Natural history of Parkinson's disease: From dopamine to multiple system involvement

Parkinson's disease is a neurodegenerative disease involving melanine-containing nerve cells in the substantia nigra and locus coeruleus, and widespread nervous structures including the brainstem, cerebral cortex and the autonomic nervous system. In addition, dopaminergic medication and the aging process in the brain contribute to development of clinical features that are variable in each patient. Amongst core motor symptoms, tremor and rigidity are attributed to dysfunctions of the nigrostriatal dopamine system. Akinesia/bradykinesia is the expression of dysfunctions in neural processes from sensory perception to motor output, and postural-gait disturbances are due to lesions in gait control systems including basal ganglia, pedunculopontine nucleus and frontal lobe. Cognitive dysfunctions due to frontal lobe and perceptual-motor dysfunctions appear from the early stages of the disease. Cortical and subcortical dementias appear with motor disturbances and/or aging. Autonomic disorders may appear prior to motor symptoms, and various signs are attributable to lesions in the hypothalamus, spinal cord, sympathetic and parasympathetic nerves. Sleep-related disorders have attracted recent attention and may be side effects of dopaminergic medication or due to disease-associated lesions in locus coeruleus, raphe nuclei, pedunculopontine nucleus and thalamo-cortical loops.