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Background <p>In Parkinson’s disease (PD), two pathogenetic subtypes have been proposed: a ‘brain-first’, with α-synuclein pathology arising in one hemisphere and spreading secondarily to the peripheral autonomic nervous system, and a ‘body-first’ subtype, with the pathology originating in the enteric or peripheral autonomic nervous system and subsequently spreading symmetrically to the brain. To dissect these subtypes, we assessed the association between pupillary dysfunction, mesencephalic raphe and substantia nigra changes, vagus nerve atrophy and vagal electrocardiographic parameters in PD patients and controls.</p> Methods <p>In this single-center cross-sectional study, we included 54 people with PD and 60 matched healthy controls. Participants underwent clinical assessments, electrocardiography, and sonographic measurements of substantia nigra echoic area, midbrain raphe echo-score and vagus nerve caliber. Dynamic ultrasound pupillometry was performed in drug-naïve de&#xa0;novo PD patients and matched controls. The brain-first and body-first subtypes were classified based on the REM-sleep Behavior Disorder Screening Questionnaire and gastrointestinal symptoms.</p> Results <p>Vagal atrophy increased with disease duration and severity. During the first decade of motor disease, vagal atrophy and dysfunction occurred in body-first but not brain-first PD. Sympathetic pupillary innervation was reduced in de novo body-first but not brain-first PD patients. However, parasympathetic pupillary innervation was reduced in both subtypes at the de novo stage. Substantia nigra hyperechoic area was asymmetrical in brain-first but more symmetrical in body-first PD.</p> Conclusions <p>Our findings support the concept of two subtypes of PD in which the mesencephalic and vagal parasympathetic systems are affected in opposite sequences. Ultrasonic and electrocardiographic examination could facilitate early subtyping.</p>

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Brain-first versus body-first Parkinson’s disease: Differential findings on pupillary, brainstem and vagus sonography

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月2日

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  • Uwe Walter,
  • Michael Batchakaschvili,
  • Hanna Rebekka Kleinlein,
  • Jakub Radziwon,
  • Wiebke Hermann,
  • Hartmut Walter,
  • Alexander Storch,
  • Matthias Löhle

摘要

Background

In Parkinson’s disease (PD), two pathogenetic subtypes have been proposed: a ‘brain-first’, with α-synuclein pathology arising in one hemisphere and spreading secondarily to the peripheral autonomic nervous system, and a ‘body-first’ subtype, with the pathology originating in the enteric or peripheral autonomic nervous system and subsequently spreading symmetrically to the brain. To dissect these subtypes, we assessed the association between pupillary dysfunction, mesencephalic raphe and substantia nigra changes, vagus nerve atrophy and vagal electrocardiographic parameters in PD patients and controls.

Methods

In this single-center cross-sectional study, we included 54 people with PD and 60 matched healthy controls. Participants underwent clinical assessments, electrocardiography, and sonographic measurements of substantia nigra echoic area, midbrain raphe echo-score and vagus nerve caliber. Dynamic ultrasound pupillometry was performed in drug-naïve de novo PD patients and matched controls. The brain-first and body-first subtypes were classified based on the REM-sleep Behavior Disorder Screening Questionnaire and gastrointestinal symptoms.

Results

Vagal atrophy increased with disease duration and severity. During the first decade of motor disease, vagal atrophy and dysfunction occurred in body-first but not brain-first PD. Sympathetic pupillary innervation was reduced in de novo body-first but not brain-first PD patients. However, parasympathetic pupillary innervation was reduced in both subtypes at the de novo stage. Substantia nigra hyperechoic area was asymmetrical in brain-first but more symmetrical in body-first PD.

Conclusions

Our findings support the concept of two subtypes of PD in which the mesencephalic and vagal parasympathetic systems are affected in opposite sequences. Ultrasonic and electrocardiographic examination could facilitate early subtyping.