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Publications

Journal Article Review Ahead of print 2 citations

PubMed: 42463844 DOI: 10.1038/s41582-026-01241-8

Brain-first and body-first subtypes of Lewy body disease.

Nat Rev Neurol

Authors: Per Borghammer, Nathalie Van Den Berge, Daniela Berg, Ryosuke Takahashi, Ronald B Postuma, Jacob Horsager

Affiliations

  • Lundbeck Foundation Parkinson's Disease Research Center (PACE), Aarhus University, Aarhus, Denmark.
  • Department of Nuclear Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Lundbeck Foundation Parkinson's Disease Research Center (PACE), Aarhus University, Aarhus, Denmark.
  • Core Centre for Molecular Morphology, Section for Stereology and Microscopy, Aarhus University, Aarhus, Denmark.
  • Department of Neurology, Christian-Albrechts-University, Kiel, Germany.
  • Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • Department of Neurology, Montreal Neurological Institute, Montreal, Canada.
  • Department of Nuclear Medicine, Aarhus University Hospital, Aarhus, Denmark.

Abstract

People with Lewy body disease exhibit heterogeneous clinical symptoms, diverse patterns of neurodegeneration on imaging and variable Lewy body pathology at post-mortem. The brain-first versus body-first (BvB) model provides a unifying framework that may account for much of this variability. According to the BvB model, Lewy pathology originates either in autonomic nerves of the gut or other peripheral neurons (body first) or in the olfactory bulb with subsequent spread to the limbic system (brain first). Both subtypes are thought to begin largely outside the CNS, possibly triggered by exogenous factors such as infectious agents or toxins. The model is supported by several observations. First, some individuals develop autonomic dysfunction and sleep disorders years before diagnosis, whereas other individuals experience these symptoms only after diagnosis. Second, in people with prodromal sleep disorders, cardiac sympathetic denervation precedes nigrostriatal degeneration by approximately a decade, whereas in individuals without sleep disorders, these systems degenerate in the opposite sequence. Third, post-mortem studies often reveal bottom-up or top-down gradients of Lewy pathology, consistent with body-first versus olfactory-first origins. This Review provides a critical appraisal of the BvB model, highlighting supporting evidence and current limitations. The article also considers implications for diagnostics, therapy and prevention, and outlines key avenues for future research.

MeSH

Lewy Bodies, Sleep, Brain, Pathology, Lewy Body Disease, Signs And Symptoms, Diagnosis, Nervous System Diseases