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- Brolin, Kajsa, et al.
(författare)
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Insights on Genetic and Environmental Factors in Parkinson's Disease from a Regional Swedish Case-Control Cohort
- 2022
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Ingår i: Journal of Parkinson's Disease. - 1877-718X. ; 12:1, s. 153-171
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Risk factors for Parkinson's disease (PD) can be more or less relevant to a population due to population-specific genetic architecture, local lifestyle habits, and environmental exposures. Therefore, it is essential to study PD at a local, regional, and continental scale in order to increase the knowledge on disease etiology.OBJECTIVE: We aimed to investigate the contribution of genetic and environmental factors to PD in a new Swedish case-control cohort.METHODS: PD patients (n = 929) and matched population-based controls (n = 935) from the southernmost county in Sweden were included in the cohort. Information on environmental exposures was obtained using questionnaires at inclusion. Genetic analyses included a genome-wide association study (GWAS), haplotype assessment, and a risk profile analysis using cumulative genetic risk scores.RESULTS: The cohort is a representative PD case-control cohort (64% men, mean age at diagnosis = 67 years, median Hoehn and Yahr score 2.0), in which previously reported associations between PD and environmental factors, such as tobacco, could be confirmed. We describe the first GWAS of PD solely composed of PD patients from Sweden, and confirm associations to well-established risk alleles in SNCA. In addition, we nominate an unconfirmed and potentially population-specific genome-wide significant association in the PLPP4 locus (rs12771445).CONCLUSION: This work provides an in-depth description of a new PD case-control cohort from southern Sweden, giving insights into environmental and genetic risk factors for PD in the Swedish population.
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- Garcia-Moreno, Hector, et al.
(författare)
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Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3
- 2022
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 29:8, s. 2439-2452
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND PURPOSE: Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures.METHODS: To evaluate total tau (t-tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCHL1) and neurofilament light-chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD-1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t-tau and phosphorylated tau (p-tau181 ). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t-tau levels.RESULTS: Plasma t-tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non-Ataxia Signs was associated with t-tau in ataxic patients (p = 0.004). Pre-ataxic carriers showed higher cerebrospinal fluid t-tau and p-tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t-tau was elevated in MJDTg mice compared to wild-type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001).CONCLUSION: Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.
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- Gorcenco, Sorina, et al.
(författare)
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Patients’ Perspective in Hereditary Ataxia
- 2022
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Ingår i: Cerebellum. - : Springer Science and Business Media LLC. - 1473-4222.
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary ataxia represents a heterogeneous group of rare disorders with the chronic progression of motor symptoms that often become debilitating. Many forms include additional neurological, cognitive, or other symptoms. Most of these disorders lack specific treatment. We aimed to investigate aspects of patients’ quality of life, experiences, and expectations. Patients with a diagnosis of hereditary ataxia were identified from our center’s diagnostic register, direct referrals, and from a patient organization. We designed a questionnaire with 32 multiple-choice or open-ended questions on disability and impairment of daily life activities, the perceived effect of symptomatic and supportive therapies, coping strategies, and how they used and experienced various sources of information about their neurological disease. We also included the EQ-5D-3L quality-of-life instrument. Results were analyzed statistically for gender, age, and groups with and without a genetic diagnosis, and were compared to published data from the general population. Seventy-five patients returned the questionnaire. Patients reported considerable disease-related disability and impairment and had significantly lower quality-of-life scores than the general population. Physiotherapy and support from family or friends were important for patients’ overall well-being. Patients with a genetic diagnosis had a lower average age at onset and felt more well-informed about their disease than patients without a genetic diagnosis. Patients used internet sources but relied primarily on their doctors to obtain information about their disease. Our study provides insights into hereditary ataxia patients’ experiences that can lead to improvements in medical and nursing care for these patients.
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- Liu, Hui, et al.
(författare)
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Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors
- 2022
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Ingår i: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 92:2, s. 270-278
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.METHODS: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses.RESULTS: A higher polygenic resilience score was associated with a lower risk for PD (β = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.INTERPRETATION: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278.
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- Ygland Rödström, Emil, et al.
(författare)
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Serum Neurofilament Light Chain as a Marker of Progression in Parkinson's Disease : Long-Term Observation and Implications of Clinical Subtypes
- 2022
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Ingår i: Journal of Parkinson's Disease. - 1877-7171. ; 12:2, s. 571-584
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Tidskriftsartikel (refereegranskat)abstract
- Background: Biochemical and clinical biomarkers correlate with progression rate and disease severity in Parkinson's disease (PD) but are not sufficiently studied in late PD. Objective: To examine how serum neurofilament light chain (S-NfL) alone or combined with clinical classifications predicts PD outcome in later disease stages. Methods: Eighty-five patients with 7.9±5.1 years of PD duration were included in an observational cohort. Clinical scores were obtained at two separate examinations 8.2±2.0 years apart. S-NfL levels were determined with single molecule array (SiMoA). Five predefined disease progression milestones were assessed. After affirming combination potential of S-NfL and either of two clinical classifications, three combined models were constructed based on these factors and age at onset in different combinations. Results: S-NfL levels showed significant hazard ratios for four out of five disease progression milestones: walking-aid usage (HR 3.5; 95% CI 1.4-8.5), nursing home living (5.1; 2.1-12.5), motor end-stage (6.2; 2.1-17.8), and death (4.1; 1.7-9.7). Higher S-NfL levels were associated with lower ability in activities of daily living and poorer cognition at baseline and/or at follow-up. Combined models showed significantly improved area under receiver operating characteristic curves (0.77-0.91) compared to S-NfL levels alone (0.68-0.71) for predicting the five disease milestones. Conclusion: S-NfL levels stratified patients according to their likelihood to reach clinically relevant progression milestones during this long-term observational study. S-NfL alone reflected motor and social outcomes in later stages of PD. Combining S-NfL with clinical factors was possible and exploratory combined models improved prognostic accuracy.
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