Challenges in the Long-term Evolution of Parkinson’s Disease
Challenges in the Long-term Evolution of Parkinson’s Disease
Abstract
Substantial progress has been made in the treatment of Parkinson’s disease (PD) over the last few decades. Many dopaminergic drugs are now available and different delivery methods ensure a more continuous effect, which better serves to control motor complications. Surgery of the subthalamic nucleus and globus pallidus pars interna is also effective for motor complications. However, disease progression remains unaltered, although the phenotype of PD has changed. Nowadays, problems such as disequilibrium, freezing, poor gait, autonomic dysfunction and, in particular, cognitive impairment predominate in patients after 15–20 years. Thus, a major outstanding challenge in PD today is the management – or preferably prevention – of the levodopa-resistant symptoms, which are now the greatest source of impairment in quality of life for patients and families. These levodopa-resistant manifestations are the result of extensive neuropathological changes in PD after long-term progression. Recognition that the degeneration is part of a widespread, multisystemic effect strongly supports the notion that concentrating on restoring the nigrostriatal dopamine system should not be the ultimate goal of future research efforts in the therapy of PD. Instead, understanding the mechanism of neurodegeneration and developing therapies to stop it is the real challenge.
There is a change in the clinical manifestation of Parkinson’s disease (PD) over time. Figure 1 provides a schematic overview of this process, starting with a pre-symptomatic phase, which lasts for approximately seven years. Following that, for anything from six to 15 years, patients develop symptoms and complications, but these respond very well to dopaminergic drugs and surgical intervention. This early stage of dopaminergic deficit has been the subject of the most attention over the past decades and, as a result, a range of therapeutic options now exist.
In late-stage PD, which more patients reach as their life expectancy increases, other problems begin to manifest, including cognitive decline, dementia and equilibrium problems, which are theorised to relate to a wider pathology. This stage can last for 10–15 years or more, and there are currently few treatment options available. Understanding the underlying structural changes in the brain that drive this evolution is essential.
Pathology of Parkinson’s Disease
The basal ganglia, in simple terms, comprises two systems. The first is the nigrostriatal dopaminergic projection, which is a dopaminedependent modulator of corticostriatal and thalamostriatal afferent. The second is the subthalamic glutamatergic circuitry, which modulates the globus pallidus pars externa (GPe) and globus pallidus pars interna (GPi) and therefore the output of the basal ganglia, which feeds back to the thalamus and cortex/brainstem. These two systems effectively control much of the motor state of a patient. Denervation in this section of the brain reduces dopamine modulation and hence motor control. This results in the typical PD fluctuations from ‘off’ to ‘on’ states with characteristic patterns, including biphasic dyskinesias at the beginning and end of a dose and levodopa-induced dyskinesias during the on state.1
The remarkable effect of deep-brain stimulation of the subthalamic nucleus (STN-DBS) on motor fluctuations in parkinsonian patients, even in the absence of other medication, emphasises the importance of the nigrostriatal and globus pallidus systems of the basal ganglia in terms of motor control. Despite the intra-patient variation, the overall success of STN-DBS demonstrates the power of modulating these systems. Even a very small stimulation in a highly localised area of the basal ganglia can turn tremor into dyskinesia. Therefore, the motor system in PD can be explained simply by modulation of these two systems in the basal ganglia: dopamine in the striatum, particularly in the putamen, and activity in the STN modulating basal ganglia output. This is a remarkable arrangement and it is unlikely that there is another target as good as the basal ganglia and its subsystems for modifying motor activity.
- Cenci MA, Lindgren HS, Advances in understanding L-DOPAinduced dyskinesia, Curr Opin Neurobiol, 2007;17(6):665–71.
- Stibe C, Lees A, Stern G, Subcutaneous infusion of apomorphine and lisuride in the treatment of parkinsonian onoff fluctuations, Lancet, 1987;1(8537):871.
- Juncos J, Serrati C, Fabbrini G, Chase TN, Fluctuating levodopa concentrations and Parkinson’s disease, Lancet, 1985;2(8452): 440.
- Halliday G, Clarifying Lewy-body parkinsonism with visual hallucinations, Lancet Neurol, 2005;4(10):588–9.
- Rodriguez-Oroz, et al., in preparation.
- Huang C, Mattis P, Perrine K, et al., Metabolic abnormalities associated with mild cognitive impairment in Parkinson disease, Neurology, 2008;70(16 Pt 2):1470–77.
- Kordower JH, Chu Y, Hauser RA, et al., Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease, Nat Med, 2008;14(5):504–6.
- Li JY, Englund E, Holton JL, et al., Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-tograft disease propagation, Nat Med, 2008;14(5):501–3.
- Mendez I, Viñuela A, Astradsson A, et al., Dopamine neurons implanted into people with Parkinson’s disease survive without pathology for 14 years, Nat Med, 2008;14(5):507–9.
