WashU weekly Neuroscience publications

Psychometric properties of the Peceived Benefits of Thinness Scale in college-aged women
(2022) Body Image, 40, pp. 103-109. 

Flatt, R.E.^a , Karam, A.M.^b , Fitzsimmons-Craft, E.E.^b , Balantekin, K.N.^c , Graham, A.K.^d , Eichen, D.M.^e , Monterubio, G.E.^b , Goel, N.J.^f , Fowler, L.A.^b , Sadeh-Sharvit, S.^g h i , Wilfley, D.^b , Mazina, V.^j k , Taylor, C.B.^g h , Trockel, M.^g

^a Department of Psychology & Neuroscience, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
^b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^c University of New York at Buffalo, Buffalo, NY, United States
^d Department of Medical Social Sciences, Northwestern University, Chicago, IL, United States
^e Department of Pediatrics, University of California, San Diego, San Diego, CA, United States
^f Department of Psychology, Virginia Commonwealth University, Richmond, VA, United States
^g Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States
^h Center for m2Health, Palo Alto University, Palo Alto, CA, United States
ⁱ Baruch Ivcher School of Psychology, Interdisciplinary Center, Herzliya, Israel
^j Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, United States
^k Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA, United States

Abstract
Thin ideal internalization is a risk factor for disordered eating behaviors, poor body image, and eating disorders (EDs). This paper evaluated the psychometric properties of a novel measure, the Perceived Benefits of Thinness Scale (PBTS), which assesses how individuals feel being thinner would affect various aspects of their lives. Three separate studies with unique samples of college-aged women over 18 years were conducted to assess reliability and validity. In Study 1, exploratory and confirmatory factor analyses suggested all PBTS items loaded onto one factor that was distinct from a measure of weight and shape concerns. A large correlation between changes in PTBS scores and changes in ED psychopathology scores over 8 months (r = .57, p < .01) suggested sensitivity to change. Greater severity in ED pathology was also associated with higher scores on the PBTS. In Study 2, the PBTS showed good test-retest reliability (r = .84, p < .001) and, in Study 3, expected correlations with existing measures of thin ideal internalization (rs = .38–.60, ps < .001). Overall, the PBTS displayed good factor structure, reliability, concurrent validity, and sensitivity to change. By emphasizing social, emotional, and quality of life benefits, the PBTS may serve clinicians, researchers, and patients in understanding thin ideal internalization and associated ED risk. © 2021 Elsevier Ltd

Author Keywords
College women;  Eating disorders;  Thin ideal;  Thinness

Funding details
National Science FoundationNSFDGE-1650116
National Institutes of HealthNIHF31 MD015679, K01 DK116925, K01 DK120778, K08 MH120341, K23 DK114480
National Institute of Mental HealthNIMHR01 MH100455, T32 HL130357
National Heart, Lung, and Blood InstituteNHLBI

Smell Changes and Efficacy of Nasal Theophylline (SCENT) irrigation: A randomized controlled trial for treatment of post-viral olfactory dysfunction
(2022) American Journal of Otolaryngology – Head and Neck Medicine and Surgery, 43 (2), art. no. 103299, . 

Lee, J.J.^a , Peterson, A.M.^a b , Kallogjeri, D.^a , Jiramongkolchai, P.^a , Kukuljan, S.^a , Schneider, J.S.^a , Klatt-Cromwell, C.N.^a , Drescher, A.J.^a , Brunworth, J.D.^c , Piccirillo, J.F.^a

^a Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
^b University of Missouri Kansas City School of Medicine, Kansas City, MO, United States
^c Department of Otolaryngology-Head and Neck Surgery, Saint Louis University School of Medicine, St. Louis, MO, United States

Abstract
Objective: To evaluate the efficacy and safety of intranasal theophylline saline irrigation on olfactory recovery in patients with post-viral olfactory dysfunction (PVOD). Methods: Between May 2019 and April 2020, we conducted a double-blinded, placebo-controlled randomized clinical trial of adults with 6–36 months of PVOD. Patients were randomized to nasal theophylline saline irrigation or placebo saline irrigation twice a day for 6 weeks. The primary outcome was the Global Rating of Smell Change. Secondary outcomes were changes in the University of Pennsylvania Smell Identification Test (UPSIT) and Questionnaire of Olfactory Disorders-Negative Statements (QOD-NS). Results: Twenty-two patients (n = 12, theophylline; n = 10, placebo) completed the study. Slightly more patients in the theophylline group (33%) reported improved smell compared to the placebo group (30%, difference 3.3%, 95% CI -35.6% to 42.3%). The median differences in pre- and post-treatment UPSIT and QOD-NS change between the two groups were 1 (95% CI -3 to 5) and -10 (95% CI -15 to -4), respectively in favor of theophylline. Three patients receiving theophylline and 2 receiving placebo had clinically meaningful improvements on the UPSIT (difference 5%, 95% CI -30% to 40%). There were no adverse events, and serum theophylline levels were undetectable in 10/10 patients. Conclusions: While safe, there were no clinically meaningful differences in olfactory change between the two groups except for olfaction-related quality of life, which was better with theophylline. The imprecise estimates suggest future trials will need substantially larger sample sizes or treatment modifications, such as increasing the theophylline dose, to observe larger treatment effects. © 2021

Author Keywords
Anosmia;  Hyposmia;  Olfaction;  Quality of life;  Smell;  Theophylline;  Therapeutics;  Viral

Funding details
National Institute on Deafness and Other Communication DisordersNIDCD5T32DC000022-30
National Center for Advancing Translational SciencesNCATSUL1TR002345
Foundation for Barnes-Jewish Hospital154092

rPOP: Robust PET-only processing of community acquired heterogeneous amyloid-PET data
(2022) NeuroImage, 246, art. no. 118775, . 

Iaccarino, L.^a , La Joie, R.^a , Koeppe, R.^b , Siegel, B.A.^c , Hillner, B.E.^d , Gatsonis, C.^e f , Whitmer, R.A.^g h , Carrillo, M.C.ⁱ , Apgar, C.^j , Camacho, M.R.^k l , Nosheny, R.^k m , Rabinovici, G.D.^a n , Alzheimer’s Disease Neuroimaging Initiative^o

^a Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, United States
^b Department of Radiology, University of Michigan, Ann Arbor, MI, United States
^c Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine in St Louis, St Louis, MO, United States
^d Department of Medicine, Virginia Commonwealth University, Richmond, VA, United States
^e Center for Statistical Sciences, Brown University School of Public Health, Providence, RI, United States
^f Department of Biostatistics, Brown University School of Public Health, Providence, RI, United States
^g Division of Research, Kaiser Permanente, Oakland, CA, United States
^h Department of Public Health Sciences, University of California Davis, Davis, CA, United States
ⁱ Medical and Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
^j American College of Radiology, Reston, VA, United States
^k San Francisco VA Medical Center, San Francisco, CA, United States
^l Northern California Institute for Research and Education (NCIRE), San Francisco, CA, United States
^m Department of Psychiatry, University of California San Francisco, San Francisco, CA, United States
ⁿ Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States

Abstract
The reference standard for amyloid-PET quantification requires structural MRI (sMRI) for preprocessing in both multi-site research studies and clinical trials. Here we describe rPOP (robust PET-Only Processing), a MATLAB-based MRI-free pipeline implementing non-linear warping and differential smoothing of amyloid-PET scans performed with any of the FDA-approved radiotracers (18F-florbetapir/FBP, 18F-florbetaben/FBB or 18F-flutemetamol/FLUTE). Each image undergoes spatial normalization based on weighted PET templates and data-driven differential smoothing, then allowing users to perform their quantification of choice. Prior to normalization, users can choose whether to automatically reset the origin of the image to the center of mass or proceed with the pipeline with the image as it is. We validate rPOP with n = 740 (514 FBP, 182 FBB, 44 FLUTE) amyloid-PET scans from the Imaging Dementia—Evidence for Amyloid Scanning – Brain Health Registry sub-study (IDEAS-BHR) and n = 1,518 scans from the Alzheimer’s Disease Neuroimaging Initiative (n = 1,249 FBP, n = 269 FBB), including heterogeneous acquisition and reconstruction protocols. After running rPOP, a standard quantification to extract Standardized Uptake Value ratios and the respective Centiloids conversion was performed. rPOP-based amyloid status (using an independent pathology-based threshold of ≥24.4 Centiloid units) was compared with either local visual reads (IDEAS-BHR, n = 663 with complete valid data and reads available) or with amyloid status derived from an MRI-based PET processing pipeline (ADNI, thresholds of &gt;20/&gt;18 Centiloids for FBP/FBB). Finally, within the ADNI dataset, we tested the linear associations between rPOP- and MRI-based Centiloid values. rPOP achieved accurate warping for N = 2,233/2,258 (98.9%) in the first pass. Of the N = 25 warping failures, 24 were rescued with manual reorientation and origin reset prior to warping. We observed high concordance between rPOP-based amyloid status and both visual reads (IDEAS-BHR, Cohen’s k = 0.72 [0.7–0.74], ∼86% concordance) or MRI-pipeline based amyloid status (ADNI, k = 0.88 [0.87–0.89], ∼94% concordance). rPOP- and MRI-pipeline based Centiloids were strongly linearly related (R2:0.95, p&lt;0.001), with this association being significantly modulated by estimated PET resolution (β= -0.016, p&lt;0.001). rPOP provides reliable MRI-free amyloid-PET warping and quantification, leveraging widely available software and only requiring an attenuation-corrected amyloid-PET image as input. The rPOP pipeline enables the comparison and merging of heterogeneous datasets and is publicly available at https://github.com/leoiacca/rPOP. © 2021

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDODW81XWH-12-2-0012
National Institute on AgingNIAK99-AG065501, R35-AG072362
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s AssociationAASG-21-876655, ZEN-21-848216
Genentech
Johnson and JohnsonJ&J
Merck
California Department of Public HealthCDPH
Janssen Research and DevelopmentJRD
University of Southern CaliforniaUSC
Radiological Society of North AmericaRSNA
GE Healthcare
Alzheimer’s Disease Neuroimaging InitiativeADNIU01 AG024904
Lantheus Medical Imaging
Northern California Institute for Research and EducationNCIRE
American College of RadiologyACR
Avid Radiopharmaceuticals
Fujirebio US
Eisai
H. Lundbeck A/S
IXICO

Neurocognition after motor vehicle collision and adverse post-traumatic neuropsychiatric sequelae within 8 weeks: Initial findings from the AURORA study
(2022) Journal of Affective Disorders, 298, pp. 57-67. 

Germine, L.T.^a b c , Joormann, J.^d , Passell, E.^a , Rutter, L.A.^a b , Scheuer, L.^a , Martini, P.^c , Hwang, I.^e , Lee, S.^e , Sampson, N.^e , Barch, D.M.^f , House, S.L.^g , Beaudoin, F.L.^h i j , An, X.^k , Stevens, J.S.^l , Zeng, D.^m , Linnstaedt, S.D.^k , Jovanovic, T.ⁿ , Clifford, G.D.^o p , Neylan, T.C.^q r s , Rauch, S.L.^b t , Lewandowski, C.^u , Hendry, P.L.^v , Sheikh, S.^v , Storrow, A.B.^w , Musey, P.I.^x , Jones, C.W.^y , Punches, B.E.^z , McGrath, M.E.^aa , Pascual, J.L.^ab , Mohiuddin, K.^ac , Pearson, C.^ad , Peak, D.A.^ae , Domeier, R.M.^af , Bruce, S.E.^ag , Rathlev, N.K.^ah , Sanchez, L.D.^ai aj , Pietrzak, R.H.^ak al , Pizzagalli, D.A.^b t , Harte, S.E.^am an , Elliott, J.M.^ao ap aq , Koenen, K.C.^ar , Ressler, K.J.^b as , McLean, S.A.^k at , Kessler, R.C.^e

^a Institute for Technology in Psychiatry, McLean Hospital, 1010 Pleasant Street, Belmont, MA 02478, United States
^b Department of Psychiatry, Harvard Medical School, Boston, MA, United States
^c The Many Brains Project, Belmont, MA, United States
^d Department of Psychology, Yale University, New Haven, CT, United States
^e Department of Health Care Policy, Harvard Medical School, Boston, MA, United States
^f Department of Psychological and Brain Sciences, College of Arts and Sciences, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Emergency Medicine, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Emergency Medicine and Health Services, Policy, and Practice, The Alpert Medical School of Brown University, United States
ⁱ Department of Emergency Medicine, Rhode Island Hospital, Providence, RI, United States
^j Department of Emergency Medicine, The Miriam Hospital, Providence, RI, United States
^k Institute for Trauma Recovery, Department of Anesthesiology, University of North Carolina at Chapel Hill, Chapel HillNC, United States
^l Department of Psychiatry and Behavioral Sciences, School of Medicine, Emory University, Atlanta, GA, United States
^m Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina, Chapel HillNC, United States
ⁿ Department of Psychiatry and Behavioral Neurosciences, Wayne State University, Detroit, MI, United States
^o Department of Biomedical Informatics, School of Medicine, Emory University, United States
^p Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
^q San Francisco VA Healthcare System, San Francisco, CA, United States
^r Departments of Psychiatry, University of California, San Francisco, CA, United States
^s Departments of Neurology, University of California, San Francisco, CA, United States
^t McLean Hospital, Belmont, MA, United States
^u Department of Emergency Medicine, Henry Ford Health System, Detroit, MI, United States
^v Department of Emergency Medicine, University of Florida College of Medicine, Jacksonville, FL, United States
^w Department of Emergency Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
^x Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
^y Department of Emergency Medicine, Cooper Medical School of Rowan University, Camden, NJ, United States
^z Department of Emergency Medicine, University of Cincinnati College of Medicine, University of Cincinnati College of Nursing, Cincinnati, OH, United States
^aa Department of Emergency Medicine, Boston Medical Center, Boston, MA, United States
^ab Department of Surgery and Department of Neurosurgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
^ac Dept. of Emergency Medicine/Internal Medicine, Einstein Medical Center, Philadelphia, PA, United States
^ad Department of Emergency Medicine, Wayne State University, Ascension St. John Hospital, Detroit, MI, United States
^ae Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
^af Department of Emergency Medicine, Saint Joseph Mercy Hospital, Ann Arbor, MI, United States
^ag Department of Psychological Sciences, University of Missouri – St. Louis, St. Louis, MO, United States
^ah Department of Emergency Medicine, University of Massachusetts Medical School-Baystate, Springfield, MA, United States
^ai Department of Emergency Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States
^aj Department of Emergency Medicine, Harvard Medical School, Boston, MA, United States
^ak U.S. Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, VA Connecticut Healthcare System, West Haven, CT, United States
^al Department of Psychiatry, Yale School of Medicine, New Haven, CT, United States
^am Chronic Pain and Fatigue Research Center, Departments of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, United States
^an Internal Medicine-Rheumatology, University of Michigan Medical School, Ann Arbor, MI, United States
^ao The Kolling Institute of Medical Research, Northern Clinical School, University of Sydney, St Leonards, New South Wales, Australia
^ap Faculty of Medicine and Health, University of Sydney, Camperdown, New South Wales, Australia
^aq Physical Therapy & Human Movement Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
^ar Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, United States
^as Division of Depression and Anxiety Disorders, McLean hospital, Belmont, MA, United States
^at Department of Emergency Medicine, University of North Carolina at Chapel Hill, Chapel HillNC, United States

Abstract
Background: Previous work has indicated that differences in neurocognitive functioning may predict the development of adverse post-traumatic neuropsychiatric sequelae (APNS). Such differences may be vulnerability factors or simply correlates of APNS-related symptoms. Longitudinal studies that measure neurocognitive functioning at the time of trauma are needed to determine whether such differences precede the development of APNS. Methods: Here, we present findings from a subsample of 666 ambulatory patients from the AURORA (Advancing Understanding of RecOvery afteR trumA) study. All patients presented to EDs after a motor vehicle collision (MVC). We examined associations of neurocognitive test performance shortly after MVC with peritraumatic symptoms in the ED and APNS (depression, post-traumatic stress, post-concussive symptoms, and pain) 2 weeks and 8 weeks later. Neurocognitive tests assessed processing speed, attention, verbal reasoning, memory, and social perception. Results: Distress in the ED was associated with poorer processing speed and short-term memory. Poorer short-term memory was also associated with depression at 2 weeks post-MVC, even after controlling for peritraumatic distress. Finally, higher vocabulary scores were associated with pain 2 weeks post-MVC. Limitations: Self-selection biases among those who present to the ED and enroll in the study limit generalizability. Also, it is not clear whether observed neurocognitive differences predate MVC exposure or arise in the immediate aftermath of MVC exposure. Conclusions: Our results suggest that processing speed and short-term memory may be useful predictors of trauma-related characteristics and the development of some APNS, making such measures clinically-relevant for identifying at-risk individuals. © 2021

Author Keywords
Cognition;  Digital cognitive assessment;  Digital neuropsychology;  Longitudinal;  Neuropsychology;  Trauma

Funding details
R33AG05654
National Institutes of HealthNIHR01HD079076, R03HD094577
National Institute of Mental HealthNIMH
AstraZeneca
Blue Cross and Blue Shield of Florida Foundation
National Center for Medical Rehabilitation ResearchNCMRR
Janssen Pharmaceuticals
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

Regional age-related atrophy after screening for preclinical alzheimer disease
(2022) Neurobiology of Aging, 109, pp. 43-51. 

Koenig, L.N.^a , LaMontagne, P.^a , Glasser, M.F.^a b , Bateman, R.^c d , Holtzman, D.^c d e , Yakushev, I.^f , Chhatwal, J.^g , Day, G.S.^h , Jack, C.ⁱ , Mummery, C.^j , Perrin, R.J.^d e g k , Gordon, B.A.^c d l , Morris, J.C.^c d , Shimony, J.S.^a , Benzinger, T.L.S.^a d , Dominantly Inherited Alzheimer Network (DIAN)^m

^a Department of Radiology, Washington Universit, St Louis, MO, United States
^b Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
^c Department of Neurology, Washington University, St. Louis, MO, United States
^d Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, School of Medicine, St. Louis, MO, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Nuclear Medicine, Technical University of MunichMunich, Germany
^g Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^h Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
ⁱ Department of Radiology, Mayo Clinic, Rochester, MN, United States
^j Dementia Research Center, UCL Queen Square Institute of Neurology, London, United Kingdom
^k Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^l Department of Psychological & Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Brain atrophy occurs in aging even in the absence of dementia, but it is unclear to what extent this is due to undetected preclinical Alzheimer disease. Here we examine a cross-sectional cohort (ages 18-88) free from confounding influence of preclinical Alzheimer disease, as determined by amyloid PET scans and three years of clinical evaluation post-imaging. We determine the regional strength of age-related atrophy using linear modeling of brain volumes and cortical thicknesses with age. Age-related atrophy was seen in nearly all regions, with greatest effects in the temporal lobe and subcortical regions. When modeling age with the estimated derivative of smoothed aging curves, we found that the temporal lobe declined linearly with age, subcortical regions declined faster at later ages, and frontal regions declined slower at later ages than during midlife. This age-derivative pattern was distinct from the linear measure of age-related atrophy and significantly associated with a measure of myelin. Atrophy did not detectably differ from a preclinical Alzheimer disease cohort when age ranges were matched. © 2021

Author Keywords
Magnetic Resonance Imaging (MRI);  Normal Aging;  Preclinical Alzheimer disease;  Volumetrics

White matter microstructure associations to amyloid burden in adults with Down syndrome
(2022) NeuroImage: Clinical, 33, art. no. 102908, . 

Bazydlo, A.M.^a , Zammit, M.D.^a , Wu, M.^c , Lao, P.J.^a , Dean, D.C., III^a b , Johnson, S.C.^a , Tudorascu, D.L.^c , Cohen, A.^c , Cody, K.A.^a , Ances, B.^d , Laymon, C.M.^c , Klunk, W.E.^c , Zaman, S.^e , Handen, B.L.^c , Hartley, S.L.^b , Alexander, A.L.^a b , Christian, B.T.^a b

^a School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
^b Waisman Center, Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, United States
^c University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^d Washington University, St. Louis, MO, United States
^e Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, United Kingdom

Abstract
Introduction: Individuals with Down syndrome (DS) are at an increased risk of developing Alzheimer’s Disease (AD). One of the early underlying mechanisms in AD pathology is the accumulation of amyloid protein plaques, which are deposited in extracellular gray matter and signify the first stage in the cascade of neurodegenerative events. AD-related neurodegeneration is also evidenced as microstructural changes in white matter. In this work, we explored the correlation of white matter microstructure with amyloid load to assess amyloid-related neurodegeneration in a cohort of adults with DS. Methods: In this study of 96 adults with DS, the relation of white matter microstructure using diffusion tensor imaging (DTI) and amyloid plaque burden using [11C]PiB PET were examined. The amyloid load (AβL) derived from [11C]PiB was used as a global measure of amyloid burden. AβL and DTI measures were compared using tract-based spatial statistics (TBSS) and corrected for imaging site and chronological age. Results: TBSS of the DTI maps showed widespread age-by-amyloid interaction with both fractional anisotropy (FA) and mean diffusivity (MD). Further, diffuse negative association of FA and positive association of MD with amyloid were observed. Discussion: These findings are consistent with the white matter microstructural changes associated with AD disease progression in late onset AD in non-DS populations. © 2021

Author Keywords
Alzheimer’s Disease;  Amyloid-β;  Down syndrome;  DTI;  PET

Funding details
National Institutes of HealthNIHR01AG031110, T32CA009206, U01AG0514
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU54 HD090256

The effect of context on mind-wandering in younger and older adults
(2022) Consciousness and Cognition, 97, art. no. 103256, . 

Diede, N.T.^a , Gyurkovics, M.^b , Nicosia, J.^a , Diede, A.^c , Bugg, J.M.^a

^a Washington University in St. Louis, United States
^b University of Illinois at Urbana-Champaign, United States
^c WestminsterCO, United States

Abstract
Older adults report less mind-wandering (MW) during tasks of sustained attention than younger adults. The control failure × current concerns account argues that this is due to age differences in how contexts cue personally relevant task-unrelated thoughts. For older adults, the university laboratory contains few reminders of their current concerns and unfinished goals. For younger adults, however, the university laboratory is more directly tied to their current concerns. Therefore, if the context for triggering current concerns is the critical difference between younger and older adults’ reported MW frequencies, then testing the two groups in contexts that equate the salience of self-relevant cues (i.e., their homes) should result in an increase in older but not younger adults’ MW rates. The present study directly compared rates of MW and involuntary autobiographical memories (IAMs) in the home versus in the lab for younger and older adults using a within-subjects manipulation of context. Inconsistent with the control failure × current concerns account, no significant reduction in the age-gap in MW was found. Suggesting a lack of cues rather than an abundance of cues elicits MW, participants in both age groups reported more MW in the lab than at home. The number of IAMs recalled did not differ across contexts but was lower in older than younger adults. These findings suggest that a cognitive rather than an environmental mechanism may be behind the reduction in spontaneous cognition in aging. © 2021 Elsevier Inc.

Author Keywords
Aging;  Cognitive control;  Context;  Current concerns;  Inhibitory deficit;  Involuntary autobiographical memories;  Mind-wandering

Funding details
National Institute on AgingNIAT32AG000030-40

Translating RDoC to real-world impact in developmental psychopathology: A neurodevelopmental framework for application of mental health risk calculators
(2021) Development and Psychopathology, 33 (5), pp. 1665-1684. 

MacNeill, L.A.^a b , Allen, N.B.^b c , Poleon, R.B.^b , Vargas, T.^d , Osborne, K.J.^d , Damme, K.S.F.^d , Barch, D.M.^e f g , Krogh-Jespersen, S.^a b , Nielsen, A.N.^h , Norton, E.S.^a b i , Smyser, C.D.^g h j , Rogers, C.E.^f j , Luby, J.L.^f , Mittal, V.A.^{a b d k l} , Wakschlag, L.S.^a b

^a Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^b Institute for Innovations in Developmental Sciences, Northwestern University, Chicago, IL, United States
^c Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
^d Department of Psychology, Northwestern University, Evanston, IL, United States
^e Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
^f Department of Psychiatry, 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 Neurology, Washington University School of Medicine, St. Louis, MO, United States
ⁱ Department of Communication Sciences and Disorders, Northwestern University, Evanston, IL, United States
^j Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^k Department of Psychiatry, Northwestern University, Chicago, IL, United States
^l Institute for Policy Research, Northwestern University, Evanston, IL, United States

Abstract
The National Institute of Mental Health’s Research Domain Criteria (RDoC) framework has prompted a paradigm shift from categorical psychiatric disorders to considering multiple levels of vulnerability for probabilistic risk of disorder. However, the lack of neurodevelopmentally based tools for clinical decision making has limited the real-world impact of the RDoC. Integration with developmental psychopathology principles and statistical methods actualize the clinical implementation of RDoC to inform neurodevelopmental risk. In this conceptual paper, we introduce the probabilistic mental health risk calculator as an innovation for such translation and lay out a research agenda for generating an RDoC-and developmentally informed paradigm that could be applied to predict a range of developmental psychopathologies from early childhood to young adulthood. We discuss methods that weigh the incremental utility for prediction based on intensity and burden of assessment, the addition of developmental change patterns, considerations for assessing outcomes, and integrative data approaches. Throughout, we illustrate the risk calculator approach with different neurodevelopmental pathways and phenotypes. Finally, we discuss real-world implementation of these methods for improving early identification and prevention of developmental psychopathology. We propose that mental health risk calculators can build a needed bridge between the RDoC multiple units of analysis and developmental science. Copyright © The Author(s), 2021. Published by Cambridge University Press.

Author Keywords
developmental change;  prevention/intervention;  psychopathology;  RDoC;  risk calculator

Funding details
National Institute of Mental HealthNIMHR01 MH120088, R01MH121877

Trajectory of emotion dysregulation in positive and negative affect across childhood predicts adolescent emotion dysregulation and overall functioning
(2021) Development and Psychopathology, 33 (5), pp. 1722-1733. 

Vogel, A.C.^a , Tillman, R.^a , El-Sayed, N.M.^b , Jackson, J.J.^b , Perlman, S.B.^a , Barch, D.M.^a b , Luby, J.L.^a

^a Department of Psychiatry, Washington University in St. Louis School of Medicine, St Louis, MO, United States
^b Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States

Abstract
Emotion dysregulation is cross-diagnostic and impairing. Most research has focused on dysregulated expressions of negative affect, often measured as irritability, which is associated with multiple forms of psychopathology and predicts negative outcomes. However, the Research Domain Criteria (RDoC) include both negative and positive valence systems. Emerging evidence suggests that dysregulated expressions of positive affect, or excitability, in early childhood predict later psychopathology and impairment above and beyond irritability. Typically, irritability declines from early through middle childhood; however, the developmental trajectory of excitability is unknown. The impact of excitability across childhood on later emotion dysregulation is also yet unknown. In a well-characterized, longitudinal sample of 129 children studied from ages 3 to 5.11 years through 14 to 19 years, enriched for early depression and disruptive symptoms, we assessed the trajectory of irritability and excitability using multilevel modeling and how components of these trajectories impact later emotion dysregulation. While irritability declines across childhood, excitability remains remarkably stable both within and across the group. Overall levels of excitability (excitability intercept) predict later emotion dysregulation as measured by parent and self-report and predict decreased functional magnetic resonance imaging activity in cognitive emotion regulation regions during an emotion regulation task. Irritability was not related to any dysregulation outcome above and beyond excitability. Copyright © The Author(s), 2021. Published by Cambridge University Press.

Author Keywords
emotion lability;  excitability;  fMRI;  irritability;  neuroimaging

Funding details
National Institute of Mental HealthNIMHMH090786, R01 MH064769, T32 MH100019

Lyl-1 regulates primitive macrophages and microglia development
(2021) Communications Biology, 4 (1), art. no. 1382, . 

Wang, S.^a d , Ren, D.^a e , Arkoun, B.^a , Kaushik, A.-L.^a f , Matherat, G.^a g , Lécluse, Y.^b , Filipp, D.^c , Vainchenker, W.^a , Raslova, H.^a , Plo, I.^a , Godin, I.^a

^a Gustave Roussy, INSERM UMR1287, Université Paris-Saclay, Villejuif, France
^b PFIC, lUMS AMMICa (US 23 INSERM/UMS 3655 CNRS; Gustave Roussy, Villejuif, France
^c Laboratory of Immunobiology, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic
^d Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States
^e Ministry of Education Key Laboratory of Model Animal for Disease study; Model Animal Research Center, Medical school of Nanjing University, Chemistry and Biomedicine Innovation center, Nanjing University, Nanjing, 210093, China
^f Plasseraud IP, Bordeaux, 33064, France
^g Agence Nationale pour la Recherche, Paris, France

Abstract
During ontogeny, macrophage populations emerge in the Yolk Sac (YS) via two distinct progenitor waves, prior to hematopoietic stem cell development. Macrophage progenitors from the primitive/”early EMP” and transient-definitive/”late EMP” waves both contribute to various resident primitive macrophage populations in the developing embryonic organs. Identifying factors that modulates early stages of macrophage progenitor development may lead to a better understanding of defective function of specific resident macrophage subsets. Here we show that YS primitive macrophage progenitors express Lyl-1, a bHLH transcription factor related to SCL/Tal-1. Transcriptomic analysis of YS macrophage progenitors indicate that primitive macrophage progenitors present at embryonic day 9 are clearly distinct from those present at later stages. Disruption of Lyl-1 basic helix-loop-helix domain leads initially to an increased emergence of primitive macrophage progenitors, and later to their defective differentiation. These defects are associated with a disrupted expression of gene sets related to embryonic patterning and neurodevelopment. Lyl-1-deficiency also induce a reduced production of mature macrophages/microglia in the early brain, as well as a transient reduction of the microglia pool at midgestation and in the newborn. We thus identify Lyl-1 as a critical regulator of primitive macrophages and microglia development, which disruption may impair resident-macrophage function during organogenesis. © 2021, The Author(s).

Funding details
Association pour la Recherche sur le CancerARCTA DERE 17
National Outstanding Youth Science Fund Project of National Natural Science Foundation of ChinaIUSS32000669
Institut National de la Santé et de la Recherche MédicaleInserm
National Natural Science Foundation of ChinaNSFC
Grantová Agentura České RepublikyGA ČR19–23154 S
Ligue Contre le Cancer
Centre National de la Recherche ScientifiqueCNRS
Institut National Du CancerINCa
Université Paris-Saclay
Institut Gustave-Roussy

Bruton’s tyrosine kinase drives neuroinflammation and anxiogenic behavior in mouse models of stress
(2021) Journal of Neuroinflammation, 18 (1), art. no. 289, . 

Ghosh, S.^a b , Mohammed, Z.^b , Singh, I.^c d

^a Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Psychology, Ashoka University, Rai, India
^c Department of Neurosurgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Ambedkar Center for Biomedical Research, Delhi University, New Delhi, India

Abstract
Background: Current therapies targeting several neurotransmitter systems are only able to partially mitigate the symptoms of stress- and trauma-related disorder. Stress and trauma-related disorders lead to a prominent inflammatory response in humans, and in pre-clinical models. However, mechanisms underlying the induction of neuroinflammatory response in PTSD and anxiety disorders are not clearly understood. The present study investigated the mechanism underlying the activation of proinflammatory NLRP3 inflammasome and IL1β in mouse models of stress. Methods: We used two mouse models of stress, i.e., mice subjected to physical restraint stress with brief underwater submersion, and predator odor stress. Mice were injected with MCC950, a small molecule specific inhibitor of NLRP3 activation. To pharmacologically inhibit BTK, a specific inhibitor ibrutinib was used. To validate the observation from ibrutinib studies, a separate group of mice was injected with another BTK-specific inhibitor LFM-A13. Seven days after the induction of stress, mice were examined for anxious behavior using open field test (OFT), light–dark test (LDT), and elevated plus maze test (EPM). Following the behavior tests, hippocampus and amygdale were extracted and analyzed for various components of NLRP3–caspase 1–IL1β pathway. Plasma and peripheral blood mononuclear cells were also used to assess the induction of NLRP3–Caspase 1–IL-1β pathway in stressed mice. Results: Using two different pre-clinical models of stress, we demonstrate heightened anxious behavior in female mice as compared to their male counterparts. Stressed animals exhibited upregulation of proinflammatory IL1β, IL-6, Caspase 1 activity and NLRP3 inflammasome activation in brain, which were significantly higher in female mice. Pharmacological inhibition of NLRP3 inflammasome activation led to anxiolysis as well as attenuated neuroinflammatory response. Further, we observed induction of activated Bruton’s tyrosine kinase (BTK), an upstream positive-regulator of NLRP3 inflammasome activation, in hippocampus and amygdala of stressed mice. Next, we conducted proof-of-concept pharmacological BTK inhibitor studies with ibrutinib and LFM-A13. In both sets of experiments, we found BTK inhibition led to anxiolysis and attenuated neuroinflammation, as indicated by significant reduction of NLRP3 inflammasome and proinflammatory IL-1β in hippocampus and amygdala. Analysis of plasma and peripheral blood mononuclear cells indicated peripheral induction of NLRP3–caspase 1–IL1β pathway in stressed mice. Conclusion: Our study identified BTK as a key upstream regulator of neuroinflammation, which drives anxiogenic behavior in mouse model of stress. Further, we demonstrated the sexually divergent activation of BTK, providing a clue to heightened neuroinflammation and anxiogenic response to stress in females as compared to their male counterparts. Our data from the pharmacological inhibition studies suggest BTK as a novel target for the development of potential clinical treatment of PTSD and anxiety disorders. Induction of pBTK and NLRP3 in peripheral blood mononuclear cells of stressed mice suggest the potential effect of stress on systemic inflammation. © 2021, The Author(s).

Author Keywords
Bruton’s tyrosine kinase;  Ibrutinib;  LFM-A13;  Neuroinflammation;  NLRP3 inflammasome;  Physical restraint stress, Systemic inflammation;  Posttraumatic stress disorder;  Predator odor stress;  Stress

Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia
(2021) Nature Communications, 12 (1), art. no. 7122, . 

Chatterjee, J.^a , Sanapala, S.^a , Cobb, O.^a , Bewley, A.^a , Goldstein, A.K.^a , Cordell, E.^a , Ge, X.^b , Garbow, J.R.^b , Holtzman, M.J.^c , Gutmann, D.H.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4–6 weeks of age (WOA), Nf1OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1OPG mice at 4–6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma. © 2021, The Author(s).

Funding details
5-T35-HL007815
CDI-CORE-2015-505, CDI-CORE-2019-813
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBIR35-HL145242
National Eye InstituteNEIP30EY002687
National Cancer InstituteNCIP30-CA091842
National Institute of Neurological Disorders and StrokeNINDS1-R35-NS07211-01
National Center for Research ResourcesNCRR
Alex’s Lemonade Stand Foundation for Childhood CancerALSF
Foundation for Barnes-Jewish Hospital3770, 4642
Institute of Clinical and Translational SciencesICTS
Center for Cellular Imaging, Washington UniversityWUCCI
Georgia Clinical and Translational Science AllianceGaCTSAUL1TR002345

Neuropathology of murine Sanfilippo D syndrome
(2021) Molecular Genetics and Metabolism, 134 (4), pp. 323-329. 

Takahashi, K.^a , Le, S.Q.^a , Kan, S.-H.^b , Jansen, M.J.^a , Dickson, P.I.^a , Cooper, J.D.^a

^a Department of Pediatrics, Washington University in St. Louis, St. Louis, MO 63110, United States
^b Children’s Hospital Orange County Research Institute, Orange, CA 92868, United States

Abstract
Sanfilippo D syndrome (mucopolysaccharidosis type IIID) is a lysosomal storage disorder caused by the deficiency of N-acetylglucosamine-6-sulfatase (GNS). A mouse model was generated by constitutive knockout of the Gns gene. We studied affected mice and controls at 12, 24, 36, and 48 weeks of age for neuropathological markers of disease in the somatosensory cortex, primary motor cortex, ventral posterior nuclei of the thalamus, striatum, hippocampus, and lateral and medial entorhinal cortex. We found significantly increased immunostaining for glial fibrillary associated protein (GFAP), CD68 (a marker of activated microglia), and lysosomal-associated membrane protein-1 (LAMP-1) in Sanfilippo D mice compared to controls at 12 weeks of age in all brain regions. Intergroup differences were marked for GFAP and CD68 staining, with levels in Sanfilippo D mice consistently above controls at all age groups. Intergroup differences in LAMP-1 staining were more pronounced in 12- and 24-week age groups compared to 36- and 48-week groups, as control animals showed some LAMP-1 staining at later timepoints in some brain regions. We also evaluated the somatosensory cortex, medial entorhinal cortex, reticular nucleus of the thalamus, medial amygdala, and hippocampal hilus for subunit c of mitochondrial ATP synthase (SCMAS). We found a progressive accumulation of SCMAS in most brain regions of Sanfilippo D mice compared to controls by 24 weeks of age. Cataloging the regional neuropathology of Sanfilippo D mice may aid in understanding the disease pathogenesis and designing preclinical studies to test brain-directed treatments. © 2021 Elsevier Inc.

Author Keywords
Glycosaminoglycan;  Lysosomal storage disease;  Mucopolysaccharidosis

Funding details
National Institutes of HealthNIH1R01NS088766, 2R44NS089061
Genzyme

Successful Treatment of Noise-Induced Hearing Loss by Mesenchymal Stromal Cells: An RNAseq Analysis of Protective/Repair Pathways
(2021) Frontiers in Cellular Neuroscience, 15, art. no. 656930, . 

Warnecke, A.^a b , Harre, J.^a b , Shew, M.^c , Mellott, A.J.^d , Majewski, I.^a , Durisin, M.^a , Staecker, H.^e

^a Clinic for Otolaryngology–Head & Neck Surgery, Hanover Medical School, Hanover, Germany
^b Cluster of Excellence “Hearing4all, German Research Foundation (EXC 2177/1), Oldenburg, Germany
^c Department of Otolaryngology–Head Neck Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Ronawk Inc, Olathe, KS, United States
^e Department of Otolaryngology–Head Neck Surgery, University of Kansas, School of Medicine, Kansas City, KS, United States

Abstract
Mesenchymal stromal cells (MSCs) are an adult derived stem cell-like population that has been shown to mediate repair in a wide range of degenerative disorders. The protective effects of MSCs are mainly mediated by the release of growth factors and cytokines thereby modulating the diseased environment and the immune system. Within the inner ear, MSCs have been shown protective against tissue damage induced by sound and a variety of ototoxins. To better understand the mechanism of action of MSCs in the inner ear, mice were exposed to narrow band noise. After exposure, MSCs derived from human umbilical cord Wharton’s jelly were injected into the perilymph. Controls consisted of mice exposed to sound trauma only. Forty-eight hours post-cell delivery, total RNA was extracted from the cochlea and RNAseq performed to evaluate the gene expression induced by the cell therapy. Changes in gene expression were grouped together based on gene ontology classification. A separate cohort of animals was treated in a similar fashion and allowed to survive for 2 weeks post-cell therapy and hearing outcomes determined. Treatment with MSCs after severe sound trauma induced a moderate hearing protective effect. MSC treatment resulted in an up-regulation of genes related to immune modulation, hypoxia response, mitochondrial function and regulation of apoptosis. There was a down-regulation of genes related to synaptic remodeling, calcium homeostasis and the extracellular matrix. Application of MSCs may provide a novel approach to treating sound trauma induced hearing loss and may aid in the identification of novel strategies to protect hearing. Copyright © 2021 Warnecke, Harre, Shew, Mellott, Majewski, Durisin and Staecker.

Author Keywords
cochlear transcriptome;  hearing loss;  hearing protection;  mesenchymal stroma cells;  noise trauma;  Wharton’s jelly

Funding details
EXC 2177/1
P30 GM122731-03, S10OD021743, UL1TR002366
National Institutes of HealthNIHU54 HD 090216
National Cancer InstituteNCIP30 CA168524
National Institute of General Medical SciencesNIGMSP20GM103418
Intellectual and Developmental Disabilities Research CenterIDDRC
Deutsche ForschungsgemeinschaftDFG

Live imaging reveals the cellular events downstream of sarm1 activation
(2021) eLife, 10, art. no. e71148, . 

Ko, K.W.^a , Devault, L.^a , Sasaki, Y.^b , Milbrandt, J.^c , Diantonio, A.^d

^a Washington University School of Medicine, St Louis, United States
^b Genetics Washington University School of Medicine, St Louis, United States
^c Genetics Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, United States
^d Developmental Biology, Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St Louis, United States

Abstract
SARM1 is an inducible NAD+ hydrolase that triggers axon loss and neuronal cell death in the injured and diseased nervous system. While SARM1 activation and enzyme function are well defined, the cellular events downstream of SARM1 activity but prior to axonal demise are much less well understood. Defects in calcium, mitochondria, ATP, and membrane homeostasis occur in injured axons, but the relationships among these events have been difficult to disentangle because prior studies analyzed large collections of axons in which cellular events occur asynchronously. Here, we used live imaging of mouse sensory neurons with single axon resolution to investigate the cellular events downstream of SARM1 activity. Our studies support a model in which SARM1 NADase activity leads to an ordered sequence of events from loss of cellular ATP, to defects in mitochondrial movement and depolarization, followed by calcium influx, externalization of phosphatidylserine, and loss of membrane permeability prior to catastrophic axonal self-destruction. © Ko et al.

Funding details
National Institutes of HealthNIHF32NS117784, R01CA219866, RF1-AG013730, RO1NS087632

A primate temporal cortex–zona incerta pathway for novelty seeking
(2021) Nature Neuroscience, . 

Ogasawara, T.^a , Sogukpinar, F.^b , Zhang, K.^c , Feng, Y.-Y.^c , Pai, J.^a , Jezzini, A.^a , Monosov, I.E.^{a b c d e}

^a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Electrical Engineering, Washington University, St. Louis, MO, United States
^c Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
^d Department of Neurosurgery School of Medicine, Washington University, St. Louis, MO, United States
^e Pain Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Primates interact with the world by exploring visual objects; they seek opportunities to view novel objects even when these have no extrinsic reward value. How the brain controls this novelty seeking is unknown. Here we show that novelty seeking in monkeys is regulated by the zona incerta (ZI). As monkeys made eye movements to familiar objects to trigger an opportunity to view novel objects, many ZI neurons were preferentially activated by predictions of novel objects before the gaze shift. Low-intensity ZI stimulation facilitated gaze shifts, whereas ZI inactivation reduced novelty seeking. ZI-dependent novelty seeking was not regulated by neurons in the lateral habenula or by many dopamine neurons in the substantia nigra, traditionally associated with reward seeking. But the anterior ventral medial temporal cortex, an area important for object vision and memory, was a prominent source of novelty predictions. These data uncover a functional pathway in the primate brain that regulates novelty seeking. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
HR0011-16-2-0022
National Institute of Mental HealthNIMHR01MH110594, R01MH116937
Defense Advanced Research Projects AgencyDARPA
McKnight Foundation

Association between long-term donepezil treatment and brain regional amyloid and tau burden among individuals with mild cognitive impairment assessed using 18F-AV-45 and 18F-AV-1451 PET
(2021) Journal of Neuroscience Research, . 

Li, J.^a b , Zheng, C.^b c , Ge, Q.^c , Yan, S.^b , Paranjpe, M.D.^d , Hu, S.^a e f , Zhou, Y.^b c , Alzheimer’s Disease Neuroimaging Initiative^g

^a Department of Nuclear Medicine (PET Center), Xiangya Hospital Central South University, Changsha, China
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Central Research Institute, United Imaging Healthcare Group Co., Ltd, Shanghai, China
^d Harvard-MIT Program in Health Sciences and Technology, Harvard Medical School, Boston, MA, United States
^e Key Laboratory of Biological Nanotechnology of National Health Commission, Xiangya Hospital Central South University, Changsha, China
^f National Clinical Research Center for Geriatric Disorders, Xiangya Hospital Central South University, Changsha, China

Abstract
This study aims to investigate the association between long-term donepezil treatment and brain neuropathological burden and cognitive function in mild cognitive impairment (MCI) patients. Preprocessed 18F-AV-45 amyloid and 18F-AV-1451 tau positron emission tomography (PET) images, magnetic resonance imaging images (MRIs), demographic information, and donepezil use status were downloaded from 255 MCI participants enrolled in the Alzheimer’s Disease Neuroimaging Initiative database. Partial volume correction was applied to all PET images. Structural MRIs were used for PET spatial normalization. Regions of interest (ROIs) were defined in standard space, and standardized uptake value ratio (SUVR) images relative to the cerebellum were computed. Multiple linear regression with the least absolute shrinkage selector operator was performed to analyze the effect of long-term donepezil treatment on (a) the SUVR of each 18F-AV-45 or 18F-AV-1451 brain PET ROI after adjusting for age, sex, education, ApoE ε4 status, and AD-associated disease risk factors; and (b) cognitive performance after adjusting for age, sex education, ApoE ε4 status, AD-associated disease risk factors, and regional amyloid or tau burden. In adjusted models, long-term donepezil treatment was associated with greater amyloid load in the orbital frontal, superior frontal, parietal, posterior precuneus, posterior cingulate, lateral temporal, inferior temporal and fusiform regions, and tau burden in the posterior cingulate, entorhinal and parahippocampal gyrus. Long-term donepezil treatment was also associated with worse performance on the 13-item Alzheimer’s Disease Assessment Scale-Cognitive subscale after adjusting for AD-related risk factors and regional brain amyloid or tau load. These results indicate that long-term donepezil treatment is associated with increased regional amyloid and tau burden and worse cognitive performance among individuals with MCI. Our study highlights the importance of using noninvasive and quantitative 18F-AV-45 and 18F-AV-1451 PET to elucidate the consequences of drug administration in AD studies. © 2021 Wiley Periodicals LLC.

Author Keywords
Alzheimer’s disease;  amyloid β;  donepezil;  PET;  tau

Funding details
National Institutes of HealthNIHU01 AG024904
U.S. Department of DefenseDODW81XWH‐12‐2‐0012
National Institute on AgingNIA
National Institute of Biomedical Imaging and BioengineeringNIBIB
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDF
Biogen
AbbVie
Alzheimer’s Disease Neuroimaging InitiativeADNI
BioClinica
Washington University School of Medicine in St. LouisWUSM

PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans
(2021) Nature Medicine, . 

Barak, T.^a b c d , Ristori, E.^b e , Ercan-Sencicek, A.G.^a b c d , Miyagishima, D.F.^a b c d , Nelson-Williams, C.^b , Dong, W.^b f , Jin, S.C.^b f g , Prendergast, A.^e , Armero, W.^b e , Henegariu, O.^a b c d , Erson-Omay, E.Z.^a b c d , Harmancı, A.S.^a b c d , Guy, M.^h , Gültekin, B.^a , Kilic, D.^a , Rai, D.K.^a b c d , Goc, N.^a , Aguilera, S.M.^a , Gülez, B.^a , Altinok, S.^a , Ozcan, K.^a , Yarman, Y.^a , Coskun, S.^a b c d , Sempou, E.ⁱ , Deniz, E.ⁱ , Hintzen, J.^e , Cox, A.^b , Fomchenko, E.^a , Jung, S.W.^j , Ozturk, A.K.^k , Louvi, A.^a d , Bilgüvar, K.^b d l , Connolly, E.S., Jr.^m , Khokha, M.K.^b i , Kahle, K.T.^a n o p , Yasuno, K.^a b c d , Lifton, R.P.^b f , Mishra-Gorur, K.^a b c d , Nicoli, S.^b e q , Günel, M.^a b c d

^a Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
^b Department of Genetics, Yale School of Medicine, New Haven, CT, United States
^c Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
^d Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, United States
^e Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale School of Medicine, New Haven, CT, United States
^f Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
^g Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^h Yale Center for Research Computing, Yale University, New Haven, CT, United States
ⁱ Department of Pediatrics, Yale School of Medicine, New Haven, CT, United States
^j Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, South Korea
^k Department of Neurosurgery, Pennsylvania Hospital, University of Pennsylvania Health System, Philadelphia, PA, United States
^l Yale Center for Genome Analysis, Yale University, New Haven, CT, United States
^m Department of Neurosurgery, Columbia University College of Physicians and Surgeons, New York, NY, United States
ⁿ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^o Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States
^p Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, Cambridge, MA, United States
^q Department of Pharmacology, Yale School of Medicine, New Haven, CT, United States

Abstract
Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-trans isomerase-like 4, in both familial and index IA cases. Ppil4 depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4 gene mutations in the pathogenesis of IA. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIH4R01NS057756-10
Yale University

Insulin and glucose metabolism with olanzapine and a combination of olanzapine and samidorphan: exploratory phase 1 results in healthy volunteers
(2021) Neuropsychopharmacology, . 

Toledo, F.G.S.^a , Martin, W.F.^b , Morrow, L.^c , Beysen, C.^c , Bajorunas, D.^d h , Jiang, Y.^b , Silverman, B.L.^b , McDonnell, D.^e , Namchuk, M.N.^b i , Newcomer, J.W.^f g , Graham, C.^b

^a Division of Endocrinology and Metabolism, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States
^b Alkermes, Inc., Waltham, MA, United States
^c ProSciento, Inc., Chula Vista, CA, United States
^d Vault Bioventures, San Diego, CA, United States
^e Alkermes Pharma Ireland Limited, Dublin, Ireland
^f Thriving Mind South Florida, Miami, FL, United States
^g Washington University School of Medicine, St. Louis, MO, United States
^h DBMD Consulting, Pompano Beach, FL, United States
ⁱ Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, United States

Abstract
A combination of olanzapine and samidorphan (OLZ/SAM) received US Food and Drug Administration approval in May 2021 for the treatment of adults with schizophrenia or bipolar I disorder. OLZ/SAM provides the efficacy of olanzapine, while mitigating olanzapine-associated weight gain. This exploratory study characterized the metabolic profile of OLZ/SAM in healthy volunteers to gain mechanistic insights. Volunteers received once-daily oral 10 mg/10 mg OLZ/SAM, 10 mg olanzapine, or placebo for 21 days. Assessments included insulin sensitivity during an oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, other measures of glucose/lipid metabolism, and adverse event (AE) monitoring. Treatment effects were estimated with analysis of covariance. In total, 60 subjects were randomized (double-blind; placebo, n = 12; olanzapine, n = 24; OLZ/SAM, n = 24). Olanzapine resulted in hyperinsulinemia and reduced insulin sensitivity during an OGTT at day 19, changes not observed with OLZ/SAM or placebo. Insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp, was decreased in all treatment groups relative to baseline, but this effect was greatest with olanzapine and OLZ/SAM. Although postprandial (OGTT) glucose and fasting cholesterol concentrations were similarly increased with olanzapine or OLZ/SAM, other early metabolic effects were distinct, including post-OGTT C-peptide concentrations and aspects of energy metabolism. Forty-nine subjects (81.7%) experienced at least 1 AE, most mild or moderate in severity. OLZ/SAM appeared to mitigate some of olanzapine’s unfavorable postprandial metabolic effects (e.g., hyperinsulinemia, elevated C-peptide) in this exploratory study. These findings supplement the body of evidence from completed or ongoing OLZ/SAM clinical trials supporting its role in the treatment of schizophrenia and bipolar I disorder. © 2021, The Author(s).

Funding details
National Institutes of HealthNIH
Substance Abuse and Mental Health Services AdministrationSAMHSA
Sunovion

Evaluating older adults with cognitive dysfunction: A qualitative study with emergency clinicians
(2021) Journal of the American Geriatrics Society, . 

Chary, A.N.^{a b c d e} , Castilla-Ojo, N.^f , Joshi, C.^g , Santangelo, I.^a , Carpenter, C.R.^h i , Ouchi, K.^b j , Naik, A.D.^d e , Liu, S.W.^a f , Kennedy, M.^a f

^a Department of Emergency Medicine, Massachusetts General Hospital, Boston, MA, United States
^b Department of Emergency Medicine, Brigham and Women’s Hospital, Boston, MA, United States
^c Department of Emergency Medicine, Baylor College of Medicine, Houston, TX, United States
^d Department of Medicine, Baylor College of Medicine, Houston, TX, United States
^e Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey VA Medical Center, Houston, TX, United States
^f School of Medicine, Harvard Medical School, Boston, MA, United States
^g School of Medicine, University of Texas Southwestern Medical School, Dallas, TX, United States
^h Department of Emergency Medicine, Barnes Jewish Hospital, St. Louis, MO, United States
ⁱ Emergency Care Research Core, Washington University School of Medicine, St. Louis, MO, United States
^j Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA, United States

Abstract
Background: Evaluating older adults with cognitive dysfunction in emergency departments (EDs) requires obtaining collateral information from sources other than the patient. Understanding the challenges emergency clinicians face in obtaining collateral information can inform development of interventions to improve geriatric emergency care and, more specifically, detection of ED delirium. The objective was to understand emergency clinicians’ experiences obtaining collateral information on older adults with cognitive dysfunction, both before and during the COVID-19 pandemic. Methods: From February to May 2021, we conducted semi-structured interviews with a purposive sample of 22 emergency physicians and advanced practice providers from two urban academic hospitals and one community hospital in the Northeast United States. Interviews lasted 10–20 min and were digitally recorded and transcribed. Interview transcripts were analyzed for dominant themes using a combined deductive–inductive approach. Responses regarding experiences before and during the pandemic were compared. Results: Five major challenges emerged regarding (1) availability of caregivers, (2) reliability of sources, (3) language barriers, (4) time constraints, and (5) incomplete transfer documentation. Participants perceived all challenges, but those relating to transfer documentation were amplified by the COVID-19 pandemic. Conclusion: Emergency clinicians’ perspectives can inform efforts to support caregiver presence at bedside and develop standardized communication tools to improve recognition of delirium and, more broadly, geriatric emergency care. © 2021 The American Geriatrics Society.

Author Keywords
cognitive dysfunction;  collateral information;  COVID-19;  delirium;  geriatric emergency medicine

Funding details
Aaniiih Nakoda CollegeANC

Reduction in cerebral oxygen metabolism in subcortical regions may be a biomarker of cognitive decline in people living with human immunodeficiency virus
(2021) European Journal of Neurology, . 

Sen, S.^a , An, H.^b , Sollman, M.^a , Oakes, J.^c , Eron, J.^c , Robertson, K.^c , Powers, W.^c

^a Prisma Health/University of South Carolina, Columbia, SC, United States
^b Washington University, Saint Louis, MO, United States
^c University of North Carolina, Chapel Hill, NC, United States

Abstract
Background and purpose: Regional cerebral blood flow (rCBF) and oxygen metabolism (rCMRO2) in whole brain, white matter, gray matter and lenticular nuclei were studied in people living with human immunodeficiency virus (PLHIV) as well as HIV-associated neurocognitive disorder (HAND). Methods: Treatment-naïve PLHIV underwent neurocognitive assessment and magnetic resonance (MR) measurement of rCBF and rCMRO2 with repeat after 12 months of antiretroviral therapy (ART). Age- and sex-matched controls underwent single MR measurements. Regional CBF and rCMRO2 were compared amongst symptomatic, asymptomatic, normal HAND and controls using analysis of variance. Longitudinal analysis of HAND worsening (≥1 category) was assessed after 12 months of ART and correlated with rCBF and rCMRO2 measured by MR imaging using the paired-sample t test. Results: Thirty PLHIV completed baseline and 12-month assessments (29 with rCMRO2 measurement). At baseline HAND assessment, 13% had no cognitive impairment, 27% had asymptomatic neurocognitive impairment, 60% had mild neurocognitive disorder and none had HIV-associated dementia. At 12 months, 13% had no cognitive impairment, 20% had asymptomatic neurocognitive impairment, 50% had mild neurocognitive disorder and 17% had HIV-associated dementia. In those without HAND worsening (N = 21) rCMRO2 remained stable and in those with HAND worsening (N = 8) rCMRO2 measurement declined from baseline to 12 months in white matter (2.05 ± 0.40 to 1.73 ± 0.51, p = 0.03) and lenticular nuclei (4.32 ± 0.39 to 4.00 ± 0.51, p = 0.05). Conclusions: In recently diagnosed PLHIV, no association was found between rCBF or rCMRO2 and cognitive impairment at baseline. There was a reduction in rCMRO2 in those with worsening of cognitive function at 12 months on ART. Reduction in rCMRO2 may be a biomarker of cognitive decline in PLHIV. © 2021 European Academy of Neurology

Author Keywords
antiretroviral therapy;  cerebral blood flow;  cerebral oxygen metabolism;  HAND;  HIV

Funding details
National Institute of Neurological Disorders and StrokeNINDSR01NS062754

An Ecological Examination of Loneliness and Social Functioning in People With Schizophrenia
(2021) Journal of Abnormal Psychology, 130 (8), pp. 899-908. 

Culbreth, A.J.^a , Barch, D.M.^b c d , Moran, E.K.^b

^a Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, United States
^b Department of Psychiatry, Washington University School of Medicine, United States
^c Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
^d Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, United States

Abstract
Loneliness is associated with a myriad of detrimental outcomes in mental and physical health. Previous studies have found that people with schizophrenia report greater loneliness than controls, and that loneliness is related to depressive symptoms. However, research has been limited, particularly regarding contributions of loneliness to social and occupational functioning. Further, few studies have examined associations between loneliness and daily experience in schizophrenia. Thus, we recruited 35 individuals with schizophrenia and 37 controls. All participants completed the UCLA loneliness scale, symptom assessments, and measures of social and occupational functioning. Additionally, participants with schizophrenia completed an ecological momentary assessment (EMA) protocol that indexed daily social and emotional experiences, including loneliness. Similar to previous reports, we found that those with schizophrenia reported greater loneliness than controls. Further, loneliness was positively associated with depressive and negative symptoms, and negatively associated with self-reported social functioning. Interestingly, loneliness remained a significant predictor of functioning even when controlling for other symptoms, suggesting that severity of depressive and negative symptoms cannot fully explain the relationship between loneliness and functioning. In our EMA analyses, loneliness did not significantly differ when individuals were alone versus with others, underscoring the notion that being alone is not the same as feeling lonely. However, self-reported engagement during social interactions was negatively associated with loneliness, at a trend-level, suggesting that quality of social interactions is a potentially important consideration. Taken together, these findings suggest that loneliness is an important treatment target and provide understanding for how loneliness may manifest in daily life in schizophrenia. © 2021 American Psychological Association

Author Keywords
loneliness;  negative symptoms;  schizophrenia;  social functioning

Funding details
National Institute of Mental HealthNIMHR37MH066031
Amgen
Pfizer
Roche
Takeda Pharmaceuticals U.S.A.TPUSA