Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson's disease enrolled in PPMI

Young Eun Huh; Hyejung Park; Ming Sum Ruby Chiang; Idil Tuncali; Ganqiang Liu; Joseph J Locascio; Julia Shirvan; Samantha J Hutten; Melissa S Rotunno; Catherine Viel; Lamya S Shihabuddin; Bing Wang; Sergio Pablo Sardi; Clemens R Scherzer

doi:10.1038/s41531-021-00241-3

Glucosylceramide in cerebrospinal fluid of patients with GBA-associated and idiopathic Parkinson's disease enrolled in PPMI

NPJ Parkinsons Dis. 2021 Nov 22;7(1):102. doi: 10.1038/s41531-021-00241-3.

Authors

Young Eun Huh^{1

2

3

4}, Hyejung Park⁵, Ming Sum Ruby Chiang⁶, Idil Tuncali^{1

2

3}, Ganqiang Liu^{1

2

3

7}, Joseph J Locascio^{1

2

3

8}, Julia Shirvan^{1

8}, Samantha J Hutten⁹, Melissa S Rotunno⁶, Catherine Viel⁶, Lamya S Shihabuddin⁶, Bing Wang⁵, Sergio Pablo Sardi^#⁶, Clemens R Scherzer^#^{10

11

12

13}

Affiliations

¹ Center for Advanced Parkinson Research, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, 02115, USA.
² Precision Neurology Program, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, 02115, USA.
³ Department of Neurology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
⁴ Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, 13496, South Korea.
⁵ NA Pre-Development Sciences, Sanofi, Waltham, MA, 02451, USA.
⁶ Rare and Neurologic Diseases Therapeutic Area, Sanofi, Framingham, MA, 01701, USA.
⁷ School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China.
⁸ Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁹ The Michael J. Fox Foundation for Parkinson's Research, New York, NY, 10163, USA.
¹⁰ Center for Advanced Parkinson Research, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, 02115, USA. [email protected].
¹¹ Precision Neurology Program, Harvard Medical School, Brigham & Women's Hospital, Boston, MA, 02115, USA. [email protected].
¹² Department of Neurology, Brigham and Women's Hospital, Boston, MA, 02115, USA. [email protected].
¹³ Department of Neurology, Massachusetts General Hospital, Boston, MA, 02114, USA. [email protected].

^# Contributed equally.

Abstract

Protein-coding variants in the GBA gene modulate susceptibility and progression in ~10% of patients with Parkinson's disease (PD). GBA encodes the β-glucocerebrosidase enzyme that hydrolyzes glucosylceramide. We hypothesized that GBA mutations will lead to glucosylceramide accumulation in cerebrospinal fluid (CSF). Glucosylceramide, ceramide, sphingomyelin, and lactosylceramide levels were measured by liquid chromatography-tandem mass spectrometry in CSF of 411 participants from the Parkinson's Progression Markers Initiative (PPMI) cohort, including early stage, de novo PD patients with abnormal dopamine transporter neuroimaging and healthy controls. Forty-four PD patients carried protein-coding GBA variants (GBA-PD) and 227 carried wild-type alleles (idiopathic PD). The glucosylceramide fraction was increased (P = 0.0001), and the sphingomyelin fraction (a downstream metabolite) was reduced (P = 0.0001) in CSF of GBA-PD patients compared to healthy controls. The ceramide fraction was unchanged, and lactosylceramide was below detection limits. We then used the ratio of glucosylceramide to sphingomyelin (the GlcCer/SM ratio) to explore whether these two sphingolipid fractions altered in GBA-PD were useful for stratifying idiopathic PD patients. Idiopathic PD patients in the top quartile of GlcCer/SM ratios at baseline showed a more rapid decline in Montreal Cognitive Assessment scores during longitudinal follow-up compared to those in the lowest quartile with a P-value of 0.036. The GlcCer/SM ratio was negatively associated with α-synuclein levels in CSF of PD patients. This study highlights glucosylceramide as a pathway biomarker for GBA-PD patients and the GlcCer/SM ratio as a potential stratification tool for clinical trials of idiopathic PD patients. Our sphingolipids data together with the clinical, imaging, omics, and genetic characterization of PPMI will contribute a useful resource for multi-modal biomarkers development.

Abstract

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