The main symptoms of Parkinson disease result from a lack of a chemical substance in the brain, a specific neuro-transmitter (so called because it transmits messages from one cell to another) called dopamine. In PD, dopamine is lacking in the region of the brain called the substantia nigra, as well as in the connections of the substantia nigra with another region called the striatum The substantia nigra contains darkly pigmented, black cells (its name means “black sub-stance” in Latin). The cells targeted by PD contain one or more round bodies, called Lewy bodies, which in turn contain a protein called alpha synuclein.
It is not yet known why the substantia nigra is targeted in PD. There are two types of neurons in the nigra, one type contains a protein called calmodulin, and the other does not. The calmodulin-containing neurons are the ones targeted. Among the theories proposed are: that the calmodulin neurons are genetically more vulnera-ble; that they are more susceptible to a number of toxins or viruses; that their membranes contain openings (or channels) that permit an increased entry of calcium and/or iron which damage the neurons; that the mito-chondria (which act as the neurons’ power-plants) are defective and do not generate enough energy to sustain the neurons; or that the mitochondria generate too many toxic products, called free radicals, and that these damage the neurons.
Other theories propose that an enzyme in the mitochondria, called monoamine oxidase B (MAO-B), increases with age, resulting in an increased production of toxic free radicals. This has led to the use of MAO-B blockers (inhibitors), such as rasagiline (Azilect) and selegiline (Eldepryl, Zelapar) to slow the progression of PD. Still other theories propose that the neurons die because of a lack of specific growth or trophic factors including glial derived neurotrophic factor (GDNF) and nurturin. Recently, researchers Braak and Del Tredici have pro-posed that PD does not begin in the substantia nigra; rather the earliest changes are in a region of the brain-stem called the dorsal vagal nucleus. The dorsal vagal nucleus is the “head” or “chief ” nucleus of the parasympathetic nervous system (part of the autonomic nervous system, or ANS).
The parasympathetic nervous system is the “calming” part of the ANS and its involvement may be partly responsible for the increased anxiety and depression that occurs in patients with PD. Following the dorsal vagal nucleus, another part of the brainstem, the locus ceruleus, is involved and may account in part for the sleep disturbances involved in PD.
After the dorsal vagal nucleus and the locus ceruleus, the following neurons are involved: neurons of the olfactory cortex (the part of our brains responsible for sense of smell); neurons of the substantia nigra; and neurons of the amygdala and hypothalamus, the nuclei of the sympathetic part of the ANS, which controls our heart rate, heart contractility, blood pressure, rate and depth of breathing, and endocrine glands. Finally, the neurons of the hippocampus and the nucleus basalis (the memory banks of the brain), and the neurons of the cortex, are involved.