Parkinson Disease

 

Abstract

Parkinson disease (PD) is the most common neurodegenerative movement disorder. In Europe, prevalence and incidence rates for PD are estimated at approximately 108–257/100 000 and 11–19/100 000 per year, respectively. Risk factors include age, male gender and some environmental factors. The aetiology of the disease in most patients is unknown, but different genetic causes have been identified. Although familial forms of PD account for only 5%–15% of cases, studies on these families provided interesting insight on the genetics and the pathogenesis of the disease allowing the identification of genes implicated in its pathogenesis and offering critical insights into the mechanisms of disease. The cardinal motor symptoms of PD are tremor, rigidity, bradykinesia/akinesia and postural instability, but the clinical picture includes other motor and non-motor symptoms. Its diagnosis is principally clinical, although specific investigations can help the differential diagnosis from other forms of parkinsonism. Pathologically, PD is characterized by the loss of dopaminergic neurons in the pars compacta of the substantia nigra and by accumulation of misfolded α-synuclein, which is found in intra-cytoplasmic inclusions called Lewy bodies. Currently available treatments offer good control of motor symptoms but do not modify the evolution of the disease. This article is intended to provide a comprehensive, general and practical review of PD for the general neurologist.

 

Introduction

Parkinson disease (PD) is the most common neurodegenerative movement disorder 1. Its cardinal motor symptoms are tremor, rigidity, bradykinesia/akinesia and postural instability, but the clinical picture includes other motor and non-motor symptoms (NMSs). The diagnosis is principally clinical, although specific investigations can help the differential diagnosis from other forms of parkinsonism.

 

The pathological hallmarks of PD are loss of dopaminergic neurons in the substantia nigra (SN) pars compacta (SNpc) and accumulation of misfolded α-synuclein, which is found in intra-cytoplasmic inclusions called Lewy bodies (LBs). When patients are first diagnosed, a substantial proportion of dopaminergic neurons in the SNpc has already been lost, and neurodegeneration has spread to other central nervous system regions. The aetiology of the disease in most patients is unknown, but different genetic causes have been identified in approximately 5%–10% of cases. Current treatment of PD is based on the replacement of dopamine, although alternative approaches such as deep brain stimulation (DBS) are suitable for later-stage disease. Currently available treatments offer good control of motor symptoms but do not halt the progression of neurodegeneration, the evolution of the disease and the increasing disability. This article is intended to provide a comprehensive, general and practical review of PD for the general neurologist.

 

Epidemiology and risk factors

In industrialized countries the estimated prevalence of PD is 0.3% in the general population, 1.0% in people older than 60 years and 3.0% in people older than 80 years; incidence rates of PD are estimated to range between 8 and 18 per 100 000 person-years 2. In Europe, estimated prevalence and incidence rates for PD range between 65 and 12,500 per 100 000 and between 5 and 346 per 100 000 person-years respectively 3. Age is the most important risk factor for the disease 2; male gender confers a moderate risk 4. Some environmental factors have been linked to the risk of PD, including certain pesticides and rural-living 5. It is of interest that some substances such as 1-methyl-4-phenyl tetrahydropyridine (MPTP) 6 and annonacin can cause nigrostriatal cell death and a form of atypical parkinsonism 7, 8. Exposure to toxic levels of manganese, trichloroethylene, carbon monoxide and other agents can likewise sometimes lead to a type of parkinsonism, but with clinical and pathological features distinct from PD. β2-adrenoreceptor antagonists have been linked to an increased risk for PD, whilst in contrast β2-adrenoreceptor agonists seem to reduce it 9. Conversely, there is an inverse association between the risk of PD and cigarette smoking 5, coffee drinking 10 calcium channel blockers 11 and statins 12, whilst contrasting evidence is available regarding the use of nonsteroidal anti-inflammatory drugs 13, 14 and uric acid levels or gout 15, 16.

 

Family history is a risk factor for PD and the relative risk in first-degree relatives of PD cases increases by approximately two- to three-fold compared to controls 17. Familial forms of PD account for 5%–15% of cases. The most important genes linked to PD are summarized in Table 1. Parkinson disease comprises a range of motor and non-motor features (Table 2), the expression of which may vary to some degree between patients; however, all patients must exhibit the core clinical features and respond to dopaminergic therapy to satisfy the criteria for the diagnosis of PD 48. The cardinal motor symptoms include tremor, bradykinesia/hypokinesia/akinesia, rigidity – which are usually asymmetric – and postural instability; other motor features are postural abnormalities (camptocormia and Pisa syndrome), gait disturbances and ‘freezing’, micrography, disturbances of speech, hypomimia, and alteration of blinking and eye movements, amongst others. The responsiveness of motor symptoms to levodopa administration is an important and diagnostic feature of PD.