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Item 3,4-Diaminopyridine Base Effectively Treats the Weakness of Lambert-Eaton Myasthenia(Wiley, 2018) Sanders, Donald B.; Juel, Vern C.; Harati, Yadollah; Smith, A. Gordon; Peltier, Amanda C.; Marburger, Tessa; Lou, Jau-Shin; Pascuzzi, Robert M.; Richman, David P.; Xie, Tai; Demmel, Valentin; Jacobus, Laura R.; Aleš, Kathy L.; Jacobus, David P.; Neurology, School of MedicineIntroduction: 3,4-diaminopyridine has been used to treat Lambert Eaton myasthenia (LEM) for thirty years despite the lack of conclusive evidence of efficacy. Methods: We conducted a randomized double-blind placebo-controlled withdrawal study in LEM patients who had been on stable regimens of 3,4-diaminopyridine base (3,4-DAP) for ≥ 3 months. The primary efficacy endpoint was >30% deterioration in Triple Timed Up-and-Go (3TUG) times during tapered drug withdrawal. The secondary endpoint was self-assessment of LEM–related weakness (W-SAS). Results: 32 participants were randomized to continuous 3,4-DAP or placebo. None of the 14 receiving continuous 3,4-DAP had >30% deterioration in 3TUG time vs 72% of the 18 who tapered to placebo (p<0.0001). W-SAS similarly demonstrated an advantage for continuous treatment over placebo (p<0.0001). Need for rescue and adverse events were more common in the placebo group. Discussion: This trial provides significant evidence of efficacy of 3,4-DAP in the maintenance of strength in LEM.Item A comparison of techniques for deriving clustering and switching scores from verbal fluency word lists(Frontiers Media, 2022-09-14) Bushnell, Justin; Svaldi, Diana; Ayers, Matthew R.; Gao, Sujuan; Unverzagt, Frederick; Del Gaizo, John; Wadley, Virginia G.; Kennedy, Richard; Goñi, Joaquín; Clark, David Glenn; Neurology, School of MedicineObjective: To compare techniques for computing clustering and switching scores in terms of agreement, correlation, and empirical value as predictors of incident cognitive impairment (ICI). Methods: We transcribed animal and letter F fluency recordings on 640 cases of ICI and matched controls from a national epidemiological study, amending each transcription with word timings. We then calculated clustering and switching scores, as well as scores indexing speed of responses, using techniques described in the literature. We evaluated agreement among the techniques with Cohen's κ and calculated correlations among the scores. After fitting a base model with raw scores, repetitions, and intrusions, we fit a series of Bayesian logistic regression models adding either clustering and switching scores or speed scores, comparing the models in terms of several metrics. We partitioned the ICI cases into acute and progressive cases and repeated the regression analysis for each group. Results: For animal fluency, we found that models with speed scores derived using the slope difference algorithm achieved the best values of the Watanabe-Akaike Information Criterion (WAIC), but with good net reclassification improvement (NRI) only for the progressive group (8.2%). For letter fluency, different models excelled for prediction of acute and progressive cases. For acute cases, NRI was best for speed scores derived from a network model (3.4%), while for progressive cases, the best model used clustering and switching scores derived from the same network model (5.1%). Combining variables from the best animal and letter F models led to marginal improvements in model fit and NRI only for the all-cases and acute-cases analyses. Conclusion: Speed scores improve a base model for predicting progressive cognitive impairment from animal fluency. Letter fluency scores may provide complementary information.Item A peptide-centric quantitative proteomics dataset for the phenotypic assessment of Alzheimer's disease(Springer Nature, 2023-04-14) Merrihew, Gennifer E.; Park, Jea; Plubell, Deanna; Searle, Brian C.; Keene, C. Dirk; Larson, Eric B.; Bateman, Randall; Perrin, Richard J.; Chhatwal, Jasmeer P.; Farlow, Martin R.; McLean, Catriona A.; Ghetti, Bernardino; Newell, Kathy L.; Frosch, Matthew P.; Montine, Thomas J.; MacCoss, Michael J.; Neurology, School of MedicineAlzheimer's disease (AD) is a looming public health disaster with limited interventions. Alzheimer's is a complex disease that can present with or without causative mutations and can be accompanied by a range of age-related comorbidities. This diverse presentation makes it difficult to study molecular changes specific to AD. To better understand the molecular signatures of disease we constructed a unique human brain sample cohort inclusive of autosomal dominant AD dementia (ADD), sporadic ADD, and those without dementia but with high AD histopathologic burden, and cognitively normal individuals with no/minimal AD histopathologic burden. All samples are clinically well characterized, and brain tissue was preserved postmortem by rapid autopsy. Samples from four brain regions were processed and analyzed by data-independent acquisition LC-MS/MS. Here we present a high-quality quantitative dataset at the peptide and protein level for each brain region. Multiple internal and external control strategies were included in this experiment to ensure data quality. All data are deposited in the ProteomeXchange repositories and available from each step of our processing.Item A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease(Springer Nature, 2021) Salloway, Stephen; Farlow, Martin; McDade, Eric; Clifford, David B.; Wang, Guoqiao; Llibre-Guerra, Jorge J.; Hitchcock, Janice M.; Mills, Susan L.; Santacruz, Anna M.; Aschenbrenner, Andrew J.; Hassenstab, Jason; Benzinger, Tammie L.S.; Gordon, Brian A.; Fagan, Anne M.; Coalier, Kelley A.; Cruchaga, Carlos; Goate, Alison A.; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Snider, B. Joy; Mummery, Catherine; Surti, G. Mustafa; Hannequin, Didier; Wallon, David; Berman, Sarah B.; Lah, James J.; Jimenez-Velazquez, Ivonne Z.; Roberson, Erik D.; van Dyck, Christopher H.; Honig, Lawrence S.; Sánchez-Valle, Raquel; Brooks, William S.; Gauthier, Serge; Galasko, Douglas R.; Masters, Colin L.; Brosch, Jared R.; Hsiung, Ging-Yuek Robin; Jayadev, Suman; Formaglio, Maité; Masellis, Mario; Clarnette, Roger; Pariente, Jérémie; Dubois, Bruno; Pasquier, Florence; Jack, Clifford R., Jr.; Koeppe, Robert; Snyder, Peter J.; Aisen, Paul S.; Thomas, Ronald G.; Berry, Scott M.; Wendelberger, Barbara A.; Andersen, Scott W.; Holdridge, Karen C.; Mintun, Mark A.; Yaari, Roy; Sims, John R.; Baudler, Monika; Delmar, Paul; Doody, Rachelle S.; Fontoura, Paulo; Giacobino, Caroline; Kerchner, Geoffrey A.; Bateman, Randall J.; Dominantly Inherited Alzheimer Network–Trials Unit; Neurology, School of MedicineDominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.Item Accelerated functional brain aging in pre-clinical familial Alzheimer’s disease(Springer Nature, 2021-09-09) Gonneaud, Julie; Baria, Alex T.; Binette, Alexa Pichet; Gordon, Brian A.; Chhatwal, Jasmeer P.; Cruchaga, Carlos; Jucker, Mathias; Levin, Johannes; Salloway, Stephen; Farlow, Martin; Gauthier, Serge; Benzinger, Tammie L.S.; Morris, John C.; Bateman, Randall J.; Breitner, John C.S.; Poirier, Judes; Vachon-Presseau, Etienne; Villeneuve, Sylvia; Neurology, School of MedicineResting state functional connectivity (rs-fMRI) is impaired early in persons who subsequently develop Alzheimer’s disease (AD) dementia. This impairment may be leveraged to aid investigation of the pre-clinical phase of AD. We developed a model that predicts brain age from resting state (rs)-fMRI data, and assessed whether genetic determinants of AD, as well as beta-amyloid (Aβ) pathology, can accelerate brain aging. Using data from 1340 cognitively unimpaired participants between 18–94 years of age from multiple sites, we showed that topological properties of graphs constructed from rs-fMRI can predict chronological age across the lifespan. Application of our predictive model to the context of pre-clinical AD revealed that the pre-symptomatic phase of autosomal dominant AD includes acceleration of functional brain aging. This association was stronger in individuals having significant Aβ pathology.Item Accumulation of high magnitude acceleration events predicts cerebrovascular reactivity changes in female high school soccer athletes(Springer, 2018) Svaldi, Diana O.; Joshi, Chetas; McCuen, Emily C.; Music, Jacob P.; Hannemann, Robert; Leverenz, Larry J.; Nauman, Eric A.; Talavage, Thomas M.; Neurology, School of MedicineMitigating the effects of repetitive exposure to head trauma has become a major concern for the general population, given the growing body of evidence that even asymptomatic exposure to head accelerations is linked with increased risk for negative life outcomes and that risk increases as exposure is prolonged over many years. Among women's sports, soccer currently exhibits the highest growth in participation and reports the largest number of mild traumatic brain injuries annually, making female soccer athletes a relevant population in assessing the effects of repetitive exposure to head trauma. Cerebrovascular biomarkers may be useful in assessing the effects of repetitive head trauma, as these are thought to contribute directly to neurocognitive symptoms associated with mild traumatic brain injury. Here we use fMRI paired with a hypercapnic breath hold task along with monitoring of head acceleration events, to assess the relationship between cerebrovascular brain changes and exposure to repetitive head trauma over a season of play in female high school soccer athletes. We identified longitudinal changes in cerebrovascular reactivity that were significantly associated with prolonged accumulation to high magnitude (> 75th percentile) head acceleration events. Findings argue for active monitoring of athletes during periods of exposure to head acceleration events, illustrate the importance of collecting baseline (i.e., pre-exposure) measurements, and suggest modeling as a means of guiding policy to mitigate the effects of repetitive head trauma.Item ACMT Position Statement: Determining Brain Death in Adults After Drug Overdose(Springer Nature, 2017-09) Neavyn, Mark J.; Stolbach, Andrew; Greer, David M.; Nelson, Lewis S.; Smith, Silas W.; Brent, Jeffrey; Tormoehlen, Laura M.; Neurology, School of MedicineItem Acute and Delayed Cerebrovascular Injury From Gunshot to the Head in a 12-Year-Old Child During the COVID-19 Pandemic(Elsevier, 2022) Golomb, Meredith R.; Tejada, Juan G.; Ducis, Katrina A.; Martinez, Mesha L.; Neurology, School of MedicineItem Acute Ischemic Stroke, Depressed Left Ventricular Ejection Fraction, and Sinus Rhythm: Prevalence and Practice Patterns(American Heart Association, 2022) Baker, Anna D.; Schwamm, Lee H.; Sanborn, Danita Y.; Furie, Karen; Stretz, Christoph; Grory, Brian Mac; Yaghi, Shadi; Kleindorfer, Dawn; Sucharew, Heidi; Mackey, Jason; Walsh, Kyle; Flaherty, Matt; Kissela, Brett; Alwell, Kathleen; Khoury, Jane; Khatri, Pooja; Adeoye, Opeolu; Ferioli, Simona; Woo, Daniel; Martini, Sharyl; De Los Rios La Rosa, Felipe; Demel, Stacie L.; Madsen, Tracy; Star, Michael; Coleman, Elisheva; Slavin, Sabreena; Jasne, Adam; Mistry, Eva A.; Haverbusch, Mary; Merkler, Alexander E.; Kamel, Hooman; Schindler, Joseph; Sansing, Lauren H.; Faridi, Kamil F.; Sugeng, Lissa; Sheth, Kevin N.; Sharma, Richa; Neurology, School of MedicineBackground: There are limited data about the epidemiology and secondary stroke prevention strategies used for patients with depressed left ventricular ejection fraction (LVEF) and sinus rhythm following an acute ischemic stroke (AIS). We sought to describe the prevalence of LVEF ≤40% and sinus rhythm among patients with AIS and antithrombotic treatment practice in a multi-center cohort from 2002 to 2018. Methods: This was a multi-center, retrospective cohort study comprised of patients with AIS hospitalized in the Greater Cincinnati Northern Kentucky Stroke Study and 4 academic, hospital-based cohorts in the United States. A 1-stage meta-analysis of proportions was undertaken to calculate a pooled prevalence. Univariate analyses and an adjusted multivariable logistic regression model were performed to identify demographic, clinical, and echocardiographic characteristics associated with being prescribed an anticoagulant upon AIS hospitalization discharge. Results: Among 14 338 patients with AIS with documented LVEF during the stroke hospitalization, the weighted pooled prevalence of LVEF ≤40% and sinus rhythm was 5.0% (95% CI, 4.1-6.0%; I2, 84.4%). Of 524 patients with no cardiac thrombus and no prior indication for anticoagulant who survived postdischarge, 200 (38%) were discharged on anticoagulant, 289 (55%) were discharged on antiplatelet therapy only, and 35 (7%) on neither. There was heterogeneity by site in the proportion discharged with an anticoagulant (22% to 45%, P<0.0001). Cohort site and National Institutes of Health Stroke Severity scale >8 (odds ratio, 2.0 [95% CI, 1.1-3.8]) were significant, independent predictors of being discharged with an anticoagulant in an adjusted analysis. Conclusions: Nearly 5% of patients with AIS have a depressed LVEF and are in sinus rhythm. There is significant variation in the clinical practice of antithrombotic therapy prescription by site and stroke severity. Given this clinical equipoise, further study is needed to define optimal antithrombotic treatment regimens for secondary stroke prevention in this patient population.Item Acute penetrating injury of the spinal cord by a wooden spike with delayed surgery: a case report(Wolters Kluwer, 2023) Guest, James D.; Luo, Zhuojing; Liu, Yansheng; Gao, Hongkun; Wang, Dianchun; Xu, Xiao-Ming; Zhu, Hui; Neurology, School of MedicineRarely, penetrating injuries to the spinal cord result from wooden objects, creating unique challenges to mitigate neurological injury and high rates of infection and foreign body reactions. We report a man who sustained a penetrating cervical spinal cord injury from a sharpened stick. While initially tetraparetic, he rapidly recovered function. The risks of neurological deterioration during surgical removal made the patient reluctant to consent to surgery despite the impalement of the spinal cord. A repeat MRI on day 3 showed an extension of edema indicating progressive inflammation. On the 7th day after injury, fever and paresthesias occurred with a large increase in serum inflammatory indicators, and the patient agreed to undergo surgical removal of the wooden object. We discuss the management nuances related to wood, the longitudinal evolution of MRI findings, infection risk, surgical risk mitigation and technique, an inflammatory marker profile, long-term recovery, and the surprisingly minimal neurological deficits associated with low-velocity midline spinal cord injuries. The patient had an excellent clinical outcome. The main lessons are that a wooden penetrating central nervous system injury has a high risk for infection, and that surgical removal from the spinal cord should be performed soon after injury and under direct visualization.