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  • 1
    In: Journal of Neurochemistry, Wiley, Vol. 153, No. 5 ( 2020-06), p. 650-661
    Abstract: Promising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q‐linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes in the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof‐of‐concept and feasibility study, we evaluated non‐targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age‐ and gender‐matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via ProteomeXchange with identifier PXD016757. Comparative CSF proteomic analysis in adult SMA patients before and after treatment with nusinersen‐identified subgroups and treatment‐related changes and may therefore be suitable for diagnostic and predictive analyses. image
    Type of Medium: Online Resource
    ISSN: 0022-3042 , 1471-4159
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2020528-4
    SSG: 12
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  • 2
    In: European Journal of Neurology, Wiley, Vol. 31, No. 1 ( 2024-01)
    Abstract: To assess compound muscle action potential (CMAP) amplitudes as electrophysiologic markers in relation to clinical outcome in adult patients with 5q‐linked spinal muscular atrophy (SMA) before and during treatment with risdiplam. Methods In this monocentric longitudinal cohort study, CMAP of 18 adult patients with SMA type 2 or 3 were assessed at baseline ( T 0 ) and after 10 months ( T 10 ) of risdiplam treatment. CMAP amplitudes of the median, ulnar, peroneal, and tibial nerves were compared with established clinical outcome scores, and with the course of disease before start of treatment. Results During a pharmacotherapy‐naive pre‐treatment period of 328 ± 46 days, Revised Upper Limb Module (RULM) score and peroneal nerve CMAP amplitudes decreased, while CMAP of tibial and upper limb nerves remained unchanged. CMAP amplitudes positively correlated with clinical scores (Hammersmith Functional Motor Scale‐Expanded [HFMSE], RULM) at T 0 . During risdiplam treatment, HFMSE and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scores increased, paralleled by marked increase of CMAP amplitudes in both median nerves ( T 10 – T 0 ; right: Δ = 1.4 ± 1.4 mV, p = 0.0003; left: Δ = 1.3 ± 1.4 mV, p = 0.0007), but not in ulnar, peroneal, or tibial nerves. A robust increase of median nerve CMAP amplitudes correlated well with an increase in the HFMSE score ( T 10 – T 0 ). Median nerve CMAP amplitudes at T 0 were associated with subsequent risdiplam‐related improvement of HFMSE and CHOP INTEND scores at T 10 . Conclusions Median nerve CMAP amplitudes increase with risdiplam treatment in adult SMA patients, and should be further evaluated as potential easy‐to‐use electrophysiologic markers in assessing and monitoring clinical response to therapy.
    Type of Medium: Online Resource
    ISSN: 1351-5101 , 1468-1331
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2024
    detail.hit.zdb_id: 2020241-6
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  • 3
    In: European Journal of Neurology, Wiley, Vol. 29, No. 6 ( 2022-06), p. 1782-1790
    Abstract: Knowledge about the exact underlying pathophysiological changes involved in the genesis and progression of spinocerebellar ataxia type 3 (SCA3) is limited. Lower extremity peripheral nerve lesions in clinically, genetically and electrophysiologically classified ataxic and pre‐ataxic SCA3 mutation carriers were characterized and quantified by magnetic resonance neurography (MRN). Methods Eighteen SCA3 mutation carriers and 20 age‐/sex‐matched healthy controls were prospectively enrolled. All SCA3 mutation carriers underwent detailed neurological and electrophysiological examinations. 3 T MRN covered the lumbosacral plexus and proximal thigh to the tibiotalar joint by using T2‐weighted inversion recovery sequences, dual‐echo relaxometry sequences with spectral fat saturation, and two gradient‐echo sequences with and without an off‐resonance saturation rapid frequency pulse. Detailed quantification of nerve lesions by morphometric and microstructural MRN markers, including T2 relaxometry and magnetization transfer contrast imaging, was conducted in all study participants. Results MRN detected peripheral nerve damage in ataxic and pre‐ataxic SCA3. The quantitative markers proton spin density ( ρ ), T2 relaxation time, magnetization transfer ratio and cross‐sectional area were decreased in SCA3, indicating chronic axonopathy. MTR and ρ identified early, subclinical nerve damage in pre‐ataxic SCA3 and in SCA3 mutation carriers without polyneuropathy and were superior in differentiating between all subgroups. Additionally, microstructural markers correlated well with clinical symptom scores and electrophysiological results. Conclusions Our data provide a comprehensive characterization of peripheral nerve damage in SCA3 and assist in understanding the mechanisms of the multisystemic disease evolution. Evidence of peripheral nerve involvement prior to the onset of clinically overt ataxia might have important implications for designing early intervention studies.
    Type of Medium: Online Resource
    ISSN: 1351-5101 , 1468-1331
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2020241-6
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  • 4
    In: European Journal of Neurology, Wiley, Vol. 30, No. 8 ( 2023-08), p. 2442-2452
    Abstract: Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders. While peripheral nerve involvement is frequent in spastic paraplegia 7 (SPG7), the evidence of peripheral nerve involvement in SPG4 is more controversial. We aimed to characterize lower extremity peripheral nerve involvement in SPG4 and SPG7 by quantitative magnetic resonance neurography (MRN). Methods Twenty‐six HSP patients carrying either the SPG4 or SPG7 mutation and 26 age‐/sex‐matched healthy controls prospectively underwent high‐resolution MRN with large coverage of the sciatic and tibial nerve. Dual‐echo turbo‐spin‐echo sequences with spectral fat‐saturation were utilized for T2‐relaxometry and morphometric quantification, while two gradient‐echo sequences with and without an off‐resonance saturation rapid frequency pulse were applied for magnetization transfer contrast (MTC) imaging. HSP patients additionally underwent detailed neurologic and electroneurographic assessments. Results All microstructural (proton spin density [ρ], T2‐relaxation time, magnetization transfer ratio) and morphometric (cross‐sectional area) quantitative MRN markers were decreased in SPG4 and SPG7 indicating chronic axonopathy. ρ was superior in differentiating subgroups and identifying subclinical nerve damage in SPG4 and SPG7 without neurophysiologic signs of polyneuropathy. MRN markers correlated well with clinical scores and electroneurographic results. Conclusions MRN characterizes peripheral nerve involvement in SPG4 and SPG7 as a neuropathy with predominant axonal loss. Evidence of peripheral nerve involvement in SPG4 and SPG7, even without electroneurographically manifest polyneuropathy, and the good correlation of MRN markers with clinical measures of disease progression, challenge the traditional view of the existence of HSPs with isolated pyramidal signs and suggest MRN markers as potential progression biomarkers in HSP.
    Type of Medium: Online Resource
    ISSN: 1351-5101 , 1468-1331
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2020241-6
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  • 5
    Online Resource
    Online Resource
    Wiley ; 2014
    In:  Hydrological Processes Vol. 28, No. 4 ( 2014-02-15), p. 1916-1930
    In: Hydrological Processes, Wiley, Vol. 28, No. 4 ( 2014-02-15), p. 1916-1930
    Abstract: Monitoring runoff generation processes in the field is a prerequisite for developing conceptual hydrological models and theories. At the same time, our perception of hydrological processes strongly depends on the spatial and temporal scale of observation. Therefore, the aim of this study is to investigate interactions between runoff generation processes of different spatial scales (plot scale, hillslope scale, and headwater scale). Different runoff generation processes of three hillslopes with similar topography, geology and soil properties, but differences in vegetation cover (grassland, coniferous forest, and mixed forest) within a small v‐shaped headwater were measured: water table dynamics in wells with high spatial and temporal resolution, subsurface flow (SSF) of three 10 m wide trenches at the bottom of the hillslopes subdivided into two trench sections each, overland flow at the plot scale, and catchment runoff. Bachmair et al . ( ) found a high spatial variability of water table dynamics at the plot scale. In this study, we investigate the representativity of SSF observations at the plot scale versus the hillslope scale and vice versa, and the linkage between hillslope dynamics (SSF and overland flow) and streamflow. Distinct differences in total SSF within each 10 m wide trench confirm the high spatial variability of the water table dynamics. The representativity of plot scale observations for hillslope scale SSF strongly depends on whether or not wells capture spatially variable flowpaths. At the grassland hillslope, subsurface flowpaths are not captured by our relatively densely spaced wells (3 m), despite a similar trench flow response to the coniferous forest hillslope. Regarding the linkage between hillslope dynamics and catchment runoff, we found an intermediate to high correlation between streamflow and hillslope hydrological dynamics (trench flow and overland flow), which highlights the importance of hillslope processes in this small watershed. Although the total contribution of SSF to total event catchment runoff is rather small, the contribution during peak flow is moderate to substantial. Additionally, there is process synchronicity between spatially discontiguous measurement points across scales, potentially indicating subsurface flowpath connectivity. Our findings stress the need for (i) a combination of observations at different spatial scales, and (ii) a consideration of the high spatial variability of SSF at the plot and hillslope scale when designing monitoring networks and assessing hydrological connectivity. Copyright © 2013 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0885-6087 , 1099-1085
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 1479953-4
    SSG: 14
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  • 6
    Online Resource
    Online Resource
    Wiley ; 2018
    In:  Hydrological Processes Vol. 32, No. 1 ( 2018-01), p. 160-166
    In: Hydrological Processes, Wiley, Vol. 32, No. 1 ( 2018-01), p. 160-166
    Abstract: Quantifying the components of rain, snowmelt, and glacier ice melt in river discharge is an important but difficult task in hydrology. Although it forms the basis of many climate impact assessments, many published modelling results do not clearly describe how they derived the discharge components. Consequently, reported components such as absolute amounts or relative percentages of snow and ice melt from different studies are rarely comparable. This commentary revisits the differences in the terminology used, the modelling approaches, and the possible conclusions for effects at different time scales. We argue that for questions related to changes in discharge, not particle tracking, for which methodology is widely available, but instead, an “effect tracking” of the input contributions is important, that is, the representation of the signals of rainfall, snowmelt, and glacier ice melt in the discharge at the catchment outlet. We introduce and briefly describe a method for effect tracking and discuss the differences and advantages compared to other methods. This comparison supports our call to the modelling community for more precise descriptions of how the generated input contributions into a catchment from rainfall, snowmelt, and glacier ice melt are tracked through the catchments' multiple stores to finally compose the presented hydrographs.
    Type of Medium: Online Resource
    ISSN: 0885-6087 , 1099-1085
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 1479953-4
    SSG: 14
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  • 7
    In: Annals of Neurology, Wiley, Vol. 78, No. 6 ( 2015-12), p. 939-948
    Abstract: The aim of this work was to localize and quantify alterations of nerve microstructure in diabetic polyneuropathy (DPN) by magnetic resonance (MR) neurography with large anatomical coverage. Methods Patients (N = 25) with mild‐to‐moderate (Neuropathy‐Symptom‐Score [NSS]/Neuropathy Deficit Score [NDS] 3.8 ± 0.3/2.6 ± 0.5) and patients (n = 10) with severe DPN (6.2 ± 0.6/7.4 ± 0.5) were compared to patients (n = 15) with diabetes but no DPN and to age‐/sex‐matched nondiabetic controls (n = 25). All subjects underwent MR neurography with large spatial coverage and high resolution from spinal nerve to ankle level: four slabs per leg, each with 35 axial slices (T2‐ and proton‐density–weighted two dimensional turbo‐spin‐echo sequences; voxel size: 0.4 × 0.3 × 3.5 mm 3 ) and a three‐dimensional T2‐weighted sequence to cover spinal nerves and plexus. Nerve segmentation was performed on a total of 280 slices per subject. Nerve lesion voxels were determined independently from operator input by statistical classification against the nondiabetic cohort. At the site with highest lesion‐voxel burden, signal quantification was performed by calculating nerve proton spin density and T2 relaxation time. Results Total burden of nerve lesion voxels was significantly increased in DPN ( p  = 0.003) with strong spatial predominance at thigh level, where average lesion voxel load was significantly higher in severe (57 ± 18.4; p  = 0.0022) and in mild‐to‐moderate DPN (35 ± 4.0; p   〈  0.001) than in controls (18 ± 3.6). Signal quantification at the site of predominant lesion burden (thigh) revealed a significant increase of nerve proton spin density in severe (360 ± 22.9; p  = 0.043) and in mild‐to‐moderate DPN (365 ± 15.2; p  = 0.001) versus controls (288 ± 13.4), but not of T2 relaxation time ( p  = 0.49). Nerve proton spin density predicted severity of DPN with an odds ratio of 2.9 (95% confidence interval: 2.4–3.5; p   〈  0.001) per 100 proton spins. Interpretation In DPN, the predominant site of microstructural nerve alteration is at the thigh level with a strong proximal‐to‐distal gradient. Nerve proton spin density at the thigh level is a novel quantitative imaging biomarker of early DPN and increases with neuropathy severity. Ann Neurol 2015;78:939–948
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 2037912-2
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  • 8
    In: Hydrological Processes, Wiley, Vol. 25, No. 20 ( 2011-09-30), p. 3187-3203
    Abstract: Hydrologic models have increasingly been used in forest hydrology to overcome the limitations of paired watershed experiments, where vegetative recovery and natural variability obscure the inferences and conclusions that can be drawn from such studies. Models are also plagued by uncertainty, however, and parameter equifinality is a common concern. Physically‐based, spatially‐distributed hydrologic models must therefore be tested with high‐quality experimental data describing a multitude of concurrent internal catchment processes under a range of hydrologic regimes. This study takes a novel approach by not only examining the ability of a pre‐calibrated model to realistically simulate watershed outlet flows over a four year period, but a multitude of spatially‐extensive, internal catchment process observations not previously evaluated, including: continuous groundwater dynamics, instantaneous stream and road network flows, and accumulation and melt period spatial snow distributions. Many hydrologic model evaluations are only on the comparison of predicted and observed discharge at a catchment outlet and remain in the ‘infant stage’ in terms of model testing. This study, on the other hand, tests the internal spatial predictions of a distributed model with a range of field observations over a wide range of hydroclimatic conditions. Nash‐Sutcliffe model efficiency was improved over prior evaluations due to continuing efforts in improving the quality of meteorological data collection. Road and stream network flows were generally well simulated for a range of hydrologic conditions, and snowpack spatial distributions were well simulated for one of two years examined. The spatial variability of groundwater dynamics was effectively simulated, except at locations where strong stream–groundwater interactions exist. Model simulations overall were quite successful in realistically simulating the spatiotemporal variability of internal catchment processes in the watershed, but the premature onset of simulated snowmelt for one of the simulation years has prompted further work in model development. Copyright © 2011 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0885-6087 , 1099-1085
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2011
    detail.hit.zdb_id: 1479953-4
    SSG: 14
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  • 9
    Online Resource
    Online Resource
    Wiley ; 2017
    In:  Hydrological Processes Vol. 31, No. 1 ( 2017-01), p. 15-19
    In: Hydrological Processes, Wiley, Vol. 31, No. 1 ( 2017-01), p. 15-19
    Abstract: Preferential flow is of high relevance for runoff generation, transport of chemicals and nutrients, and the transit time distribution of water in the soil or watershed. However, preferential flow effects are generally ignored in lumped hydrological models. And even most physically‐based models ignore macropores and preferential flow features at the soil and hillslope scale. Keith Beven was never satisfied with this situation and he tried again and again to convince the scientific community to focus their research on the complex topic of macropore and preferential flow. Although he recognized how difficult it is to correctly include preferential flow in hydrological models, he made substantial progress defining and describing macropore flow and showing its relevance, developing models to simulate preferential flow, and in particular, the interaction between macropores and the soil matrix. In this short commentary, I reflect on these achievements and outline a vision for research in preferential flow experiments and modeling.
    Type of Medium: Online Resource
    ISSN: 0885-6087 , 1099-1085
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2017
    detail.hit.zdb_id: 1479953-4
    SSG: 14
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  • 10
    In: Hydrological Processes, Wiley, Vol. 35, No. 5 ( 2021-05)
    Type of Medium: Online Resource
    ISSN: 0885-6087 , 1099-1085
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 1479953-4
    SSG: 14
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