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
SeminarParkinson'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
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