The Evolving Distribution Pattern of Lewy Pathology Associated with sPD Renders Neuropathological Staging Possible

Lewy pathology occurs as an incidental finding in nonsymptomatic individuals (Forno 1969). Such LNs and LBs are considered by some to be either natural products of neuronal aging or epiphenomena of other neurobiological processes (Tompkins and Hill 1997; Porta 2002; Jellinger 2004; Saito et al. 2003, 2004; Parkkinen et al. 2005). However, because most individuals examined in nonselected autopsy-based studies typically do not exhibit LNs and LBs, not even at an advanced age (Gibb and Lees 1989; Hughes et al. 1992; Forno 1996; Saito et al. 2004; Chu and Kordower 2007), and since sPD is a dynamic process, incidental lesions can also be viewed as nonbenign entities in a very early phase of the disorder—comparable to the first malignant cells in a carcinoma—that fail to produce clinically detectable symptoms but mark the beginning of a pathological process (Del Tredici et al. 2002; Orimo et al. 2008; Dickson et al. 2008). In two recent studies, incidental cases were shown to have reduced striatal tyrosine hydroxylase (Beach et al. 2008; Dickson et al. 2008), which indicates that even mild pathology may be a precursor of sPD. We regard incidental LNs and LBs as clinically mute but disease-related inclusions and have argued that their existence poses a potential threat to the nervous system because they can result in neuronal dysfunction and nerve cell loss in the course of sPD (Braak and Del Tredici 2008).