Quality of Life since Pre-Ataxic Phases of Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.

Although health-related quality of life (HRQoL) has been increasingly valued in healthcare and in clinical trials, there is scarce information about it in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD). This study describes the HRQoL results obtained from ataxic SCA3/MJD subjects, and their non-ataxic offspring included in the BIGPRO (Biomarkers and genetic modifiers in a study of presymptomatic and symptomatic SCA3/MJD carriers) study. Demographic data, clinical scales, and HRQoL instruments EQ-5D-3L and SF-36 were collected. Subjects at 50% risk were genotyped in a double-blind manner. The time left until the onset of the disease was estimated for mutation carriers with a SARA < 3 and combined with disease duration of ataxic subjects (TimeToAfterOnset). Analyses were performed using PASW Statistics version 18.0, R version 4.0.0, and G*Power 3.1, and p < 0.05 was considered statistically significant. Twenty-three ataxic carriers, 33 pre-ataxic carriers, and 21 controls were enrolled. Significant differences between ataxic carriers and controls were seen in EQ-VAS, EQ-5D Index, and in some domains of EQ-5D-3L and SF-36. EQ-5D Index showed the best effect size between ataxic and controls (Cohen's d = 2.423). Stepwise changes were seen in pre-ataxic subjects, although not statistically significant. TimeToAfterOnset correlated with EQ-5D Index, EQ-VAS, and SF-36 Physical functioning, Role Physical, Pain, and General Health. EQ-5D Index and EQ-VAS correlated with clinical scales in the ataxic group. These results suggest that HRQoL worsens among carriers since pre-ataxic stages and that they might encompass the underlying disease process. In this cohort, SF-36 Physical Functioning, SF-36 General health, and especially EQ-5D Index and EQ-VAS were the best HRQoL instruments to be used as ancillary evidence to support biological and social meanings for future interventions.

Variants in Genes of Calpain System as Modifiers of Spinocerebellar Ataxia Type 3 Phenotype.

Calpain-mediated proteolysis has been proposed to modulate the pathogenesis of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), a disorder due to a CAG repeat expansion (CAGexp) at ATXN3. We aimed to investigate if single-nucleotide polymorphisms (SNPs) at calpain gene CAPN2 and at calpastatin gene CAST modulate the age at onset (AO) and disease progression in SCA3/MJD. A total of 287 SCA3/MJD symptomatic subjects (151 families) were included. AO was analyzed and controlled by the CAG repeat length of expanded allele and family. Candidate polymorphisms were chosen based on the literature and on a priori criteria. The CAG repeat length and SNPs were genotyped according to standard methods. AO of carriers of AA and AG + GGrs1559085 genotypes in CAST and with the median value of 75 repeats at the expanded allele were 34.23 (33.07-35.38) and 36.42 years (34.50-38.34), respectively (p = 0.049, mixed model treating the expanded CAG repeat size as fixed effect and family as random effect). Carriers of haplotype Crs27852/Grs1559085 had mean AO of 37.23 (12.76) and 33.42 years (12.20) (p = 0.047, Student's t test). Our data suggest an association between allele Grs1559085 and haplotype Crs27852/Grs1559085 at CAST and variations in the AO of SCA3/MJD subjects, independent from the effects of the CAGexp and family. The present results support the potential role of calpain cleavage pathway over modulation of SCA3/MJD phenotype.

Pre-ataxic Changes of Clinical Scales and Eye Movement in Machado-Joseph Disease: BIGPRO Study.

BACKGROUND: The pathological burden of spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), accumulates before the beginning of symptoms. Our study aims at validating biomarkers for disease progression since pre-ataxic periods. We report on baseline findings of clinical scales and oculomotor neurophysiology. METHODS: Ataxic (Scale for the Assessment and Rating of Ataxia > 2.5) and at 50% risk subjects were included. The latter were subdivided into noncarriers, pre-ataxic carriers near (PAN), or pre-ataxic carriers far from (PAFF) ataxia onset (AO), with 4 years from the predicted age at onset being the cutoff. The subjects were assessed by Neurological Examination Score for Spinocerebellar Ataxia (NESSCA), International Cooperative Ataxia Rating Scale (ICARS), Inventory of Non-Ataxic Signs (INAScount), Composite Cerebellar Functions Score and SCA Functional Index, and video-oculography, including the regression slope of vestibulo-ocular reflex gain (VORr), main sequence of volitional and reflexive vertical saccades, slow-phase velocity of central and gaze-evoked (SPV-GE) nystagmus, and vertical pursuit gain. Correction for multiple comparisons was performed; the threshold for statistical significance was P < 0.05. RESULTS: A total of 35 ataxic, 14 PAN, 24 PAFF, and 22 noncarriers were included. All variables showed significant differences between groups and correlated to time to onset or time after onset, among all 73 SCA3/MJD carriers; none significantly changed with age in controls. NESSCA, ICARS, INAScount, VORr, main sequence of volitional saccades, and SPV-GE not only distinguished PAN from controls but also correlated with time left to AO. CONCLUSIONS: Clinical scales and video-oculography variables were already altered in pre-ataxic SCA3/MJD carriers and worsened with time. NESSCA, ICARS, INAScount, VORr, main sequence of vertical volitional saccades, and SPV-GE are good candidates to measure preclinical changes in SCA3/MJD. © 2021 International Parkinson and Movement Disorder Society.

Influence of genetic, biological and pharmacological factors on levodopa dose in Parkinson's disease.

AIM: Levodopa is first-line treatment of Parkinson's disease motor symptoms but, dose response is highly variable. Therefore, the aim of this study was to determine how much levodopa dose could be explained by biological, pharmacological and genetic factors. PATIENTS & METHODS: A total of 224 Parkinson's disease patients were genotyped for SV2C and SLC6A3 polymorphisms by allelic discrimination assays. Comedication, demographic and clinical data were also assessed. RESULTS: All variables with p < 0.20 were included in a multiple regression analysis for dose prediction. The final model explained 23% of dose variation (F = 11.54; p < 0.000001). CONCLUSION: Although a good prediction model was obtained, it still needs to be tested in an independent sample to be validated.

Val66Met BDNF polymorphism is associated with Parkinson's disease cognitive impairment.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Besides characteristic PD motor features, the disease has important non-motor characteristics such as cognitive impairment. The role of genetic factors in cognitive impairment associated with PD is still unclear. In this study, we examined whether BDNF Val66Met was associated with impaired cognition in Parkinson's disease. One hundred and seventy five patients with a clinical diagnosis of Parkinson's disease were included. Global cognitive abilities of the patients were measured by the Mini-Mental State Examination (MMSE). Poisson Regression models were used to test for association between 66Met carriers and cognitive impairment controlling for covariates. Carriers of at least one BDNF 66Met allele presented a higher prevalence of cognitive impairment (p=0.005 RR=1.45 IC=95% [1.1-1.8]). These results suggest a role for BDNF Val66Met polymorphism on cognitive impairment in PD.

Is there a role for ADORA2A polymorphisms in levodopa-induced dyskinesia in Parkinson's disease patients?

AIM: Levodopa is first line treatment of Parkinson's disease (PD). However, its use is associated with the presence of motor fluctuations and dyskinesias. In recent years, adenosine A2A receptor (A2AR) is rising as a therapeutic target for PD. The aim of the present study was to investigate whether ADORA2A is associated with levodopa adverse effects. PATIENTS & METHODS: Two hundred and eight PD patients on levodopa therapy were investigated. rs2298383 and rs3761422 at the ADORA2A gene were genotyped by allelic discrimination assays. RESULTS: A trend for association was observed for both polymorphism and diplotypes with dyskinesia. CONCLUSION: The present results should be considered as positive preliminary evidence. Further studies are needed to determine the association between ADORA2A and dyskinesia. Original submitted 3 December 2014; Revision submitted 13 February 2015.

DRD2 haplotype is associated with dyskinesia induced by levodopa therapy in Parkinson's disease patients.

AIM: Dyskinesia and motor fluctuation are frequent and serious complications of chronic levodopa therapy in patients with Parkinson's disease. Since genetic factors could play a role in determining the occurrence of these problems, the aim of the present study was to investigate whether possible functional polymorphisms among DRD2 and ANKK1 genes are associated with the risk of developing dyskinesia and motor fluctuations in Parkinson's disease patients. PATIENTS & METHODS: One hundred and ninety nine patients in treatment with levodopa were genotyped for the -141CIns/Del, rs2283265, rs1076560, C957T, TaqIA and rs2734849 polymorphisms at the DRD2/ANKK1 gene region. RESULTS: Carriers of the TTCTA haplotype showed an increased risk for the presence of dyskinesia (p = 0.007; 1.538 [95% CI: 1.126-2.101]). CONCLUSION: Our data suggest an influence of the DRD2/ANKK1 gene region on levodopa-induced dyskinesia.