Browsing by Author "van der Plas, Ellen"

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    Blood-Based Markers of Neuronal Injury in Adult-Onset Myotonic Dystrophy Type 1
    (Frontiers Media, 2022-01-20) van der Plas, Ellen; Long, Jeffrey D.; Koscik, Timothy R.; Magnotta, Vincent; Monckton, Darren G.; Cumming, Sarah A.; Gottschalk, Amy C.; Hefti, Marco; Gutmann, Laurie; Nopoulos, Peggy C.; Neurology, School of Medicine
    Introduction: The present study had four aims. First, neuronal injury markers, including neurofilament light (NF-L), total tau, glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase (UCH-L1), were compared between individuals with and without adult-onset myotonic dystrophy type 1 (DM1). Second, the impact of age and CTG repeat on brain injury markers was evaluated. Third, change in brain injury markers across the study period was quantified. Fourth, associations between brain injury markers and cerebral white matter (WM) fractional anisotropy (FA) were identified. Methods: Yearly assessments, encompassing blood draws and diffusion tensor imaging on a 3T scanner, were conducted on three occasions. Neuronal injury markers were quantified using single molecule array (Simoa). Results: The sample included 53 patients and 70 controls. NF-L was higher in DM1 patients than controls, with individuals in the premanifest phases of DM1 (PreDM1) exhibiting intermediate levels ( χ 2 ( 2 ) = 38.142, P < 0.001). Total tau was lower in DM1 patients than controls (Estimate = -0.62, 95% confidence interval [CI] -0.95: -0.28, P < 0.001), while GFAP was elevated in PreDM1 only (Estimate = 30.37, 95% CI 10.56:50.19, P = 0.003). Plasma concentrations of UCH-L1 did not differ between groups. The age by CTG interaction predicted NF-L: patients with higher estimated progenitor allelege length (ePAL) had higher NF-L at a younger age, relative to patients with lower CTG repeat; however, the latter exhibited faster age-related change (Estimate = -0.0021, 95% CI -0.0042: -0.0001, P = 0.045). None of the markers changed substantially over the study period. Finally, cerebral WM FA was significantly associated with NF-L (Estimate = -42.86, 95% CI -82.70: -3.02, P = 0.035). Interpretation: While NF-L appears sensitive to disease onset and severity, its utility as a marker of progression remains to be determined. The tau assay may have low sensitivity to tau pathology associated with DM1.
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    Brain Imaging in Pediatric Cancer Survivors: Correlates of Cognitive Impairment
    (American Society of Clinical Oncology, 2021) Kesler, Shelli R.; Sleurs, Charlotte; McDonald, Brenna C.; Deprez, Sabine; van der Plas, Ellen; Nieman, Brian J.; Radiology and Imaging Sciences, School of Medicine
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    Cognitive Deficits, Apathy, and Hypersomnolence Represent the Core Brain Symptoms of Adult-Onset Myotonic Dystrophy Type 1
    (Frontiers Media, 2021-07) Miller, Jacob N.; Kruger, Alison; Moser, David J.; Gutmann, Laurie; van der Plas, Ellen; Koscik, Timothy R.; Cumming, Sarah A.; Monckton, Darren G.; Nopoulos, Peggy C.; Neurology, School of Medicine
    Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults, and is primarily characterized by muscle weakness and myotonia, yet some of the most disabling symptoms of the disease are cognitive and behavioral. Here we evaluated several of these non-motor symptoms from a cross-sectional time-point in one of the largest longitudinal studies to date, including full-scale intelligence quotient, depression, anxiety, apathy, sleep, and cerebral white matter fractional anisotropy in a group of 39 adult-onset myotonic dystrophy type 1 participants (27 female) compared to 79 unaffected control participants (46 female). We show that intelligence quotient was significantly associated with depression (P < 0.0001) and anxiety (P = 0.018), but not apathy (P < 0.058) or hypersomnolence (P = 0.266) in the DM1 group. When controlling for intelligence quotient, cerebral white matter fractional anisotropy was significantly associated with apathy (P = 0.042) and hypersomnolence (P = 0.034), but not depression (P = 0.679) or anxiety (P = 0.731) in the myotonic dystrophy type 1 group. Finally, we found that disease duration was significantly associated with apathy (P < 0.0001), hypersomnolence (P < 0.001), IQ (P = 0.038), and cerebral white matter fractional anisotropy (P < 0.001), but not depression (P = 0.271) or anxiety (P = 0.508). Our results support the hypothesis that cognitive deficits, hypersomnolence, and apathy, are due to the underlying neuropathology of myotonic dystrophy type 1, as measured by cerebral white matter fractional anisotropy and disease duration. Whereas elevated symptoms of depression and anxiety in myotonic dystrophy type 1 are secondary to the physical symptoms and the emotional stress of coping with a chronic and debilitating disease. Results from this work contribute to a better understanding of disease neuropathology and represent important therapeutic targets for clinical trials.
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    Fully Automated 3D Segmentation of MR-Imaged Calf Muscle Compartments: Neighborhood Relationship Enhanced Fully Convolutional Network
    (Elsevier, 2021) Guo, Zhihui; Zhang, Honghai; Chen, Zhi; van der Plas, Ellen; Gutmann, Laurie; Thedens, Daniel; Nopoulos, Peggy; Sonka, Milan; Neurology, School of Medicine
    Automated segmentation of individual calf muscle compartments from 3D magnetic resonance (MR) images is essential for developing quantitative biomarkers for muscular disease progression and its prediction. Achieving clinically acceptable results is a challenging task due to large variations in muscle shape and MR appearance. In this paper, we present a novel fully convolutional network (FCN) that utilizes contextual information in a large neighborhood and embeds edge-aware constraints for individual calf muscle compartment segmentations. An encoder-decoder architecture is used to systematically enlarge convolution receptive field and preserve information at all resolutions. Edge positions derived from the FCN output muscle probability maps are explicitly regularized using kernel-based edge detection in an end-to-end optimization framework. Our method was evaluated on 40 T1-weighted MR images of 10 healthy and 30 diseased subjects by fourfold cross-validation. Mean DICE coefficients of 88.00-91.29% and mean absolute surface positioning errors of 1.04-1.66 mm were achieved for the five 3D muscle compartments.
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    Longitudinal changes in white matter as measured with diffusion tensor imaging in adult-onset myotonic dystrophy type 1
    (Elsevier, 2023) Koscik, Timothy R.; van der Plas, Ellen; Long, Jeffrey D.; Cross, Stephen; Gutmann, Laurie; Cumming, Sarah A.; Monckton, Darren G.; Shields, Richard K.; Magnotta, Vincent; Nopoulos, Peggy C.; Neurology, School of Medicine
    Myotonic dystrophy type 1 is characterized by neuromuscular degeneration. Our objective was to compare change in white matter microstructure (fractional anisotropy, radial and axial diffusivity), and functional/clinical measures. Participants underwent yearly neuroimaging and neurocognitive assessments over three-years. Assessments encompassed full-scale intelligence, memory, language, visuospatial skills, attention, processing speed, and executive function, as well as clinical symptoms of muscle/motor function, apathy, and hypersomnolence. Mixed effects models were used to examine differences. 69 healthy adults (66.2% women) and 41 DM1 patients (70.7% women) provided 156 and 90 observations, respectively. There was a group by elapsed time interaction for cerebral white matter, where DM1 patients exhibited declines in white matter (all p<0.05). Likewise, DM1 patients either declined (motor), improved more slowly (intelligence), or remained stable (executive function) for functional outcomes. White matter was associated with functional performance; intelligence was predicted by axial (r = 0.832; p<0.01) and radial diffusivity (r = 0.291, p<0.05), and executive function was associated with anisotropy (r = 0.416, p<0.001), and diffusivity (axial: r = 0.237, p = 0.05 and radial: r = 0.300, p<0.05). Indices of white matter health are sensitive to progression in DM1. These results are important for clinical trial design, which utilize short intervals to establish treatment efficacy.
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    Quantitative muscle MRI as a sensitive marker of early muscle pathology in myotonic dystrophy type 1
    (Wiley, 2021) van der Plas, Ellen; Gutmann, Laurie; Thedens, Dan; Shields, Richard K.; Langbehn, Kathleen; Guo, Zhihui; Sonka, Milan; Nopoulos, Peggy; Neurology, School of Medicine
    Background: Quantitative muscle MRI as a sensitive marker of early muscle pathology and disease progression in adult-onset myotonic dystrophy type 1. The utility of muscle MRI as a marker of muscle pathology and disease progression in adult-onset myotonic dystrophy type 1 (DM1) was evaluated. Methods: This prospective, longitudinal study included 67 observations from 36 DM1 patients (50% female), and 92 observations from 49 healthy adults (49% female). Lower-leg 3T magnetic resonance imaging (MRI) scans were acquired. Volume and fat fraction (FF) were estimated using a three-point Dixon method, and T2-relaxometry was determined using a multi-echo spin-echo sequence. Muscles were segmented automatically. Mixed linear models were conducted to determine group differences across muscles and image modality, accounting for age, sex, and repeated observations. Differences in rate of change in volume, T2-relaxometry, and FF were also determined with mixed linear regression that included a group by elapsed time interaction. Results: Compared with healthy adults, DM1 patients exhibited reduced volume of the tibialis anterior, soleus, and gastrocnemius (GAS) (all, P < .05). T2-relaxometry and FF were increased across all calf muscles in DM1 compared to controls. (all, P < .01). Signs of muscle pathology, including reduced volume, and increased T2-relaxometry and FF were already noted in DM1 patients who did not exhibit clinical motor symptoms of DM1. As a group, DM1 patients exhibited a more rapid change than did controls in tibialis posterior volume (P = .05) and GAS T2-relaxometry (P = .03) and FF (P = .06). Conclusions: Muscle MRI renders sensitive, early markers of muscle pathology and disease progression in DM1. T2 relaxometry may be particularly sensitive to early muscle changes related to DM1.