Stage 4

Since clinical protocols of some individuals with stage 3 Lewy pathology and those of many stage 4 cases mention incipient disease-related motor symptoms, we postulated in 2002 that perhaps at some point during stages 3–4 the nonsymptomatic phase of “incidental” sPD yields to the clinically recognizable phase of the illness (Fig. 4e; Braak et al. 2003a; Braak and Del Tredici 2008).

The lesions in previously involved nuclei become more severe in stage 4 (Fig. 22). The loss of neuromelanin-containing neurons in the coeruleus—subcoeruleus complex becomes macroscopically visible. Cases without LNs/LBs in the ventral teg-mental area and upper raphe nuclei in the preceding stage begin to display them at stage 4. Impairment of the diffusely projecting nonthalamic nuclei probably begins to reduce the input to the cerebral cortex. Of equal importance in stage 4, however, is the involvement of additional subnuclei of the amygdala (Fig. 15b), the intrala-minar and midline nuclei of the thalamus (Fig. 19a), and a specific portion of the cerebral cortex. In most cases, the vulnerable cortical site is the anteromedial temporal mesocortex (Fig. 20a). At about the same time, but with somewhat greater irregularity, subtle changes also appear in insular, subgenual, and anterior cingu-late cortical areas, as well as in the second sector of the Ammon's horn (Fig. 20b,c). Initial changes may also be visible in the striatum, thalamic relay nuclei with projections to the cerebral cortex, and the claustrum. The involvement of these sites is described more extensively below under stages 5 and 6 (Sects. 8.3–8.5). Lewy pathology is not seen in neocortical areas, and the same applies to the pallidum and subthalamic nucleus. Similarly, the small melanized neurons (corresponding to the rodent A12 group) of the infundibular and periventricular nuclei that comprise the dopaminergic system of the hypothalamus remain untouched by the pathological process (Matzuk and Saper 1985). It is noteworthy that these nerve cells generate a short axon and do not establish connections to other nuclei that consistently develop LNs and LBs.