WashU weekly Neuroscience publications

Genetic and heritable considerations in patients or families with both intracranial and extracranial aneurysms
(2021) Journal of Neurosurgery, 134 (6), pp. 1999-2006. 

Huguenard, A.L.^a , Gupta, V.P.^a , Braverman, A.C.^b , Dacey, R.G.^a

^a Department of Neurosurgery, Washington University, St. Louis, United States
^b Cardiovascular Division, Department of Medicine, Washington University, St. Louis, MO, United States

Cognitive Impairment in Survivors of Pediatric Extracranial Solid Tumors and Lymphomas
(2021) Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 39 (16), pp. 1727-1740. 

Foster, R.^a b , Zheng, D.J.^c , Netson-Amore, K.L.^d , Kadan-Lottick, N.S.^e

^a St Louis Children’s Hospital, St Louis, MO
^b Washington University, St Louis, MO
^c Boston Children’s Hospital, MA, Boston
^d University of Kansas School of Medicine-Wichita, Wichita, United States
^e Yale University School of Medicine and Yale Cancer Center, CT, New Haven, United States

MiR-124 synergism with ELAVL3 enhances target gene expression to promote neuronal maturity
(2021) Proceedings of the National Academy of Sciences of the United States of America, 118 (22), art. no. e2015454118, . 

Lu, Y.-L.^a b c , Liu, Y.^a b , McCoy, M.J.^a b d e , Yoo, A.S.^a b

^a Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Center for Regenerative Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
^c Program in Developmental, Regenerative and Stem Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, United States
^d Program in Molecular Genetics and Genomics, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, United States

Abstract
Neuron-enriched microRNAs (miRNAs), miR-9/9* and miR-124 (miR-9/9*-124), direct cell fate switching of human fibroblasts to neurons when ectopically expressed by repressing antineurogenic genes. How these miRNAs function after the repression of fibroblast genes for neuronal fate remains unclear. Here, we identified targets of miR-9/9*-124 as reprogramming cells activate the neuronal program and reveal the role of miR-124 that directly promotes the expression of its target genes associated with neuronal development and function. The mode of miR-124 as a positive regulator is determined by the binding of both AGO and a neuron-enriched RNA-binding protein, ELAVL3, to target transcripts. Although existing literature indicates that miRNA–ELAVL family protein interaction can result in either target gene up-regulation or down-regulation in a context-dependent manner, we specifically identified neuronal ELAVL3 as the driver for miR-124 target gene up-regulation in neurons. In primary human neurons, repressing miR-124 and ELAVL3 led to the down-regulation of genes involved in neuronal function and process outgrowth and cellular phenotypes of reduced inward currents and neurite outgrowth. Our results highlight the synergistic role between miR-124 and RNA-binding proteins to promote target gene regulation and neuronal function. © 2021 National Academy of Sciences. All rights reserved.

Author Keywords
Direct reprogramming;  MicroRNA target;  MiR-124;  Neuronal maturity;  RNA-binding protein

Funding details
National Institutes of HealthNIHDP2NS083372, R01NS107488, RF1AG056296
University of WashingtonUWT32GM081739

Exome sequencing revealed PDE11A as a novel candidate gene for early-onset Alzheimer’s disease
(2021) Human Molecular Genetics, 30 (9), pp. 811-822. 

Qin, W.^a , Zhou, A.^a , Zuo, X.^a , Jia, L.^a , Li, F.^a , Wang, Q.^a , Li, Y.^a , Wei, Y.^a , Jin, H.^a , Cruchaga, C.^b c d , Benitez, B.A.^b c , Jia, J.^a e f g

^a Innovation Center for Neurological Disorders and Department of Neurology, Xuanwu Hospital, Capital Medical University, National Clinical Research Center for Geriatric DiseasesBeijing 100053, China
^b Department of Psychiatry, Washington University, St. Louis, MO 63110, USA
^c NeuroGenomics and Informatics Center, Washington University, St. Louis, MO 63110, USA
^d Department of Genetics, Washington University, St. Louis, MO 63110, USA
^e Beijing Key Laboratory of Geriatric Cognitive Disorders, Capital Medical UniversityBeijing 10053, China
^f Clinical Center for Neurodegenerative Disease and Memory Impairment, Capital Medical UniversityBeijing 10053, China
^g Center of Alzheimer’s Disease, Beijing Institute of Brain Disorders, Collaborative Innovation Center for Brain Disorders, Capital Medical UniversityBeijing 10053, China

Abstract
To identify novel risk genes and better understand the molecular pathway underlying Alzheimer’s disease (AD), whole-exome sequencing was performed in 215 early-onset AD (EOAD) patients and 255 unrelated healthy controls of Han Chinese ethnicity. Subsequent validation, computational annotation and in vitro functional studies were performed to evaluate the role of candidate variants in EOAD. We identified two rare missense variants in the phosphodiesterase 11A (PDE11A) gene in individuals with EOAD. Both variants are located in evolutionarily highly conserved amino acids, are predicted to alter the protein conformation and are classified as pathogenic. Furthermore, we found significantly decreased protein levels of PDE11A in brain samples of AD patients. Expression of PDE11A variants and knockdown experiments with specific short hairpin RNA (shRNA) for PDE11A both resulted in an increase of AD-associated Tau hyperphosphorylation at multiple epitopes in vitro. PDE11A variants or PDE11A shRNA also caused increased cyclic adenosine monophosphate (cAMP) levels, protein kinase A (PKA) activation and cAMP response element-binding protein phosphorylation. In addition, pretreatment with a PKA inhibitor (H89) suppressed PDE11A variant-induced Tau phosphorylation formation. This study offers insight into the involvement of Tau phosphorylation via the cAMP/PKA pathway in EOAD pathogenesis and provides a potential new target for intervention. © The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Long-term Intake of Gluten and Cognitive Function among US Women
(2021) JAMA Network Open, 4 (5), . 

Wang, Y.^a b , Lebwohl, B.^c d , Mehta, R.^a b , Cao, Y.^e f , Green, P.H.R.^c , Grodstein, F.^g h , Jovani, M.ⁱ , Lochhead, P.^a , Okereke, O.I.^j k l , Sampson, L.^m , Willett, W.C.^j l m , Sun, Q.^j l m , Chan, A.T.^a b j m

^a Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, United States
^b Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
^c Celiac Disease Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, United States
^d Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States
^e Division of Public Health Sciences, Department of Surgery, Washington University in St Louis, St Louis, MO, United States
^f Division of Gastroenterology, Department of Medicine, Washington University in St Louis, St Louis, MO, United States
^g Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, United States
^h Department of Internal Medicine, Rush Medical College, Chicago, IL, United States
ⁱ Division of Gastroenterology and Hepatology, Johns Hopkins Hospital, Baltimore, MD, United States
^j Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
^k Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, United States
^l Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^m Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, United States

Abstract
Importance: Gluten avoidance has been suggested as having a benefit to cognitive health among the general population, given the link between gluten and cognitive impairment in patients with celiac disease. However, data are lacking in individuals without celiac disease. Objective: To examine whether gluten intake is associated with cognitive function in women without celiac disease. Design, Setting, and Participants: This cohort study included US women who participated in the longitudinal, population-based Nurses’ Health Study II and had not previously or subsequently been diagnosed with celiac disease. Dietary data were collected from 1991 to 2015, and data on cognitive function were collected from 2014 to 2019. Data analysis was conducted from October 2020 to April 2021. Exposures: Energy-adjusted gluten intake, cumulatively averaged across questionnaire cycles prior to cognitive assessment. Main Outcomes and Measures: Three standardized cognitive scores assessed by the validated Cogstate Brief Battery: (1) psychomotor speed and attention score, (2) learning and working memory score, and (3) global cognition score. Higher scores indicated better performance. Results: The cohort included 13494 women (mean [SD] age, 60.6 [4.6] years). The mean (SD) gluten intake was 6.3 (1.6) g/d. After controlling for demographic and lifestyle risk factors in linear regression, no significant differences in standardized cognitive scores (mean [SD], 0 [1]) by quintile of gluten intake were found across highest and lowest quintiles of gluten intake (psychomotor speed and attention: -0.02; 95% CI, -0.07 to 0.03; P for trend =.22; learning and working memory: 0.02; 95% CI, -0.03 to 0.07; P for trend =.30; global cognition: -0.002; 95% CI, -0.05 to 0.05; P for trend =.78). The null associations persisted after additional adjustment for major sources of dietary gluten (ie, refined grains or whole grains), comparing decile categories of gluten intake, using gluten intake updated at each previous questionnaire cycle, or modeling changes in gluten intake. Similarly, these associations were not materially altered in sensitivity analyses that excluded women who had reported cancer or dementia diagnosis or had not completed all dietary assessments. Conclusions and Relevance: In this study, long-term gluten intake was not associated with cognitive scores in middle-aged women without celiac disease. Our results do not support recommendations to restrict dietary gluten to maintain cognitive function in the absence of celiac disease or established gluten sensitivity. © 2021 American Medical Association. All rights reserved.

Funding details
National Institutes of HealthNIHK07 CA218377, K24 DK098311, R01 CA202704, R21 AA027608, R35 CA253185, R37 CA246175, U01 CA176726, UM1 CA167552, UM1 CA186107
Massachusetts General HospitalMGH

A Rapid Motor Task-Based Screening Tool for Parkinsonism in Community-Based Studies
(2021) Frontiers in Neurology, 12, art. no. 653066, . 

Dlamini, W.W.^a , Nielsen, S.^a , Ushe, M.^a , Nelson, G.^b c , Racette, B.A.^a b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Faculty of Health Sciences, School of Public Health, University of the Witwatersrand, Parktown, Johannesburg, South Africa
^c Institute for Global Health, University College London, London, United Kingdom

Abstract
Background: The prevalence of parkinsonism in developing countries is largely unknown due to difficulty in ascertainment because access to neurologists is often limited. Objective: Develop and validate a parkinsonism screening tool using objective motor task-based tests that can be administered by non-clinicians. Methods: In a cross-sectional population-based sample from South Africa, we evaluated 315 adults, age >40, from an Mn-exposed (smelter) community, using the Unified Parkinson Disease Rating Scale motor subsection 3 (UPDRS3), Purdue grooved pegboard, and kinematic-UPDRS3-based motor tasks. In 275 participants (training dataset), we constructed a linear regression model to predict UPDRS3. We selected motor task summary measures independently associated with UPDRS3 (p < 0.05). We validated the model internally in the remaining 40 participants from the manganese-exposed community (test dataset) using the area under the receiver operating characteristic curve (AUC), and externally in another population-based sample of 90 participants from another South African community with only background levels of environmental Mn exposure. Results: The mean UPDRS3 score in participants from the Mn-exposed community was 9.1 in both the training and test datasets (standard deviation = 6.4 and 6.1, respectively). Together, 57 (18.1%) participants in this community had a UPDRS3 ≥ 15, including three with Parkinson’s disease. In the non-exposed community, the mean UPDRS3 was 3.9 (standard deviation = 4.3). Three (3.3%) had a UPDRS3 ≥ 15. Grooved pegboard time and mean velocity for hand rotation and finger tapping tasks were strongly associated with UPDRS3. Using these motor task summary measures and age, the UPDRS3 predictive model performed very well. In the test dataset, AUCs were 0.81 (95% CI 0.68, 0.94) and 0.91 (95% CI 0.81, 1.00) for cut points for neurologist-assessed UPDRS3 ≥ 10 and UPDRS3 ≥ 15, respectively. In the external validation dataset, the AUC was 0.85 (95% CI 0.73, 0.97) for UPDRS3 ≥ 10. AUCs were 0.76–0.82 when excluding age. Conclusion: A predictive model based on a series of objective motor tasks performs very well in assessing severity of parkinsonism in both Mn-exposed and non-exposed population-based cohorts. © Copyright © 2021 Dlamini, Nielsen, Ushe, Nelson and Racette.

Author Keywords
kinematics;  manganese;  parkinsonism;  predictive model;  receiver operating characteristic

Funding details
K01ES028295, R01ES025991, R01ES026891-S1

Recovery of consciousness and cognition after general anesthesia in humans
(2021) eLife, 10, . 

Mashour, G.A.^a , Palanca, B.J.^b , Basner, M.^c , Li, D.^a , Wang, W.^d , Blain-Moraes, S.^a , Lin, N.^d , Maier, K.^c , Muench, M.^b , Tarnal, V.^a , Vanini, G.^a , Ochroch, E.A.^c , Hogg, R.^c , Schwartz, M.^c , Maybrier, H.^b , Hardie, R.^c , Janke, E.^a , Golmirzaie, G.^a , Picton, P.^a , McKinstry-Wu, A.R.^c , Avidan, M.S.^b , Kelz, M.B.^c

^a Center for Consciousness Science, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, United States
^b Department of Anesthesiology, Washington University School of Medicine, St. Louis, United States
^c Department of Anesthesiology and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
^d Department of Mathematics and Statistics, Washington University, St. Louis, United States

Abstract
Understanding how the brain recovers from unconsciousness can inform neurobiological theories of consciousness and guide clinical investigation. To address this question, we conducted a multicenter study of 60 healthy humans, half of whom received general anesthesia for 3 hr and half of whom served as awake controls. We administered a battery of neurocognitive tests and recorded electroencephalography to assess cortical dynamics. We hypothesized that recovery of consciousness and cognition is an extended process, with differential recovery of cognitive functions that would commence with return of responsiveness and end with return of executive function, mediated by prefrontal cortex. We found that, just prior to the recovery of consciousness, frontal-parietal dynamics returned to baseline. Consistent with our hypothesis, cognitive reconstitution after anesthesia evolved over time. Contrary to our hypothesis, executive function returned first. Early engagement of prefrontal cortex in recovery of consciousness and cognition is consistent with global neuronal workspace theory. © 2021, Mashour et al.

Anesthesia is a state of reversable, controlled unconsciousness. It has enabled countless medical procedures. But it also serves as a tool for scientists to study how the brain regains consciousness after disruptions such as sleep, coma or medical procedures requiring general anesthesia. It is still unclear how exactly the brain regains consciousness, and less so, why some patients do not recover normally after general anesthesia or fail to recover from brain injury. To find out more, Mashour et al. studied the patterns of reemerging consciousness and cognitive function in 30 healthy adults who underwent general anesthesia for three hours. While the volunteers were under anesthesia, their brain activity was measured with an EEG; and their sleep-wake activity was measured before and after the experiment. Each participant took part in a series of cognitive tests designed to measure the reaction speed, memory and other functions before receiving anesthesia, right after the return of consciousness, and then every 30 minutes thereafter. Thirty healthy volunteers who did not have anesthesia also completed the scans and tests as a comparison group. The experiments showed that certain normal EEG patterns resumed just before a person wakes up from anesthesia. The return of thinking abilities was an extended, multistep process, but volunteers recovered their cognitive abilities to nearly the same level as the volunteers within three hours of being deeply anesthetized. Mashour et al. also unexpectedly found that abstract problem-solving resumes early in the process, while other functions such as reaction time and attention took longer to recover. This makes sense from an evolutionary perspective. Sleep leaves individuals vulnerable. Quick evaluation and decision-making skills would be key to respond to a threat upon waking. The experiments confirm that the front of the brain, which handles thinking and decision-making, was especially active around the time of recovery. This suggests that therapies targeting this part of the brain may help people who experience loss of consciousness after a brain injury or have difficulties waking up after anesthesia. Moreover, disorders of cognition, such as delirium, in the days following surgery may be caused by factors other than the lingering effects of anesthetic drugs on the brain.

Author Keywords
anesthesia;  cognition;  consciousness;  frontal cortex;  human;  medicine;  neuroscience

Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration
(2021) Neurology, 96 (18), pp. e2296-e2312. 

Rojas, J.C., Wang, P., Staffaroni, A.M., Heller, C., Cobigo, Y., Wolf, A., Goh, S.-Y.M., Ljubenkov, P.A., Heuer, H.W., Fong, J.C., Taylor, J.B., Veras, E., Song, L., Jeromin, A., Hanlon, D., Yu, L., Khinikar, A., Sivasankaran, R., Kieloch, A., Valentin, M.-A., Karydas, A.M., Mitic, L.L., Pearlman, R., Kornak, J., Kramer, J.H., Miller, B.L., Kantarci, K., Knopman, D.S., Graff-Radford, N., Petrucelli, L., Rademakers, R., Irwin, D.J., Grossman, M., Ramos, E.M., Coppola, G., Mendez, M.F., Bordelon, Y., Dickerson, B.C., Ghoshal, N., Huey, E.D., Mackenzie, I.R., Appleby, B.S., Domoto-Reilly, K., Hsiung, G.-Y.R., Toga, A.W., Weintraub, S., Kaufer, D.I., Kerwin, D., Litvan, I., Onyike, C.U., Pantelyat, A., Roberson, E.D., Tartaglia, M.C., Foroud, T., Chen, W., Czerkowicz, J., Graham, D.L., van Swieten, J.C., Borroni, B., Sanchez-Valle, R., Moreno, F., Laforce, R., Graff, C., Synofzik, M., Galimberti, D., Rowe, J.B., Masellis, M., Finger, E., Vandenberghe, R., de Mendonça, A., Tagliavini, F., Santana, I., Ducharme, S., Butler, C.R., Gerhard, A., Levin, J., Danek, A., Otto, M., Sorbi, S., Cash, D.M., Convery, R.S., Bocchetta, M., Foiani, M., Greaves, C.V., Peakman, G., Russell, L., Swift, I., Todd, E., Rohrer, J.D., Boeve, B.F., Rosen, H.J., Boxer, A.L., ALLFTD and GENFI consortia

From the University of California, San Francisco (J.C.R., P.W., A.M.S., Y.C., A.W., S.-Y.M.G., P.A.L., H.W.H., J.C.F., J.B.T., A.M.K., L.L.M., J.K., J.H.K., B.L.M., H.J.S., A.L.B.); UK Dementia Research Centre (C.H., D.M.C., R.S.C., M.B., M.F., C.V.G., G.P., L.R., I.S., E.T., J.D.R.), UCL Institute of Neurology, Queen Square, London; Quanterix Corp (E.V., L.S., A.J., D.H.), Lexington; Novartis Institutes for Biomedical Research Inc (L.Y., A. Khinikar, R.S.), Cambridge, MA; Novartis Pharma AG (A. Kieloch, M.-A.V.), Basel, Switzerland; Bluefield Project to Cure Frontotemporal Dementia (L.L.M., R.P.), San Francisco, CA; Mayo Clinic (K.K., D.S.K., B.F.B.), Rochester, MN; Mayo Clinic (N.G.-R., L.P., R.R.), Jacksonville, FL; University of Pennsylvania (D.J.I., M.G.), Philadelphia; University of California, Los Angeles (E.M.R., G.C., M.F.M., Y.B.); Harvard University/Massachusetts General Hospital (B.D.C.), Boston, MA; Washington University (N.G.), St. Louis, MO; Columbia University (E.D.H.), New York, NY; University of British Columbia (I.R.M., G.-Y.R.H.), Vancouver, Canada; Case Western Reserve University (B.S.A.), Cleveland, OH; University of Washington (K.D.-R.), Seattle; Laboratory of Neuroimaging (A.W.T.), University of Southern California, Los Angeles; Northwestern University (S.W.), Chicago, IL; University of North Carolina (D.I.K.)

Abstract
OBJECTIVE: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. METHODS: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. RESULTS: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. CONCLUSIONS: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Deficits in the Skeletal Muscle Transcriptome and Mitochondrial Coupling in Progressive Diabetes-Induced CKD Relate to Functional Decline
(2021) Diabetes, 70 (5), pp. 1130-1144. Cited 1 time.

Bittel, D.C.^a , Bittel, A.J.^a , Varadhachary, A.S.^b , Pietka, T.^c , Sinacore, D.R.^a d

^a Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO
^b Department of Neurology, Washington University School of Medicine, St. Louis, MO
^c Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO
^d Department of Physical Therapy, Congdon School of Health Sciences, High Point University, High Point

Abstract
Two-thirds of people with type 2 diabetes mellitus (T2DM) have or will develop chronic kidney disease (CKD), which is characterized by rapid renal decline that, together with superimposed T2DM-related metabolic sequelae, synergistically promotes early frailty and mobility deficits that increase the risk of mortality. Distinguishing the mechanisms linking renal decline to mobility deficits in CKD progression and/or increasing severity in T2DM is instrumental both in identifying those at high risk for functional decline and in formulating effective treatment strategies to prevent renal failure. While evidence suggests that skeletal muscle energetics may relate to the development of these comorbidities in advanced CKD, this has never been assessed across the spectrum of CKD progression, especially in T2DM-induced CKD. Here, using next-generation sequencing, we first report significant downregulation in transcriptional networks governing oxidative phosphorylation, coupled electron transport, electron transport chain (ETC) complex assembly, and mitochondrial organization in both middle- and late-stage CKD in T2DM. Furthermore, muscle mitochondrial coupling is impaired as early as stage 3 CKD, with additional deficits in ETC respiration, enzymatic activity, and increased redox leak. Moreover, mitochondrial ETC function and coupling strongly relate to muscle performance and physical function. Our results indicate that T2DM-induced CKD progression impairs physical function, with implications for altered metabolic transcriptional networks and mitochondrial functional deficits as primary mechanistic factors early in CKD progression in T2DM. © 2021 by the American Diabetes Association.

Medial olivocochlear reflex effects on amplitude growth functions of long- and short-latency components of click-evoked otoacoustic emissions in humans
(2021) Journal of Neurophysiology, 125 (5), pp. 1938-1953. 

Goodman, S.S.^a , Boothalingam, S.^b , Lichtenhan, J.T.^c

^a Department of Communication Sciences and Disorders, University of Iowa, Iowa City, IA, United States
^b Department of Communication Sciences and Disorders, Waisman Center, University of Wisconsin-Madison, Madison, WI, United States
^c Department of Otolaryngology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Functional outcomes of medial olivocochlear reflex (MOCR) activation, such as improved hearing in background noise and protection from noise damage, involve moderate to high sound levels. Previous noninvasive measurements of MOCR in humans focused primarily on otoacoustic emissions (OAEs) evoked at low sound levels. Interpreting MOCR effects on OAEs at higher levels is complicated by the possibility of the middle-ear muscle reflex and by components of OAEs arising from different locations along the length of the cochlear spiral. We overcame these issues by presenting click stimuli at a very slow rate and by time-frequency windowing the resulting click-evoked (CE)OAEs into short-latency (SL) and long-latency (LL) components. We characterized the effects of MOCR on CEOAE components using multiple measures to more comprehensively assess these effects throughout much of the dynamic range of hearing. These measures included CEOAE amplitude attenuation, equivalent input attenuation, phase, and slope of growth functions. Results show that MOCR effects are smaller on SL components than LL components, consistent with SL components being generated slightly basal of the characteristic frequency region. Amplitude attenuation measures showed the largest effects at the lowest stimulus levels, but slope change and equivalent input attenuation measures did not decrease at higher stimulus levels. These latter measures are less commonly reported and may provide insight into the variability in listening performance and noise susceptibility seen across individuals.NEW & NOTEWORTHY The auditory efferent system, operating at moderate to high sound levels, may improve hearing in background noise and provide protection from noise damage. We used otoacoustic emissions to measure these efferent effects across a wide range of sound levels and identified level-dependent and independent effects. Previous reports have focused on level-dependent measures. The level-independent effects identified here may provide new insights into the functional relevance of auditory efferent activity in humans.

Author Keywords
auditory;  efferent;  medial olivocochlear;  otoacoustic emissions

Protein kinase D1 variant associated with human epilepsy and peripheral nerve hypermyelination
(2021) Clinical Genetics, . 

Omer, S.^a b , Jin, S.C.^c d , Koumangoye, R.^a , Robert, S.M.^e , Duran, D.^e , Nelson-Williams, C.^c , Huttner, A.^f , DiLuna, M.^e , Kahle, K.T.^e , Delpire, E.^a b

^a Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, United States
^b Neuroscience Graduate Program, Vanderbilt University Nashville, Nashville, TN, United States
^c Department of Genetics, Yale University School of Medicine, New Haven, CT, United States
^d Department of Genetics and the McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, United States
^f Department of Pathology, Yale University School of Medicine, New Haven, CT, United States

Abstract
We report the case of a patient with severe progressive epilepsy and peripheral neuropathy and a novel de novo inactivating variant (p.E79X) in Protein Kinase D1 (PKD1). Using CRISPR/Cas9, we engineered the homologous variant in mice and showed that in the homozygote mouse, it recapitulated the patient peripheral nerve hypermyelination pathology. The lethality of the homozygote mouse prevented us from performing an assessment of locomotor behavior. The mutant heterozygote mouse; however, exhibited a significant increase in kainate-induced seizure activity over wild-type mice, supporting the hypothesis that the PKD1 variant is a candidate for the cause of the patient epilepsy. Because PKD1 was previously identified in a kinomic screen as an interacting partner of the K-Cl cotransporter 3 (KCC3), and since KCC3 is involved in peripheral nerve disease and brain hyperexcitability, one possible mechanism of action of PKD1 in disease is through KCC3. We show that catalytically inactive PKD1 stimulates KCC3 activity, consistent with tonic relief of inhibitory phosphorylation. Our findings implicate a novel role for PKD1 in the human nervous system, and uncover a mechanism that could serve as a potential target to promote nervous system myelination. © 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Author Keywords
biotinylation;  CRISPR/Cas9;  hypermyelination;  kanaic acid;  mouse model;  myelin thickness;  seizure susceptibility;  Xenopus oocytes

Funding details
National Institutes of HealthNIHDK093501
Foundation for Cardiovascular ResearchFCR17CVDO5, CA68485, DK20593, DK58404, DK59637, EY08126, U54HD083211

Are efficient learners of verbal stimuli also efficient and precise learners of visuospatial stimuli?
(2021) Memory, . 

Zerr, C.L.^a , Spaventa, T.^a , McDermott, K.B.^a b

^a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, United States
^b Department of Radiology, Washington University in St. Louis, St. Louis, United States

Abstract
People differ in how quickly they learn information and how long they remember it, and these two variables are correlated such that people who learn more quickly tend to retain more of the newly learned information. Zerr and colleagues [2018. Learning efficiency: Identifying individual differences in learning rate and retention in healthy adults. Psychological Science, 29(9), 1436–1450] termed the relation between learning rate and retention as learning efficiency, with more efficient learners having both a faster acquisition rate and better memory performance after a delay. Zerr et al. also demonstrated in separate experiments that how efficiently someone learns is stable across a range of days and years with the same kind of stimuli. The current experiments (combined N = 231) replicate the finding that quicker learning coincides with better retention and demonstrate that the correlation extends to multiple types of materials. We also address the generalisability of learning efficiency: A person’s efficiency with learning Lithuanian-English (verbal-verbal) pairs predicts their efficiency with Chinese-English (visuospatial-verbal) and (to a lesser extent) object-location (visuospatial-visuospatial) paired associates. Finally, we examine whether quicker learners also remember material more precisely by using a continuous measure of recall accuracy with object-location pairs. © 2021 Informa UK Limited, trading as Taylor & Francis Group.

Author Keywords
generalisability;  individual differences;  Learning efficiency;  learning rate;  memory

Childhood amyotrophic lateral sclerosis caused by excess sphingolipid synthesis
(2021) Nature Medicine, . Cited 1 time.

Mohassel, P.^a , Donkervoort, S.^a , Lone, M.A.^b , Nalls, M.^a , Gable, K.^c , Gupta, S.D.^c , Foley, A.R.^a , Hu, Y.^a , Saute, J.A.M.^d , Moreira, A.L.^e , Kok, F.^f , Introna, A.^g , Logroscino, G.^g h , Grunseich, C.ⁱ , Nickolls, A.R.^a , Pourshafie, N.ⁱ , Neuhaus, S.B.^a , Saade, D.^a , Gangfuß, A.^j , Kölbel, H.^j , Piccus, Z.^k , Le Pichon, C.E.^k , Fiorillo, C.^l , Ly, C.V.^m , Töpf, A.ⁿ , Brady, L.^o , Specht, S.ⁿ , Zidell, A.^p , Pedro, H.^q , Mittelmann, E.^r , Thomas, F.P.^r , Chao, K.R.^s , Konersman, C.G.^t , Cho, M.T.^u , Brandt, T.^u , Straub, V.ⁿ , Connolly, A.M.^v , Schara, U.^j , Roos, A.^j , Tarnopolsky, M.^o , Höke, A.^w , Brown, R.H.^x , Lee, C.-H.^y , Hornemann, T.^b , Dunn, T.M.^c , Bönnemann, C.G.^a

^a Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
^b Institute of Clinical Chemistry, University Hospital Zurich, University of Zurich, Zurich, Switzerland
^c Department of Biochemistry and Molecular Biology, Uniformed Services University of Health Sciences, Bethesda, MD, United States
^d Medical Genetics division and Neurology division, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Graduate Program in Medicine: Medical Sciences, and Internal Medicine Department; Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil
^e Neurology Department, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
^f Neurogenetics Outpatient Service, Neurology Department, Hospital das Clínicas da Universidade de São Paulo, São Paulo, Brazil and Mendelics, São Paulo, Brazil
^g Neurology Unit, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari ‘Aldo Moro’, Bari, Italy
^h Department of Clinical Research in Neurology, Center for Neurodegenerative Diseases and the Aging Brain, University of Bari at ‘Pia Fondazione Card G. Panico’ Hospital Tricase (Le), Bari, Italy
ⁱ Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
^j Department of Paediatric Neurology, Center for Neuromuscular Disorders in Children and Adolescents, University Clinic Essen, University of Duisburg-Essen, Duisburg-Essen, Germany
^k Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
^l Paediatric Neurology and Muscular Diseases Unit, G. Gaslini Institute and Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health University of Genoa, Genoa, Italy
^m Department of Neurology, Washington University in Saint Louis School of Medicine, Saint Louis, MO, United States
ⁿ John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
^o Division of Neuromuscular & Neurometabolic Disorders, Department of Paediatrics, McMaster University, Hamilton Health Sciences Centre, Hamilton, ON, Canada
^p Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack, NJ, United States
^q Center for Genetic and Genomic Medicine, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, United States
^r Department of Neurology, Hereditary Neuropathy Foundation Center of Excellence, Neuroscience Institute, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Hackensack, NJ, United States
^s Center for Mendelian Genomics, Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
^t Department of Neurosciences, University of California, San Diego, San Diego, CA, United States
^u GeneDx, Gaithersburg, MD, United States
^v Department of Paediatrics, Neurology Division, Nationwide Children’s Hospital, Ohio State University, Columbus, OH, United States
^w Department of Neurology, Neuromuscular Division, Johns Hopkins School of Medicine, Baltimore, MD, United States
^x Department of Neurology, University of Massachusetts Medical School, Worcester, MA, United States
^y Department of Structural Biology, St. Jude Children’s Research Hospital, Memphis, TN, United States

Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease of the lower and upper motor neurons with sporadic or hereditary occurrence. Age of onset, pattern of motor neuron degeneration and disease progression vary widely among individuals with ALS. Various cellular processes may drive ALS pathomechanisms, but a monogenic direct metabolic disturbance has not been causally linked to ALS. Here we show SPTLC1 variants that result in unrestrained sphingoid base synthesis cause a monogenic form of ALS. We identified four specific, dominantly acting SPTLC1 variants in seven families manifesting as childhood-onset ALS. These variants disrupt the normal homeostatic regulation of serine palmitoyltransferase (SPT) by ORMDL proteins, resulting in unregulated SPT activity and elevated levels of canonical SPT products. Notably, this is in contrast with SPTLC1 variants that shift SPT amino acid usage from serine to alanine, result in elevated levels of deoxysphingolipids and manifest with the alternate phenotype of hereditary sensory and autonomic neuropathy. We custom designed small interfering RNAs that selectively target the SPTLC1 ALS allele for degradation, leave the normal allele intact and normalize sphingolipid levels in vitro. The role of primary metabolic disturbances in ALS has been elusive; this study defines excess sphingolipid biosynthesis as a fundamental metabolic mechanism for motor neuron disease. © 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBIR01 HG009141, UM1 HG008900
National Human Genome Research InstituteNHGRI
National Eye InstituteNEI
National Institute of Neurological Disorders and StrokeNINDS
Congressionally Directed Medical Research ProgramsCDMRPK08 NS10762, W81XWH-20-1-0219
Stiftung für die Erforschung der MuskelkrankheitenSSEMR01 NS072446
Broad Institute
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF31003A_179371

Maternal Depression, Child Temperament, and Early-Life Stress Predict Never-Depressed Preadolescents’ Functional Connectivity During a Negative-Mood Induction
(2021) Clinical Psychological Science, . 

Liu, P.^a , Vandermeer, M.R.J.^a , Mohamed Ali, O.^a , Daoust, A.R.^a , Joanisse, M.F.^a , Barch, D.M.^b , Hayden, E.P.^a

^a Department of Psychology, Brain & Mind Institute, Western University, Canada
^b Psychological and Brain Sciences, Washington University in St. Louis, United States

Abstract
Understanding the development of depression can inform etiology and prevention/intervention. Maternal depression and maladaptive patterns of temperament (e.g., low positive emotionality [PE] or high negative emotionality, especially sadness) are known to predict depression. Although it is unclear how these risks cause depression, altered functional connectivity (FC) during negative-emotion processing may play an important role. We investigated whether maternal depression and age-3 emotionality predicted FC during negative mood reactivity in never-depressed preadolescents and whether these relationships were augmented by early-life stress. Maternal depression predicted decreased medial prefrontal cortex (mPFC)–amygdala and mPFC–insula FC but increased mPFC–posterior cingulate cortex (PCC) FC. PE predicted increased dorsolateral prefrontal cortex–amygdala FC, whereas sadness predicted increased PCC-based FC in insula, orbitofrontal cortex, and anterior cingulate cortex (ACC). Sadness was more strongly associated with PCC–insula and PCC–ACC FC as early stress increased. Findings indicate that early depression risks may be mediated by FC underlying negative-emotion processing. © The Author(s) 2021.

Author Keywords
functional connectivity;  maternal depression;  negative mood reactivity;  stress;  temperamental risk

Drivers of Hsp104 potentiation revealed by scanning mutagenesis of the middle domain
(2021) Protein Science, . 

Ryan, J.J., Bao, A., Bell, B., Ling, C., Jackrel, M.E.

Department of Chemistry, Washington University, St. Louis, MO, United States

Abstract
Hsp104, a yeast protein disaggregase, can be potentiated via numerous missense mutations at disparate locations throughout the coiled-coil middle domain (MD). Potentiated Hsp104 variants can counter the toxicity and misfolding of TDP-43, FUS, and α-synuclein, proteins which are implicated in neurodegenerative disorders. However, potentiated MD variants typically exhibit off-target toxicity. Further, it has remained confounding how numerous degenerate mutations confer potentiation, hampering engineering of therapeutic Hsp104 variants. Here, we sought to comprehensively define the key drivers of Hsp104 potentiation. Using scanning mutagenesis, we iteratively studied the effects of modulation at each position in the Hsp104 MD. Screening this library to identify enhanced variants reveals that missense mutations at 26% of positions in the MD yield variants that counter FUS toxicity. Modulation of the helix 2–helix 3/4 MD interface potentiates Hsp104, whereas mutations in the analogous helix 1–2 interface do not. Surprisingly, we find that there is a higher likelihood of enhancing Hsp104 activity against human disease substrates than impairing Hsp104 native function. We find that single mutations can broadly destabilize the MD structure and lead to functional potentiation, suggesting this may be a common mechanism conferring Hsp104 potentiation. Using this approach, we have demonstrated that modulation of the MD can yield engineered variants with decreased off-target effects. © 2021 The Protein Society.

Author Keywords
alpha-synuclein;  amyloid;  fused in sarcoma;  Hsp104;  protein disaggregase;  protein misfolding;  TAR DNA-binding protein 43 (TDP-43)

Funding details
National Institutes of HealthNIH
National Institute of General Medical SciencesNIGMSR35GM128772

A Critical Review of Network-Based and Distributional Approaches to Semantic Memory Structure and Processes
(2021) Topics in Cognitive Science, . 

Kumar, A.A.^a , Steyvers, M.^b , Balota, D.A.^a

^a Psychological & Brain Sciences, Washington University in St. Louis, United States
^b Department of Cognitive Sciences, University of California, Irvine, United States

Abstract
Some of the earliest work on understanding how concepts are organized in memory used a network-based approach, where words or concepts are represented as nodes, and relationships between words are represented by links between nodes. Over the past two decades, advances in network science and graph theoretical methods have led to the development of computational semantic networks. This review provides a modern perspective on how computational semantic networks have proven to be useful tools to investigate the structure of semantic memory as well as search and retrieval processes within semantic memory, to ultimately model performance in a wide variety of cognitive tasks. Regarding representation, the review focuses on the distinctions and similarities between network-based (based on behavioral norms) approaches and more recent distributional (based on natural language corpora) semantic models, and the potential overlap between the two approaches. Capturing the type of relation between concepts appears to be particularly important in this modeling endeavor. Regarding processes, the review focuses on random walk models and the degree to which retrieval processes demand attention in pursuit of given task goals, which dovetails with the type of relation retrieved during tasks. Ultimately, this review provides a critical assessment of how the network perspective can be reconciled with distributional and machine-learning-based perspectives to meaning representation, and describes how cognitive network science provides a useful conceptual toolkit to probe both the structure and retrieval processes within semantic memory. © 2021 Cognitive Science Society LLC

Author Keywords
Cognitive network science;  Distributional semantic models;  Semantic memory;  Semantic networks

Behavioral and cognitive functioning in individuals with Cantú syndrome
(2021) American Journal of Medical Genetics, Part A, . 

Roessler, H.I.^a , van der Heuvel, L.M.^b , Shields, K.^c , Guilliams, K.P.^d e , Knoers, N.V.A.M.^f , van Haaften, G.^a , Grange, D.K.^c g , van Haelst, M.M.^b h

^a Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
^b Department of Clinical Genetics, Amsterdam University Medical Centers, Amsterdam, Netherlands
^c Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^d Division of Pediatric Neurology, Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Division of Pediatric Critical Care, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Genetics, University Medical Center Groningen, Groningen, Netherlands
^g Center for the Investigation of Membrane Excitability Diseases (CIMED), St. Louis, MO, United States
^h Department of Clinical Genetics, VU Medical Center, Amsterdam University Medical Centers, Amsterdam, Netherlands

Abstract
Cantú syndrome (CS) is caused by pathogenic variants in ABCC9 and KCNJ8 encoding the regulatory and pore-forming subunits of ATP-sensitive potassium (KATP) channels. CS is characterized by congenital hypertrichosis, distinctive facial features, peripheral edema, and cardiac and neurodevelopmental abnormalities. Behavioral and cognitive issues have been self-reported by some CS individuals, but results of formal standardized investigations have not been published. To assess the cognitive profile, social functioning, and psychiatric symptoms in a large group of CS subjects systematically in a cross-sectional manner, we invited 35 individuals (1–69 years) with confirmed ABCC9 variants and their relatives to complete various commonly applied standardized age-related questionnaires, including the Kaufman brief intelligence test 2, the social responsiveness scale-2, and the Achenbach system of empirically based assessment. The majority of CS individuals demonstrated average verbal and nonverbal intelligence compared to the general population. Fifteen percent of cases showed social functioning strongly associated with a clinical diagnosis of autism spectrum disorder. Both externalizing and internalizing problems were also present in this cohort. In particular, anxiety, anxiety or attention deficit hyperactivity disorder, and autism spectrum behaviors were predominantly observed in the younger subjects in the cohort (≥25%), but this percentage decreased markedly in adults. © 2021 Wiley Periodicals LLC.

Author Keywords
autism;  behavior;  Cantú syndrome;  DSM V;  intelligence;  psychiatric symptoms

Funding details
National Institutes of HealthNIHHD103347

An Update from the American Stroke Association and the Stroke Council
(2021) Stroke, pp. E269-E271.

Schwamm, L.H.a , Panagos, P.D.b , Mohl, S.M.c

^a Massachusetts General Hospital, Wang Ambulatory Care Center, 55 Fruit St, Boston, MA 02114, United States
^b Washington University of St. LouisMO, United States
^c American Stroke Association Division, American Heart Association, Dallas, TX, United States

Author Keywords
brain;  COVID-19;  goal;  racism;  registries

Characterizing Family Contextual Factors and Relationships with Child Behavior and Sleep Across the Buffering Toxic Stress Consortium
(2021) Prevention Science, .

Phu, T.^a , Miles, E.^a , Dominguez, A.^a , Hustedt, J.^b , Watamura, S.E.^a , Berlin, L.^c , Harden, B.J.^c , Blair, C.^d , Constantino, J.N.^e , Hallam, R.A.^f , Han, M.^f , Hustedt, J.T.^f , Vu, J.A.^f , Sarche, M.^g , BTS Consortium Principal Investigators^h

^a Department of Psychology, University of Denver, Denver, CO, United States
^b Department of Human Development and Family Sciences, University of Delaware, Newark, DE, United States
^c University of Maryland, United States
^d New York University, United States
^e Washington University in St. Louis, United States
^f University of Delaware, United States
^g University of Colorado Anschutz, United States

Abstract
The Buffering Toxic Stress (BTS) consortium included six sites in locations that varied widely in racial/ethnic composition and population density. Each site tested a promising parent–child intervention designed to supplement Early Head Start (EHS) services and prevent “toxic stress.” To better understand family risk in a large and diverse EHS sample, studies gathered extensive data on family risk exposure, including demographic risk factors (single mother, unemployed, less than high school education or its equivalent, and neighborhood safety), income-to-needs ratio, household resource constraints, perceptions of economic hardship and pressure, caregiver mental health, and caregiver-reported dysfunctional parent–child interactions. Results presented here for all six sites offer context for the more targeted studies in this special issue. Average levels of family characteristics and child behavior varied by site. We also characterized associations between family characteristics, observer-rated child temperament, and child outcomes (i.e., caregiver-reported child behavior problems and behavioral sleep quality), controlling for child age; these relationships were similar across sites. Demographic risk and caregiver mental health problems were positively associated with child behavior problems, with low income-to-needs ratio and increased financial strain relating to behavioral problems in infancy and toddlerhood. Caregiver mental health problems, financial strain, and social and affect temperament dimensions were related to increased behavioral sleep problems. Dysfunctional parent–child interactions and household resource constraints did not demonstrate statistically significant associations. Findings suggest helpful targets to increase effectiveness of parent–child interventions in early childhood on behavior and sleep outcomes. © 2021, Society for Prevention Research.

Author Keywords
Child behavior;  Child sleep;  Early Head Start;  Family risk and protective factors

Funding details
90YR0058
Administration for Children and FamiliesACF
University of DelawareUD90YR0055
New York UniversityNYU90YR0057
Washington University in St. LouisWUSTL90YR0054
University of DenverDU90YR0056
Office of Planning, Research and EvaluationOPRE
School of Social Work, University of MarylandSSW, UMB90YR0059

Endovascular reperfusion of M2 occlusions in acute ischemic stroke reduced disability and mortality: ETIS Registry results
(2021) Journal of NeuroInterventional Surgery, . 

Muszynski, P.^a , Anadani, M.^b c , Richard, S.^d , Marnat, G.^e , Bourcier, R.^f , Sibon, I.^g , Dargazanli, C.^h , Arquizan, C.ⁱ , Maïer, B.^j , Blanc, R.^j , Lapergue, B.^k , Consoli, A.^l , Eugene, F.^m , Vannier, S.ⁿ , Spelle, L.^o , Denier, C.^p , Boulanger, M.^q , Gauberti, M.^r , Saleme, S.^s , Macian, F.^t , Clarençon, F.^u v , Rosso, C.^w , Naggara, O.^x , Turc, G.^y , Ozkul-Wermester, O.^z , Papagiannaki, C.^aa , Viguier, A.^ab , Cognard, C.^ac , Le Bras, A.^ad , Evain, S.^ae , Wolff, V.^af , Pop, R.^ag , Timsit, S.^ah , Gentric, J.-C.^ai , Bourdain, F.^aj , Veunac, L.^ak , Gory, B.^a al , Finitsis, S.N.^am an

^a Diagnostic and Therapeutic Neuroradiology, Université de Lorraine, CHRU-Nancy, Nancy, France
^b Washington University, School of Medicine in St Louis, St Louis, MO, United States
^c Neurology, Medical University of South Carolina, College of Medicine, Charleston, SC, United States
^d Neurology, Stroke Unit, Université de Lorraine, CHRU-Nancy, Nancy, France
^e Interventional and Diagnostic Neuroradiology, CHU Bordeaux, Bordeaux, France
^f Neuroradiology, University Hospital of Nantes, Nantes, France
^g Neurology, Stroke Unit, CHU Bordeaux, Bordeaux, France
^h Neuroradiology, CHRU Gui de Chauliac, Montpellier, France
ⁱ Neurology, CHRU Gui de Chauliac, Montpellier, France
^j Interventional Neuroradiology, Rothschild Foundation, Paris, France
^k Neurology, Stroke Unit, Foch Hospital, Suresnes, France
^l Diagnostic and Therapeutic Neuroradiology, Foch Hospital, Suresnes, France
^m Neuroradiology, CHU Rennes, Rennes, France
ⁿ Neurology, Stroke Unit, CHU Rennes, Rennes, France
^o Interventional Neuroradiolology, CHU Bicêtre, Le Kremlin-Bicêtre, France
^p Neurology, Stroke Unit, CHU Bicêtre, Le Kremlin-Bicêtre, France
^q Neurology, Stroke Unit, CHU Caen, Caen, France
^r Neuroradiolology, CHU Caen, Caen, France
^s Neuroradiology, CHU Limoges, Limoges, France
^t Neurology, Stroke Unit, CHU Limoges, Limoges, France
^u Sorbonne Université, Paris, France
^v Neuroradiology, CHU Pitié-Salpêtrière, Paris, France
^w Neurology, Stroke Unit, CHU Pitié-Salpêtrière, Paris, France
^x Neuroradiology, Hôpital St Anne, Paris, France
^y Neurology, Stroke Unit, Hôpital Saint Anne, Paris, France
^z Neurology, Stroke Unit, CHU Rouen, Rouen, France
^aa Interventional Neuroradiolology, CHU Rouen, Rouen, France
^ab Neurology, Stroke Unit, CHU Toulouse, Toulouse, France
^ac Diagnostic and Therapeutic Neuroradiology, CHU Toulouse, Toulouse, France
^ad Radiology, CH Bretagne Atlantique, Vannes, France
^ae Neurology, Stroke Unit, CH Bretagne Atlantique, Vannes, France
^af Stroke Unit, CHU Strasbourg, Strasbourg, France
^ag Interventional Neuroradiolology, CHU Strasbourg, Strasbourg, France
^ah Neurology, Stroke Unit, CHU Brest, Brest, France
^ai Interventionl Neuroradiolology, CHU Brest, Brest, France
^aj Neurology, Stroke Unit, CH Côte Basque, Bayonne, France
^ak Radiolology, CH Côte Basque, Bayonne, France
^al IADI, INSERM U1254, Université de Lorraine, Nancy, France
^am Neuroradiolology, University General Hospital of Thessaloniki AHEPA, Thessaloniki, Greece
^an Radiology, Centre Hospitalier de l’Universite de Montreal, Montreal, QC, Canada

Abstract
Background: The predictors of successful reperfusion and the effect of reperfusion after endovascular treatment (EVT) for M2 occlusions have not been well studied. We aimed to identify predictors of successful reperfusion and the effect of reperfusion on outcomes of EVT for M2 occlusions in current practice. Methods: Patients with acute ischemic stroke due to isolated M2 occlusions who were enrolled in the prospective multicenter Endovascular Treatment in Ischemic Stroke (ETIS) Registry in France between January 2015 and March 2020 were included. The primary outcome was a favorable outcome, defined as modified Rankin Scale (mRS) score of 0-2 at 90 days. Successful reperfusion was defined as an improvement of ≥1 points in the modified Thrombolysis In Cerebral Infarction score between the first and the last intracranial angiogram. Results: A total of 458 patients were included (median National Institutes of Health Stroke Scale (NIHSS) score 14; 61.4% received prior intravenous thrombolysis). Compared with the non-reperfused patients, reperfused patients had an increased rate of excellent outcome (OR 2.3, 95% CI 0.98 to 5.36; p=0.053), favorable outcome (OR 2.79, 95% CI 1.31 to 5.93; p=0.007), and reduced 90-day mortality (OR 0.39, 95% CI 0.19 to 0.79; p<0.01). Admission NIHSS score was the only predictor of successful reperfusion. First-line strategy was not a predictor of successful reperfusion or favorable outcome, but the use of a stent retriever, alone or with an aspiration catheter, was associated with higher rates of procedural complications and 90-day mortality. Conclusions: Successful reperfusion of M2 occlusions reduced disability and mortality. However, safety is a concern, especially if the procedure failed. © Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
stroke;  thrombectomy

Blood Pressure Management after Endovascular Therapy: An Ongoing Debate
(2021) Stroke, pp. E263-E265.

Anadani, M.^a , De Havenon, A.^b , Mistry, E.^c , Anderson, C.S.^d

^a Department of Neurology, Washington University in St. Louis, School of Medicine, St Louis, MO 63110, United States
^b University of Utah, Salt Lake City, United States
^c Vanderbilt University Medical CenterTN, United States
^d George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia

Author Keywords
acute ischemic stroke;  blood pressure;  clinical trial;  meta-analysis;  thrombectomy