Akinesia

Parkinson’s disease is characterized by poverty of movement. Voluntary actions are initiated with effort and performed slowly (e.g. turning in bed, rising from a chair). Gait freezing is common and may be associated with a frustrating sense of being stuck to the floor. All spontaneous movements are reduced, including facial expressions and blinking. This creates a mask-like appearance, referred to as facial amimia (the ‘parkinsonian stare’). On examination, there is progressive reduction in the speed and amplitude of repetitive movements such as apposition of the thumb and index finger. The voice may be slow and quiet (hypophonia), the handwriting small and illegible (micrographia).

Muscular rigidity

Increased muscle tone (rigidity) may present as stiffness, muscle pain or fatigue. On examination, there is uniform resistance to joint flexion and extension which has been compared to bending a piece of lead pipe. In contrast to spasticity, lead-pipe rigidity is constant (not velocity-dependent) and may be due to over-activity in the long-latency component of the stretch reflex (see Ch. 4).

Abnormal posture and gait

Patients with Parkinson’s disease have a characteristic flexed posture. A slow shuffling gait is combined with reduced or absent arm swing and the hands are held in front of the body. Crossing boundaries such as doorways may be difficult and turning is often slow and awkward. Excessive trunk flexion brings the centre of gravity forward and the walking pace tends to accelerate as the feet try to keep up, termed a festinating gait (Latin: festinare, to hurry). This increases the risk of falling, particularly since impairment of postural reflexes is another common feature.

Rest tremor

Tremor is a rhythmic ‘back-and-forth’ movement in the limbs, head or jaw and occurs in 75% of patients with Parkinson’s disease. The parkinsonian tremor is usually asymmetric and often begins in one hand or arm. It is classified as a rest tremor because it is much more prominent between movements. It is of large amplitude and low frequency (4–6 Hz) and is not present during sleep. Some patients have a classical ‘pill-rolling’ tremor (Fig. 13.2) which is strongly suggestive of idiopathic Parkinson’s disease. The combination of lead-pipe rigidity and tremor creates a jerky or ‘ratchet-like’ sensation on examination. This is termed cogwheeling and is best appreciated at the wrist.

Other features

Non-motor symptoms in Parkinson’s disease reflect: (i) the role of the basal ganglia in cognition, emotion and behaviour (see Ch. 3); and (ii) the presence of widespread pathological changes in the brain stem, limbic lobe and neocortex. Anxiety, depression or apathy occurs in 40% of patients. There may be sleep disorders including: nocturnal hallucinations, excessive daytime somnolence, vivid dreams, nightmares or sleepwalking. Subtle cognitive changes are common, such as bradyphrenia (generalized slowing of thought) or executive dysfunction (difficulty with organization, planning and decision-making). One in five patients will eventually be diagnosed with dementia (Clinical Box 13.1).

Diagnosis and course

The diagnosis of Parkinson’s disease is primarily clinical. Routine MRI scans are often normal, but dopamine deficiency in the basal ganglia can be demonstrated using specialized tests (Fig. 13.3). Without treatment there is progressive decline over a 5–10-year period, with gradual deterioration of motor function, worsening postural instability, gait freezing and frequent falls. However, symptoms can usually be controlled for a number of years with dopamine replacement therapy and this is associated with a near-normal life expectancy.

Drug-induced parkinsonism

Administration of antipsychotic (neuroleptic) agents may cause ‘extrapyramidal side effects’ that mimic Parkinson’s disease and this is the most common cause of parkinsonism. It occurs because neuroleptic drugs antagonize central dopamine receptors, including those within the basal ganglia.

Vascular pseudoparkinsonism

Patients with cerebrovascular disease may develop an akinetic-rigid syndrome. This is due to microinfarcts (small ischaemic strokes, see Ch. 10) in the basal ganglia or hemispheric white matter. In contrast to idiopathic Parkinson’s disease, symptoms tend to be more severe in the lower limbs, response to dopamine replacement is poor and tremor is usually absent.

Neurodegenerative causes

A number of other neurodegenerative disorders may be confused with Parkinson’s disease. The most important are progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), each with a prevalence of approximately 1 in 20,000. An even rarer form is corticobasal degeneration (CBD), discussed in Clinical Box 13.2.

Progressive supranuclear palsy

This is the most common neurodegenerative mimic of Parkinson’s disease, accounting for about 5% of people with a parkinsonian syndrome. In more than 50% of cases there is axial rigidity, a hyperextended posture and a characteristic supranuclear gaze palsy with failure in the cortical (‘supranuclear’) control of vertical eye movements. There may also be apathy, cognitive decline and outbursts of inappropriate laughter or tearfulness, termed emotional incontinence. This classical form of PSP is also referred to as Richardson’s syndrome. In up to a third of cases the clinical features closely resemble idiopathic Parkinson’s disease. In this subtype, referred to as PSP-P, the pathological changes are less severe and the clinical course is more favourable. Features of PSP and Parkinson’s disease are compared in Figure 13.4.

Neuronal loss

The substantia nigra is a large midbrain nucleus that can be divided into compact and reticular parts. The pars compacta contains the cell bodies of dopaminergic neurons contributing to the nigrostriatal tract, whereas the pars reticulata consists of GABAergic neurons and is analogous to the globus pallidus. The substantia nigra is almost black in the adult brain (Latin: nigra, black) due to the accumulation of neuromelanin as a by-product of dopamine synthesis (see Ch. 7). Loss of dopaminergic neurons in Parkinson’s disease causes pallor of the substantia nigra which can be seen at post-mortem examination. The lateral part of the substantia nigra (which projects to the putamen or ‘motor striatum’) is more severely affected than the medial portion (which projects to the caudate nucleus).

Neuronal loss is also seen in other parts of the nervous system in patients with Parkinson’s disease. These include the noradrenergic locus coeruleus of the pons (see Ch. 1). Post-mortem examination of the brain in Parkinson’s disease may therefore show pallor of the loci coerulei as well as the substantia nigra. Despite normal age-related degeneration of the substantia nigra, most people have sufficient reserve capacity so that striatal dopamine levels never fall below 20% of normal.

Lewy bodies

The pathological hallmark of Parkinson’s disease is the Lewy body (Fig. 13.6). This is a type of pathological inclusion (abnormal protein aggregate) found in the cytoplasm of surviving neurons. Lewy bodies are spherical structures, measuring 5–30 µm in diameter. They are pink on standard histological preparations (because they take up the red tissue dye eosin) and are surrounded by a pale halo.

Progression of Lewy body pathology

Lewy body pathology begins in the medulla and olfactory bulbs, spreading progressively through six Braak stages to involve the pons, midbrain, limbic lobe, amygdala and neocortex (Fig. 13.7). Cortical Lewy bodies are similar to those encountered in the brain stem, but do not have a halo and are present even in cases without dementia. Pathological inclusions are also found in the autonomic nervous system, including the enteric nervous system in the gastrointestinal tract.

Spread of Lewy body pathology may reflect selective vulnerability of certain brain regions (so that they are affected earlier) or could be due to stepwise spread along anatomical pathways. Since the olfactory bulb is affected first, the possibility of a pathogenic virus infection gaining access to the brain via the nasal mucosa has been postulated.

Alpha-synuclein

The main constituent of Lewy bodies is alpha-synuclein. This is a synaptic protein that is present in presynaptic terminals in association with synaptic vesicles. It seems to be involved in neurotransmitter release and synaptic plasticity (which is critical for learning and memory; see Ch. 7). It may also take part in the regulation of dopamine storage and synaptic vesicle recycling.

The synuclein gene (SNCA, on chromosome 4) has six exons and encodes a natively unfolded 140-amino-acid protein. This has three domains, including a central hydrophobic region that is involved in protein aggregation. The most common familial forms of Parkinson’s disease are caused by duplications or triplications of the synuclein gene. In other cases SNCA point mutations encourage alpha-synuclein aggregation and Lewy body formation.

Accumulation of alpha-synuclein (within neurons and glia) occurs in several other parkinsonian syndromes including Parkinson’s disease with dementia, dementia with Lewy bodies (DLB) and MSA (Fig. 13.8) which are all classified as synucleinopathies. In other forms of parkinsonism such as PSP and CBD there is accumulation of the microtubule-associated protein tau and these disorders are therefore classified as tauopathies. The molecular classification of neurodegenerative diseases is discussed in Ch. 8.

Key Points

 The key pathological change in idiopathic Parkinson’s disease is loss of dopaminergic neurons in the substantia nigra (pars compacta) of the midbrain, resulting in degeneration of the nigrostriatal tract.

 This leads to profound reduction in striatal dopamine (<20% of normal at presentation). The projection to the putamen (‘motor striatum’) is most severely affected, with less pronounced dopamine deficiency in the caudate nucleus.

 The pathological hallmark of Parkinson’s disease is the Lewy body, a cytoplasmic neuronal inclusion composed predominantly of the synaptic protein alpha-synuclein.

 Lewy body pathology begins in the olfactory bulb and medulla, progressing through six Braak stages to involve the pons, midbrain, amygdala, limbic lobe and neocortex.

Autosomal dominant PD

The first Parkinson’s disease gene to be identified was SNCA (also known as PARK1/PARK4), which encodes alpha-synuclein. This led to the discovery that alpha-synuclein is the main constituent of Lewy bodies. The gene was identified by genetic linkage analysis in a large Italian family known as the Contursi kindred. This family carries an alanine to threonine point mutation (A53T) in the alpha-synuclein gene on chromosome 4. Different point mutations (A30P, E46K) have been found in other families, all of which produce a severe, autosomal dominant Parkinson’s disease with variable penetrance. The clinical and pathological features are similar to sporadic Parkinson’s disease.

The most common form of autosomal dominant Parkinson’s disease is caused by mutation of the leucine-rich repeat kinase 2 gene (LRRK2/PARK8). This is a large gene composed of 51 exons which encodes a 2,527-amino-acid protein called Dardarin (Basque: dadara, tremor). The protein is part of an intracellular second messenger cascade which activates intracellular kinases. A number of pathogenic mutations have been identified. These produce a late-onset, dopamine-responsive parkinsonian syndrome that resembles idiopathic Parkinson’s disease.