Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease

Lunde, Kristin Aaser; Chung, Janete; Dalen, Ingvild; Pedersen, Kenn Freddy; Lindér, Jan; Domellöf, Magdalena Eriksson; Elgh, Eva; Macleod, Angus; Tzoulis, Charalampos; Larsen, Jan Petter; Tysnes, Ole‐Bjørn; Forsgren, Lars; Counsell, Carl; Alves, Guido; Maple‐Grødem, Jodi

doi:10.1016/j.jalz.2018.04.006

Cited by 24 publications

(44 citation statements)

References 38 publications

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“…32 Our observed association may reflect less severe diffuse α-synuclein pathology in levodoparesponsive patients who develop early MF, but it is a finding that requires further replication in an independent cohort. We observed an increased LID risk in GBA mutation carriers, in line with reports that GBA mutations are associated with more rapid motor progression, 19,33 earlier age at onset, [33][34][35] and possibly earlier DBS surgery. 36 GBA-PD is also generally associated with rapid cognitive decline and earlier dementia, 19,33,34 whereas we found higher baseline MMSE also increased LID risk.…”

Section: Discussionsupporting

confidence: 91%

“…We observed an increased LID risk in GBA mutation carriers, in line with reports that GBA mutations are associated with more rapid motor progression, earlier age at onset, and possibly earlier DBS surgery . GBA‐PD is also generally associated with rapid cognitive decline and earlier dementia, whereas we found higher baseline MMSE also increased LID risk.…”

Section: Discussionsupporting

confidence: 90%

“…GBA‐PD is also generally associated with rapid cognitive decline and earlier dementia, whereas we found higher baseline MMSE also increased LID risk. However, longitudinal studies have shown that GBA status does not determine cognitive status at baseline, and we propose that the GBA association with LID is driven by the more aggressive pathology that tends to characterize this condition.…”

Section: Discussionmentioning

confidence: 99%

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Motor Complications in Parkinson's Disease: 13‐Year Follow‐up of the CamPaIGN Cohort

et al. 2019

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Background Long‐term population‐representative data on motor fluctuations and levodopa‐induced dyskinesias in Parkinson's disease is lacking. Methods The Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) cohort comprises incident PD cases followed for up to 13 years (n = 141). Cumulative incidence of motor fluctuations and levodopa‐induced dyskinesias and risk factors were assessed using Kaplan‐Meyer and Cox regression analyses. Results Cumulative incidence of motor fluctuations and levodopa‐induced dyskinesias was 54.3% and 14.5%, respectively, at 5 years and 100% and 55.7%, respectively, at 10 years. Higher baseline UPDRS‐total and SNCA rs356219(A) predicted motor fluctuations, whereas higher baseline Mini‐mental State Examination and GBA mutations predicted levodopa‐induced dyskinesias. Early levodopa use did not predict motor complications. Both early motor fluctuations and levodopa‐induced dyskinesias predicted reduced mortality in older patients (age at diagnosis >70 years). Conclusions Our data support the hypothesis that motor complications are related to the severity of nigrostriatal pathology rather than early levodopa use and indicate that early motor complications do not necessarily confer a negative prognosis. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Motor Complications in Parkinson's Disease: 13‐Year Follow‐up of the CamPaIGN Cohort

et al. 2019

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“…Interestingly, β-glucocerebrosidase activity is reduced in the cerebrospinal fluid (CSF) of PD patients even if they do not carry any GBA1 mutations [219]. Variants in the GBA gene may be highly useful in the prediction of PD course [220]. Accumulation of glucosyl compounds and cholesterol has attracted most attention as the pathomechanism in GBA mutations/deficiency [221], but changes in ceramide levels cannot be excluded as an important contributing factor [214, 222].…”

Section: The Role Of Bioactive Sphingolipids In Parkinson’s Diseasementioning

confidence: 99%

The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders

et al. 2019

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Bioactive sphingolipids—ceramide, sphingosine, and their respective 1-phosphates (C1P and S1P)—are signaling molecules serving as intracellular second messengers. Moreover, S1P acts through G protein-coupled receptors in the plasma membrane. Accumulating evidence points to sphingolipids' engagement in brain aging and in neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and amyotrophic lateral sclerosis. Metabolic alterations observed in the course of neurodegeneration favor ceramide-dependent pro-apoptotic signaling, while the levels of the neuroprotective S1P are reduced. These trends are observed early in the diseases’ development, suggesting causal relationship. Mechanistic evidence has shown links between altered ceramide/S1P rheostat and the production, secretion, and aggregation of amyloid β/α-synuclein as well as signaling pathways of critical importance for the pathomechanism of protein conformation diseases. Sphingolipids influence multiple aspects of Akt/protein kinase B signaling, a pathway that regulates metabolism, stress response, and Bcl-2 family proteins. The cross-talk between sphingolipids and transcription factors including NF-κB, FOXOs, and AP-1 may be also important for immune regulation and cell survival/death. Sphingolipids regulate exosomes and other secretion mechanisms that can contribute to either the spread of neurotoxic proteins between brain cells, or their clearance. Recent discoveries also suggest the importance of intracellular and exosomal pools of small regulatory RNAs in the creation of disturbed signaling environment in the diseased brain. The identified interactions of bioactive sphingolipids urge for their evaluation as potential therapeutic targets. Moreover, the early disturbances in sphingolipid metabolism may deliver easily accessible biomarkers of neurodegenerative disorders.

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“…Identifying all these variants will strengthen our understanding of the effect of GBA1 variants, and it facilitates recruitment for the upcoming GBA1-targeted trials, hopefully resulting in a first disease-modifying drug for PD. 12 Comparing different countries, 3,4,8,[13][14][15][16][17][18][19][20][21][22][23][24][25][26] the p.E326K variant is reported most frequently in the Netherlands (present study) and Scandinavian countries. 20,24 Table 2 compares the most common GBA1 variants and the p.D140H + p.E326K complex allele in large PD cohorts from single countries that performed full GBA1 ORF sequencing.…”

Section: Discussionmentioning

confidence: 48%

A Large‐Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands

et al. 2020

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Background The most common genetic risk factor for Parkinson's disease known is a damaging variant in the GBA1 gene. The entire GBA1 gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entire GBA1 gene in Parkinson's disease from a single large population. Methods The GBA1 gene was assessed in 3402 Dutch Parkinson's disease patients using next‐generation sequencing. Frequencies were compared with Dutch controls (n = 655). Family history of Parkinson's disease was compared in carriers and noncarriers. Results Fifteen percent of patients had a GBA1 nonsynonymous variant (including missense, frameshift, and recombinant alleles), compared with 6.4% of controls (OR, 2.6; P < 0.001). Eighteen novel variants were detected. Variants previously associated with Gaucher's disease were identified in 5.0% of patients compared with 1.5% of controls (OR, 3.4; P < 0.001). The rarely reported complex allele p.D140H + p.E326K appears to likely be a Dutch founder variant, found in 2.4% of patients and 0.9% of controls (OR, 2.7; P = 0.012). The number of first‐degree relatives (excluding children) with Parkinson's disease was higher in p.D140H + p.E326K carriers (5.6%, 21 of 376) compared with p.E326K carriers (2.9%, 29 of 1014); OR, 2.0; P = 0.022, suggestive of a dose effect for different GBA1 variants. Conclusions Dutch Parkinson's disease patients display one of the largest frequencies of GBA1 variants reported so far, consisting in large part of the mild p.E326K variant and the more severe Dutch p.D140H + p.E326K founder allele. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.

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Association of glucocerebrosidase polymorphisms and mutations with dementia in incident Parkinson's disease

Abstract: GBA variants are of great clinical relevance for the development of dementia in Parkinson's disease, especially due to the relatively higher frequency of these alleles compared with other risk alleles.

Cited by 24 publications

References 38 publications

Motor Complications in Parkinson's Disease: 13‐Year Follow‐up of the CamPaIGN Cohort

Motor Complications in Parkinson's Disease: 13‐Year Follow‐up of the CamPaIGN Cohort

The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer’s Disease and Other Neurodegenerative Disorders

A Large‐Scale Full GBA1 Gene Screening in Parkinson's Disease in the Netherlands

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