347 research outputs found
Genetic studies of LRRK2 and PINK1 in Parkinson's disease
No full textBackground and objectives
Parkinson’s disease (PD) is a common neurodegenerative disorder affecting 1% of the elderly. The disease causes a significant burden of illness and cost to society. The causes of PD have remained unknown, and the influence of genetic factors used to be controversial. In 2004, several mutations were identified in familial PD within two genes: PINK1 and the novel gene LRRK2. The aims of this thesis were to further investigate genetic, clinical and pathological aspects of these genes in PD and other neurodegenerative disorders causing parkinsonism. Five papers based on data from studies of these genes are included in this thesis.
Methods
- DNA from probands of families with autosomal dominant parkinsonism were sequenced to identify novel mutations in the LRRK2 gene. After the identification of a novel heterozygous LRRK2 mutation, we assessed the frequency of this mutation in a total of 248 families from different populations. We also screened samples of patients with idiopathic PD from three populations (Norway, Ireland, and Poland). Family members of mutation carriers were examined, and analyses of segregation, mutation haplotypes and penetrance were performed (Paper I).
- A clinicogenetic study of PD in Central Norway was initiated several years ago at the Department of Neurology, St. Olav’s University Hospital in Trondheim. We screened 435 Norwegian patients diagnosed with PD and 519 control subjects from this study for the presence of seven known LRRK2 mutations. The clinical presentation of disease was studied in patients with mutations (Paper II).
-A series of 242 patients from a clinicogenetic study of dementia in Central Norway (Trønderbrain) were screened for the presence of seven known pathogenic mutations previously reported in the LRRK2 gene (Paper III).
- We examined several brain banks for cases with clinical or pathological features of parkinsonian disorders. DNA was obtained from frozen brain tissue of cases with parkinsonism, other neurodegenerative disorders and controls (total n=1584) and genotyped for the exon 41 LRRK2 g.6055G>A (G2019S) mutation. Available medical records of mutation carriers were reviewed and neuropathological examination was performed (Paper IV).
- Comprehensive PINK1 mutation analysis was performed in a total of 131 patients from Norway with early-onset parkinsonism (onset =50 years) or familial late-onset PD. Mutations identified were examined in 350 Norwegian control individuals (Paper V).
Results
- We identified a novel heterozygous LRRK2 g.6055G>A mutation (G2019S). Seven of 248 families with autosomal dominant parkinsonism (2.8%) and six of 806 patients with idiopathic PD (0.7%) carried this mutation. All patients with this mutation shared an ancestral haplotype, indicative of a common founder. The mutation segregates with disease (multipoint LOD score 2.41). Penetrance is age dependent, increasing from 17% at age 50 years to 85% at age 70 years (Paper I).
- Ten Norwegian PD patients were found to be heterozygote carriers of the Lrrk2 G2019S mutation. The clinical features included asymmetric resting tremor, bradykinesia, and rigidity with a good response to levodopa and could not be distinguished from idiopathic Parkinson’s disease. No Parkinson’s disease patient carried any of the other LRRK2 mutations (Paper II). We did not identify LRRK2 mutations in our series of dementia patients (Paper III).
- Lrrk2 G2019S was found in 2% (n=8) of the pathologically confirmed PD/Lewy body disease (LBD) cases (n=405). Neuropathological examination showed typical LBD in all cases (Paper IV).
-Heterozygous missense mutations in PINK1 were found in three of 131 patients; homozygous or compound heterozygous mutations were not identified. A parkinsonian phenotype, with asymmetric onset and without atypical features, characterised these patients clinically (Paper V).
Conclusions
We identified a novel mutation in the LRRK2 gene, g.6055G>A (G2019S). This mutation is a relatively common cause of both familial and sporadic PD, and it is found in a number of populations from North America and Europe, including Norway. This specific mutation is today the most prevalent known cause of PD, but seems to be rare in other neurodegenerative disorders.
Clinically, patients with the Lrrk2 G2019S substitution present with a levodopa–responsive parkinsonian syndrome with asymmetric resting tremor, bradykinesia, and rigidity. Both clinically and pathologically LRRK2-associated PD appears to be indistinguishable from idiopathic disease.
PINK1 mutations were rare in our Norwegian population, but heterozygote mutation carriers might be at increased risk for disease.PhD i nevrovitenskapPhD in Neuroscienc
Pseudo-differential operators with isotropic symbols, Wick and anti-Wick operators, and hypoellipticity
No full textWe study the link between ilidos and Wick operators via the Bargmann transform. We deduce a formula for the symbol of the Wick operator in terms of the short-time Fourier transform of the Weyl symbol. This gives characterizations of Wick symbols of ilidos of Shubin type and of infinite order, and results on composition. We prove a series expansion of Wick operators in terms of anti-Wick operators which leads to a sharp Garding inequality and transition of hypoellipticity between Wick and Shubin symbols. Finally we show continuity results for anti-Wick operators, and estimates for the Wick symbols of anti-Wick operators.(c) 2022 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians.
No full textTo discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2×10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33×10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77×10(-9)) and rs3781834 (P = 1.04×10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71×10(-5)) and rs744373 near BIN1 (P = 1.39×10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations
Markers of disease severity are associated with malnutrition in Parkinson's disease
No full textObjective: In Parkinson's disease (PD), commonly reported risk factors for malnutrition in other populations commonly occur. Few studies have explored which of these factors are of particular importance in malnutrition in PD. The aim was to identify the determinants of nutritional status in people with Parkinson's disease (PWP). Methods: Community-dwelling PWP (>18 years) were recruited (n = 125; 73M/52F; Mdn 70 years). Self-report assessments included Beck's Depression Inventory (BDI), Spielberger Trait Anxiety Inventory (STAI), Scales for Outcomes in Parkinson's disease - Autonomic (SCOPA-AUT), Modified Constipation Assessment Scale (MCAS) and Freezing of Gait Questionnaire (FOG-Q). Information about age, PD duration, medications, co-morbid conditions and living situation was obtained. Addenbrooke's Cognitive Examination (ACE-R), Unified Parkinson's Disease Rating Scale (UPDRS) II and UPDRS III were performed. Nutritional status was assessed using the Subjective Global Assessment (SGA) as part of the scored Patient-Generated Subjective Global Assessment (PG-SGA). Results: Nineteen (15%) were malnourished (SGA-B). Median PG-SGA score was 3. More of the malnourished were elderly (84% vs. 71%) and had more severe disease (H&Y: 21% vs. 5%). UPDRS II and UPDRS III scores and levodopa equivalent daily dose (LEDD)/body weight(mg/kg) were significantly higher in the malnourished (Mdn 18 vs. 15; 20 vs. 15; 10.1 vs. 7.6 respectively). Regression analyses revealed older age at diagnosis, higher LEDD/body weight (mg/kg), greater UPDRS III score, lower STAI score and higher BDI score as significant predictors of malnutrition (SGA-B). Living alone and higher BDI and UPDRS III scores were significant predictors of a higher log-adjusted PG-SGA score. Conclusions: In this sample of PWP, the rate of malnutrition was higher than that previously reported in the general community. Nutrition screening should occur regularly in those with more severe disease and depression. Community support should be provided to PWP living alone. Dopaminergic medication should be reviewed with body weight changes
A Bayesian mathematical model of motor and cognitive outcomes in Parkinson's disease.
No full textThere are few established predictors of the clinical course of PD. Prognostic markers would be useful for clinical care and research.To identify predictors of long-term motor and cognitive outcomes and rate of progression in PD.Newly diagnosed PD participants were followed for 7 years in a prospective study, conducted at 55 centers in the United States and Canada. Analyses were conducted in 244 participants with complete demographic, clinical, genetic, and dopamine transporter imaging data. Machine learning dynamic Bayesian graphical models were used to identify and simulate predictors and outcomes. The outcomes rate of cognition changes are assessed by the Montreal Cognitive Assessment scores, and rate of motor changes are assessed by UPDRS part-III.The most robust and consistent longitudinal predictors of cognitive function included older age, baseline Unified Parkinson's Disease Rating Scale (UPDRS) parts I and II, Schwab and England activities of daily living scale, striatal dopamine transporter binding, and SNP rs11724635 in the gene BST1. The most consistent predictor of UPDRS part III was baseline level of activities of daily living (part II). Key findings were replicated using long-term data from an independent cohort study.Baseline function near the time of Parkinson's disease diagnosis, as measured by activities of daily living, is a consistent predictor of long-term motor and cognitive outcomes. Additional predictors identified may further characterize the expected course of Parkinson's disease and suggest mechanisms underlying disease progression. The prognostic model developed in this study can be used to simulate the effects of the prognostic variables on motor and cognitive outcomes, and can be replicated and refined with data from independent longitudinal studies
Correction: Monitoring for myelopathic progression with multiparametric quantitative MRI.
No full text[This corrects the article DOI: 10.1371/journal.pone.0195733.]
A study of Parkinson´s disease and multiple sclerosis omics data to identify molecular disease mechanisms
No full textParkinson´s disease (PD) and multiple sclerosis (MS) are two of the most common complex neurological disorders affecting millions of people worldwide. PD is characterized by the loss of dopaminergic neurons in the midbrain and by the presence of protein aggregates, called Lewy bodies, in many regions of the brain. These pathological hallmarks ultimately cause characteristic motor symptoms and, in later stages of the disease, also cognitive impairment. MS is an autoimmune disease characterized by chronic inflammation and demyelination in the central nervous system that lead to both cognitive and physical deficits. Therefore, both PD and MS present with debilitating symptoms that negatively affect patients´ life. Currently, there is no cure for these diseases, only symptomatic treatment, for PD, and disease modifying therapies, for MS are available. This is due to the still poor understanding of the molecular mechanisms causing these diseases. In the last years, the development of novel technologies has enabled whole genome studies and the identification of several genetic variants associated with increased risk of developing complex diseases such as PD or MS. However, the biological mechanisms behind these associations remain to be elucidated. A central goal of this thesis has been to perform advanced analyses of omics data, i.e RNA-sequencing and quantitative proteomics, for the identification of biological processes implicated in PD and MS that could ultimately be used as targets for the development of novel disease-modifying therapies. By comparing the brain transcriptome of PD patients and neuropathologically healthy donors, we found that gene expression and many related biological processes are highly disease-stage specific, whereas ATP-metabolic processes are involved at all disease stages. Additionally, we linked the expression of MAP4K4 and PHYHIP to genetic and epigenetic factors previously associated with increased risk of PD. Further, we showed that brain gene expression and age-related gene expression can be influenced in a sex-specific manner by both known PD variants and newly identified loci manifesting pleiotropy between PD and sex-specific traits. By doing so, we demonstrated that there is a genetic component to the sex difference observed in PD prevalence. Next, by investigating the proteome of unstimulated and stimulated CD4+ T cells of MS patients and healthy controls, we showed dysregulation in T cell activation in MS samples and identified the Nur77 signaling pathway as potential target for future studies. Collectively, the work presented in this thesis comprises a wide range of analytical methods that permitted the identification of genes, proteins and biological processes involved in PD and MS, but the same analyses methods could be used to study other complex diseases. Furthermore, our studies have identified several genes and biological pathways that could be prioritized in future functional studies enabling a deeper understanding of the molecular mechanisms causing PD and MS and ultimately leading to improved therapeutic options for the patients.
Parkinsons sykdom og multippel sklerose er to av de vanligste komplekse nevrologiske sykdommene. Parkinsons sykdom er preget av tap av dopaminproduserende hjerneceller i midthjernen og av tilstedeværelsen av proteinaggregater, såkalte Lewy-legemer, i mange hjerneregioner. Disse patologiske kjennetegnene forårsaker til slutt motoriske symptomer og, i senere stadier av sykdommen, også kognitiv svikt. Multippel sklerose er en autoimmun sykdom, karakterisert ved kronisk betennelse i sentralnervesystemet. Dette resulterer i demyelinisering av nervefibre som fører til både kognitive og fysiske utfordringer for pasientene. Foreløpig finnes ingen behandling som kan kurere disse sykdommene. I dag finnes det kun sykdomsmodifiserende medikamenter, såkalte bremsemedisiner, for multippel sklerose, mens ved Parkinsons sykdom finnes utelukkende symptombehandling. Mangel på gode medisiner skyldes at vi ikke forstår de molekylære mekanismene som forårsaker disse sykdommene fullt ut. I de siste årene har utviklingen av nye teknologier muliggjort helgenom-studier og identifisering av et stort antall genetiske varianter som er assosiert med økt risiko for å utvikle komplekse sykdommer som Parkinsons sykdom og multippel sklerose. Det gjenstår imidlertid å forstå den biologiske betydningen av disse genetiske funnene. Hovedmålet med denne oppgaven har vært å benytte avanserte metoder for analyser av «omics» data (RNA sekvensering og kvantitativ proteomikk) for å bedre forståelsen av sykdomsprosesser i Parkinsons sykdom og multippel sklerose. Gener og biologiske reaksjonsveier som er identifisert i disse studiene kan i fremtiden være angrepspunkter for utvikling av nye sykdomsmodifiserende terapier. Vi har sammenliknet transkriptomet i hjernevev til Parkinsons sykdom pasienter med transkriptomet i hjernevev fra nevropatologisk friske givere. Vi har funnet en rekke biologiske prosesser som var sykdomsstadier spesifikke, mens ATP-avhengige metabolske prosesser ser ut til å være involvert i alle sykdomsstadier i Parkinsons sykdom. I tillegg har vi funnet at genuttrykket av MAP4K4 og PHYHIP er koblet til genetiske og epigenetiske faktorer som tidligere var vist å være assosiert med Parkinsons sykdom. Det er velkjent at Parkinsons sykdom er vanligere hos menn enn kvinner. Vi har gjennomført avanserte genetiske analyser av risiko for Parkinsons sykdom og kjønnsspesifikke egenskaper. Vi har med disse analysene vist at det er en genetisk komponent til kjønnsforskjellen som er observert i forekomsten av Parkinsons sykdom. I multippel sklerose pasienter undersøkte vi proteomet til ustimulerte og stimulerte CD4+ T-celler fra blod og sammenliknet med celler fra friske kontroller. Det var en anrikning av proteiner kodet for av mottakelighetsgener for multippel sklerose blant proteiner som endret ekspresjon ved T celleaktivering, og vi fant at Nur77-signalveien var deregulert i prøver fra multippel sklerose pasienter. Dette arbeidet omfatter et bredt spekter av analytiske metoder som resulterte i identifisering av gener, proteiner og biologiske prosesser som er involvert sykdomsprosessene ved Parkinsons sykdom og multippel sklerose. Tilsvarende analysemetode kan brukes til studier av andre komplekse sykdommer. I vår studie har vi identifisert gener og biologiske reaksjonsveier som bør prioriteres i fremtidige funksjonelle studier. På den måten kan man bedre forståelsen av de bakenforliggende molekylære sykdomsmekanismene ved Parkinsons sykdom og multippel sklerose, og dette kan være et utgangspunkt for å identifisere nye terapeutiske angrepspunkt.publishedVersio
Structured approach to design of diagnostic test evaluation studies for chronic progressive infections in animals
No full textDiagnostic test evaluations (DTEs) for chronic infections are challenging because a protracted incubation period has to be considered in the design of the DTE, and the adverse effects of infection may be widespread and progressive over an animal's entire life. Frequently, the specific purpose of the test is not formally considered when a test is evaluated. Therefore, the result is often a DTE where test sensitivity and specificity estimates are biased, either because of problems with establishing the true infection status or because the test detects another aspect of the infection (and analyte) than originally intended. The objective of this paper is to outline a structured approach to the design and conduct of a DTE for diagnostic tests used for chronic infections in animals, and intended for different purposes. We describe the process from reflections about test purpose and the underlying target condition through considerations of the pathogenesis, and specification of a practical case definition, which can subsequently be used in the DTE for the specific purpose. The process is illustrated by two examples of Mycobacterium avium subsp. paratuberculosis (MAP) infections in cattle. MAP infections are chronic and can result in different adverse effects at different time points during the incubation period. The description provides input on the process and deductive reasoning which are integral parts to develop a high-quality design of a DTE for chronic infectious diseases.ID: S0378113511000381; M3: Article; Accession Number: S0378113511000381; Author: Søren Saxmose Nielsen (a, b, ⁎); Author: Nils Toft (a, b); Author: Ian Andrew Gardner (a, b); Affiliation: Department of Large Animal Sciences, Faculty of Life Sciences, University of Copenhagen, Grønnegårdsvej 8, DK-1870 Frederiksberg C, Denmark; Affiliation: Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, CA 95616, USA; Keyword: Chronic infectious diseases; Keyword: Design strategy; Keyword: Diagnostic test evaluation; Keyword: Paratuberculosis; Number of Pages: 11; Language: English
Opportunities in Advanced Space Transportation Systems
No full textFuture Programs
Session Chairman: Robert F. Freitag, Deputy Director, Advanced Programs, NASA Headquarters
Session Organizer: Paul D. Toft, Sciences, Technology and Applications Office, NASA, Kennedy Space Cente
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