Progress in Parkinson’s disease

Parkinson’s disease (PD) research continues to provide important insights into aetiology and pathogenesis, its complex clinical phenotype and, importantly into novel or improved forms of treatment. Several papers in this issue of the journal reflect progress in these areas. Dementia is a common non-motor feature of PD, with some reports indicating that up to 80% of patients develop this complication. Cognitive deficits may be present at an early stage and are usually of a subcortical nature, but progress and become more florid with time. Perhaps somewhat arbitrarily, PD with dementia (PDD) is distinguished from dementia with Lewy bodies (DLB) by the development of parkinsonism at least 1 year before the onset of dementia. In this issue Chang et al. [1] have sought to investigate cerebral perfusion using 99mTc-ethyl cysteinate dimer brain imaging by single photon emission computerized tomography and correlate this with cognitive function in early DLB, PDD and matched controls. The DLB patients demonstrated reduced perfusion in inferior frontal, parietal and temporal cortex and thalamus compared with controls and in the temporal lobe only in comparison with PD. Fifteen of the 17 patients had features of rapid eye movement behaviour disorder with onset 3–5 years before they manifested with DLB. The DLB patients had evidence of widespread cognitive deficits which matched the diffuse hypoperfusion. The PD patients showed deficiencies in abstract thinking compared with controls. Both PD and DLB involve alpha-synuclein aggregation as a core feature of pathology and both have been found as a consequence of separate mutations of the alpha-synuclein gene. Chang et al. [1] propose that their results and those of others support the view that these two disorders are part of the same continuum. Rapid eye movement behaviour disorder may also precede the diagnosis of PD and multiple system atrophy by several years. Sleep disturbance in general is a common problem in PD and worsens as the disease progresses. It is a consequence of the neurodegeneration that underlies PD, co-morbidities and the drugs used to treat the motor features of the disease. In a community-based survey, Porter et al. [2] found that 22% of 122 patients in a UK-based population had a marked sleep disorder. This study also turned-up some other interesting information: the mean dose of levodopa remained relatively low despite advanced disease and this was not offset by the use of a catechol-O-methyl transferase (COMT) inhibitor. Around 40–42% of patients were on dopamine agonists in the early stages of disease, declining to 30% and 18% with progression to advanced stages. Twenty percent had possible depression. Although small, this study emphases how common some of the non-motor problems are in PD. Since its introduction 40 years ago, dopamine replacement therapy for PD has revolutionized the management of this disease. Levodopa has been shown to improve the quality of life and lifespan in PD patients. Despite its clear benefit, the limiting factor in levodopa therapy has been the development of motor complications, comprising ‘wearing off’ and dyskinesias. Although subtle at first and often missed or mis-diagnosed, these complications progress to the level where they result in a significant impairment of quality of life and complicate treatment schedules. They are common, with a prevalence of approximately 30% at 3 years after introduction of levodopa, although this figure is 70% in young onset PD patients. They are the most common indication for the use of deep-brain stimulation. Several strategies are available to reduce the risk for, or to delay motor complications. An important concept that is common to these strategies is that of continuous dopaminergic stimulation (CDS) and is the subject of a review by Steiger in this issue [3]. The CDS concept has two components: the first component is practical and seeks to provide continuous dopaminergic cover for the dopamine deficiency of PD, thereby maximizing motor control. This can be achieved using longer acting dopaminergic agents e.g. dopamine agonists, increasing the half-life of levodopa with COMT inhibition, or by infusion therapy using a dopamine agonist or levodopa. A further development of this strategy is the use of prolonged release formulations of these drugs e.g. once a day preparations of existing oral dopamine agonists or the transdermal (rotigotine) patch. The second component is more theoretical and involves the potential for drugs with a longer half-life to delay the onset of motor complications when used as initial therapy. Indeed this has been confirmed with several dopamine agonist monotherapy studies, although it remains possible that some additional properties of agonists contribute to this effect. Nevertheless, the observation that continuous delivery of levodopa by infusion reduces established dyskinesias certainly supports the CDS hypothesis. What has not yet been demonstrated is whether a dopamine agonist added as a supplement to levodopa can also delay dyskinesias. Although CDS has many attractions, there are several issues that remain to be addressed. We still do not know the 24-h profile of physiological dopamine stimulation in humans. During the awake phase, dopamine firing is enhanced by novel stimuli and certain motor actions, although the background rate is relatively stable. The CDS therapies to date have involved either a decline in stimulation during the night, either as a result of pharmacokinetic profile or by switching the infusion off. Thus true 24-h dopamine CDS may carry with it the potential for pharmacological tolerance. This phenomenon can be seen at the routine level with the gastrointestinal side effects of dopamine therapy that diminish following introduction of drug. Whilst the issue of tolerance remains theoretical, its relevance may become more important with greater experience of 24-h delivery systems.