Single-cell peripheral immunoprofiling of lewy body and Parkinson's disease in a multi-site cohort

Thanaphong Phongpreecha; Kavita Mathi; Brenna Cholerton; Eddie J Fox; Natalia Sigal; Camilo Espinosa; Momsen Reincke; Philip Chung; Ling-Jen Hwang; Chandresh R Gajera; Eloise Berson; Amalia Perna; Feng Xie; Chi-Hung Shu; Debapriya Hazra; Divya Channappa; Jeffrey E Dunn; Lucas B Kipp; Kathleen L Poston; Kathleen S Montine; Holden T Maecker; Nima Aghaeepour; Thomas J Montine

doi:10.1186/s13024-024-00748-2

Single-cell peripheral immunoprofiling of lewy body and Parkinson's disease in a multi-site cohort

Mol Neurodegener. 2024 Aug 1;19(1):59. doi: 10.1186/s13024-024-00748-2.

Authors

Thanaphong Phongpreecha^{1

2

3}, Kavita Mathi⁴, Brenna Cholerton¹, Eddie J Fox¹, Natalia Sigal⁴, Camilo Espinosa^{2

3

5}, Momsen Reincke^{2

3

5}, Philip Chung², Ling-Jen Hwang³, Chandresh R Gajera¹, Eloise Berson^{1

2

3}, Amalia Perna¹, Feng Xie^{2

3

5}, Chi-Hung Shu^{2

3

5}, Debapriya Hazra^{2

3

5}, Divya Channappa⁶, Jeffrey E Dunn⁶, Lucas B Kipp⁶, Kathleen L Poston⁶, Kathleen S Montine¹, Holden T Maecker⁴, Nima Aghaeepour^{2

3

5}, Thomas J Montine⁷

Affiliations

¹ Department of Pathology, Stanford University, Stanford, CA, USA.
² Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, USA.
³ Department of Biomedical Data Science, Stanford University, Stanford, CA, USA.
⁴ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
⁵ Department of Pediatrics, Stanford University, Stanford, CA, USA.
⁶ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
⁷ Department of Pathology, Stanford University, Stanford, CA, USA. tmontine@stanford.edu.

Abstract

Background: Multiple lines of evidence support peripheral organs in the initiation or progression of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson's Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). However, the potential contribution of the peripheral immune response to LBD remains unclear. This study aims to characterize peripheral immune responses unique to participants with LBD at single-cell resolution to highlight potential biomarkers and increase mechanistic understanding of LBD pathogenesis in humans.

Methods: In a case-control study, peripheral mononuclear cell (PBMC) samples from research participants were randomly sampled from multiple sites across the United States. The diagnosis groups comprise healthy controls (HC, n = 159), LBD (n = 110), Alzheimer's disease dementia (ADD, n = 97), other neurodegenerative disease controls (NDC, n = 19), and immune disease controls (IDC, n = 14). PBMCs were activated with three stimulants (LPS, IL-6, and IFNa) or remained at basal state, stained by 13 surface markers and 7 intracellular signal markers, and analyzed by flow cytometry, which generated 1,184 immune features after gating.

Results: The model classified LBD from HC with an AUROC of 0.87 ± 0.06 and AUPRC of 0.80 ± 0.06. Without retraining, the same model was able to distinguish LBD from ADD, NDC, and IDC. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations under specific activation. The immune responses characteristic for LBD were not associated with other common medical conditions related to the risk of LBD or dementia, such as sleep disorders, hypertension, or diabetes.

Conclusions and relevance: Quantification of PBMC immune response from multisite research participants yielded a unique pattern for LBD compared to HC, multiple related neurodegenerative diseases, and autoimmune diseases thereby highlighting potential biomarkers and mechanisms of disease.

Keywords: Alzheimer’s Disease; Biomarkers; Dementia; Inflammation; Parkinson’s Disease.

Publication types

Multicenter Study

MeSH terms

Aged
Aged, 80 and over
Biomarkers / metabolism
Case-Control Studies
Cohort Studies
Female
Humans
Leukocytes, Mononuclear* / immunology
Leukocytes, Mononuclear* / metabolism
Lewy Bodies / metabolism
Lewy Bodies / pathology
Lewy Body Disease* / immunology
Male
Middle Aged
Parkinson Disease* / immunology
Parkinson Disease* / metabolism
Single-Cell Analysis / methods

Substances

Biomarkers