PARKINSON'S DISEASE

Parkinson's disease (PD) is the second most common neurodegenerative disease after AD, and the most frequent subcortical degenerative disease. It affects 1-2% of persons older than 60 years. It begins usually in the sixth decade and is characterized by motor symptoms (rigidity, tremor at rest, slowness of voluntary movement, stooped posture, a shuffling, small-step gait, difficulty with balance), and nonmotor symptoms (expressionless face, soft voice, olfactory loss, mood disturbances, dementia, sleep disorders, and autonomic dysfunction, including constipation, cardiac arrhythmias, and hypotension). Constipation, in particular, affects 24.6% to 63% of PD patients and may appear before the onset of motor manifestations.

The vast majority of PD cases are sporadic and are probably caused by interaction of environmental and genetic factors. Approximately 5-10 % of patients have a monogenic, autosomal dominant or recessive form of PD. The first autosomal dominant form of PD identified is that caused by mutations of α-synuclein, a synaptic protein encoded by SNCA on 4q22, which regulates dopamine levels. This discovery led to identification of α-synuclein in Lewy bodies and Lewy neurites (see below). The gene most commonly associated with autosomal recessive PD is Parkin.

Patients with GAucher disease (GD), including carriers of GBA1 mutations, have a 20- to 30-fold risk for developing PD, and 7-10% of PD patients have GBA1 mutations. The clinical and pathological phenotype of PD in GD is similar to idiopathic PD except that it has an earlier onset and causes more cognitive impairment. The mechanism by which GD causes PD is unknown but it is thought to be a combination of lysosomal impairment, mitochondrial dysfunction, oxidative and endoplasmic reticulum stress induced by GD. These changes impair α-synuclein degradation, leading to its accumulation.

The key pathology in PD is α-synuclein accumulation. Large α-synuclein aggregates form round lamellated eosinophilic cytoplasmic inclusions, Lewy bodies (LBs), in the neuronal body, and fibrils made of insoluble polymers of a-synuclein (Lewy neurites) are deposited in neuronal processes and in astrocytes and oligodendroglial cells. Accumulation of α-synuclein impairs the functions of mitochondria, lysosomes, and endoplasmic reticulum, and interferes with microtubular transport.

Left:PD; Right: normal SN	Lewy body
Normal SN-zona compacta	SN in PD-same location

The core pathology of Parkinson's PD primarily affects the dopamine-producing neurons of the substantia nigra (SN). These neurons are distinguished by their extensive and highly branched axons, numerous synapses, and high energy demands. The mid-section of the SN, known as the zona compacta, is the first and most severely affected region. In advanced stages of PD, the loss of pigmented neurons results in a conspicuous loss of pigment in the SN. As these dying neurons release neuromelanin, macrophages and astrocytes pick it up, with a small amount remaining free in the neuropil.

Dopamine, a crucial neurotransmitter, is synthesized by SN neurons from DOPA (which is also a precursor of melanin). Dopamine is then transported along the axons of these neurons to the striatum. The classic triad of symptoms in PD, rigidity, bradykinesia (slowness of movement), and resting tremor, corresponds to the degeneration of the dopaminergic nigrostriatal pathway and the resulting decrease in dopamine levels in the striatum.

Beyond the substantia nigra, abnormal deposits of a-synuclein protein and Lewy bodies (LBs) are also found in various regions throughout the CNS, including the cerebral cortex, limbic system, and multiple extra-nigral neuronal groups such as the reticular activating system, locus coeruleus, dorsal motor nucleus of the vagus, nucleus basalis of Meynert, and olfactory nerves. Alpha-synuclein deposits are also found in the sympathetic and parasympathetic autonomic nervous system (ANS) including sympathetic ganglia, and myenteric plexus. This widespread distribution leads to impairment in the function of neurotransmitters like noradrenaline, serotonin, and acetylcholine.

This comprehensive pathology has only been fully understood in recent years, aided by the development of antibodies targeting α-synuclein, which make it easier to detect LBs and synuclein deposits outside the SN. Consequently, Parkinson's disease should be viewed as a systemic disorder affecting the entire CNS and ANS, not just the dopaminergic system. In fact, there is a proposal that some instances of PD might originate in the ANS, with α-synuclein spreading from the ANS to the CNS. This extensive involvement accounts for the diverse range of motor and non-motor symptoms seen in PD. Although LBs are characteristic of PD, they can also be found nonspecifically in various other neurodegenerative conditions.

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 AD 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. An additional therapy for PD patients whose motor symptoms respond to but are not optimally controlled by medication and who do not have dementia is deep brain stimulation (DBS). In DBS, electrodes implanted into the subthalamic nucleus or inner part of the globus pallidus provide electrical stimulation to these and surrounding structures. This stimulation induces physiological and chemical changes that ameliorate some of the motor symptoms of PD by a poorly understood mechanism. Unilateral tremor and rigidity may also respond to stereotactic ablation of the contralateral globus pallidus, ventrolateral thalamus, or subthalamic nucleus.

DIFFUSE LEWY BODY DISEASE

Diffuse Lewy body disease

Diffuse Lewy body disease (DLBD) (Lewy body dementia)is a sporadic neurodegenerative disease, which is thought to be the second most common cause of dementia after AD. It combines the neurological manifestations of dementia and parkinsonism. Unlike AD in which short term memory is affected early, patients with DLBD present with fluctuating attention and cognition and visual hallucinations. Motor parkinsonian manifestations (bradykinesia, rigidity, and less frequently tremor) vary in severity and may appear later. DLBD patients have also depression, sleep disorder, and autonomic dysfunction. The brain in DLBD is not as atrophic as it is in AD, and shows small, inconspicuous Lewy bodies in the neocotex, limbic system, and brainstem. A large proportion of DLBD patients also have AD pathology.

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 ALS-PARKINSON-DEMENTIA COMPLEX (ALS/PDC)

A A combination of amyotrophic lateral sclerosis, PD and dementia was frequent in Guam and other Western Pacific locations. In ALS/PDC there is a deposition of tau protein, α-synuclein, ubiquitin, TDP-43 and β-amyloid in the brain. NFTs are seen in the cortex and subcortical nuclei, including the SN, α-synuclein inclusions are present in the entorrhinal cortex, amygdala, and SN, and TDP-43 inclusions are seen in neurons, oligodendrocytes and astrocytes. There are few Alzheimer plaques. The appearance of this disease in successive generations implicated genetic factors. However, in recent years, the incidence of ALS/PDC has declined dramatically. Epidemiological work and animal experiments support the hypothesis that ALS/PDC is caused by cycasin and other neurotoxic compounds in the seed of cycad plant which was used to make flour and was a staple in the local diet. The decline of ALS/PDC in recent years has been attributed to changes in diet and improved nutrition. ALS/PDC underlines the importance of environmental and nutritional factors 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.