Clinical neuroprotection in Parkinson's disease — Still waiting for the breakthrough

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Abstract

Recent research in the pharmacotherapy of Parkinson's disease (PD) has been able to provide numerous agents for the symptomatic control of motor impairments, but has failed to identify substances capable to slow down or even halt the progression of the disease. In the absence of disease-modifying therapies, affected patients develop marked disability within some years after the onset of motor symptoms, which can be alleviated but eventually not prevented with currently available medical and surgical therapies. Despite promising results from preclinical studies, outcomes of clinical neuroprotection trials have been repeatedly disappointing, which calls for a review of our approach to this topic. This article attempts to explain the need for neuroprotective therapies in PD, discusses results and limitations of previous clinical trials and provides some food for thought for the future research of neuroprotection in PD. Previous experiences from neuroprotection studies may have been discouraging, but also teach us some important lessons for the next generation of preclinical and clinical trials. Firstly, our currently used animal models for PD need to be refined in order to more reliably predict the efficacy of putative neuroprotective agents in subsequent clinical studies. Furthermore, changes in the methodology and design of future neuroprotection trials are required in order to exclude an impact of confounding symptomatic effects on observations. Finally, coordination and concentration of future research on the most promising agents will be necessary in order to accelerate the search for neuroprotective therapies in PD. Just as the pathogenesis of the disease is manifold, it may be this multilateral approach that eventually leads us to a breakthrough in finding neuroprotective agents for PD, if they exist.

Introduction

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's and is estimated to affect 1% of individuals over the age of 65. In the most populous nations, the approximate number of PD patients over age 50 was 4.1 million in 2005 and, as worldwide life expectancy increases, is projected to reach 8.7 million in 2030 [1]. This development constitutes an enormous public health challenge for the future since affected individuals need to be identified and offered cost-effective medical treatment.

Before initiation of treatment, it is crucial to properly diagnose idiopathic PD, which is clinically characterized by the cardinal symptoms bradykinesia, rigidity, resting tremor and postural instability, and to differentiate the disease from disorders that may manifest with similar symptoms, such as multiple cerebral infarct state, drug-induced Parkinsonism or normal pressure hydrocephalus. Thus, cerebral imaging (preferably magnet resonance imaging) is recommended to exclude structural abnormalities before diagnosing PD. Furthermore, PD needs to be distinguished from Parkinson's plus syndromes such as multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration. Differential diagnosis of PD has shown to be difficult, as even movement disorder specialists misdiagnose about 10% of cases [2]. Therefore, functional imaging of the post synapse can be helpful in order to differentiate PD from Parkinson-plus syndromes that usually show no response to antiparkinsonian medication and have a worse prognosis.

Data from placebo groups of randomized controlled intervention trials of 6 to 18 month duration have been able to provide information on the progression of motor dysfunction in the natural course of PD by using the Unified Parkinson's Disease Rating Scale (UPDRS) [3], [4], [5], [6], [7]. From these trials, annual decline in total UPDRS score in early PD patients without medication can be averaged to 8 to 11 points. Due to this rapid deterioration in motor function, untreated PD can be expected to result in severe disability within less than 10 years [8], [9], [10] emphasizing the need for therapies that slow the progression of the underlying neurodegenerative processes of the disease and the development of disability. In recent years, it has however become clear that there is also considerable heterogeneity in the natural course of PD [11] and that a classification based on phenotypic patterns of the disease may be useful for a better prediction of disease progression for different groups of patients [12]. For example, tremor dominant PD has been associated with slower disease progression and less cognitive impairment than PD with predominant postural instability and gait disturbance [12]. Furthermore, an increasing age at disease onset has been shown to be associated with higher Hoehn and Yahr stages, level of disability and lower perceived quality of life [13].

Section snippets

The need for neuroprotective treatment

Since the first intravenous administration of levodopa in PD patients by Birkmeyer and Hornykiewicz [14] substantial progress has taken place in the development of symptomatic dopaminergic therapies. Some studies after the introduction of levodopa and dopamine agonists demonstrated a prolonged latency from symptom onset to the development of significant disability in comparison to the pre-levodopa era and thus nourished hope that antiparkinsonian treatment could also have disease-modifying

Limitations of clinical neuroprotection trials

In the past, numerous clinical trials attempted to investigate neuroprotective properties of various substances used for the treatment of PD. It is crucial to understand the limitations of these studies in order to determine which trial methodologies are sufficient to identify substances that slow or halt the progressive loss of dopaminergic projections from the substantia nigra to the striatum. Since the number of remaining dopaminergic neurons cannot be measured directly in vivo, outcome

Results of clinical neuroprotection trials

Several randomized controlled trials have intended to examine the effect of therapeutic agents on disease progression in PD (Table 1), which will be discussed according to substance classes in alphabetical order.

Conclusions

Despite numerous ambitious efforts in the search for disease-modifying therapies in PD, clinical trials so far have failed to identify any compound with compelling proof for neuroprotective properties. The results of clinical studies have been repeatedly disappointing, but also teach us important lessons for the future evaluation of neuroprotective therapies in PD and call for a change in our approach to this topic [122].

The striking discrepancy between often promising data from preclinical

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