Sporadic Parkinson's disease (PD) entails the selective degeneration of circumscribed portions of the human nervous system (Wakabayashi et al., 1990; Takahashi and Wakabayashi, 2001, 2005; Jellinger and Mizuno, 2003; Braak et al., 2004).
At neuropathological examination, all of the patients suffering from this disorder reveal the presence of a-synuclein-immunoreac-tive inclusion bodies in vulnerable neuronal types. These inclusions occur as spindle-shaped and, in part, branching Lewy neurites (LNs) within the dendrites and axons of involved nerve cells. Somatic inclusions may appear as punctate aggregations close to the deposits of neuromelanin or lipofuscin granules. Larger but more weakly immu-noreactive globular inclusions can also be observed in the form of pale bodies, which probably go on to evolve into strongly labeled Lewy bodies (LBs) (Lowe, 1994;
Goedert, 2001; Takahashi and Wakabayashi, 2001, 2005; Kuusisto et al., 2003; Saito et al., 2003; Braak et al., 2004; Mikolaenko et al., 2005).
Individuals with clinical symptoms of ' ' parkinsonism'' in the absence of LNs or LBs form a heterogeneous group of motor dysfunctions, including multiple system atrophy, progressive supranuclear palsy, neurodegeneration with brain iron accumulation I, and some forms of familial PD (Galvin et al., 2001; Lantos and Quinn, 2003; Jellinger, 2003a; Pankratz and Foroud, 2004), so that neuropathological confirmation of the clinical diagnosis is essential in each instance.
Only a few of the many neuronal types within the human nervous system are prone to develop the PD-related lesions. This selective involvement is reflected in the regional distribution pattern of the pathology. The disease process is not haphazard (Braak et al., 2003a, 2004; Del Tredici and Braak, 2004). These features enable the observer to recognize the presence of the pathological process even in individuals without PD-related motor symptoms.
Although LNs and LBs are more prevalent with advancing age, they do not occur in all elderly non-symptomatic individuals or age- and gender-matched controls. Thus, we refrain from viewing incidental LB pathology as a normal concomitant of aging (Braak et al., 1995; Dickson, 1998; Del Tredici et al., 2002; Mikolaenko et al., 2005).
Sporadic PD requires years to develop. As in nearly every illness, some individuals arrive at, and cross, the threshold from a subclinical phase to the symptomatic manifestation of disease (Thal et al., 2004). The symptoms begin almost imperceptibly and worsen over time. In the autopsy material available to us, symptomatic cases can be assigned to one of four subgroups that can be differentiated based on changes in the topographic distribution pattern of the lesions in the brain. Each subgroup displays newly affected regions in addition to the lesions in previously involved ones (Fig. 1a). The majority of sporadic PD autopsy cases can be grouped in this way. Given the consistency of this finding and assuming that the disease process increases in extent and severity in a predetermined manner, the four clinical subgroups can be arranged in an ordered sequence (Fig. 1b). Support for this hypothetical reconstruction comes from a number of non-motor symptoms that become manifest during the clinical disease course and possibly correspond to the gradual progress of the pathological process (Abbott et al., 2001; Doty, 2001; Tissingh et al., 2001; Hawkes, 2003; Ponsen et al., 2004; Ahlskog, 2005; Stiasny-Kolster et al., 2005; Braak et al., 2005).
By comparison, relatively little is known about the presymptomatic phase in PD (Koller et al., 1991; Sawle, 1993; Wolters et al., 2000; Ahlskog, 2005). That such a phase in PD exists, however, has been shown
Fig. 1. a Virtually all clinically diagnosed PD cases can be assigned to one of four subgroups based on the topographic distribution pattern of the brain pathology. Each subgroup displays newly affected regions in addition to the inclusion body pathology in previously involved regions. b Given the assumption that the disease process increases in extent and severity, the four clinical subgroups can be arranged in an ordered sequence. c The presymptomatic cases fall into one of three different subgroups. d Once again, the subgroups can be arranged such that the pathological process can be seen to progress in extent and severity. e In both the presymptomatic and the symptomatic phases of sporadic PD, inclusion bodies occur in the same vulnerable neuronal types. Taken together, both phases presumably reflect the entire spectrum of the disease process in six neuropathological stages. Increasing density of the gray shading in areas underneath the diagonal indicates the growing severity of the pathology in vulnerable brain regions indicated at right hand margin. f-i Diagrams showing the gradual ascent of the pathological process underlying sporadic PD (white arrows) that begins in the lower brain stem and olfactory bulb (black arrows in f) and ends in the cerebral cortex
by PET studies (Morrish et al., 1998; Brooks, 2000). In our material, non-symptomatic cases that show PD-associated brain pathology fall into one of three subgroups (Fig. 1c). As in the symptomatic cases, these subgroups differ with respect to their lesional distribution patterns (Del Tredici et al., 2002; Braak et al., 2003a). Once again, it is the changes in the regional distribution pattern of the inclusion bodies that provide the logic for arranging the subgroups such that the disease process is seen to increase in extent and severity in a methodical sequence (Fig. 1d). According to this view, incidental LNs and LBs, even when minimally present, are innately pathological entities (Forno, 1969; Del Tredici et al., 2002; Thal et al., 2004; Takahashi and Wakabayashi, 2005).
By the time subtle symptoms become recognizable, susceptible brain stem nuclei, including the dorsal motor nucleus, the lower raphe system, and locus coeruleus, are already heavily involved. Assuming that all of these sites are not affected with identical severity from the very outset of the disease process, a more likely explanation would be that a mild to moderate burden of pathology develops over time in each of these nuclei until the cumulative threshold from presymptomatic to symptomatic disease manifestation is crossed. The pathological process underlying both phases is marked by the presence of the same types of inclusion bodies in the same susceptible neuronal types in specific brain regions. Insofar as the lesional pattern of the last presymptomatic subgroup closely resembles that of the first symptomatic subgroup, both sets of subgroups combined reflect the entire spectrum of the pathology associated with sporadic PD (Fig. 1e).
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