- Browse by Author
Browsing by Author "Gutmann, Laurie"
Now showing 1 - 8 of 8
Results Per Page
Sort Options
Item 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 MedicineIntroduction: 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.Item 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 MedicineMyotonic 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.Item Cognitive Function and its Relationship with Brain Structure in Myotonic Dystrophy Type 1(Wiley, 2021) Langbehn, Kathleen E.; van der Plas, Ellen; Moser, David J.; Long, Jeffrey D.; Gutmann, Laurie; Nopoulos, Peg; Neurology, School of MedicineStudies have shown relationships between white matter abnormalities and cognitive dysfunction in myotonic dystrophy type 1 (DM1), but comprehensive analysis of potential structure-function relationships are lacking. Fifty adult-onset DM1 individuals (33 female) and 68 unaffected adults (45 female) completed the Wechsler Adult Intelligence Scale-IV (WAIS-IV) to determine the levels and patterns of intellectual functioning. Neuroimages were acquired with a 3T scanner and were processed with BrainsTools. Regional brain volumes (regions of interest, ROIs) were adjusted for inter-scanner variation and intracranial volume. Linear regression models were conducted to assess if group by ROI interaction terms significantly predicted WAIS-IV composite scores. Models were adjusted for age and sex. The DM1 group had lower Perceptual Reasoning Index (PRI), Working Memory Index (WMI), and Processing Speed Index (PSI) scores than the unaffected group (PRI t(113) = -3.28, p = 0.0014; WMI t(114) = -3.49, p = 0.0007; PSI t(114) = -2.98, p = 0.0035). The group by hippocampus interaction term was significant for both PRI and PSI (PRI (t(111) = -2.82, p = 0.0057; PSI (t(112) = -2.87, p = 0.0049)). There was an inverse association between hippocampal volume and both PRI and PSI in the DM1 group (the higher the volume, the lower the intelligence quotient scores), but no such association was observed in the unaffected group. Enlarged hippocampal volume may underlie some aspects of cognitive dysfunction in adult-onset DM1, suggesting that increased volume of the hippocampus may be pathological.Item Contemporary Neuroscience Core Curriculum for Medical Schools(Wolters Kluwer, 2021-10-04) Gelb, Douglas J.; Kraakevik, Jeff; Safdieh, Joseph E.; Agarwal, Sachin; Odia, Yazmin; Govindarajan, Raghav; Quick, Adam; Soni, Madhu; AAN Undergraduate Education Subcommittee (UES); Bickel, Jennifer; Gamaldo, Charlene; Hannon, Peter; Hatch, Hayden A. M.; Hernandez, Christian; Merlin, Lisa R.; Noble, James M.; Reyes-Iglesias, Yolanda; Salas, Rachel Marie E.; Sandness, David James; Treat, Lauren; AAN Education Committee; Benameur, Karima; Brown, Robert D., Jr.; DeLuca, Gabriele C.; Garg, Neeta; Goldstein, Larry B.; Gutmann, Laurie; Henchcliffe, Claire; Hessler, Amy; Jordan, Justin T.; Kilgore, Shannon M.; Khan, Jaffar; Levin, Kerry H.; Mohile, Nimish A.; Nevel, Kathryn S.; Roberts, Kirk; Said, Rana R.; Simpson, Ericka P.; Sirven, Joseph I.; Smith, A. Gordon; Southerland, Andrew Mebane; Wilson, Rujuta B.; Neurology, School of MedicineMedical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their clinical experiences in all other medical disciplines also because the nervous system plays such a critical role in the function of every organ system. Because of the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the preclerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are reassessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the preclerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors.Item 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 MedicineAutomated 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.Item Investigating Late-Onset Pompe Prevalence in Neuromuscular Medicine Academic Practices: The IPaNeMA Study(Wolters Kluwer, 2021-10-18) Wencel, Marie; Shaibani, Aziz; Goyal, Namita A.; Dimachkie, Mazen M.; Trivedi, Jaya; Johnson, Nicholas E.; Gutmann, Laurie; Wicklund, Matthew P.; Bandyopadhay, Sankar; Genge, Angela L.; Freimer, Miriam L.; Goyal, Neelam; Pestronk, Alan; Florence, Julaine; Karam, Chafic; Ralph, Jeffrey W.; Rasheed, Zinah; Hays, Melissa; Hopkins, Steve; Mozaffar, Tahseen; Neurology, School of MedicineBackground and objectives: We investigated the prevalence of late-onset Pompe disease (LOPD) in patients presenting to 13 academic, tertiary neuromuscular practices in the United States and Canada. Methods: All successive patients presenting with proximal muscle weakness or isolated hyperCKemia and/or neck muscle weakness to these 13 centers were invited to participate in the study. Whole blood was tested for acid alpha-glucosidase (GAA) assay through the fluorometric method, and all cases with enzyme levels of ≤10 pmoL/punch/h were reflexed to molecular testing for mutations in the GAA gene. Clinical and demographic information was abstracted from their clinical visit and, along with study data, entered into a purpose-built REDCap database, and analyzed at the University of California, Irvine. Results: GAA enzyme assay results were available on 906 of the 921 participants who consented for the study. LOPD was confirmed in 9 participants (1% prevalence). Another 9 (1%) were determined to have pseudodeficiency of GAA, whereas 19 (1.9%) were found to be heterozygous for a pathogenic GAA mutation (carriers). Of the definite LOPD participants, 8 (89%) were Caucasian and were heterozygous for the common leaky (IVS1) splice site mutation in the GAA gene (c -32-13T>G), with a second mutation that was previously confirmed to be pathogenic. Discussion: The prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles.Item 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 MedicineMyotonic 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.Item 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 MedicineBackground: 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.