| 1. |
- Manning, Alisa, et al.
(author)
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A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk
- 2017
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In: Diabetes. - : AMER DIABETES ASSOC. - 0012-1797 .- 1939-327X. ; 66:7, s. 2019-2032
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Journal article (peer-reviewed)abstract
- To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
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| 2. |
- Blauw, Hylke M, et al.
(author)
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A large genome scan for rare CNVs in amyotrophic lateral sclerosis
- 2010
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In: Human Molecular Genetics. - : Oxford Journals. - 0964-6906 .- 1460-2083. ; 19:20, s. 4091-4099
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Journal article (peer-reviewed)abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease selectively affecting motor neurons in the brain and spinal cord. Recent genome-wide association studies (GWASs) have identified several common variants which increase disease susceptibility. In contrast, rare copy-number variants (CNVs), which have been associated with several neuropsychiatric traits, have not been studied for ALS in well-powered study populations. To examine the role of rare CNVs in ALS susceptibility, we conducted a CNV association study including over 19,000 individuals. In a genome-wide screen of 1875 cases and 8731 controls, we did not find evidence for a difference in global CNV burden between cases and controls. In our association analyses, we identified two loci that met our criteria for follow-up: the DPP6 locus (OR = 3.59, P = 6.6 × 10(-3)), which has already been implicated in ALS pathogenesis, and the 15q11.2 locus, containing NIPA1 (OR = 12.46, P = 9.3 × 10(-5)), the gene causing hereditary spastic paraparesis type 6 (HSP 6). We tested these loci in a replication cohort of 2559 cases and 5887 controls. Again, results were suggestive of association, but did not meet our criteria for independent replication: DPP6 locus: OR = 1.92, P = 0.097, pooled results: OR = 2.64, P = 1.4 × 10(-3); NIPA1: OR = 3.23, P = 0.041, pooled results: OR = 6.20, P = 2.2 × 10(-5)). Our results highlight DPP6 and NIPA1 as candidates for more in-depth studies. Unlike other complex neurological and psychiatric traits, rare CNVs with high effect size do not play a major role in ALS pathogenesis.
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| 3. |
- Buervenich, Silvia, et al.
(author)
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A rare truncating mutation in ADH1C (G78Stop) shows significant association with Parkinson disease in a large international sample.
- 2005
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In: Archives of neurology. - : American Medical Association (AMA). - 0003-9942. ; 62:1, s. 74-8
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Journal article (peer-reviewed)abstract
- BACKGROUND: Alcohol dehydrogenases (ADHs) may be involved in the pathogenesis of neurodegenerative disorders because of their multiple roles in detoxification pathways and retinoic acid synthesis. In a previous study, significant association of an ADH class IV allele with Parkinson disease (PD) was found in a Swedish sample. PATIENTS: The previously associated single-nucleotide polymorphism plus 12 further polymorphisms in the ADH cluster on human chromosome 4q23 were screened for association in an extension of the original sample that now included 123 Swedish PD patients and 127 geographically matched control subjects. A rare nonsense single-nucleotide polymorphism in ADH1C (G78stop, rs283413) was identified in 3 of these patients but in no controls. To obtain sufficient power to detect a possible association of this rare variant with disease, we screened a large international sample of 1076 PD patients of European ancestry and 940 matched controls. RESULTS: The previously identified association with an ADH class IV allele remained significant (P<.02) in the extended Swedish study. Furthermore, in the international collaboration, the G78stop mutation in ADH1C was found in 22 (2.0%) of the PD patients but only in 6 controls (0.6%). This association was statistically significant (chi(2)(1) = 7.5; 2-sided P = .007; odds ratio, 3.25 [95% confidence interval, 1.31-8.05]). In addition, the G78stop mutation was identified in 4 (10.0%) of 40 Caucasian index cases with PD with mainly hereditary forms of the disorder. CONCLUSION: Findings presented herein provide further evidence for mutations in genes encoding ADHs as genetic risk factors for PD.
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| 4. |
- Hampel, Harald, et al.
(author)
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Lithium trial in Alzheimer's disease : a randomized, single-blind, placebo-controlled, multicenter 10-week study
- 2009
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In: Journal of Clinical Psychiatry. - 0160-6689 .- 1555-2101. ; 70:6, s. 922-931
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer's disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in Alzheimer's disease. In the current study, we tested the effect of short-term lithium treatment in patients with Alzheimer's disease. METHOD: A total of 71 patients with mild Alzheimer's disease (Mini-Mental State Examination score > or = 21 and < or = 26) were successfully randomly assigned to placebo (N = 38) or lithium treatment (N = 33) at 6 academic expert memory clinics. The 10-week treatment included a 6-week titration phase to reach the target serum level of lithium (0.5-0.8 mmol/L). The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and GSK-3 activity in lymphocytes. Secondary outcome measures were CSF concentration of total tau and beta-amyloid(1-42) (Abeta(1-42)), plasma levels of Abeta(1-42), Alzheimer's Disease Assessment Scale (ADAS)-Cognitive summary scores, MMSE, and Neuropsychiatric Inventory (NPI). Patients were enrolled in the study from November 2004 to July 2005. RESULTS: No treatment effect on GSK-3 activity or CSF-based biomarker concentrations (P > .05) was observed. Lithium treatment did not lead to change in global cognitive performance as measured by the ADAS-Cog subscale (P = .11) or in depressive symptoms. CONCLUSIONS: The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer's disease target population.
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| 5. |
- Koellensperger, Martin, et al.
(author)
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Presentation, Diagnosis, and Management of Multiple System Atrophy in Europe: Final Analysis of the European Multiple System Atrophy Registry
- 2010
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In: Movement Disorders. - : Wiley. - 0885-3185. ; 25:15, s. 2604-2612
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Journal article (peer-reviewed)abstract
- Multiple system atrophy (MSA) is a Parkinson's Disease (PD)-like alpha-synucleinopathy clinically characterized by dysautonomia, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination. We aimed to determine whether the clinical presentation of MSA as well as diagnostic and therapeutic strategies differ across Europe and Israel. In 19 European MSA Study Group centres all consecutive patients with a clinical diagnosis of MSA were recruited from 2001 to 2005. A standardized minimal data set was obtained from all patients. Four-hundred thirty-seven MSA patients from 19 centres in 10 countries were included. Mean age at onset was 57.8 years; mean disease duration at inclusion was 5.8 years. According to the consensus criteria 68% were classified as parkinsonian type (MSA-P) and 32% as cerebellar type (MSA-C) (probable MSA: 72%, possible MSA: 28%). Symptomatic dysautonomia was present in almost all patients, and urinary dysfunction (83%) more common than symptomatic orthostatic hypotension (75%). Cerebellar ataxia was present in 64%, and parkinsonism in 87%, of all cases. No significant differences in the clinical presentation were observed between the participating countries. In contrast, diagnostic work up and therapeutic strategies were heterogeneous. Less than a third of patients with documented orthostatic hypotension or neurogenic bladder disturbance were receiving treatment. This largest clinical series of MSA patients reported so far shows that the disease presents uniformly across Europe. The observed differences in diagnostic and therapeutic management including lack of therapy for dysautonomia emphasize the need for future guidelines in these areas. (C) 2010 Movement Disorder Society
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| 6. |
- Koellensperger, Martin, et al.
(author)
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Red flags for multiple system atrophy
- 2008
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In: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 23:8, s. 1093-1099
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Journal article (peer-reviewed)abstract
- The clinical diagnosis Of Multiple system atrophy (MSA) is fraught with difficulty and there are no pathognomonic features to discriminate the parkinsonian variant (MSA-P) from Parkinson's disease (PD). Besides the poor response to levodopa, and the additional presence of pyramidal or cerebellar signs (ataxia) or autonomic failure as major diagnostic criteria, certain other clinical features known as "red flags" or warning signs may raise the clinical suspicion of MSA. To study the diagnostic role of these features in MSA-P versus PD patients, a standardized red flag check list (RFCL) developed by the European MSA Study Group (EMSA-SG) was administered to 57 patients with probable MSA-P and 116 patients with probable PD diagnosed according to established criteria. Those red flags with a specifity over 95% were selected for further analysis. Factor analysis was applied to reduce the number of red flags. The resulting set was then applied to 17 patients with possible MSA-P who on follow-up fulfilled criteria of probable MSA-P. Red flags were grouped into related categories. With two or more of six red flag categories present specificity was 98.3% and sensitivity was 84.2% in our cohort. When applying these criteria to patients with possible MSA-P, 76.5% of them would have been correctly diagnosed as probable MSA-P 15.9 (+/- 7.0) months earlier than with the Consensus criteria alone. We propose a combination of two out of six red flag categories as additional diagnostic criteria for probable MSA-P. (C) 2008 Movement Disorder Society.
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| 7. |
- Leyhe, Thomas, et al.
(author)
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Increase of BDNF serum concentration in lithium treated patients with early Alzheimer's disease
- 2009
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In: Journal of Alzheimer's Disease. - 1387-2877 .- 1875-8908. ; 16:3, s. 649-656
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Journal article (peer-reviewed)abstract
- Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). In experimental investigations, lithium induces brain-derived neurotrophic factor (BDNF). Recent studies have found a decrease of BDNF in the serum and brains of AD patients with potentially consecutive lack of neurotrophic support. We assessed the influence of a lithium treatment on BDNF serum concentration in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. In AD patients treated with lithium, a significant increase of BDNF serum levels, and additionally a significant decrease of ADAS-Cog sum scores in comparison to placebo-treated patients, were found. Diminution of cognitive impairment was inversely correlated with lithium serum concentration. Upregulation of BDNF might be part of a neuroprotective effect of lithium in AD patients. The results of the present investigation encourage performing studies with longer treatment phases to observe potential positive long-term effects of lithium in AD patients.
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| 8. |
- Qiu, Chunjing, et al.
(author)
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A strong mitigation scenario maintains climate neutrality of northern peatlands
- 2022
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In: One Earth. - : Elsevier BV. - 2590-3330 .- 2590-3322. ; 5:1, s. 86-97
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Journal article (peer-reviewed)abstract
- Northern peatlands store 300–600 Pg C, of which approximately half are underlain by permafrost. Climate warming and, in some regions, soil drying from enhanced evaporation are progressively threatening this large carbon stock. Here, we assess future CO2 and CH4 fluxes from northern peatlands using five land surface models that explicitly include representation of peatland processes. Under Representative Concentration Pathways (RCP) 2.6, northern peatlands are projected to remain a net sink of CO2 and climate neutral for the next three centuries. A shift to a net CO2 source and a substantial increase in CH4 emissions are projected under RCP8.5, which could exacerbate global warming by 0.21°C (range, 0.09–0.49°C) by the year 2300. The true warming impact of peatlands might be higher owing to processes not simulated by the models and direct anthropogenic disturbance. Our study highlights the importance of understanding how future warming might trigger high carbon losses from northern peatlands.
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| 9. |
- Roberts, Sean, et al.
(author)
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CHIELD: the causal hypotheses in evolutionary linguistics database
- 2020
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In: Journal of Language Evolution. - : Oxford University Press (OUP). - 2058-458X. ; 5:2, s. 101-120
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Journal article (peer-reviewed)abstract
- Language is one of the most complex of human traits. There are many hypotheses about how it originated, what factors shaped its diversity, and what ongoing processes drive how it changes. We present the Causal Hypotheses in Evolutionary Linguistics Database (CHIELD, https://chield.excd.org/), a tool for expressing, exploring, and evaluating hypotheses. It allows researchers to integrate multiple theories into a coherent narrative, helping to design future research. We present design goals, a formal specification, and an implementation for this database. Source code is freely available for other fields to take advantage of this tool. Some initial results are presented, including identifying conflicts in theories about gossip and ritual, comparing hypotheses relating population size and morphological complexity, and an author relation network.
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| 10. |
- Straten, Guido, et al.
(author)
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Influence of Lithium Treatment on GDNF Serum and CSF Concentrations in Patients with Early Alzheimer΄s Disease
- 2011
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In: Current Alzheimer research. - : Bentham Science Publishers Ltd.. - 1567-2050 .- 1875-5828. ; 8:8, s. 853-859
-
Journal article (peer-reviewed)abstract
- Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer΄s disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebocontrolled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.
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| 11. |
- Wenning, Gregor K., et al.
(author)
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The natural history of multiple system atrophy: a prospective European cohort study
- 2013
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In: Lancet Neurology. - 1474-4465. ; 12:3, s. 264-274
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Journal article (peer-reviewed)abstract
- Background Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA. Methods Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test. Findings 141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56.2 (SD 8.4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9.8 years (95% CI 8.1-11.4). The parkinsonian variant of MSA (hazard ratio [HR] 2.08,95% CI 1.09-3.97; p=0.026) and incomplete bladder emptying (HR 2.10,1.02-4.30; p=0.044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9.4 [SD 5.9]), 74% (12.9 [8.5]), and 57% (21.9 [11.9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0.68, 0.5-0.9; p=0.006) and absent levodopa response (OR 3.4, 1.1-10.2; p=0.03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power. Interpretation Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.
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| 12. |
- Auer, Martin, et al.
(author)
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Automatic Displacement and Strain measuring in the Aorta from dynamic electrocardiographically-gated Computed Tomographic Angiography
- 2010
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Conference paper (peer-reviewed)abstract
- Introduction Image modalities like Duplex Ultrasound, Transesophageal Echocardiography, Intravascular Ultrasound, Computed Tomography and Magnetic Resonance provide vascular interventionists and surgeons with useful diagnostic information for treatment planning. Recent developments in cross-sectional imaging, including multi-modality image fusion and new contrast agents have resulted in improved spatial resolution. Specifically, dynamic Electrocardiographically-Gated Computed Tomographic Angiography (ECG-gated CTA) provides valuable information regarding motion and deformation of the normal and diseased aorta during the cardiac cycle. Extracting and presenting (visualization) of accurate quantitative information from the recorded image data, however remains a challenging task of image post processing. Method The algorithm proposed within this paper processes ECG-gated CTA data (here goes the scanner model and manufacturer) in DICOM (digital imaging and communication in medicine) format, within which the user manually defines an Eulerian Region of Interest (ROI). 2D deformable (active) contour models are used to pre-segment the luminal surfaces of the selected vessels at an arbitrary time point during the cardiac cycle. A tessellation algorithm is used to define the initial configuration of a 3D deformable (active) contour model, which in turn is used for the final segmentation of the luminal surfaces continuously during the cardiac cycle. Specifically, Finite Element (FE) formulations [1] for frames and shells, as known from structural mechanics, are used to define the deformable contour modes. This allows a direct mechanical interpretation of the applied set of reconstruction parameters and leads to an efficient FE implementation of the models [2]; parallel processor architecture is used to solve the global set of non-linear FE equations. Finally displacement and strain measures are derived from the dynamic segmentations and color coded plots are used to visualize them. Results and Conclusions The clinical relevance of dynamic imaging has not been fully exploited and accurate and fast image processing tools are critical to extract valuable information from ECG-gated CTA data. Such information is not only of direct clinical relevance but also critical to process our current understanding regarding normal and pathological aortic motions and deformations. The image processing concept proposed in this paper leads to efficient and clinically applicable software that facilitates an analysis of the entire aorta on a standard Personal Computer within a few minutes. Deformable (active) contour models are known to be more accurate compared to threshold based segmentation concepts [3] and the accuracy of the present approach is in the range of the in-plane image resolution. Apart from direct diagnostic information the extracted geometrical data could also be used (once enriched by accurate pressure measurements) for none invasive (minimal invasive) estimation of biomechanical aortic tissue properties. References [1] O. C. Zienkiewicz and R. L. Taylor, vol.1,2, 5th ed. Oxford: Butterworth Heinemann, 2000. [2] M. Auer and T. C. Gasser, IEEE T. Med. Imaging, 2010 (in press). [3] M. Sonka and J. M. Fitzpatrick, editors., Bellingham: Spie press, 2000
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| 13. |
- Biasetti, Jacopo, et al.
(author)
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A Blood Flow based model for Platelet Activation in Abdominal Aortic Aneurisms
- 2010
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Conference paper (peer-reviewed)abstract
- Introduction Thrombus formation is the physiological response to vascular injury, it prevents loss of blood and permits wound healing, however, it is also associated with pathological conditions like hypoxia, anoxia and infarction [1]. Consequently, thrombus development must be carefully modulated to avoid uncontrolled growth, which in turn could lead to organ malfunctions. Specifically, an Intra-Luminal Thrombus (ILT) is found in almost all larger (clinically relevant) Abdominal Aortic Aneurysms (AAAs) and multiple biochemical [2] and biomechanical [3] implications on the underlying wall tissue have been reported. Despite the dominant role played by the ILT in AAA disease little is known regarding its development, and hence, the present study investigates ILT formation with particular emphasis on platelet activation triggered by biomechanical and biochemical field variables. Method The proposed model assumes that platelet activation is defined by a single field variable representing the accumulation of mechanical [4] and chemical [5] factors as the platelet moves along its path line. Platelet activation is given as soon asovercomes a certain threshold thought to be a constitutive property of blood. Specifically, the rate of the activation variable is determined by the maximum shear stress and the local concentrations of agonists and antagonists. To implement the model the fluid mechanical problem was solved in (COMSOL, COMSOL AB) and a particle tracking analysis (MATLAB, The MathWorks) was applied as a post processing step. The flow in a circular tube and the Backward Facing Step (BFS) problem under varying initial conditions were used for a basic investigation of the model and to relate its predictions to available data in the literature. Finally, platelet activation in patient specific AAAs was predicted and related to ILT development, which was estimated from Computer Tomography-Angiography (CT-A) data recorded from patient follow-up studies. Results and Conclusions The platelet activation variable is complex distributed (highly heterogeneous) in the flow field, where, specifically, at the boundary of vortexes [6] and in the boundary layer of the non- endothelialized wall highest values were predicted. Continuous release of antagonists from the endothelialized wall lowers in its vicinity, and hence, despite the high shear stress platelet activation is prevented. The proposed model links biomechanical and biochemical mechanisms of platelet activation and is able to predict the onset of thrombus formation of the BFS problem. The model is also able to predict some features of ILT development in the AAA, however, the change in luminal geometry is a cumulative effect of ILT growth, wall growth and their mechanical interactions, and hence, data recorded form patient follow-up studies needs to be analyzed carefully when validating the present model. References [1] J. D. Humphrey, Springer-Verlag, New York, 2002. [2] M. Kazi, et. al. J. Vasc. Surg., 38:1283-1292, 2003. [3] W. R. Mower et. al., J. Vasc. Surg., 33:602-608, 1997. [4] J. D. Hellums, Ann. Biomed. Eng., 22: 445-455, 1994. [5] B. Alberts et. al. Molecular Biology of the cell, 2002. [6] J. Biasetti et. al. Ann. Biomed. Eng., 38: 380–390 2010.
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| 14. |
- Biasetti, Jacopo, et al.
(author)
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A Fluid-chemical model of thrombus formation
- 2011
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In: CMBE2011.
-
Conference paper (peer-reviewed)abstract
- Our understanding of the genesis and evolution of Abdominal Aortic Aneurysms (AAAs), withparticular emphasis on Intra-Luminal Thrombus’ evolution, may be improved by studying thecomplex interplay between fluid-dynamics and biochemistry. To investigate the evolution of prothromboticchemicals inside the blood flow, in particular thrombin (factor IIa), a fluido-chemicalmodel has been developed. To this end a series of convection-diffusion-reaction (CDR) equationsdescribing the tissue factor pathway to thrombin have been solved on top of the biofluiddynamics problem. The proposed model integrates biochemistry and fluids dynamics, and hence,supports a comprehensive understanding of how ILT in AAAs may develop.
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| 15. |
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| 16. |
- Erhart, P., et al.
(author)
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Finite Element Analysis in Asymptomatic, Symptomatic, and Ruptured Abdominal Aortic Aneurysms : In Search of New Rupture Risk Predictors
- 2015
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In: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1078-5884 .- 1532-2165. ; 49:3, s. 239-245
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Journal article (peer-reviewed)abstract
- Objectives: To compare biomechanical rupture risk parameters of asymptomatic, symptomatic and ruptured abdominal aortic aneurysms (AAA) using finite element analysis (FEA). Study design: Retrospective biomechanical single center analysis of asymptomatic, symptomatic, and ruptured AAAs. Comparison of biomechanical parameters from FEA. Materials and methods: From 2011 to 2013 computed tomography angiography (CTA) data from 30 asymptomatic, 15 symptomatic, and 15 ruptured AAAs were collected consecutively. FEA was performed according to the successive steps of AAA vessel reconstruction, segmentation and finite element computation. Biomechanical parameters Peak Wall Rupture Risk Index (PWRI), Peak Wall Stress (PWS), and Rupture Risk Equivalent Diameter (RRED) were compared among the three subgroups. Results: PWRI differentiated between asymptomatic and symptomatic AAAs (p < .0004) better than PWS (p < .1453). PWRI-dependent RRED was higher in the symptomatic subgroup compared with the asymptomatic subgroup (p < .0004). Maximum AAA external diameters were comparable between the two groups (p < .1355). Ruptured AAAs showed the highest values for external diameter, total intraluminal thrombus volume, PWS, RRED, and PWRI compared with asymptomatic and symptomatic AAAs. In contrast with symptomatic and ruptured AAAs, none of the asymptomatic patients had a PWRI value >1.0. This threshold value might identify patients at imminent risk of rupture: Conclusions: From different FEA derived parameter, PWRI distinguishes most precisely between asymptomatic and symptomatic AAAs. If elevated, this value may represent a negative prognostic factor for asymptomatic AAAs.
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| 17. |
- Gasser, Thomas Christian
(author)
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Aorta
- 2017
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In: Biomechanics of Living Organs. - : Elsevier. - 9780128040607 - 9780128040096 ; , s. 169-191
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Book chapter (peer-reviewed)abstract
- The aorta is a dynamic structure that is able to maintain conditions for optimal mechanical operation through the continuous turnover of its internal structure. The aorta's properties are critical to the entire cardiovascular system, and the study of its biomechanics may help us to better understand the role of tissue stress and strain in aortic aging and pathology, help to optimize medical devices, and improve therapeutic and diagnostic methods that are currently used in clinics. The present chapter reviews aortic wall histology and morphology in relation to its key mechanical properties. Specifically, the biomechanical role of cells (endothelial cells, smooth muscle cells, fibroblasts, etc.), as well as the extracellular matrix components (elastin, collagen, proteoglycans, water, etc.), will be discussed. Then this information is related to reported constitutive descriptions for aortic tissues. The focus is on histo-mechanical approaches and modeling frames, related to hyperelasticity as well as a superposition of fiber contributions according to a general theory of fibrous connective tissue. Concluding remarks relate to open problems in aorta biomechanics, such as uncertainty and variability of input information. Remarks are also made on the admissible degree of complexity in aortic simulations, in the context of such uncertainties.
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| 18. |
- Giampaolo, Martufi, et al.
(author)
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Abdominal Aortic Aneurysm development over time : Experimental evidence and constitutive modeling
- 2010
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In: Proceedings of the 6th World Congress of Biomechanics. - : Springer. - 9783642145148
-
Conference paper (peer-reviewed)abstract
- Abdominal Aortic Aneurysms (AAAs) are defined as a localized permanent dilatation of the infrarenal aorta at least 50 % of its normal diameter. AAAs are frequently diagnosed in the elderly male population and evaluating rupture risk is critically important as aneurysm rupture carries high mortality rates. Growth predictors might be helpful to assess AAA rupture risk and could therefore give a better graded indication for elective repair in order to reduce related mortality without unnecessarily increasing the rate of interventions. Factors associated with AAA growth are still limited but there are some evidence that higher initial AAA diameter is related to faster AAA expansion [1]. The initial dilatation is dependent on elastin degradation, but strength of the AAA is maintained by increased production of collagen. It has been suggested that rupture occurs when collagen production is insufficient to counteract load-bearing at high pressure [2]. AAA growth quantification 30 patients with infrarenal AAAs were included in this study. Criteria for inclusion were 1-year follow-up and availability of at least two high-resolution Computer Tomography-Angiography (CTA) scans. Consequently, 60 CT-A scans were systematically segmented, reconstructed and analyzed (A4research, VASCOPS GmbH), in order to investigate geometrical and mechanical factors likely to be correlated with AAA growth. Derived results were analyzed with an especially developed (automatic) analyzing schema (MatLab, The MathWorks), and the derived information aims at guiding the development of an analytical growth model for AAAs. Constitutive Modeling Collagen is a structural protein responsible for the mechanical strength, stiffness and toughness of biological tissues like skin, tendon, bone, cornea, lung and vasculature. In the present study we considered the enlargement of the aneurysm as a consequence of a pathological degradation and synthesis of collagen, i.e. malfunction of collagen turn-over. Consequently, the vascular wall is modeled by an (inert) matrix material representing the elastin, which is reinforced by a dynamic structure of bundles of collagen. Specifically, collagen is formed by a continuous stress-mediated process and deposited in the current configuration [3] and removed by a constant degradation rate. Finally the micro-plane concept [4] is used for the Finite Element implementation [5] of the constitutive model. Results and conclusions The quantitative description of AAA growth by examining patient follow-up data revealed novel insights into the natural history of this disease. Most interestingly not all portions of the AAA seem to enlarge, some might be stable or even shrink over time; a feature that has not yet been considered by models reported in the literature. The model proposed within this study has a strong biological motivation and captures saline feature of AAA growth. Besides that, the micro-plane approach allows a straight forward FE implementation and preliminary results indicate its numerical robustness. References [1] F.J.V. Schlösser, et al., J Vasc Surg, 47:1127–1133 2008. [2] E. Choke, et al., Eur.j.Vasc.endovasc.surg, 30(3):227-44 2005. [3] J.D.Humphrey, J Biomech Eng, 121:591–597 1999. [4] Z.P. Bazant and P.C. Prat, J Eng Mech, 113(7) 1050-1064 1987. [5] S. Federico and T.C Gasser, J R Soc Interface (in press)
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| 19. |
- Grover, Sandeep, et al.
(author)
-
Replication of a Novel Parkinson's Locus in a European Ancestry Population
- 2021
-
In: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 36:7, s. 1689-1695
-
Journal article (peer-reviewed)abstract
- BACKGROUND: A recently published East Asian genome-wide association study of Parkinson;s disease (PD) reported 2 novel risk loci, SV2C and WBSCR17.OBJECTIVES: The objective of this study were to determine whether recently reported novel SV2C and WBSCR17 loci contribute to the risk of developing PD in European and East Asian ancestry populations.METHODS: We report an association analysis of recently reported variants with PD in the COURAGE-PD cohort (9673 PD patients; 8465 controls) comprising individuals of European and East Asian ancestries. In addition, publicly available summary data (41,386 PD patients; 476,428 controls) were pooled.RESULTS: Our findings confirmed the role of the SV2C variant in PD pathogenesis (rs246814, COURAGE-PD PEuropean = 6.64 × 10-4 , pooled PD P = 1.15 × 10-11 ). The WBSCR17 rs9638616 was observed as a significant risk marker in the East Asian pooled population only (P = 1.16 × 10-8 ).CONCLUSIONS: Our comprehensive study provides an up-to-date summary of recently detected novel loci in different PD populations and confirmed the role of SV2C locus as a novel risk factor for PD irrespective of the population or ethnic group analyzed. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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| 20. |
- Grytsan, Andrii, et al.
(author)
-
Growth Description for Vessel Wall Adaptation : A Thick-Walled Mixture Model of Abdominal Aortic Aneurysm Evolution
- 2017
-
In: Materials. - : MDPI AG. - 1996-1944. ; 10:9
-
Journal article (peer-reviewed)abstract
- (1) Background: Vascular tissue seems to adapt towards stable homeostatic mechanical conditions, however, failure of reaching homeostasis may result in pathologies. Current vascular tissue adaptation models use many ad hoc assumptions, the implications of which are far from being fully understood; (2) Methods: The present study investigates the plausibility of different growth kinematics in modeling Abdominal Aortic Aneurysm (AAA) evolution in time. A structurally motivated constitutive description for the vessel wall is coupled to multi-constituent tissue growth descriptions; Constituent deposition preserved either the constituent's density or its volume, and Isotropic Volume Growth (IVG), in-Plane Volume Growth (PVG), in-Thickness Volume Growth (TVG) and No Volume Growth (NVG) describe the kinematics of the growing vessel wall. The sensitivity of key modeling parameters is explored, and predictions are assessed for their plausibility; (3) Results: AAA development based on TVG and NVG kinematics provided not only quantitatively, but also qualitatively different results compared to IVG and PVG kinematics. Specifically, for IVG and PVG kinematics, increasing collagen mass production accelerated AAA expansion which seems counterintuitive. In addition, TVG and NVG kinematics showed less sensitivity to the initial constituent volume fractions, than predictions based on IVG and PVG; (4) Conclusions: The choice of tissue growth kinematics is of crucial importance when modeling AAA growth. Much more interdisciplinary experimental work is required to develop and validate vascular tissue adaption models, before such models can be of any practical use.
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| 21. |
- Grytsan, Andrii, 1986-, et al.
(author)
-
Growth description for vessel wall adaptation : a thick-walled mixture model of abdominal aortic aneurysm evolution
- 2016
-
Reports (other academic/artistic)abstract
- Modeling the soft tissue volumetric growth has received considerable attention in the literature.However, due to the lack of experimental observations, the growth kinematics, that are reported in the literature, are based on a number of assumptions.The present study tested the plausibility of different growth descriptions when applied to the abdominal aortic aneurysm (AAA) evolution.A structurally motivated material model and the multi-constituent tissue growth descriptions were utilized. The mass increment of the individual constituents preserved either the density or the volume.Four different growth descriptions were tested, namely isotropic (IVG), in-plane (PVG), in-thickness (TVG) growth and no volume growth (NVG) models.Based on the model sensitivity to the increased collagen deposition, TVG and NVG models were found to be plausible scenarios, while IVG and PVG were found to be implausible. In addition, TVG and NVG models were less sensitive to the initial constituent volume fractions, than IVG and PVG models.In conclusion, the choice of the growth kinematics is of crucial importance when modeling the AAA growth and remodeling, and,probably, also for other soft biological tissues.
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| 22. |
- Holzapfel, Gerhard A., et al.
(author)
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Computational stress-deformation analysis of arterial walls including high-pressure response
- 2007
-
In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 116:1, s. 78-85
-
Journal article (peer-reviewed)abstract
- Background: Changes in the mechanical behavior of arteries after balloon angioplasty cause cell reactions that may be responsible for restenosis. Hence, the study of the stress-deforination changes in arterial walls following supraphysiological tissue loading is an essential task. Methods: A normal LAD coronary artery was modeled and computationally analyzed as a two-layer, thick-walled, anisotropic and inelastic circular tube including residual strains. Each layer was treated as a fibre-matrix composite. The tube was subjected to an axial stretch of 1. 1 and a transmural pressure of 750 min Hg. Since overstretch of rerrmant non-diseased tissue in lesions is a primary mechanism of lumen enlargement this model approach represents a reasonable first step. Results: At physiological loading, the residual stresses led to a significant reduction of the high circumferential stress values at the inner wall, and the stress gradients. At low pressure level the media was the mechanically relevant layer, while at supraphysiological loading, the adventitia was the predominant load-carrying constituent providing a stiff support for 'redistribution' of soft plaque components by means of radial compression. After unloading to physiological loading conditions the stress state in the arterial wall differed significantly from that before inflation; the stress gradient in the media even changed its sign. Complete unloading indicated lumen enlargement, material softening and energy dissipation, which is in agreement with experimental studies. Conclusions: This method may be useful to improve interventional protocols for reducing the dilatational trauma, and thereby the adverse biological reaction in arterial walls following balloon angioplasty.
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| 23. |
- Hyhlik-Dürr, A., et al.
(author)
-
Finite-Elemente-Analyse abdomineller Aortenaneurysmen : Erste Ergebnisse der Intra- und Interobserver Validierung
- 2010
-
Conference paper (peer-reviewed)abstract
- Hintergrund: Die Therapie des abdominellen Aortenaneurysmas (AAA) ist indiziert, wenn das Rupturrisiko das Risiko der elektiven Operation übersteigt. Die Abschätzung des individuellen Rupturrisikos gilt als Basis der Indikationsstellung zur offenen oder endovaskulären Chirurgie. Bisher wird der Durchmesser des AAA als maßgeblicher Risikofaktor für die Ruptur herangezogen. Für eine sensitivere Indikationsstellung sollten jedoch andere morphologische oder biomechanische Faktoren wie die Volumenveränderung im Verlauf und/oder die Wandspannung im Aneurysma untersucht werden. Ziel dieser Studie ist die Analyse der Reproduzierbarkeit der Durchmesserbestimmung sowie der Volumen- und Wandspannungsberechnung anhand eines geometrischen Modells, basierend auf der Finite Elemente Methode. Methode: Computertomographische Daten von vier gesunden und zehn Patienten mit infrarenalen abdominellen Aneurysmen werden von drei unabhängigen Untersuchern analysiert. Die abdominelle Aorta wird semiautomatisch von Computertomographie-Angiographie (CTA) Bilddaten segmentiert, wobei zwei und drei-dimensionale aktive Konturmodelle, wie sie aus der Bildverarbeitung bekannt sind, zum Einsatz kommen. Der maximale Durchmesser (cernterline-basiert) sowie das aortale Volumen werden aus den rekonstruierten dreidimensionalen Modellen berechnet. Zusätzlich werden nicht-lineare Finite Elemente Modelle verwendet, um die mechanische Spannung in der Aortenwand zwischen der Aortenbifurkation und den Nierenarterien zu bestimmen. Zu diesen Zweck wird der mittlere arterielle Druck als Belastung angenommen und nicht-lineare isotrope Materialmodelle erfassen die mechanischen Eigenschaften der Aortenwand und des Thrombusgewebes. Die Intra- und Interobserver Variabilität der fünf Messungen des maximalen Durchmessers, des Volumens und der maximalen Wandspannung wurden durch die Berechnung des Variationskoeffizienten (CV=SD*100/Arithmethisches Mittel in %) ausgedrückt. Die methodische Variation berechnet sich aus der Abweichung des Duchmessers (mm), des Volumens (ml) und der maximalen Wandspannung (kPA) zwischen den drei Untersuchern. Ergebnisse: Die Reproduzierbarkeit gesunder Gefäßen lag bei einem Durchmesser zwischen 16.1mm und 16.6mm zwischen CV=2,5% und CV=4,9%. Das aortale Volumen lag zwischen 14ml und 15ml, die Reproduzierbarkeit bei den gesunden Gefäßen streute zwischen CV=5.8% und CV=11.5%. Die maximale Wandspannung variierte zwischen 53 kPA and 55 kPa, der CV% lag hierbei zwischen 3 und 13. Die Interobserver Variabilität lag < 10% für den Durchmesser, die Volumenbestimmung und die Bestimmung der maximale Wandspannung. Der maximale Durchmesser der Aorta bei 3 Patienten mit infrarenalem Aneurysma wurde mit durchschnittlich 58.9mm, 54.6mm und 71.2mm berechnet (Stand bei Abstracteinreichung). Der Variationskoeffizient zeigte dabei eine hohe Übereinstimmung mit Werten unter 5%. Das Volumen der Aneurysmen schwankte zwischen 130 ml und 300 ml (CV<10%), die berechnete Wandspannung lag zwischen 172 kPA und 296 kPA (CV<10%). Die Variabilität zwischen den drei Untersuchern betrug 0,7-6,0 mm für den Durchmesser, 11-28 ml für das Volumen und 4-27 kPA für die maximale Wandspannung. Zusammenfassung: Sowohl an gesunden als auch an degenerativ veränderten Gefäßen ergibt die Reproduzierbarkeit des Aortendurchmessers und des aortalen Volumens basierend auf dem dreidimensionalen rekonstruierten Modellen eine hohe Übereinstimmung. Die berechnete Wandspannung basierend auf den Finiten Elemente Modellen zeigt einen geringen Grad an Variabilität sowohl zwischen verschiedenen Untersuchern als auch bei wiederholter Messung. Daher könnten die Volumenbestimmung und die Analyse der Wandspannung zusätzliche Größen bei der Bestimmung des individuellen Rupturrisikos bei Patienten mit Aortenaneurysmen darstellen, um eine präzisere Indikationsstellung zu ermöglichen.
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| 24. |
- Kiousis, Dimitrios, et al.
(author)
-
Smooth contact strategies with emphasis on the modeling of balloon angioplasty with stenting
- 2008
-
In: International Journal for Numerical Methods in Engineering. - : Wiley. - 0029-5981 .- 1097-0207. ; 75:7, s. 826-855
-
Journal article (peer-reviewed)abstract
- Critical to the simulation of balloon angioplasty is the modeling of the contact between the artery wall and the medical devices. In standard approaches, the 3D contact surfaces are described by means of C0-continuous facet-based techniques, which may lead to numerical problems. This work introduces a novel contact algorithm where the target surfaces are described by polynomial expressions with C2-continuity. On the basis of uniform cubic B-splines, two different parametrization techniques are presented and compared, while the related implementation of the algorithm into a finite element analysis program is described. Two numerical examples are selected to demonstrate the special merits of the proposed contact formulation. The first example is a benchmark contact problem selected to point out the special features of the proposed strategies. The second example is concerned with the simulation of balloon angioplasty and stenting, where the contact between the balloon, the stent and the artery wall is numerically modeled. A patient-specific 3D model of a stenotic femoral artery serves as a basis. The study concludes by identifying the changes in the mechanical environment of the artery in terms of contact forces and strains by considering two different stent designs.
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| 25. |
- Krüger, Rejko, et al.
(author)
-
A large-scale genetic association study to evaluate the contribution of Omi/HtrA2 (PARK13) to Parkinson's disease
- 2011
-
In: Neurobiology of Aging. - : Elsevier BV. - 1558-1497 .- 0197-4580. ; 32:3, s. 9-548
-
Journal article (peer-reviewed)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.
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| 26. |
- Lade, Steven J., et al.
(author)
-
Analytically tractable climate-carbon cycle feedbacks under 21st century anthropogenic forcing
- 2018
-
In: Earth System Dynamics. - : Copernicus GmbH. - 2190-4979 .- 2190-4987. ; 9:2, s. 507-523
-
Journal article (peer-reviewed)abstract
- Changes to climate-carbon cycle feedbacks may significantly affect the Earth system's response to greenhouse gas emissions. These feedbacks are usually analysed from numerical output of complex and arguably opaque Earth system models. Here, we construct a stylised global climate-carbon cycle model, test its output against comprehensive Earth system models, and investigate the strengths of its climate-carbon cycle feedbacks analytically. The analytical expressions we obtain aid understanding of carbon cycle feedbacks and the operation of the carbon cycle. Specific results include that different feedback formalisms measure fundamentally the same climate-carbon cycle processes; temperature dependence of the solubility pump, biological pump, and CO2 solubility all contribute approximately equally to the ocean climate-carbon feedback; and concentration-carbon feedbacks may be more sensitive to future climate change than climate-carbon feedbacks. Simple models such as that developed here also provide workbenches for simple but mechanistically based explorations of Earth system processes, such as interactions and feedbacks between the planetary boundaries, that are currently too uncertain to be included in comprehensive Earth system models.
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| 27. |
- Lambrechts, Diether, et al.
(author)
-
Meta-analysis of VEGF variations in ALS : increased susceptibility in male carriers of the -2578AA genotype
- 2008
-
In: Journal of Medical Genetics. - London : BMJ Publishing Group. - 0022-2593 .- 1468-6244. ; 46:12, s. 840-846
-
Journal article (peer-reviewed)abstract
- Background: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. Methods and findings: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (−2578C/A, −1154G/A and −634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the −2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. Conclusions: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF −2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.
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| 28. |
- Lerche, Stefanie, et al.
(author)
-
Cognitive impairment in Glucocerebrosidase (GBA)-associated PD: Not primarily associated with cerebrospinal fluid Abeta and Tau profiles.
- 2017
-
In: Movement disorders : official journal of the Movement Disorder Society. - : Wiley. - 1531-8257. ; 32:12, s. 1780-1783
-
Journal article (peer-reviewed)abstract
- A proportion of idiopathic Parkinson's disease patients (PDidiopathic ) with dementia show altered CSF profiles of amyloid β (Aβ) and Tau. PD patients with Glucocerebrosidase (GBA) mutations (PDGBA ) present with even more cognitive decline than seen in PDidiopathic .The objective of this study was to evaluate whether CSF profiles of Aβ and tau are associated with the prominent cognitive impairment in PDGBA .CSF levels of Aβ1-42 , t-Tau, p-Tau, and total alpha-synuclein were assessed in 479 participants (50 PDGBA , 308 PDidiopathic , 121 healthy controls).Older age was associated with cognitive impairment in PDGBA and PDidiopathic . Despite prominent cognitive impairment, PDGBA showed similar CSF levels of Aβ1-42 , t-Tau, and p-Tau as seen in healthy controls. In contrast, lower levels of Aβ1-42 and higher levels of t-Tau and p-Tau were associated with worse cognitive performance in PDidiopathic .The prominent cognitive impairment in PDGBA seems not primarily associated with Aβ and Tau profiles in CSF. © 2017 International Parkinson and Movement Disorder Society.
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| 29. |
- Lerche, Stefanie, et al.
(author)
-
Parkinson's disease : Evolution of cognitive impairment and CSF Aβ1-42 profiles in a prospective longitudinal study
- 2019
-
In: Journal of Neurology, Neurosurgery and Psychiatry. - : BMJ. - 0022-3050 .- 1468-330X. ; 90:2, s. 165-170
-
Journal article (peer-reviewed)abstract
- Objective: To evaluate the evolution of cognitive impairment in relation to cerebrospinal fluid (CSF) profiles of amyloid-β (Aβ), total-Tau and phosphorylated-Tau in Parkinson's disease (PD). Methods: Prospective, longitudinal, observational study up to 10 years with follow-up every 2 years. We assessed CSF profiles in 415 patients with sporadic PD (median age 66; 63% men) and 142 healthy controls (median age 62; 43% men). Results: Patients with PD with low CSF Aβ1-42 levels at baseline were more often cognitively impaired than patients with intermediate and high Aβ1-42 levels. Sixty-seven per cent of the patients with low Aβ1-42 levels at baseline and normal cognition developed cognitive impairment during follow-up, compared with 41% and 37% of patients having intermediate and high CSF Aβ1-42 levels. Kaplan-Meier survival curves and Cox regression revealed that patients with low CSF Aβ1-42 levels at baseline developed cognitive impairment more frequently and earlier during follow-up. Conclusion: We conclude that in patients with sporadic PD, low levels of Aβ1-42 are associated with a higher risk of developing cognitive impairment earlier in the disease process at least in a subgroup of patients.
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| 30. |
- Liu, Hui, et al.
(author)
-
Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors
- 2022
-
In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 92:2, s. 270-278
-
Journal article (peer-reviewed)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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| 31. |
- Man, V., et al.
(author)
-
Impact of isotropic constitutive descriptions on the predicted peak wall stress in abdominal aortic aneurysms
- 2018
-
In: Medical Engineering and Physics. - : Elsevier. - 1350-4533 .- 1873-4030. ; 53, s. 49-57
-
Journal article (peer-reviewed)abstract
- Biomechanics-based assessment of Abdominal Aortic Aneurysm (AAA) rupture risk has gained considerable scientific and clinical momentum. However, computation of peak wall stress (PWS) using state-ofthe-art finite element models is time demanding. This study investigates which features of the constitutive description of AAA wall are decisive for achieving acceptable stress predictions in it. Influence of five different isotropic constitutive descriptions of AAA wall is tested; models reflect realistic non-linear, artificially stiff non-linear, or artificially stiff pseudo-linear constitutive descriptions of AAA wall. Influence of the AAA wall model is tested on idealized (n = 4) and patient-specific (n = 16) AAA geometries. Wall stress computations consider a (hypothetical) load-free configuration and include residual stresses homogenizing the stresses across the wall. Wall stress differences amongst the different descriptions were statistically analyzed. When the qualitatively similar non-linear response of the AAA wall with low initial stiffness and subsequent strain stiffening was taken into consideration, wall stress (and PWS) predictions did not change significantly. Keeping this non-linear feature when using an artificially stiff wall can save up to 30% of the computational time, without significant change in PWS. In contrast, a stiff pseudo-linear elastic model may underestimate the PWS and is not reliable for AAA wall stress computations.
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| 32. |
- Martufi, Giampaolo, et al.
(author)
-
Review : The role of biomechanical modeling in the rupture risk assessment for abdominal aortic aneurysms
- 2013
-
In: Journal of Biomechanical Engineering. - : ASME International. - 0148-0731 .- 1528-8951. ; 135:2, s. 021010-
-
Research review (peer-reviewed)abstract
- AAA disease is a serious condition and a multidisciplinary approach including biomechanics is needed to better understand and more effectively treat this disease. A rupture risk assessment is central to the management of AAA patients, and biomechanical simulation is a powerful tool to assist clinical decisions. Central to such a simulation approach is a need for robust and physiologically relevant models. Vascular tissue senses and responds actively to changes in its mechanical environment, a crucial tissue property that might also improve the biomechanical AAA rupture risk assessment. Specifically, constitutive modeling should not only focus on the (passive) interaction of structural components within the vascular wall, but also how cells dynamically maintain such a structure. In this article, after specifying the objectives of an AAA rupture risk assessment, the histology and mechanical properties of AAA tissue, with emphasis on the wall, are reviewed. Then a histomechanical constitutive description of the AAA wall is introduced that specifically accounts for collagen turnover. A test case simulation clearly emphasizes the need for constitutive descriptions that remodels with respect to the mechanical loading state. Finally, remarks regarding modeling of realistic clinical problems and possible future trends conclude the article.
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| 33. |
- Matthews, Evan O., et al.
(author)
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Athero-occlusive Disease Appears to be Associated with Slower Abdominal Aortic Aneurysm Growth : An Exploratory Analysis of the TEDY Trial
- 2022
-
In: European Journal of Vascular and Endovascular Surgery. - : Elsevier BV. - 1078-5884 .- 1532-2165. ; 63:4, s. 632-640
-
Journal article (peer-reviewed)abstract
- Objective: The role of atherosclerosis in abdominal aortic aneurysm (AAA) pathogenesis is controversial. The aim of this study was to compare AAA growth in patients who did and did not have concurrent athero-occlusive disease (AOD). Methods: Patients with an AAA measuring 35 - 49 mm in maximum diameter were recruited as part of the TElmisartan in the management of abdominal aortic aneurysm (TEDY) trial. TEDY participants who had infrarenal aortic volume and orthogonal diameter assessed by computed tomography at entry and at least one other time point during the trial (12 and/or 24 months) were included. AOD was defined by prior diagnoses of coronary heart disease, stroke, or peripheral arterial disease or an ankle brachial pressure index < 0.90. The increase in AAA volume and diameter from entry for participants who did and did not have AOD was assessed using linear mixed effects models; 131 of the 210 participants recruited to TEDY were included. Results: In an unadjusted analysis, the mean (95% confidence interval) annual increases in AAA volume and diameter for participants with AOD were 3.26 (0.82 - 5.70) cm(3) and 0.70 (0.19 - 1.22) mm slower than those without AOD, p = .008 and.007 respectively. The association between AOD and significantly slower AAA growth was maintained after adjusting for risk factors and medications, significantly unequally distributed between participants with and without an AOD diagnosis. Conclusion: In an exploratory analysis of a selective cohort from the TEDY trial, AOD was associated with slower AAA growth. Validation of these findings in other cohorts is needed.
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| 34. |
- Riveros, F., et al.
(author)
-
Influence of intraluminal thrombus topology on AAA passive mechanics
- 2013
-
In: 2013 40th Computing in Cardiology Conference, CinC 2013. - : IEEE Computer Society. - 9781479908844 ; , s. 899-902
-
Conference paper (peer-reviewed)abstract
- An intraluminal thrombus (ILT) is found in most AAAs of clinically relevant size. Even though some studies seem to indicate a protective role of the ILT against AAA rupture, there is still great controversy on this regard. In addition, patient-specific AAA models are generated from gated medical images in which the artery is under pressure. Identification of the AAA zero pressure geometry would allow for a more realistic estimate of the aneurysmal wall mechanics and a better understanding of the role of the ILT. This study looks into the influence of the ILT on patient specific AAA accounting for the zero pressure geometry. Ten patient specific AAA of similar maximum diameter (4.8-5.2cm) and ILT volume were considered. For the stress analysis, the arterial wall is modeled as an anisotropic hyperelastic solid. Our results suggest that the geometrical configuration of the ILT relative to the arterial wall may be an influential factor not only on the ensuing peak wall stress, but also on its location within the lesion. The effects of the ILT topology are enhanced when the zero pressure configuration of the lesion is accounted for, where as the location of the peak wall stress in the lesion corresponds to the region of minimal ILT thickness. These suggest that the topology of the ILT, which greatly influence the zero-pressure geometry of the AAA, affects the stress field at the systolic pressure on AAA.
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| 35. |
- Rofes, Adrià, et al.
(author)
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Survey on current cognitive practices within the European Low-Grade Glioma Network : towards a European assessment protocol.
- 2017
-
In: Acta Neurochirurgica. - : Springer Science and Business Media LLC. - 0001-6268 .- 0942-0940. ; 159:7, s. 1167-1178
-
Journal article (peer-reviewed)abstract
- BACKGROUND: The European Low-Grade Glioma network indicated a need to better understand common practices regarding the managing of diffuse low-grade gliomas. This area has experienced great advances in recent years.METHOD: A general survey on the managing of diffuse low-grade gliomas was answered by 21 centres in 11 European countries. Here we focused on specific questions regarding perioperative and intraoperative cognitive assessments.RESULTS: More centres referred to the same speech and language therapist and/or neuropsychologist across all assessments; a core of assessment tools was routinely used across centres; fluency tasks were commonly used in the perioperative stages, and object naming during surgery; tasks that tapped on attention, executive functions, visuospatial awareness, calculation and emotions were sparsely administered; preoperative assessments were performed 1 month or 1 week before surgery; timing for postoperative assessments varied; finally, more centres recommended early rehabilitation, whenever needed.CONCLUSIONS: There is an emerging trend towards following similar practices for the management of low-grade gliomas in Europe. Our results are descriptive and formalise current discussions in our group. Also, they contribute towards the development of a European assessment protocol.
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| 36. |
- Ross, Owen A., et al.
(author)
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Genomic investigation of alpha-synuclein multiplication and parkinsonism
- 2008
-
In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 63:6, s. 743-750
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Journal article (peer-reviewed)abstract
- Objective: Copy number variation is a common polymorphic phenomenon within the human genome. Although the majority of these events are non-deleterious they can also be highly pathogenic. Herein we characterize five families with parkinsonism that have been identified to harbor multiplication of the chromosomal 4q21 locus containing the a-synuclein gene (SNCA). Methods: A methodological approach using fluorescent in situ hybridization and Affymetrix (Santa Clara, CA) 250K SNP microarrays was used to characterize the multiplication in each family and to identify the genes encoded within the region. The telomeric and centromeric breakpoints of each family were further narrowed using semiquantitative polymerase chain reaction with microsatellite markers and then screened for transposable repeat elements. Results: The severity of clinical presentation is correlated with SNCA dosage and does not appear to be overtly affected by the presence of other genes in the multiplicated region. With the exception of the Lister kindred, in each family the multiplication event appears de novo. The type and position of Alu/LINE repeats are also different at each breakpoint. Microsatellite analysis demonstrates two genomic mechanisms are responsible for chromosome 4q21 multiplications, including both SNCA duplication and recombination. Interpretation: SNCA dosage is responsible for parkinsonism, autonomic dysfunction, and dementia observed within each family. We hypothesize dysregulated expression of wild-type (alpha-synuclein results in parkinsonism and may explain the recent association of common SNCA variants in sporadic Parkinson's disease. SNCA genomic duplication results from intraallelic (segmental duplication) or interallelic recombination with unequal crossing over, whereas both mechanisms appear to be required for genomic SNCA triplication.
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| 37. |
- Sailer, Anna, et al.
(author)
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A genome-wide association study in multiple system atrophy
- 2016
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In: Neurology. - 0028-3878. ; 87:15, s. 1591-1598
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Journal article (peer-reviewed)abstract
- Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS). Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed. Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10-6, including SNPs in the genes FBXO47, ELOVL7, EDN1, and MAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA. Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including the MAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCA and COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.
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| 38. |
- Sproll, Véronique, et al.
(author)
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Radiostation Grafted Ion-Conducting Membranes: The Influence of Variations in Base Film Nanostructure
- 2016
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In: Macromolecules. - : American Chemical Society (ACS). - 0024-9297 .- 1520-5835. ; 49:11, s. 4253-4264
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Journal article (peer-reviewed)abstract
- The proton exchange membrane (PEM) is a key element of a polymer electrolyte fuel cell, and radiation-grafting is an attractive option for the synthesis of PEMs. Via a systematic investigation of a well-defined model material, sulfonated polystyrene grafted poly(ethylene-alt-tetrafluoroethylene), ETFE-g-PS(SA), we show that the performance and stability of radiation-grafted PEMs in fuel cells strongly depends on the microstructure of the underlying base polymer. The nanoscale structure of the base polymers, grafted films, and membranes is probed by small-angle scattering, and the nanoscale proton dynamics is probed by quasi-elastic neutron scattering. The results of these techniques correlated with fuel cell relevant properties—including proton conductivity and water uptake—and fuel cell performance clearly indicate that differences in the arrangement of the crystalline phase in the otherwise chemically identical semicrystalline base films can have considerable impact, representing an essential aspect to consider in the development of proton exchange membranes prepared via preirradiation grafting.
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| 39. |
- Sproll, Veronique, et al.
(author)
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Structure-property correlations of ion-containing polymers for fuel cell applications
- 2016
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In: Radiation Physics and Chemistry. - : Elsevier BV. - 0969-806X. ; 118, s. 120-123
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Journal article (peer-reviewed)abstract
- In order to investigate the structure-property correlations of grafted proton conducting membranes, the model system consisting of an ETFE base film grafted with polystyrene and subsequent sulfonation (ETFE-g-PSSA) along with crosslinked derivatives ETFE-g-P(SSA-co-DiPB) were synthesized. The characteristics of the final membranes were characterized by PFG-NMR diffusometry, in-plane conductivity and by investigations of the dimensional changes of the grafted membranes. The collected data were correlated with the inherent anisotropy of the ETFE base film. (C) 2015 Elsevier Ltd. All rights reserved.
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| 40. |
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| 41. |
- van Es, Michael A, et al.
(author)
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Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis
- 2011
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In: Annals of Neurology. - : Wiley-Blackwell. - 0364-5134 .- 1531-8249. ; 70:6, s. 964-973
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD.METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios.RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD.INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.
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