e , cardiovascular, gastrointestinal) [21] Table 1 provides a no

e., cardiovascular, gastrointestinal) [21]. Table 1 provides a non-exhaustive overview of susceptible CNS and ANS neuronal populations affected in PD, together with their known or putative clinical correlates. PD pathology requires years to reach its full extent throughout the nervous system and the temporal relationships of the lesions are still not well established. Braak and co-workers proposed a neuroanatomical staging system based on α-SYN immunoreactivity distribution Talazoparib nmr in the brains of PD patients and clinically asymptomatic incidental Lewy pathology cases. The authors predicted that PD pathology follows a stereotyped and selective

caudo-rostral progression within vulnerable structures of the CNS (Table 1). In this scenario, the

disease begins in the DMV and in the olfactory bulb (Braak 1), ascends in the brainstem to reach the raphe nuclei and the locus coeruleus (Braak 2) before affecting the SN (Braak 3). Finally, in later stages (Braak 4–6), the disease enters the temporal mesocortex and eventually the neocortex. Stage 1 and 2 are considered as pre-motor stages, with motor symptoms emerging only in stage 3 when SN neurodegeneration Selleckchem Lumacaftor begins [17] and [22]. The predictive validity of Braak’s concept of neuropathological staging has been somehow disputed as it does not seem to correlate with PD clinical severity and duration [23]. In fact, there is a considerable variability in the temporal sequence and topographical distribution of Lewy pathology among patients. Some

studies have reported cases of aged individuals dying with Braak stages 4–6 without any clinical record of neurological impairment [24], [25] and [26]. Moreover, the relationship between Lewy pathology and neuronal dysfunction or death is still uncertain, representing an additional challenge Alanine-glyoxylate transaminase for the Braak’s hypothesis. Although Braak’s staging might require further clinical and pathological validation, it is still widely accepted as it broadly concurs with clinical observations and might be accurate in about 80% of the cases [27]. A more sensitive PD staging system might include neurodegeneration patterns in addition to Lewy pathology. Braak and co-workers suggested that an unknown environmental insult initiates the pathological process, which may spread trans-synaptically from one susceptible brain region to another via thin, long and unmyelinated axons [28]. CNS may be accessed through both a nasal and a gastric route via preganglionic fibers of the DMV which innervate the enteric nervous system [47], [48] and [49]. This hypothesis fits with the neuropathological evidence of LB in the olfactory and enteric systems of both PD and incidental cases [32], [50] and [51] as well as the clinical observations of olfactory deficit and gastrointestinal dysfunction in PD patients, which precede the disease motor onset [52] and [53].

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