The Parkinson's-Reversing Breakthrough

Parkinson Disease Handbook

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Parkinson's disease (PD) is an age-related progressive neurodegenerative disorder that affects approximately 1-2% of the population (see Volume II, Chapter 35). It is characterized by bradykinesia, rigidity, postural instability and tremor (Lang and Lozano, 1998; Olanow et al., 2001). Pathologically the hallmark of PD is degeneration of the substantia nigra pars compacta (SNc) with the loss of midbrain dopaminergic neurons combined with the presence of intraneuronal inclusion (Lewy) bodies. Importantly, degeneration also occurs in non-dopaminergic regions including epinephrine neurons of the locus coeruleus, serotonin neurons of the dorsal raphe, cholinergic neurons of the nucleus basalis of Meynert, and nerve cells in the dorsal motor nucleus of the vagus, the pedunculopontine nucleus, and peripheral autonomic system. Despite the involvement of multiple brain regions and multiple transmitter systems, treatment of PD is primarily based on a dopamine replacement strategy. Levodopa is the most widely employed and most effective symptomatic agent. It is converted to dopamine within the brain by an aromatic acid decarboxylase (AADC). Treatment with levodopa is extremely effective in the early stages of the disease, however, chronic levodopa treatment is associated with the development of motor complications (motor fluctuations and dyskinesias) which affect as many as 80% of patients after 5-10 years of treatment (Marsden and Parkes, 1976; Ahlskog and Muenter, 2001; Olanow,

2004). Motor complications can be an important source of disability for many patients who cycle between "on" periods in which they respond to lev-odopa but have complicating dyskinesia, and "off" periods in which they do not respond to the drug and suffer features of parkinsonism. Dopamine agonists are associated with reduced motor complications, but patients eventually require levodopa treatment with the risk of motor complications (Olanow, 2003). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus pars interna (GPi) is now widely used to reduce the incidence and severity of levodopa-induced dyskinesias, but this treatment is associated with side-effects related to the surgery, the implantation system and stimulation (2001). PD is also associated with features that do not respond to levodopa or other available treatments. These include freezing of gait, postural instability, dysphagia, speech difficulties, sleep disturbances, autonomic impairment (orthostatic hypotension and gastrointestinal, urinary and sexual dysfunction), depression, and dementia, which likely reflect degeneration of non-dopaminergic neurons (Lang and Lozano, 1998; Olanow et al., 2001). Finally, the disease continues to progress despite levodopa treatment. Indeed, there is a theoretical concern that exogenous administration of levodopa may be toxic to dopamine neurons based on its oxidative metabolism and its capacity to damage dopamine neurons in tissue culture. While the drug has not been shown to be toxic in the in vivo experiments (Olanow et al., 2004), the imaging component of the recently completed

ELLDOPA study noted a faster rate of decline in an imaging biomarker of the nigrostriatal system in lev-odopa compared to placebo-treated patients consistent with a toxic effect of levodopa (Fahn et al., 2004).

It is thus clear that PD patients can suffer intolerable disability despite currently available therapies, and a treatment that slows disease progression and/or restores function is an urgent priority. At present, no treatment intervention has been demonstrated to provide such an effect in PD. Much attention has focused on transplantation strategies as a treatment option because of the potential of transplanted dopamine nerve cells to replace degenerating dopamine neurons. While transplantation of dopaminergic cells may not address all of the problems in PD, dopamine cell loss is primarily responsible for the motor features of the disease. Restoration of dopamine in a more physiologic manner might provide the benefits of levodopa with a reduced risk of motor complications. Further, successful transplantation could obviate the need for levodopa therapy and protect against the potentially toxic effects of exogenously administered levodopa. It is also theoretically possible that early and physiologic replacement of dopamine might prevent degeneration in non-dopaminergic regions that occurs secondary to dopamine loss (Rodriguez et al., 1998).

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