Peripheral Sphingolipids as Potential Biomarkers of Parkinson disease Including Sex-Related Differences (P3-11.007)

Abstract

<h3>Objective:</h3> 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. <h3>Background:</h3> 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. <h3>Design/Methods:</h3> 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). <h3>Results:</h3> 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. <h3>Conclusion:</h3> 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. <b>Disclosure:</b> Roberto Ortega has nothing to disclose. Prof. Burbulla has nothing to disclose. Izolda Mileva has nothing to disclose. Mr. Taylor has nothing to disclose. Dr. Cuperlovic-Culf has nothing to disclose. Ms. Glickman has nothing to disclose. The institution of Dr. Pullman has received research support from Empire Clinical Research Investigator Program. Dr. Scherzer has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. The institution of Dr. Scherzer has received research support from NIH. The institution of Dr. Scherzer has received research support from Michael J. Fox Foundation. The institution of Dr. Scherzer has received research support from American Parkinson’s Disease Association. Dr. Scherzer has received intellectual property interests from a discovery or technology relating to health care. The institution of Ms. Raymond has received research support from NIH. Gabriel Miltenyi-Miltenberger has nothing to disclose. Dr. Yoo has received research support from Edmond J Safra Foundation. William Nichols has nothing to disclose. Dr. Krainc has nothing to disclose. The institution of Dr. Bressman has received research support from Michael J Fox Foundation . The institution of Dr. Bressman has received research support from NIH . Lina Obeid has nothing to disclose. Yusuf Hannun, 9207 has nothing to disclose. The institution of Dr. Bennett has received research support from Prevail. The institution of Dr. Saunders-Pullman has received research support from NIH, Bigglesworth Family Foundation, Empire Clinical Research Investigatory Program.