2 Aetiology and Pathogenesis of Parkinson’s Disease
Dr D J Nicholl
Consultant Neurologist & Honorary Senior Lecturer, City Hospital, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham & Queen Elizabeth Hospital, Birmingham
Parkinson’s disease (PD) is one of the commonest neurodegenerative disorders, with a cumulative life-time incidence of 2%. The diagnosis is typically made via the clinical features of bradykinesia in association with tremor, rigidity or postural instability, with responsiveness to dopaminergic therapy as a supportive phenomenon. The term parkinsonism - used to describe the motor features of PD – needs to be distinguished from Parkinson’s disease, which implies a clinically and pathologically defined process, often established via the United Kingdom Parkinson’s Disease Society (UKPDS) brain bank criteria. This distinction is important when considering genetically mediated parkinsonism, which may manifest in a clinically indistinguishable manner to PD, but will often lack specific pathological features. Lewy bodies (LB), in particular, are an essential brain bank criterion, but are not consistently found in genetically mediated parkinsonism.1
Braak and colleagues have used synuclein immunostaining techniques to document the stereotyped progression of Lewy bodies from brainstem and olfactory nuclei, through the substantia nigra pars compacta, to the cortex (Table 2.1). This work supports the possibility of presymptomatic PD in those with a restricted number of Lewy bodies in brainstem structures (10% of people over the age of 60 years of age who have died without evidence of neurological disease, Lewy bodies are present in the brain). However, this pathological model does have problems which include its inability to explain the presentation of Lewy body dementia with cognitive dysfunction appearing before any motor features.
Dorsal motor nucleus of vagus and intermediate reticular zone
Stage 1 plus caudal raphe and gigantocellular reticular nuclei and locus coeruleus-subcoeruleus complex
Stage 2 plus midbrain lesions, particularly pars compacta of substantia nigra
Stage 3 plus cortex in temporal mesocortex and allocortex (CA2-plexus). Not neocortex
Stage 4 plus high order sensory association areas of neocortex and prefrontal neocortex
Stage 5 plus first order sensory association areas of neocortex and premotor areas and occasionally primary sensory and motor areas
The aetiology of PD remains poorly understood, with the vast majority of cases considered to be idiopathic, with a complex interplay between genetic and environmental factors leading to an individual risk of developing the disease. Environmental factors (such as the protective effect of smoking and negative associations with pesticide use and head injury) are covered in Yoav Ben-Shlomo’s talk, thus I shall focus on genetic factors- not least as there has been so much published on this in the last 5 years, but also as relatively few environmental agents have been identified.
After increasing age, a family history of PD remains the biggest risk factor for developing PD with a genetic influence noted for over a hundred years - Gowers observed that 15% of his patients had a positive family history of PD2 and a subsequent early study of familial aggregation of PD observed that 41% of PD patients surveyed had a positive family history. It is likely that these early studies were hampered by broad definitions of PD, but more recent epidemiological studies using better defined populations have confirmed the increased risk in families of probands with PD. This varies significantly according to the population examined, with the relative risk to first-degree relatives 2.7 in the United States,3 2.9 in Finland,4 6.7 in Iceland,5 and 7.7 in France.6 These analyses are complicated by several factors, including the age of onset of disease in the surveyed groups. This variable is likely to be an important reflection of a genetic component to the development of disease, as earlier disease is associated with an increased chance of a genetic aetiology and therefore family history. This can be seen in the large family study from the Mayo clinic group which suggested an overall relative risk for first-degree relatives of 1.71. Segregation of the PD patients into younger (under age 67) and older onset disease groups resulted in risks of 2.62 and 1 (i.e. no significantly increased risk in older onset disease) respectively.7 This interpretation should be viewed in the context of the unusual age definitions of younger and older onset disease, which may be rather artificial as the median age of onset of PD is 59.
The identification of families with parkinsonian syndromes following classical Mendelian inheritance patterns has led to major advances in the past decade, with relevant loci and mutations assigned for several types of hereditary PD. Although these are likely to account for a small proportion of all cases of PD, these findings have generated considerable interest, particularly as the detailed analysis of these rare inherited forms may significantly promote our understanding of the pathogenesis of idiopathic PD. In particular, there are several pointers to disease pathways centred around defects in protein quality control, observations potentially common to several other neurodegenerative disease.8 At present there is robust evidence linking seven genes to hereditary PD: alpha-synuclein, DJ-1, LRRK2, Parkin, PINK1, ATP13A2 and GBA (Table). Less conclusive evidence implicates other possible PD genes, including NURR1, synphilin-1 and UCH-L1.9-16 This review will discuss autosomal dominant and recessive PD, the relevant PARK loci with implicated genes and proteins, or likely candidates. In addition, we will highlight the potential impact of these findings on the diagnosis and management clinical PD, including genetic testing.