Pathophysiological process underlying Parkinson's disease: Motor & Non-motor symptoms

It is proposed that alpha-synucleinopathy initially affects the medulla oblongata and then progresses to more rostral brain areas ("Braak hypothesis"). According to this hypothesis, substantia nigra is affected in the later stages of PD. Another region affected in the earlier stages was reported to be olfactory bulb, although the following processes were not described in detail. On the other hand, several lines of evidence suggest that non-motor symptoms including constipation, depression, REM-sleep behavior disorder (RBD) and hyposmia may be prodromal symptoms in PD. The pathological staging postulated by the Braak hypothesis is in good agreement with the fact that these non-motor symptoms precede motor symptoms in PD, because affected brain areas in the early stages, such as dorsal vagal nucleus, locus ceruleus and olfactory bulb, are related to these non-motor features. Recently, it was reported that although half of brains corresponded to the Braak hypothesis, there were a high proportion of cases which did not fit the Braak's staging system and majority of the latter demonstrated amygdale-predominant alpha-synucleinopathy. It was also demonstrated that the Lewy pathology in olfactory bulb was closely related to the presence of alpha-synuclein pathology in amygdala. The amygdala is one of the main systems in odor perception and in PD, cortical neurons in corticomedial complex of amygdale, which have major olfactory connections, are selectively affected even in the early stages of the disease. We recently obtained the data suggesting that metabolic changes in the amygdala were associated with low scores in odor identification test. These data suggest that not only the olfactory bulb, but also the amygdala is also responsible for hyposmia in PD and that there may be another pathological process, which starts from the olfactory bulb and involves the amygdala.