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Sökning: WFRF:(Riess Olaf)

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  • Krüger, Rejko, et al. (författare)
  • A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease
  • 2011
  • Ingår i: Neurobiology of Aging. - : Elsevier. - 1558-1497. ; 32:3, s. 9-548
  • Tidskriftsartikel (refereegranskat)abstract
    • High-profile studies have provided conflicting results regarding the involvement of the Omi/HtrA2 gene in Parkinson's disease (PD) susceptibility. Therefore, we performed a large-scale analysis of the association of common Omi/HtrA2 variants in the Genetic Epidemiology of Parkinson's disease (GEO-PD) consortium. GEO-PD sites provided clinical and genetic data including affection status, gender, ethnicity, age at study, age at examination (all subjects); age at onset and family history of PD (patients). Genotyping was performed for the five most informative SNPs spanning the Omi/HtrA2 gene in approximately 2-3 kb intervals (rs10779958, rs2231250, rs72470544, rs1183739, rs2241028). Fixed as well as random effect models were used to provide summary risk estimates of Omi/HtrA2 variants. The 20 GEO-PD sites provided data for 6378 cases and 8880 controls. No overall significant associations for the five Omi/HtrA2 SNPs and PD were observed using either fixed effect or random effect models. The summary odds ratios ranged between 0.98 and 1.08 and the estimates of between-study heterogeneity were not large (non-significant Q statistics for all 5 SNPs; I(2) estimates 0-28%). Trends for association were seen for participants of Scandinavian descent for rs2241028 (OR 1.41, p=0.04) and for rs1183739 for age at examination (cut-off 65 years; OR 1.17, p=0.02), but these would not be significant after adjusting for multiple comparisons and their Bayes factors were only modest. This largest association study performed to define the role of any gene in the pathogenesis of Parkinson's disease revealed no overall strong association of Omi/HtrA2 variants with PD in populations worldwide.
  • Siebzehnrübl, Florian A., et al. (författare)
  • Early postnatal behavioral, cellular, and molecular changes in models of Huntington disease are reversible by HDAC inhibition
  • 2018
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Acad Sciences. - 0027-8424 .- 1091-6490. ; 115:37, s. 8765-8774
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by expanded CAG repeats in the huntingtin gene (HTT). Although mutant HTT is expressed during embryonic development and throughout life, clinical HD usually manifests later in adulthood. A number of studies document neurodevelopmental changes associated with mutant HTT, but whether these are reversible under therapy remains unclear. Here, we identify very early behavioral, molecular, and cellular changes in preweaning transgenic HD rats and mice. Reduced ultrasonic vocalization, loss of prepulse inhibition, and increased risk taking are accompanied by disturbances of dopaminergic regulation in vivo, reduced neuronal differentiation capacity in subventricular zone stem/progenitor cells, and impaired neuronal and oligodendrocyte differentiation of mouse embryo-derived neural stem cells in vitro. Interventional treatment of this early phenotype with the histone deacetylase inhibitor (HDACi) LBH589 led to significant improvement in behavioral changes and markers of dopaminergic neurotransmission and complete reversal of aberrant neuronal differentiation in vitro and in vivo. Our data support the notion that neurodevelopmental changes contribute to the prodromal phase of HD and that early, presymptomatic intervention using HDACi may represent a promising novel treatment approach for HD.
  • Bode, Felix J., et al. (författare)
  • Sex differences in a transgenic rat model of Huntington's disease: decreased 17 beta-estradiol levels correlate with reduced numbers of DARPP32(+) neurons in males
  • 2008
  • Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906. ; 17:17, s. 2595-2609
  • Tidskriftsartikel (refereegranskat)abstract
    • Recent clinical studies have highlighted that female sex hormones represent potential neuroprotective mediators against damage caused by acute and chronic brain diseases. This evidence has been confirmed by experimental studies documenting the protective role of female sex hormones both in vitro and in vivo, although these studies did not specifically focus on Huntington's disease (HD). We therefore investigated the onset and course of HD in female and male transgenic (tg) HD (CAG(n51)) and control rats across age and focused on three aspects: (i) behavioral and physiological alterations (energy expenditure, home-cage activity, emotional disturbance and motor dysfunction), (ii) morphological markers (numbers and characteristics of striatal DARPP32(+) medium-sized spiny neurons (MSNs) and dopamine receptor autoradiography) and (iii) peripheral sex hormone levels as well as striatal estrogen receptor expression. Independent of their sex, tgHD rats exhibited increased levels of food intake, elevated home-cage activity scores and anxiolytic-like behavior, whereas only males showed an impairment of motor function. In line with the latter finding, loss and atrophy of DARPP32(+) MSNs were apparent only in male tgHD rats. This result was associated with a decreased striatal dopamine D1 receptor density and lower plasma levels of 17 beta-estradiol at the age of 14 months. As DARPP32(+) MSNs expressed both alpha-and beta-estrogen receptors and showed a correlation between cell numbers and 17 beta-estradiol levels, our findings suggest sex-related differences in the HD phenotype pointing to a substantial neuroprotective effect of sex hormones and opening new perspectives on the therapy of HD.
  • Clemensson, Erik Karl Håkan, et al. (författare)
  • The BACHD rat model of Huntington disease shows slowed learning in a Go/No-Go-like test of visual discrimination
  • 2019
  • Ingår i: Behavioural Brain Research. - : Elsevier. - 0166-4328 .- 1872-7549. ; 359, s. 116-126
  • Tidskriftsartikel (refereegranskat)abstract
    • Huntington disease is a hereditary neurodegenerative disease, in which patients display a broad range of clinical symptoms. Among these, impaired inhibitory control has been noted. The BACHD rat is a recently developed and established transgenic animal model for Huntington disease, and characterizing the presence of Huntington disease-like behavioural phenotypes in these animals is of importance. Prior studies have indicated that BACHD rats suffer from impaired inhibitory control, although further studies are necessary to fully understand the scope and specific nature of these phenotypes. In the current study, BACHD rats were trained to perform a Go/No-Go-like test of visual discrimination, akin to behavioural tests that have revealed suspected response inhibition impairments in Huntington disease patients. The results indicate that although BACHD rats showed a slow rate of learning to inhibit responses on No-Go trials, once they had learned to handle the basic discrimination, they had an unchanged ability to withhold lever responses during extended periods of time. This suggests that BACHD rats have specific impairments when applying inhibitory control to a new or changed situation. The findings are in line with previous studies of BACHD rats and support the continued use and characterization of this animal model.
  • Gainotti, Sabina, et al. (författare)
  • Improving the informed consent process in international collaborative rare disease research : effective consent for effective research
  • 2016
  • Ingår i: European Journal of Human Genetics. - 1018-4813 .- 1476-5438. ; 24:9, s. 1248-1254
  • Tidskriftsartikel (refereegranskat)abstract
    • The increased international sharing of data in research consortia and the introduction of new technologies for sequencing challenge the informed consent (IC) process, adding complexities that require coordination between research centres worldwide. Rare disease consortia present special challenges since available data and samples may be very limited. Thus, it is especially relevant to ensure the best use of available resources but at the same time protect patients' right to integrity. To achieve this aim, there is an ethical duty to plan in advance the best possible consent procedure in order to address possible ethical and legal hurdles that could hamper research in the future. Therefore, it is especially important to identify key core elements (CEs) to be addressed in the IC documents for international collaborative research in two different situations: (1) new research collections (biobanks and registries) for which information documents can be created according to current guidelines and (2) established collections obtained without IC or with a previous consent that does not cover all CEs. We propose here a strategy to deal with consent in these situations. The principles have been applied and are in current practice within the RD-Connect consortia - a global research infrastructure funded by the European Commission Seventh Framework program but forward looking in terms of issues addressed. However, the principles established, the lessons learned and the implications for future research are of direct relevance to all internationally collaborative rare-disease projects.
  • Gispert, Suzana, et al. (författare)
  • The modulation of Amyotrophic Lateral Sclerosis risk by Ataxin-2 intermediate polyglutamine expansions is a specific effect
  • 2012
  • Ingår i: Neurobiology of Disease. - : Elsevier. - 0969-9961 .- 1095-953X. ; 45:1, s. 356-361
  • Tidskriftsartikel (refereegranskat)abstract
    • Full expansions of the polyglutamine domain (polyQ >= 34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27 <= polyQ <= 33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30 <= polyQ <= 35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor. (C) 2011 Elsevier Inc. All rights reserved.
  • Hansson, Mats G., et al. (författare)
  • The risk of re-identification versus the need to identify individuals in rare disease research
  • 2016
  • Ingår i: European Journal of Human Genetics. - 1018-4813 .- 1476-5438. ; 24:11, s. 1553-1558
  • Tidskriftsartikel (refereegranskat)abstract
    • There is a growing concern in the ethics literature and among policy makers that de-identification or coding of personal data and biospecimens is not sufficient for protecting research subjects from privacy invasions and possible breaches of confidentiality due to the possibility of unauthorized re-identification. At the same time, there is a need in medical science to be able to identify individual patients. In particular for rare disease research there is a special and well-documented need for research collaboration so that data and biosamples from multiple independent studies can be shared across borders. In this article, we identify the needs and arguments related to de-identification and re-identification of patients and research subjects and suggest how the different needs may be balanced within a framework of using unique encrypted identifiers.
  • Huebener, Jeannette, et al. (författare)
  • Automated Behavioral Phenotyping Reveals Presymptomatic Alterations in a SCA3 Genetrap Mouse Model
  • 2012
  • Ingår i: Journal of Genetics and Genomics. - : Elsevier. - 1673-8527. ; 39:6, s. 287-299
  • Tidskriftsartikel (refereegranskat)abstract
    • Characterization of disease models of neurodegenerative disorders requires a systematic and comprehensive phenotyping in a highly standardized manner. Therefore, automated high-resolution behavior test systems such as the homecage based LabMaster system are of particular interest. We demonstrate the power of the automated LabMaster system by discovering previously unrecognized features of a recently characterized atxn3 mutant mouse model. This model provided neurological symptoms including gait ataxia, tremor, weight loss and premature death at the age of 12 months usually detectable just 2 weeks before the mice died. Moreover, using the LabMaster system we were able to detect hypoactivity in presymptomatic mutant mice in the dark as well as light phase. Additionally, we analyzed inflammation, immunological and hematological parameters, which indicated a reduced immune defense in phenotypic mice. Here we demonstrate that a detailed characterization even of organ systems that are usually not affected in SCA3 is important for further studies of pathogenesis and required for the preclinical therapeutic studies.
  • Mascalzoni, Deborah, et al. (författare)
  • International Charter of principles for sharing bio-specimens and data
  • 2015
  • Ingår i: European Journal of Human Genetics. - 1018-4813 .- 1476-5438. ; 23, s. 721-728
  • Tidskriftsartikel (refereegranskat)abstract
    • There is a growing international agreement on the need to provide greater access to research data and bio-specimen collections to optimize their long-term value and exploit their potential for health discovery and validation. This is especially evident for rare disease research. Currently, the rising value of data and bio-specimen collections does not correspond with an equal increase in data/sample-sharing and data/sample access. Contradictory legal and ethical frameworks across national borders are obstacles to effective sharing: more specifically, the absence of an integrated model proves to be a major logistical obstruction. The Charter intends to amend the obstacle by providing both the ethical foundations on which data sharing should be based, as well as a general Material and Data Transfer Agreement (MTA/DTA). This Charter is the result of a careful negotiation of different stakeholders' interest and is built on earlier consensus documents and position statements, which provided the general international legal framework. Further to this, the Charter provides tools that may help accelerate sharing. The Charter has been formulated to serve as an enabling tool for effective and transparent data and bio-specimen sharing and the general MTA/DTA constitutes a mechanism to ensure uniformity of access across projects and countries, and may be regarded as a consistent basic agreement for addressing data and material sharing globally. The Charter is forward looking in terms of emerging issues from the perspective of a multi-stakeholder group, and where possible, provides strategies that may address these issues.
  • Rolfs, Arndt, et al. (författare)
  • Acute Cerebrovascular Disease in the Young The Stroke in Young Fabry Patients Study
  • 2013
  • Ingår i: Stroke: a journal of cerebral circulation. - : American Heart Association. - 1524-4628. ; 44:2, s. 340-349
  • Tidskriftsartikel (refereegranskat)abstract
    • Background and Purpose-Strokes have especially devastating implications if they occur early in life; however, only limited information exists on the characteristics of acute cerebrovascular disease in young adults. Although risk factors and manifestation of atherosclerosis are commonly associated with stroke in the elderly, recent data suggests different causes for stroke in the young. We initiated the prospective, multinational European study Stroke in Young Fabry Patients (sifap) to characterize a cohort of young stroke patients. Methods-Overall, 5023 patients aged 18 to 55 years with the diagnosis of ischemic stroke (3396), hemorrhagic stroke (271), transient ischemic attack (1071) were enrolled in 15 European countries and 47 centers between April 2007 and January 2010 undergoing a detailed, standardized, clinical, laboratory, and radiological protocol. Results-Median age in the overall cohort was 46 years. Definite Fabry disease was diagnosed in 0.5% (95% confidence interval, 0.4%-0.8%; n=27) of all patients; and probable Fabry disease in additional 18 patients. Males dominated the study population (2962/59%) whereas females outnumbered men (65.3%) among the youngest patients (18-24 years). About 80.5% of the patients had a first stroke. Silent infarcts on magnetic resonance imaging were seen in 20% of patients with a first-ever stroke, and in 11.4% of patients with transient ischemic attack and no history of a previous cerebrovascular event. The most common causes of ischemic stroke were large artery atherosclerosis (18.6%) and dissection (9.9%). Conclusions-Definite Fabry disease occurs in 0.5% and probable Fabry disease in further 0.4% of young stroke patients. Silent infarcts, white matter intensities, and classical risk factors were highly prevalent, emphasizing the need for new early preventive strategies.
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