Elsevier

The Lancet

Volume 386, Issue 9996, 29 August–4 September 2015, Pages 896-912
The Lancet

Seminar
Parkinson's disease

https://doi.org/10.1016/S0140-6736(14)61393-3 Get rights and content

Summary

Parkinson's disease is a neurological disorder with evolving layers of complexity. It has long been characterised by the classical motor features of parkinsonism associated with Lewy bodies and loss of dopaminergic neurons in the substantia nigra. However, the symptomatology of Parkinson's disease is now recognised as heterogeneous, with clinically significant non-motor features. Similarly, its pathology involves extensive regions of the nervous system, various neurotransmitters, and protein aggregates other than just Lewy bodies. The cause of Parkinson's disease remains unknown, but risk of developing Parkinson's disease is no longer viewed as primarily due to environmental factors. Instead, Parkinson's disease seems to result from a complicated interplay of genetic and environmental factors affecting numerous fundamental cellular processes. The complexity of Parkinson's disease is accompanied by clinical challenges, including an inability to make a definitive diagnosis at the earliest stages of the disease and difficulties in the management of symptoms at later stages. Furthermore, there are no treatments that slow the neurodegenerative process. In this Seminar, we review these complexities and challenges of Parkinson's disease.

Introduction

Parkinson's disease is a common and complex neurological disorder. The first detailed description of Parkinson's disease was made almost two centuries ago, but the conceptualisation of the disease continues to evolve. At its core, Parkinson's disease is a neurodegenerative disease with early prominent death of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The resultant dopamine deficiency within the basal ganglia leads to a movement disorder characterised by classical parkinsonian motor symptoms. Parkinson's disease is also associated with numerous non-motor symptoms, some of which precede the motor dysfunction by more than a decade. The mainstay of Parkinson's disease management is symptomatic treatment with drugs that increase dopamine concentrations or directly stimulate dopamine receptors. However, Parkinson's disease involves neurotransmitters other than dopamine and regions of the nervous system outside the basal ganglia. Previously, Parkinson's disease was thought to be caused primarily by environmental factors, but research is revealing that the disease develops from a complicated interplay of genetics and environment. Thus, Parkinson's disease is now viewed as a slowly progressive neurodegenerative disorder that begins years before diagnosis can be made, implicates multiple neuroanatomical areas, results from a combination of genetic and environmental factors, and manifests with a broad range of symptoms. These complexities of Parkinson's disease are accompanied by clinical challenges. In particular, diagnostic tests which allow for definitive diagnosis at early stages of the disease do not exist. The gold standard for diagnosis of Parkinson's disease has been the presence of SNpc degeneration and Lewy pathology at post-mortem pathological examination. Lewy pathology consists of abnormal aggregates of α-synuclein protein, called Lewy bodies and Lewy neurites. The association between Lewy pathology and pathogenesis of the disease is poorly understood. Management strategies for many of the disabling features that occur in late stages of the disease are poor. These features include motor symptoms that do not respond to dopaminergic therapies or develop as complications of long-term dopaminergic drug use, as well as an array of non-motor symptoms. Disease-modifying treatments that reduce the rate of neurodegeneration or stop the disease process have remained elusive and are the greatest unmet therapeutic need in Parkinson's disease. However, the understanding of the pathogenesis of Parkinson's disease is expanding and thereby helping to identify potential targets for disease modification.

Section snippets

Clinical features

The classical motor symptoms of Parkinson's disease have been recognised as prominent components of the disease since James Parkinson's initial description in the 19th century, later refined by Jean-Martin Charcot.1 These parkinsonian symptoms include bradykinesia, muscular rigidity, rest tremor, and postural and gait impairment (panel 1).2 Motor features in patients with Parkinson's disease are heterogeneous, which has prompted attempts to classify subtypes of the disease.3 A consensus on the

Risk factors

Parkinson's disease is recognised as the most common neurodegenerative disorder after Alzheimer's disease.19, 20 Prevalence of Parkinson's disease seems higher in Europe, North America, and South America (estimated crude prevalence for all ages: 66–1500 per 100 000,21 111–329 per 100 000,22 and 31–470 per 100 000,23 respectively) compared with African, Asian, and Arabic countries (estimated crude prevalence for all ages: 10–43 per 100 000,24 15–119 per 100 000,25 and 27–43 per 100 000,26

Pathology

The crucial pathological feature of Parkinson's disease is loss of dopaminergic neurons within the SNpc. The most profoundly affected area of the SNpc is typically the ventrolateral tier, which contains neurons that project to the dorsal putamen of the striatum. Results of clinical-pathological correlation studies45 showed that moderate to severe dopaminergic neuronal loss within this area is probably the cause of motor features, bradykinesia and rigidity in particular, in advanced Parkinson's

Genetics

The past 15 years have been marked by important discoveries in the genetics of Parkinson's disease. Early investigations used linkage analysis in rare kindreds with inherited parkinsonism to find genes related to Parkinson's disease. The first gene identified was SNCA,36 and SNCA mutations are associated with autosomal dominant parkinsonism. Disease-causing mutations include missense mutations, which result in aminoacid substitutions, and multiplications of the gene locus.73 Aminoacid

Pathogenesis

Substantial advances in the understanding of the pathogenesis of Parkinson's disease have resulted from the epidemiological findings, pathological observations, and genetic discoveries described above. For example, key molecular pathways presumed to be important in both familial and sporadic Parkinson's disease have been identified by fitting genes that are associated with the disease into common intracellular networks.103 Impairments in cellular processes involved in the regulation of protein

Diagnosis

Clinical diagnosis of Parkinson's disease is based on the presence of parkinsonian motor features, namely bradykinesia plus rigidity and resting tremor. Postural instability is typically a feature of more advanced disease. There should be no red flags that suggest an alternate cause of parkinsonism, including other neurodegenerative diseases, such as progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration. The UK Parkinson's Disease Society Brain Bank criteria2

Neuroprotection and disease modification

Available therapies for Parkinson's disease only treat symptoms of the disease. A major goal of Parkinson's disease research is the development of disease-modifying drugs that slow or stop the underlying neurodegenerative process. In hindsight, earlier expectations that a single agent could be capable of achieving this might have been naive. The underlying causes of the disease are heterogeneous, and multiple cellular processes are variably involved in neurodegeneration in Parkinson's disease (

Conclusion

Parkinson's disease is complex in its clinical expression and treatment. Lessons from epidemiology, pathology, and genetics have directed investigations of the pathogenesis of Parkinson's disease. Further understanding of the molecular and cellular pathways involved in the neurodegenerative process are expected to yield useful biomarkers for the diagnosis of early prodromal disease, although a single biomarker is likely to be insufficient. The ultimate deliverable from ongoing research is the

Search strategy and selection criteria

The authors searched personal files and PubMed for peer-reviewed articles published in English from Jan 1, 2000, to Feb 28, 2015. The search terms “parkinson”, “motor features”, “non-motor features”, “prevalence”, “incidence”, “risk factors”, “pathology”, “genetics”, “pathogenesis”, “treatment”, and “deep brain stimulation” were used. The search term “parkinson” with the “clinical trials” filter was also used. Additional articles were identified by searching the reference lists of identified

References (173)

  • S Phani et al.

    Neurodegeneration and inflammation in Parkinson's disease

    Parkinsonism Relat Disord

    (2012)
  • I Martin et al.

    Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson's disease

    Cell

    (2014)
  • C Paisán-Ruíz et al.

    Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease

    Neuron

    (2004)
  • DG Healy et al.

    Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study

    Lancet Neurol

    (2008)
  • A Zimprich et al.

    A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease

    Am J Hum Genet

    (2011)
  • C Vilariño-Güell et al.

    VPS35 mutations in Parkinson disease

    Am J Hum Genet

    (2011)
  • M-C Chartier-Harlin et al.

    Translation initiator EIF4G1 mutations in familial Parkinson disease

    Am J Hum Genet

    (2011)
  • M Funayama et al.

    CHCHD2 mutations in autosomal dominant late-onset Parkinson's disease: a genome-wide linkage and sequencing study

    Lancet Neurol

    (2015)
  • JS Bonifacino et al.

    Retromer

    Curr Opin Cell Biol

    (2008)
  • A Tucci et al.

    Study of the genetic variability in a Parkinson's Disease gene: EIF4G1

    Neurosci Lett

    (2012)
  • A Schrag et al.

    Epidemiological, clinical, and genetic characteristics of early-onset parkinsonism

    Lancet Neurol

    (2006)
  • C Klein et al.

    Deciphering the role of heterozygous mutations in genes associated with parkinsonism

    Lancet Neurol

    (2007)
  • A Puschmann

    Monogenic Parkinson's disease and parkinsonism: clinical phenotypes and frequencies of known mutations

    Parkinsonism Relat Disord

    (2013)
  • CG Goetz

    The history of Parkinson's disease: early clinical descriptions and neurological therapies

    Cold Spring Harb Perspect Med

    (2011)
  • WR Gibb et al.

    The relevance of the Lewy body to the pathogenesis of idiopathic Parkinson's disease

    J Neurol Neurosurg Psychiatry

    (1988)
  • C Marras et al.

    Parkinson's disease subtypes: lost in translation?

    J Neurol Neurosurg Psychiatry

    (2013)
  • J Jankovic et al.

    Variable expression of Parkinson's disease: a base-line analysis of the DATATOP cohort. The Parkinson Study Group

    Neurology

    (1990)
  • TK Khoo et al.

    The spectrum of nonmotor symptoms in early Parkinson disease

    Neurology

    (2013)
  • P Martinez-Martin et al.

    The impact of non-motor symptoms on health-related quality of life of patients with Parkinson's disease

    Mov Disord

    (2011)
  • GW Duncan et al.

    Health-related quality of life in early Parkinson's disease: the impact of nonmotor symptoms

    Mov Disord

    (2014)
  • RB Postuma et al.

    Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease

    Mov Disord

    (2012)
  • International classification of sleep disorders: diagnostic and coding manual

    (2005)
  • RN Aurora et al.

    Best practice guide for the treatment of REM sleep behavior disorder (RBD)

    J Clin Sleep Med

    (2010)
  • RB Postuma et al.

    Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder

    Neurology

    (2009)
  • AJ Noyce et al.

    Meta-analysis of early nonmotor features and risk factors for Parkinson disease

    Ann Neurol

    (2012)
  • A Siderowf et al.

    Premotor Parkinson's disease: concepts and definitions

    Mov Disord

    (2012)
  • 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 multicenter study of Parkinson's disease: the inevitability of dementia at 20 years

    Mov Disord

    (2008)
  • M Coelho et al.

    Late-stage Parkinson disease

    Nat Rev Neurol

    (2012)
  • ER Dorsey et al.

    Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030

    Neurology

    (2007)
  • 2014 Alzheimer's disease facts and figures

    Alzheimers Dement

    (2014)
  • D Strickland et al.

    Parkinson's prevalence estimated by a state registry

    Mov Disord

    (2004)
  • DJ Bauso et al.

    Incidence and prevalence of Parkinson's disease in Buenos Aires City, Argentina

    Eur J Neurol

    (2012)
  • NU Okubadejo et al.

    Parkinson's disease in Africa: a systematic review of epidemiologic and genetic studies

    Mov Disord

    (2006)
  • W Muangpaisan et al.

    Systematic review of the prevalence and incidence of Parkinson's disease in Asia

    J Epidemiol

    (2009)
  • HTS Benamer et al.

    Parkinson's disease in Arabs: a systematic review

    Mov Disord

    (2008)
  • SK Van Den Eeden

    Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity

    Am J Epidemiol

    (2003)
  • JA Driver et al.

    Incidence and remaining lifetime risk of Parkinson disease in advanced age

    Neurology

    (2009)
  • T Pringsheim et al.

    The prevalence of Parkinson's disease: a systematic review and meta-analysis

    Mov Disord

    (2014)
  • B Ritz et al.

    Parkinson disease and smoking revisited: ease of quitting is an early sign of the disease

    Neurology

    (2014)
  • Cited by (3882)

    View all citing articles on Scopus
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