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REVIEW

Milestones in Parkinson’s Disease Therapeutics

Olivier Rascol, MD, PhD,1* Andres Lozano, MD,2 Matthew Stern, MD,3 and Werner Poewe, MD4

1Departments of Clinical Pharmacology and Neurosciences, University Hospital of Toulouse and Clinical Investigation Center INSERM CIC9302 and UMR825, University of Toulouse III, Toulouse, France 2Department of Neurosurgery, University of Toronto, Toronto, Ontario, Canada 3Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania, USA 4Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria

ABSTRACT: In the mid-1980s, the treatment of dine opened the door for novel nondopaminergic Parkinson’s disease was quite exclusively centered on approaches of Parkinson’s disease therapy. More dopatherapy and was focusing on systems recently, nonmotor symptoms (depression, dementia, and motor symptoms. A few dopamine and a and psychosis) have been the focus of the first random- inhibitor () were used as ized controlled trials in this field. Despite therapeutic adjuncts in advanced Parkinson’s disease. In the early advances, Parkinson’s disease continues to be a relent- 2010s, levodopa remains the gold standard. New lessly progressive disorder leading to severe disability. insights into the organization of the basal ganglia paved Neuroprotective interventions able to modify the pro- the way for deep brain stimulation, especially of the gression of Parkinson’s disease have stood out as a subthalamic nucleus, providing spectacular improve- failed therapeutic goal over the last 2 decades, despite ment of drug-refractory levodopa-induced motor com- potentially encouraging results with compounds like plications. Novel dopamine agonists (, . Newer molecular targets, new animal mod- , ), catecholmethyltransferase inhibi- els, novel clinical trial designs, and biomarkers to tors (), and monoamine oxidase B inhibitors assess disease modification have created hope for (rasagiline) have also been developed to provide more future therapeutic interventions. VC 2011 Movement Disor- continuous oral delivery of stimulation in der Society order to improve motor outcomes. Using dopamine agonists early, before levodopa, proved to delay the onset of , although this is achieved at the Key Words: Parkinson’s disease; treatment; levodopa; price of potentially disabling daytime somnolence or dopamine agonists; catecholmethyltransferase inhibi- impulse control disorders. The demonstration of an anti- tors; monoamine oxidase B inhibitors; deep brain dyskinetic effect of the glutamate antagonist amanta- stimulation

------Since the late 1960s, the introduction of dopamine *Correspondence to: Professor Olivier Rascol, Department of Clinical replacement via oral levodopa as a treatment to con- Pharmacology, Faculty of Medicine, 37 Alle´ es J Guesde, 31000 Toulouse, France; [email protected] trol the motor symptoms of Parkinson’s disease (PD) Relevant conflicts of interest/financial disclosures: Olivier Rascol has stands out as one of the most astounding successes of received honoraria for consultancy and lecture fees from Abbott, Addex, translational research in modern neuroscience. In the Boehringer Ingelheim, Eisai, GlaxosmithKline, Impax Pharmaceuticals, Lundbeck, Merck Serono, Movement Disorders Society, Novartis, Oxford mid-1980s, after nearly 2 decades of routine clinical Biomedica, Schering-Plough, Servier, Teva Neuroscience, UCB and use of levodopa þ dopa-decarboxylase (DDCI) inhibi- XenoPort. Andres Lozano is a consultant for Medtronic and Boston Scientific. Matthew Stern is a consultant for Adamas, Ipsen, Teva, tors, the medical treatment of PD was quite exclu- Medtronic, and Schering-Plough. Werner Poewe has received honoraria sively centered on dopatherapy. The use of older for consultancy and lecture fees from Astra Zeneca, Teva, Novartis, drugs like antimuscarinics had dramatically declined, GSK, Boehringer-Ingelheim, UCB, Orion Pharma, and Merck Serono in relation to clinical drug development programs for Parkinson’s disease. whereas that of the first ergolinic dopamine agonists Full financial disclosures and author roles may be found in the online (DAs) and monoamine oxidase B (MAO-B) inhibitors version of this article. had entered the clinical arena as an adjunct to levo- Received: 13 December 2010; Accepted: 22 February 2011 Published online in Wiley Online Library (wileyonlinelibrary.com). dopa in advanced PD. In these times, clinical concepts DOI: 10.1002/mds.23714 as well as pharmacological research were still almost

1072 Movement Disorders, Vol. 26, No. 6, 2011 MILESTONES IN PD THERAPEUTICS

TABLE 1. The history of PD therapy—from J. Parkinson to the present 1817 —J. Parkinson proposes to take blood from the upper part of the neck to relieve congestion in the medulla oblongata 1860s —Ordenstein introduces the use of belladonna extracts 1940s —Introduction of synthetic 1950s —Introduction of stereotactic surgery for PD —Largely unnoticed reports on the antiparkinsonian effects of by Struppler123 and Schwab124 1960s —Reports by Birkmayer þ Hornykiewicz125 and Cotzias et al126 on efficacy of levodopa —Report on antiparkinsonian effects of 1970s —Start of development of DA agonists 1980s —Development of the concept of neuroprotection via MAO-B inhibition —First proof-of-concept studies with continuous inrravenous delivery of L-dopa to treat motor complications 1990s —Introduction of COMT inhibitors —Introduction of nonergoline DA agonists —First reports on STN-DBS for advanced PD127–129 —First reports of successful striatal fetal cell transplantation in PD130 2000–2010 —Trials establishing delay of dyskinesia when initiating therapy with DA agonists — efficacy of in PD psychoses —Efficacy of rivastigmine to improve PD dementia —Controlled trials of fetal cell transplantation —Proof-of-concept studies of gene therapy exclusively focused on control of motor symptoms necting the basal ganglia and frontal motor areas, pav- and the dopamine system. Major challenges were ing the way for the introduction of deep brain related to understanding and treating motor complica- stimulation. Recent years have also seen an increasing tions associated with chronic levodopa therapy. Phar- awareness of nonmotor symptoms as driving factors macologists had begun to unravel the multitude of for disability in late-stage PD. Indeed, depression, dopamine receptors with the hope that selective target- dementia, and psychosis have been the focus of new ing of subtypes might lead to effec- randomized controlled trials (Table 1). tive motor control with fewer side effects. The notion Despite therapeutic advances over the last 25 years, PD of ‘‘neuroprotection’’ was developing in laboratories continues to be a relentlessly progressive disorder leading but had never been tested in patients. Randomized to severe motor disability, dementia, nursing home place- controlled trials and evidence-based medicine had not ment, and premature death for a majority of patients after reached modern standards,1–3 and novel assessment 15 or more years of disease.6 Neuroprotective interven- tools like the UPDRS and patient diaries had just tions able to modify the progression of PD have therefore emerged to assess novel antiparkinsonian medica- stood out as a failed therapeutic goal over the last 2 deca- tions.4,5 The fear of adverse reactions had not devel- des. Recent insights into the molecular mechanisms lead- oped the concept of the ‘‘principle of cautiousness.’’ ing to PD have provided novel targets for disease- The antiparkinsonian market was small, sales were far modifying interventions as well as new approaches to ex- from the current estimated $4 billion, and issues such perimental disease modeling. Further, newer clinical trial as conflicts of interest were not of major concern. designs and surrogate markers to assess disease modifica- At the present time, after another 25 years of sus- tion have created hope for therapeutic interventions that tained efforts in drug development, levodopa has will prove to alter the course of PD. remained the gold standard of symptomatic efficacy. At the same time, there have been advances in our under- standing of the importance of levodopa pharmacoki- Milestones in the Medical netics (PKs) and drug delivery as critical factors for the Management of Parkinson’s Disease development of motor complications. This has modified our use of levodopa and other dopaminergic medica- L-Dopa: Facing the Challenges of Motor tions to minimize motor complications. However, Complications and Drug Delivery increased use of DAs has created new challenges includ- Soon after the introduction of levodopa to the rou- ing awareness of more recently recognized adverse drug tine treatment of PD in the 1970s, it became apparent reactions, raising interest in the underrecognized role of that chronic treatment with this agent was associated dopamine in wakefulness and impulse control. with the development of motor complications. Fluctu- The most significant breakthrough in the fight ations in motor performance were shown to reflect against motor complications has emerged from new rises and falls of levodopa plasma levels following insights into the organization of neuronal loops con- individual doses (wearing-off effect),7 whereas some

Movement Disorders, Vol. 26, No. 6, 2011 1073 RASCOL ET AL. cases showed seemingly random and sudden switches cation of catheters, local inflammation around the gas- between ‘‘on’’ and ‘‘off’’ states.8 At the same time, trostomy site, and mechanical pump problems are most of the patients exhibiting these motor fluctua- common complications during long-term use19 and, tions also developed various types of levodopa- together with high costs, still limit the broad-scale use induced involuntary movements with chorea accompa- of this approach. nying ‘‘on’’ periods and painful dystonia of the distal During the late 1980s, ‘‘controlled-release’’ oral for- lower limbs complicating ‘‘off’’ periods.9 More than mulations of levodopa (Sinemet CR and Madopar 30 years after the original clinical descriptions of levo- HBS) were developed in another attempt to increase dopa-related motor complications, their exact underly- the levodopa plasma elimination half-life and improve ing pathophysiology still remains incompletely oral drug delivery. Unfortunately, such formulations understood. However, a growing body of preclinical did not really improve ‘‘off’’ problems in patients with evidence together with clinical observations suggests established fluctuations. Moreover, the early use of the that most levodopa-related motor complications are CR versus standard formulations failed to reduce the related to several factors10: (1) the severity of dopa- incidence of motor complications in the long term.22 mine denervation, as demonstrated by the rapid and It is likely that these disappointing results were related severe occurrence of motor complications in monkeys to insufficient improvement in levodopa PKs that did 11,12 and humans acutely intoxicated with MPTP ; (2) not achieve adequate CDD. the dose of levodopa, as demonstrated in the ELL- A more successful PKs improvement resulted from DOPA study that was the first clinical trial conducted the development in the 1990s of catecholmethyltrans- to assess the efficacy and safety of different doses of ferase (COMT) inhibitors as adjunct therapies, leading the drug in a randomized, double-blind, placebo-con- to an increase in both the half-life and bioavailability 13 trolled design ; and (3) the discontinuous delivery of of single levodopa doses. Clinical trials with levodopa to the brain resulting in intermittent pulses and entacapone in patients with wearing-off fluctua- of striatal dopamine receptor stimulation that in turn tions have consistently shown reductions in ‘‘off’’ time triggers neuroplastic changes in striatal pallidothala- between 1 and 2.5 hours, with somewhat greater 14 mocortical motor loops. Therefore, attempts have effect sizes with tolcapone than with entacapone.23 been made during the last 25 years to optimize levo- These trials, however, have also consistently shown dopa delivery in order to provide more continuous increases in , requiring a reduction in total dopamine stimulation (CDS) or at least more continu- daily levodopa intake. Conversely, animal experiments ous dopamine delivery (CDD) and to ‘‘spare’’ the provided evidence that the combined use of levodopa cumulative dose of levodopa with the use of other with the COMT inhibitor entacapone induced lesser dopaminergic . degrees of dyskinesias compared with standard levo- Two landmark proof-of-concept studies published in dopa when administered to drug-naive animals.24 the mid-1980s provided the first clinical evidence that These observations suggested that combined treatment continuous delivery of levodopa via intravenous infu- with levodopa and a COMT inhibitor might reduce sions is associated with dramatic improvement in the pulsatility of dopaminergic stimulation in the stria- motor oscillations in patients with advanced PD.15,16 tum. The STRIDE-PD trial was then initiated to inves- Similar results were soon reported using continuous tigate whether the early combination of standard duodenal levodopa infusions.17 Although these early levodopa/ with entacapone versus levodopa/ proof-of-concept studies using intravenous or duode- carbidopa could delay the time to first occurrence of nal constant rate infusions focused on the treatment of dyskinesias in levodopa-naive patients. After approxi- motor fluctuations, more recent work also showed mately 3 years of follow-up, patients treated with the that preexisting levodopa-induced dyskinesias can be triple combination had shorter delays and greater inci- markedly downregulated when switching to intrajeju- dences of dyskinesias compared with those on stand- nal infusion schemes.18 Routine use of enteral levo- ard levodopa/carbidopa.25 This finding contradicts the dopa infusions, however, was initially limited by the CDD hypothesis. It remains unclear whether this was poor solubility of the drug. Within the last decade, the caused by a failure to achieve sufficient CDD (4 times development of a new carboxymethylcellulose gel for- the administrations of levodopa/carbidopa/entacapone mulation enabled concentrations of levodopa of 20 every 3.5 hours may still lead to plasma level fluctua- mg/mL and short- and long-term studies using intra- tions)26 or whether factors other than CDD are to be duodenal infusions via external pump systemspre and considered. intraduodenal permanent catheters placed via percuta- Therefore, after more than 40 years of routine clini- neous external gastrostomy have demonstrated both cal use, the optimum way of delivering levodopa to marked reductions in motor response oscillations and the brains of patients with PD still remains an elusive significant amelioration of preexisting levodopa- goal in current therapy, and clinical research and de- induced dyskinesias.19–21 Nevertheless, system-related velopment into novel delivery routes including new complications such as kinking and occlusions or dislo- oral sustained-release formulations are ongoing.

1074 Movement Disorders, Vol. 26, No. 6, 2011 MILESTONES IN PD THERAPEUTICS Optimizing Striatal Dopamine Substitution: ger elimination half-life provides any further benefit The Early Use of DAs on CDD and dyskinesia. Dopamine agonists (DAs) have longer plasma elimi- In 2010, after more than a decade of widespread nation half-lives than levodopa. Their use has there- use of DAs in early PD, long-term clinical experience fore been considered an opportunity to improve CDD. has taught us that the initial innovative and attractive By the late 1980s, ergot-derived DAs (, finding of delaying time to dyskinesia with a DA is far , , and ) already had an from being the sole relevant outcome to consider. established role as adjuncts to levodopa in advanced Indeed, our knowledge has extended to several other PD because of their ability to reduce ‘‘off’’ time and, important issues: in many instances, allow a lowering of the levodopa • The large-scale use of DAs revealed that these dose, reducing dyskinesias. drugs carry a greater risk than levodopa of previ- Since 1985, the place of DAs in the treatment of PD ously unknown or underestimated and potentially has changed in 2 ways. First, the continuous subcuta- troublesome adverse drug reactions including neous infusion of DAs like apomorphine or lisuride abnormal daytime somnolence,47–50 leg edema,51 was reported to improve ‘‘off’’ problems and dyskine- and impulse control disorders.52–54 sia in small uncontrolled series.27,28 Such observations • Levodopa must almost inevitably be added to a provided further support to the concept of CDD, and DA to keep control of parkinsonism after a in Europe the use of subcutaneous pumps of apomor- few years of treatment, although the early use of phine is indeed marketed to treat PD patients with 29 a DA reduces the cumulative dose of levodopa severe levodopa-induced motor complications. Sec- and explains the long-term benefit of DAs on ond, the use of oral DAs has moved to earlier stages dyskinesia.55–57 of PD. DAs proved to induce less dyskinesia than levo- • The long-term disability and quality of life of 30 dopa in levodopa-naive MPTP-intoxicated monkeys. patients initially randomized to an or lev- Following early pilot uncontrolled observations in PD odopa do not differ,58 although the impact of dys- 31,32 patients, the first levodopa-controlled trials were kinesia on quality of life can vary greatly from published in the mid-1980s, suggesting that patients patient to patient. starting on an agonist had a lower risk of subsequent • Motor complications, although occurring in the motor complications than those starting on levo- majority of PD patients, may no longer be as dopa.33,34 This was subsequently confirmed within the problematic as they were 30 years ago, as lower last decade by double-blind trials demonstrating that doses of levodopa are generally used, and novel ‘‘time to dyskinesia’’ was delayed in patients random- medical and surgical therapies have emerged to ized to an agonist early as compared with levo- manage such problems (see below). dopa.35–38 This consistent finding thereby changed our • It is now realized that in most PD patients long- standard of care from the primary use of levodopa to term disability (15 years) is driven by problems the primary and early use of DAs, especially in such as falls or dementia, and these are not influ- 6 younger-onset patients. Levodopa is now commonly enced by early treatment with agonists. • held in reserve to supplement DAs when adequate Finally, it is also now agreed that there is no control of symptoms cannot be achieved with an ago- clinical evidence supporting the theoretical nist alone. Whether the long-term treatment of PD is rationale to avoid levodopa because of its potential oxidative ‘‘toxicity’’ toward dopamine best achieved with the initial use of a DA followed by 59 levodopa or with lower doses of initial levodopa with neurons. the early addition of DAs remains to be seen. Most experts now agree that withholding levodopa should In summary, after 20 years of an increasing use of never be at the expense of good symptomatic control, DAs in PD, their place remains a matter of debate. which may itself be a strong predictor of better long- We first learned that using them early spares levodopa term outcomes. and reduces dyskinesia. This approach, commonly By the late 1990s, ergot DAs had been largely promoted by drug companies, has sometimes induced replaced by nonergot drugs like ropinirole and prami- an inappropriate ‘‘levodopa phobia,’’ especially among 60 pexole because of reports of fibrotic adverse reactions, patients. We now know that DAs can cause somno- including cardiac valvular damage from pergolide and lence and impulse control disorders, and a novel ‘‘pho- bromocriptine.39–41 Recently, controlled-release for- bia,’’ this time toward DAs, is currently emerging, mulations of oral ropinirole42,43 and pramipexole44 especially among physicians. In this context, after and transdermal formulations of rotigotine have been years of attempting to spare levodopa with DAs, it is developed,45,46 offering the convenience of a once- possible that a future popular alternative will be using daily regimen. It remains unknown whether their lon- MAO-B inhibitors early to spare DAs!

Movement Disorders, Vol. 26, No. 6, 2011 1075 RASCOL ET AL. From Symptomatic Therapies to the Concept same benefit. Therefore, the importance of these of ‘‘Neuroprotection’’: MAO-B Inhibitors results for clinical practice remains controversial.75 and Beyond Definitive evidence for clinically meaningful disease Twenty-five years ago, oxidative stress was consid- modification remains an unsolved methodological issue, and most published trials remain negative or ered an important contributor to neurodegeneration 76–78 in PD. With the recent discovery of MPTP toxicity61 inconclusive. Other trial designs have been and its blockade by MAO-B inhibitors, a clinical trial employed to look further. For example, in the long- term simple design, patients on PD medications are of an MAO-B inhibitor as a neuroprotective agent treated with an investigational agent or placebo and seemed logical, leading to the launch of the first followed for upwards of 5 years with a composite of major trial of a putative disease-modifying agent. end points, including nondopaminergic features such The Deprenyl and Tocopheral Antioxidative Therapy as freezing, falls, and dementia. Future advances will of Parkinsonism trial (DATATOP) was positive in also depend on better understanding of the mecha- showing a significant delay in the need for levodopa nisms governing cell death in PD and better animal treatment in patients treated with deprenyl versus models, taking advantage of the recent progress in PD placebo62 but also illustrated that a mild sympto- genetics.79 It is hoped that these approaches will open matic effect in a trial so designed would confound 63 up new therapeutic targets and new molecules, any neuroprotective interpretation, such that the addressing oxidative stress, excitotoxicity, mitochon- debate whether this and subsequent trials of deprenyl drial dysfunction, inflammation, growth factors, apo- support a ‘‘neuroprotective’’ effect is still ongoing. ptosis, autophagy, or proteosome dysfunction.69 However, DATATOP provided a strong stimulus to develop and study numerous compounds for their potential to modify the course of PD and to further refine clinical trial methodology to better assess dis- Motor Control Beyond Dopamine ease progression.64 Replacement : The Antidyskinetic Properties In the 1990s, rasagiline was another MAO-B inhibi- of Amantadine tor, with different metabolites than selegiline, to be Within the past 25 years, animal models of PD have successfully developed for PD therapy. From a symp- strongly emphasized how nondopaminergic mecha- tomatic perspective, rasagiline 1 mg/day proved to be nisms contribute to brain dysfunction in PD. This is efficacious both as monotherapy in early PD65,66 and caused by the direct degeneration of nondopaminergic as an adjunct to levodopa to treat ‘‘off’’ episodes in cholinergic, adrenergic, and nuclei80 and more advanced patients,67 this last effect being compa- by the indirect functional impairment of nondopami- rable to that of entacapone.68 The good tolerability of nergic relays of cortico-subcortical loops as a result of rasagiline and its ease of use (1 dose, once daily, no ti- basal ganglia dopamine denervation.81 This back- tration) makes this drug an appealing option to start ground constituted the rationale for attempts to therapy in PD,69 whereas the use of selegiline has been develop new nondopaminergic antiparkinsonian medi- largely abandoned, despite a lack of head-to-head cations targeting transmitter systems outside the stria- comparisons of the 2 compounds. The current popu- tal dopamine synapse82–84 (Fig. 1). This approach has larity of rasagiline is also related to the finding that raised great hopes, and the validity of the concept is the drug has neuroprotective properties in vitro70,71 supported by the long known antiparkinsonian effi- and was the first putative disease-modifying agent to cacy of antimuscarinic drugs, although their use has be tested with a randomized delayed-start design in largely declined in the levodopa era because of their PD.72 The recent ADAGIO trial showed that early poor safety profile. therapy with 1 mg/day of rasagiline induced less cu- Despite sustained pharmacological efforts, only mulative disability over 18 months than the same ther- amantadine, discovered to have antiparkinson effects apy initiated 9 months later.73 The mechanisms in the 1960s,85 seems to relate to these novel mecha- underlying this effect remain unclear: enhanced sur- nisms. Following the discovery of an increased phos- vival/functioning of dopaminergic neurons (‘‘neuropro- phorylation state of the NMDA glutamate receptors in tective’’ effect) or improved brain compensatory striatal spiny neurons of dyskinetic MPTP-intoxicated plasticity. Nevertheless, this result supports the con- levodopa-treated monkeys, it was hypothesized that cept that patients may benefit from being treated early hyperactivity of glutamatergic transmission is a key in the course of PD and not when disability has pro- mechanism underlying dyskinesia.86,87 Amantadine’s gressed to more substantially affecting activities of mechanism of action remains poorly understood, but daily living.74 It remains unknown whether the benefit it is one of the few noncompetitive NMDA antago- reported in ADAGIO on rasagiline 1 mg/day after 18 nists that can be used in humans.88 This is why it was months persists over longer follow-up and why chosen to test the antiglutamate antidyskinetic concept another tested dose (2 mg/day) did not provide the in pilot proof-of-concept clinical trials during the late

1076 Movement Disorders, Vol. 26, No. 6, 2011 MILESTONES IN PD THERAPEUTICS

FIG. 1. Nondopamine targets and candidate drugs studied in recent trials in PD (5-HT1A-R, 5-HT1A receptor; a2, a2-adrenergic receptor; Glu, gluta- mate; Glu-R, glutamate receptor; STN, subthalamic nucleus; SN, substantia nigra; Gpe, globus pallidus externus; Gpi, globus pallidus internus; DA, dopamine agonists; GABA, gamma-aminobutyric acid). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

1990s which confirmed its antidyskinetic effects in functions like cognition, regulation of mood and hedo- PD patients.89,90 nistic tone, sleep–wake cycle regulation, and auto- Other nondopaminergic drugs have been devel- nomic nervous system function, as well as sensory oped based on the same concept during the last disorders and pain. In their various combinations, decade, including the A2A adenosine antagonist nonmotor symptoms may eventually become the chief ,91 the AMPA antagonist perampanel,92 source of disability of advanced PD. A recent 20-year and the 5HT1A agonist sarizotan93 (Fig. 1). follow-up of a prospective cohort of PD patients Unfortunately, translation from animal models to showed that more than 80% of survivors had cogni- clinical trials failed or provided inconsistent results. tive decline, with dementia and hallucinosis present in Poor model predictability, inadequate drug selectiv- 50%, depression in 50%, and between 30% and 40% ity, or wrong dosages may account for these disap- of patients showing autonomic features like ortho- pointing results. static hypotension or urinary incontinence.58,95 Despite the impact of nonmotor features of PD on Advances in the Treatment of Nonmotor long-term disability, there is a striking paucity of Symptoms randomized controlled clinical trials assessing inter- PD continues to be clinically defined as a movement ventions specifically targeting these features. When the disorder, and for the past decades treatment research MDS Task Force on evidence-based medicine reviewed has almost exclusively targeted the cardinal motor all English-language publications of randomized con- symptoms or the complications induced by chronic trolled trials assessing interventions to treat the differ- levodopa therapy. However, the neuropathology of ent symptoms of PD, only 2 level I studies were PD involves many brain areas beyond the nigrostriatal identified that had assessed interventions specifically dopaminergic system including parts of the limbic area targeting a nonmotor PD symptom in a PD cohort of and neocortex, the diencephalon, and multiple brain greater than 10 patients for more than 4 weeks using stem areas not related to motor control, as well as the an established and validated outcome instrument cov- peripheral autonomic nervous system.94 Although ering a review period ending in January 2002.1 Both exact clinicopathological correlations are not always these trials had established the efficacy of low-dose clear, nonmotor symptoms in PD are likely related to clozapine therapy to treat PD psychosis in a placebo- the disseminated pathology in PD and include multiple controlled design. Since then, no further trials of drugs

Movement Disorders, Vol. 26, No. 6, 2011 1077 RASCOL ET AL. to treat PD psychosis have matched clozapine’s effi- A number of events led to the reemergence of sur- cacy. In particular, 3 placebo-controlled studies have gery for PD in the last 25 years. First was the emer- failed to demonstrate the antipsychotic efficacy of que- gence of levodopa-related complications with long- tiapine in PD patients despite a consistent body of evi- term therapy and disease progression, particularly dence from open-label studies showing some degree of motor fluctuations and the emergence of drug-induced improvement in psychotic symptoms and a small dyskinesias. Some patients with PD thus continued to randomized comparator trial with clozapine showing be disabled despite best available medical treatment. similar effect sizes for .96 Second, a number of advances occurred in the under- Since this MDS-sponsored review, several new standing of basal ganglia pathophysiology, aided in randomized controlled trials have targeted PD demen- large part by the development of the MPTP model of tia. The first large-scale randomized controlled trial parkinsonism in nonhuman primates.106 Such studies ever focusing on nonmotor symptoms of PD has showed the important role of the subthalamic nucleus shown that the cholinesterase inhibitor rivastigmine and the internal segment of the globus pallidus in the provides a benefit in patients with mild to moderate cardinal motor symptoms in PD and paved the way 97 dementia, and this was also later suggested for done- for experimental surgical therapeutics. Third, there pezil in another placebo-controlled randomized were important advances in neurosurgical techniques, 98 study. Two more recent placebo-controlled trials of including better imaging with CT and MR, the refine- the antiglutamatergic agent in mixed popu- ment of neurophysiological mapping with microelec- lations of patients with PDD and DLB failed to show 107–109 99,100 trode recordings, and the development of deep consistent benefits in patients with PDD. Never- brain stimulation (DBS), first in the thalamus to repro- theless, cognitive dysfunction, dementia and psychosis duce the effects of thalamotomy for tremor and from continue to be major therapeutic challenges of there expansion to other basal ganglia targets. advanced PD. Early experiments by groups in Baltimore and Man- In 2010, the only large placebo-controlled, random- chester showed that the overactivity of the globus pal- ized trial targeting depressive symptoms in PD used lidus interna (GPi) and subthalamic nucleus (STN) in the pramipexole and reported small parkinsonian models could be neutralized by precise but statistically significant improvements that could 110,111 lesioning. These seminal observations paved the not be fully explained by concomitant improvement in way for high-frequency deep brain stimulation (DBS) motor symptoms101 In contrast, the evidence for effi- in experimental animals112 and PD patients. At about cacy of classical remains sparse and the same time, in a landmark study published in 1992, only supports the efficacy of imipraminic agents like Laitinen reintroduced pallidotomy,113 which had been desipramine102 and ,103 whereas the most resuscitated from the 1950s and 1960s to the world of commonly used group of agents—the SSRIs—lacks Parkinson’s. A large number of pallidotomies were solid evidence for efficacy in PD depression from prop- performed with excellent clinical results, particularly erly designed clinical trials. The most recent review of for unilateral procedures.107 In the 1990s pallidotomy clinical trials on the treatment of the nonmotor symp- toms of PD failed to identify any randomized, con- was the most common surgical procedure for PD. In trolled clinical trial meeting class I criteria for the decade starting in 2000, however, pallidotomy interventions targeting constipation, urinary inconti- procedures have been overtaken by DBS, as the nence, sexual dysfunction, or orthostatic hypoten- adverse effects of bilateral pallidotomy became too im- sion.104 Taken together, well-designed, controlled portant to tolerate. Using the number of citations per pallidotomy clinical trials of therapeutic interventions targeting the decade in PUB MED with the words or deep brain stimulation nonmotor symptoms of PD remain a key clinical revealed interesting trends, as research priority. shown in Table 2. In the Western world, DBS has virtually eliminated the practice of ablative procedures and provided noth- The Renaissance of PD Surgery ing less than dramatic improvement for many patients with advanced PD and complications of drug therapy. Although a variety of surgical approaches to PD STN DBS was first reported to have a major impact were tried in the 1940s, it was only Cooper’s acciden- on the symptoms of PD by Benabid and his col- tal thalamotomy in the 1950s105 that resulted in a leagues114,115 and in the last decade, numerous studies standard ablative procedure for parkinsonian features have confirmed the major impact of this procedures in the prelevodopa era. Because of its excellent effect on the symptoms of PD.116 The latest DBS study com- on tremor, it continued to be used sparingly. With the paring DBS of both the GPi and STN suggests that introduction of levodopa in the 1960s and the realiza- both targets might offer similar motoric benefits,117 tion of its striking benefits, surgical treatments were although this remains a matter of debate. In compari- temporarily largely abandoned. son, the best adjunctive medications developed in the

1078 Movement Disorders, Vol. 26, No. 6, 2011 MILESTONES IN PD THERAPEUTICS

TABLE 2. Number of Pub Med citations of ‘‘pallidotomy’’ or ‘‘deep brain stimulation’’ across 10-year epochs from 1950 to 2010

Procedure 1950–60 1961–70 1971–80 1981–90 1991–00 2001–10

Pallidotomy 14 17 5 3 428 273 Deep brain stimulation 0 0 7 29 196 3555 last 25 years improved ‘‘off’’ time in PD by 1–2 hours. Therefore, the development of ‘‘neuroprotective’’ DBS improves ‘‘off’’ time by 5–6 hours, allows a sub- treatments via identification of novel molecular tar- stantial reduction in medications in many patients, gets and drug candidates through improved animal and often eliminates dyskinesias entirely. Although we models is the central challenges for future PD therapy. will continue to refine our target choice and study To detect signals of efficacy and monitor disease-mod- novel targets for stimulation, DBS is indeed a major ifying effects, reliable surrogate markers for PD pro- therapeutic milestone. The late David Marsden said he gression are badly needed. A central focus of current saw 2 miracles in PD in his career. The first was the clinical PD research, therefore, is the identification of introduction of levodopa and the second, the develop- markers, both for disease progression and, more ment of deep brain stimulation for PD (personal com- importantly, for the identification of at-risk subjects. munication to Andres Lozano). In 2010, a variety of genomic, proteomic, neurophys- iological, and imaging marker candidates emerged, with some of them, like hyposmia, carrying the poten- Future Perspectives tial for use as first-step screening instruments on a population basis. Large-scale, prospective studies in Cell-based therapies trying to restore the nigrostria- healthy subjects are needed to define the sensitivity tal dopamine projection have been at the forefront of and specificity of different PD risk markers with the neuroscientific research for more than 2 decades, but aim of eventually defining a set of markers with suffi- clinical trials using human fetal mesencephalic dopa- cient predictive value to begin planning large neuro- minergic cells or other sources of dopaminergic cells preventive interventional trials in PD risk so far have not stood the test of sham-surgery- populations. Such screening programs will likely controlled clinical trials.118,119 In addition, these involve multistep procedures, starting off with easily approaches have resulted in uncontrollable off-medica- available and low-cost tests that can be used on a tion dyskinesias, and Lewy body degeneration has population basis, with more costly secondary screens been observed in grafted fetal neurons.120,121 Still, involving imaging and other markers to further nar- cell-based therapy may be one of the future row these high-risk groups, which would then be can- approaches to physiological continuous dopamine didates for neuropreventive interventions. PD-risk replacement in PD if alternative sources, in particular prediction and neuroprevention may well be another stem cells, can be developed to a stage where routine major milestone in PD therapy that could be reached clinical use will become safe and feasible. within the next 25 years. 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