ORCID Profile
0000-0002-1921-9542
Current Organisation
Sun Yat-Sen University
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Publisher: Springer Science and Business Media LLC
Date: 30-10-2023
Publisher: Springer Science and Business Media LLC
Date: 06-05-2021
Publisher: Wiley
Date: 10-09-2022
DOI: 10.1002/MDS.29213
Abstract: Cognitive decline in Parkinson's disease (PD) is prevalent, insidious, and burdensome during the progression of the disease. We aimed to find transcriptome-wide biomarkers in blood to predict cognitive decline and identify patients at high risk with cognitive impairment in PD. We carried out joint modeling analysis to characterize transcriptome-wide longitudinal gene expression and its association with the progression of mild cognitive impairment (MCI) in PD patients. The average time-dependent area under the curves (AUCs) were used for evaluating the accuracy of the significant joint models. A cognitive survival score (CogSs) derived from joint model was leveraged to predict the occurrence of MCI. All predicting models were built in a discovery cohort with 272 patients and replicated in an independent cohort with 177 patients. We identified five longitudinal varied expression of transcripts that were significantly associated with MCI progression in patients with PD. The most significant transcript IGLC1 joint model accurately predicted the progression of MCI in PD patients in the discovery and replication cohorts (average time-dependent AUCs >0.82). The CogSs derived from the optimal IGLC1 joint model had a high accuracy at early study stage in both cohorts (AUC ≥0.91). Our transcriptome-wide joint modeling analysis uncovered five blood-based transcripts related to cognitive decline in PD. The joint models will serve as a useful resource for clinicians and researchers to screen PD patients with high risk of development of cognitive impairment and pave the path for Parkinson's personalized medicine. © 2022 International Parkinson and Movement Disorder Society.
Publisher: Wiley
Date: 10-2020
DOI: 10.1002/MDS.28312
Publisher: Springer Science and Business Media LLC
Date: 22-11-2021
DOI: 10.1038/S41531-021-00241-3
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.
Publisher: Wiley
Date: 02-02-2022
DOI: 10.1002/MDS.28932
Abstract: Common genetic variance in apolipoprotein E ( APOE ), β‐glucocerebrosidase ( GBA ), microtubule‐associated protein tau ( MAPT ), and α‐synuclein ( SNCA ) has been linked to cognitive decline in Parkinson's disease (PD), although studies have yielded mixed results. To evaluate the effect of genetic variants in APOE , GBA , MAPT , and SNCA on cognitive decline and risk of dementia in a pooled analysis of six longitudinal, non‐selective, population‐based cohorts of newly diagnosed PD patients. 1002 PD patients, followed for up to 10 years (median 7.2 years), were genotyped for at least one of APOE ‐ε4, GBA mutations, MAPT H1 / H2 , or SNCA rs356219. We evaluated the effect of genotype on the rate of cognitive decline (Mini‐Mental State Examanation, MMSE ) using linear mixed models and the development of dementia (diagnosed using standardized criteria) using Cox regression multiple comparisons were accounted for using Benjamini−Hochberg corrections. Carriers of APOE ‐ε4 (n = 281, 29.7%) and GBA mutations (n = 100, 10.3%) had faster cognitive decline and were at higher risk of progression to dementia ( APOE ‐ε4, HR 3.57, P 0.001 GBA mutations, HR 1.76, P = 0.001) than non‐carriers. The risk of cognitive decline and dementia (HR 5.19, P 0.001) was further increased in carriers of both risk genotypes (n = 23). No significant effects were observed for MAPT or SNCA rs356219. GBA and APOE genotyping could improve the prediction of cognitive decline in PD , which is important to inform the clinical trial selection and potentially to enable personalized treatment © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Publisher: Oxford University Press (OUP)
Date: 08-11-2022
Abstract: Mitochondria are a culprit in the onset of Parkinson’s disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson’s disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10−6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A& G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56–0.81) and P = 2.46 × 10−5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson’s disease over time.
No related grants have been discovered for Ganqiang Liu.