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I thought this might be of interest. Rick Ferber Neuroprotective therapy for Parkinson disease Author Daniel Tarsy, MD Section Editor Howard I Hurtig, MD Deputy Editor John F Dashe, MD, PhD INTRODUCTION — The pharmacologic treatment of Parkinson disease (PD) can be divided into neuroprotective and symptomatic therapy. In practice, however, nearly all of the available treatments are symptomatic in nature and do not appear to slow or reverse the natural course of the disease. This topic will review potential neuroprotective therapies for PD. Other aspects of PD are discussed separately. (See "Etiology and pathogenesis of Parkinson disease" and "Clinical manifestations of Parkinson disease" and "Diagnosis of Parkinson disease" and "Pharmacologic treatment of Parkinson disease".) BACKGROUND — Neuroprotective therapy of PD is still theoretical, but it is based on the concept that the three to four hundred thousand at-risk dopaminergic neurons in the human substantia nigra can somehow be protected from the complex degenerative process that causes premature cell death and depletion of dopamine. Once identified and shown to be effective, neuroprotective drugs could be used in patients with early clinical signs of disease or potentially even prior to the appearance of disease in those shown to be at genetic risk. Several potential neuroprotective agents for PD have shown some promise in animals and/or humans and are undergoing further investigation [1-5]. Selegiline and rasagiline (both monoamine oxidase inhibitors), dopamine agonists, and the complex I mitochondrial fortifier coenzyme Q10 have been evaluated in clinical trials and are receiving the most attention as possible neuroprotective agents. LEVODOPA — Accumulating clinical trial data suggest that levodopa either slows the progression of PD or has a prolonged benefit even after the drug has been stopped. These data are presented separately. (See "Pharmacologic treatment of Parkinson disease", section on 'Levodopa'.) The 2006 American Academy of Neurology (AAN) practice parameter concluded that levodopa is possibly neuroprotective for at least nine months and does not accelerate disease progression [6]. MAO B INHIBITORS — Monoamine oxidase (MAO B) inhibitors such as selegiline and rasagiline have been studied as neuroprotective agents due to their ability to block free radical formation from the oxidative metabolism of dopamine; these agents may also inhibit apoptosis (programmed cell death) [4]. In addition to a possible neuroprotective effect, selegiline has a mild symptomatic benefit. (See "Pharmacologic treatment of Parkinson disease".) Selegiline — The possibility of long-term neuroprotection with selegiline has neither been confirmed nor disproven: A large prospective, double-blind, placebo-controlled multicenter study (the DATATOP study) found that selegiline (deprenyl) 10 mg daily delayed the progression of parkinsonian signs in previously untreated patients by nine months [7]. However, a small but measurable reduction of parkinsonian symptoms attributable to selegiline confounded the findings of this study, thereby casting doubt on the likelihood that the delayed progression of symptoms was due to a true neuroprotective effect. A subsequent trial that took this symptomatic effect into account noted a mild neuroprotective effect [8]. Selegiline treatment of patients with early Parkinson disease (PD) in the absence of levodopa was associated with a decreased risk for developing later freezing of gait [9], suggesting a possible neuroprotective effect. Prior treatment with selegiline in the DATATOP cohort did not reduce the occurrence of subsequent levodopa-associated motor fluctuations in this population [10]; no persistent, long-term benefit in slowing the progression of PD was demonstrated with selegiline. This lack of long-term benefit in part accounted for the conclusion issued in a 2002 report of the Quality Standards Subcommittee of the American Academy of Neurology (AAN) that there is insufficient evidence to recommend the use of selegiline for a neuroprotective effect [11]. A practice parameter from the AAN issued in 2006 found no interim studies that would alter this conclusion [6]. Rasagiline — The selective MAO B inhibitor rasagiline has neuroprotective properties in animal models. However, human trials have yielded inconsistent findings: A short-term randomized controlled trial (TEMPO) published in 2004 suggested that rasagiline could slow progression of parkinsonian disability [12]. Using a delayed start design, the trial found that patients assigned to early treatment with rasagiline monotherapy had a smaller increase in mean adjusted total Unified Parkinson Disease Rating Scale (UPDRS) score (table 1) than those who were initially assigned to placebo for six months before starting rasagiline [12]. However, the symptomatic benefit of rasagiline, rather than a neuroprotective effect, may have been responsible for this result [6]. In an open-label extension of the TEMPO trial with 6.5 years of follow-up published in 2009, the group assigned to earlier initiation of rasagiline showed a statistically significant slower progression of PD, as measured by the UPDRS score [13]. This finding could be interpreted to support a neuroprotective or disease modifying effect of rasagiline. Alternatively, it might reflect an effect on endogenous compensatory mechanisms in early PD, such that the early introduction of any symptomatic treatment for PD results in a better clinical outcome than delayed administration [14]. The extension study must be interpreted very cautiously because of its open-label design, high (approximately 50 percent) drop-out rate, and statistical methodology that did not account for missing data due to loss of follow-up [13]. The ADAGIO trial also used a delayed start design to evaluate rasagiline at two doses (1 mg and 2 mg daily) in 1176 subjects with untreated PD [15]. The group assigned to early start with rasagiline 1 mg daily met all prespecified criteria for a possible disease-modifying effect. However, the group assigned to early start with rasagiline 2 mg did not, because the change in total UPDRS score between baseline and week 72 was not significantly different compared with the 2 mg late start group. Thus, the two different doses were associated with different outcomes, and the overall trial results are inconclusive regarding a possible neuroprotective effect of rasagiline. The 2006 AAN practice parameter concluded that there is insufficient evidence to support or refute the use rasagiline for neuroprotection in patients with PD [6]. This conclusion remains valid despite the additional data from the 2009 TEMPO extension study and the 2009 ADAGIO trial. DOPAMINE AGONISTS — Dopamine agonists are neuroprotective in the laboratory because they are antioxidants and free radical scavengers and because of feedback reduction of endogenous dopamine turnover [2,16]. These findings have led to the hypothesis that the use of agonists early in the clinical course of PD may slow progression of the underlying neurodegeneration [17]. Later studies employing radiographic markers of basal ganglia function, although highly controversial, have provided further, tentative support for a possible neuroprotective effect of dopamine agonists. One potential biologic marker uses single photon emission computed tomography (SPECT) with the dopamine transporter ligand [123I]beta-CIT (B-CIT) as an anatomic measure of nigrostriatal integrity and as a surrogate marker of PD progression. Earlier investigations of the natural history of PD had shown a 5 to 10 percent reduction of B-CIT uptake per year in a heterogeneous mix of patients with PD. Pramipexole — The CALM-PD study evaluated 82 patients with early PD, using SPECT B-CIT scans as a surrogate marker of neuroprotection, and found that the patients who were randomly assigned to receive pramipexole (0.5 mg three times per day) demonstrated less of a decline in striatal B-CIT uptake over four years compared with those treated with carbidopa-levodopa (25/100 mg three times per day) [18]. There was no difference between the two treatment groups for the change in the UPDRS scores (table 1) from baseline. Ropinirole — A randomized trial studied 162 patients eligible for analysis who were assigned to ropinirole or levodopa treatment, using positron emission tomography (PET) scanning and the dopa decarboxylase ligand 18F-fluorodopa ((18)F-dopa) as a measure of nigrostriatal integrity [19]. There was significantly less decline in (18)F-dopa uptake in patients assigned to ropinirole compared with those assigned to levodopa. Another randomized trial employing (18)F-dopa PET as a surrogate marker of neuroprotection studied 45 patients who were assigned to ropinirole or levodopa [20]. At two years, the ropinirole treatment group showed a smaller reduction in the primary endpoint of putamenal (18)F-dopa uptake compared with placebo, but the difference was not statistically significant (13 versus 18 percent, respectively). Interpretation — It is uncertain whether these imaging studies reflect changes in the underlying pathology of PD or differential pharmacologic "regulatory" changes directly attributable to the drugs themselves [21]. Therefore, these findings raise the possibility that dopamine agonists are neuroprotective, but confirmation is required in additional clinical studies, including prospective data in untreated patients [3,22]. The 2006 AAN practice parameter noted that significance of the studies evaluating pramipexole and ropinirole is uncertain, given the lack of validation for the surrogate measures of neuroprotection employed (ie, SPECT B-CIT and (18)F-dopa PET scans) and the absence of placebo control groups [6]. The AAN concluded that there is insufficient evidence to support or refute the use of pramipexole or ropinirole for neuroprotection in patients with PD. Other clinical data argue against a neuroprotective effect of dopamine agonists [23]. In a study reporting 14 year follow-up of patients who were enrolled in an early trial comparing the dopamine agonist bromocriptine with levodopa, initial treatment with bromocriptine did not reduce long-term mortality or motor disability, and the initial reduction in motor complications associated with bromocriptine was not sustained [24]. Similarly, there was no sustained benefit for early dopamine agonist treatment in a 15 year follow-up study of patients from another early trial comparing bromocriptine with levodopa [25]. OTHER AGENTS Coenzyme Q10 — Interest in coenzyme Q10 has been stimulated by evidence that mitochondrial dysfunction may play a role in the pathogenesis of PD [26-28]. In a small clinical trial, 80 subjects with early untreated PD were randomly assigned to three dosage groups of coenzyme Q10 or to placebo, and were followed for progression of disease as measured by the Unified Parkinson Disease Rating Scale (UPDRS) (table 1) [29]. Treatment with coenzyme Q10 at the highest dosage (1200 mg daily) was associated with a lower rate of disability progression over 16 months compared with placebo. Although the results did not achieve statistical significance, they did meet the prespecified criteria for a positive trend for the trial [29]. However, the study was underpowered to detect a neuroprotective effect [6]. As with selegiline, it is not entirely clear whether the benefit of coenzyme Q10 was due to neuroprotection or to symptomatic improvement [30]; the study investigators considered the symptomatic effect of coenzyme Q10 to be negligible. In support of this opinion, a later randomized controlled trial of 131 patients with midstage PD found no symptomatic benefit at three months for coenzyme Q10 compared with placebo [31]. Subsequent futility analyses have been inconsistent regarding whether coenzyme Q10 warrants further study [32]. The 2006 AAN practice parameter concluded that there is insufficient evidence to support or refute the use of coenzyme Q10 for neuroprotection in patients with PD [6]. Vitamin E — In the randomized controlled DATATOP trial of patients with early PD, Vitamin E (tocopherol) was included as a treatment arm [7]. There was no beneficial effect of vitamin E compared with placebo for the primary end point of average time to onset of disability requiring levodopa use. Given these data, the 2006 AAN practice parameter concluded that vitamin E should not be considered for neuroprotection [6]. Riluzole — A randomized controlled trial of patients with early PD found no beneficial effect of riluzole compared with placebo as measured by change in the UPDRS (table 1) [33]. However, this study was not sufficiently powered to exclude a modest neuroprotective effect of riluzole [6]. Uric acid — Uric acid (urate) has antioxidant properties, suggesting that it may prevent oxidative damage and cell death in PD. In support of this hypothesis, several observational studies have found that a high plasma uric acid concentration is associated with a reduced risk of developing PD [34-36], and a large population-based study with a 14-year follow-up reported that dietary intake expected to increase plasma uric acid level is associated with a lower risk of PD [37]. In addition, patients with a history of gout appear to have a lower risk of PD than those without gout [38]. Nonetheless, the finding of an association between uric acid concentration and the risk of PD does not prove that urate is neuroprotective. Furthermore, the therapeutic utility of urate (and diets designed to increase plasma uric acid) is likely to be limited by adverse effects with regard to the risk of developing gout and renal disease [37]. SUMMARY AND CONCLUSIONS Neuroprotective therapy of Parkinson disease (PD) is still theoretical, but it is based on the concept that dopaminergic neurons in the substantia nigra can be protected from the degenerative process that causes premature cell death and depletion of dopamine, leading to the development of PD. However, no treatment for PD has been proven to be neuroprotective. (See 'Background' above.) While not established to be neuroprotective, levodopa is possibly neuroprotective and does not accelerate disease progression. (See "Pharmacologic treatment of Parkinson disease", section on 'Levodopa'.) Monoamine oxidase (MAO B) inhibitors such as selegiline and rasagiline have been studied as neuroprotective agents due to their ability to block free radical formation from the oxidative metabolism of dopamine; these agents may also inhibit apoptosis. Dopamine agonists are neuroprotective in the laboratory because they are antioxidants and free radical scavengers and because of feedback reduction of endogenous dopamine turnover. Interest in coenzyme Q10 has been stimulated by evidence that mitochondrial dysfunction may play a role in the pathogenesis of PD. Nevertheless, existing clinical trial evidence in patients with PD is insufficient to support or refute the possibility of neuroprotection for MAO B inhibitors (selegiline, rasagiline), dopamine agonists (pramipexole, ropinirole), coenzyme Q10, or riluzole. (See 'MAO B inhibitors' above and 'Dopamine agonists' above and 'Coenzyme Q10' above and 'Riluzole' above.) There is no evidence that Vitamin E is neuroprotective. (See 'Vitamin E' above.) REFERENCES 1 Ravina, BM, Fagan, SC, Hart, RG, et al. Neuroprotective agents for clinical trials in Parkinson's disease: A systematic assessment. Neurology 2003; 60:1234. 2 Schapira, AH, Olanow, CW. 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Neurology 2007; 69:1696. ---------------------------------------------------------------------- To sign-off Parkinsn send a message to: mailto:[log in to unmask] In the body of the message put: signoff parkinsn