Neuropathological Staging of Brain Pathology in Sporadic Parkinson's disease: Separating the Wheat from the Chaff

Abstract

A relatively small number of especially susceptible nerve cell types within multiple neurotransmitter systems of the human central, peripheral, and enteric nervous systems (CNS, PNS, ENS) become involved in the degenerative process underlying sporadic Parkinson's disease (sPD). The six-stage model we proposed for brain pathology related to sPD (Neurobiol Aging 2003) was a retrospective study of incidental and clinically diagnosed cases performed on unconventionally thick tissue sections (100 μm) from a large number of brain regions.The staging model emphasized what we perceived to be a sequential development of increasing degrees of Lewy pathology in anatomically interconnected regions together with the loss of aminergic projection neurons in, but not limited to, the locus coeruleus and substantia nigra. The same weight was assigned to axonal and somatodendritic Lewy pathology, and the olfactory bulb was included for the first time in a sPD staging system. After years of research, it now appears that the earliest lesions could develop at nonnigral (dopamine agonist nonresponsive) sites, where the surrounding environment is potentially hostile: the olfactory bulb and, possibly, the ENS. The current lack of knowledge regarding the development of Lewy pathology within the peripheral autonomic nervous system, however, means that alternative extra-CNS sites of origin cannot be disregarded as possible candidates. The PD staging system not only caused controversy but contributed a framework for (1) assessing pathology in the spinal cord, ENS, and PNS in relationship to that evolving in the brain, (2) defining prodromal disease and cohorts of at-risk individuals, (3) developing potential prognostic biomarkers for very early disease, (4) testing novel hypotheses and experimental models of α-synuclein propagation and disease progression, and (5) finding causally-oriented therapies that intervene before the substantia nigra becomes involved. The identification of new disease mechanisms at the molecular and cellular levels indicates that physical contacts (transsynaptic) and transneuronal transmission between vulnerable nerve cells are somehow crucial to the pathogenesis of sPD.

Keywords: Lewy body disease; Parkinson’s disease; autonomic nervous system; cell-to-cell transfer; central nervous system; dorsal motor nucleus of the vagal nerve; enteric nervous system; locus coeruleus; olfactory bulb; peripheral nervous system; prion-like; protein aggregation; protein misfolding; spinal cord; substantia nigra; α-synuclein.

Fig.1

(a-f) Lewy pathology in the olfactory bulb and gastric Auerbach plexus visualized in α-synuclein immunohistochemistry (100 μm polyethylene glycol sections). a. Olfactory bulb and anterior olfactory nucleus (aon) (50-year-old male, stage 2). The dorsal motor nucleus of the vagal nerve and intermediate reticular zone in the medulla also contained Lewy neurites and Lewy bodies. Presumably, this non-demented individual would have gone on to develop PD had he lived longer. b. Olfactory bulb and aon (63-year-old female, stage 2). Much less severe pathology was also present in the dorsal motor nucleus of the vagal nerve, intermediate reticular zone, nucleus raphes magnus, and locus coeruleus. c. Tangential section from the gastric cardia showing Lewy neurites (arrowheads, same case as in b). Again, it is presumed that, had she lived longer, this cognitively intact individual would have been diagnosed with PD. d. Intramural Lewy pathology in a section cut tangentially to the surface of the gastric cardia. Also visible (in background) is a large, branching blood vessel lined by thread-like immunoreactive sympathetic nerve fibers. In addition to the occurrence of Lewy neurites and Lewy bodies in the dorsal motor nucleus of the vagal nerve, intermediate reticular zone, nucleus raphes magnus, locus coeruleus, and substantia nigra, some nigral cell loss was also evident in the pars compacta (65-year-old male, stage 3). e. Detail of Lewy neurites in PD penetrating the muscularis mucosa and reaching upwards into the lamina propria (mucosa) where they extend between the gastric glands (g) in a perpendicularly cut section (69-year-old female, stage 4). f. Tangential section from the gastric cardia of a PD patient with disease duration of 11 years (78-year-old female, stage 5). Scale bars: a is valid for b; c also applies to d. Stages in parentheses refer to neuropathological stages 1–6 of sporadic PD. Micrographs e, f reproduced with permission from [70].