The autonomic higher order processing nuclei of the lower brain stem are among the early targets of the Alzheimer's disease-related cytoskeletal pathology

The nuclei of the pontine parabrachial region (medial parabrachial nucleus, MPB; lateral parabrachial nucleus, LPB; subpeduncular nucleus, SPP) togeth er with the intermediate zone of the medullary reticular formation (IRZ) ar e pivotal relay stations within central autonomic regulatory feedback syste ms. This study was undertaken to investigate the evolution of the Alzheimer 's disease-related cytoskeletal pathology in these four sites of the lower brain stem. We examined the MPB, LPB, SPP and IRZ in 27 autopsy cases and c lassified the cortical Alzheimer-related cytoskeletal anomalies according t o an established staging system (neurofibrillary tangle/neuropil threads [N FT/NT] stages I-VI). The lesions were visualized either with the antibody A T8, which is immunospecific for the abnormally phosphorylated form of the c ytoskeletal protein tau, or with a modified Gallyas silver iodide stain. Th e MPB, SPB, and IRZ display cytoskeletal pathology in stage I and the LPB i n stage II, whereby bothstages correspond to the preclinical phase of Alzhe imer's disease (AD). In stages HI-IV (incipient AD), the MPB and SPP are se verely affected. In all of the stage III-IV cases, the lesions in the LPB a nd IRZ are well developed. In stages V and VI (clinical phase of AD), the M PB and SPP are filled with the abnormal intraneuronal material. At stages V -VI, the LPB is moderately involved and the IRZ shows severe damage. The pa thogenesis of the AD-related cytoskeletal lesions in the nuclei of the pont ine parabrachial region and in the IRZ conforms with the cortical NFT/NT st aging sequence I-VI. In the event that the cytoskeletal pathology observed in this study impairs the function of the nerve cells involved, it is conce ivable that autonomic mechanisms progressively deteriorate with advancing c ortical NFT/NT stages. This relationship remains to be established, but it could provide insights into the illusive correlation between the AD-related cytoskeletal pathology and the function of affected neurons.