WashU weekly Neuroscience publications: March 28, 2022

Domain-general cognitive motivation: Evidence from economic decision-making – Final Registered Report
(2022) Cognitive Research: Principles and Implications, 7 (1), art. no. 23, . 

Crawford, J.L.^a , Eisenstein, S.A.^b c , Peelle, J.E.^d , Braver, T.S.^a

^a Department of Psychological and Brain Sciences, Washington University in St. Louis, 1 Brookings Dr, Box 1125, St. Louis, MO 63130, United States
^b Department of Psychiatry, Washington University in St. Louis, 660 South Euclid Avenue, Box 8225, St. Louis, MO 63110, United States
^c Department of Radiology, Washington University in St. Louis, 660 South Euclid Avenue, Box 8225, St. Louis, MO 63110, United States
^d Department of Otolaryngology, Washington University in St. Louis, 660 South Euclid Avenue, Box 8115, Saint Louis, MO 63110, United States

Abstract
Stable individual differences in cognitive motivation (i.e., the tendency to engage in and enjoy effortful cognitive activities) have been documented with self-report measures, yet convergent support for a trait-level construct is still lacking. In the present study, we used an innovative decision-making paradigm (COG-ED) to quantify the costs of cognitive effort, a metric of cognitive motivation, across two distinct cognitive domains: working memory (an N-back task) and speech comprehension (understanding spoken sentences in background noise). We hypothesized that cognitive motivation operates similarly within individuals, regardless of domain. Specifically, in 104 adults aged 18–40 years, we tested whether individual differences in effort costs are stable across domains, even after controlling for other potential sources of shared individual variation. Conversely, we evaluated whether the costs of cognitive effort across domains may be better explained in terms of other relevant cognitive and personality-related constructs, such as working memory capacity or reward sensitivity. We confirmed a reliable association among effort costs in both domains, even when these other sources of individual variation, as well as task load, are statistically controlled. Taken together, these results add support for trait-level variation in cognitive motivation impacting effort-based decision making across multiple domains. © 2022, The Author(s).

Author Keywords
Cognitive motivation;  Listening effort;  Speech comprehension;  Working memory

Funding details
National Institutes of HealthNIH

Characterisation of PDGF-BB:PDGFRβ signalling pathways in human brain pericytes: evidence of disruption in Alzheimer’s disease
(2022) Communications Biology, 5 (1), art. no. 235, . 

Smyth, L.C.D.^a b c d , Highet, B.^b e , Jansson, D.^a b f , Wu, J.^b e , Rustenhoven, J.^a b d , Aalderink, M.^a b , Tan, A.^b e , Li, S.^a b , Johnson, R.^a b , Coppieters, N.^a b g , Handley, R.^b h , Narayan, P.^b h , Singh-Bains, M.K.^b e , Schweder, P.^b i , Turner, C.^b i , Mee, E.W.^b i , Heppner, P.^b i , Correia, J.^b i , Park, T.I.-H.^a b , Curtis, M.A.^b e , Faull, R.L.M.^b e , Dragunow, M.^a b

^a Department of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Auckland, Grafton, 1023, New Zealand
^b Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
^c Centre for Free Radical Research, Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
^d Center for Brain Immunology and Glia, Department of Pathology and Immunology, Washington University in St Louis, Missouri, United States
^e Department of Anatomy with Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Road, Auckland, 1023, New Zealand
^f Department of Psychiatry and Behavioural Sciences, University of Washington, Seattle, WA, United States
^g Laboratory of Nervous System Disorders and Therapy, GIGA-Neurosciences Research Centre, University of Liège, Liège, 4000, Belgium
^h School of Biological Sciences, University of Auckland, Auckland, New Zealand
ⁱ Auckland City Hospital, 2 Park Road, Auckland, 1023, New Zealand

Abstract
Platelet-derived growth factor-BB (PDGF-BB):PDGF receptor-β (PDGFRβ) signalling in brain pericytes is critical to the development, maintenance and function of a healthy blood-brain barrier (BBB). Furthermore, BBB impairment and pericyte loss in Alzheimer’s disease (AD) is well documented. We found that PDGF-BB:PDGFRβ signalling components were altered in human AD brains, with a marked reduction in vascular PDGFB. We hypothesised that reduced PDGF-BB:PDGFRβ signalling in pericytes may impact on the BBB. We therefore tested the effects of PDGF-BB on primary human brain pericytes in vitro to define pathways related to BBB function. Using pharmacological inhibitors, we dissected distinct aspects of the PDGF-BB response that are controlled by extracellular signal-regulated kinase (ERK) and Akt pathways. PDGF-BB promotes the proliferation of pericytes and protection from apoptosis through ERK signalling. In contrast, PDGF-BB:PDGFRβ signalling through Akt augments pericyte-derived inflammatory secretions. It may therefore be possible to supplement PDGF-BB signalling to stabilise the cerebrovasculature in AD. © 2022, The Author(s).

Funding details
Hugh Green FoundationHGF
Health Research Council of New ZealandHRC

Distinct neurocognitive bases for social trait judgments of faces in autism spectrum disorder
(2022) Translational Psychiatry, 12 (1), art. no. 104, . 

Yu, H.^a , Cao, R.^b , Lin, C.^c , Wang, S.^b d

^a Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, United States
^b Lane Department of Computer Science and Electrical Engineering, West Virginia University, Morgantown, WV 26506, United States
^c Department of Psychological and Brain Sciences, Dartmouth College, Hanover, NH 03755, United States
^d Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States

Abstract
Autism spectrum disorder (ASD) is characterized by difficulties in social processes, interactions, and communication. Yet, the neurocognitive bases underlying these difficulties are unclear. Here, we triangulated the ‘trans-diagnostic’ approach to personality, social trait judgments of faces, and neurophysiology to investigate (1) the relative position of autistic traits in a comprehensive social-affective personality space, and (2) the distinct associations between the social-affective personality dimensions and social trait judgment from faces in individuals with ASD and neurotypical individuals. We collected personality and facial judgment data from a large sample of online participants (N = 89 self-identified ASD; N = 307 neurotypical controls). Factor analysis with 33 subscales of 10 social-affective personality questionnaires identified a 4-dimensional personality space. This analysis revealed that ASD and control participants did not differ significantly along the personality dimensions of empathy and prosociality, antisociality, or social agreeableness. However, the ASD participants exhibited a weaker association between prosocial personality dimensions and judgments of facial trustworthiness and warmth than the control participants. Neurophysiological data also indicated that ASD participants had a weaker association with neuronal representations for trustworthiness and warmth from faces. These results suggest that the atypical association between social-affective personality and social trait judgment from faces may contribute to the social and affective difficulties associated with ASD. © 2022, The Author(s).

Funding details
FA9550-21-1-0088
National Science FoundationNSFBCS-1945230
Dana Foundation
Oak Ridge Associated UniversitiesORAU

Prevalence and perception of substance abuse and associated economic indicators and mental health disorders in a large cohort of Kenyan students: towards integrated public health approach and clinical management
(2022) BMC Psychiatry, 22 (1), art. no. 191, . 

Mutiso, V.N.^a b , Ndetei, D.M.^a b c , N.Muia, E.^d , Musyimi, C.^a b , Osborn, T.L.^e f g , Kasike, R.^a , Onsinyo, L.^a , Mbijjiwe, J.^d , Karambu, P.^d , Sounders, A.^h , Weisz, J.R.^e , Swahn, M.H.ⁱ , Mamah, D.^j

^a Africa Mental Health Research and Training Foundation, Nairobi, Kenya
^b World Psychiatric Association Collaborating Centre for Research and Training, Nairobi, Kenya
^c Department of Psychiatry, University of Nairobi, Kenya and Africa Mental Health Research and Training Foundation, Mawensi Road, Off Elgon road, Mawensi Garden, P.O. Box 48423-00100, Nairobi, Kenya
^d Department of Public and Community Health, Machakos University, Machakos, Kenya
^e Department of Psychology, Harvard University, Cambridge, MA, United States
^f Shamiri Institute, Allston, MA, United States
^g Shamiri Institute, Nairobi, Kenya
^h Department of Child Psychiatry, Turku University Hospital, Turku, Finland
ⁱ Department of Population Health Sciences, Georgia State University, Atlanta, United States
^j Department of Psychiatry, Washington University Medical School, St. Louis, MO, United States

Abstract
Background: The earlier younger people begin to use drugs, the more vulnerable they become to both their short term and long-term harmful effects. The overall aim of this study is to determine the prevalence of alcohol and drug abuse, the socio-demographic characteristic, perception of abuse and associated economic indicators and mental disorders and how they inform potential intervention in a cohort of Kenyan students. Methods: This was a cross-sectional study on a total of 9742 high school, college and university students. We used tools to document socio-demographic characteristics, economic indicators, drug and alcohol use and related perceptions and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) related psychiatric disorders. Basic descriptive statistics (means and standard deviations for numerical variables and frequencies for nominal and ordinal variables) were done. Logistic regression models were used to assess the association and odds ratios between the use of a given substance and the use of the other substances, as well as associations with the various available socio-demographic factors and economic indicators. Chi-squared tests were used in socio-economic characteristics disaggregated by current alcohol use. Results: The mean age was 21.4 ± 2.4; median = 21.3 (range 15–43) years. We found a wide range of different drugs of abuse. Alcohol abuse was the commonest and inhalants were the least, with different perceptions.Both alcohol and drug abuse were associated with various economic indicators and various mental disorders. Conclusion: This study has established for the first time in Kenya the multifaceted associations and predictors of alcohol and drug abuse in a cross-sectional student population ranging from high school to college and university levels. In the process, the study contributes to global data on the subject. These associations call for an integrated and multifaceted approach in addressing alcohol and substance abuse. This approach should take into account various associations and predictors as part of holistic approach in both public awareness and clinical interventions. © 2022, The Author(s).

Author Keywords
Economic indicators;  Interventions;  Kenya;  Mental health disorders;  Student;  Substance use

Funding details
National Institutes of HealthNIH

Fetal hemoglobin modulates neurocognitive performance in sickle cell anemia✰,✰✰
(2022) Current Research in Translational Medicine, 70 (3), art. no. 103335, . 

Heitzer, A.M.^a , Longoria, J.^a , Rampersaud, E.^b , Rashkin, S.R.^b c , Estepp, J.H.^c , Okhomina, V.I.^d , Wang, W.C.^c , Raches, D.^a , Potter, B.^a , Steinberg, M.H.^e , King, A.A.^f , Kang, G.^a d , Hankins, J.S.^c

^a Departments of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^b Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN, United States
^c Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
^d Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States
^e Department of Medicine, Boston University School of Medicine, MA, Boston
^f Program in Occupational Therapy and Departments of Pediatrics and Medicine, Washington University, MO, St. Louis

Abstract
Purpose of the study: Fetal hemoglobin (HbF) is a modifier of the clinical and hematologic phenotype of sickle cell anemia (SCA). Three quantitative trait loci (QTL) modulate HbF expression. The neurocognitive effects of variants in these QTL have yet to be explored. We evaluated the relation between 11 SNPs in the three HbF QTL: BCL11A, MYB, the HBB gene cluster, and full-scale intelligence (IQ) in SCA. Patients and methods: The prospective longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program, was used as a discovery cohort (n = 166). The genotypes for 11 SNPs were extracted through whole genome sequencing and were analyzed using an additive model. A polygenic score for HbF (PGSHbF) integrating the numbers of low HbF alleles from 11 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (n = 156) and the Silent Cerebral Infarction Transfusion (n = 114) Trial were used as two independent replication cohorts. Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (pFDR). Results: HbF was positively associated with IQ (minimum raw p = 0·0018) at pFDR<0·05. HbF mediated the relationship between two BCL11A SNPs, rs1427407 and rs7606173, HBS1L-MYB: rs9494142, and PGSHbF with IQ (minimum raw p = 0·0035) at pFDR<0·05. Conclusion: As the major modulator of the severity of SCA, HbF also influences neurocognition, which is done through mediation of its QTL. These findings have implications for early identification of neurocognitive risk and targeted intervention. © 2022 Elsevier Masson SAS

Author Keywords
Anemia;  Fetal hemoglobin;  Genetic;  Hematology;  Intelligence;  Neurocognitive;  Neuropsychology;  Sickle cell

Analgesic and neuroprotective effects of Baimai Ointment on diabetic peripheral neuropathy
(2022) Journal of Ethnopharmacology, 292, art. no. 115122, . 

Li, Z.^a b , Wang, W.^a b , Meng, F.^a b , Zhou, Z.^a b , Zhao, Z.^c d , Mei, Z.^a b

^a School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, 430074, China
^b Institute of Ethnomedicine, South-Central University for Nationalities, Wuhan, 430074, China
^c Washington University School of Medicine, St. Louis, MO 63110, United States
^d Barnes-Jewish Hospital, St. Louis, MO 63110, United States

Abstract
Ethnopharmacology relevance: Baimai (BM) ointment, a traditional Tibetan medicine, has been widely used to treat “white vein” disease, paralysis, hemiplegia and claudication caused by trauma, because of its great effects on muscle stretching and collateral activation. As one of the most terrible complications in diabetes patients, diabetes peripheral neuropathy (DPN) is mainly manifested as abnormal pain or numbness in extremities. However, whether BM ointment is a potential drug for DPN treatment is unclear. Aims of the study: The aim of this study was to investigate the therapeutic effects of BM on DPN in a high-fat diet/low-dose of streptozotocin induced type 2 diabetes rat model and explore underlying mechanisms. Methods: The chemical components of BM were determined by high performance liquid chromatography (HPLC), and the possible targets and related pathways candidates involved in the effects of BM on DPN were predicted using network pharmacology methods. Next, the effects of different doses (1.5, 3.0 and 6.0 g/kg) of BM on physiological changes, pain behaviors, motor nerve conduction velocity (MNCV) in DPN rats were assessed and compared with placebo- and mecobalamine (Meco)-treated DPN controls. Then, the effects of BM on the expression of pain associated genes as well as the phosphorylation of PI3K/AKT and MAPKs pathways in DRG of DPN rats were examined. Results: Through HPLC analysis, curcumin was identified as one of the primary contents of BM. The information from network pharmacology indicated a series of target candidates for BM including IL6, IL10, TNF, CCL2, CXCL12, EGF, VEGFA, BDNF, TGFβ1 and TNF, as well as PI3K-AKT and MAPK signaling pathways. Topical treatment of BM significantly improved the hypersensitivity of mechanical and thermal pain, MNCV and the morphological changes and demyelination of sciatic nerve fibers, without affecting the body weight, serum metabolism or blood glucose. The up-regulated levels of neuropeptides Cgrp, Sst, Sp and chemokines Ccl2 and Ccl3 along with the abnormal expression of p-P38, p-ERK and p-AKT in the DRG of DPN rats were alleviated by BM application. Conclusion: BM ointment has great activities in relieving pain hypersensitivity, neuroprotecting peripheral nerves damage caused by DPN, which may be related to the inhibition of related neuropeptide (Cgrp, Sst, Sp) and chemokine (Ccl2, Ccl3) expression and the regulation of PI3K/AKT and MAPKs signaling pathways in DRG. © 2022 Elsevier B.V.

Author Keywords
Baimai ointment;  Diabetes peripheral neuropathy;  Neuroprotection;  Pain hypersensitivity

Funding details
National Key Research and Development Program of ChinaNKRDPC2019YFC1712402
Hubei Technological Innovation Special Fund2019AGB110

Low housing quality, unmet social needs, stress and depression among low-income smokers
(2022) Preventive Medicine Reports, 27, art. no. 101767, . 

Garg, R.^a , McQueen, A.^a b , Wolff, J.M.^a , Skinner, K.E.^a , Kegler, M.C.^c , Kreuter, M.W.^a

^a Health Communication Research Laboratory, Brown School at Washington University in St. Louis, MO, St. Louis
^b Division of General Medical Sciences, Washington University in St. Louis, School of Medicine, MO, St. Louis
^c Behavioral Sciences and Health Education, Rollins School of Public Health, Emory University, GA, Atlanta

Abstract
Smokers are at greater risk of multiple health conditions that are exacerbated by environmental hazards associated with low housing quality. However, little is known about the prevalence of low housing quality among low-income smokers. Using correlations and logistic regression, we examined associations among eight housing quality indicators – pests, water leaks, mold, lead paint, and working smoke detectors, appliances, heating, and air conditioning – and between housing quality and social needs, depressive symptoms, perceived stress, sleep problems, and self-rated health in a community-based sample of 786 low-income smokers from 6 states. Most participants were female (68%), and White (45%) or African-American (43%). One in four (27%) completed less than high school education, and 41% reported annual pre-tax household income of less than $10,000. Housing quality problems were common. Most participants (64%) reported at least one problem in their home, and 41% reported two or more problems, most commonly pest infestations (40%), water leaks (22%), lack of air conditioning (22%) and mold (18%). Lack of heat and air conditioning were correlated, as were water leaks and mold. Using logistic regression analyses controlling for participant demographic characteristics, we found that reporting more housing quality problems was associated with greater odds of worse mental and physical health outcomes. Multiple health threats, including housing quality, depressive symptoms, stress, poor sleep, and financial strain may be mutually reinforcing and compound the health consequence of smoking. Future research should seek to replicate these findings in other samples, and examine associations longitudinally to better understand causality. © 2022

Author Keywords
Housing quality;  Low-income;  Mental health;  Smokers;  Social needs

Funding details
National Cancer InstituteNCIR01CA235773

Synthesizing pseudo-T2w images to recapture missing data in neonatal neuroimaging with applications in rs-fMRI
(2022) NeuroImage, 253, art. no. 119091, . 

Kaplan, S.^a , Perrone, A.^f g , Alexopoulos, D.^a , Kenley, J.K.^a , Barch, D.M.^b d e , Buss, C.^i k , Elison, J.T.^f , Graham, A.M.^g , Neil, J.J.^a c , O’Connor, T.G.^h , Rasmussen, J.M.ⁱ , Rosenberg, M.D.^j , Rogers, C.E.^c e , Sotiras, A.^b , Fair, D.A.^f , Smyser, C.D.^a b c

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
^b Department of Radiology and Institute for Informatics, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Psychological and Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Pediatrics and the Masonic Institute for the Developing Brain, Institute of Child Development, University of Minnesota, Minneapolis, MN, United States
^g Department of Psychiatry, Oregon Health and Science University, Portland, OR, United States
^h Department of Psychiatry, University of Rochester, Rochester, NY, United States
ⁱ Department of Pediatrics, University of California Irvine, Irvine, CA, United States
^j Department of Psychology, University of Chicago, Chicago, IL, United States
^k Department of Medical Psychology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Augustenburger Platz 1, Berlin, 13353, Germany

Abstract
T1- and T2-weighted (T1w and T2w) images are essential for tissue classification and anatomical localization in Magnetic Resonance Imaging (MRI) analyses. However, these anatomical data can be challenging to acquire in non-sedated neonatal cohorts, which are prone to high amplitude movement and display lower tissue contrast than adults. As a result, one of these modalities may be missing or of such poor quality that they cannot be used for accurate image processing, resulting in subject loss. While recent literature attempts to overcome these issues in adult populations using synthetic imaging approaches, evaluation of the efficacy of these methods in pediatric populations and the impact of these techniques in conventional MR analyses has not been performed. In this work, we present two novel methods to generate pseudo-T2w images: the first is based in deep learning and expands upon previous models to 3D imaging without the requirement of paired data, the second is based in nonlinear multi-atlas registration providing a computationally lightweight alternative. We demonstrate the anatomical accuracy of pseudo-T2w images and their efficacy in existing MR processing pipelines in two independent neonatal cohorts. Critically, we show that implementing these pseudo-T2w methods in resting-state functional MRI analyses produces virtually identical functional connectivity results when compared to those resulting from T2w images, confirming their utility in infant MRI studies for salvaging otherwise lost subject data. © 2022 The Authors

Author Keywords
Deep learning;  Multi-atlas fusion;  Neonate;  Neuroimaging;  Structural MRI;  Synthetic medical images

Funding details
National Institutes of HealthNIHP50 HD103525, R01 MH096773, R01 MH105538, R01 MH113883, R01 MH115357, R01 MH125829, UH3 OD023349
Bill and Melinda Gates FoundationBMGFINV-015711, OPP1184813

Transportation and other social needs as markers of mental health conditions
(2022) Journal of Transport and Health, 25, art. no. 101357, . 

Garg, R.^a , Muhammad, S.N.^b , Cabassa, L.J.^c , McQueen, A.^a d , Verdecias, N.^a , Greer, R.^e , Kreuter, M.W.^a

^a Health Communication Research Laboratory, Brown School at Washington University in St. Louis, St. Louis, MO, United States
^b Saint Louis Mental Health Board, St. Louis, MO, United States
^c Center for Mental Health Services Research, Brown School at Washington University in St. Louis, St. Louis, MO, United States
^d Division of General Medical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^e United Way of Greater St. Louis and 2-1-1 Missouri, St. Louis, MO, United States

Abstract
Objective: The study sought to determine whether reporting a history of depression, anxiety, PTSD, bipolar disorder, drug or alcohol use disorder, ADHD, schizophrenia, or current depressive symptoms was associated with requesting help for any of 12 social needs. Methods: A community-based sample of 1,944 low-income adult smokers in Missouri who had called a telephone helpline for social needs were recruited between June 1, 2017 and November 15, 2020. Helpline data on callers’ requests for assistance with utilities, housing, food, household goods, healthcare, transportation, adult care, financial assistance, employment, legal assistance, personal safety and childcare were merged with self-reported mental health data collected in a subsequent phone survey with the same callers. Using binary logistic regression, we examined which mental health conditions were associated with each social need. Results: Reporting mental health conditions were associated with greater odds of requests for assistance with transportation, food, healthcare and personal safety. Of these, the strongest and most consistent associations were with transportation needs. In post-hoc analyses, most associations between transportation needs and mental health remained significant after adjusting for possible confounders. Conclusions: Compared to participants who did not report histories of mental health conditions, those who reported mental health conditions were more likely to call 2-1-1 seeking transportation assistance. Community-based agencies providing transportation or mental health services could partner to provide linkages between services and increase capacity to address transportation and mental health needs. © 2022

Author Keywords
Community-based;  Low-income;  Mental health;  Social needs;  Transportation assistance

Funding details
National Institute of Mental HealthNIMH1R01MH104574, P50MH115843
National Cancer InstituteNCIR01CA201429
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK1R01DK115916-01

Early Hearing Preservation Outcomes Following Cochlear Implantation With New Slim Lateral Wall Electrode Using Electrocochleography
(2022) Otology & Neurotology: Official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology, 43 (4), pp. 443-451. 

Walia, A.^a , Shew, M.A.^a , Ettyreddy, A.^b , Lefler, S.M.^a , Jiramongkolchai, P.^a , Wick, C.C.^a , Durakovic, N.^a , Buchman, C.A.^a , Herzog, J.A.^a

^a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine in St. Louis, St Louis, MO, United States
^b Department of Otolaryngology-Head and Neck Surgery, University of Pittsburgh, Pittsburgh, PA, United States

Abstract
OBJECTIVE: Describe early hearing preservation (HP) cochlear implantation (CI) outcomes using a new slim lateral wall electrode (SLWE). STUDY DESIGN: Prospective cohort study. SETTING: Tertiary referral center. PATIENTS: Adult CI candidates with preoperative low-frequency pure-tone average (LFPTA; 125, 250, 500 Hz) ≤60 dB HL. INTERVENTION: CI with and without intracochlear real-time electrocochleography (RT-ECochG). MAIN OUTCOME MEASURE: HP (LFPTA ≤80 dB HL), LFPTA shift, speech-perception performance measures, postoperative CT reconstruction. RESULTS: Forty-two subjects were implanted with the SLWE. Thirty patients underwent full insertion without RT-ECochG feedback, and HP was maintained at 3-months postactivation for 7 (23.3%) patients with mean LFPTA shift of 57.5 ± 25.6 dB HL. RT-ECochG feedback was utilized on 12 patients, of whom 6 patients had full insertions and 6 patients had anywhere from 1 to 3 electrodes left outside of the cochlea based on RT-ECochG feedback. At 3 months postoperatively, HP was achieved on 10 (83.3%) patients and mean LFPTA shift was 18.9 c 11.7 dB HL. Mean difference between LFPTA threshold shift at 3-months postactivation with and without RT-ECochG was 38.6 dB HL (95% CI, 25.6-51.67). There was an improvement in delta CNC from preoperative to 3-months postactivation when using RT-ECochG, with mean difference 20.7% (95% CI, 3.3-38.1). CONCLUSIONS: Use of RT-ECochG monitoring during SLWE placement results in fewer full electrode insertions and significantly better HP rates and speech-perception outcomes when compared with unmonitored insertions. Further investigation is needed to evaluate long-term audiologic outcomes to better understand the relationships among ECochG, cochlear trauma, functional outcomes, and HP. Copyright © 2022, Otology & Neurotology, Inc.

Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer’s disease: a longitudinal observational study
(2022) The Lancet Neurology, 21 (4), pp. 329-341. 

Morenas-Rodríguez, E.^a b , Li, Y.^e , Nuscher, B.^a b x , Franzmeier, N.^c , Xiong, C.^e , Suárez-Calvet, M.^i j k , Fagan, A.M.^f , Schultz, S.^g , Gordon, B.A.^g , Benzinger, T.L.S.^g , Hassenstab, J.^f , McDade, E.^f , Feederle, R.^a l m n , Karch, C.M.^h , Schlepckow, K.^a b , Morris, J.C.^f , Kleinberger, G.^a b , Nellgard, B.^o p , Vöglein, J.^a d , Blennow, K.^q r , Zetterberg, H.^{q r s t u} , Ewers, M.^a c , Jucker, M.^v w , Levin, J.^a d l , Bateman, R.J.^f , Haass, C.^a b l , Adams, S.^x , Allegri, R.^x , Araki, A.^x , Barthelemy, N.^x , Bechara, J.^x , Berman, S.^x , Bodge, C.^x , Brandon, S.^x , Brooks, W.B.^x , Brosch, J.^x , Buck, J.^x , Buckles, V.^x , Carter, K.^x , Cash, L.^x , Chen, C.^x , Chhatwal, J.^x , Chrem, P.^x , Chua, J.^x , Chui, H.^x , Cruchaga, C.^x , Day, G.S.^x , De La Cruz, C.^x , Denner, D.^x , Diffenbacher, A.^x , Dincer, A.^x , Donahue, T.^x , Douglas, J.^x , Duong, D.^x , Egido, N.^x , Esposito, B.^x , Farlow, M.^x , Feldman, B.^x , Fitzpatrick, C.^x , Flores, S.^x , Fox, N.^x , Franklin, E.^x , Friedrichsen, N.^x , Fujii, H.^x , Gardener, S.^x , Ghetti, B.^x , Goate, A.^x , Goldberg, S.^x , Goldman, J.^x , Gonzalez, A.^x , Gräber-Sultan, S.^x , Graff-Radford, N.^x , Graham, M.^x , Gray, J.^x , Gremminger, E.^x , Grilo, M.^x , Groves, A.^x , Häsler, L.^x , Hellm, C.^x , Herries, E.^x , Hoechst-Swisher, L.^x , Hofmann, A.^x , Holtzman, D.^x , Hornbeck, R.^x , Igor, Y.^x , Ihara, R.^x , Ikeuchi, T.^x , Ikonomovic, S.^x , Ishii, K.^x , Jack, C.^x , Jerome, G.^x , Johnson, E.^x , Käser, S.^x , Kasuga, K.^x , Keefe, S.^x , Klunk, W.B.^x , Koeppe, R.^x , Koudelis, D.^x , Kuder-Buletta, E.^x , Laske, C.^x , Levey, A.^x , Lopez, O.^x , Marsh, J.^x , Martinez, R.^x , Martins, R.^x , Mason, N.S.^x , Masters, C.^x , Mawuenyega, K.^x , McCullough, A.^x , Mejia, A.^x , MountzMD, J.^x , Mummery, C.^x , Nadkarni, N.^x , Nagamatsu, A.^x , Neimeyer, K.^x , Niimi, Y.^x , Noble, J.^x , Norton, J.^x , O’Connor, A.^x , Obermüller, U.^x , Patira, R.^x , Perrin, R.^x , Ping, L.^x , Preische, O.^x , Renton, A.^x , Ringman, J.^x , Salloway, S.^x , Schofield, P.^x , Senda, M.^x , Seyfried, N.^x , Shady, K.^x , Shimada, H.^x , Sigurdson, W.^x , Smith, J.^x , Smith, L.^x , Snitz, B.^x , Sohrabi, H.^x , Stephens, S.^x , Taddei, K.^x , Thompson, S.^x , Wang, P.^x , Wang, Q.^x , Weamer, E.^x , Xu, J.^x , Xu, X.^x , Dominantly Inherited Alzheimer Network^y

^a German Center for Neurodegenerative Diseases, Munich, Germany
^b Metabolic Biochemistry, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany
^c Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany
^d Department of Neurology, University Hospital of Munich, Ludwig-Maximilians University, Munich, Germany
^e Division of Biostatistics, Washington University School of Medicine, St Louis, MO, United States
^f Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^g Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
^h Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
ⁱ Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
^j Servei de Neurologia, Hospital del Mar Medical Research Institute, Barcelona, Spain
^k Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, Madrid, Spain
^l Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^m Institute for Diabetes and Obesity, Monoclonal Antibody Core Facility, Helmholtz Center, Munich, Germany
ⁿ German Research Center for Environmental Health, Neuherberg, Germany
^o Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Mölndal, Sweden
^p Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
^q Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
^r Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^s Department of Neurodegenerative Disease, UCL Queens Square Institute of Neurology, University College London, UK, London, United Kingdom
^t UK Dementia Research Institute, University College London, UK, London, United Kingdom
^u Hong Kong Center for Neurodegenerative Diseases, Hong Kong Special Administrative Region, China
^v German Center for Neurodegenerative Diseases, Tübingen, Germany
^w Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany

Abstract
Background: Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer’s disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer’s pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer’s disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer’s disease. Methods: We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer’s disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models. Findings: In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=–4·28 × 10–2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=–5·51 × 10–3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=–0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020). Interpretation: Our findings in autosomal dominant Alzheimer’s disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing. Funding: German Research Foundation, US National Institutes of Health. © 2022 Elsevier Ltd

Funding details
ALFGBG-715986
JPND2019-466-236
ALFGBG-720931
National Institutes of HealthNIH1R01AG068398-01
National Institute on AgingNIA
Alzheimer’s AssociationAAZEN-21-848495
Alzheimer’s Drug Discovery FoundationADDFRDAPB-201809-2016615
Genentech
Biogen
F. Hoffmann-La Roche
Janssen Pharmaceuticals
Japan Agency for Medical Research and DevelopmentAMED
Ministerio de Ciencia, Innovación y UniversidadesMCIU2017-00915, IJC2018-037478-I
GHR FoundationGHR
European Research CouncilERC681712
Deutsche ForschungsgemeinschaftDFG390857198
Korea Health Industry Development InstituteKHIDIHA1737/16-1
Eisai
VetenskapsrådetVR2018-02532
Instituto de Salud Carlos IIIISCIIIPI19/00155
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Horizon 2020948677
AlzheimerfondenAF-742881, FO2017-0243

Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models
(2022) Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 28 (6), pp. 1229-1239. Cited 1 time.

Campian, J.L.^a , Ghosh, S.^b , Kapoor, V.^b , Yan, R.^a , Thotala, S.^b , Jash, A.^a , Hu, T.^a c , Mahadevan, A.^b , Rifai, K.^b , Page, L.^b , Lee, B.H.^d , Ferrando-Martinez, S.^d , Wolfarth, A.A.^d , Yang, S.H.^d , Hallahan, D.^a e , Chheda, M.G.^a c , Thotala, D.^b e

^a Department of Medicine, Division of Oncology, Washington University in St. Louis, St. Louis, MO, United States
^b Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
^d Rockville, MD, United States
^e Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, United States

Abstract
PURPOSE: Patients with glioblastoma (GBM) are treated with radiotherapy (RT) and temozolomide (TMZ). These treatments may cause prolonged systemic lymphopenia, which itself is associated with poor outcomes. NT-I7 is a long-acting IL7 that expands CD4 and CD8 T-cell numbers in humans and mice. We tested whether NT-I7 prevents systemic lymphopenia and improves survival in mouse models of GBM. EXPERIMENTAL DESIGN: C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day × 5 days), TMZ (33 mg/kg/day × 5 days), and/or NT-I7 (10 mg/kg on the final day of RT). We followed the mice for survival while serially analyzing levels of circulating T lymphocytes. We assessed regulatory T cells (Treg) and cytotoxic T lymphocytes in the tumor microenvironment, cervical lymph nodes, spleen, and thymus, and hematopoietic stem and progenitor cells in the bone marrow. RESULTS: GBM tumor-bearing mice treated with RT+NT-I7 increased T lymphocytes in the lymph nodes, thymus, and spleen, enhanced IFNγ production, and decreased Tregs in the tumor which was associated with a significant increase in survival. NT-I7 also enhanced central memory and effector memory CD8 T cells in lymphoid organs and tumor. Depleting CD8 T cells abrogated the effects of NT-I7. Furthermore, NT-I7 treatment decreased progenitor cells in the bone marrow. CONCLUSIONS: In orthotopic glioma-bearing mice, NT-I7 mitigates RT-related lymphopenia, increases cytotoxic CD8 T lymphocytes systemically and in the tumor, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957). ©2022 American Association for Cancer Research.

Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation
(2022) Cells, 11 (6), art. no. 1053, . Cited 1 time.

Dang, X.^a , Walton, E.K.^a , Zablocka, B.^b , Baloh, R.H.^c , Shy, M.E.^d , Dorn, G.W., II^a

^a Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
^b Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, 02-106, Poland
^c Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
^d Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States

Abstract
Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot–Marie– Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson’s and Alzheimer’s disease patients, implicating addressable mitochondrial dysdynamism in these illnesses. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Mitochondrial dynamics;  Mitofusin;  Neurodegenerative diseases

Funding details
National Institutes of HealthNIH628906, R35135736, R42NS115184
Muscular Dystrophy AssociationMDA

Serologic and Cytokine Signatures in Children with Multisystem Inflammatory Syndrome and Coronavirus Disease 2019
(2022) Open Forum Infectious Diseases, 9 (3), art. no. ofac070, . 

Lapp, S.A.^a b , Abrams, J.^c , Lu, A.T.^a b , Hussaini, L.^a b , Kao, C.M.^d , Hunstad, D.A.^d , Rosenberg, R.B.^e f , Zafferani, M.J.^e f , Ede, K.C.^f g , Ballan, W.^f h , Laham, F.R.ⁱ , Beltran, Y.ⁱ , Hsiao, H.-M.^a b , Sherry, W.^a b , Jenkins, E.^a b , Jones, K.^b , Horner, A.^a b , Brooks, A.^a b , Bryant, B.^c j , Meng, L.^c k , Hammett, T.A.^c , Oster, M.E.^a b c , Bamrah-Morris, S.^c , Godfred-Cato, S.^c , Belay, E.^c , Chahroudi, A.^a b , Anderson, E.J.^a b l , Jaggi, P.^a b , Rostad, C.A.^a b

^a Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
^b Children’s Healthcare of Atlanta, Atlanta, GA, United States
^c COVID-19 Response Team, Centers for Disease Control and Prevention, Atlanta, GA, United States
^d Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
^e Division of Pediatric Critical Care Medicine, Phoenix Children’s Hospital, Phoenix, AZ, United States
^f Department of Child Health, University of Arizona, College of Medicine-Phoenix, Phoenix, AZ, United States
^g Division of Pediatric Rheumatology, Phoenix Children’s Hospital, Phoenix, AZ, United States
^h Pediatric Infectious Diseases, Phoenix Children’s Hospital, Phoenix, AZ, United States
ⁱ Arnold Palmer Hospital for Children, Orlando, FL, United States
^j Oak Ridge Institute for Science and Education, Oak Ridge, TN, United States
^k Apex Systems Affiliated with General Dynamics Information Technology, Falls Church, VA, United States
^l Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States

Abstract
Background: The serologic and cytokine responses of children hospitalized with multisystem inflammatory syndrome (MIS-C) vs coronavirus disease 2019 (COVID-19) are poorly understood. Methods: We performed a prospective, multicenter, cross-sectional study of hospitalized children who met the Centers for Disease Control and Prevention case definition for MIS-C (n = 118), acute COVID-19 (n = 88), or contemporaneous healthy controls (n = 24). We measured severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (RBD) immunoglobulin G (IgG) titers and cytokine concentrations in patients and performed multivariable analysis to determine cytokine signatures associated with MIS-C. We also measured nucleocapsid IgG and convalescent RBD IgG in subsets of patients. Results: Children with MIS-C had significantly higher SARS-CoV-2 RBD IgG than children with acute COVID-19 (median, 2783 vs 146; P <.001), and titers correlated with nucleocapsid IgG. For patients with MIS-C, RBD IgG titers declined in convalescence (median, 2783 vs 1135; P =.010) in contrast to patients with COVID-19 (median, 146 vs 4795; P <.001). MIS-C was characterized by transient acute proinflammatory hypercytokinemia, including elevated levels of interleukin (IL) 6, IL-10, IL-17A, and interferon gamma (IFN-γ). Elevation of at least 3 of these cytokines was associated with significantly increased prevalence of prolonged hospitalization ≥8 days (prevalence ratio, 3.29 [95% CI, 1.17-9.23]). Conclusions: MIS-C was associated with high titers of SARS-CoV-2 RBD IgG antibodies and acute hypercytokinemia with IL-6, IL-10, IL-17A, and IFN-γ. © 2022 The Author(s). Published by Oxford University Press on behalf of Infectious Diseases Society of America.

Author Keywords
Children;  COVID-19;  Cytokines;  MIS-C;  PIMS;  SARS-CoV-2;  Serology

A Physician-Led Communication Initiative to Inform OAB Patients of Dementia Risk Associated With Anticholinergic Medications
(2022) Female Pelvic Medicine & Reconstructive Surgery, 28 (3), pp. e16-e21. 

Millimet, H.^a , Falk, K.^b , Harroche, J.^c , Littman, A.^d , Metcalfe, N.^c , Northington, G.M.^c

^a From the Department of Obstetrics and Gynecology, Barnes Jewish Hospital, Washington University School of Medicine, St. Louis, MO
^b Department of Obstetrics and Gynecology, University of Nevada Reno School of Medicine, NV, Reno, United States
^c Division of Female Pelvic Medicine and Reconstructive Surgery, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, United States
^d Emory University School of Medicine, Atlanta, United States

Abstract
OBJECTIVES: Anticholinergic medications are a core treatment strategy for overactive bladder (OAB). There is evidence that exposure to anticholinergic medications is associated with an increased risk of developing dementia. We launched an initiative to inform our patients of this risk and give them an opportunity to engage in shared decision-making about their treatment. This quality improvement initiative encompassed 3 aims: (1) to evaluate the feasibility of 2 different routes to deliver the written outreach; (2) to evaluate if and how patients changed their OAB treatment; and (3) to assess satisfaction with the outreach initiative. METHODS: A query was performed via the electronic medical record for all patients who had been prescribed an anticholinergic for treatment of OAB. We sent either electronic messages or traditional mail to patients. We contacted patients by telephone to assess if they received the message, were satisfied with their respective method of communication, and decided for ongoing treatment. Health care provider satisfaction was also measured. RESULTS: Of the 231 patients sent the outreach, 32 were still taking the anticholinergic at the time they received the communication. The majority of patients, 84.38%, were satisfied with the initiative and elected to change therapy after learning about the increased risk of dementia. The physicians also uniformly reported satisfaction with the initiative. CONCLUSIONS: Overall, this outreach initiative resulted in an increase in patient counseling that led to a change in treatment for most patients. This initiative was received favorably by patients and health care providers. Copyright © 2022 American Urogynecologic Society. All rights reserved.

Association of a Perioperative Multicomponent Fall Prevention Intervention With Falls and Quality of Life After Elective Inpatient Surgical Procedures
(2022) JAMA Network Open, 5 (3), p. e221938. 

Fritz, B.A.^a , King, C.R.^a , Mehta, D.^a , Somerville, E.^b , Kronzer, A.^a , Ben Abdallah, A.^a , Wildes, T.^a , Avidan, M.S.^a , Lenze, E.J.^c , Stark, S.^b , ENGAGES Research Group^d

^a Department of Anesthesiology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^b Program in Occupational Therapy, Washington University School of Medicine in St Louis, St Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States

Abstract
Importance: Falls after elective inpatient surgical procedures are common and have physical, emotional, and financial consequences. Close interactions between patients and health care teams before and after surgical procedures may offer opportunities to address modifiable risk factors associated with falls. Objective: To assess whether a multicomponent intervention that incorporates education, home medication review, and home safety assessment is associated with reductions in the incidence of falls after elective inpatient surgical procedures. Design, Setting, and Participants: This prospective propensity score-matched cohort study was a prespecified secondary analysis of data from the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized clinical trial, which was conducted at a single academic medical center between January 16, 2015, and May 7, 2018. Patients in the intervention group of the present study were enrolled in either arm of the ENGAGES clinical trial. Patients in the control group were selected from the Systematic Assessment and Targeted Improvement of Services Following Yearly Surgical Outcomes Surveys prospective observational cohort study, which created a registry of patient-reported postoperative outcomes at the same single center. The propensity score-matched cohort in the present study included 1396 patients (698 pairs) selected from a pool of 2013 eligible patients. All patients underwent elective surgical procedures with general anesthesia and had a hospital stay of 2 or more days. Data were analyzed from January 2, 2020, to January 11, 2022. Interventions: The multicomponent safety intervention (offered to all patients in the ENGAGES clinical trial) included patient education on fall prevention techniques, home medication review by a geriatric psychiatrist (with communication of recommended changes to the surgeon), a self-administered home safety assessment, and targeted occupational therapy home visits with home hazard removal (offered to patients with a preoperative history of falls). Main Outcomes and Measures: The primary outcome was patient-reported falls within 1 year after an elective inpatient surgical procedure. The secondary outcome was quality of life 1 year after an elective surgical procedure, which was measured using the physical and mental composite summary scores on the Veterans RAND 12-item health survey (score range, 0-100 points, with 0 indicating lowest quality of life and 100 indicating highest quality of life). Results: Among 1396 patients, the median age was 69 years (IQR, 64-75 years), and 739 patients (52.9%) were male. With regard to race, 5 patients (0.4%) were Asian, 97 (6.9%) were Black or African American, 2 (0.1%) were Native Hawaiian or Pacific Islander, 1237 (88.6%) were White, 3 (0.2%) were of other race, and 52 (3.7%) were of unknown race; with regard to ethnicity, 12 patients (0.9%) were Hispanic or Latino, 1335 (95.6%) were non-Hispanic or non-Latino, and 49 (3.5%) were of unknown ethnicity. Adherence to individual intervention components was modest (from 22.9% for completion of the self-administered home safety assessment to 28.2% for implementation of the geriatric psychiatrist’s recommended medication changes). Falls within 1 year after surgical procedures were reported by 228 of 698 patients (32.7%) in the intervention group and 225 of 698 patients (32.2%) in the control group. No significant difference was found in falls between the 2 groups (standardized risk difference, 0.4%; 95% CI, -4.5% to 5.3%). After adjusting for preoperative quality of life, patients in the intervention group had higher physical composite summary scores (3.8 points; 95% CI, 2.4-5.1 points) and higher mental composite summary scores (5.7 points; 95% CI, 4.7-6.7 points) at 1 year compared with patients in the control group. Conclusions and Relevance: In this cohort study, a multicomponent safety intervention was not associated with reductions in falls within the first year after an elective surgical procedure; however, an increase in quality of life at 1 year was observed. These results suggest a need for other interventions, such as those designed to increase adherence, to lower the incidence of falls after surgical procedures.

The Social Cerebellum: A Large-Scale Investigation of Functional and Structural Specificity and Connectivity
(2022) Cerebral Cortex, 32 (5), pp. 987-1003. Cited 2 times.

Metoki, A.^a b , Wang, Y.^c , Olson, I.R.^a

^a Department of Psychology, Temple University, Philadelphia, PA 19122, United States
^b Department of Neurology, Washington University in St. Louis, St. Louis, MO 63108, United States
^c State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, 100875, China

Abstract
The cerebellum has been traditionally disregarded in relation to nonmotor functions, but recent findings indicate it may be involved in language, affective processing, and social functions. Mentalizing, or Theory of Mind (ToM), is the ability to infer mental states of others and this skill relies on a distributed network of brain regions. Here, we leveraged large-scale multimodal neuroimaging data to elucidate the structural and functional role of the cerebellum in mentalizing. We used functional activations to determine whether the cerebellum has a domain-general or domain-specific functional role, and effective connectivity and probabilistic tractography to map the cerebello-cerebral mentalizing network. We found that the cerebellum is organized in a domain-specific way and that there is a left cerebellar effective and structural lateralization, with more and stronger effective connections from the left cerebellar hemisphere to the right cerebral mentalizing areas, and greater cerebello-thalamo-cortical and cortico-ponto-cerebellar streamline counts from and to the left cerebellum. Our study provides novel insights to the network organization of the cerebellum, an overlooked brain structure, and mentalizing, one of humans’ most essential abilities to navigate the social world. © 2021 Published by Oxford University Press 2021.

Author Keywords
cerebellum;  effective connectivity;  human connectome project;  structural connectivity;  theory of mind

Partial Ablation of Postsynaptic Dopamine D2 Receptors in the Central Nucleus of the Amygdala Increases Risk Avoidance in Exploratory Tasks
(2022) eNeuro, 9 (2), art. no. ENEURO.0528-21.2022, . 

Casey, E.^a d , Avale, M.E.^a b , Kravitz, A.^c d e , Rubinstein, M.^a b

^a Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, 1428, Argentina
^b Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, 1428, Argentina
^c Department of Anesthesiology, Washington University St. Louis, St. Louis, MO 63108, United States
^d Department of Psychiatry, Washington University St. Louis, St. Louis, MO 63108, United States
^e Department of Neuroscience and Biomedical Engineering, Washington University St. Louis, St. Louis, MO 63108, United States

Abstract
The central nucleus of the amygdala (CeA) is involved in the expression of fear and has been implicated in several anxiety disorders. This structure is densely innervated by DAergic projections that impinge on amygdalar neurons expressing various dopamine (DA) receptor subtypes, including D2 receptors (D2Rs). Although various pharmacological approaches have assessed the role of D2Rs in the CeA, the actual participation of postsynaptic D2Rs in the CeA to defensive behaviors remains unclear. Here, we investigated the distribution of D2Rs in the CeA and their role in modifying neuronal activity and fear related behaviors in mice. First, using the mouse reporter strain D2R-EGFP, we verified that D2Rs are present both in neurons of the CeA and in A10 dorsocaudal (A10dc) DAergic neurons that innervate the CeA. Moreover, we showed that pharmacological stimulation of D2Rs increases the activity of protein kinase C (PKC)δ cells present in the CeA, a type of neuron previously associated with reduced defensive behaviors. Finally, using a molecular genetics approach that discriminates postsynaptic D2Rs from presynaptic D2 autoreceptors, we demonstrated that mice carrying targeted deletions of postsynaptic D2Rs in the CeA display increased risk avoidance in exploratory tasks. Together, our results indicate that postsynaptic D2Rs in the CeA attenuate behavioral reactions to potential environmental threats. © 2022 Casey et al.

Funding details
Consejo Nacional de Investigaciones Científicas y TécnicasCONICET
Agencia Nacional de Promoción Científica y TecnológicaANPCyT

Selected Histone Deacetylase Inhibitors Reverse the Frataxin Transcriptional Defect in a Novel Friedreich’s Ataxia Induced Pluripotent Stem Cell-Derived Neuronal Reporter System
(2022) Frontiers in Neuroscience, 16, art. no. 836476, . 

Schreiber, A.M.^a , Li, Y.^a , Chen, Y.-H.^b , Napierala, J.S.^a , Napierala, M.^a

^a Department of Biochemistry and Molecular Genetics, Stem Cell Institute, University of Alabama at Birmingham, Birmingham, AL, United States
^b Genome Engineering and iPSC Center, Washington University, St. Louis, MO, United States

Abstract
Friedreich’s ataxia (FRDA) is a neurodegenerative disorder caused by the expansion of guanine–adenine–adenine repeats within the first intron of the frataxin (FXN) gene. The location and nature of the expansion have been proven to contribute to transcriptional repression of FXN by decreasing the rate of polymerase II (RNA polymerase II) progression and increasing the presence of histone modifications associated with a heterochromatin-like state. Targeting impaired FXN transcription appears as a feasible option for therapeutic intervention, while no cure currently exists. We created a novel reporter cell line containing an FXN-Nanoluciferase (FXN-NLuc) fusion in induced pluripotent stem cells (iPSCs) reprogrammed from the fibroblasts of patients with FRDA, thus allowing quantification of endogenous FXN expression. The use of iPSCs provides the opportunity to differentiate these cells into disease-relevant neural progenitor cells (NPCs). NPCs derived from the FXN-NLuc line responded to treatments with a known FXN inducer, RG109. Results were validated by quantitative PCR and Western blot in multiple FRDA NPC lines. We then screened a commercially available library of compounds consisting of molecules targeting various enzymes and pathways critical for silencing or activation of gene expression. Only selected histone deacetylase inhibitors were capable of partial reactivation of FXN expression. This endogenous, FRDA iPSC-derived reporter can be utilized for high-throughput campaigns performed in cells most relevant to disease pathology in search of FXN transcription activators. Copyright © 2022 Schreiber, Li, Chen, Napierala and Napierala.

Author Keywords
Friedreich’s ataxia (FRDA);  induced pluripotent stem cells;  Nanoluciferase;  neural progenitor cells (NPCs);  reporter cell line;  screening

Funding details
National Institutes of HealthNIHR01NS081366, R01NS121038
National Institute of Neurological Disorders and StrokeNINDS
Friedreich’s Ataxia Research AllianceFARA

Perspectives and experiences with COVID-19 vaccines in people with MS
(2022) Multiple Sclerosis Journal – Experimental, Translational and Clinical, 8 (1), . 

Ciotti, J.R.^a , Perantie, D.C.^a , Moss, B.P.^b , Fitzgerald, K.C.^c , Cohen, J.A.^b , Mowry, E.M.^c , Naismith, R.T.^a , Chahin, S.^a

^a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
^b Mellen Center, Cleveland Clinic, Cleveland, OH, United States
^c Department of Neurology, Johns Hopkins University, Baltimore, MD, United States

Abstract
Background: People with MS may have unique perspectives on COVID-19 vaccines due to their condition and/or medications. Objective: Assess perspectives and experiences with COVID-19 vaccination, and quantify variables impacting COVID-19 vaccine willingness in people with MS. Methods: A survey captured demographics, MS characteristics, and COVID-19 infection and exposures data; opinions on COVID-19 vaccine safety, side effects, and efficacy; and experiences following vaccination. Chi-square tests and a logistic regression model were used to denote between-group differences and variables predicting vaccine willingness, respectively. Results: Most (87.8%) of the 237 participants were willing to receive the vaccine. Fifteen percent held or delayed a DMT dose for vaccination. MS symptoms worsened in a minority (7.6% first/only dose; 14.7% second dose), and most side effects were mild (80.0%; 55.3%). Those not planning to receive the vaccine were primarily concerned with long-term safety (70.4%). Medical comorbidities (adjusted odds ratio [aOR]=5.222; p=0.04) and following infection prevention precautions (aOR=6.330; p=0.008) were associated with vaccine willingness. Conclusion: Most individuals with MS surveyed plan to receive the COVID-19 vaccine. People with MS experience similar side effects to the general population, and few experience transient MS symptom worsening. These results can inform conversations on vaccination between providers and people with MS. © The Author(s), 2022.

Author Keywords
COVID-19;  Multiple sclerosis;  vaccine

Funding details
National Multiple Sclerosis SocietyNMSS
Genentech
Biogen

Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels
(2022) Nature Neuroscience, . 

Mazzitelli, J.A.^a b c d , Smyth, L.C.D.^a b , Cross, K.A.^b e , Dykstra, T.^a b , Sun, J.^c , Du, S.^a b f , Mamuladze, T.^a b f , Smirnov, I.^a b , Rustenhoven, J.^a b g , Kipnis, J.^{a b c d e f}

^a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^b Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St. Louis, MO, United States
^c Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States
^d Neuroscience Graduate Program, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^f Immunology Graduate Program, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand

Abstract
It remains unclear how immune cells from skull bone marrow niches are recruited to the meninges. Here we report that cerebrospinal fluid (CSF) accesses skull bone marrow via dura–skull channels, and CSF proteins signal onto diverse cell types within the niches. After spinal cord injury, CSF-borne cues promote myelopoiesis and egress of myeloid cells into meninges. This reveals a mechanism of CNS-to-bone-marrow communication via CSF that regulates CNS immune responses. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIHAT010416, NS096967
Cure Alzheimer’s FundCAFT32NS121881

Associations Between Atrial Arrhythmias and Brain Amyloid Deposition: The ARIC-PET Study
(2022) Journal of Alzheimer’s Disease: JAD, 86 (1), pp. 43-48. 

Johansen, M.C.^a , Wang, W.^b , Zhang, M.J.^c , Alonso, A.^d , Wong, D.F.^e , Gottesman, R.F.^f , Chen, L.Y.^c

^a Department of Neurology, Johns Hopkins University School of Medicine, MD, Baltimore, United States
^b Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, MN, Minneapolis, United States
^c Cardiovascular Division, Department of Medicine, University of Minnesota Medical School, MN, Minneapolis, United States
^d Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, United States
^e Department of Radiology, Washington University, St Louis, MO, USA
^f Stroke Branch, National Institute of Neurological Disorders and Stroke Intramural Research Program, MD, Bethesda, United States

Abstract
The aim of this study is to determine if there is an association between atrial arrhythmias and brain amyloid-β (Aβ), measured on florbetapir (FBP) PET. 346 nondemented participants from the Atherosclerosis Risk in Communities study underwent FBP-PET, 185 also wore Zio® XT Patch. The associations between global cortical Aβ (> 1.2 standardized uptake value ratio) and history of atrial fibrillation, zio-defined atrial tachycardia and premature atrial contractions, each, were evaluated. Among nondemented community-dwelling older adults, we did not find an association between atrial arrhythmias and Aβ. Other brain pathology may underlie the association described between atrial arrhythmias and cognition.

Author Keywords
Arrhythmias;  atrial fibrillation;  cognitive impairment;  imaging

Reproducible brain-wide association studies require thousands of individuals
(2022) Nature, . 

Marek, S.^a , Tervo-Clemmens, B.^b c , Calabro, F.J.^d e , Montez, D.F.^f , Kay, B.P.^f , Hatoum, A.S.^a , Donohue, M.R.^a , Foran, W.^d , Miller, R.L.^a f , Hendrickson, T.J.^g , Malone, S.M.^h , Kandala, S.^a , Feczko, E.^i j , Miranda-Dominguez, O.^i j , Graham, A.M.^k , Earl, E.A.^i k , Perrone, A.J.^i k , Cordova, M.^k , Doyle, O.^k , Moore, L.A.^k , Conan, G.M.^i k , Uriarte, J.^k , Snider, K.^k , Lynch, B.J.^i l , Wilgenbusch, J.C.^i l , Pengo, T.^g , Tam, A.^m n o p , Chen, J.^m n o p , Newbold, D.J.^f , Zheng, A.^f , Seider, N.A.^f , Van, A.N.^f q , Metoki, A.^f , Chauvin, R.J.^f , Laumann, T.O.^a , Greene, D.J.^r , Petersen, S.E.^{f q s t u} , Garavan, H.^v , Thompson, W.K.^w , Nichols, T.E.^x , Yeo, B.T.T.^{m n o p y z} , Barch, D.M.^a u , Luna, B.^c d , Fair, D.A.^i j aa , Dosenbach, N.U.F.^{f q s ab ac}

^a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^b Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^c Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States
^d Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
^e Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
^f Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^g University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN, United States
^h Department of Psychology, University of Minnesota, Minneapolis, MN, United States
ⁱ Masonic Institute for the Developing Brain, University of Minnesota Medical School, Minneapolis, MN, United States
^j Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, United States
^k Department of Psychiatry, Oregon Health and Science University, Portland, OR, United States
^l Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, United States
^m Department of Electrical and Computer Engineering, National University of Singapore, Singapore, Singapore
ⁿ Centre for Sleep and Cognition, National University of Singapore, Singapore, Singapore
^o Centre for Translational MR Research, National University of Singapore, Singapore, Singapore
^p N.1 Institute for Health, Institute for Digital Medicine, National University of Singapore, Singapore, Singapore
^q Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, United States
^r Department of Cognitive Science, University of California San Diego, La Jolla, CA, United States
^s Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
^t Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
^u Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
^v Department of Psychiatry, University of Vermont, Burlington, VT, United States
^w Division of Biostatistics, University of California San Diego, La Jolla, CA, United States
^x Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
^y Integrative Sciences and Engineering Programme, National University of Singapore, Singapore, Singapore
^z Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
^aa Institute of Child Development, University of Minnesota Medical School, Minneapolis, MN, United States
^ab Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO, United States
^ac Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States

Abstract
Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions1–3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain–behavioural phenotype associations5,6. Here we used three of the largest neuroimaging datasets currently available—with a total sample size of around 50,000 individuals—to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain–phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
PSC TG-IBN200009
1U54MH091657, U54 MH091657
National Science FoundationNSFACI-1445606, ACI-1548562
National Institutes of HealthNIHAA02969, DA007261, DA04112, DA041148, MH096773, MH100019, MH104592, MH112473, MH115357, MH121276, MH121518, MH122066, MH124567, MH125023, NS088590, NS090978, NS110332, NS115672, U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041156, U01DA041174, U24DA041123, U24DA041147
NIH Blueprint for Neuroscience Research
Minnesota Department of HealthMDH
University of WashingtonUW
Intellectual and Developmental Disabilities Research CenterIDDRCP50 HD103525
Institute of Clinical and Translational SciencesICTSUL1 TR002345
College of Health, Education, and Human Development, Clemson UniversityHEHD
McDonnell Center for Systems Neuroscience
Scottish Government
Medical Research CouncilMRC
British Heart FoundationBHF
Cancer Research UKCRUK
Jacobs Foundation2016121703
Northwest Regional Development AgencyNWDA

An analysis of post-operative pain and narcotic use following robotic assisted laparoscopic prostatectomy for same day discharge
(2022) Journal of Robotic Surgery, . 

Palka, J.K., Argade, S.P., Gross, J.T., Vetter, J., Figenshau, R.S.

Division of Urologic Surgery, Washington University School of Medicine, 4960 Children’s Place, Campus Box 8242, St. Louis, MO 63110, United States

Abstract
Robotic assisted laparoscopic prostatectomy (RALP) has become the primary surgical modality in the treatment of prostate cancer. Most patients are discharged on postoperative day one. Same-day discharge is emerging as a potential new standard. We sought to establish factors correlating with post-operative pain after RALP procedures to design a same-day discharge protocol. We retrospectively reviewed 150 of recently performed RALP procedures from March 2020 to January 2021. Patient demographics and intra-operative variables were compared to Numeric Rating Scale (NRS) pain scores and total morphine milliequivalents (MME) at 2 h, 8 h, and averaged over the patient’s admission post-operatively or first 48 h, whichever occurred first. We performed univariable and multivariable logistic regression to assess correlations with postoperative pain and narcotic use. NRS average &gt; 3 or any MME given at 2 h postoperatively was significantly associated with continued post-operative pain averaged over admission (rs = 0.32, 0.38, respectively; p &lt; 0.001). MME given was also associated with longer operative time and negative related to body mass index. No other demographic data or intraoperative variables such as diabetes or pneumoperitoneum pressure were correlated with worsened post-operative pain scores &gt; 3 or narcotic use. Local bupivacaine dose was also not associated with improved post-operative pain scores or narcotic use at 8 h (p = 0.98, 0.13). These findings suggest that patients with adequate postoperative pain control at 2 hours may be discharged same day from a pain control perspective. Further clinical evaluation regarding the role of local anesthetic use in RALPs is warranted. © 2022, The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.

Author Keywords
Opioid;  Post-operative pain;  Prostatectomy;  Same-day discharge

Therapeutic Targets for Alzheimer’s Disease: Amyloid Vs. Non-Amyloid. Where Does Consensus Lie Today? An CTAD Task Force Report
(2022) Journal of Prevention of Alzheimer’s Disease, . 

Gauthier, S.^a , Boxer, A.^b , Knopman, D.^c , Sims, J.^d , Doody, R.^e , Aisen, P.^f , Iwatsubo, T.^g , Bateman, R.^h , Vellas, B.ⁱ

^a McGill Center for Studies in Aging, Montreal, Canada
^b Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, United States
^c Department of Neurology, Mayo Clinic, Rochester, MN, United States
^d Eli Lilly and Company, Indianapolis, IN, United States
^e Genentech and F. Hoffman LaRoche, Basel, Switzerland
^f Keck Scholl of Medicine of USC, San Diego, CA, United States
^g Department of Neuropathology, The University of Tokyo, Tokyo, Japan
^h Department of Neurology, Washington University, St-Louis, MO, United States
ⁱ Toulouse University Hospital, Inserm 1295, University of Toulouse, UPS, Toulouse, France

Abstract
There was consensus that both amyloid and tau pathologies should be targeted in Alzheimer’s disease, as well as additional pathophysiological mechanisms such as neuroinflammation. The selection of one or both of these targets may depend upon a personalized approach that takes into account the genetic and acquired factors that cause AD in any given person as well as their stage of disease as reflected in a biomarker profile. The validation of this therapeutic approach will be made possible by new methodologies for subdividing into predominant pathology, by efficient methods for identifying people in the earliest stages of disease, and by combination studies. © 2022, The Author(s).

Author Keywords
Alzheimer disease;  Amyloid;  tau;  therapeutic targets

Funding details
National Institutes of HealthNIH
Foundation for the National Institutes of HealthFNIH
National Institute on AgingNIA
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDFR01AG038791, U01AG045390, U19AG063911, U54NS092089
Eli Lilly and Company
GlaxoSmithKlineGSK
Merck
Roche
Biogen
AbbVie
University of California, San FranciscoUCSF
Janssen Pharmaceuticals
Applied Genetic Technologies CorporationAGTC
GHR FoundationGHR
Eisai
H. Lundbeck A/S

Neutral Ligands as Potential 64Cu Chelators for Positron Emission Tomography Imaging Applications in Alzheimer’s Disease
(2022) Inorganic Chemistry, . 

Huang, Y.^a , Huynh, T.T.^b c , Sun, L.^a , Hu, C.-H.^a , Wang, Y.-C.^a , Rogers, B.E.^b , Mirica, L.M.^a d

^a Department of Chemistry, University of Illinois at Urbana-Champaign (UIUC), 600 South Mathews Avenue, Urbana, IL 61801, United States
^b Department of Radiation Oncology, Washington University, School of Medicine, St. Louis, MO 63108, United States
^c Department of Chemistry, Washington University, St. Louis, MO 63130, United States
^d Hope Center for Neurological Disorders, Washington University, School of Medicine, St. Louis, MO 63110, United States

Abstract
Positron emission tomography (PET), which uses positron-emitting radionuclides to visualize and measure processes in the human body, is a useful noninvasive diagnostic tool for Alzheimer’s disease (AD). The development of longer-lived radiolabeled compounds is essential for further expansion of the use of PET imaging in healthcare, and diagnostic agents employing longer-lived radionuclides such as 64Cu (t1/2 = 12.7 h, β+ = 17%, β- = 39%, electron capture EC = 43%, and Emax = 0.656 MeV) can accomplish this task. One limitation of 64Cu PET agents for neuroimaging applications is their limited lipophilicity due to the presence of several anionic groups needed to ensure strong Cu chelation. Herein, we evaluate a series of neutral chelators containing the 1,4,7-triazacyclononane or 2,11-diaza[3.3](2,6)pyridinophane macrocycles that have pyridyl-containing arms incorporating Aβ-peptide-interacting fragments. The crystal structures of the corresponding Cu complexes confirm that the pyridyl N atoms are involved in binding to Cu. Radiolabeling and autoradiography studies show that the compounds efficiently chelate 64Cu, and the resulting complexes exhibit specific binding to the amyloid plaques in the AD mouse brain sections versus wild-type controls. ©

Funding details
National Institutes of HealthNIHR01GM114588

Age-dependent white matter disruptions after military traumatic brain injury: Multivariate analysis results from ENIGMA brain injury
(2022) Human Brain Mapping, . 

Bouchard, H.C.^a b c , Sun, D.^a b , Dennis, E.L.^d e , Newsome, M.R.^f g , Disner, S.G.^h i , Elman, J.^j k , Silva, A.^l , Velez, C.^d m , Irimia, A.^n o , Davenport, N.D.^h i , Sponheim, S.R.^h i , Franz, C.E.^j k , Kremen, W.S.^j k p , Coleman, M.J.^l , Williams, M.W.^f q , Geuze, E.^r s , Koerte, I.K.^l , Shenton, M.E.^l , Adamson, M.M.^t u , Coimbra, R.^v , Grant, G.^w , Shutter, L.^x , George, M.S.^y , Zafonte, R.D.^z , McAllister, T.W.^aa , Stein, M.B.^j ab , Thompson, P.M.^{ac ad ae af ag ah ai aj} , Wilde, E.A.^d f m , Tate, D.F.^d m , Sotiras, A.^aj , Morey, R.A.^a b

^a Duke-UNC Brain Imaging and Analysis Center, Duke University, Durham, NC, United States
^b Mid-Atlantic Mental Illness Research Education and Clinical Center, Durham VA Medical Center, Durham, NC, United States
^c Center for Brain, Biology & Behavior, University of Nebraska-Lincoln, Lincoln, NE, United States
^d Department of Neurology, University of Utah, Salt Lake City, UT, United States
^e Department of Radiology, Stanford University, Stanford, CA, United States
^f Michael E. DeBakey VA Medical Center, Houston, TX, United States
^g H. Ben Taub Department of Physical Medicine and Rehabilitation, Baylor College of Medicine, Houston, TX, United States
^h Minneapolis VA Health Care System, Minneapolis, MN, United States
ⁱ Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN, United States
^j Department of Psychiatry, University of California San Diego, La Jolla, CA, United States
^k Center for Behavior Genetics of Aging, University of California, San Diego, San Diego, CA, United States
^l Psychiatry Neuroimaging Laboratory, Brigham & Women’s Hospital, Boston, MA, United States
^m George E. Wahlen Veterans Affairs Medical Center, Salt Lake City, UT, United States
ⁿ Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, United States
^o Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, United States
^p Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA, United States
^q Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, United States
^r Department of Psychiatry, University Medical Center, Utrecht, Netherlands
^s Brain Research & Innovation Centre, Ministry of Defence, Utrecht, Netherlands
^t Rehabilitation Service, VA Palo Alto, Palo Alto, CA, United States
^u Neurosurgery, Stanford School of Medicine, Stanford, CA, United States
^v Department of Surgery, University of California San Diego, La Jolla, CA, United States
^w Department of Neurosurgery, Stanford University Medical Center, Palo Alto, CA, United States
^x Department of Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^y Department of Psychiatry, Medical University of South Carolina, Charleston, SC, United States
^z Spaulding Rehabilitation Hospital, Massachusetts General Hospital, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, United States
^aa Geisel School of Medicine at Dartmouth, Hanover, NH, United States
^ab Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, United States
^ac Imaging Genetics Center, Stevens Neuroimaging & Informatics Institute, Keck School of Medicine of USC, Marina del Rey, CA, United States
^ad Department of Neurology, Pediatrics, Psychiatry, Radiology, Engineering, and Ophthalmology, University of Southern California (USC), Los AngelesCA, United States
^ae Department of Pediatrics, USC, Los Angeles, CA, United States
^af Department of Psychiatry, USC, Los Angeles, CA, United States
^ag Department of Radiology, USC, Los Angeles, CA, United States
^ah Department of Engineering, USC, Los Angeles, CA, United States
^ai Department of Ophthalmology, USC, Los Angeles, CA, United States
^aj Department of Radiology and Institute for Informatics, School of Medicine, Washington University St. Louis, St. Louis, MO, United States

Abstract
Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age-related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non-negative matrix factorization (NMF) is a data-driven approach that detects covarying patterns (components) within high-dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self-reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta-Analysis) Military Brain Injury working group. Regressions were used to examine TBI- and mTBI-related associations in NMF-derived components while adjusting for age, sex, post-traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age-dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age-dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans. © 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Author Keywords
diffusion MRI;  ENIGMA;  military;  mTBI;  nonnegative matrix factorization;  traumatic brain injury

Funding details
National Institutes of HealthNIHR01AG067103, R01NS086885, R01NS100973, U54 EB020403
U.S. Department of DefenseDODW81XWH08‐2‐0159, W81XWH‐18‐1‐0413
Medical Research and Materiel CommandMRMCPT108802‐SC104835, W81XWH‐13‐2‐0025
U.S. Department of Veterans AffairsVAI01CX001820, I01CX002293, I01RX002174, I21RX001608, IK2RX002922‐01A1
University of Southern CaliforniaUSC

Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II
(2022) Multiple Sclerosis Journal, . 

Gärtner, J.^a , Hauser, S.L.^b , Bar-Or, A.^c , Montalban, X.^d , Cohen, J.A.^e , Cross, A.H.^f , Deiva, K.^g , Ganjgahi, H.^h l , Häring, D.A.ⁱ , Li, B.^j , Pingili, R.^j , Ramanathan, K.ⁱ , Su, W.^j , Willi, R.ⁱ , Kieseier, B.ⁱ , Kappos, L.^k

^a Department of Paediatrics and Adolescent Medicine, Division of Paediatric Neurology, University Medical Centre Göttingen, Georg August University Göttingen, Göttingen, Germany
^b UCSF Weill Institute for Neurosciences, Department of Neurology, University of California – San Francisco, San Francisco, CA, United States
^c Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^d Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Barcelona, Spain
^e Department of Neurology, Mellen MS Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
^f Department of Neurology, Section of Neuroimmunology, Washington University School of Medicine, St Louis, MO, United States
^g Department of Pediatric Neurology, University Hospitals Paris Saclay, Hôpital Bicêtre, National Reference Center for Rare Inflammatory Brain and Spinal Diseases, Le Kremlin-Bicêtre, France
^h Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
ⁱ Novartis Pharma AG, Basel, Switzerland
^j Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States
^k Research Center for Clinical Neuroimmunology and Neuroscience Basel, RC2NB) and MS Center, and Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital of Basel, University of Basel, Basel, Switzerland
^l Statistics Department, University of Oxford, Oxford, United Kingdom

Abstract
Background: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide. Objectives: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS. Methods: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events. Results: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population. Conclusion: The favourable benefit–risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients. ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231). © The Author(s), 2022.

Author Keywords
neurofilament light chain;  no evidence of disease activity;  progression independent of relapse activity;  recently diagnosed;  Relapsing multiple sclerosis;  treatment-naive

Funding details
Bayer
Novartis
Biogen
European CommissionEC
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF
MedImmune
Schweizerische Multiple Sklerose Gesellschaft

Three facets of collective memory
(2021) The American Psychologist, 76 (9), pp. 1388-1400. 

Roediger, H.L.

Department of Psychological and Brain Sciences, Washington University in St. Louis

Abstract
Collective memory refers to the memories that individuals have as members of the groups to which they belong, whether small (family, school) or large (political party, nation). Membership in some groups can form a strong part of a person’s individual identity. Collective memory is history as people remember it; it is not formal history, because the “memories” of a group are often contradicted by historical fact. Although collective memory is held within individuals, it has rarely been studied by psychologists, because they have concentrated on studying the learning of individual events (such as word lists) in the laboratory or retrieving events of one’s life (autobiographical memory). Three facets of collective memory are the focus of this article. First, collective memory can be a body of knowledge about a topic. However, this knowledge base may change over generations of a people. Second, collective memory often portrays an image of a people, and often this image arises from the group’s origin story or charter. Third, collective memory is a process; collective remembering can reveal disputes and contestations about how the past should be remembered. One useful purpose of collective memory studies is to capture how different groups and societies remember their history and to discern their shared perspective on the world and how such perspectives differ among groups. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Analysis workflow to assess de novo genetic variants from human whole-exome sequencing
(2021) STAR Protocols, 2 (1), p. 100383. 

Diab, N.S.^a , King, S.^b c , Dong, W.^a d , Allington, G.^a , Sheth, A.^e , Peters, S.T.^b , Kahle, K.T.^e f g , Jin, S.C.^b

^a Department of Genetics, Yale School of Medicine, CT, New Haven, United States
^b Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
^c Department of Computer Science & Engineering, Washington University in St. Louis, St. Louis, MO, USA
^d Laboratory of Human Genetics and Genomics, Rockefeller University, NY, NY, United States
^e Department of Neurosurgery, Yale School of Medicine, CT, New Haven, United States
^f Department of Pediatrics, Yale School of Medicine, CT, New Haven, United States
^g Department of Cellular & Molecular Physiology, Yale School of Medicine, CT, New Haven, United States

Abstract
Here, we present a protocol to analyze de novo genetic variants derived from the whole-exome sequencing (WES) of proband-parent trios. We provide stepwise instructions for using existing pipelines to call de novo mutations (DNMs) and determine whether the observed number of such mutations is enriched relative to the expected number. This protocol may be extended to any human disease trio-based cohort. Cohort size is a limiting determinant to the discovery of high-confidence pathogenic DNMs. For complete details on the use and execution of this protocol, please refer to Dong et al. (2020). © 2021 The Author(s).

Author Keywords
Bioinformatics;  Genetics;  Genomics;  High-throughput screening;  Sequence analysis;  Sequencing

Validation of diffusion MRI as a biomarker for efficacy using randomized phase III trial of bevacizumab with or without VB-111 in recurrent glioblastoma
(2021) Neuro-Oncology Advances, 3 (1), art. no. vdab082, . 

Ellingson, B.M.^a b c , Patel, K.^a e , Wang, C.^a b , Raymond, C.^a , Brenner, A.^f , De Groot, J.F.^g , Butowski, N.A.^h , Zach, L.ⁱ , Campian, J.L.^j , Schlossman, J.^a b , Rizvi, S.^a b , Cohen, Y.C.^k , Lowenton-Spier, N.^k , Minei, T.R.^k , Shmueli, S.F.^k , Wen, P.Y.^l , Cloughesy, T.F.^c d

^a UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
^b Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
^c UCLA Neuro Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
^d Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
^e Department of Neurosurgery, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, United States
^f University of Texas Health San Antonio Cancer Center, San Antonio, TX, United States
^g Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
^h Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States
ⁱ Oncology Institute, Chaim Sheba Medical Center, Tel HaShomer, Israel
^j Division of Medical Oncology, Washington University School of Medicine, St. Louis, MO, United States
^k VBL Therapeutics, Modi’in, Israel
^l Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States

Abstract
Background. Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial. Methods. Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (&gt;1.24 μm2/ms) or low (&lt;1.24 μm2/ms) ADCL, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor. Results. Baseline tumor volume (P = .3460) and ADCL (P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADCLhad a significant survival advantage in all patients (P = .0006), as well as BV (P = .0159) and BV+VB-111 individually (P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADCLidentified continuous measures of tumor volume (P &lt; .0001; HR = 1.0212) and ADCLphenotypes (P = .0012; HR = 0.5574) as independent predictors of OS. Conclusion. Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111. © 2021 Neuro-Oncology Advances. All right reserved.

Author Keywords
Anti-VEGF therapy;  bevacizumab;  diffusion MRI;  imaging biomarker;  recurrent GBM;  VB-111

Funding details
National Institutes of HealthNIH
American Cancer SocietyACSRSG-15-003-01-CCE
National Cancer InstituteNCI1P50CA211015-01A1, 1R21CA223757-01
American Brain Tumor AssociationABTAARC1700002
University of California, Los AngelesUCLA
Janssen Pharmaceuticals

(2021) Neuro-Oncology Advances, 3 (1), art. no. vdab068, . 

Chen, J.^a b , Sinha, N.^a c , Cobb, O.^d , Liu, C.^e , Ersen, A.^f , Phillips, J.J.^g h , Tihan, T.^g , Gutmann, D.H.^d , Dahiya, S.^a

^a Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
^c Department of Pathology, Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada
^d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Neurological Surgery, University of Nebraska Medical Center, Omaha, NE, United States
^f Department of Pathology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
^g Department of Pathology, University of California, San Francisco, San Francisco, CA, United States
^h Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States

Funding details
National Institute of Neurological Disorders and StrokeNINDS1-R35-NS097211-01

Salvage therapies for radiation-relapsed isocitrate dehydrogenase-mutant astrocytoma and 1p/19q codeleted oligodendroglioma
(2021) Neuro-Oncology Advances, 3 (1), art. no. vdab081, . 

Ma, S.^a , Rudra, S.^b , Campian, J.L.^c e , Chheda, M.G.^c e , Johanns, T.M.^c e , Ansstas, G.^c e , Abraham, C.D.^a e e , Chicoine, M.R.^d e e , Leuthardt, E.C.^d e e , Dowling, J.L.^d e e , Dunn, G.P.^d e e , Kim, A.H.^d e e , Huang, J.^a

^a Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
^c Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, MO, United States
^d Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
^e Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background. Optimal management for recurrent IDH-mutant glioma after radiation therapy (RT) is not well-defined. This study assesses practice patterns for managing recurrent IDH-mutant astrocytoma (Astro) and 1p/19q codeleted oligodendroglioma (Oligo) after RT and surveys their clinical outcomes after different salvage approaches. Methods. Ninety-four recurrent Astro or Oligo patients after RT who received salvage systemic therapy (SST) between 2001 and 2019 at a tertiary cancer center were retrospectively analyzed. SST was defined as either alkylating chemotherapy (AC) or nonalkylating therapy (non-AC). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method from the start of SST. Multivariable analysis (MVA) was conducted using Cox regression analysis. Results. Recurrent Oligo (n = 35) had significantly higher PFS (median: 3.1 vs 0.8 years, respectively, P = .002) and OS (median: 6.3 vs 1.5 years, respectively, P < .001) than Astro (n = 59). Overall, 90% of recurrences were local. Eight-three percent received AC as the first-line SST; 50% received salvage surgery before SST; approximately 50% with local failure >2 years after prior RT received reirradiation. On MVA, non-AC was associated with worse OS for both Oligo and Astro; salvage surgery was associated with improved PFS and OS for Astro; early reirradiation was associated with improved PFS for Astro. Conclusions. Recurrent radiation-relapsed IDH-mutant gliomas represent a heterogeneous group with variable treatment approaches. Surgery, AC, and reirradiation remain the mainstay of salvage options for retreatment. © The Author(s) 2021.

Author Keywords
Chemotherapy;  IDH-mutant glioma;  recurrence;  reirradiation;  salvage therapy;  surgery

Funding details
Intel Corporation