Information on the progression or development over time of the signs and symptoms, impairments and need for care in patients with Parkinson’s disease (PD) are important in the management of these patients. Also, the study of risk factors for the progression and clinical heterogeneity of the disease are important research issues related to PD. In addition, the development of the Braak hypothesis on the disease progression in the brain has increased the interest in long-term information on the clinical development of PD. Such information is also essential for defining and measuring disease progression in studies of potential neuromodulatory therapies for the disease. Large longitudinal prospective cohort studies of unselected patients with incident PD and a comparable control group are the optimal research design to obtain this information.
Long-term cohort studies
A cohort study is a form of longitudinal study used in medicine to describe the development, risk factors, or aetiology of present or future diseases or symptoms in a group of people. Long-term cohort studies are usually defined as lasting at least five years when studying specific diseases and should preferably include a control group to compare for the general effect of health events related to aging.
Long-term cohort studies in PD
We will in this review discuss both available and lacking information from long-term longitudinal cohort studies on the clinical progression of PD. Although few studies fulfil the desired optimal study design to investigate the progression of PD, we have identified several long-term cohort studies that may bring important information on this issue. In addition, several studies are in progress and hopefully they will further improve this knowledge. We have chosen not to include therapeutic studies and instead focused on cohort studies that have examined the broad spectre of the symptoms in PD. A PubMed search using the terms “Parkinson” and “cohort study” was performed, in addition to examining review papers on the issue for references to relevant studies.
We identified four long-term studies in PD that fulfilled our search requirements [1,4] but only the CamPaIGN study has been following an unselected cohort of patients with incident PD for at least five years (Table 1). In addition, we found three on-going potentially long-term cohort studies [5,7] that had published at least one-year follow-up results (Table 2). Also, several studies are planned but are still in a recruitment phase or have not yet published longitudinal data. Among these, the Michael J. Fox Foundation has initiated and financed the Parkinson’s Progression Markers Initiative (PPMI).
The progression of motor symptoms and disability in PD
To study and describe the progression of symptoms associated with motor function in PD is indeed difficult to perform. This is caused by the heterogeneity of the clinical picture and disease development among individual patients, different temporal changes of key motor symptoms in PD (ie. tremor, bradykinesia, rigidity, and postural abnormalities), and the impact of different symptomatic treatment strategies that influence the apparent level of motor impairment. In addition, there is so far not available any longitudinal cohort study of unselected patients with incident PD that includes detailed information on the motor symptoms. Based on the above mentioned cohort studies and other relevant studies it is, however, possible to draw some conclusions.
Results from studies in the pre-levodopa era indicated that the progression was fast with the majority of patients reaching a bedridden state within 10-14 years [8]. This was supported also by short-term evaluations of patients in the placebo arms of treatment studies. The more recent prospective cohort studies do indicate a much slower progression [9,10]. These studies have, however, included patients with more advanced parkinsonism. Taken together, it seems that there are different rates of decline in different phases of the disease with faster decline in the early stages [11]. This different rate of decline can be either driven by the disease biology or by factors related to the scales that are applied to measure progression. Moreover, features like older age, cognitive impairment, and lack of tremor seem to be associated with a more severe motor decline in PD [12].
The development of the different key motor symptoms of the disease is also important to address as the presence of a motor pattern dominated by postural instability gait disorder (PIGD) is a risk factor for both increased cognitive and motor decline. The evaluation of PIGD is based on the relative presence of different motor symptoms and it has been shown that early PD is usually found to be tremor dominant, while during the development of the disease the PIGD pattern becomes evident in nearly all patients [13]. This implies that the PIGD form of parkinsonism is not a specific type of PD, but in most patients represent a more advanced stage of the disease process. Reaching this stage of disease development could therefore represent a milestone along the trajectory of disease progression.
The apparently established facts regarding development of motor complications in PD is that 50 % of the patients have such problems after five years with the disease. Results from available epidemiological studies indicate that this is a marked overestimation [14,15]. Both motor fluctuations and dyskinesia seem to develop in less than 30% after about six years with medication. These studies have, however, examined and followed groups of patients from cross-sectional studies. Also motor complications are potential markers or milestones to be used in the evaluation of disease progression.
The progression of non-motor symptoms in PD
While PD has traditionally been considered a motor system disorder, it is now widely recog- nised that non-motor symptoms are not only common but also a key determinant of reduced functioning and quality of life [16]. Non-motor symptoms such as olfactory loss, constipation, depression, and rapid eye movement (REM) sleep behaviour disorder (RBD) might even precede the onset of motor symptoms by several years [17]. A combination of some of these non-motor symptoms may therefore potentially be used to identify a population “at risk of PD”, perhaps together with functional imaging and future biological markers, which will be particularly important if neuroprotective therapies become available.
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Although non-motor symptoms can present at any stage of the disease, they tend to become more prominent in late or advanced PD. For example, non-motor symptoms such as falls, hallucinations, and dementia have consistently been reported as strong predictors of nursing home placement and mortality in advanced cases. Also, two recent longitudinal studies found that more than 80% of PD patients ultimately develop dementia [2,18]. However, cognitive impairment is also a frequent finding in patients with early PD, as shown in the CamPaIGN study were 17% of an incident PD cohort developed dementia during the first five years [3]. In one of the few long-term prospective studies that have addressed non-motor symptoms in PD, the Sydney multicentre study, non levodopa-responsive problems such as hallucinations, falls, symptomatic orthostatic hypotension and urinary dysfunction were reported to be more disabling than levodopa-induced dyskinesias in patients who were still alive 15 years from diagnosis [19]. Other long-term studies have reported that excessive daytime sleepiness [20] and fatigue [21] become more frequent with disease progression, although the latter seems to have a more non-persistent course in individual patients. In contrast, the frequency of RBD seems to vary over time and existing longitudinal data on depression in PD suggest that some patients might have a persistent or variable course with repeated remissions and relapses of depression, and that the more severe cases often seen to become chronic.
Compared to the motor symptoms of PD, little is known about the natural history of non-motor symptoms. As non-motor symptoms seem to have a greater impact on functioning and quality of life than motor problems duringthe course of PD, future studies should assess these symptoms in a cohort of newly diagnosed PD with sufficient long-term follow-up evaluations for a better understanding of these issues. For this purpose, validated scales that broadly cover the non-motor symptom complex as well as symptom-specific features should be applied. Such longitudinal studies are important to gain information about the temporal changes of non-motor symptoms and the effect of therapeutic interventions.
What can we learn?
Information from long-term cohort studies of patients with PD may have several important implications for the management of the disease. Primarily, they will provide more reliable data on the progression of PD. This information is important for education of patient and caregiver and can also be used to establish milestones or clinical markers that may be used to examine possible therapeutic interventions that aim to modulate or halt disease progression. In addition, such long-term studies may be used to identify clinical or biological markers that are risk factors for a more severe disease development either in terms of motor progression or non-motor complications such as cognitive decline. Interventions that aim to modulate disease progression should select these subgroups of patients with a high risk for a faster decline as this will provide a study population with a higher probability to detect effects of the intervention within a reasonable time frame. It is, however, important that long-term cohort studies examine the disease progression in patients with incident PD and preferably with a control group. The available data today from such studies are scarce. Only the CamPaIGN study has followed incident patients for more than five years, but without a control group. However, several large studies are planned or started and they will therefore within a few years give us a lot more information on these important issues in PD.
References
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