Objective
The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory ...challenges. To facilitate trial planning, we characterize its responsiveness (including subitem‐level relations to ataxia severity and patient‐focused outcomes) across a large number of ataxias, and provide first natural history data for several of them.
Methods
Subitem‐level correlation and distribution‐based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia (370 with 2–8 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes.
Results
Although SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA < 25). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions (“static periods”), and fluctuating decreases/increases. All subitems except nose‐finger showed moderate‐to‐strong correlations to activities of daily living, indicating that metric properties—not content validity—limit SARA responsiveness. SARA captured mild‐to‐moderate progression in many genotypes (eg, SYNE1‐ataxia: 0.55 points/yr, ataxia with oculomotor apraxia type 2: 1.14 points/yr, POLG‐ataxia: 1.56 points/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix‐Saguenay, COQ8A‐ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA < 10), it substantially deteriorated in advanced ataxia (SARA > 25; 2.7‐fold sample size). Use of a novel rank‐optimized SARA without subitems finger‐chase and nose‐finger reduces sample sizes by 20 to 25%.
Interpretation
This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ANN NEUROL 2023;94:470–485
Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS ...data to identify novel risk loci and gain further insight into the causes of Parkinson's disease.
We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation.
Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7).
These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data.
The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).
•We studied five polymorphisms previously associated to PD, in PD-patients and healthy controls.•Only two loci (ACMSD/TMEM163 and MAPT) were related with the susceptibility to PD in our population.•A ...suggestive association between ACMSD/TMEM163 and an increased risk of PD was found.•A suggestive association between MAPT and a decreased risk of PD was found.
Recently, 5 previously Parkinson’s disease (PD)-related loci: ACMSD/TMEM163, STK39, MIR4697, SREBF1/RAI1PD and MAPT, have been associated to PD in a Southern Spanish population. However, due to the small sample size of the cohort, this association did not reach genome wide significance. Our aim was to investigate the robustness of this association in a larger and independent cohort from the South of Spain. Variants were genotyped employing TaqMan SNP Genotyping Assay and high resolution melting analysis in 738 PD patients and 1138 healthy controls. Furthermore, a meta-analysis study was carried out with both cohorts. In the replication analysis, only two loci (ACMSD/TMEM163 and MAPT) were replicated with a Bonferroni significance level. In the meta-analysis study no loci reached a genome-wide significance level (P<5xE-8), but a suggestive association (P-value = 1.04E-6) between rs6430538 (ACMSD/TMEM163) and an increased risk of PD was found. In addition, rs9468 (MAPT) was associated with a decreased risk of PD (P-value = 5.70E-7). Our results add further support for the genetic involvement of these two loci in the susceptibility to PD in population from the South of Spain. We believe that our findings will be very useful for future genetic studies on PD.
Peripheral inflammatory immune responses are thought to play a major role in the pathogenesis of Parkinson's disease (PD). The neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic ...inflammation, has been reported to be higher in patients with PD than in healthy controls (HCs). The present study was aimed at determining if the peripheral inflammatory immune response could be influenced by the genetic background of patients with PD. We included a discovery cohort with 222 patients with PD (132 sporadic PD, 44 LRRK2-associated PD (with p.G2019S and p.R1441G variants), and 46 GBA-associated PD), as well as 299 HCs. Demographic and clinical data were recorded. Leukocytes and their subpopulations, and the NLR were measured in peripheral blood. Multivariate lineal regression and post-hoc tests were applied to determine the differences among the groups. Subsequently, a replication study using the Parkinson's Progression Markers Initiative cohort was performed which included 401 patients with PD (281 sPD patients, 66 LRRK2-PD patients, 54 GBA-PD patients) and a group of 174 HCs. Patients with sporadic PD and GBA-associated PD showed a significantly lower lymphocyte count, a non-significantly higher neutrophil count and a significantly higher NLR than HCs. The peripheral inflammatory immune response of patients with LRRK2-associated PD did not differ from HCs. Our study supports the involvement of a peripheral inflammatory immune response in the pathophysiology of sPD and GBA-associated PD. However, this inflammatory response was not found in LRRK2-associated PD, probably reflecting different pathogenic inflammatory mechanisms.
Brain cholesterol metabolism has been described as altered in Parkinson's disease (PD) patients. Serum lipid levels have been widely studied in PD with controversial results among different ...populations and age groups. The present study is aimed at determining if the serum lipid profile could be influenced by the genetic background of PD patients. We included 403 PD patients (342 sporadic PD patients, 30 GBA-associated PD patients, and 31 LRRK2-associated PD patients) and 654 healthy controls (HCs). Total cholesterol, HDL, LDL, and triglycerides were measured in peripheral blood. Analysis of covariance adjusting for sex and age (ANCOVA) and post hoc tests were applied to determine the differences within lipid profiles among the groups. Multivariate ANCOVA revealed significant differences among the groups within cholesterol and LDL levels. GBA-associated PD patients had significantly lower levels of total cholesterol and LDL compared to LRRK2-associated PD patients and HCs. The different serum cholesterol levels in GBA-associated PD might be related to diverse pathogenic mechanisms. Our results support the hypothesis of lipid metabolism disruption as one of the main PD pathogenic mechanisms in patients with GBA-associated PD. Further studies would be necessary to explore their clinical implications.
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