The review by Hawkes, Del Tredici, and Braak proposes a "dual-hit" hypothesis to explain the pathogenesis of sporadic Parkinson's disease (PD). They suggest that PD may be initiated by a neurotropic pathogen, likely viral, entering the brain through two routes: the nasal route and the gastric route. The nasal route involves the olfactory bulb and temporal lobe, while the gastric route involves the enteric plexus of the stomach and the vagus nerve. Early signs of PD, such as olfactory dysfunction, autonomic dysfunction, and sleep disorders, are reviewed, along with evidence from psychophysical and neurophysiological tests. The authors argue that these early symptoms, particularly olfactory dysfunction, are early indicators of PD and suggest that the disease progresses through a presymptomatic phase before clinical symptoms appear. The pathological process is described as a sequential progression from the lower brainstem to the cerebral cortex, with specific vulnerable regions being affected in a predictable sequence. The review also discusses the possible role of viral invasion and altered protein handling in the pathogenic process, emphasizing the importance of both anterograde and retrograde routes of pathogen entry into the nervous system.The review by Hawkes, Del Tredici, and Braak proposes a "dual-hit" hypothesis to explain the pathogenesis of sporadic Parkinson's disease (PD). They suggest that PD may be initiated by a neurotropic pathogen, likely viral, entering the brain through two routes: the nasal route and the gastric route. The nasal route involves the olfactory bulb and temporal lobe, while the gastric route involves the enteric plexus of the stomach and the vagus nerve. Early signs of PD, such as olfactory dysfunction, autonomic dysfunction, and sleep disorders, are reviewed, along with evidence from psychophysical and neurophysiological tests. The authors argue that these early symptoms, particularly olfactory dysfunction, are early indicators of PD and suggest that the disease progresses through a presymptomatic phase before clinical symptoms appear. The pathological process is described as a sequential progression from the lower brainstem to the cerebral cortex, with specific vulnerable regions being affected in a predictable sequence. The review also discusses the possible role of viral invasion and altered protein handling in the pathogenic process, emphasizing the importance of both anterograde and retrograde routes of pathogen entry into the nervous system.