Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals

Katrine B. Andersen; Anushree Krishnamurthy; Mie Kristine Just; Nathalie Van Den Berge; Casper Skjærbæk; Jacob Horsager; Karoline Knudsen; Jacob W. Vogel; Jon B. Toledo; Johannes Attems; Tuomo Polvikoski; Yuko Saito; Shigeo Murayama; Per Borghammer

doi:10.1038/s41593-025-01910-9

Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals

Katrine B. Andersen, Anushree Krishnamurthy, Mie Kristine Just, Nathalie Van Den Berge, Casper Skjærbæk, Jacob Horsager, Karoline Knudsen, Jacob W. Vogel, Jon B. Toledo, Johannes Attems, Tuomo Polvikoski, Yuko Saito, Shigeo Murayama, Per Borghammer^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Recent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson’s disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression.

Original language	English
Article number	1255555
Journal	Nature Neuroscience
ISSN	1097-6256
DOIs	https://doi.org/10.1038/s41593-025-01910-9
Publication status	E-pub / Early view - 2025

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Andersen, K. B., Krishnamurthy, A., Just, M. K., Van Den Berge, N., Skjærbæk, C., Horsager, J., Knudsen, K., Vogel, J. W., Toledo, J. B., Attems, J., Polvikoski, T., Saito, Y., Murayama, S., & Borghammer, P. (2025). Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals. Nature Neuroscience, Article 1255555. Advance online publication. https://doi.org/10.1038/s41593-025-01910-9

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title = "Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals",

abstract = "Recent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson{\textquoteright}s disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression.",

author = "Andersen, {Katrine B.} and Anushree Krishnamurthy and Just, {Mie Kristine} and {Van Den Berge}, Nathalie and Casper Skj{\ae}rb{\ae}k and Jacob Horsager and Karoline Knudsen and Vogel, {Jacob W.} and Toledo, {Jon B.} and Johannes Attems and Tuomo Polvikoski and Yuko Saito and Shigeo Murayama and Per Borghammer",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

doi = "10.1038/s41593-025-01910-9",

language = "English",

journal = "Nature Neuroscience",

issn = "1097-6256",

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Andersen, KB , Krishnamurthy, A , Just, MK , Van Den Berge, N , Skjærbæk, C , Horsager, J , Knudsen, K, Vogel, JW, Toledo, JB, Attems, J, Polvikoski, T, Saito, Y, Murayama, S & Borghammer, P 2025, 'Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals', Nature Neuroscience. https://doi.org/10.1038/s41593-025-01910-9

Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals. / Andersen, Katrine B.; Krishnamurthy, Anushree ; Just, Mie Kristine et al.
In: Nature Neuroscience, 2025.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

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T1 - Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals

AU - Andersen, Katrine B.

AU - Krishnamurthy, Anushree

AU - Just, Mie Kristine

AU - Van Den Berge, Nathalie

AU - Skjærbæk, Casper

AU - Horsager, Jacob

AU - Knudsen, Karoline

AU - Vogel, Jacob W.

AU - Toledo, Jon B.

AU - Attems, Johannes

AU - Polvikoski, Tuomo

AU - Saito, Yuko

AU - Murayama, Shigeo

AU - Borghammer, Per

PY - 2025

Y1 - 2025

N2 - Recent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson’s disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression.

AB - Recent studies suggest the existence of brain-first and body-first subtypes within the Lewy body disorder (LBD) spectrum, including Parkinson’s disease. These studies primarily focused on α-synuclein propagation through the parasympathetic vagal and olfactory bulb routes, leaving the possibility of a sympathetic nervous system spreading route unexplored. In the present study, we analyzed two postmortem datasets, which included 173 and 129 cases positive for Lewy pathology. We observed a clear distinction between brain-first and body-first subtypes in early prediagnostic cases with mild Lewy pathology. Brain-first cases displayed minimal peripheral organ pathology in prediagnostic phases, contrasting with marked autonomic involvement in prediagnostic body-first cases. Utilizing the SuStaIn machine learning algorithm, we identified two distinct body-first subtypes, one with vagal predominance and another with sympathetic predominance, in equal proportions. Our study supports the existence of three prediagnostic LBD subtypes and highlights the sympathetic nervous system alongside the parasympathetic system in LBD onset and progression.

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DO - 10.1038/s41593-025-01910-9

M3 - Journal article

C2 - 40082617

AN - SCOPUS:105000039510

SN - 1097-6256

JO - Nature Neuroscience

JF - Nature Neuroscience

M1 - 1255555

ER -

Sympathetic and parasympathetic subtypes of body-first Lewy body disease observed in postmortem tissue from prediagnostic individuals

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