References for this Review were identified by searches of PubMed with the search term “parkinson” in combination with either “longitudinal study”, “disease duration”, or “disease progression” until September, 2009. The references within selected articles and recent reviews were also screened for relevant papers. Only papers in English were reviewed. From treatment studies, only placebo arms were included, and post-mortem and histological investigations if these were relevant for features
ReviewProgression of Parkinson's disease in the clinical phase: potential markers
Introduction
In Parkinson's disease (PD), therapeutic strategies might soon be available with prolonged benefits that might affect the underlying pathogenesis, thereby preventing or delaying progression.1, 2 Nevertheless, in researching such strategies, it becomes evident that little is known about both onset and progression rate of symptoms and markers in PD (ie, whether they progress linearly or not).
PD has been considered as a motor disease for a long time, and hence motor symptoms are the symptoms primarily assessed in clinical studies. However, there is an increasing awareness of the non-motor aspects of the disease, including cognitive decline, behavioural changes, and autonomic dysfunction.
Some evidence of the onset and the progression rate of different symptoms and markers can be drawn from a broad range of studies. In this Review, we summarise these findings to help understand the course of the disease and to help advise the design of future studies. We mainly focus on results of longitudinal studies concerning changes of frequency (including studies that describe the first timepoint of occurrence) and severity of different symptoms associated with PD. We also review cross-sectional studies investigating the association between the onset or the severity of PD-related features and disease duration.
We define a progression marker as a disease-associated feature that changes in frequency of occurrence or severity, or both, over time. The definitions used in our evaluation of the progression of features are explained in table 1, and the panel provides the classification for levels of evidence. Levels of evidence (panel) were adapted from the American Academy of Neurology (AAN) guidelines for treatment efficacy and used to characterise the quality of every selected study. Prospective studies were defined as studies which follow a group of similar individuals from baseline over time with a predefined endpoint, and retrospective studies as studies which look backwards and examine factors in relation to an outcome. Conclusions concerning the evidence for markers of progression were also based on AAN criteria (table 1).
Section snippets
Progression of symptoms associated with motor function
Owing to the success of pharmacological treatment, assessment of the natural progression of the key features of PD over the whole disease course is impossible at present. Unfortunately, the two fundamental studies from the pre-levodopa era did not provide details on the rate of progression of key PD symptoms (ie, tremor, bradykinesia, rigidity, and postural instability).3, 4 The results of these studies suggested a fast progression of motor disability, reaching Hoehn and Yahr stage 5, which
Dementia
During the past two decades, increasing attention has been dedicated to cognitive dysfunction. Data from independent studies have found a higher incidence of dementia in patients with PD compared with healthy individuals of the same age.47, 48 The reported annual incidence of dementia in community-based patients with PD varies between 30·0 per 1000 person-years after 3·5 years49 of disease duration and 95·3 per 1000 person-years after 4 years.48 Five evidence level I and four evidence level II
Sleep disturbances
Several studies have assessed general aspects of sleep in PD. In an evidence level I study with assessment after 8 years of follow-up, an increase of “sleeping problems which are discussed with the physician” was detected.84 Use of polysomnography has led to more detailed information concerning the type of sleep disturbances. An evidence level III study found that sleep latency increased with longer disease duration, whereas total sleep time, deep sleep time, rapid eye movement (REM) sleep
Progression of symptoms associated with autonomic and sensory function
Progression of autonomic dysfunction in patients with PD might be assessed with questionnaires, as two evidence level III studies found a positive correlation of the severity of autonomic dysfunction with disease duration.91, 92 One study91 used a self-developed 9-point autonomic dysfunction score, whereas the other study92 used a previously validated 29-point autonomic symptom questionnaire.
Activities of daily living
In patients with PD, there is progression of motor dysfunction relevant to activities of daily living, as prospectively assessed with the UPDRS II score in the placebo arm of treatment studies10, 12, 14, 15, 17 and longitudinal observation studies7, 8, 13, 19 (figure 1). Studies have shown an annual increase of motor disability from 0·3 to 4·7 points per year, which was more pronounced at early stages than late stages. Additionally, a retrospective study has shown a strong association between
Quality of life
Following patients with advanced disease over 8 years, two evidence level I studies that used the same cohort reported a highly significant decrease in quality of life, as assessed with the total and subscores of the Nottingham health profile.76, 112 Three level II studies in patients with more recent-onset PD than those studied in the two evidence level I studies confirmed this finding by using the Parkinson's disease questionnaire.113, 114, 115 Thus, there is definite reduction of quality of
Nutrition
There is probable positive association between PD duration and weight loss and malnutrition, particularly at late stages. In an evidence level I study, a significant weight loss was reported in patients with PD after an observation period of 13 years, a finding that was not seen in controls.116 Data from a level II evidence study showed a significant reduction in the mini nutritional assessment score after 3 years in patients with advanced PD.117
Disease progression assessed with neuroimaging methods
Neuroimaging in PD deserves a separate and extensive discussion and is beyond the scope of this Review. Here, we provide an overview on general aspects of functional neuroimaging in association with PD progression.
Biochemical methods to assess PD progression
Overall, there are few data about progression markers in body fluids, particularly neurodegenerative markers (eg, total tau, phospho-tau, Aβ42, total and oligomeric alpha-synuclein) in relation to PD progression. One longitudinal study in five patients at very early disease stage showed a negative correlation of complex I and IV activity in platelet mitochondria with disease duration.148 This association was not detectable in a cross-sectional comparison of 27 patients with disease duration
Conclusions
Deterioration of motor function, in particular bradykinesia and rigidity, and deterioration of the activities of daily living are accelerated in the first years of the disease course, might have an exponential decline, and show pronounced parallels to functional presynaptic dopaminergic imaging (ie, 18F-fluorodopa-PET and DAT scan imaging). Deterioration of gait (in particular freezing), speech, cognition, visuospatial and colour discrimination, and quality of life affect all PD stages and
Search strategy and selection criteria
References (145)
- et al.
Longitudinal metric properties of disability rating scales for Parkinson's disease
Value Health
(2006) - et al.
Dopa-sensitive and dopa-resistant gait parameters in Parkinson's disease
J Neurol Sci
(1991) - et al.
Postural reactions to soleus muscle vibration in Parkinson's disease: scaling deteriorates as disease progresses
Neurosci Lett
(2006) - et al.
Gait festination in Parkinson's disease
Parkinsonism Relat Disord
(2001) - et al.
Motor fluctuations in Parkinson's disease
J Neurol Sci
(1999) - et al.
A longitudinal of Parkinson's disease: clinical and neuropsychological correlates of dementia
J Clin Neurosci
(1996) - et al.
Visual hallucinations in the diagnosis of idiopathic Parkinson's disease: a retrospective autopsy study
Lancet Neurol
(2005) - et al.
Depression in Parkinson's disease: clinical correlates and outcome
Parkinsonism Relat Disord
(2003) - et al.
Progressive sleep ‘destructuring’ in Parkinson's disease. A polysomnographic study in 46 patients
Sleep Med
(2005) - et al.
Evaluation of sympathetic skin response in Parkinson's disease
Parkinsonism Relat Disord
(2006)
Where do we stand on neuroprotection? Where do we go from here?
Mov Disord
A double-blind, delayed-start trial of rasagiline in Parkinson's disease
N Engl J Med
Parkinsonism: onset, progression and mortality
Neurology
Disability and progression in Parkinson's disease
Acta Neurol Scand
Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years
Mov Disord
The sydney multicentre study of Parkinson's disease: progression and mortality at 10 years
J Neurol Neurosurg Psychiatry
Progression of motor impairment and disability in Parkinson disease: a population-based study
Neurology
Rate of clinical progression in Parkinson's disease. A prospective study
Mov Disord
Prognosis of Parkinson's disease: time to stage III, IV, V, and to motor fluctuations
Mov Disord
A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease
Neurology
Influence of clinical and demographic variables on quality of life in patients with Parkinson's disease
J Neurol Neurosurg Psychiatry
Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group
N Engl J Med
Functional decline in Parkinson disease
Arch Neurol
Selegiline slows the progression of the symptoms of Parkinson disease
Neurology
Levodopa and the progression of Parkinson's disease
N Engl J Med
Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression
JAMA
Effect of lazabemide on the progression of disability in early Parkinson's disease. The Parkinson Study Group
Ann Neurol
Progression of parkinsonian signs in Parkinson disease
Arch Neurol
A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease
Arch Neurol
Motor subtype and cognitive decline in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies
J Neurol Neurosurg Psychiatry
Differential progression of motor impairment in levodopa-treated Parkinson's disease
Mov Disord
Effect of age and disease duration on parkinsonian motor scores under levodopa therapy
J Neural Transm Park Dis Dement Sect
Clinical observations on the rate of progression of idiopathic parkinsonism
Brain
Which clinical sign of Parkinson's disease best reflects the nigrostriatal lesion?
Ann Neurol
The segmental progression of early untreated Parkinson disease: a novel approach to clinical rating
J Neurol Neurosurg Psychiatry
Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): process, format, and clinimetric testing plan
Mov Disord
Correlation between tremor parameters
Funct Neurol
Clinical correlates of action tremor in Parkinson disease
Arch Neurol
A randomized controlled trial of the effects of weights on amplitude and frequency of postural hand tremor in people with Parkinson's disease
Clin Rehabil
Effects of cognitive challenge on gait variability in patients with Parkinson's disease
J Geriatr Psychiatry Neurol
Freezing of gait in PD: prospective assessment in the DATATOP cohort
Neurology
Motor blocks in Parkinson's disease
Neurology
Freezing of gait in patients with advanced Parkinson's disease
J Neural Transm
Predictors of freezing in Parkinson's disease: a survey of 6,620 patients
Mov Disord
Incidence and prediction of falls in Parkinson's disease: a prospective multidisciplinary study
J Neurol Neurosurg Psychiatry
Progression of dysprosody in Parkinson's disease over time—a longitudinal study
Mov Disord
Progression of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders
Arch Neurol
Speech rate and rhythm in Parkinson's disease
Mov Disord
Repetitive speech phenomena in Parkinson's disease
J Neurol Neurosurg Psychiatry
Prevalence and pattern of perceived intelligibility changes in Parkinson's disease
J Neurol Neurosurg Psychiatry
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