Parkinson's Disease

Aetiology

Pathology

The duration of pre-symptomatic Parkinson’s disease (PD) is unknown, but estimates extrapolated from brain-imaging studies suggest 3–5 years. However, tremor , which is often an early sign, is only present in 75% of cases and may be transient. Tremor-dominant PD may be detected earlier than the akinetic, rigid forms.

The pathological changes in PD involve the progressive loss of dopaminergic neurons  in the substantia nigra  and of their processes projecting into the striatum, with processes to the putamen more affected than those to the caudate. Cells in the striatum are not lost or damaged.

In the Parkinson’s-Plus disorders (PD-Plus), cells in the striatum are also affected and loss of processes from the substantia nigra into various brain structures such as the putamen, caudate, pons , brainstem  and others also occurs, depending on the type of PD-Plus disorder.

The neurological damage in PD and PD-Plus disorders is only apparent at post-mortem. However, increasingly, technological advances in single photon emission computed tomography (SPECT) and positron emission tomography (PET), coupled with proper choice of isotopes and interpretative expertise, can identify dopaminergic activity in the striatum in vivo and are increasingly able to distinguish between PD and PD-Plus disorders. In spite of this, the technology and expertise are costly and not yet widely available.

The PD-Plus disorders produce symptoms of Parkinsonism, often coupled with symptoms that are rare or unknown in PD. These disorders can be distinguished from PD and from each other at post-mortem and their highly variable and generally poor response to levodopa and dopamine agonists may be used to distinguish them from PD during life. Most people with PD who have pathologically confirmed PD respond moderately to excellently to levodopa during life, whereas in the PD-Plus disorder progressive system palsy nearly one-third of people respond incompletely to dopa. However, in the PD-Plus disorder multiple system atrophy, response to levodopa may beinitially high, with response being maintained for a period of time.

Post-mortem examination of substantia nigra cells from people with PD reveal Lewy bodies in the cytoplasm of most dying cells. Microscopically, the Lewy body virtually fills the cell. The origin, composition and exact implications of Lewy bodies remain uncertain, but they are known to contain a structural protein of alpha synuclein and ubiquitin. A thorough understanding of Lewy bodies could perhaps enable us to develop a comprehensive knowledge of PD.

Pathogenesis

Some causes of Parkinsonism are well established, see Table 4 , but the root cause of PD is not. Hypotheses for the cause of PD exist, including:

• PD is an accelerated form of ageing
• genetic predisposition is a major risk for PD
• PD is caused by exposure of the brain to certain toxins
• PD is caused by acute or chronic exposure to some common, but yet unidentified, environmental stressor that may act directly or by inducing destructive endogenous processes.

Accelerated Ageing
Lewy bodies in the substantia nigra are characteristic of PD brains at post-mortem and are sometimes also found in the brains of people without apparent PD. Therefore, it has been suggested that people with PD experience an accelerated ageing process (Adams et al, 1997).

In addition, loss of approximately 50% of the pigmented cells in the substantia nigra has been observed in the brains of people who are 80 years old and do not have PD, whilst in age-matched brains from people who do have PD approximately 85% have been lost.

There are also differences in the patterns of neuronal loss between the normal ageing brain and PD brains: losses in the latter are predominantly in the ventral  regions of the substantia nigra and the former are predominantly in the dorsal  regions of the substantia nigra (Gibb and Lees, 1994).

However, as the location and speed of neuronal loss differs bewteen normal ageing and PD brains, it seems unlikely that PD is simply an acceleration of normal ageing, although it is indisputable that the risk of PD increases with age.

Genetics
There is compelling evidence of a genetically linked risk for PD, 2–3 times higher than normal among first-degree relatives of PD probands (Gasser, 1998). Schrag et al. noted that half of the 10 people with juvenile-onset PD whom they investigated had a family history of PD among first-degree relatives (Schrag et al, 1998). PET studies of mono- and dizygotic twins have demonstrated greater similarity of subclinical dysfunction in the substantia nigra among monozygotes (Piccini et al, 1999).

The large US World War II veteran’s twin study indicates a risk of about 50% for a genetic cause of earlyonset PD (EOPD). People with EOPD are likely to have a strong monogenic factor; among these people the PARKIN+ subtype has a particularly benign course, whereas other forms of genetic PD may be more unpromising.

Data from Iceland suggest that the risk of PD among siblings of a person with PD may be 6 times higher than normal by age 60 years and 12 times higher than normal by 70 years. Specific genetic mutations have also been detected in some kindred that predict a high risk for PD, but the great majority of cases remain idiopathic (National Parkinson’s Foundation, 2002). Continuing intensive investigation into the genetics of PD may ultimately reveal its roots and a means to control or prevent its progression, but that goal appears to be some way off yet.

Toxins
The MPP+ ion, a metabolite of MPTP resulting from oxidation by monoamine oxidase-B, is highly toxic to melanin-pigmented neurons such as those found in the substantia nigra. Exposure to this toxin leads to a form of PD that is virtually indistinguishable symptomatically, but which differs histologically as the characteristic Lewy bodies of idiopathic PD are not found. This toxin is used in primates to create an accurate model of idiopathic PD in man.

Other toxins that can produce Parkinsonism are listed in Table 4. However, unlike MPP+ exposure, these toxins do not damage the substantia nigra; instead they affect the globus pallidus. The latest toxin linked to the pathogenesis of PD is rotenone, which, like MPP+, leads to neuronal death in the substantia nigra.

Endogenous Mechanisms
Post-mortem examination of PD brains showed three major changes in the substantia nigra:

• evidence of oxidative stress and depletion of reduced glutathione
• high levels of total iron with reduced ferritin buffering
• mitochondrial complex I deficiency.

The Oxidative Stress Hypothesis

Oxidative stress follows when the production of free radicals exceeds the capacity of the body to remove them. The main free radicals are:

• superoxide anion radical
• hydrogen peroxide
• hydroxy radical
• nitric oxide
• quinine.

Superoxide is readily reduced to hydrogen peroxide, oxygen and water by enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Whilst hydrogen peroxide is itself not particularly reactive, its reaction with metals such as copper and iron generates the very toxic hydroxyl radicals that can damage almost any biological molecule.

The brain is particularly vulnerable to oxidative stress. Factors include the brain’s:

• high energy requirement
• high oxygen consumption
• richness in polyunsaturated fatty acids
• high levels of transition metals (eg iron, copper)
• relatively low antioxidant defences.

It is notable that oxidation of dopamine can generate quinines, hydrogen peroxide and free radicals that are normally removed by vitamin E and glutathione peroxidase. Whilst the mechanism is beyond the scope of this discussion, it is possible that treatment with levodopa could itself further increase oxidative stress in the brain, although this has not been demonstrated in vivo.

The concept that free radicals can promote apoptosis has been demonstrated by exposing neuronal cell cultures to conditions characteristic of disorders such as PD or Alzheimer’s disease (AD) that involve neuronal death by apoptosis, such as:

• glutathione depletion
• chronic inhibition of superoxide dismutase
• beta-amyloid fragments
• ischaemia
• dopamine.

Whilst there is a considerable body of evidence to support the idea that oxidative stress may underlie the pathological process in PD, evidence to the contrary is not insignificant. Characteristics of neuronal degeneration that should follow from the oxidative stress hypothesis have not been found in practice. It seems most likely that PD has a multifactorial basis that includes several of the risk factors identified in addition to others yet unknown.