Chapter 9

DEGENERATIVE DISEASES

PARKINSON'S DISEASE

Idiopathic Parkinson's disease (PD) is the second most common neurodegenerative disease after AD and the most frequent subcortical degenerative disease. It begins usually in the sixth decade and is characterized by rigidity, tremor at rest, slowness of voluntary movement, an expressionless (mask-like) face, stooped posture, and a shuffling, small-step gait.

The vast majority of PD cases are sporadic and are probably caused by interaction of environmental and genetic factors. Approximately 20% of PD patients have a family history of PD, and there are rare cases with Mendelian inheritance. Genetic studies have identified several chromosomal loci, designated as PARK loci (now numbering 1-18), associated with autosomal dominant and autosomal recessive forms of PD. Specific gene mutations associated with these loci include a-synuclein (a synaptic protein), parkin, a ubiquitin -related protein, and other genes.

PD is a synucleinopathy. Fibrils made of insoluble polymers of alpha synuclein are deposited in the neuronal body, forming round lamellated eosinophilic cytoplasmic inclusions, the Lewy bodies (LBs). Alpha synuclein is also deposited in neuronal processes (Lewy neurites), and in astrocytes and oligodendroglial cells. LBs cause neuronal degeneration and death.


Left:PD; Right: normal SN

Depigmentation of the substantia nigra in PD (left). Normal sustantia nigra (right).


Normal SN-zona compacta

Normal sustantia nigra-zona compacta.


SN in PD-same location

Loss of sustantia nigra neurons in PD.


Lewy body

Lewy body in a SN neuron. The melanin granules are red-brown.

The core pathology of PD affects the dopamine-producing neurons of the substantia nigra (SN). The mid-section of the SN (zonal compacta) is involved earliest and most severely. In advanced PD, loss of pigmented neurons results in gross depigmentation of the SN. Neuromelanin released from dying neurons is picked up by macrophages and astrocytes and a small amount is found free in the neuropil. LBs are also present in many extra-nigral, nondopaminergic neuronal groups, including the locus ceruleus, dorsal motor nucleus of the vagus, and the nucleus basalis of Meynert. Although they are characteristic of PD, LBs may be found nonspecifically in many other neurodegenerative conditions. Dopamine is produced by SN neurons from DOPA (also a precursor of melanin) and transported along the axons of these neurons to the striatum. The triad of rigidity, bradykinesia and tremor at rest correlates with degeneration of the dopaminergic nigrostriatal pathway and dopamine depletion in the striatum.

However, the above description gives a limited profile of PD. Its clinical spectrum includes also dementia (see diffuse Lewy disease below), sleep behaviour disorders, olfactory dysfunction, and autonomic dysfunction, such as labile blood pressure and constipation. LBs are also found in the cerebral cortex, locus ceruleus, raphe nuclei, dorsal motor nucleus of the vagus nerve, nucleus basalis of Meynert, sympathetic ganglia, and myenteric plexus, leading to impairment of noradrenergic, serotoninergic, and cholinergic neurotransmission. This widespread pathology has only been fully appreciated in recent years, when antibodies to synuclein made it easier to detect LBs outside the SN. Thus, PD should be viewed as a disorder that affects the entire brain, not just the dopaminergic system. This widespread involvement explains the diverse neurological manifestations of PD.

AD and PD (and in a broader sense tauopathies and synucleinopathies) overlap clinically and pathologically. Extrapyramidal signs develop in AD patients and dementia affects PD patients more frequently than age matched controls. Also, LBs are found in the brains of PD patients, and a large proportion of PD patients have enough SPs and NFTs to qualify for the pathological diagnosis of AD. Until recently, dementia in PD had been attributed primarily to concomitant AD. Recent studies show that cognitive decline in PD correlates better with LBs present in the hippocampus, amygdala, and neocortex.

The treatment of PD consists mainly of L-dopa given with a DOPA decarboxylase inhibitor. Unilateral tremor and rigidity may respond to stereotactic ablation of the contralateral globus pallidus and ventrolateral thalamus. An experimental therapy of PD involves implanting fetal SN into the striatum. Grafts obtained from seven to nine week fetuses survive, innervate the striatum, and supply the missing dopamine. Immunosuppression with cyclosporin A prevents rejection. Some patients show significant clinical improvement.

DIFFUSE LEWY BODY DISEASE

Diffuse Lewy body disease (DLBD) is a sporadic condition, which is thought to be the second most common cause of dementia after AD. It combines the neurological manifestations of dementia and Parkinsonism and shows also fluctuation of cognitive deficits and visual hallucinations. The brain in DLBD is not as atrophic as it is in AD, and shows small, inconspicuous Lewy bodies in cortical neurons, in addition to the characteristic pathology of the SN. A large proportion of DLBD patients also have AD.

MPTP PARKINSONISM

The pyridine analogue MPTP (1-methyl-1-4-phenyl-1,2,3,6-tetrahydropyridine) is taken up selectively by dopaminergic neurons. Its active compound, MPP (1-methyl-4-phenylpyridinium) inhibits mitochondrial function and induces cell death. Toxic damage of dopaminergic neurons causes parkinsonian symptoms. This was discovered when a drug addict accidentally injected himself with synthetic heroin made by himself, contaminated by MPTP. MPTP parkinsonism in humans and experimental animals resembles PD. Low dose intravenous infusion of the pesticide (and herbicide) rotenone, an inhibitor of complex I of the mitochondrial respiratory chain, causes degeneration of the SN and Lewy body-like inclusions in rats. The MPTP model, the rotenone experiments, and the ALS- Parkinson-Dementia cases from Guam (see below) suggest that environmental neurotoxins play a role in the pathogenesis of PD.

GUAM PARKINSON-DEMENTIA (GPD)

A combination of PD and dementia is frequent among the Chamorro people of Guam. GPD is a combination of tauopathy and synucleinopathy. NFTs are seen in the cortex and subcortical nuclei, including the SN, and alpha-synuclein inclusions are present in the entorrhinal cortex, amygdala, and SN. The appearance of this disease in successive generations implicates genetic factors. However, in recent years, the incidence of GPD has declined dramatically. Epidemiological work and animal experiments support the hypothesis that GPD is caused by a toxic amino acid in the seed of a cycad plant which is used to make flour and is a staple in the local diet. Another hypothesis implicates other environmental factors leading to deficiencies of calcium and magnesium, and high concentrations of aluminum and other minerals in drinking water, with aluminum deposition in neurons. Aluminum can disrupt the neuronal cytoskeleton and cause neurofibrillary pathology. The decline of GPD in recent years has been attributed to changes in diet and improved nutrition. GPD underlines the important role of genetics and environmental neurotoxins in the pathogenesis of neurodegenerative diseases.

Parkinsonian syndromes may also develop in the course of other conditions that damage the SN, e.g., striatonigral degeneration, postencephalitic parkinsonism, manganese poisoning, carbon monoxide poisoning, hypoxic-ischemic encephalopathy, traumatic brain injury, and stroke.

Further Reading


Updated: June, 2011

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