Peripheral Sphingolipids as Potential Biomarkers of Parkinson disease Including Sex-Related Differences
Roberto Ortega1, Lena Burbulla3, Izolda Mileva4, Graeme Taylor5, Miroslava Cuperlovic-Culf5, Amanda Glickman6, Mariel Pullman2, Clemens Scherzer7, Deborah Raymond8, Gabriel Miltenyi-Miltenberger9, Andrea Yoo10, William Nichols11, Dimitri Krainc12, Susan Bressman13, Lina Obeid14, Yusuf Hannun14, Steffany Bennett5, Rachel Saunders-Pullman15
1Neurology, Mount Sinai, 2Mount Sinai, 3The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, 4Department of Medicine and Stony Brook Cancer Center, The State University of New York at Stony Brook, 5Neural Regeneration Laboratory, Neural Regeneration Laboratory, Ottawa Institute of Systems Biology, Department of Biochemistry, Microbiology, and Immunology and Department of Chemistry, University of Ottawa, 6UC Denver, 7Brigham and Women'S Hospital/Harvard Medical School, 8Beth Isreal Medical Center, 9Instituto de Medicina Molecular Joao Lobo Antunes, University of Lisbon, 10Mount Sina Beth Israel, 11Cincinnati Children's Hospital Medical Center, 12Northwestern University, 13Mount Sinai Health System, 14Stony Brook, 15Mount Sinai Beth Israel, Neurology, Downtown Union Square
Objective:
Objective: Assessment of glucocerebrosidase pathways to better understand the pathophysiology of sphingolipids in Parkinson Disease (PD) associated with a GBA variant (GBAPD), including sex-specific features.
Background:
Background: Sex-specific differences in both idiopathic PD and GBAPD have been reported. Determining blood-based measures in the glucocerebrosidase pathway, which is perturbed in GBAPD might be useful in understanding these differences.
Design/Methods:
Methods: Tandem mass spectrometry was utilized to assess levels of targeted sphingolipid substrates and products in 109 GBAPD (62 men, 47 women) and 118 controls (50 men, 68 women) evaluated from four major studies (Mount Sinai (Beth Israel), Parkinson Disease Biomarker Program, Harvard Biomarker Study, BioFIND).
Results:
Results: GBAPD had elevated hexosylceramides when compared to controls (mean [SD] 652.6 [188.3] pmol/100 μl plasma vs 586.2 [172.8]; p=0.006), while ceramide was reduced compared to controls (498.5 [118.7] vs 530.6 [110.9]; p=0.036). Very long chain ceramides, in particular, were decreased in GBAPD compared to controls (420.16 [101.58] vs 448.53 [98.68]; p=0.034). Levels of hexosylsphingosine were increased in GBAPD compared controls (0.08 [0.04] vs. 0.07 [0.04]; p=0.001). Sex-specific differences in measured levels were found. While Hexosylceramides were increased in GBAPD compared to controls, this increase was driven by women, but not men. Alternatively, while ceramides and were decreased in GBAPD compared to controls, this decrease was driven by men and not by women. Finally, while levels of hexosylsphingosine were increased in GBAPD compared to controls, this difference was driven by GBAPD men compared controls, but not by GBAPD women compared to controls.
Conclusions:
Conclusion: While there are differences between GBAPD and controls that are detected in plasma, these depend on sex and suggest that men are preferentially shunting from hexosylceramide to hexosylsphingosine whereas women to ceramides. This supports sex-related pathophysiologic differences, and randomization schema for GBA related studies may consider accounting for sex.