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Letter to the editor
Absence of Alpha-Synuclein Pathology in the Stomach of a Patient With Prodromal Dementia With Lewy Bodies
Chaewon Shin1orcid, Seong-Ik Kim2orcid, Sung-Hye Park2orcid, Jung Hwan Shin3orcid, Chan Young Lee4orcid, Han-Joon Kim3orcid, Hyuk-Joon Lee5orcid, Seong-Ho Kong5orcid, Yun-Suhk Suh6orcid, Han-Kwang Yang5orcid, Beomseok Jeon3corresp_iconorcid
Journal of Movement Disorders 2023;16(2):213-216.
Published online: April 26, 2023

1Department of Neurology, Chungnam National University Sejong Hospital, Chungnam National University College of Medicine, Sejong, Korea

2Department of Pathology, Seoul National University College of Medicine, Seoul, Korea

3Department of Neurology, MRC and Movement Disorder Center, Seoul National University Hospital, Parkinson Study Group, Seoul National University College of Medicine, Seoul, Korea

4Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, Korea

5Department of Surgery, Cancer Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea

6Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea

Corresponding author: Beomseok Jeon, MD, PhD Department of Neurology, MRC and Movement Disorder Center, Seoul National University Hospital, Parkinson Study Group, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea / Tel: +82-2-2072-2876 / Fax: +82-2-3672-7553 / E-mail:
• Received: December 19, 2022   • Revised: February 18, 2023   • Accepted: March 7, 2023

Copyright © 2023 The Korean Movement Disorder Society

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dear Editor,
Postoperative delirium (POD) is a complication that develops after surgery and anesthesia, with a prevalence of 37%–46% among adult patients who have undergone surgery. Interestingly, hyposmia and rapid eye movement sleep behavior disorder (RBD), which are the representative prodromal nonmotor symptoms of synucleinopathy, are also risk factors for POD [1]. One study reported alpha-synuclein (AS) accumulation in the surgical specimens of patients with POD who had undergone gastrectomy, suggesting that POD may be prodromal synucleinopathy [2]. Therefore, POD may be a delirium-onset prodromal stage of dementia with Lewy bodies (DLB); however, further research is required to test this hypothesis. This study aimed to confirm whether POD is a manifestation of prodromal DLB by evaluating AS deposition in the stomach of patients with POD who were subsequently diagnosed with DLB in a prospective clinicopathological cohort.
A total of 718 patients who participated in a prospective cohort study of patients with early gastric cancer to detect prodromal Parkinson’s disease (PD) (EGC-PPD cohort study) were included [3]. Two neurologists (J. S. and C. S.) retrospectively administered the Chart-Based Instrument for Delirium During Hospitalization (CHART-DEL) to all patients to determine whether they developed POD after surgery for EGC. Initial evaluation and annual telephone follow-ups were performed according to the EGC-PPD cohort design [3]. Additional detailed clinical evaluations were performed when a clinical diagnosis of overt parkinsonian syndromes was established. Both proximal and distal marginal blocks of the patients’ stomach specimens were pathologically evaluated for this study. The detailed methods are described in the Supplementary Material in the online-only Data Supplement.
Three patients were diagnosed with POD after evaluation using the CHART-DEL. The baseline characteristics and responses to the Screening Questionnaire for Clinical Prodromal Markers (SQ-CPM) (Supplementary Tables 1 and 2 in the online-only Data Supplement) of the patients when they were initially enrolled in the EGC-PPD cohort are summarized in Supplementary Table 3 (in the online-only Data Supplement). Motor and nonmotor symptoms progressively increased in the second and third years. Consequently, patient POD01 visited the Seoul National University Hospital for an in-person evaluation during both of these years. In the third year, patient POD01 showed overt parkinsonism as well as cognitive decline and fluctuation. The patient did not complain of visual hallucinations. Therefore, patient POD01 was clinically diagnosed with de novo DLB. The changes in symptoms of patient POD01 surveyed using the SQ-CPM and the results of the diagnostic evaluation are shown in Supplementary Table 4 in the online-only Data Supplement and Figure 1A.
Objective evaluations were conducted according to the cohort protocol at the time of diagnosis, and the results are summarized in Supplementary Table 5 in the online-only Data Supplement. The patient had decreased scores in Montreal Cognitive Assessment-Korean version and Frontal Assessment Battery, confirming cognitive dysfunction in DLB. The patient complained of orthostatic dizziness, but objective orthostatic hypotension was not detected. He had moderate prostatic symptoms, moderate urinary incontinence, and borderline hyposmia. However, RBD was not suspected.
The other patients (patient POD02 and patient POD03) were followed up for 5 and 3 years, respectively. Patient POD02 complained of rigidity in the fourth year of follow-up and he refused to visit the hospital. During telephone follow-up in the fifth year, he reported that the symptoms had improved. Patient POD03 remained symptom-free until the third year and was lost to annual follow-up.
We evaluated AS accumulation in the gastric specimens of all patients. However, AS accumulation was not observed in any specimen (Figure 1B).
This is the first study showing the absence of AS accumulation in stomach tissue that was acquired in the prodromal stage of DLB via a prospective clinicopathological cohort. The collection of the patient’s pathological tissue 3 years prior to the clinical diagnosis of de novo DLB has implications for the relationship between clinical and pathologic progression. Several studies have reported that the prodromal stages of PD and DLB began 10–20 years prior to their clinical onset. Moreover, AS accumulation in the gastrointestinal (GI) tract has been found in tissues even 10–20 years before the diagnosis of PD [4]. AS accumulation has also been observed in gastric tissue that was obtained 12 years before the diagnosis of idiopathic RBD, which is well known as a prodromal stage of synucleinopathy [5]. Therefore, the 3-year interval between surgery and diagnosis of DLB in patient POD01 sufficiently establishes that the tissue was acquired in the obvious prodromal stage of DLB.
Detailed motor and nonmotor symptom profiles at the time of the clinical diagnosis of de novo DLB provide clues about the progression of brain pathologic lesions. At the time of initial cohort enrollment, patient POD01 did not exhibit any clear nonmotor symptoms, such as hyposmia, constipation, or RBD, and only showed mild parkinsonian signs (Figure 1). At the time of initial diagnosis, cognitive dysfunction and apathy along with parkinsonism were observed. A previous study found that patients with POD did not have amyloid pathology or atrophy in the amygdala [6]. Therefore, according to the pathologic diagnostic criteria for DLB, this symptom progression suggests that the pathology of patient POD01 may start within the amygdala-limbic system in the prodromal stage and progress to the neocortex and midbrain [7]. During future follow-up of this patient, further development of RBD and other autonomic symptoms will be a significant indicator of top-down progression of DLB pathology.
Unlike positive AS findings, negative results should be interpreted with great caution. Although this study evaluated a large field of surgical specimens, they represent only a small portion of the GI tract, which is approximately 9 meters long at autopsy. Therefore, the possibility of AS accumulation in other regions of the patient cannot be excluded. Moreover, this study was a substudy of the EGC-PPD cohort study that retrospectively screened patients with POD. Although we used a validated tool for POD screening (CHART-DEL), POD occurrence was underestimated in the present study. As a result, a limitation of this study is that the number of patients with POD was too small to conduct meaningful statistical analysis.
In conclusion, this is the first study showing the absence of AS accumulation in the stomach of a patient with prodromal DLB in a prospective clinicopathological cohort. The study results imply that delirium-onset DLB might have brain-originated synucleinopathy.
The online-only Data Supplement is available with this article at
Methods and steps of our genetic analysis
Supplementary Table 1.
Initial screening questionnaire for clinical prodromal markers (Initial SQ-CPM) Item
Supplementary Table 2.
Follow-up screening questionnaire for clinical prodromal markers (F/U SQ-CPM)
Supplementary Table 3.
Baseline characteristics and initial SQ-CPM of patients with POD after gastrectomy
Supplementary Table 4.
Changes of SQ-CPM during follow-up and evaluation according to the MDS-PD diagnostic criteria of the patient POD01 with DLB
Supplementary Table 5.
Clinical characteristics at the time of diagnosis of DLB of the patient POD01

Data Availability Statement

The datasets generated or analyzed during the study are available from the corresponding author on reasonable request.

Ethics Statement

This study design was approved by the Institutional Review Board of Seoul National University Hospital (IRB No. H-1411-077-626). Written informed consent was obtained from all patients.

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This study was supported by research grants from the Seoul National University Hospital (No. 0420190460), Chungnam National University Sejong Hospital (No. 2021-S4-003), and the National Research Foundation of Korea (No. 2018R1D1A1B07041440).

Author contributions

Conceptualization: Chaewon Shin, Beomseok Jeon. Data curation: Chaewon Shin. Formal analysis: Chaewon Shin, Seong-Ik Kim, Sung-Hye Park. Funding acquisition: Beomseok Jeon. Investigation: Chaewon Shin. Methodology: Chaewon Shin, Sung-Hye Park. Project administration: Beomseok Jeon. Resources: Seong-Ik Kim, Sung-Hye Park, Han-Kwang Yang, Hyuk-Joon Lee, Seong-Ho Kong, Yun-Suhk Suh. Software: Chaewon Shin. Supervision: Beomseok Jeon. Validation: Beomseok Jeon, Jung Hwan Shin, Chan Young Lee. Visualization: Chaewon Shin. Writing—original draft: Chaewon Shin, Beomseok Jeon. Writing—review & editing: Seong-Ik Kim, Sung-Hye Park, Jung Hwan Shin, Chan Young Lee, Han-Kwang Yang, Hyuk-Joon Lee, Seong- Ho Kong, Yun-Suhk Suh, Han-Joon Kim.

Figure 1.
Timeline of symptom progression and pathological findings in the stomach of patient POD01 with de novo dementia with Lewy bodies (DLB) in the early gastric cancer-prodromal Parkinson’s disease (EGC-PPD) cohort. A: The red and blue lines indicate the progression of motor symptoms and nonmotor symptoms of patient POD01, respectively. B: Pathologic evaluation of two large slides mounting proximal and distal parts of the full-depth surgical specimens confirmed the absence of alpha-synuclein (AS) accumulation in the stomach of the patient. Calibration bars: pAS = 80 μm; NF = 100 μm. pAS, phosphorylated alpha-synuclein; NF, neurofilament; f/u, follow-up; POD, postoperative delirium.
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