Showing papers by "Jan O. Aasly published in 2022"
TL;DR: Although non-randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition and advises that DBS candidates be screened for G BA mutations as part of the pre-surgical decision-making process.
Abstract: OBJECTIVE
To compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and non-carriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD).
METHODS
Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and non-carriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status.
RESULTS
Data were available for 367 subjects: 58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects who were longitudinal followed (range 36 to 60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/year more than GBA-DBS- subjects (95% CI = -2.35, -1.69), 1.71 points/year more than GBA+DBS- subjects (95% CI = -2.14, -1.28), and 1.49 points/year more than GBA-DBS+ subjects (95% CI = -1.80, -1.18).
INTERPRETATION
Although non-randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the pre-surgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS and alternative options may be considered. This article is protected by copyright. All rights reserved.
28 citations
TL;DR: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN‐DBS) in Parkinson disease.
Abstract: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN‐DBS) in Parkinson disease.
27 citations
TL;DR: In this article , the authors highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men, but it is unclear whether this association is causal or explained by reverse causation or confounding.
Abstract: Previous prospective studies highlighted dairy intake as a risk factor for Parkinson's disease (PD), particularly in men. It is unclear whether this association is causal or explained by reverse causation or confounding.
12 citations
TL;DR: It is shown that combining SAA and ELISA assays is more promising diagnostic tool than SAA alone, providing information about the disease stage by correlating with clinical measures of disease severity.
Abstract: Background and Objectives Robust biomarkers that can mirror Parkinson disease (PD) are of great significance. In this study, we present a novel approach to investigate disease-associated α-synuclein (αSyn) aggregates as biomarkers of PD clinical stage. Methods We combined both seed amplification assay (SAA) and ELISA to provide a quantitative test readout that reflects the clinical severity of patients with PD. To attain this goal, we initially explored the potential of our test using 2 sets of human brain homogenates (pilot and validation sets) and then verified it with 2 independent human CSF cohorts; discovery (62 patients with PD and 34 controls) and validation (49 patients with PD and 48 controls) cohorts. Results We showed that oligomers-specific ELISA robustly quantified SAA end product from patients with PD or dementia with Lewy bodies with high sensitivity and specificity scores (100%). Analysis also demonstrated that seeding activity could be detected earlier with oligomeric ELISA as the test readout rather than SAA alone. Of more importance, multiplexing the assays provided robust information about the patients' clinical disease stage. In the discovery cohort, levels of CSF-seeded αSyn oligomers correlated with the severity of the clinical symptoms of PD as measured by the Unified Parkinson Disease Rating Scale (UPDRS) motor (r = 0.58, p < 0.001) and Hoehn and Yahr (H&Y) scores (r = 0.43, p < 0.01). Similar correlations were observed in the validation cohort between the concentrations of CSF-seeded αSyn oligomers and both UPDRS motor (r = 0.50, p < 0.01) and H&Y scores (r = 0.49, p < 0.01). At 20 hours, receiver operating characteristic curves analysis yielded a sensitivity of 91.9% (95% CI 82.4%–96.5%) and a specificity of 85.3% (95% CI 69.8%–93.5%), with an area under the curve of 0.969 for CSF-seeded αSyn oligomers differentiating those with PD from controls in the discovery CSF cohort, whereas, a sensitivity of 80.7% (95% CI 69.1%–88.5%), a specificity of 76.5% (95% CI 60.0%–87.5%), and area under the curve of 0.860 were generated with thioflavin T maximum intensity of fluorescence at the same time point. Discussion We showed that combining SAA and ELISA assays is a more promising diagnostic tool than SAA alone, providing information about the disease stage by correlating with clinical measures of disease severity. Classification of Evidence This study provides Class III evidence that CSF-seeded αSyn oligomers can accurately discriminate patients with PD and normal controls and CSF-seeded αSyn oligomers levels correlate with PD severity.
11 citations
TL;DR: A meta-analysis was performed on the COURAGE-PD dataset as mentioned in this paper , which revealed the role of the TMEM175 variant as a genetic determinant of the age at onset (AAO) of Parkinson disease.
Abstract: Background and Objectives Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. Methods A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). Results The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10−8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10−9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10−8). Discussion Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
5 citations
TL;DR: discuss prophylactic with presymptomatic CSF1R pathogenic variant carriers and suggest a strategy to select carriers based on prior history rather than type of carrier.
Abstract: discuss prophylactic with presymptomatic CSF1R pathogenic variant carriers.
3 citations
TL;DR: Cognitive Effects of Deep Brain Stimulation in GBA-Related Parkinson’s Disease and its implications for treatment and relapse are studied.
Abstract: Reply to: Cognitive Effects of Deep Brain Stimulation in GBA-Related Parkinson’s Disease Gian Pal, MD, MS , Graziella Mangone, MD, PhD, Bichun Ouyang, MD, Debra Ehrlich, MD, Rachel Saunders-Pullman, MD, Susan Bressman, MD, Roy N. Alcalay, MD, MS, Karen Marder, MD, Jan Aasly, MD, M. Maral Mouradian, MD, Sharlet Anderson, PhD, Bryan Bernard, PhD, Glenn Stebbins, PhD, Sepehr Sani, MD, Mitra Afshari, MD, MPH, Leo Verhagen, MD, PhD, Rob M.A. de Bie, MD, PhD, Tom Foltynie, MD, PhD, MRCP, Deborah Hall, MD, PhD , Jean-Christophe Corvol, MD, PhD, and Christopher G. Goetz, MD 2
2 citations
TL;DR: Two studies that examined the interaction between HLA‐DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions.
Abstract: Two studies that examined the interaction between HLA‐DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions.
2 citations
TL;DR: In this article , the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid was described and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson's Disease.
Abstract: Parkinson’s Disease is the most common neurodegenerative movement disorder globally, with prevalence increasing. There is an urgent need for new therapeutics which are disease-modifying rather than symptomatic. Mitochondrial dysfunction is a well-documented mechanism in both sporadic and familial Parkinson’s Disease. Furthermore, ursodeoxycholic acid (UDCA) has been identified as a bile acid which leads to increased mitochondrial function in multiple in vitro and in vivo models of Parkinson’s Disease. Here, we describe the synthesis of novel C-nor-D-homo bile acid derivatives and the 12-hydroxy-methylated derivative of lagocholic acid (7) and their biological evaluation in fibroblasts from patients with either sporadic or LRRK2 mutant Parkinson’s Disease. These compounds boost mitochondrial function to a similar level or above that of UDCA in many assays; notable, however, is their ability to boost mitochondrial function to a higher level and at lower concentrations than UDCA specifically in the fibroblasts from LRRK2 patients. Our study indicates that novel bile acid chemistry could lead to the development of more efficacious bile acids which increase mitochondrial function and ultimately cellular health at lower concentrations proving attractive potential novel therapeutics for Parkinson’s Disease.
1 citations
TL;DR: Three novel loci, including thromboxane synthesis, vesicular peptidergic neurotransmitter release and the A2A adenosine receptor, may represent new candidates for disease modification in PD.
Abstract: Background: There are 90 genetic risk variants for Parkinson's disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. Methods: We studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to motor progression, defined by reaching Hoehn and Yahr stage 3 or greater, cognitive impairment as defined by serial cognitive examination, and death (mortality). Findings: There was a robust effect of the APOE {epsilon}4 allele on mortality and cognitive impairment in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity or expression quantitative trait loci data. One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10-10). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31x10-8). A genomic variant associated with the expression of ADORA2A, encoding the A2A adenosine receptor, was associated with motor progression (HR=4.83 [95% CI 2.89 to 8.08], p-value=1.94x10-9). Only the non-Gaucher disease causing GBA PD risk variant E326K, of the known PD risk variants, was associated with progression in PD. Interpretation: We report three novel loci associated with PD progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release and the A2A adenosine receptor may represent new candidates for disease modification in PD.
TL;DR: This study refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus and opens a new direction for the development of treatments to delay the onset of PD.
Abstract: Background and Objectives Considerable heterogeneity exists in the literature concerning genetic determinants of the age at onset (AAO) of Parkinson disease (PD), which could be attributed to a lack of well-powered replication cohorts. The previous largest genome-wide association studies (GWAS) identified SNCA and TMEM175 loci on chromosome (Chr) 4 with a significant influence on the AAO of PD; these have not been independently replicated. This study aims to conduct a meta-analysis of GWAS of PD AAO and validate previously observed findings in worldwide populations. Methods A meta-analysis was performed on PD AAO GWAS of 30 populations of predominantly European ancestry from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (COURAGE-PD) Consortium. This was followed by combining our study with the largest publicly available European ancestry dataset compiled by the International Parkinson Disease Genomics Consortium (IPDGC). Results The COURAGE-PD Consortium included a cohort of 8,535 patients with PD (91.9%: Europeans and 9.1%: East Asians). The average AAO in the COURAGE-PD dataset was 58.9 years (SD = 11.6), with an underrepresentation of females (40.2%). The heritability estimate for AAO in COURAGE-PD was 0.083 (SE = 0.057). None of the loci reached genome-wide significance (p < 5 × 10−8). Nevertheless, the COURAGE-PD dataset confirmed the role of the previously published TMEM175 variant as a genetic determinant of the AAO of PD with Bonferroni-corrected nominal levels of significance (p < 0.025): (rs34311866: β(SE)COURAGE = 0.477(0.203), pCOURAGE = 0.0185). The subsequent meta-analysis of COURAGE-PD and IPDGC datasets (Ntotal = 25,950) led to the identification of 2 genome-wide significant association signals on Chr 4, including the previously reported SNCA locus (rs983361: β(SE)COURAGE+IPDGC = 0.720(0.122), pCOURAGE+IPDGC = 3.13 × 10−9) and a novel BST1 locus (rs4698412: β(SE)COURAGE+IPDGC = −0.526(0.096), pCOURAGE+IPDGC = 4.41 × 10−8). Discussion Our study further refines the genetic architecture of Chr 4 underlying the AAO of the PD phenotype through the identification of BST1 as a novel AAO PD locus. These findings open a new direction for the development of treatments to delay the onset of PD.
TL;DR: In this paper , the authors assess the frequency of autonomic symptoms among Faroese PD patients compared to a control group, using the Scales for Outcome in Parkinson's Disease - Autonomic (SCOPA-AUT), and determine the relationship between autonomic and motor symptoms in PD patients using the Unified Parkinsońs Disease Rating Scale Part III (UPDRS) and Hoehn and Yahr Scale (H&Y).
TL;DR: A patient with Parkinson's disease (PD) who was examined as a candidate for DBS was initially rejected due to extensive brain calcifications. Upon second opinion and planning of trajectories she underwent successful surgery as discussed by the authors .