Elsevier

The Lancet Neurology

Volume 8, Issue 12, December 2009, Pages 1158-1171
The Lancet Neurology

Review
Progression of Parkinson's disease in the clinical phase: potential markers

https://doi.org/10.1016/S1474-4422(09)70291-1Get rights and content

Summary

Neuromodulatory or even neuroprotective therapy could soon be available for Parkinson's disease (PD), raising the question of how we should define and measure disease progression. Reported evidence suggests that several symptoms worsen with disease duration. Bradykinesia, rigidity, and activities of daily living deteriorate faster at the beginning of the disease, and this deterioration is paralleled by a decline in functional presynaptic dopaminergic activity, as shown by imaging techniques. Cognitive, speech, sleep, and gait difficulties might progress linearly in proportion to disease duration. Reduced variability in heart rate, orthostatic dysfunction, and visual hallucinations start to develop at mid-stage disease and are more common in late stages than earlier stages. In this Review, we summarise our current understanding of the progression of PD-associated symptoms and markers and conclude that an effective measurement of progression of PD must adapt to the different stages of the disease. In addition to routine clinical rating scales, new quantitative assessments of motor and non-motor symptoms, which should be more broadly available, reasonably priced, and easy-to-use, are needed.

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 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

References (145)

  • I Shoulson

    Where do we stand on neuroprotection? Where do we go from here?

    Mov Disord

    (1998)
  • CW Olanow et al.

    A double-blind, delayed-start trial of rasagiline in Parkinson's disease

    N Engl J Med

    (2009)
  • MM Hoehn et al.

    Parkinsonism: onset, progression and mortality

    Neurology

    (1967)
  • RJ Marttila et al.

    Disability and progression in Parkinson's disease

    Acta Neurol Scand

    (1977)
  • MA Hely et al.

    Sydney Multicenter Study of Parkinson's disease: non-L-dopa-responsive problems dominate at 15 years

    Mov Disord

    (2005)
  • MA Hely et al.

    The sydney multicentre study of Parkinson's disease: progression and mortality at 10 years

    J Neurol Neurosurg Psychiatry

    (1999)
  • G Alves et al.

    Progression of motor impairment and disability in Parkinson disease: a population-based study

    Neurology

    (2005)
  • A Schrag et al.

    Rate of clinical progression in Parkinson's disease. A prospective study

    Mov Disord

    (2007)
  • K Sato et al.

    Prognosis of Parkinson's disease: time to stage III, IV, V, and to motor fluctuations

    Mov Disord

    (2006)
  • A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease

    Neurology

    (2006)
  • KH Karlsen et al.

    Influence of clinical and demographic variables on quality of life in patients with Parkinson's disease

    J Neurol Neurosurg Psychiatry

    (1999)
  • Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. The Parkinson Study Group

    N Engl J Med

    (1993)
  • J Jankovic et al.

    Functional decline in Parkinson disease

    Arch Neurol

    (2001)
  • S Palhagen et al.

    Selegiline slows the progression of the symptoms of Parkinson disease

    Neurology

    (2006)
  • S Fahn et al.

    Levodopa and the progression of Parkinson's disease

    N Engl J Med

    (2004)
  • Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression

    JAMA

    (2002)
  • Effect of lazabemide on the progression of disability in early Parkinson's disease. The Parkinson Study Group

    Ann Neurol

    (1996)
  • ED Louis et al.

    Progression of parkinsonian signs in Parkinson disease

    Arch Neurol

    (1999)
  • A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease

    Arch Neurol

    (2004)
  • DJ Burn et al.

    Motor subtype and cognitive decline in Parkinson's disease, Parkinson's disease with dementia, and dementia with Lewy bodies

    J Neurol Neurosurg Psychiatry

    (2006)
  • CG Goetz et al.

    Differential progression of motor impairment in levodopa-treated Parkinson's disease

    Mov Disord

    (2000)
  • G Ransmayr et al.

    Effect of age and disease duration on parkinsonian motor scores under levodopa therapy

    J Neural Transm Park Dis Dement Sect

    (1995)
  • CS Lee et al.

    Clinical observations on the rate of progression of idiopathic parkinsonism

    Brain

    (1994)
  • FJ Vingerhoets et al.

    Which clinical sign of Parkinson's disease best reflects the nigrostriatal lesion?

    Ann Neurol

    (1997)
  • MW Schupbach et al.

    The segmental progression of early untreated Parkinson disease: a novel approach to clinical rating

    J Neurol Neurosurg Psychiatry

    (2009)
  • CG Goetz et al.

    Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): process, format, and clinimetric testing plan

    Mov Disord

    (2007)
  • I Milanov

    Correlation between tremor parameters

    Funct Neurol

    (2002)
  • ED Louis et al.

    Clinical correlates of action tremor in Parkinson disease

    Arch Neurol

    (2001)
  • RP Meshack et al.

    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

    (2002)
  • JM Hausdorff et al.

    Effects of cognitive challenge on gait variability in patients with Parkinson's disease

    J Geriatr Psychiatry Neurol

    (2003)
  • N Giladi et al.

    Freezing of gait in PD: prospective assessment in the DATATOP cohort

    Neurology

    (2001)
  • N Giladi et al.

    Motor blocks in Parkinson's disease

    Neurology

    (1992)
  • N Giladi et al.

    Freezing of gait in patients with advanced Parkinson's disease

    J Neural Transm

    (2001)
  • M Macht et al.

    Predictors of freezing in Parkinson's disease: a survey of 6,620 patients

    Mov Disord

    (2007)
  • BH Wood et al.

    Incidence and prediction of falls in Parkinson's disease: a prospective multidisciplinary study

    J Neurol Neurosurg Psychiatry

    (2002)
  • S Skodda et al.

    Progression of dysprosody in Parkinson's disease over time—a longitudinal study

    Mov Disord

    (2009)
  • J Muller et al.

    Progression of dysarthria and dysphagia in postmortem-confirmed parkinsonian disorders

    Arch Neurol

    (2001)
  • S Skodda et al.

    Speech rate and rhythm in Parkinson's disease

    Mov Disord

    (2008)
  • T Benke et al.

    Repetitive speech phenomena in Parkinson's disease

    J Neurol Neurosurg Psychiatry

    (2000)
  • N Miller et al.

    Prevalence and pattern of perceived intelligibility changes in Parkinson's disease

    J Neurol Neurosurg Psychiatry

    (2007)
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