Neurology -- Correspondence for Ahlskog, 69 (17) 1701-1711

Correspondence published:

Beating a dead horse: Dopamine and Parkinson disease: Daniel Tarsy, David K. Simon (5 February 2008)

Reply from the author: J. Eric Ahlskog (5 February 2008)

Beating a dead horse: Dopamine and Parkinson disease: William J. Burke, St. Louis MO, 63104 (4 February 2008)

Beating a dead horse: Dopamine and Parkinson disease 5 February 2008

Daniel Tarsy,
Beth Israel Deaconess Medical Center
330 Brookline Avenue, Boston MA 02215,
David K. Simon
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Re: Beating a dead horse: Dopamine and Parkinson disease

dtarsy{at}bidmc.harvard.edu Daniel Tarsy, et al.

Dr. Ahlskog presents a well reasoned review concerning the overemphasis of dopamine in Parkinson disease (PD). [1] We agree that nondopamine-mediated motor and nonmotor features demand greater attention in order to properly deal with the disabilities suffered by PD patients. However, his conclusion that chronic levodopa use does not cause “neurotoxicity” remains open to debate.
We believe the unresolved question in this ongoing debate is what is meant by levodopa toxicity? The studies Dr. Ahlskog cites, which failed to demonstrate levodopa toxicity, beg the question whether early treatment with levodopa may still be clinically harmful in terms of intrusive dyskinesias and motor fluctuations.
Dr. Ahlskog cites the ELLDOPA study which showed no accelerated clinical progression in early PD patients treated with levodopa for 40 weeks compared with placebo and better clinical scores in levodopa-treated than placebo-treated patients two weeks after drug washout. [2] However, often underemphasized is that within only 40 weeks, 15 of 91 patients who received levodopa 600 mg/day experienced dyskinesias compared with only five of 180 receiving 150-300 mg/day, and three of 90 receiving placebo.
Dr. Ahlskog minimizes the risk and severity of levodopa dyskinesias, stating that levodopa motor complications are often relatively minor and can be readily treated and that “clinically important dyskinesias are not as common as sometimes implied.” However, he also states “there are numerous patients where medication adjustments are insufficient and motor fluctuations or dyskinesias are the primary source of disability.”
While acknowledging here and previously that dyskinesias are more common in PD patients beginning treatment before age 40 [1,3] where they are also more complex and severe [4], he does not cite his previous literature review which reported that 39% of PD patients experience dyskinesias within 4-6 years of starting levodopa. [5]
The term “disease modifying” therapy has largely replaced “neuroprotective” therapy because of the difficulty obtaining pathological evidence that a treatment actually protects neurons. Similarly, we should acknowledge that as PD progresses, chronic levodopa treatment contributes to clinically significant dyskinesia and motor fluctuations without necessarily causing pathologically proven toxicity. At least for now, the available clinical observations should guide our therapeutic decisions concerning the use of levodopa in early PD.
References
1. Ahlskog JE. Beating a dead horse. Dopamine and Parkinson disease. Neurology 2007;69:1701-1711.
2. The Parkinson Study Group. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004;351:2498-2508.
3. Van Gerpen JA, Kumar N, Bower JH, Weigand S, Ahlskog JE. Levodopa- asssociated dyskinesia risk among Parkinson disease patients in Olmsted County, Minnesota, 1976-1990. Arch Neurol 2006;63:205-209.
4. Quinn N, Critchley P, Marsden CD. Young onset Parkinson’s disease. Mov Disord 1987;2:73-91.
5. Ahlskog J, Meunter MD. Frequency of levodopa-related dyskinesias and motor fluctuations as estimated from the cumulative literature. Mov Disord 2001;16:448-458.
Disclosure: The author reports no conflicts of interest.

Reply from the author 5 February 2008

J. Eric Ahlskog,
Mayo Clinic
200 First St. SW, Rochester MN 55905
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Re: Reply from the author

Email J. Eric Ahlskog

I appreciate the comments of Drs. Tarsy and Simon, who summarize their concern: “However, his conclusion that chronic levodopa use does not cause ‘neurotoxicity’ remains open to debate.”
It is true that “neurotoxicity” must be distinguished from the pharmacologic complications of chronic levodopa therapy. The dopamine oxidative stress hypothesis argued that levodopa directly contributes to the irreversible neurodegenerative process (neuronal death). This would qualify as dictionary-defined “neurotoxicity”: “destructive or poisonous to nerve tissue”. Apparently, we are in agreement that true neurotoxicity is unlikely and without compelling evidence.
Levodopa dyskinesias and motor fluctuations, however, reflect a central pharmacodynamic effect in the setting of advancing Parkinson's disease (PD), predisposed by cumulative loss of dopaminergic (presynaptic) terminals. With reduced dopaminergic terminals, poorly-regulated synaptic dopamine tends to induce downstream post-synaptic, as well as presynaptic effects that amplify the pharmacologic instability. [6,7] These levodopa-induced pharmacodynamic effects are potentially reversible, and are not truly “neurotoxic”, although sometimes quite problematic. [6]
There are two further issues implicit in the comments of Drs. Tarsy and Simon. Firstly, are levodopa motor complications so substantial and poorly treatable that we should target these problems with new and better drugs or surgeries? From my perspective, I need treatments for cognitive dysfunction, dysautonomia and levodopa-refractory motor problems.
Dyskinesias can always be abolished by lowering medication doses, albeit sometimes at the expense of increased parkinsonism. Adjunctive amantadine may allow dyskinesia control without substantial levodopa reduction. Where dyskinesias cannot be controlled, subthalamic nucleus (STN) or pallidal deep brain stimulation (DBS) typically fills the void.
Motor fluctuations can also be treated, which reflects the levodopa short-duration responses. Levodopa adjustments, adjunctive drugs and ultimately STN DBS may not result in perfect control, but sufficient to lead a reasonable life if other PD-related refractory problems do not intervene. We should shift our focus to problems that most compromise the lives of our PD patients. [1]
Finally, should levodopa be delayed, or the dose limited to avoid motor complications that progressively develop over many years? In my opinion, the treatment goal should be to maintain PD patients in the mainstreams of their lives, including social, recreational and occupational. It is certainly acceptable to initiate therapy with an alternative drug(s) to levodopa. However, both clinical trial data and clinical experience indicate that levodopa is the most efficacious medication, and by a substantial extent. Clinical trials indicate that even with aggressive dopamine agonist treatment, few patients can go without levodopa beyond a few years. Thus, if other drugs prove insufficient, levodopa in necessary doses should be considered. If patients backslide into a sedentary existence from under-treatment, it is difficult to resurrect them.
Furthermore, there is no evidence that you can save the best levodopa responses for much later. For practical and ethical reasons, this will never be addressed in a clinical trial. However, the early levodopa era experience is relevant--patients with long durations of previously untreated PD--which taught us that the development of levodopa motor complications,[5] as well as increasing parkinsonism disability [8] reflects PD progression, rather than levodopa treatment-duration.
Many independent clinical series reported substantially increased longevity time-locked to the advent of levodopa therapy. [1] If levodopa allowed patients to live longer, it can’t be that bad!
References
6. Baronti F, Mouradian MM, Davis TL, et al. Continuous lisuride effects on central dopaminergic mechanisms in Parkinson's disease. Ann. Neurol. 1992;32:776-781.
7. de la Fuente-Fernandez R, Schulzer M, Mak E, Calne DB, Stoessl AJ. Presynaptic mechanisms of motor fluctuations in Parkinson's disease: a probabilistic model. Brain 2004;127:888-899.
8. Markham CH, Diamond SG. Long-term follow-up of early dopa treatment in Parkinson's disease. Ann. Neurol. 1986;19:365-372.
Disclosure: The author reports no conflicts of interest.

Beating a dead horse: Dopamine and Parkinson disease 4 February 2008

William J. Burke
Dept. Neurology 1438 S Grand,
St. Louis MO, 63104
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Re: Beating a dead horse: Dopamine and Parkinson disease

burkewj{at}slu.edu William J. Burke, et al.

Ahlskog contends that the dopamine (DA) hypothesis of Parkinson’s disease (PD) is dead. [1] He argues that non DA neurons are affected prior to DA substantia nigra (SN) neurons in PD, DA oxyradicals cannot explain selective DA SN neuron loss, and DA replacement therapy whether by L-DOPA or by transplants does not stop disease progression. [1]
Ahlskog’s dismissal of the dopamine hypothesis of PD is based on confusion about the definition of PD and about the difference between symptomatic and neuroprotective therapy. PD is not constipation, deficient olfaction, REM sleep disorder or dementia as he suggests. [1] While these disorders may coexist with PD in some patients, they are not PD. PD is a movement disorder characterized by symptoms of tremor, rigidity and bradykinesia.
It is indisputable that these symptoms are due to the selective loss of dopamine DA SN neurons. Ahlskog correctly explains why the DA oxidation products, DA quinone (DAQ) and dopaminochrome (DAC)—which have not been detected free in human brain— cannot account for this selective loss of DA SN neurons. However, there is new evidence that the MAO metabolite of DA, 3,4-dihydroxyphenylacetaldehyde (DOPAL) explains this selective loss. DOPAL is selectively present in human DA neurons and is increased in PD SN. [2,3] At physiologically relevant levels, it induces apoptosis and triggers formation of toxic alpha-synuclein (AS) oligomers and large Lewy body-like aggregates. [2,3,4]
Furthermore, other brainstem aminergic neurons affected in PD have similar toxic aldehyde MAO metabolites. [2,3] However Braak’s hypothesis, that non DA brainstem neurons are affected first in PD, mitigating the primacy of DA SN neuron loss in PD, should be viewed with skepticism. Braak’s investigation excludes PD patients from this autopsy study, provides no neuronal counts, uses non quantitative methods, and does not use immunohistochemistry to identify neuronal types.
Secondly, DA replacement therapy by whatever means including L-DOPA provides symptomatic relief but does not prevent DA neuron loss or the progression of PD. However, newer studies, using delayed start and washout methods, provide evidence that blocking the formation of DOPAL with MAO inhibitors is neuroprotective. [5] The mechanism of DOPAL toxicity is clear and provides multiple targets for neuroprotective therapy in PD. [2,3]
Before dismissing the primacy of DA neuron loss in PD, these neuroprotective strategies need to be rigorously investigated.
References
1. Ahlskog JE. Beating a dead horse: dopamine and Parkinsons disease. Neurology 2007; 69:1701-1711.
2. Marchitti SA, Deitrich RA, Vasilou V. Neurotoxicity and metabolism of the catecholamine-derived 3,4- dihydroxyphenylacetaldehyde and 3,4-dihydroxyphenylglycolaldehyde: the role of aldehyde dehydrogenase. Pharmacol Rev 2007; 59:125-150.
3. Burke WJ, Li SW, Kristal BS et al. Neurotoxicity of MAO metabolites of catecholamine neurotransmitters: role in neurodegenerative diseases. Neurotoxicology 2004; 25:101-115.
4. Burke WJ, Kumar VB, Galvin JE et al. Aggregation of alpha- synuclein by DOPAL, the monoamine oxidase metabolite of dopamine. Acta Neuropath,2008; 115: 193-203.
5. Parkinson’s study group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson’s disease. Arch Neurol 2004;61:561-566.
Disclosure: The authors report no conflicts of interest.
The authors had the opportunity to respond to this correspondence but declined.