Neuroprotection and imaging studies in Parkinson's disease

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Abstract

The most challenging issue when testing putative neuroprotective agents for Parkinson's disease (PD) in clinical trials is the assessment of the effect of the treatment on the neurodegenerative process. By measuring changes in symptoms severity, clinical rating scales represent an important tool to rate the progression of the disease. However, the rating of clinical symptoms is dependent on the examiner and the neuroprotective effect can be masked by the symptomatic effect of the therapy. 18f-dopa PET and 123 I-β-CIT SPECT have been shown to be able to monitor the progressive loss of presynaptic nigrostriatal projections in PD and have been used as surrogate biomarkers of disease in several recent clinical trials.

In this article the value of imaging as a biomarker for testing neuroprotective agents in PD is reviewed.

Introduction

Parkinson's disease (PD), the second most common neurode-generative disorder, is characterized by severe loss of nigrostriatal neurons, which results in a deficiency of the neurotransmitter dopamine (DA). Current therapeutic options for PD mostly consist of symptomatic treatments that aim to improve the motor symptoms of the disease, namely rigidity, bradykinesia and tremor, by increasing the cerebral levels of DA.

Clear neuroprotective agents, which would prevent or slow down the degeneration of remaining nigrostriatal neurons or even induce new DA terminal sprouting, are still missing. Over the past 20 years, many different neuroprotective strategies have been investigated, including inhibition of apoptosis, oxidative stress and glutamate excitotoxicity, or enhancement of mitochondrial activity and energy function. The results of these experimental studies, although sometimes controversial, have led to several recent clinical trials to assess the effects of putative neuroprotective agents on the natural course of PD [1, 2, 3, 4, 5, 6, 7].

In clinical trials, the selection of sensitive and objective end points is vital in order to establish the efficacy of the treatment to slow down the disease process. Clinical rating scales, such as the Unified Parkinson's Disease Rating Scale (UPDRS) [8], can be used to rate the progression of the disease during neuroprotective trials. Several shortcomings associated with clinical scales, however, need be recognized. The rating of symptoms is subjective and dependent on the examiner. This can introduce bias especially when, for any reason, an investigator needs to be replaced with another during the course of the study. Furthermore, the neuroprotective effect can be masked by the symptomatic effect of the therapy. Similar considerations apply when ‘the time to requiring l-dopa treatment’ in de novo patients is the main measure of efficacy. Functional imaging of presynaptic nigrostriatal terminals should provide a more objective biological marker for severity and progression of the degenerative process in PD and thus should be a better indicator of the neuroprotective effects of drugs.

Section snippets

Imaging outcome measures in clinical trials of neuroprotection

18f-dopa PET and SPECT with tracers for presynaptic DA transporter (DAT) are currently the most used techniques to investigate the integrity of presynaptic dopaminergic neurons. 18f-dopa PET reflects dopa transport into the terminal, dopa decarboxylase activity, and DA storage capacity [9]. 18f-dopa uptake has been demonstrated to correlate well with nigral cell counts in both human cases and in primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism [10, 11].

Clinical trials of putative neuroprotective agents in PD: a review

Despite the limitations discussed above, imaging outcome measures have generally proved to be a valuable complement to clinical data when assessing neuroprotective agents in PD. In the following paragraphs we report the most significant results. These are also summarized in Table 1.

Future perspectives

Neuroprotection remains an open challenge in PD treatment and it is reasonable to predict that novel putative neuroprotective agents will become available in the near future. Further research in this field should not only aim to refine existing imaging biomarkers but also to develop new imaging techniques to longitudinally monitor disease progression and treatment effect in PD. It has recently been reported that high-resolution diffusion tensor imaging (DTI) of the caudal substantia nigra (SN)

Conflict of interest

None declared.

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