Parkinson’s disease (PD) is a neurodegenerative disease which presents principally with motor problems such as tremor, bradykinesia and rigidity, caused by the loss and disintegration of dopaminergic neurons in the substantia nigra compacta.¹ PD is a chronic illness and it is believed to have a prevalence of approximately 1%  in the population over 65 years of age, worldwide.²

Most available treatments for PD patients today involve treating and masking the symptoms, rather than trying to prevent further neurodegeneration or even regenerate dopaminergic neurons, that is, neuroprotection.³

Causes of neurodegeneration in PD

In this literature review the authors comment on various trials that have recently been undertaken to gauge the effectiveness of certain treatments in neuroprotection, and also what further trials must be undertaken to establish proper treatment options. 

The basis of the neurodegeneration in PD is unknown but there are a number of theories as to the cause of the damage, such as oxidative stress,^4,5 mitochondrial dysfunction,^6,7 apoptotic mechanisms⁸ and neuroinflammatory processes,⁹ as well as an abnormal collection of alpha-synuclein binding to ubiquitin in the damaged neurons; these form the Lewy bodies which are characteristic of PD.^5,10

In the ADAGIO double-blind, delayed start, placebo-controlled trial of rasagiline as a neuroprotective agent in PD,¹¹ although positive results were obtained, many questions were also raised. 

In this trial, 1,176 subjects were randomly assigned either to receive rasagiline (at a dose of either 1mg or 2mg a day) for 72 weeks or placebo for 36 weeks then rasagiline for 36 weeks. Subjects consisted of early PD patients who were not undergoing any treatment for PD and who presented with at least two of the three hallmark features of PD. 

The subjects’ disease progression was assessed based on the Unified Parkinson’s Disease Rating Scale (UPDRS). Three clear conclusions had to be met for a positive result to be achieved at either dose: firstly, advantage over placebo in the degree of change in UPDRS score between weeks 12 and 36; secondly, advantage of the early-start group over the delayed-start group in the difference in score between the baseline and the end of the trial (week 72); and thirdly that the early-start treatment group’s score changes would be no worse than the delayed-start group between weeks 48 and 72. 

Rasagiline

The first endpoint, if met, would show that there was a difference in disease progression between the two groups, allowing for rasagiline to be maintaining its complete effect on symptoms by week 12. 

The second conclusion is to establish whether any benefits observed in the early-start treatment group over the delayed-start group would be maintained at the end of the study, by which point both groups would be receiving the same treatment.  Any superiority of the early-start cohort at this point would suggest the treatment had a disease-modifying effect. 

The third decisive factor determines whether the dissimilarity between the two groups’ scores was lasting (as would be the case with a neuroprotective agent) or if it diminished, which would occur with a treatment that had a long-lasting and additive effect on symptoms.¹²

At the end of the trial, when all the data recorded were statistically analysed, it was determined that the dose of rasagiline at 1mg/day met all three criteria, achieving a positive result, while the dose at 2mg/day did not, as it failed to meet the second condition. This may be due to a masking of symptoms by rasagiline at this dose in patients with low UPDRS scores,¹³ although the fact that the disease-altering and symptomatic treatment mechanisms of rasagiline are very different¹⁴ challenges this theory. 

To determine if an effect on symptoms could be hiding a neuroprotective effect of rasagiline at the dose of 2mg/day, a post hoc subgroup analysis was carried out in subjects who had the highest quartile of scores at baseline. 

In this analysis, the early-start rasagiline subgroup showed a considerable advantage over the delayed-start rasagiline with regard to the difference in the UPDRS score from baseline to week 72. Although this result is consistent with the idea that the symptom effects of rasagiline at the dose of 2mg/day hid its true disease-modifying effects, it cannot be excluded that the positive findings of rasagiline at the dose of 1mg/day could be a false positive result rather than the 2mg/day dose result being a false negative.¹³ 

Thus, the cause of the differences between the results for the two different doses cannot be conclusively explained. 

There are some concerns raised by the delayed-start trial design¹⁴ but these seem to have been adequately met by the ADAGIO authors as they kept a low drop-out rate and, although there was a risk of misdiagnoses in some of the patients who were in the initial stage of PD, the randomisation should have scattered these patients out evenly among the various subgroups. 

Another clear concern is the difficulty in measuring disease progression which exists in all PD trials, as UPDRS mainly focuses on motor effects and is also perhaps not sensitive enough to measure smaller worsening in disease progression.^15,16 

However, seeing as UPDRS had not been used before as an endpoint marker in studies of PD and there is no clear evidence that the deterioration in scores is linear, results were verified by another categorical analysis. Therefore, the overall clinical impact of this study is that it implies there may be a benefit to the administration of rasagiline at a dose of 1mg/day in the initial stages of PD.¹¹

Although due to the negative result of the 2mg/day dose, it cannot be definitively said that rasagiline has a neuroprotective effect and it must be seen with time, as a phase IV clinical trial is ongoing,¹⁷ if these benefits observed at the end of the trial turn into a real clinical benefit with reduced signs of the more progressive signs of PD such as dementia.

Creatine

Another substance which has shown potential in animal models of PD¹⁸ is the nitrogenous organic acid creatine, which has been involved in many clinical trials, both pilot and futility trials. 

In the placebo-controlled randomised pilot trial carried out by Bender et al,¹⁹ 60 patients who both clinically and in their single-photon emission computed tomography (SPECT) dopamine transporter imaging correspond with PD, received oral creatine (Cr) or a placebo for two years and their endpoint outcome was assessed mainly by any changes in the dopamine transporter SPECT, but also in their UPDRS scores and the SF-36 (a health survey). 

Disappointingly, it was found that there were no significant differences in the SPECT between the Cr and control groups, there was also no advantage of the Cr in the difference in UPDRS scores, although this group did have a considerably smaller increase in their dose of dopaminergic therapy. This might explain how any neuroprotective effect of Cr could be masked by the dopaminergic therapy although, as the outstanding disease-altering effects of Cr were not evident either in the SPECT imaging, this may be dose-related. 

In the futility trial performed by NINDS-NET PD investigators²⁰ it was established through a greater than 30% reduction in the UPDRS scores, going by the recommendations of the DATATOP trial, that creatine was not considered as futile and was suggested for a phase III trial to assess any disease-altering effects on PD further as well as establishing its tolerability, safety and other clinical concerns. 

When the results of an additional six months of randomised blind phase II trial were released they showed there were no tolerability issues associated with creatine, nor were there any major adverse effects due to interference with symptomatic antiparkinsonian therapy.²¹ A large-scale phase III trial is currently underway in the US and Canada which will investigate creatine further as a potential treatment.²²

Coenzyme Q10

Coenzyme Q10 or its derivative mitoquinone (MitoQ) is of much interest to researchers in pursuit of a neuroprotective agent for PD. It shows promise as it is capable of reducing oxidative stress by reducing overproduction of ROS, and also maintaining mitochondrial function in times of glutathione loss.¹⁸

In mouse models of PD produced using MPTP, coenzyme Q10 was shown to reduce the depletion of neurons in the striatum²³ and it has also shown good tolerability and toxicity only at doses ~1,000nmol MitoQ/mouse.²⁴

Coenzyme Q10 showed evidence of neuroprotective effects in the Parkinson Study Group’s multicentre, randomised, placebo-controlled, double-blind dose-varying clinical trial.²⁵ This followed 80 early PD patients who did not require levodopa treatment, for up to 16 months or until they began to require dopaminergic treatment. Their UPDRS scores were assessed at baseline, one month and then at four-monthly intervals until the 16-month mark. 

Results showed that the 1,200mg dose of coenzyme Q10 showed a real statistically remarkable benefit over the placebo in the average change in the UPDRS score. It also demonstrated coenzyme q10 as a well-tolerated and safe treatment but a larger study needed to be carried out to assess these results further and prove their implications in PD treatment. 

This study was terminated in December, however, when CoQ10 did not show any disease-altering advantage over the placebo in the phase III trial, although it still appeared well tolerated and safe as a treatment.²⁶

Another class of substances that PD researchers are concerned with in regard to neuroprotection is dopamine agonists. These are free radical scavengers and antioxidants and which would correlate with being useful in the mitochondrial damage model of PD pathogenesis.²⁷

Pramipexole and ropinirole

Two drugs which have been involved in studies are pramipexole and ropinirole. In a parallel-group double-blind randomised trial involving pramipexole,²⁸ 82 patients received either 0.5mg pramipexole three times a day with levodopa placebo, or just carbidopa/levodopa 25/100mg three times a day with a pramipexole placebo. 

The main assessment was based on changes in the SPECT-imaged beta CIT uptake in the striatum, a measure of the degeneration of dopaminergic neurons. This was measured at 22, 34 and at the end point of 46 months. The UPDRS scale was also used here to gauge disease progression, after 12 hours off levodopa medication.  

This trial found that there was a significantly lower decline in striatal beta CIT uptake in the pramipexole group in comparison with the placebo group, suggesting less neurodegeneration.²⁹ This change in striatal measures was also in correlation with the changes in the UPDRS scores at the 46-month mark. 

In the ropinirole trial 162 patients with a clinical diagnosis of idiopathic PD and a F-dopa PET scan typical of PD, were allocated either ropinirole (3mg/day) or levodopa (300mg/day), along with a placebo, in a ‘double-dummy’ method.³⁰ This was after a two-week lead-in period where both halves received the placebo. 

The main measure of the outcome was a PET scan taken of the patients’ putamen F-dopa uptake at four weeks, ie. after the initial increase in medication, and at the two-year point. The patients were also measured clinically according to the UPDRS scoring system at months one, three, six, 12, 18 and 24. For the first year of the study, patients were also rated on the CGI improvement scale. 

Although the results showed that improvements in the UPDRS scores were not kept by the ropinirole group as they were in the levodopa group, there was a statistically significant (34%) slower rate of degeneration in the dopaminergic neurons in the putamens of the ropinirole group. 

The ropinirole group also had a much lower rate of developing dyskinesias during treatment, and was well tolerated without any major adverse effects. 

Further study is required to see how the slower loss of neurons in the putamen with ropinirole can be turned into a real clinically significant treatment as levodopa still has a clearer symptom-treating advantage. 

Summary

In conclusion, neuroprotection is an area of keen interest to those involved in PD research as it is seen as a possible cure. Although there have been promising results from trials such as the ADAGIO group, more large-scale studies need to be established. Furthermore, large-scale phase III trials do not always have the same promising results as their smaller extent versions, as was the case with the Cornell University coenzyme q10 trial. 

It is still necessary to find new biomodels and clinical and biochemical measures of PD^15,16,31 as, for example, the MMPT model does not behave exactly as PD does which allows for variation and doubt in many studies. 

Neuroprotection does however offer much promise as a means of preventing the degenerating and debilitating progression of PD, although much progress remains to be made until it can be used widespread clinically and proclaimed as a ‘cure’.  

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