1,098 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
Mauersegler weiter Wege. Mathias Enard: Kompass
No full textAnalysis of the peculiar scientific narrative in the novel of the Prix-Goncourt winning author Mathias Enard
Les commissions électorales en Afrique de l'Ouest
No full text[author: Mathias Hounkpe ; Ismaila Madior Fall]Electronic ed.: Abuja ; Bonn : FES, 201
Paul Bourget, écrivain engagé
No full textPaul Bourget, A committed writer, Yehoshua Mathias.
In the France of the early twentieth century, Paul Bourget's figure is that of a successful novelist who became gradually a «committed author». A monarchist, deeply conservative, passionate defender of religion and the family as the vital bases of the social order, he thus became the bard of the bourgeois ethic faced with the destabilization of modernity.Mathias Yehoshua. Paul Bourget, écrivain engagé. In: Vingtième Siècle, revue d'histoire, n°45, janvier-mars 1995. pp. 14-29
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.]
„Nature must be felt“ – Alexander von Humboldt, pioneer of an ecological worldview and protagonist of „transversal reason“
No full textDer Text erinnert zum 250sten Geburtsjahr an Alexander von Humboldt, ein Vordenker für eine ökologische Sicht der Welt und ein früher Protagonist „transversaler Vernunft“. Er ist als Ideengeber für die „neuen Naturtherapien“, für die Integrative Therapie und für eine ökologische Sicht in der Psychotherapie eine unverzichtbare Quelle. Einige aus dieser Perspektive wichtige Aspekte seines Denkens und Werkes werden aufgezeigt. Er ist ein Referenzautor für transversales und integratives Konzeptualisieren in unserer Zeit.The text commemorates the 250th year of birth of Alexander von Humboldt, a thought leader for an ecological view of the world and an early protagonist of „transversal reason“. He is an indispensable source of ideas for the „new nature therapies“, for integrative therapy and for an ecological viewpoint in psychotherapy. Some important aspects of his thinking and work are shown from this perspective. He is a reference author for transversal and integrative conceptualization in our time.https://www.fpi-publikation.de/gruene-texte/17-2019-petzold-h-g-mathias-wiedemann-u-natur-muss-gefuehlt-werden-alexander-v-humboldt/peerReviewedpublishedVersio
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