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Parkinson disease (PD), also known as idiopathic parkinsonism, is a neurodegenerative disease and movement disorder characterised by resting tremor, rigidity and hypokinesia due to progressive degeneration of dopaminergic neurones in the substantia nigra.
Parkinson disease is by far the most common cause of the parkinsonian syndrome, accounting for approximately 80% of cases (the remainder being due to other neurodegenerative diseases, such as Lewy body dementia) 1.
The most common form is encountered in elderly patients and is common, seen in 2-4% of all individuals older than 65 years of age.
A juvenile form of Parkinson disease is also recognised, manifesting between 20-40 years of age 1.
The majority of cases (85-90%) are sporadic. However, 10-15% of patients have a positive family history 1.
Parkinson disease is characterised by both motor and non-motor clinical features. The classic cardinal motor features of Parkinson disease, which are often asymmetric, include:
- resting tremor
- classically 5 Hz 'pill-rolling' resting tremor
- most prominent in the distal upper limbs
- often described as 'cog-wheel' in nature in the limbs due to superimposed tremor
- also affects the trunk and contributes to the stooped flexed posture that is often seen
- typically decrementing in nature and accompanied by hypokinesia
- many manifestations:
- e.g. in the gait, manifests as a festinating and shuffling short-steppage gait, that characteristically has freezing, turning en bloc, and reduced arm swing
- e.g. in writing, manifests as progressive micrographia
- e.g. in the face, manifests as hypomimia with decreased eye blinking
- postural instability
- sometimes added as a fourth cardinal feature 3
- is generally a late feature
Non-motor features include:
- constipation: often an early symptom pre-dating the cardinal features
- anosmia or hyposmia: often an early symptom predating the cardinal features
- REM sleep behavioural disorder
- autonomic dysfunction
- postural hypotension: almost 20% at diagnosis, >1/3 patients by 7 years post diagnosis 17
- psychosis, especially visual hallucinations (reported to occur in 6-75% of patients (most reports suggest an incidence of 25-50%), more frequently in patients treated with dopaminergic medication 9,10)
- bradyphrenia and dementia: generally a late feature
- in contrast, Lewy body dementia has cognitive impairment either preceding or at most within 12 months of clinical onset of parkinsonian symptoms 2
- fatigue and somnolence
The dopaminergic tract is predominantly affected in Parkinson disease, and histologically, it is characterised by nigrostriatal dopaminergic degeneration leading to neuronal loss in the substantia nigra pars compacta (SNpc), most conspicuous in the ventrolateral tier of neurones 11. A number of other regions including parts of the basal ganglia, brainstem, autonomic nervous system and cerebral cortex 3.
At least eleven genes have been implicated in various forms of Parkinson disease 3. Interestingly depending on which genes are involved, various clinical features are more or less prominent (e.g. Kufor-Rakeb syndrome).
Even more interestingly not all mutations result in Lewy bodies. For example, juvenile Parkinson disease has been linked to mutations in the PARK2 gene, which encodes for the enzyme ubiquitin ligase-L3. In normal individuals, ubiquitin ligase-L3 is involved in ubiquitination of alpha-synuclein (the main component of Lewy bodies) and allows the formation of Lewy bodies. In patients with juvenile Parkinson disease, its function is impaired, and the formation of Lewy bodies is impossible. This finding suggests that Lewy bodies cannot be thought of as synonymous with, and causative of Parkinson disease. Perhaps even Lewy bodies play a protective role in other forms of Parkinson disease, which manifests 20-40 years later 1.
Initial imaging findings are subtle and only potentially seen on MRI. With advanced disease, non-specific generalised minor cerebral volume loss can be demonstrated.
Loss of the normal swallow tail appearance of susceptibility signal pattern in the substantia nigra on axial imaging is perhaps the most promising diagnostic sign 12. Apart from these changes, the signal intensity in substantia nigra depends on loss of neuromelanin and iron accumulation. In addition to aiding diagnosis, MRI is also used to identify features which may indicate secondary parkinsonism rather than primary disease, such as extensive small vessel ischaemic change.
Features of Parkinson disease include 1:
absent swallow tail sign
- initially thought to be due to loss of nigrosome-1, but this is likely not accurate 18
- reported diagnostic accuracy of over 90%, with a 100% sensitivity and negative predictive value, 95% specificity, and 69% positive predictive value being reported in one study 12
- may show loss of normal susceptibility signal drop-out of the substantia nigra and red nuclei (due to loss of melanin-containing neurones)
- dot-like areas of hyperintensity in the compact part of the substantia nigra 1
- may show a confluence of the normal hypointense regions of substantia nigra (due to iron accumulation) 1
- absent swallow tail sign
Recent studies with ultra-high-field MRI (7 T) have shown promising results regarding both sensitivity and specificity 4,5.
Both SPECT and PET tracers can be used with high sensitivity for assessment of presynaptic dopaminergic deficits 6,8.
I-123 ioflupane SPECT
I-123 ioflupane (brand name DaTScan) is taken up by presynaptic dopamine transporters that are abundant in areas rich in axonal synapses form dopaminergic neurones. In the setting of Parkinson disease, the neurones have their cell bodies in the substantia nigra and project axons into the corpus striatum. Imaging with I-123 ioflupane, therefore, demonstrates a lack of normal uptake in the corpus striatum in individuals with Parkinson's disease 16.
This appears as a loss of the normal comma-shaped or crescent-shaped tracer uptake in the striatum. Instead, a period-shaped or oval-shaped uptake is seen within the caudate nucleus head without tracer uptake in the putamen. Eventually, even caudate uptake reduces 16. Quantitative assessment reveals reduced uptake in the putamen compared to norms.
Differentiation between Parkinson disease and atypical parkinsonism is also possible, with different tracers 7,8.
Treatment and prognosis
The mainstay of treatment of motor symptoms is medical with oral levodopa-based regimens. In patients with refractory symptoms, infusional therapies (e.g. apomorphine subcutaneous infusion, levodopa/carbidopa intestinal gel infusion via percutaneous endoscopic jejunostomy) or surgical therapies (e.g. deep brain stimulation, conventional lesioning surgeries, MRI-guided focussed ultrasound lesioning procedures) may be useful 15.
History and etymology
Parkinson disease was first described by British physician James Parkinson (1755-1824) in his 1817 seminal work "An Essay on the Shaking Palsy" 14. In this work he describes a 'shaking palsy' as an "involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported; with a propensity to bend the trunk forward, and to pass from a walking to a running pace; the senses and intellects being uninjured" 14. Remarkably, other than his comment regarding dementia not being a feature of the disease, his original clinical descriptions are still accurate after more than 200 years.
There is significant overlap between many neurodegenerative diseases, and Parkinson disease is no exception. Clinically the differential includes 1,3:
dementia with Lewy bodies
- dementia is clinically evident before, concurrently or at most within 12 months of onset of parkinsonian symptoms 2
- multiple system atrophy (MSA)
- progressive supranuclear palsy (PSP)
- corticobasal degeneration
- cerebrovascular disease
- Perry syndrome
- postencephalitic parkinsonism
- metabolic diseases with parkinsonian signs and symptoms: basal ganglia signal abnormalities are usually more pronounced 1
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