see any effects on simple reaction time, attention and executive function.56 The absence of a clear, beneficial effect of MPD on attention disorders in PD was recently confirmed in a double-blind, placebo-controlled, randomized study of 69 patients.52 However, reaction times have mainly been investigated as a secondary efficacy criteria in small patient populations and/or under non-standardized conditions. Furthermore, dopaminergic treatment may have confounding effects.
Safety Concerns Methylphenidate-associated adverse events have been widely described in children (and, to a lesser extent, adults) suffering from ADHD.57,58 The most frequently reported events are gastrointestinal pain, headaches and loss of appetite. In the PD population, the safety profile appears to be similar. Methylphenidate’s overall safety profile is good.52,57 This may partly have been due to good compliance with the
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contraindications, which mainly include psychiatric and cardiac disorders.58,59 It has been reported that confusion and hallucinations may arise in at-risk populations, which requires the exclusion of PD patients having previously suffered from hallucinations and (possibly) demented patients. Another high psychiatric risk corresponds to mood modulation in patients having already shown mania/bipolar disorder. Addiction also represents a primary psychiatric contraindication. However, ICDs did not recur during MPD treatment in patients who had experienced this type of disorder while on dopaminergic agonists earlier in the course of disease.52 It would be useful to test whether MPD induces ICDs to a lesser extent that dopamine agonists do. Lastly, cardiovascular adverse events may be serious if the drug’s contraindications are not rigorously observed - especially in view of the advanced age of the PD population. In the largest clinical trial to date, only mild, transient cardiovascular adverse events were reported.52 The mean heart rate increased significantly (by three beats per minute) but the blood pressure did not change significantly in a population with prevalent hypotension and hypervariability related to dysautonomia. Hence (like ADHD patients), PD patients should be closely monitored, via six-monthly check-ups with a cardiologist58 or, at the very least, blood pressure and heart rate monitoring every three months.59 There is a need for long-term safety studies in this context.
POTENTIATING THE CHOLINERGIC SYSTEM WITH ACETYL CHOLINESTERASE INHIBITORS Cognitive Disorders Patients with PD have particularly low cortical levels of the neurotransmitter acetylcholine. It has been shown that the use of cholinesterase inhibitors to block acetylcholine breakdown may lead to clinical improvements. The cholinesterase inhibitor rivastigmine is currently the only licensed treatment for dementia in PD. Cochrane reviews have considered the use of cholinesterase inhibitors in both PDD and cognitive impairment in non-demented PD (CINDPD).60 The findings of four randomized, double-blind, placebo-controlled trials support the use of cholinesterase inhibitors in PDD,26,61–63 since they have a positive impact on global assessment, cognitive function, behavioural disturbance and activities of daily living. Cholinesterase inhibitors were more likely to induce an adverse event as compared with placebo.
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D. Devos et al. Tremor was reported more frequently in the treatment group. Fewer deaths occurred in the treatment group than in the placebo group. Only one study assessed patients with CIND-PD.64 Although a positive impact on the Mini-Mental State Examination score was observed, there is no current evidence to support the use of cholinesterase inhibitors in CIND-PD.
Apathy before Dementia The neurochemical substrates of apathy have yet to be unambiguously identified. Although several different substrates are probably involved, the central dopaminergic system’s role in reward and motivation is often mentioned.33,65 Apathy can also occur in patients with optimal dopaminergic regimens. Apathy is more frequent in PD patients with cognitive decline and may even precede dementia.31 Cummings and Back suggested that medial frontal and limbic cholinergic deficits may underlie apathy in AD.66 This hypothesis is supported by the cholinesterase inhibitors’ beneficial effects on neuropsychiatric symptoms (including apathy67). Hence, we reasoned that cholinesterase inhibitors might compensate for impaired cholinergic transmission within the limbic and associative subcorticofrontal loops in PD. We performed a multicentre, parallel, double-blind, placebo-controlled, randomized clinical trial on dementia-free patients with moderate-to-severe apathy. Patients were randomly assigned 1:1 to a sixmonth course of rivastigmine (a transdermal patch delivering 9.5 mg/d) or placebo. The primary efficacy criterion was the change over time in the LARS score. In all, 101 consecutive patients were screened, 31 were eligible and 16 and 14 participants were randomized into the rivastigmine and placebo groups, respectively. Compared with placebo, rivastigmine was associated with a better LARS score, a lower caregiver burden and improvement in the Instrumental Activities of Daily Living score. There were no serious adverse events in the rivastigmine group.68 Rivastigmine may represent a new therapeutic option for moderate-tosevere apathy in advanced PD patients with optimized dopaminergic treatment and who are free of depression and dementia. These findings require confirmation in a larger clinical trial.
Gait Disorders with Falls Falling as a result of postural instability is a significant problem in advanced PD and is barely
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impacted by dopaminergic therapy. Anticholinergic medications increase the rate of falls in elderly patients and demented patients. It has been hypothesized that imbalance in the cholinergic pathways might contribute to the increased risk of falls observed in PD. Loss of cholinergic neurons in the nucleus basalis of Meynert and the pedunculopontine nucleus (PPN) may have a directly, harmful effect on balance and attention and may thus contribute to an increased risk of falls. In a randomized, placebo-controlled, cross-over trial in 23 PD patients with advanced postural instability and who reported falling or nearly falling more than twice a week, 10 mg of the centrally acting cholinesterase inhibitor donepezil nearly halved the frequency of falls. Subjects took six-week courses of donepezil and placebo, with a 3-week washout period between the two. The primary outcome was the frequency of falls (as reported daily in a study diary). The two phases did not differ significantly in terms of the frequency of near-falls or any of the secondary outcomes (related to on balance, cognition and motor handicap).69 Larger trials of cholinergic augmentation in PD subjects with frequent falls are warranted.
MODULATING THE GLUTAMATERGIC SYSTEM Modulation of the glutamatergic system has mainly been used to reduce levodopa-induced dyskinesia (LID). Despite a low level of evidence, the N-methyl D-aspartate (NMDA) receptor antagonist amantadine is considered to have short-term benefits in the treatment of LID and remains widely used.70 Of the novel glutamatergic molecules under development for the indication of LID, AFQ056 (a selective metabotropic glutamate receptor 5 antagonist) has recently demonstrated antidyskinetic efficacy without worsening underlying motor symptoms. Pivotal phase III clinical trials are required for licensing.71 Antiglutamatergic drugs (particularly memantine (1-amino-3,5-dimethyladamantane), an uncompetitive, partial antagonist of the open NMDA receptor) have been also developed for the treatment of cognitive disorders (mainly in AD).
Cognitive Disorders Dementia with Lewy bodies (DLB) and PDD are common forms of dementia. Recent evidence suggests that memantine might be useful for treating PDD.72 However, the parallel-group, randomized, controlled
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Clinical Therapeutics studies with memantine have yielded inconclusive results. A first 24-week, parallel-group, randomized, controlled study of memantine (20 mg/d, n ¼ 34 patients) versus placebo (n ¼ 38 patients) showed better clinical global impression of change scores (mean difference: 0.7) and improved speed in attentional tasks for the study drug.73 The second (larger) 24week, parallel-group, randomised, controlled study of 20 mg of memantine per day (n ¼ 34 patients with DLB and 62 with PDD) versus placebo (n ¼ 41 patients with DLB and 58 with PDD) found that the study drug was associated with a greater improvement in global cognitive status and behavioural symptoms for patients with mild-to-moderate DLB but not for patients with PDD.74 Memantine was well tolerated in both studies. Hence, memantine might be an option for treatment of DLB patients but it remains to be determined whether a subgroup of PDD patients (perhaps those with severe dementia) might benefit from use of this drug.
Gait and Axial Disorders Dopaminergic depletion induces glutamatergic hyperactivity in the brain in general and in the STN and its efferent pathways projecting to the PPN in particular.75,76 The PPN is particularly involved in posture and gait control.77 The NMDA receptor antagonist MK-801 was found to facilitate locomotion in a rat model of PD with bilateral PPN lesions.78 By decreasing NMDA-dependant glutamatergic hyperactivity, memantine reduces akinesia and rigidity in the 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP) rat model79 and improves locomotion in rats treated with reserpine and alpha-methyl-p-tyrosine.80 A 90-day, randomized, double-blind, pilot study of memantine (20 mg/d) versus placebo (n ¼ 25 patients in total) did not find a significant improvement in gait (in terms of the optoelectronically measured stride length) but did evidence significant better results for the overall UPDRS score, the latter’s axial subscore, the axial and overall Dyskinesia Rating Scale scores, axial hypertonia and axial strength (using an isokinetic dynamometer).81 Another double-blind, placebo-controlled study on a small number of patients also failed to evidence a beneficial effect of intravenously administered amantadine on dopamine-resistant FoG resistant.82 However, a combination of memantine and L-dopa appeared to be associated with a slight beneficial effect on axial motor handicap and LID in advanced PD patients with severe axial symptoms.81 Memantine’s good safety
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profile and its observed association with a lower motor symptom score confirmed the findings of two open-label studies83,84 and two double-blind, placebocontrolled studies.85,86 These benefits must be confirmed in a broader population of PD patients with severe axial symptoms.
PUTATIVE DISEASE-MODIFYING TREATMENTS Dopaminergic Disease Modifiers Most symptomatic treatments (and notably the ones detailed here) were assessed in short-term clinical trials in which the primary efficacy criterion was the intensity of a symptom or a syndrome. However, it would be very interesting to consider the longer-term progression of symptoms during treatment. The Elldopa study showed that L-dopa (the most efficacious treatment of PD) may have neuroprotective value. However, the study’s design prevented an analysis of levodopa’s putative disease-modifying effect because of the drug’s very long-lasting symptomatic benefits. In the ADAGIO study of an MAO-B inhibitor (rasagiline), three hierarchical, co-primary endpoints were derived from the rates of disease progression during defined treatment periods. Achievement of these co-primary endpoints was equated with the presence of a diseasemodifying effect.87,88 Thus, one can hypothesize that all dopaminergic medications may have disease-modifying properties. However, the PROUD study did not observe a disease-modifying effect for the dopaminergic agonist pramipexole.89 However, MPD (which inhibits the DaT the most powerful determinant of extracellular dopamine levels),45 may modify disease progression and should be assessed as a putative DMT.
Cholinergic Disease Modifiers Rivastigmine is licensed for the treatment of dementia in PD. Whether these or other medications can delay the progression from mild cognitive impairment to dementia in PD is a key research question.72 In a pilot study, apathetic PD patients treated over the longer term had a slightly lower rate of dementia occurrence than apathetic patients having received short-term treatment did.68 However, the pilot study’s design prevented a reliable analysis of this topic but raised the question of whether the predementia initiation of rivastigmine (ie during apathy in advanced PD or cognitive impairment in nondemented PD patients) might have an effect on the incidence of dementia.
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Calcium Blockers It has been nicely demonstrated that a calcium blocker (which antagonizes calcium entry through L-type channels) reduces the oxidative stress evoked by pace-making in dopaminergic neurons.90 This finding pointed the way to a novel neuroprotective strategy in PD. A systematic Cochrane Collaboration review noted that there is currently a lack of evidence for the use of antihypertensive drugs in either primary prevention (ie a lack of cohort studies and case-control studies in PD-free participants) or secondary prevention (ie a lack of clinical trials in patients with welldefined PD). The two cohort studies failed to observe an association between exposure to calcium channel blockers and the risk of developing PD. The results of an on-going trial (examining the effects of the calcium channel blocker isradipine on motor symptoms and disease progression) should help inform further research.91 A recent cohort study tested the effect of the length of exposure to less brain-penetrant dihydropyridines (amlodipine) and more brain-penetrant dihydropyridines (eg nifedipine and felodipine) on parkinsonism milestones (eg time to drug treatment for parkinsonism, nursing home admission, and death). In a population of 4733 hypertensive individuals with parkinsonism, there were no significant differences between those taking amlodipine and those taking other dihydropyridines. In summary, dihydropyridine calcium channel blockers are unlikely to have a clinically significant effect on the course of PD.92
Peroxisome Proliferator-activated Receptor (PPAR) Agonists The PPAR is a member of a nuclear receptor superfamily that regulates development, tissue differentiation, inflammation, mitochondrial function, wound healing, lipid metabolism and glucose metabolism. Several PPAR agonists were shown to exert neuroprotective activity against oxidative damage, inflammation, and apoptosis in several neurodegenerative diseases.93 Moreover, several epidemiological studies have observed that regular intake of PPAR-activating, non-steroidal anti-inflammatory drugs (such as indomethacin and ibuprofen) was associated with a lower incidence and slower progression of neurodegenerative diseases (including PD).93 A retrospective study of 419 patients showed a possible disease-modifying effect of fibrate and statin PPAR agonists.94 A recent, large, prospective study has demonstrated that regular use of
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statins is associated with a modest reduction in the PD risk.95 Of course, these drugs are pleiotropic and the putative beneficial effect in PD may not be solely related to PPAR activation. It has been shown that PPAR-gamma agonists are neuroprotective in animal models; pioglitazone is active in MPTP and 6hydroxydopamine rodent model96 and rosiglitazone is active in MPPþ SH-SY5Y cells.97 This preclinical evidence have the assessment of pioglitazone in a Phase II clinical trial in early PD patients. Many currently licensed drugs modulate the PPAR and thus could be assessed as DMTs. It is interesting to note that the thiazolidinediones (including rosiglitazone and pioglitazone) target ironsulphur cluster proteins in mitochondria and the endoplasmic reticulum; these proteins have vital roles in cell energetics, apoptosis and autophagy.98
Iron Chelators Iron metabolism is a tightly regulated process that is designed to render iron available for biochemical functions while minimizing the metal’s involvement in harmful radical formation.99 In various inherited and acquired disorders, the cell’s iron-storage mechanisms and antioxidant capacities are overwhelmed by misdistribution of iron and ensuing reactive oxygen species (ROS) formation and oxidative damage.99–101 The biological damage associated with siderosis mostly results from a rise in labile iron, which is comprised of redox-active and chelatable forms of the metal. In PD, excess iron is detected primarily in the substantia nigra pars compacta (SNc),102–106 where dopaminergic neurons are exposed to high ROS levels93,106–108 produced by the metabolism of dopamine.109,110 It has been recently demonstrated that iron chelation with deferiprone (a membrane-permeant, bidentate chelators with putative neuroprotective properties in Friedreich’s ataxia111) significantly reduced labile iron levels and biological damage in oxidation-stressed cells and improved motor functions while raising striataldopamine levels in animal models. In a prospective, placebo-controlled study of early-stage PD patients with stable dopaminergic regimens, early-start (n ¼ 19) patients compared to responded significantly earlier (and for longer) to deferiprone treatment (relative to delayed-start patients) in terms of brain R2* MRI sequences (indirectly reflecting iron agglomerates in the SNc) and the UPDRS score. Apart from three rapidly resolved cases of iatrogenic neutropenia, safety was
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Clinical Therapeutics maintained throughout the trial and no systemic metal loss was observed - despite uninterrupted daily treatment for up to 18 months.112 The therapeutic features of this novel chelation modality (established in translational models and assessed in a pilot clinical trial based on a delayed-start paradigm) warrant a comprehensive evaluation in PD.
CONCLUSION In advanced PD patients undergoing STN stimulation, the potentiation of noradrenergic and dopaminergic transmission with MPD improved gait and FoG and may relieve apathy; however, the drug failed to improve cognition in this population. Potentiation of the cholinergic system with acetylcholinesterase inhibitors (which are licensed for the indication of dementia) may partially relieve pre-dementia apathy and reduce the risk of the falls. These findings require confirmation in a larger clinical trial. Modulation of the glutamatergic system with NMDA receptor antagonists did not improve gait and dementia but may have improved axial rigidity. Dopamine and/or noradrenaline transporter inhibitors, anticholinesterase inhibitors, PPAR agonists and iron chelators should be investigated as putative DMTs in a delayed-start paradigm trial in a large population.
ACKNOWLEDGMENTS The authors wish to thank Dr. David Fraser (Biotech Communication, Damery, France) for helpful comments on the manuscript’s English. Drs. Devos, Moreau, Dujardin, Defebvre, Bordet, and Mr. Cabantchik were responsible to the concept of the project. Dr. Devos was responsible for the organization of the project. Drs. Devos, Moreau, Dujardin, Defebvre, and Bordet were responsible for the execution of the project. Drs. Devos and Bordet were responsible for the writing of the first draft of the manuscript. Drs. Moreau, Dujardin, Defebvre, Bordet, and Mr. Cabantchik were responsible for the review and critical comment of the manuscript.
CONFLICTS OF INTEREST No particular funding was received for preparation of this article. The authors have no financial disclosures to make or potential conflicts of interest to report in relation to this article. Dr. Moreau has served on the Scientific Advisory Board for Aguettant. Dr. Defebvre has served on the Scientific Advisory Board for
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Novartis and Aguettant. He has received various honoraria from pharmaceutical companies for consultancy and lectures on Parkinson’s disease at symposia (Abbott and Boehringer). Dr. Dujardin has served on the Scientific Advisory Board for Novartis. She has received a grant from the MJ Fox Foundation for Parkinson’s research. Mr. Cabantchik is funded by the A&M Della Pergola Chair in Life Sciences and served on the Scientific Advisory Board of Novartis ESB. In the past, he has received research grants from NIH, the European Union (FP5 and FP6), Israel Science Foundation, Novartis and Apopharma (and also lecture honoraria from the latter two) and is presently a consultant for Aferrix Ltd and Hinoman Ltd. Dr. Bordet receives funding from the French Ministry of Research. He has received various honoraria from pharmaceutical companies for consultancy and lectures at symposia. Dr. Devos has served on the Scientific Advisory Board for Novartis and Aguettant and has received PHRC grants from the French Ministry of Health and research funding from the ARSLA charity. He has received various honoraria from pharmaceutical companies for consultancy and lectures on Parkinson’s disease at symposia.
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Address correspondence to: David Devos, MD, PhD, Clinical Pharmacology Department, University of Lille Nord de France / Lille University Hospital, F-59037 Lille, France. E-mail:
[email protected]
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