The Body, the Brain, the Environment, and Parkinson's Disease

Abstract

The brain- and body-first models of Lewy body disorders predict that aggregated alpha-synuclein pathology usually begins in either the olfactory system or the enteric nervous system. In both scenarios the pathology seems to arise in structures that are closely connected to the outside world. Environmental toxicants, including certain pesticides, industrial chemicals, and air pollution are therefore plausible trigger mechanisms for Parkinson's disease and dementia with Lewy bodies. Here, we propose that toxicants inhaled through the nose can lead to pathological changes in alpha-synuclein in the olfactory system that subsequently spread and give rise to a brain-first subtype of Lewy body disease. Similarly, ingested toxicants can pass through the gut and cause alpha-synuclein pathology that then extends via parasympathetic and sympathetic pathways to ultimately produce a body-first subtype. The resulting spread can be tracked by the development of symptoms, clinical assessments, in vivo imaging, and ultimately pathological examination. The integration of environmental exposures into the brain-first and body-first models generates testable hypotheses, including on the prevalence of the clinical conditions, their future incidence, imaging patterns, and pathological signatures. The proposed link, though, has limitations and leaves many questions unanswered, such as the role of the skin, the influence of the microbiome, and the effects of ongoing exposures. Despite these limitations, the interaction of exogenous factors with the nose and the gut may explain many of the mysteries of Parkinson's disease and open the door toward the ultimate goal -prevention.

Keywords: Lewy body disease; Parkinson’s disease; air pollution; brain-gut axis; enteric nervous system; nose; nuclear medicine; pesticides; polychlorinated biphenyls; trichloroethylene.

Fig. 1

Spread of Lewy pathology via body-first and brain-first models based on pathology severity profiles from postmortem data. Sacral SC, sacral spinal cord; IML, intermediolateral column; Symp Tr, sympathetic trunk; DMV, dorsal motor nucleus of vagus; LC, locus coeruleus; SN, substantia nigra; Amy, amygdala; OB, olfactory bulb; TrE, transentorhinal cortex; Temp Cortex, temporal cortex; Fron Cortex, frontal cortex; Par Cortex, parietal cortex

Fig. 2

A proposal on how environmental exposure to toxicants may cause either body-first or brain-first Lewy body disease. The size of the brown circles reflects the amount of Lewy pathology in each region. In body-first Lewy body disease, toxicants are most likely ingested through diet and drinking water, but swallowing inhaled toxicants trapped in mucous is also a possibility. In the gut, the toxicants trigger initial a-synuclein misfolding in the enteric nervous system, which then spread centripetally towards the central nervous system via parasympathetic and sympathetic neurons. Consequently, a-synuclein in the peripheral autonomic nervous system and brainstem will be dominating, and less pathology will be found in more rostral structures. The skin could be an alternative trigger site for body-first Lewy body disease. In brain-first Lewy body disease, inhaled toxicants may trigger initial pathology in the olfactory bulb, with subsequent spread to closely related structures. Consequently, a-synuclein in amygdala and olfactory-related structures such as the transentorhinal cortex display most pathology, and less will be found in the brainstem and peripheral autonomic nervous system. Sacral SC, sacral spinal cord; IML, intermediolateral column; Symp Tr, sympathetic trunk; DMV, dorsal motor nucleus of vagus; LC, locus coeruleus; SN, substantia nigra; Amy, amygdala; OB, olfactory bulb; TrE, transentorhinal cortex; PCBs, polychlorinated biphenyls; TCE, trichloroethylene; PCE, perchloroethylene.

Fig. 3

Air pollution in London, 1700 –2016, and in Delhi, 1997–2010. Source: Our World in Data [146, 180].