Need For Levodopa Research Articles

Analysis of a precision medicine approach to treating Parkinson's disease: Analysis of the DATATOP study

IntroductionThe aim of this study was to examine the potential application of a targeted proteomic predictive biomarker comprised predominantly of inflammatory proteins in distinguishing those who responded to a previously conducted clinical trial for Parkinson's disease (PD). MethodsPlasma samples obtained from a biorepository were assayed from a total of n = 520 DATATOP (Deprenyl And Tocopherol Antioxidative Therapy Of Parkinsonism) clinical trial participants across treatment arms. Support vector machine analyses were conducted to distinguish responder status on primary (need for Levodopa) and secondary trial endpoints (UPDRS Motor and Total Scores). ResultsFor the α-tocopherol and deprenyl placebo treatment arm (TOC), the targeted proteomic biomarker was able to distinguish responder status with an accuracy (area under the curve [AUC]) of 91% for the primary endpoint while it was 100% across secondary endpoints. For the deprenyl and α-tocopherol placebo treatment arm (DEP), the AUC was 93% for the primary endpoint and 99–100% for the secondary endpoints. For the combined treatment arm, AUC was 87% for the primary and 94–96% for the secondary endpoints. DiscussionThe targeted proteomic predictive biomarker was highly accurate in distinguishing responder status across treatment arms thereby supporting the application of a precision medicine approach to treating PD.

Time until Need for Levodopa among New Users of Dopamine Agonists or MAO-B Inhibitors.

Objective To investigate the use of dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors in the Norwegian population, between 1 July 2006 and 31 December 2016. Our primary endpoint was time until need for levodopa among new monotherapy users of dopamine agonists and MAO-B inhibitors. Methods A prospective cohort study including all patients, aged 50 years or above, who had at least one prescription for a dopamine agonist or a MAO-B inhibitor dispensed in the study period. We used data from the Norwegian Prescription Database (NorPD). As we wished to focus on new Parkinson patients, we excluded patients who had levodopa dispensed less than 180 days prior to their first dopamine agonist or MAO-B inhibitor redemption. We explored the demographics and the time until monotherapy was insufficient treatment (defined as need for levodopa prescription). Results We included 22958 new monotherapy users. Of these, 22108 used dopamine agonists and 850 used MAO-B inhibitors. The mean number of days until the first prescription of levodopa was dispensed was higher among the dopamine agonist users (621 days) compared to the MAO-B inhibitor users (352 days). The proportion of dopamine agonist users who started levodopa treatment during the study period was less than 7%, while the corresponding proportion of MAO-B inhibitor users was almost 59%. Conclusions We found that new dopamine agonist users had a much greater delay in the need for levodopa than new MAO-B inhibitor users. It seems to be beneficial to initiate treatment with dopamine agonists when starting pharmacological treatment for new Parkinson patients.

Propofol Reduces Microelectrode-Recording Artefacts caused by Parkinsonian Tremor during Deep Brain Stimulation

AbstractA 51-year-old male with medically refractory Parkinson's disease was scheduled for bilateral deep brain stimulation (DBS). During microelectrode recordings (MERs) of right side DBS, the patient developed severe sustained whole-body tremors causing severe artefacts in MER. The right side DBS electrode was inserted with suboptimal MER. For the creation of left burr hole, propofol infusion at a rate of 20 μg/kg/min, was used and soon after, all tremor activity ceased. Propofol infusion was continued during left side MER. With the absence of tremors, left subthalamic nucleus spike activity was better identified and neurological testing could take place. At 6 months after DBS, the patient’s symptoms had improved significantly without the need for levodopa.

Monoamine Oxidase B Inhibitors in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder with a prevalence increasing with age. Oxidative stress and glutamate toxicity are involved in its pathomechanism. There are still many unmet needs of PD patients, including the alleviation of motor fluctuations and dyskinesias, and the development of therapies with neuroprotective potential. To give an overview of the pharmacological properties, the efficacy and safety of the monoamine oxidase B (MAO-B) inhibitors in the treatment of PD, with special focus on the results of randomized clinical trials. A literature search was conducted in PubMed for 'PD treatment', 'MAO-B inhibitors', 'selegiline', 'rasagiline', 'safinamide' and 'clinical trials' with 'MAO-B inhibitors' in 'Parkinson' disease'. MAO-B inhibitors have a favorable pharmacokinetic profile, improve the dopamine deficient state and may have neuroprotective properties. Safinamide exhibits an anti-glutamatergic effect as well. When applied as monotherapy, MAO-B inhibitors provide a modest, but significant improvement of motor function and delay the need for levodopa. Rasagiline and safinamide were proven safe and effective when added to a dopamine agonist in early PD. As add-on to levodopa, MAO-B inhibitors significantly reduced off-time and were comparable in efficacy to COMT inhibitors. Improvements were achieved as regards certain non-motor symptoms as well. Due to the efficacy shown in clinical trials and their favorable side-effect profile, MAO-B inhibitors are valuable drugs in the treatment of PD. They are recommended as monotherapy in the early stages of the disease and as add-on therapy to levodopa in advanced PD.

Central and systemic C-type Natriuretic Peptide are both reduced in Parkinson's Disease

IntroductionC-type Natriuretic Peptide is a neuropeptide widely expressed in the central nervous system including dopaminergic neurons projecting to basal ganglia. Previous work shows that concentrations of the peptide in cerebrospinal fluid are depressed in drug naïve PD subjects, decline over time and can be restored by doses of monoamine oxidase inhibitors that delay the need for levodopa. Whether plasma levels are similarly depressed in drug naïve subjects, or affected by dopaminergic drugs, is unknown. Our objectives were to determine whether (i) peptide products in plasma differ from normal in PD, and (ii) levels are affected by dopaminergic treatment. MethodsPlasma C-type Natriuretic Peptide and amino-terminal proCNP were measured in two groups – 27 drug naïve subjects with PD, and 30 subjects stabilized on dopaminergic drugs for at least 3 years. Values were compared with standard deviation scores from a population reference group without neurological disorder. Independent associations with predetermined variables known to affect plasma concentrations were assessed by multivariate analysis. ResultsIn both PD groups, plasma amino-terminal proCNP was significantly depressed compared to the reference range. Concentrations did not differ between the two groups. No correlation with disease duration or phenotype was found. Across all subjects, in a model initially comprising 7 factors, serum creatinine, PD and age were independent significant associations with amino-terminal proCNP. ConclusionsPlasma concentrations of amino-terminal proCNP are depressed in PD, are likely to result from diminished reabsorption from central sources, and may be useful in monitoring onset and effects of therapeutic interventions in PD.

Dopamine agonist monotherapy in Parkinson's disease and potential risk factors for dyskinesia: a meta‐analysis of levodopa‐controlled trials

Dopamine agonists (DAs) are generally considered to be deprived of the highly dyskinetic effect of levodopa in Parkinson's disease (PD) patients. However, the risk for dyskinesia induced by DA monotherapy and the contribution of clinically significant factors in the development of this disorder have never been systematically assessed. A systematic literature search was conducted for randomized, levodopa-controlled trials of DAs in early PD. A meta-analysis was performed to calculate the combined odds ratio (OR) for dyskinesia. Meta-regressions were subsequently performed on dyskinesia OR including individually as covariates the effects of mean disease duration, treatment duration and DA dose. In an additional analysis the effect of adjunct levodopa on the odds for dyskinesia was investigated. DA monotherapy resulted in an 87% lower risk for dyskinesia compared with treatment with levodopa (OR=0.13, 95% confidence interval0.09-0.19, P <0.001). The risk for dyskinesia was independent of the dose of DA, disease duration and treatment duration. A dose-related pattern was revealed between adjunct levodopa in the DA group and dyskinesia. Nevertheless, the odds for dyskinesia in the DA group were constantly lower than in the levodopa group. Initial DA treatment encompasses a lower risk for dyskinesia even after the unavoidable introduction of levodopa that increases the risk for dyskinesia in a dose-related manner. As the dose and treatment duration with DAs are factors independent of the risk of dyskinesia, monotherapy with DAs in early PD is suggested at doses that ensure efficacy and delay the need for levodopa, always following an adequate evaluation of the risks DAs can pose in individual patients.

Controversies in Neurology: why monoamine oxidase B inhibitors could be a good choice for the initial treatment of Parkinson's disease

BackgroundEarly initiation of pharmacotherapy in Parkinson's disease (PD) is nowadays widely advocated by experts since the delay of treatment has shown to be associated with a significant deterioration of health related quality of life in affected patients. Due to marked advances in PD treatment during the last decades, physicians are nowadays fortunately equipped with a variety of substances that can effectively ameliorate emerging motor symptoms of the disease, among them levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors. Despite numerous drug intervention trials in early PD, there is however still ongoing controversy among neurologists which substance to use for the initial treatment of the disease.DiscussionIn multiple studies, MAO-B inhibitors, such as selegiline and rasagiline, have shown to provide mild symptomatic effects, delay the need for levodopa, and to reduce the incidence of motor fluctuations. Although their symptomatic efficacy is inferior compared to dopamine agonists and levodopa, MAO-B inhibitors undoubtedly have fewer side effects and are easy to administer. In contrary to their competitors, MAO-B inhibitors may furthermore offer a chance for disease modification, which so far remains a major unmet need in the management of PD and eventually makes them ideal candidates for the early treatment of the disease.SummaryMAO-B inhibitors may constitute a preferable therapeutic option for early PD, mainly due to their favourable safety profile and their putative neuroprotective capabilities. Since the symptomatic effects of MAO-B inhibitors are comparatively mild, dopamine agonists and levodopa should however be considered for initial treatment in those PD patients, in whom robust and immediate symptomatic relief needs to be prioritized.

New considerations in the medical management of early Parkinson's disease: Impact of recent clinical trials on treatment strategy

The best approach to medical management of early Parkinson's disease remains controversial. Recent studies suggest that early use of MAO-B inhibitors may improve long-term outcome. Long-term follow-up to a delayed-start rasagiline study indicated that patients who were treated with rasagiline from the start did better through 5.5-6 years of treatment (with all PD medications) than patients who began rasagiline after a delay of 6 months. In a long-term selegiline study, patients randomized to treatment with selegiline did better over 7 years than patients randomized to treatment with placebo. Dopamine agonists provide moderate symptomatic benefit, delay the need for levodopa, and delay the emergence of motor complications, especially dyskinesia. Long-term studies have not demonstrated a clear overall benefit to introducing a dopamine agonist prior to levodopa in general PD populations, but treatment regimens tend to become increasingly similar over time, most studies have had high drop-out rates, and there may be subsets of patients who experience greater benefit with this strategy. Levodopa remains the most efficacious oral medication for the treatment of motor signs of PD but is associated with the development of motor complications. Long-acting levodopa formulations are now under development and it will be important to determine whether they cause fewer motor complications than standard levodopa. The current approach to treatment of early PD depends in part on individual patient factors including age, severity of motor signs, presence of cognitive dysfunction, and other co-morbidities.

Did levodopa vs. dopamine agonist trials teach us when and how to start symptomatic therapy?

The treatment of Parkinson’s disease (PD) with levodopa has been called one of the success stories of modern medicine [1]. As the precursor of dopamine in the catecholamine synthetic chain, it can be taken orally because it crosses the blood-brain barrier, whereas dopamine does not [1]. When first introduced in the 1960’s, the new drug’s dramatic results in even severely affected Parkinson patients raised the hope that all neurodegenerative diseases might be treated with replacement of depleted transmitters. But complications of chronic therapy soon became apparent, superimposing upon the disease-related problems an additional burden of motor fluctuations (the “on-off” reaction), dyskinesias, and visual hallucinations [2]. Unlike levodopa, dopamine agonist agents do not require conversion and storage because they bypass the failing nigrostriatal pathway to directly stimulate receptors in the normal striatum. They are the most effective class of drugs for PD after levodopa. In early disease, they provide an effective treatment strategy, delaying the need for levodopa. The oral dopamine agonists commonly used are: • Bromocriptine (Parlodel) • Pergolide (Permax) • Pramipexole (Mirapex) • Ropinirole (Requip) • Cabergoline (Casbar) The development of dyskinesia may depend on disease severity and the half-life of the dopaminergic agent. Patients who have mild disease do not develop dyskinesia with either levodopa or dopamine agonists, presumably because they still have enough dopamine terminals to regulate dopamine release and provide postsynaptic dopamine receptors with relatively physiologic dopaminergic stimulation [2]. In more advanced disease, there

Cost Effectiveness of Rasagiline and Pramipexole as Treatment Strategies in Early Parkinsonʼs Disease in the UK Setting

Levodopa is the most effective treatment for the symptoms of Parkinson's disease (PD). However, after an initial period of benefit, several limitations become apparent, including motor complications such as dyskinesia. Dyskinesia can severely affect patients' quality of life and increases healthcare resource use. Thus, delaying the need for levodopa, and therefore the onset of levodopa-induced dyskinesia, is important. The aim of this study was to compare the cost effectiveness, from a UK healthcare payer perspective, of two antiparkinsonian treatment strategies in early PD: first-line monotherapy with rasagiline, a novel monoamine oxidase B inhibitor; and the non-ergoline dopamine receptor agonist pramipexole. An economic Markov model was developed as a pragmatic tool to derive comparative information on the effectiveness, utility and costs of these two strategies over a 5-year period. Model input data were obtained from the TEMPO study for rasagiline and from a study by the Parkinson Study Group for pramipexole. Effectiveness outcomes were time to levodopa and time to levodopa-induced dyskinesia. Cost and quality-adjusted life-year (QALY) data were derived from published sources. Rasagiline was the dominant strategy. Compared with pramipexole, use of the rasagiline strategy was estimated to reduce costs by 18% per patient over 5 years and was associated with an additional 10% delay in dyskinesia onset (0.41 years; 95% CI 0.27, 0.55). This strategy was also found to prolong the time to levodopa initiation by 25% through a gain of 0.83 levodopa-free years (95% CI 0.56, 1.1). In addition, use of the rasagiline strategy was found to generate a 5% gain in QALYs over 5 years compared with the pramipexole strategy (3.7 +/- 0.02 vs 3.51 +/- 0.03). Sensitivity analyses confirmed that the model was robust. Rasagiline represents a cost-effective alternative to pramipexole in the treatment of early PD in the UK.

Improving symptom control in early Parkinson's disease.

Motor symptoms in Parkinson's disease (PD) are caused by a severe loss of pigmented dopamine-producing nigro-striatal neurons. Symptomatic therapies provide benefit for motor features by restoring dopamine receptor stimulation. Studies have demonstrated that delaying the introduction of dopaminergic medical therapy is associated with a rapid decline in quality of life. Nonmotor symptoms, such as depression, are common in early PD and also affect quality of life. Therefore, dopaminergic therapy should typically be initiated at, or shortly following, diagnosis. Monamine oxidase-B inhibitors provide mild symptomatic benefit, have excellent side effect profiles, and may improve long-term outcomes, making them an important first-line treatment option. Dopamine agonists (DAs) provide moderate symptomatic benefit but are associated with more side effects than levodopa. However, they delay the development of motor complications by delaying the need for levodopa. Levodopa (LD) is the most efficacious medication, but its chronic use is associated with the development of motor complications that can be difficult to resolve. Younger patients are more likely to develop levodopa-induced motor complications and they are therefore often treated with a DA before levodopa is added. For older patients, levodopa provides good motor benefit with a relatively low-risk of motor complications. Using levodopa with a dopa-decarboxylase inhibitor lessens adverse effects, and further adding a catechol-O-methyl transferase inhibitor can improve symptom control.

The increasing role of monoamine oxidase type B inhibitors in Parkinson's disease therapy

Background: The role of monoamine oxidase type B inhibitors in the treatment of Parkinson's disease has expanded with the new monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets. As primary therapy in early disease monoamine oxidase B inhibitors reduce motor disability and delay the need for levodopa. In more advanced disease requiring levodopa, adjunctive monoamine oxidase B inhibitors reduce ‘off’ time and may improve gait and freezing. Objective: Rasagiline and selegiline oral disintegrating tablets may reduce the safety risks associated with the amfetamine and methamfetamine metabolites of conventional oral selegiline while retaining or improving therapeutic efficacy. Methods: Articles were identified by searches of PubMed and searches on the Internet and reviewed. All articles and other referenced materials were retrieved using the keywords ‘Parkinson's disease’, ‘treatment’ and ‘monoamine oxidase B inhibitor’ and were published between 1960 and 2007, with older references selected for historical significance. Only papers published in English were reviewed. Conclusion: Accumulating data support the use of monoamine oxidase B inhibitors as monotherapy for early and mild Parkinson's disease and as adjunctive therapy for more advanced Parkinson's disease with levodopa-associated motor fluctuations. The recently released monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets, have potential advantages over conventional oral selegiline.

Pharmacologic Management of Parkinson Disease: Choice of Initial Therapy in Early Disease

The most efficacious symptomatic agent for Parkinson's disease is levodopa; however, the development of motor complications with long-term therapy is concerning. In the modern day treatment of Parkinson's disease, non-levodopa agents (eg, dopamine agonists, monoamine oxidase type B inhibitors) should be considered as appropriate initial treatments. In early Parkinson's disease, dopamine agonists provide effective symptomatic therapy, reduce the risk for motor complications, and delay the need to initiate levodopa. However, the dopamine agonists are associated with impulse control disorders and behaviors that are concerning. Monoamine oxidase type B inhibitors are also effective as monotherapy for early stage Parkinson's disease. Clinical data demonstrate that early initiation of rasagiline (in the absence of functional impairment) is associated with improved outcomes as opposed to delayed initiation. Selegiline can delay the need for levodopa, albeit its clinical effectiveness as monotherapy is equivocal. When selecting initial therapy for early Parkinson's disease, clinicians must consider both short-term and long-term benefits and risks.

Dopamine agonists in Parkinson’s disease

Dopamine agonists are established as effective drugs for the symptomatic treatment of Parkinson’s disease (PD) throughout its course. As monotherapy, they produce effective control of motor symptoms and combine this with a low risk for motor complications. As an adjunct to levodopa, they improve motor control and limit the need for levodopa in those patients in whom this may be considered relevant. The non-ergot dopamine agonists in particular have a good safety profile, although as with other agonists, sedation, and cognitive and behavioral problems may be limiting in some patients. Pramipexole has shown benefit in improving depressive symptoms in PD. Ropinirole and pramipexole have both demonstrated a reduction in the rate of loss of nigrostriatal innervation as determined by imaging in PD patients, when compared with levodopa. Thus, dopamine agonists contribute to several dimensions of the management of PD and have become an integral part of the disease treatment algorithm.

High-dose treatment with pergolide in Parkinson's disease patients with motor fluctuations and dyskinesias

Motor complications arising after long-term treatment with levodopa remain one of the main challenges in the treatment of patients with Parkinson's disease (PD). Monotherapy with dopamine agonists may delay the onset of motor complications or reduce their severity when added to levodopa treatment. Here, we retrospectively analyzed data from 62 patients with advanced PD who presented with moderate to severe response fluctuations in whom we increased the dose of oral treatment with pergolide beyond 4.5 mg daily. Patients had been treated with levodopa for 10.7±4.8 years. Pergolide was increased to 8.2±4.3 mg per day over a median titration period of 13.5 weeks. Mean daily dose of levodopa prior to pergolide high-dose treatment was 733±468 mg and decreased to 348±186 mg after pergolide titration. The duration of OFF times decreased from 7.3±3.8 to 1.7±0.9 h per day ( p<0.001) measured by patients’ diaries. Dyskinesias, present for 5.0±3.3 h per day at baseline, were reduced to 1.4±0.8 h per day ( p<0.001) and the total daily duration of motor fluctuations (off-time duration plus dyskinesia duration) decreased from 10.5±7.0 to 2.8±2.2 h ( p<0.001). There was a significant improvement in parkinsonian symptoms (baseline to endpoint reduction of UPDRS III from a median of 36 to 8; p<0.001). To reduce gastrointestinal side effects 23 patients required concomitant treatment with domperidone. Seven patients developed hallucinations during the titration period, six patients required treatment with clozapine. Our data indicate that increasing the dose of pergolide above 5 mg per day can dramatically reduce the need for levodopa, motor fluctuations and severity of clinical symptoms. Controlled trials are needed to further substantiate the efficacy and safety of this treatment strategy.

Monoamine oxidase type B inhibitors reduce motor fluctuations, disability and the need for levodopa in people with early Parkinson's disease

QuestionAre monoamine oxidase type B inhibitors (MAOBIs) safe and effective for people with early Parkinson's disease?Study designSystematic review with meta-analysis.Main resultsSeventeen trials involving 3525 people with early Parkinson's disease met inclusion criteria (thirteen selegiline, three lazabemide and one rasagiline). All trials provided information on blinding and reported follow-up data. Treatment duration varied from 6 weeks to 10 years. MAOBIs did not significantly increase deaths compared with controls (20% with MAOBIs ν 21% with control; see results table). At 3 months, selegiline improved activities of daily living scores, motor scores and total scores compared with controls (improvement in activities of daily living score: 0.9, 95%CI 0.5 to 1.4; improvement in motor score: 1.8, 95%CI 0.8 to 2.7; improvement in total score: 2.7, 95%CI 1.4 to 4.1). People taking MAOBIs were less likely to need extra levodopa or develop motor complications than controls. However, MAOBIs did not reduce dyskinesia. Adverse effects were more common with MAOBIs, although there was no difference in study withdrawal between the two groups (see results table).Authors’ conclusionsMAOBIs reduce motor fluctuations, disability and the need for levodopa in people with early Parkinson's disease. There is no evidence that selegiline increases death compared with controls. MAOBIs appear to be safe and effective, but long-term studies are needed.

Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients

Objective To quantify more reliably the benefits and risks of monoamine oxidase type B inhibitors (MAOBIs) in early Parkinson's disease.Data sources Searches of the Cochrane Library, Medline, Embase, PubMed, and...

Neuroprotection in Parkinson's disease: clinical trials.

Advances in our understanding of the cause and pathogenesis of Parkinson's disease (PD) have permitted the rational selection of putative neuroprotective agents for study in PD. However, the list of agents that might provide neuroprotective effects derived from laboratory studies is daunting, and we face the challenge of determining which agents to bring to the clinic and how to find the resources (patients and funds) to properly study so many promising therapeutic opportunities.1 Appropriate outcome variables that are not confounded by any symptomatic effect of the drug and are acceptable to clinicians and regulatory authorities also remain to be defined. The first clinical trials designed to test the capacity of putative neuroprotective agents to alter the natural history of PD have now been performed and illustrate some of these problems. The DATATOP (Deprenyl and Tocopherol Antioxidant Therapy of PD) study used the time to reach a disease milestone in untreated PD patients (ie, need for levodopa) as the primary end point. However, interpretation of results was confounded by the drug's symptomatic effect. The SINDEPAR (Sinemet-Deprenyl-Parlodel) study used the change in motor score between initial visit and final visit after washout of all study medications as the primary end point. However, here too there were concerns about confounding symptomatic effects, because antiparkinsonian medications have now been shown to have a long duration response that can persist for weeks and perhaps even months after withdrawal. More recent studies have used surrogate markers of the integrity of nigrostriatal function such as striatal uptake of fluorodopa on positron emission tomography (PET) or beta-CIT-on single-photon emission computerized tomography (SPECT) as primary outcome measures. However, it has not yet been confirmed that striatal uptake of these isotopes does in fact correlate with the remaining number of dopamine neurons or terminals, and the possibility of a confounding pharmacological effect has not yet been completely excluded. To date, no drug has been established to have a neuroprotective effect in PD, and none has been approved for a neuroprotective indication. Furthermore, regulatory agencies have not yet agreed that any of the outcome measures currently used will be acceptable for approval of a new drug. Resolution of these issues is of critical importance to convince pharmaceutical companies to expend the hundreds of millions of dollars necessary to bring a new drug to market. Drugs that already have been approved in PD for their symptomatic effects, such as dopamine agonists or propargylamines (eg, selegiline), offer the best opportunity for establishing that a drug is neuroprotective in PD in the immediate future, but herein also lies the difficulty of establishing that any benefits observed are not solely because of the drug's symptomatic properties. Currently, this will most likely entail demonstrating that the drug provides benefit for PD patients for both imaging and clinical markers of disease progression.

Early Parkinson's disease: what is the best approach to treatment.

Early and correct diagnosis and treatment of Parkinson's disease (PD) are crucial for the patient's well being. At the first visit, it is important to deal with the patient's misconceptions of the disease and its course, to offer sources of information and to suggest exercises. To make a correct initial diagnosis of PD we need to assess the course of the initial levodopa responsiveness. The most frequent challenges in diagnosing PD are the conditions of essential tremor and multiple system atrophy. PD has 3 stages of development: (i) early--from the onset of symptoms to the appearance of motor fluctuations; (ii) middle--from motor fluctuations to the appearance of moderate-to-severe disability; and (iii) advanced--when moderate-to-severe disability is present. The medical treatment of early PD should be started when functional disability appears, which is a different threshold for each patient. For patients below 65 years old, or above 65 years old but with preserved mental function and with no severe comorbidity, initial monotherapy with a dopamine agonist is advisable. This approach appears to delay the appearance and reduce the amount of late motor complications with subsequent levodopa treatment. All dopamine agonists have similar efficacy, which is less than that of levodopa. It is important to consider the adverse effect profile when a choice for initial or adjunctive therapy is made. When levodopa therapy is started as an adjunct in younger patients or as initial monotherapy in older patients, sustained-release levodopa preparations are preferred. They have a longer half-life and possibly stimulate the dopamine receptors more continuously. Anticholinergic drugs are appropriate for younger patients with tremor-dominant PD. Amantadine is mainly used for dyskinesia control. Catechol-O-methyl-transferase inhibitors and neurosurgery are not treatments of choice for early PD but can be very effective for more advanced disease. The presence of presymptomatic markers of PD, such as changes in odour detection, handwriting, speech, movement time of self-initiated motor acts, personality traits, presence of antibodies against dopaminergic neurons, pattern of positron emission tomography results, appearance of mitochondrial DNA mutation profiles, etc., appear to be very important in the light of the emerging neuroprotective therapies. Neuroprotection is aimed at slowing the rate of disease progression. Selegiline has been shown to cause a mild delay in the need for levodopa, possibly suggesting some protection. However, this initial benefit was not sustained in long term studies. Currently, there is no neuroprotective drug for PD.

The natural history of Parkinson's disease.

There are still insufficient data on the natural course of Parkinson's disease (PD) owing to lack of standardized longitudinal follow-up studies. Reported progression rates in early PD vary considerably by a factor of 2 to 3. Similarly, data from sequential [18F]dopa PET studies in PD patients have produced variable decline rates of PET indices ranging between 7 and 70% per decade. Risk factors for rapid progression include old age at onset, concomitant major depression, dementia, and akinetic-rigid symptom presentation. The introduction of levodopa into the routine treatment of PD patients had a dramatic impact on symptomatic control without affecting the underlying rate of disease progression. By contrast, monoamine oxidase (MAO) B inhibition by deprenyl monotherapy in early PD was shown to delay the need for levodopa by around 9 months. However, the neuroprotective action disappeared after 2 years of follow-up. Furthermore, deprenyl also failed to influence the subsequent development of levodopa-induced motor complications. Available studies on mortality in PD provide heterogeneous mortality rates, probably because of discrepancies between patient populations with respect to co-morbidity, disease stage at study entry, and diagnostic accuracy. However, the most recent follow-up from the DATATOP cohort suggests normal life expectancy in carefully selected patients without significant co-morbidity and with adequate treatment and expert follow-up.