Trusting Your Gut When it Comes to the Origin of Parkinson's Disease

We read with interest the viewpoint article by Totsune et al. ¹ and welcome the opportunity to respond to their claims.

Claim 1: The brain‐first versus body‐first (BvB) hypothesis is oversimplified, relying solely on neuron‐to‐neuron transmission of Lewy pathology. ¹ This misrepresents our work. While the BvB model emphasizes different origin sites and the subsequent propagation of Lewy‐type pathology (LTP), we have always highlighted the roles of inflammation, genetics, oxidative stress, mitochondria, lysosomes, and other factors. Furthermore, we hypothesize that while most Lewy body cases start in either the gut or olfactory bulb/amygdala, a minority (~10%) originate multifocally. ²

Claim 2: Body‐first Parkinson's disease (PD) starts in the heart, not the gut. ¹ Totsune et al. base this entirely on Orimo et al., ³ yet that study provides almost no evidence for this claim. Orimo analyzed 17 incidental LBD cases with sympathetic pathology: 14 were LTP‐positive in both the myocardium and stellate ganglion (SG), one in the SG only, and two in the myocardium only. Additionally, the Japanese Brain Bank for Aging Research ⁴ observed nine cases with isolated sympathetic pathology without central nervous system involvement: three cases in both the SG and heart, five in the SG only, and one in the heart only. Neither of these studies supports the claim that Lewy pathology appears in the myocardium prior to the SG.

Orimo et al. argued that the relatively higher myocardial LTP burden (compared with SG) in early incidental Lewy body disease (ILBD) could signify that LTP starts in the myocardium. However, alpha‐synuclein is concentrated presynaptically, ⁵ while proteostatic machinery, including lysosomes, is mainly somatic. Thus, even in universally affected neurons, alpha‐synuclein pathology would be expected to precipitate first in synapses due to this imbalance between alpha‐synuclein concentration and proteostatic capacity.

Additionally, the figure by Totsune et al. misrepresents the BvB model. We have consistently stated that gut‐first pathology spreads via the coeliac/mesenteric ganglia to the sympathetic trunk and then anterogradely to the heart. We have never claimed that it must reach the intermediolateral cell column first, so this argument by Totsune et al. is moot.

Claim 3: PD is caused by hematogenous spreading of alpha‐synuclein. ¹ This hypothesis is unlikely for several reasons. Brain pathologies caused by hematogenous spreading (eg, cerebral metastases, or abscesses) typically generate random patterns of pathology. In contrast, LTP follows highly ordered patterns and gradients. Figure 1 shows 123 cases of LTP categorized as body‐first or brain‐first and ranked by disease extent. ⁴ , ⁶ While cross‐sectional data should be interpreted with caution, they strongly suggest that: (i) LTP does not originate from hematogenous propagation, as the initial patterns are distinctly non‐random; (ii) LTP typically begins in either the autonomic (body‐first) or olfactory/amygdala (brain‐first) regions; and (iii) LTP accumulates over time, forming stereotypical landscapes compatible with spreading through the connectome.

FIG. 1.

Plots of 123 cases from the Brain Bank for Aging Research, ⁶ divided into eight categories according to how many of 16 regions were Lewy‐type pathology (LTP)‐positive. The LTP in each region was assessed semi‐quantitatively and plotted as average (standard error of the mean). All body‐first (blue) cases were defined as those with more pathology in the sympathetic trunk and dorsal motor nucleus of the vagus than in the amygdala and olfactory bulb. Brain‐first cases (red) showed the opposite pattern. The final two categories (13–14 and 15–16 positive regions) are considered post‐diagnostic stages, the 11–12 positive category is mostly pre‐diagnostic, and the first five categories (1–10 regions positive) are pre‐diagnostic, since not a single case had an antemortem Parkinson's disease (PD) or dementia with Lewy bodies (DLB) diagnosis. The earliest stages of LTP are clearly non‐random, arguing against hematogenous seeding of the brain. Early LTP is predominantly seen either in the sympathetic and/or parasympathetic system, compatible with an autonomic start, or in the amygdala and/or olfactory bulb, compatible with an olfactory‐ or amygdala‐first origin. ADR, adrenal gland; ESO, esophagus; HE, heart; SY, sympathetic trunk; DMV, dorsal motor nucleus of the vagus; LC, locus coeruleus; SN, substantia nigra; NBM, nucleus basalis of Meynert; AMY, amygdala; OB, olfactory bulb; TrE, transentorhinal cortex; CIN, cingulum; T, temporal; F, frontal; P, parietal. The figure is adapted from Andersen et al. ⁶ (2025) published open access under Creative Commons Attribution v. 4.0 international license (http://creativecommons.org/licenses/by/4.0/). [Color figure can be viewed at wileyonlinelibrary.com]

Claim 4: Totsune's published subtypes disprove the BvB model. ¹ , ⁷ Based on their recent imaging‐based cluster analysis of PD subtypes, ⁷ the authors claim that cardiac sympathetic degeneration associates with cortical atrophy but not nigrostriatal degeneration. Furthermore, they argue that their subtyping reflects alpha‐synuclein pathology distribution rather than the BvB model. However, their study does not invalidate BvB.

First, it lacks data on de novo patients, limiting its relevance to BvB. Second, they report a strong trend toward asymmetric striatal degeneration in the “normal MIBG”‐cluster, aligning with brain‐first PD. Third, cortical atrophy is influenced by co‐pathologies, making magnetic resonance imaging‐based atrophy in small PD samples an unreliable marker of alpha‐synuclein distribution. Finally, the authors emphasized that the clusters with shortest disease duration resemble BvB subtypes, contradicting their current opinion.

In conclusion, while we welcome constructive criticism, none of Totsune et al.'s arguments undermine the plausibility of the BvB model. Nevertheless, our recently published study suggests the existence of parasympathetic‐ and sympathetic‐predominant subtypes of PD. ⁶ We acknowledge that in some patients, the first alpha‐synuclein aggregates could theoretically form in sympathetic synapses of the gut, skin, kidney, vessels, or heart. However, that would still be a bona fide body‐first PD subtype encompassed within the overall framework of the BvB hypothesis.

Author Roles

(1) Research Project: A. Conceptualization, B. Organization, C. Execution; (2) Statistical Analysis: A. Design. B. Execution. C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique.

P.B: 1A, 1B, 1C, 3A, 3B.

N.V.D.B: 1A, 3A, 3B.

C.S: 1A, 3B.

J.H: 1A, 3A, 3B.

Financial Disclosures of All Authors (for the Previous 12 Months)

The authors report no financial conflicts of interest pertaining to this work. All authors certify that they have no affiliations or involvements in any organization or entity with any financial interests or non‐financial interests in the subject matter or materials discussed in this article.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.