Scopus list of publications for October 3, 2022
Identifying moderating factors during the preschool period in the development of borderline personality disorder: a prospective longitudinal analysis
(2022) Borderline Personality Disorder and Emotion Dysregulation, 9 (1), art. no. 26, .
Boone, K.a , Vogel, A.C.b , Tillman, R.b , Wright, A.J.a , Barch, D.M.a b , Luby, J.L.b , Whalen, D.J.b
a Department of Psychology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine in St. Louis, 4444 Forest Park, Suite 2100, St. Louis, MO 63108, United States
Abstract
Background: Despite a growing literature detailing early childhood risk factors for borderline personality disorder (BPD), few studies have examined moderating factors that might mitigate or exacerbate the effects of those risk factors. The current study examined whether three preschool-age characteristics—impulsivity, emotional lability, and initiative-taking—moderated the relationship between known preschool-age risk factors and adolescent BPD symptoms. Methods: We performed multilevel modeling analyses in a sample (n = 151) from the Preschool Depression Study, a prospective longitudinal study with assessments from preschool through adolescence. Preschool risk factors included adverse childhood experiences, internalizing symptoms, and externalizing symptoms measured with parent clinical interviews. Preschool moderating factors were assessed via parent report and observational coding of temperament and behavior. The Borderline Personality Features Scale for Children measured BPD symptoms in adolescence. Results: We found that observed initiative-taking moderated the relationship between preschool internalizing symptoms and adolescent BPD symptoms (b = 0.57, p =.011) and moderated the relationship between preschool externalizing symptoms and adolescent BPD symptoms (b = 1.42, p =.013). Greater initiative-taking was associated with lower BPD risk for children with high internalizing or externalizing symptoms. Conversely, for children with low internalizing or externalizing symptoms, greater initiative-taking was associated with increased BPD risk. Conclusions: We identify a potential moderating factor in BPD development, offer novel targets for screening and intervention, and provide a framework for using early childhood observational assessments in BPD research. Our findings suggest the need for future research on early moderating factors in BPD development, which could inform early childhood interventions targeting those factors to mitigate the effects of potentially less malleable risk factors. © 2022, The Author(s).
Author Keywords
Borderline personality disorder; Developmental psychopathology; Moderating factors; Observational coding; Resilience
Funding details
National Institute of Mental HealthNIMHK23 MH118426, L30 MH108015, R01 5R01MH090786
Document Type: Article
Publication Stage: Final
Source: Scopus
Regulation of human cortical interneuron development by the chromatin remodeling protein CHD2
(2022) Scientific Reports, 12 (1), art. no. 15636, .
Lewis, E.M.A., Chapman, G., Kaushik, K., Determan, J., Antony, I., Meganathan, K., Narasimhan, M., Gontarz, P., Zhang, B., Kroll, K.L.
Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO 63110, United States
Abstract
Mutations in the chromodomain helicase DNA binding protein 2 (CHD2) gene are associated with neurodevelopmental disorders. However, mechanisms by which CHD2 regulates human brain development remain largely uncharacterized. Here, we used a human embryonic stem cell model of cortical interneuron (hcIN) development to elucidate its roles in this process. We identified genome-wide CHD2 binding profiles during hcIN differentiation, defining direct CHD2 targets related to neurogenesis in hcIN progenitors and to neuronal function in hcINs. CHD2 bound sites were frequently coenriched with histone H3 lysine 27 acetylation (H3K27ac) and associated with high gene expression, indicating roles for CHD2 in promoting gene expression during hcIN development. Binding sites for different classes of transcription factors were enriched at CHD2 bound regions during differentiation, suggesting transcription factors that may cooperatively regulate stage-specific gene expression with CHD2. We also demonstrated that CHD2 haploinsufficiency altered CHD2 and H3K27ac coenrichment on chromatin and expression of associated genes, decreasing acetylation and expression of cell cycle genes while increasing acetylation and expression of neuronal genes, to cause precocious differentiation. Together, these data describe CHD2 direct targets and mechanisms by which CHD2 prevents precocious hcIN differentiation, which are likely to be disrupted by pathogenic CHD2 mutation to cause neurodevelopmental disorders. © 2022, The Author(s).
Funding details
National Institutes of HealthNIHR01GM66815, R01MH124808
Office of Extramural Research, National Institutes of HealthOERR01NS114551
Children’s Discovery InstituteCDI
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIH, NIH-ORIP, ORIP
Clinical and Translational Science Institute, University of FloridaCTSIP50HD103525
Document Type: Article
Publication Stage: Final
Source: Scopus
The Core Rehabilitation Outcome Set for Single-Sided Deafness (CROSSSD) study: International consensus on outcome measures for trials of interventions for adults with single-sided deafness
(2022) Trials, 23 (1), art. no. 764, .
Katiri, R.a b c , Hall, D.A.a d , Hoare, D.J.a b , Fackrell, K.a b e , Horobin, A.b f , Hogan, N.b , Buggy, N.b , Van de Heyning, P.H.g h , Firszt, J.B.i , Bruce, I.A.j k , Kitterick, P.T.a l , Snik, A.m , Sygrove, C.m , Campbell-Bell, C.m , Parker, C.m , Zeitler, D.M.m , Williams, L.m , Oxford, M.m , Boyle, P.m , James, P.K.m , Hill-Feltham, P.R.m , Toth, P.m , Bowles, R.m , Nicholson, R.m , Bayston, R.m , Rosenbom, T.m , for the Core Rehabilitation Outcome Set for Single-Sided Deafness (CROSSSD) initiativem
a Hearing Sciences, Mental Health and Clinical Neurosciences, School of Medicine, University of Nottingham, Nottingham, NG7 2UH, United Kingdom
b National Institute for Health Research Nottingham Biomedical Research Centre, Ropewalk House, 113 The Ropewalk, Nottingham, NG1 5DU, United Kingdom
c Audiology Department, Mater Misericordiae University Hospital, North Circular Road, Dublin, D07 R2WY, Ireland
d Department of Psychology, School of Social Sciences, Heriot-Watt University Malaysia, Putrajaya, Malaysia
e Wessex Institute, University of Southampton, University Road, Southampton, SO17 1BJ, United Kingdom
f Nottingham University Hospitals NHS Trust, Queen’s Medical Centre, Derby Road, Nottingham, NG7 2UH, United Kingdom
g Department of Otorhinolaryngology, Head and Neck Surgery, Antwerp University Hospital (UZA), 2650, Edegem, Antwerp, Belgium
h Experimental Laboratory of Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, 2610, Belgium
i Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110-1010, United States
j Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Oxford Road, Manchester, M13 9WL, United Kingdom
k Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health University of Manchester, Oxford Road, Manchester, M13 9PL, United Kingdom
l National Acoustic Laboratories, Australian Hearing Hub, Macquarie University, Sydney, NSW 2109, Australia
Abstract
Background: Single-sided deafness (SSD) has functional, psychological, and social consequences. Interventions for adults with SSD include hearing aids and auditory implants. Benefits and harms (outcome domains) of these interventions are until now reported inconsistently in clinical trials. Inconsistency in reporting outcome measures prevents meaningful comparisons or syntheses of trial results. The Core Rehabilitation Outcome Set for Single-Sided Deafness (CROSSSD) international initiative used structured communication techniques to achieve consensus among healthcare users and professionals working in the field of SSD. The novel contribution is a set of core outcome domains that experts agree are critically important to assess in all clinical trials of SSD interventions. Methods: A long list of candidate outcome domains compiled from a systematic review and published qualitative data, informed the content of a two-round online Delphi survey. Overall, 308 participants from 29 countries were enrolled. Of those, 233 participants completed both rounds of the survey and scored each outcome domain on a 9-point scale. The set of core outcome domains was finalised via a web-based consensus meeting with 12 participants. Votes involved all stakeholder groups, with an approximate 2:1 ratio of professionals to healthcare users participating in the Delphi survey, and a 1:1 ratio participating in the consensus meeting. Results: The first round of the survey listed 44 potential outcome domains, organised thematically. A further five outcome domains were included in Round 2 based on participant feedback. The structured voting at round 2 identified 17 candidate outcome domains which were voted on at the consensus meeting. Consensus was reached for a core outcome domain set including three outcome domains: spatial orientation, group conversations in noisy social situations, and impact on social situations. Seventy-seven percent of the remaining Delphi participants agreed with this core outcome domain set. Conclusions: Adoption of the internationally agreed core outcome domain set would promote consistent assessment and reporting of outcomes that are meaningful and important to all relevant stakeholders. This consistency will in turn enable comparison of outcomes reported across clinical trials comparing SSD interventions in adults and reduce research waste. Further research will determine how those outcome domains should best be measured. © 2022, The Author(s).
Author Keywords
Clinical trial design; Consensus methods; Core outcome set; Hearing interventions; Outcome domains; Single-sided deafness
Funding details
National Institute for Health and Care ResearchNIHR
Zepler Institute, University of Southampton
NIHR Nottingham Biomedical Research CentreBRCBRC-1215-20003
Document Type: Article
Publication Stage: Final
Source: Scopus
The Efficacy and Safety of Regional Nerve Blocks in Total Knee Arthroplasty: Systematic Review and Direct Meta-Analysis
(2022) Journal of Arthroplasty, 37 (10), pp. 1906-1921.e2.
Fillingham, Y.A.a , Hannon, C.P.b , Kopp, S.L.c , Austin, M.S.a , Sershon, R.A.d , Stronach, B.M.e , Meneghini, R.M.f , Abdel, M.P.g , Griesemer, M.E.h , Woznica, A.i , Casambre, F.D.i , Nelson, N.i , Hamilton, W.G.d , Della Valle, C.J.j
a Rothman Institute at Thomas Jefferson University, Philadelphia, Pennsylvania
b Department of Orthopedic Surgery, Washington University in St. Louis, St. Louis, Missouri
c Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Rochester, Minnesota
d Anderson Orthopaedic Research Institute, Alexandria, Virginia
e Department of Orthopaedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States
f Department of Orthopaedic Surgery, Indiana University Health, Indianapolis, IN, United States
g Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota
h Department of Anesthesiology, Rush University Medical Center, Chicago, Illinois
i Department of Clinical Quality and Value, American Academy of Orthopaedic Surgeons, Rosemont, Illinois
j Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, Illinois
Abstract
Background: Regional nerve blocks are widely used in primary total knee arthroplasty (TKA) to reduce postoperative pain and opioid consumption. The purpose of our study was to evaluate the efficacy and safety of regional nerve blocks after TKA in support of the combined clinical practice guidelines of the American Association of Hip and Knee Surgeons, American Academy of Orthopaedic Surgeons, Hip Society, Knee Society, and American Society of Regional Anesthesia and Pain Management. Methods: We searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for studies published before March 24, 2020 on femoral nerve block, adductor canal block, and infiltration between Popliteal Artery and Capsule of Knee in primary TKA. All included studies underwent qualitative and quantitative homogeneity testing followed by a systematic review and direct comparison meta-analysis to assess the efficacy and safety of the regional nerve blocks compared to a control, local peri-articular anesthetic infiltration (PAI), or between regional nerve blocks. Results: Critical appraisal of 1,673 publications yielded 56 publications representing the best available evidence for analysis. Femoral nerve and adductor canal blocks are effective at reducing postoperative pain and opioid consumption, but femoral nerve blocks are associated with quadriceps weakness. Use of a continuous compared to single shot adductor canal block can improve postoperative analgesia. No difference was noted between an adductor canal block or PAI regarding postoperative pain and opioid consumption, but the combination of both may be more effective. Conclusion: Single shot adductor canal block or PAI should be used to reduce postoperative pain and opioid consumption following TKA. Use of a continuous adductor canal block or a combination of single shot adductor canal block and PAI may improve postoperative analgesia in patients with concern of poor postoperative pain control. © 2022 Elsevier Inc.
Author Keywords
adductor canal block; femoral nerve block; infiltration between popliteal artery and capsule of knee; regional nerve block; total knee arthroplasty
Document Type: Article
Publication Stage: Final
Source: Scopus
Incisionless targeted adeno-associated viral vector delivery to the brain by focused ultrasound-mediated intranasal administration
(2022) eBioMedicine, 84, art. no. 104277, .
Ye, D.a , Yuan, J.a , Yang, Y.a , Yue, Y.a , Hu, Z.a , Fadera, S.a , Chen, H.a b
a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, United States
b Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO 63108, United States
Abstract
Background: Adeno-associated viral (AAV) vectors are currently the leading platform for gene therapy with the potential to treat a variety of central nervous system (CNS) diseases. There are numerous methods for delivering AAVs to the CNS, such as direct intracranial injection (DI), intranasal delivery (IN), and intravenous injection with focused ultrasound-induced blood–brain barrier disruption (FUS-BBBD). However, non-invasive and efficient delivery of AAVs to the brain with minimal systemic toxicity remain the major challenge. This study aims to investigate the potential of focused ultrasound-mediated intranasal delivery (FUSIN) in AAV delivery to brain. Methods: Mice were intranasally administered with AAV5 encoding enhanced green fluorescence protein (AAV5-EGFP) followed by FUS sonication in the presence of systemically injected microbubbles. Mouse brains and other major organs were harvested for immunohistological staining, PCR quantification, and in situ hybridization. The AAV delivery outcomes were compared with those of DI, FUS-BBBD, and IN delivery. Findings: FUSIN achieved safe and efficient delivery of AAV5-EGFP to spatially targeted brain locations, including a superficial brain site (cortex) and a deep brain region (brainstem). FUSIN achieved comparable delivery outcomes as the established DI, and displayed 414.9-fold and 2073.7-fold higher delivery efficiency than FUS-BBBD and IN. FUSIN was associated with minimal biodistribution in peripheral organs, which was comparable to that of DI. Interpretation: Our results suggest that FUSIN is a promising technique for non-invasive, efficient, safe, and spatially targeted AAV delivery to the brain. Funding: National Institutes of Health (NIH) grants R01EB027223, R01EB030102, R01MH116981, and UG3MH126861. © 2022 The Author(s)
Author Keywords
Adeno-associated viral vectors; Blood–brain barrier; Focused ultrasound; Gene therapy; Intranasal delivery
Funding details
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981, UG3MH126861
Document Type: Article
Publication Stage: Final
Source: Scopus
Multidimensional analysis and therapeutic development using patient iPSC-derived disease models of Wolfram syndrome
(2022) JCI insight, 7 (18), .
Kitamura, R.A.a , Maxwell, K.G.a b , Ye, W.c , Kries, K.a , Brown, C.M.a , Augsornworawat, P.a b , Hirsch, Y.d , Johansson, M.M.d , Weiden, T.e , Ekstein, J.d , Cohen, J.f , Klee, J.f , Leslie, K.f , Simeonov, A.c , Henderson, M.J.c , Millman, J.R.a b , Urano, F.a g
a Department of Medicine, Division of Endocrinology, Metabolism, Lipid Research, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
c National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), Rockville, MD, United States
d Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, United States
e Committee for Prevention of Jewish Genetic DiseasesJerusalem, Israel
f Amylyx Pharmaceuticals Inc., Cambridge, MA, United States
g Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
Abstract
Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant, which is highly prevalent in the Ashkenazi Jewish population. Clinical investigation indicated that patients carrying the homozygous WFS1 c.1672C>T, p.R558C variant showed mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C was more stable compared with the other known recessive pathogenic variants associated with Wolfram syndrome. Human induced pluripotent stem cell-derived (iPSC-derived) islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulated genotype-related Wolfram syndrome phenotypes. Enhancing residual WFS1 function through a combination treatment of chemical chaperones mitigated detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and increased insulin secretion in SC-islets. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient iPSC-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome.
Author Keywords
Beta cells; Diabetes; Endocrinology; Genetic diseases; Genetics
Document Type: Article
Publication Stage: Final
Source: Scopus
Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
(2022) The New England Journal of Medicine, 387 (12), pp. 1099-1110.
Miller, T.M., Cudkowicz, M.E., Genge, A., Shaw, P.J., Sobue, G., Bucelli, R.C., Chiò, A., Van Damme, P., Ludolph, A.C., Glass, J.D., Andrews, J.A., Babu, S., Benatar, M., McDermott, C.J., Cochrane, T., Chary, S., Chew, S., Zhu, H., Wu, F., Nestorov, I., Graham, D., Sun, P., McNeill, M., Fanning, L., Ferguson, T.A., Fradette, S., VALOR and OLE Working Group
From the Washington University School of Medicine, St. Louis (T.M.M., R.C.B.); the Sean M. Healey and AMG Center for ALS, Massachusetts General Hospital, Harvard Medical School, Boston (M.E.C., S.B.), and Biogen, Cambridge (T.C., S. Chary, S. Chew, H.Z., F.W., I.N., D.G., P.S., L.F., T.A.F., S.F.) – both in Massachusetts; Montreal Neurological Institute and Hospital, Montreal (A.G.); the Sheffield Institute for Translational Neuroscience, University of Sheffield, and the National Institute for Health and Care Research Sheffield Biomedical Research Centre and Clinical Research Facility, University of Sheffield and Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield (P.J.S., C.J.M.), and Biogen, Maidenhead (M.M.) – both in the United Kingdom; Aichi Medical University, Aichi, Japan (G.S.); the University of Turin, Turin, Italy (A.C.); KU Leuven, VIB Center for Brain and Disease Research, University Hospitals Leuven, Leuven, Belgium (P.V.D.); the University of Ulm, Ulm, and Deutsches Zentrum für Neurodegenerative Erkrankungen, Bonn – both in Germany (A.C.L.); Emory University, Atlanta (J.D.G.); the Neurological Institute, Columbia University Irving Medical Center, New York (J.A.A.); and the Department of Neurology, University of Miami, Miami (M.B.)
Abstract
BACKGROUND: The intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS). METHODS: In this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort). RESULTS: A total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients. CONCLUSIONS: In persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.). Copyright © 2022 Massachusetts Medical Society.
Document Type: Article
Publication Stage: Final
Source: Scopus
Laser stimulation of the skin for quantitative study of decision-making and motivation
(2022) Cell Reports Methods, 2 (9), art. no. 100296, .
Pai, J.a , Ogasawara, T.a , Bromberg-Martin, E.S.a , Ogasawara, K.a , Gereau, R.W.a b c d , Monosov, I.E.a b d e f
a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
b Washington University Pain Center, Washington University, St. Louis, MO, United States
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Biomedical Engineering, Washington University, St. Louis, MO, United States
e Department of Neurosurgery, Washington University, St. Louis, MO, United States
f Department of Electrical Engineering, Washington University, St. Louis, MO, United States
Abstract
Neuroeconomics studies how decision-making is guided by the value of rewards and punishments. But to date, little is known about how noxious experiences impact decisions. A challenge is the lack of an aversive stimulus that is dynamically adjustable in intensity and location, readily usable over many trials in a single experimental session, and compatible with multiple ways to measure neuronal activity. We show that skin laser stimulation used in human studies of aversion can be used for this purpose in several key animal models. We then use laser stimulation to study how neurons in the orbitofrontal cortex (OFC), an area whose many roles include guiding decisions among different rewards, encode the value of rewards and punishments. We show that some OFC neurons integrated the positive value of rewards with the negative value of aversive laser stimulation, suggesting that the OFC can play a role in more complex choices than previously appreciated. © 2022 The Authors
Author Keywords
aversion; decision; motivation; neuroeconomics; orbitofrontal; value
Funding details
National Institute of Mental HealthNIMHMH106435, R01MH110594, R01MH116937
Army Research OfficeARO78259-NS-MUR
McKnight FoundationR01NS106953
University of WashingtonUW
Document Type: Article
Publication Stage: Final
Source: Scopus
Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma
(2022) Immunity, 55 (9), pp. 1627-1644. Cited 1 time.
Margeta, M.A.a , Yin, Z.b , Madore, C.c , Pitts, K.M.a , Letcher, S.M.a , Tang, J.d , Jiang, S.e , Gauthier, C.D.b , Silveira, S.R.b , Schroeder, C.M.b , Lad, E.M.f , Proia, A.D.g , Tanzi, R.E.h , Holtzman, D.M.i , Krasemann, S.j , Chen, D.F.e , Butovsky, O.k
a Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA
b Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States
c Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Univ. Bordeaux, INRAE, Bordeaux INP, NutriNeuro, UMR 1286, F-33000 Bordeaux, France
d Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu, China
e Schepens Eye Research Institute of Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
f Department of Ophthalmology, Duke University Medical Center, Durham, NC, United States
g Department of Pathology, Duke University Medical Center, Durham, NC, USA; Department of Pathology, Campbell University School of Osteopathic Medicine, Lillington, NC, USA
h Genetics and Aging Research Unit, McCance Center for Brain Health, Mass General Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States
i Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer Disease Research Center, Washington University, St. Louis, MO, United States
j Institute of Neuropathology, University Medical Center Hamburg-EppendorfHamburg, Germany
k Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Evergrande Center for Immunologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Abstract
The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease. Copyright © 2022 Elsevier Inc. All rights reserved.
Author Keywords
Alzheimer disease; APOE4; Galectin-3; glaucoma; Lgals3; microglia; neurodegeneration; neuroprotection; retina
Document Type: Article
Publication Stage: Final
Source: Scopus
Validation of blood-based transcriptomic circadian phenotyping in older adults
(2022) Sleep, 45 (9), .
Smith, S.K.a b , Tran, P.c , Madden, K.A.c , Boyd, J.c , Braun, R.d , Musiek, E.S.a b c e , Ju, Y.-E.S.a b c e
a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Center on Biological Rhythms and Sleep (COBRAS), Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Molecular Biosciences, Northwestern University, Chicago, IL, United States
e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
Document Type: Article
Publication Stage: Final
Source: Scopus
Binary acoustic metasurfaces for dynamic focusing of transcranial ultrasound
(2022) Frontiers in Neuroscience, 16, art. no. 984953, .
Hu, Z.a , Yang, Y.a , Xu, L.a , Hao, Y.b , Chen, H.a b
a Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO, United States
b Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, MO, United States
Abstract
Transcranial focused ultrasound (tFUS) is a promising technique for non-invasive and spatially targeted neuromodulation and treatment of brain diseases. Acoustic lenses were designed to correct the skull-induced beam aberration, but these designs could only generate static focused ultrasound beams inside the brain. Here, we designed and 3D printed binary acoustic metasurfaces (BAMs) for skull aberration correction and dynamic ultrasound beam focusing. BAMs were designed by binarizing the phase distribution at the surface of the metasurfaces. The phase distribution was calculated based on time reversal to correct the skull-induced phase aberration. The binarization enabled the ultrasound beam to be dynamically steered along wave propagation direction by adjusting the operation frequency of the incident ultrasound wave. The designed BAMs were manufactured by 3D printing with two coding bits, a polylactic acid unit for bit “1” and a water unit for bit “0.” BAMs for single- and multi-point focusing through the human skull were designed, 3D printed, and validated numerically and experimentally. The proposed BAMs with subwavelength scale in thickness are simple to design, easy to fabric, and capable of correcting skull aberration and achieving dynamic beam steering. Copyright © 2022 Hu, Yang, Xu, Hao and Chen.
Author Keywords
aberration correction; acoustic lens; beam steering; binary acoustic metasurface; dynamic focusing; FUS-BBBD; neuromodulation; transcranial focused ultrasound
Funding details
National Institutes of HealthNIHR01EB027223, R01EB030102, R01MH116981, UG3MH126861
Office of Naval ResearchONRN00014-19-1-2335
Document Type: Article
Publication Stage: Final
Source: Scopus
Recovery of continuous 3D refractive index maps from discrete intensity-only measurements using neural fields
(2022) Nature Machine Intelligence, 4 (9), pp. 781-791.
Liu, R.a e , Sun, Y.a f , Zhu, J.b , Tian, L.b c , Kamilov, U.S.a d
a Department of Computer Science and Engineering, Washington University in St. Louis, St. Louis, MO, United States
b Department of Electrical and Computer Engineering, Boston University, Boston, MA, United States
c Department of Biomedical Engineering, Boston University, Boston, MA, United States
d Department of Electrical and Systems Engineering, Washington University in St. Louis, St. Louis, MO, United States
e Washington University in St. Louis, Google Inc., St. Louis, MO, United States
f Washington University in St. Louis, Caltech, St. Louis, MO, United States
Abstract
Intensity diffraction tomography (IDT) refers to a class of optical microscopy techniques for imaging the three-dimensional refractive index (RI) distribution of a sample from a set of two-dimensional intensity-only measurements. The reconstruction of artefact-free RI maps is a fundamental challenge in IDT due to the loss of phase information and the missing-cone problem. Neural fields has recently emerged as a new deep learning approach for learning continuous representations of physical fields. The technique uses a coordinate-based neural network to represent the field by mapping the spatial coordinates to the corresponding physical quantities, in our case the complex-valued refractive index values. We present Deep Continuous Artefact-free RI Field (DeCAF) as a neural-fields-based IDT method that can learn a high-quality continuous representation of a RI volume from its intensity-only and limited-angle measurements. The representation in DeCAF is learned directly from the measurements of the test sample by using the IDT forward model without any ground-truth RI maps. We qualitatively and quantitatively evaluate DeCAF on the simulated and experimental biological samples. Our results show that DeCAF can generate high-contrast and artefact-free RI maps and lead to an up to 2.1-fold reduction in the mean squared error over existing methods. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.
Funding details
National Science FoundationNSFCCF-1813848, CCF-1813910, CCF-2043134, EPMD-1846784
Document Type: Article
Publication Stage: Final
Source: Scopus
Multiscale photoacoustic tomography of neural activities with GCaMP calcium indicators
(2022) Journal of Biomedical Optics, 27 (9), .
Zhang, R.a , Li, L.S.b , Rao, B.a , Rong, H.a , Sun, M.-Y.c , Yao, J.a , Chen, R.d , Zhou, Q.d , Mennerick, S.c , Raman, B.a , Wang, L.V.b
a Washington University in Saint Louis, Department of Biomedical Engineering, Saint Louis, Missouri, United States, United States
b California Institute of Technology, Caltech Optical Imaging Laboratory, rew and Peggy Cherng Department of Medical Engineering, Department of Electrical Engineering, Pasadena, CA, United States
c Washington University School of Medicine, Department of Psychiatry, Saint Louis, Missouri, United States, United States
d University of Southern California, Department of Biomedical Engineering, Los Angeles, CA, United States
Abstract
SIGNIFICANCE: Optical imaging of responses in fluorescently labeled neurons has progressed significantly in recent years. However, there is still a need to monitor neural activities at divergent spatial scales and at depths beyond the optical diffusion limit. AIM: To meet these needs, we aim to develop multiscale photoacoustic tomography (PAT) to image neural activities across spatial scales with a genetically encoded calcium indicator GCaMP. APPROACH: First, using photoacoustic microscopy, we show that depth-resolved GCaMP signals can be monitored in vivo from a fly brain in response to odor stimulation without depth scanning and even with the cuticle intact. In vivo monitoring of GCaMP signals was also demonstrated in mouse brains. Next, using photoacoustic computed tomography, we imaged neural responses of a mouse brain slice at depths beyond the optical diffusion limit. RESULTS: We provide the first unambiguous demonstration that multiscale PAT can be used to record neural activities in transgenic flies and mice with select neurons expressing GCaMP. CONCLUSIONS: Our results indicate that the combination of multiscale PAT and fluorescent neural activity indicators provides a methodology for imaging targeted neurons at various scales.
Author Keywords
calcium indicators; GCaMP; neural imaging; photoacoustic tomography
Document Type: Article
Publication Stage: Final
Source: Scopus
Comparative study of on-label versus off-label treatment of intracranial aneurysms with the Pipeline embolization device
(2022) Journal of Neurosurgery, 137 (3), pp. 685-690
Cler, S.J.a , Lauzier, D.C.a , Chatterjee, A.R.a b c , Osbun, J.W.a b c , Moran, C.J.a b , Kansagra, A.P.a b c
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
OBJECTIVE The Pipeline embolization device (PED) is widely used for the treatment of intracranial aneurysms, including in off-label applications. In this work, the authors compared the real-world efficacy and safety of PED use in on-label and off-label aneurysm treatments. METHODS Clinical and angiographic data of patients who underwent PED placement at a high-volume academic medical center were retrospectively obtained. Treatments were classified as on-label if they fell within the applications approved by the United States Food and Drug Administration as of 2021. Recorded outcomes included aneurysm occlusion, procedural complications, ischemic events, in-stent stenosis, intracranial hemorrhage, postprocedural functional status, and death. RESULTS In total, 416 aneurysms in 330 patients were treated with PED, comprising 256 aneurysms that received on-label treatments and 160 that received off-label treatments. The overall rate of complete aneurysm occlusion was 76.4% for on-label aneurysms and 75.6% for off-label aneurysms (p = 0.898). The risk of ischemic stroke in patients who underwent off-label treatments was 15.2%, which was higher than the 4.2% rate in patients who underwent on-label treatment (p = 0.003). All other clinical complications, procedural complications, and long-term functional status were comparable between the on-label and off-label groups. CONCLUSIONS In real-world practice, off-label use of PED is common and can achieve similar efficacy as on-label use. However, in aggregate, off-label use was found to carry an increased rate of ischemic complications. With judicious attention to safety and individual patient characteristics, these results highlight the scale and general feasibility of off-label PED use by experts. ©AANS 2022.
Author Keywords
aneurysm; endovascular; flow diversion; off-label; Pipeline embolization device; vascular disorders
Document Type: Article
Publication Stage: Final
Source: Scopus
Effects of Segmental and Suprasegmental Speech Perception on Reading in Pediatric Cochlear Implant Recipients
(2022) Journal of Speech, Language, and Hearing Research, 65 (9), pp. 3583-3594.
Grantham, H.a b , Davidson, L.S.b , Geers, A.E.c , Uchanski, R.M.b
a Central Institute for the Deaf, St. Louis, MO, United States
b Washington University School of Medicine, St. Louis, MO, United States
c The University of Texas at Dallas, United States
Abstract
Purpose: The aim of this study was to determine whether suprasegmental speech perception contributes unique variance in predictions of reading decoding and comprehension for prelingually deaf children using two devices, at least one of which is a cochlear implant (CI). Method: A total of 104, 5-to 9-year-old CI recipients completed tests of segmental perception (e.g., word recognition in quiet and noise, recognition of vowels and consonants in quiet), suprasegmental perception (e.g., talker and stress discrimination, nonword stress repetition, and emotion identification), and nonverbal intelligence. Two years later, participants completed standardized tests of reading decoding and comprehension. Using regression analyses, the unique contribution of suprasegmental perception to reading skills was determined after controlling for demographic characteristics and segmental perception performance. Results: Standardized reading scores of the CI recipients increased with nonverbal intelligence for both decoding and comprehension. Female gender was associated with higher comprehension scores. After controlling for gender and nonverbal intelligence, segmental perception accounted for approximately 4% and 2% of the variance in decoding and comprehension, respectively. After controlling for nonverbal intelligence, gender, and segmental perception, suprasegmental perception accounted for an extra 4% and 7% unique variance in reading decoding and reading comprehension, respectively. Conclusions: Suprasegmental perception operates independently from segmental perception to facilitate good reading outcomes for these children with CIs. Clinicians and educators should be mindful that early perceptual skills may have longterm benefits for literacy. Research on how to optimize suprasegmental perception, perhaps through hearing-device programming and/or training strategies, is needed. © 2022 American Speech-Language-Hearing Association.
Funding details
National Institute on Deafness and Other Communication DisordersNIDCDRO1 DC012778
University of MiamiUM
Document Type: Article
Publication Stage: Final
Source: Scopus
Apoptosis Detection in Retinal Ganglion Cells Using Quantitative Changes in Multichannel Fluorescence Colocalization
(2022) Biosensors, 12 (9), art. no. 693, .
Qiu, X.a , Gammon, S.T.a , Johnson, J.R.b , Pisaneschi, F.a , Millward, S.W.a , Barnett, E.M.c , Piwnica-Worms, D.a
a Department of Cancer Systems Imaging, University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States
b Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO 63130, United States
c Department of Ophthalmology & Visual Sciences, Medical College of Wisconsin, Milwaukee, WI 53226, United States
Abstract
KcapTR488 is a dual-fluorophore peptide sensor for the real-time reporting of programmed cell death by fluorescence imaging. KcapTR488 contains a nuclear localization sequence (NLS) conjugated with Texas Red, a caspase-cleavable sequence (DEVD), and a C-terminus conjugated to Alexa Fluor 488 (AF488). The synthesis and preliminary evaluation in cellulo of KcapTR488 for monitoring cell death by fluorescence imaging has been previously reported, but its utility in vivo has yet to be tested or validated. Herein, in vitro solution experiments verified the intramolecular fluorescence resonance energy transfer (FRET) between the two fluorophores and enabled a quantitative analysis of enzyme rates and selectivity. The sensor delivery kinetics in live rat models were quantified by ex vivo fluorescence microscopy. Studies in healthy control retinas demonstrated that KcapTR488 concentrated in the nucleus of retinal ganglion cells (RGC), with a strong colocalization of red and green fluorescence signals producing robust FRET signals, indicating an intact reporter. By contrast, using an acute but mild NMDA-induced retinal injury model, dual-color confocal ex vivo microscopy of cleaved KcapTR488 identified sensor activation as early as 2 h after injection. Quantitative changes in fluorescence colocalization were superior to changes in FRET for monitoring injury progression. Longitudinal monitoring revealed that the NLS-Texas Red fragment of the cleaved sensor moved out of the cell body, down the axon, and exited the retina, consistent with anterograde axonal transport. Thus, KcapTR488 may be a powerful tool to study RGC death pathways in live preclinical models of glaucoma. © 2022 by the authors.
Author Keywords
anterograde axonal transport; apoptosis; dual-fluorophore peptide sensor; fluorescence colocalization; fluorescence resonance energy transfer; glaucoma; multispectral detection; NMDA; retinal ganglion cell
Funding details
National Institutes of HealthNIHR01 EY019587
Document Type: Article
Publication Stage: Final
Source: Scopus
Modeling Neonatal Intraventricular Hemorrhage through Intraventricular Injection of Hemoglobin
(2022) Journal of Visualized Experiments: JoVE, (186), .
Miller, B.A.a , Pan, S.b , Yang, P.H.b , Wang, C.c , Trout, A.L.c , DeFreitas, D.b , Ramagiri, S.b , Olson, S.D.d , Strahle, J.M.e
a Department of Neurosurgery, University of Kentucky; Department of Pediatric Surgery, University of Texas
b Department of Neurological Surgery, Washington University in St. Louis School of Medicine
c Department of Neurosurgery, University of Kentucky
d Department of Pediatric Surgery, University of Texas
e Department of Neurological Surgery, Washington University in St. Louis School of Medicine; Department of Orthopedic Surgery, Washington University in St. Louis School of Medicine; Department of Pediatrics, Washington University in St. Louis School of Medicine;
Abstract
Neonatal intraventricular hemorrhage (IVH) is a common consequence of premature birth and leads to brain injury, posthemorrhagic hydrocephalus (PHH), and lifelong neurological deficits. While PHH can be treated by temporary and permanent cerebrospinal fluid (CSF) diversion procedures (ventricular reservoir and ventriculoperitoneal shunt, respectively), there are no pharmacological strategies to prevent or treat IVH-induced brain injury and hydrocephalus. Animal models are needed to better understand the pathophysiology of IVH and test pharmacological treatments. While there are existing models of neonatal IVH, those that reliably result in hydrocephalus are often limited by the necessity for large-volume injections, which may complicate modeling of the pathology or introduce variability in the clinical phenotype observed. Recent clinical studies have implicated hemoglobin and ferritin in causing ventricular enlargement after IVH. Here, we develop a straightforward animal model that mimics the clinical phenotype of PHH utilizing small-volume intraventricular injections of the blood breakdown product hemoglobin. In addition to reliably inducing ventricular enlargement and hydrocephalus, this model results in white matter injury, inflammation, and immune cell infiltration in periventricular and white matter regions. This paper describes this clinically relevant, simple method for modeling IVH-PHH in neonatal rats using intraventricular injection and presents methods for quantifying ventricle size post injection.
Document Type: Article
Publication Stage: Final
Source: Scopus
Deep profiling of multiple ischemic lesions in a large, multi-center cohort: Frequency, spatial distribution, and associations to clinical characteristics
(2022) Frontiers in Neuroscience, 16, art. no. 994458, .
Bonkhoff, A.K.a , Ullberg, T.b c , Bretzner, M.a d , Hong, S.a , Schirmer, M.D.a , Regenhardt, R.W.a , Donahue, K.L.a , Nardin, M.J.a , Dalca, A.V.e f , Giese, A.-K.g , Etherton, M.R.a , Hancock, B.L.f , Mocking, S.J.T.f , McIntosh, E.C.h , Attia, J.i j , Cole, J.W.k , Donatti, A.l , Griessenauer, C.J.m n , Heitsch, L.o p , Holmegaard, L.q r , Jood, K.q r , Jimenez-Conde, J.s t , Kittner, S.J.k , Lemmens, R.u v , Levi, C.R.w x , McDonough, C.W.y , Meschia, J.F.z , Phuah, C.-L.p , Ropele, S.aa , Rosand, J.a f ab , Roquer, J.s t , Rundek, T.j , Sacco, R.L.j , Schmidt, R.aa , Sharma, P.ac , Slowik, A.ad , Sousa, A.l , Stanne, T.M.ae , Strbian, D.af , Tatlisumak, T.q r , Thijs, V.ag ah , Vagal, A.ai , Woo, D.aj , Zand, R.ak , McArdle, P.F.al , Worrall, B.B.am an , Jern, C.ae ao , Lindgren, A.G.ap aq , Maguire, J.ar , Wu, O.f , Frid, P.aq , Rost, N.S.a , Wasselius, J.b c , the MRI-GENIE GISCOME Investigators, the International Stroke Genetics Consortiumas
a J Philip Kistler Stroke Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
b Department of Clinical Sciences Lund, Radiology, Lund University, Lund, Sweden
c Department of Radiology and Neuroradiology, Skå University Hospital, Lund, Sweden
d U1171, LilNCog (JPARC), Lille Neurosciences Cognition and University of Lille, Inserm, CHU Lille, Lille, France
e Computer Science and Artificial Intelligence Lab, Massachusetts Institute of Technology, Boston, MA, United States
f Department of Radiology, Athinoula A Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
g Department of Neurology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
h Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, MD, United States
i Hunter Medical Research Institute, Newcastle, NSW, Australia
j School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
k Department of Neurology, University of Maryland, School of Medicine and Veterans Affairs Maryland Health Care System, Baltimore, MD, United States
l School of Medical Sciences, The Brazilian Institute of Neuroscience and Neurotechnology (BRAINN), University of Campinas (UNICAMP), Campinas, Brazil
m Department of Neurosurgery, Geisinger, Danville, PA, United States
n Department of Neurosurgery, Christian Doppler Clinic, Paracelsus Medical University, Salzburg, Austria
o Department of Emergency Medicine, Washington University School of Medicine, St Louis, MO, United States
p Department of Neurology, Barnes-Jewish Hospital, Washington University School of Medicine, St Louis, MO, United States
q Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
r Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden
s Department of Neurology, Neurovascular Research Group (NEUVAS), IMIM-Hospital del Mar (Institut Hospital del Mar d’Investigacions Mèdiques), Universitat Pompeu Fabra, Barcelona, Spain
t Department of Medicine and Life Sciences (MELIS), Universitat Pompeu Fabra, Barcelona, Spain
u Department of Neurosciences, Experimental Neurology, Leuven Research Institute for Neuroscience, Disease (LIND), KU Leuven – University of Leuven, Leuven, Belgium
v Laboratory of Neurobiology, Department of Neurology, Vesalius Research Center (VIB), University Hospitals Leuven, Leuven, Belgium
w Department of Neurology, John Hunter Hospital, Newcastle, NSW, Australia
x Department of Pharmacotherapy, Translational Research, Center for Pharmacogenomics, University of Florida, Gainesville, FL, United States
y Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
z Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz, Austria
aa Henry and Allison McCance Center for Brain Health, Massachusetts General Hospital, Boston, MA, United States
ab Department of Neurology, Evelyn F McKnight Brain Institute, Miller School of Medicine, University of Miami, Miami, FL, United States
ac Institute of Cardiovascular Research, St Peter’s, Ashford Hospitals, Royal Holloway University of London (ICR2UL), Egham, United Kingdom
ad Department of Neurology, Jagiellonian University Medical College, Krakó, Poland
ae Department of Laboratory Medicine, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
af Department of Neurology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
ag Division of Stroke, Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia
ah Department of Neurology, Austin Health, Heidelberg, VIC, Australia
ai Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH, United States
aj Department of Neurology, Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States
ak Department of Neurology, Pennsylvania State University, Hershey, PA, United States
al Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, United States
am Department of Neurology, University of Virginia, Charlottesville, VA, United States
an Department of Public Health Sciences, University of Virginia, Charlottesville, VA, United States
ao Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, Gothenburg, Sweden
ap Department of Neurology, Skå University Hospital, Lund, Sweden
aq Department of Clinical Sciences Lund, Neurology, Lund University, Lund, Sweden
ar University of Technology, Faculty of Health, Sydney, NSW, Australia
Abstract
Background purpose: A substantial number of patients with acute ischemic stroke (AIS) experience multiple acute lesions (MAL). We here aimed to scrutinize MAL in a large radiologically deep-phenotyped cohort. Materials and methods: Analyses relied upon imaging and clinical data from the international MRI-GENIE study. Imaging data comprised both Fluid-attenuated inversion recovery (FLAIR) for white matter hyperintensity (WMH) burden estimation and diffusion-weighted imaging (DWI) sequences for the assessment of acute stroke lesions. The initial step featured the systematic evaluation of occurrences of MAL within one and several vascular supply territories. Associations between MAL and important imaging and clinical characteristics were subsequently determined. The interaction effect between single and multiple lesion status and lesion volume was estimated by means of Bayesian hierarchical regression modeling for both stroke severity and functional outcome. Results: We analyzed 2,466 patients (age = 63.4 ± 14.8, 39% women), 49.7% of which presented with a single lesion. Another 37.4% experienced MAL in a single vascular territory, while 12.9% featured lesions in multiple vascular territories. Within most territories, MAL occurred as frequently as single lesions (ratio ∼1:1). Only the brainstem region comprised fewer patients with MAL (ratio 1:4). Patients with MAL presented with a significantly higher lesion volume and acute NIHSS (7.7 vs. 1.7 ml and 4 vs. 3, pFDR < 0.001). In contrast, patients with a single lesion were characterized by a significantly higher WMH burden (6.1 vs. 5.3 ml, pFDR = 0.048). Functional outcome did not differ significantly between patients with single versus multiple lesions. Bayesian analyses suggested that the association between lesion volume and stroke severity between single and multiple lesions was the same in case of anterior circulation stroke. In case of posterior circulation stroke, lesion volume was linked to a higher NIHSS only among those with MAL. Conclusion: Multiple lesions, especially those within one vascular territory, occurred more frequently than previously reported. Overall, multiple lesions were distinctly linked to a higher acute stroke severity, a higher total DWI lesion volume and a lower WMH lesion volume. In posterior circulation stroke, lesion volume was linked to a higher stroke severity in multiple lesions only. Copyright © 2022 Bonkhoff, Ullberg, Bretzner, Hong, Schirmer, Regenhardt, Donahue, Nardin, Dalca, Giese, Etherton, Hancock, Mocking, McIntosh, Attia, Cole, Donatti, Griessenauer, Heitsch, Holmegaard, Jood, Jimenez-Conde, Kittner, Lemmens, Levi, McDonough, Meschia, Phuah, Ropele, Rosand, Roquer, Rundek, Sacco, Schmidt, Sharma, Slowik, Sousa, Stanne, Strbian, Tatlisumak, Thijs, Vagal, Woo, Zand, McArdle, Worrall, Jern, Lindgren, Maguire, Wu, Frid, Rost and Wasselius.
Author Keywords
acute ischemic stroke; Bayesian hierarchical regression; lesion volume; magnetic resonance imaging; multiple acute ischemic lesions; quantitative imaging
Funding details
ALFGBG-720081
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSR01 NS100417, R01 NS103824, R01NS086905, RF1 NS117643, U01NS100699, U01NS110772
Medtronic
Crafoordska Stiftelsen20180610, 20200548, 96437, 96438, YF-aALF-43435
Hjärt-Lungfonden2019-01757, 20190203
VetenskapsrådetVR2018-02543, 2021-01114
Société Française de RadiologieSFR
Skånes universitetssjukhusSUS1R01NS114045-01, R01NS082285, U19NS115388
Forschungsfabrik Mikroelektronik DeutschlandFMD
Document Type: Article
Publication Stage: Final
Source: Scopus
Examining virtual driving test performance and its relationship to individuals with HIV-associated neurocognitive disorders
(2022) Frontiers in Neuroscience, 16, art. no. 912766, .
Grethlein, D.a b , Pirrone, V.c , Devlin, K.N.d , Dampier, W.c , Szep, Z.e , Winston, F.K.f g , Ontañón, S.b , Walshe, E.A.f , Malone, K.h , Tillman, S.h , Ances, B.M.i , Kandadai, V.a , Kolson, D.L.j , Wigdahl, B.c
a Diagnostic Driving, Inc, Philadelphia, PA, United States
b Department of Computer Science, The Games Artificial Intelligence and Media Systems (GAIMS) Center, College of Computing and Informatics, Drexel University, Philadelphia, PA, United States
c Department of Microbiology and Immunology, College of Medicine, Institute for Molecular Medicine and Infectious Disease, Drexel University, Philadelphia, PA, United States
d Applied Neuro-Technologies Lab, Department of Psychological and Brain Sciences, College of Arts and Sciences, Drexel University, Philadelphia, PA, United States
e Division of Infectious Diseases and HIV Medicine, Department Medicine, Partnership Comprehensive Care Practice, College of Medicine, Drexel University, Philadelphia, PA, United States
f Center for Injury Research and Prevention, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
g Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
h College of Medicine, Drexel University, Philadelphia, PA, United States
i Department of Neurology, Hope Center for Neurological Disorders, School of Medicine, Washington University, St. Louis, MO, United States
j Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
Abstract
Significance: Existing screening tools for HIV-associated neurocognitive disorders (HAND) are often clinically impractical for detecting milder forms of impairment. The formal diagnosis of HAND requires an assessment of both cognition and impairment in activities of daily living (ADL). To address the critical need for identifying patients who may have disability associated with HAND, we implemented a low-cost screening tool, the Virtual Driving Test (VDT) platform, in a vulnerable cohort of people with HIV (PWH). The VDT presents an opportunity to cost-effectively screen for milder forms of impairment while providing practical guidance for a cognitively demanding ADL. Objectives: We aimed to: (1) evaluate whether VDT performance variables were associated with a HAND diagnosis and if so; (2) systematically identify a manageable subset of variables for use in a future screening model for HAND. As a secondary objective, we examined the relative associations of identified variables with impairment within the individual domains used to diagnose HAND. Methods: In a cross-sectional design, 62 PWH were recruited from an established HIV cohort and completed a comprehensive neuropsychological assessment (CNPA), followed by a self-directed VDT. Dichotomized diagnoses of HAND-specific impairment and impairment within each of the seven CNPA domains were ascertained. A systematic variable selection process was used to reduce the large amount of VDT data generated, to a smaller subset of VDT variables, estimated to be associated with HAND. In addition, we examined associations between the identified variables and impairment within each of the CNPA domains. Results: More than half of the participants (N = 35) had a confirmed presence of HAND. A subset of twenty VDT performance variables was isolated and then ranked by the strength of its estimated associations with HAND. In addition, several variables within the final subset had statistically significant associations with impairment in motor function, executive function, and attention and working memory, consistent with previous research. Conclusion: We identified a subset of VDT performance variables that are associated with HAND and assess relevant functional abilities among individuals with HAND. Additional research is required to develop and validate a predictive HAND screening model incorporating this subset. Copyright © 2022 Grethlein, Pirrone, Devlin, Dampier, Szep, Winston, Ontañón, Walshe, Malone, Tillman, Ances, Kandadai, Kolson and Wigdahl.
Author Keywords
driving simulator; HIV-associated neurocognitive disorders; impairment detection; screening tool; variable selection
Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMHP30MH092177, R43MH122035
Small Business Innovation ResearchSBIR
Document Type: Article
Publication Stage: Final
Source: Scopus
Analysis of neuronal injury transcriptional response identifies CTCF and YY1 as co-operating factors regulating axon regeneration
(2022) Frontiers in Molecular Neuroscience, 15, art. no. 967472, .
Avraham, O.a , Le, J.a , Leahy, K.a , Li, T.b c , Zhao, G.a d , Cavalli, V.a c e
a Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
b Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
c Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
d Department of Pathology and Immunology, 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
Abstract
Injured sensory neurons activate a transcriptional program necessary for robust axon regeneration and eventual target reinnervation. Understanding the transcriptional regulators that govern this axon regenerative response may guide therapeutic strategies to promote axon regeneration in the injured nervous system. Here, we used cultured dorsal root ganglia neurons to identify pro-regenerative transcription factors. Using RNA sequencing, we first characterized this neuronal culture and determined that embryonic day 13.5 DRG (eDRG) neurons cultured for 7 days are similar to e15.5 DRG neurons in vivo and that all neuronal subtypes are represented. This eDRG neuronal culture does not contain other non-neuronal cell types. Next, we performed RNA sequencing at different time points after in vitro axotomy. Analysis of differentially expressed genes revealed upregulation of known regeneration associated transcription factors, including Jun, Atf3 and Rest, paralleling the axon injury response in vivo. Analysis of transcription factor binding sites in differentially expressed genes revealed other known transcription factors promoting axon regeneration, such as Myc, Hif1α, Pparγ, Ascl1a, Srf, and Ctcf, as well as other transcription factors not yet characterized in axon regeneration. We next tested if overexpression of novel candidate transcription factors alone or in combination promotes axon regeneration in vitro. Our results demonstrate that expression of Ctcf with Yy1 or E2f2 enhances in vitro axon regeneration. Our analysis highlights that transcription factor interaction and chromatin architecture play important roles as a regulator of axon regeneration. Copyright © 2022 Avraham, Le, Leahy, Li, Zhao and Cavalli.
Author Keywords
axon regeneration; bioinformatics analyses; CTCF; dorsal root ganglia; E2F2; sensory neurons; transcription factors; YY1
Funding details
National Institutes of HealthNIHR01 NS096034, R35 NS122260
Center of Regenerative Medicine, Washington University in St. LouisCRM, WUSTL
Document Type: Article
Publication Stage: Final
Source: Scopus
Enhancing neuroimaging genetics through meta-analysis for Tourette syndrome (ENIGMA-TS): A worldwide platform for collaboration
(2022) Frontiers in Psychiatry, 13, art. no. 958688, .
Paschou, P.a , Jin, Y.a , Müller-Vahl, K.b , Möller, H.E.c , Rizzo, R.d , Hoekstra, P.J.e , Roessner, V.f , Mol Debes, N.g , Worbe, Y.h , Hartmann, A.i , Mir, P.j k , Cath, D.e , Neuner, I.l m n , Eichele, H.o , Zhang, C.p , Lewandowska, K.q , Munchau, A.r , Verrel, J.r , Musil, R.s , Silk, T.J.t , Hanlon, C.A.u , Bihun, E.D.v , Brandt, V.w , Dietrich, A.e , Forde, N.x , Ganos, C.y , Greene, D.J.z , Chu, C.p , Grothe, M.J.j k , Hershey, T.v , Janik, P.aa , Koller, J.M.v , Martin-Rodriguez, J.F.j k , Müller, K.c , Palmucci, S.d , Prato, A.ab , Ramkiran, S.l m n , Saia, F.ac , Szejko, N.aa , Torrecuso, R.c , Tumer, Z.ad ae , Uhlmann, A.f , Veselinovic, T.l , Wolańczyk, T.af , Zouki, J.-J.t , Jain, P.a , Topaloudi, A.a , Kaka, M.a , Yang, Z.a , Drineas, P.ag , Thomopoulos, S.I.ah , White, T.ai , Veltman, D.J.aj , Schmaal, L.ak , Stein, D.J.al , Buitelaar, J.x , Franke, B.x , van den Heuvel, O.am , Jahanshad, N.ah , Thompson, P.M.ah , Black, K.J.v , the ENIGMA-TS Working Groupan
a Department of Biological Sciences, Purdue University, West Lafayette, IN, United States
b Department of Psychiatry, Hannover University Medical School, Hannover, Germany
c Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
d Radiology Unit 1, Department of Medical Surgical Sciences and Advanced Technologies, University of Catania, Catania, Italy
e University Medical Center Groningen, Department of Psychiatry, University of Groningen, Groningen, Netherlands
f Department of Child and Adolescent Psychiatry, Technische Universität (TU) Dresden, Dresden, Germany
g Department of Pediatrics, Herlev University Hospital, Herlev, Denmark
h Department of Neurophysiology, Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
i Pitié-Salpêtrière Hospital, Paris, France
j Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC, University of Seville, Seville, Spain
k Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain
l Department of Psychiatry, Psychotherapy and Psychosomatic, RWTH Aachen University, Aachen, Germany
m Institute of Neuroscience and Medicine 4, Forschungszentrum Jülich GmbH, Jülich, Germany
n JARA BRAIN—Translational Medicine, Aachen, Germany
o Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway
p Shanghai Research Center for Brain Science and Brain-Inspired Intelligence, Shanghai, China
q Department of Psychiatry, Medical University of Warsaw, Warsaw, Poland
r Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany
s Department of Psychiatry and Psychotherapy, Ludwig Maximilians University of Munich, Munich, Germany
t Deakin University, Geelong, VIC, Australia
u Wake Forest School of Medicine, Winston-Salem, NC, United States
v Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
w Centre for Innovation in Mental Health, School of Psychology, University of Southampton, Southampton, United Kingdom
x Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, Netherlands
y Department of Neurology, Charité-University Medicine Berlin, Berlin, Germany
z Department of Cognitive Science, University of California, San Diego, La Jolla, CA, United States
aa Department of Neurology, Medical University of Warsaw, Warsaw, Poland
ab Child and Adolescent Neurology and Psychiatric Section, Department of Clinical and Experimental Medicine, Catania University, Catania, Italy
ac Child Neuropsychiatry Unit, Department of Clinical and Experimental Medicine, School of Medicine, University of Catania, Catania, Italy
ad Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
ae Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital Rigshospitalet, Glostrup, Denmark
af Department of Child Psychiatry, Medical University of Warsaw, Warsaw, Poland
ag Department of Computer Science, Purdue University, West Lafayette, IN, United States
ah Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
ai Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC–Sophia Children’s Hospital, University Medical Center Rotterdam, Rotterdam, Netherlands
aj Department of Psychiatry, Amsterdam Neuroscience, Amsterdam UMC, Amsterdam, Netherlands
ak Centre for Youth Mental Health, University of Melbourne, Melbourne, VIC, Australia
al South African Medical Research Council (SAMRC) Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Neuroscience Institute, University of Cape Town, Cape Town, South Africa
am Department Psychiatry, Department Anatomy and Neuroscience, Amsterdam University Medical Center (UMC), Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, Netherlands
Abstract
Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice. Copyright © 2022 Paschou, Jin, Müller-Vahl, Möller, Rizzo, Hoekstra, Roessner, Mol Debes, Worbe, Hartmann, Mir, Cath, Neuner, Eichele, Zhang, Lewandowska, Munchau, Verrel, Musil, Silk, Hanlon, Bihun, Brandt, Dietrich, Forde, Ganos, Greene, Chu, Grothe, Hershey, Janik, Koller, Martin-Rodriguez, Müller, Palmucci, Prato, Ramkiran, Saia, Szejko, Torrecuso, Tumer, Uhlmann, Veselinovic, Wolańczyk, Zouki, Jain, Topaloudi, Kaka, Yang, Drineas, Thomopoulos, White, Veltman, Schmaal, Stein, Buitelaar, Franke, van den Heuvel, Jahanshad, Thompson and Black.
Author Keywords
brain MRI; ENIGMA; genetics; neuroimaging; Tourette syndrome
Funding details
National Science FoundationNSF1715202
National Institutes of HealthNIHK01MH104592, P41EB015922, R01MH116147, R01MH118217
National Institute of Mental HealthNIMHR01MH126213
Dagmar Marshalls Fond
Universidad de SevillaUSE-18817-A
Innovative Medicines InitiativeIMI777394
Document Type: Article
Publication Stage: Final
Source: Scopus
Profiles of Odorant Specific Performance in Olfactory Testing
(2022) American Journal of Rhinology and Allergy, .
Schlosser, R.J.a , Soler, Z.M.a , Mace, J.b , Farrell, N.b c , Rimmer, R.b d , Alt, J.A.e , Ramakrishnan, V.R.f , Edwards, T.S.a , Smith, T.L.b
a Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, Charleston, SC, United States
b Department of Otolaryngology-Head and Neck Surgery, Oregon Health Sciences University, Portland, OR, United States
c Department of Otolaryngology-Head and Neck Surgery, Washington University, St Louis, MO, United States
d Department of Otolaryngology-Head and Neck Surgery, Yale University, New Haven, CT, United States
e Division of Otolaryngology-Head and Neck Surgery, University of Utah, Salt Lake City, UT, United States
f Department of Otolaryngology-Head and Neck Surgery, Indiana University School of Medicine, Indianapolis, IN, United States
Abstract
Background: Olfactory dysfunction (OD) can occur from a variety of etiologies. However, there are few reports examining whether varying etiologies have unique profiles of psychophysical testing that may provide insight into the pathophysiology of OD. Methods: Adults with chronic rhinosinusitis with and without nasal polyps (CRSwNP/CRSsNP) and healthy control adults with no sinus complaints underwent olfactory assessment with Sniffin’ Sticks. Profiles of identification and discrimination were compared between CRS and non-CRS subjects across the spectrum of OD. Results: Normosmics with or without CRS identified apple, pineapple, and turpentine less frequently than expected (range 52%-68% correct). Hyposmics with CRS correctly identified orange more frequently than control hyposmics (83%-93% vs 68% for controls) with similar findings for rose. Hyposmics of all cohorts were unable to identify apple (26%). Discrimination profiles were similar across the spectrum of OD and between diagnostic groups. Conclusions: Identification and discrimination rates of specific odorants may provide unique information regarding the etiology of OD, however psychophysical testing is a complex interplay of olfactory and trigeminal function, the strength of target odorant, distractor choices, and familiarity with odorants. © The Author(s) 2022.
Author Keywords
olfaction; olfactory disorder
Funding details
National Institutes of HealthNIHK23 DC014747, R01DC005805, R01DC019078
National Institute on Deafness and Other Communication DisordersNIDCD
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Effects of Age and Attentional Focus on the Performance and Coordination of the Sit-to-Stand Task
(2022) Journal of Motor Behavior, .
Andrade, V.a , Mazoni, A.b , Vasconcelos, C.c , Mattos, D.d , Mitra, S.e , Ocarino, J.c , Vaz, D.c
a Center for Cognition, Action, & Perception, Department of Psychology, University of Cincinnati, Cincinnati, OH, United States
b InSySPo, System Innovation Institute of Geosciences, UniversidadeEstadualde Campinas, São Paulo, Campinas, Brazil
c Department of Physical Therapy, School of Physical Education, Physical Therapy, and Occupational Therapy, Universidade Federal de Minas Gerais, Minas Gerais, Belo Horizonte, Brazil
d Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
e Department of Psychology, Nottingham Trent University, Nottingham, United Kingdom
Abstract
This study investigated whether age and attentional focus affect synergy organization of sit-to-stand (STS). Young and older adults performed STS while holding a cup under internal (IF) and external focus (EF) instructions. Uncontrolled manifold analysis was used to decompose trial-to-trial variability in joint kinematics into variability that preserves (VUCM) and interferes (VORT) with the horizontal and vertical positions of the center of mass (CoM) and cup. VUCM was significantly higher than VORT for all variables in both age groups and focus conditions. Older adults demonstrated higher VUCM for all variables and higher VORT for all variables except the vertical position of the cup. IF instructions benefited older adults, leading to decreased VORT of the vertical position of CoM and horizontal and vertical positions of the cup. © Copyright © 2022 Taylor & Francis Group, LLC.
Author Keywords
aging; attentional focus; sit-to-stand; uncontrolled manifold
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Personalized Prediction of Behaviors and Experiences: An Idiographic Person–Situation Test
(2022) Psychological Science, .
Beck, E.D.a b , Jackson, J.J.c
a Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, United States
b Department of Psychology, University of California, Davis, United States
c Department of Psychological and Brain Sciences, Washington University in St. Louis, United States
Abstract
A longstanding goal of psychology is to predict the things that people do and feel, but tools to accurately predict future behaviors and experiences remain elusive. In the present study, we used intensive longitudinal data (N = 104 college-age adults at a midwestern university; total assessments = 5,971) and three machine-learning approaches to investigate the degree to which three future behaviors and experiences—loneliness, procrastination, and studying—could be predicted from past psychological (i.e., personality and affective states), situational (i.e., objective situations and psychological situation cues), and time (i.e., trends, diurnal cycles, time of day, and day of the week) phenomena from an idiographic, person-specific perspective. Rather than pitting persons against situations, such an approach allows psychological phenomena, situations, and time to jointly predict future behaviors and experiences. We found (a) a striking degree of prediction accuracy across participants, (b) that a majority of participants’ future behaviors are predicted by both person and situation features, and (c) that the most important features vary greatly across people. © The Author(s) 2022.
Author Keywords
experience-sampling method (ESM); idiographic; machine learning; open data; open materials; personality; prediction; preregistered
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Association of Mental Health Burden with Prenatal Cannabis Exposure from Childhood to Early Adolescence: Longitudinal Findings from the Adolescent Brain Cognitive Development (ABCD) Study
(2022) JAMA Pediatrics, .
Baranger, D.A.A.a , Paul, S.E.a , Colbert, S.M.C.b , Karcher, N.R.b , Johnson, E.C.b , Hatoum, A.S.b , Bogdan, R.a
a Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine in St Louis, St Louis, MO, United States
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Self-reported emotional health and social support but not executive function are associated with participation after stroke
(2022) Topics in Stroke Rehabilitation, .
Ianni, C.a , Magee, L.a , Dagli, C.b , Nicholas, M.L.c , Connor, L.T.b d
a Department of Occupational Therapy, MGH Institute of Health Professions, Boston, MA, United States
b Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United States
c Department of Communication Sciences and Disorders, MGH Institute of Health Professions, Boston, MA, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Participation restrictions continue to be prevalent for community-dwelling stroke survivors. Research is needed to understand the associated post-stroke factors that limit or facilitate optimal participation and quality of life. Objectives: To investigate emotional health, executive functioning (EF), and social support as predictors of participation restrictions post-stroke. Methods: Cross-sectional data collected from participants ≥ 6 months after mild stroke with and without aphasia (N = 114) were analyzed using three participation outcome measures: Reintegration to Normal Living Index (RNL), Activity Card Sort (ACS), and the Stroke Impact Scale (SIS) Version 2.0 Participation/Role Function domain. Predictor variables investigated were emotional health (SIS Emotion domain scores), EF (Delis Kaplan Executive Function System Trail Making Condition 4: DKEFS), social support (Medical Outcomes Study Social Support Survey: MOS-SSS), stroke severity (National Institutes of Health Stroke Scale: NIHSS), and education level. Results: Using multiple regression, these predictors accounted for 26.4% to 40% of the variance for the three participation outcomes. Emotional health was a significant independent predictor across all three measures. Social support was a significant predictor of participation as measured on the RNL. Executive function was not a significant predictor of participation when controlling for the other predictor variables. Conclusions: Emotional health and social support should be considered as modifiable factors that could optimize meaningful participation and quality of life. © 2022 Taylor & Francis Group, LLC.
Author Keywords
emotional health; executive function; participation; social support; stroke
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Neuropsychological and Neuroanatomical Features of Patients with Behavioral/Dysexecutive Variant Alzheimer’s Disease (AD): A Comparison to Behavioral Variant Frontotemporal Dementia and Amnestic AD Groups
(2022) Journal of Alzheimer’s Disease: JAD, 89 (2), pp. 641-658.
Dominguez Perez, S.a b c , Phillips, J.S.a b , Norise, C.b , Kinney, N.G.a b , Vaddi, P.a b , Halpin, A.a b d , Rascovsky, K.a b , Irwin, D.J.a b e , McMillan, C.T.a b , Xie, L.b f , Wisse, L.E.M.b f g , Yushkevich, P.A.b f , Kallogjeri, D.h , Grossman, M.a b , Cousins, K.A.Q.a b
a Penn Frontotemporal Degeneration Center (FTDC), University of Pennsylvania, Philadelphia, PA, United States
b Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
c Department of Psychological Sciences, University of Connecticut, Storrs, CT, United States
d Department of Psychology, University of Maine, Orono, ME, United States
e Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
f Penn Image Computing and Science Lab & Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
g Department of Diagnostic Radiology, Lund University, Lund, Sweden
h Department of Otolaryngology, Washington University, St. Louis, MO, United States
Abstract
BACKGROUND: An understudied variant of Alzheimer’s disease (AD), the behavioral/dysexecutive variant of AD (bvAD), is associated with progressive personality, behavior, and/or executive dysfunction and frontal atrophy. OBJECTIVE: This study characterizes the neuropsychological and neuroanatomical features associated with bvAD by comparing it to behavioral variant frontotemporal dementia (bvFTD), amnestic AD (aAD), and subjects with normal cognition. METHODS: Subjects included 16 bvAD, 67 bvFTD, 18 aAD patients, and 26 healthy controls. Neuropsychological assessment and MRI data were compared between these groups. RESULTS: Compared to bvFTD, bvAD showed more significant visuospatial impairments (Rey Figure copy and recall), more irritability (Neuropsychological Inventory), and equivalent verbal memory (Philadelphia Verbal Learning Test). Compared to aAD, bvAD indicated more executive dysfunction (F-letter fluency) and better visuospatial performance. Neuroimaging analysis found that bvAD showed cortical thinning relative to bvFTD posteriorly in left temporal-occipital regions; bvFTD had cortical thinning relative to bvAD in left inferior frontal cortex. bvAD had cortical thinning relative to aAD in prefrontal and anterior temporal regions. All patient groups had lower volumes than controls in both anterior and posterior hippocampus. However, bvAD patients had higher average volume than aAD patients in posterior hippocampus and higher volume than bvFTD patients in anterior hippocampus after adjustment for age and intracranial volume. CONCLUSION: Findings demonstrated that underlying pathology mediates disease presentation in bvAD and bvFTD.
Author Keywords
frontal variant; Alzheimer’s disease; behavioral; behavioral variant frontotemporal dementia; cognitive domains; cortical thinning; hippocampal volumes; neuropsychiatric symptoms
Document Type: Article
Publication Stage: Final
Source: Scopus
MRI-guided laser interstitial thermal therapy for deep-seated gliomas in children with neurofibromatosis type 1: report of two cases
(2022) Child’s Nervous System, .
Cross, K.A.a , Salehi, A.b , Abdelbaki, M.S.c , Gutmann, D.H.d , Limbrick, D.D., Jr.e
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b Division of Pediatric Neurosurgery, Department of Neurological Surgery, University of Nebraska Medical Center, Omaha Children’s Hospital Medical Center, Omaha, NE, United States
c Division of Hematology and Oncology, Department of Pediatrics, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Division of Pediatric Neurosurgery, Department of Neurological Surgery, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Purpose: Nearly a quarter of neurofibromatosis type 1 (NF 1)- associated diencephalic low-grade tumors are refractory to chemotherapy. Addition of alternative treatment options with laser interstitial thermal therapy will have a positive impact on the outcome of these patients. Methods: We report on two illustrated cases of pediatric NF1- associated, chemoresistant, WHO grade 1 pilocytic astrocytomas treated with laser interstitial thermal therapy (LITT). Results: Both tumors responded favorably to LITT. Conclusion: LITT should be considered as a treatment option for chemoresistant deep-seated NF1-associated low-grade gliomas. © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
Author Keywords
Deep-seated gliomas; Laser interstitial thermal therapy; Neurofibromatosis type 1; Thalamic tumors
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A Randomized Controlled Trial for Audiovisual Multisensory Perception in Autistic Youth
(2022) Journal of Autism and Developmental Disorders, .
Feldman, J.I.a b , Dunham, K.c d , DiCarlo, G.E.c e f , Cassidy, M.g h , Liu, Y.g i , Suzman, E.j k , Williams, Z.J.b c d f , Pulliam, G.g , Kaiser, S.l , Wallace, M.T.b c d m n o p , Woynaroski, T.G.a b c m
a Department of Hearing and Speech Sciences, Vanderbilt University Medical Center, MCE 8310 South Tower, 1215 21st Avenue South, Nashville, TN 37232, United States
b Frist Center for Autism & Innovation, Vanderbilt University, Nashville, TN, United States
c Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, United States
d Department of Hearing and Speech Sciences, Vanderbilt University, Nashville, TN, United States
e Mass General Brigham Neurology Residency Program, Harvard Medical School, Boston, MA, United States
f Medical Scientist Training Program, Vanderbilt University, Nashville, TN, United States
g Neuroscience Undergraduate Program, Vanderbilt University, Nashville, TN, United States
h National Institutes of Health, Bethesda, MD, United States
i Washington University School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
j Master’s Program in Biomedical Science, Vanderbilt University, Nashville, TN, United States
k Southwestern School of Medicine, University of Texas, Dallas, TX, United States
l Cognitive Studies Undergraduate Program, Vanderbilt University, Nashville, TN, United States
m Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, United States
n Department of Psychology, Vanderbilt University, Nashville, TN, United States
o Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, United States
p Department of Pharmacology, Vanderbilt University, Nashville, TN, United States
Abstract
Differences in audiovisual integration are commonly observed in autism. Temporal binding windows (TBWs) of audiovisual speech can be trained (i.e., narrowed) in non-autistic adults; this study evaluated a computer-based perceptual training in autistic youth and assessed whether treatment outcomes varied according to individual characteristics. Thirty autistic youth aged 8–21 were randomly assigned to a brief perceptual training (n = 15) or a control condition (n = 15). At post-test, the perceptual training group did not differ, on average, on TBWs for trained and untrained stimuli and perception of the McGurk illusion compared to the control group. The training benefited youth with higher language and nonverbal IQ scores; the training caused widened TBWs in youth with co-occurring cognitive and language impairments. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author Keywords
audiovisual integration; autism spectrum disorder; multisensory integration; perceptual training; temporal binding window
Funding details
DGE 19-22697
National Institutes of HealthNIHU54 HD083211
National Institute on Deafness and Other Communication DisordersNIDCDR21 DC016144
Nancy Lurie Marks Family FoundationNLMFF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A novel, likely pathogenic variant in UBTF-related neurodegeneration with brain atrophy is associated with a severe divergent neurodevelopmental phenotype
(2022) Molecular Genetics and Genomic Medicine, .
Tinker, R.J.a , Guess, T.b , Rinker, D.C.c , Sheehan, J.H.d , Lubarsky, D.a , Porath, B.b , Mosera, M.a , Mayo, P.b , Solem, E.b , Lee, L.A.b , Sharam, A.e , Brault, J.a
a Division of Medical Genetics and Genomic Medicine, Vanderbilt University Medical Center, Nashville, TN, United States
b Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, United States
c Department of Biological Sciences, Vanderbilt University, Nashville, TN, United States
d Department of Internal Medicine, Division of Infectious Diseases, Washington University School of Medicine, St. Louis, MO, United States
e Department of Radiology, Vanderbilt University Medical Center, Nashville, TN, United States
Abstract
Background: A de novo, pathogenic, missense variant in UBTF, c.628G>A p.Glu210Lys, has been described as the cause of an emerging neurodegenerative disorder, Childhood-Onset Neurodegeneration with Brain Atrophy (CONDBA). The p.Glu210Lys alteration yields a positively charged stretch of three lysine residues. Functional studies confirmed this change results in a stronger interaction with negatively charged DNA and gain-of-function activity when compared to the wild-type sequence. The CONDBA phenotype reported in association with p.Glu210Lys consists of normal early-neurodevelopment followed by progressive motor, cognitive, and behavioral regression in early-to-middle childhood. Methods and Results: The current proband presented at 9 months of age with baseline developmental delay and more extensive neuroradiological findings, including pontine hypoplasia, thalamic volume loss and signal abnormality, and hypomyelination. Like the recurrent CONDBA p.Glu210Lys variant, this novel variant, c.608A>G p.(Gln203Arg) lies within the highly conserved second HMG-box homology domain and involves the replacement of the wild-type residue with a positively charged residue, arginine. Computational structural modeling demonstrates that this amino acid substitution potentiates the interaction between UBTF and DNA, likely resulting in a gain-of-function effect for the UBTF protein, UBF. Conclusion: Here we present a new divergent phenotype associated with a novel, likely pathogenic, missense variant at a different position in the UBTF gene, c.608A>G p.(Gln203Arg). © 2022 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.
Author Keywords
CONDBA; UBTF; whole exome sequencing
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Genome-wide meta-analysis for Alzheimer’s disease cerebrospinal fluid biomarkers
(2022) Acta Neuropathologica, .
Jansen, I.E.a b c , van der Lee, S.J.a b d , Gomez-Fonseca, D.e f g , de Rojas, I.h i , Dalmasso, M.C.j k , Grenier-Boley, B.l , Zettergren, A.m , Mishra, A.n , Ali, M.e f g , Andrade, V.j o , Bellenguez, C.l , Kleineidam, L.j o p , Küçükali, F.q r , Sung, Y.J.e f g , Tesí, N.a b d , Vromen, E.M.a b , Wightman, D.P.c , Alcolea, D.i s , Alegret, M.h i , Alvarez, I.t u , Amouyel, P.l , Athanasiu, L.v , Bahrami, S.v , Bailly, H.w , Belbin, O.i s , Bergh, S.x y , Bertram, L.z , Biessels, G.J.aa , Blennow, K.ab ac , Blesa, R.i s , Boada, M.h i , Boland, A.ad , Buerger, K.ae af , Carracedo, Á.ag ah , Cervera-Carles, L.i s , Chene, G.n ai , Claassen, J.A.H.R.aj ak , Debette, S.n ai al , Deleuze, J.-F.ad , de Deyn, P.P.am , Diehl-Schmid, J.an ao , Djurovic, S.ap aq , Dols-Icardo, O.i s , Dufouil, C.n ar , Duron, E.as , Düzel, E.at au , Fladby, T.av aw , Fortea, J.i s , Frölich, L.ax , García-González, P.h i , Garcia-Martinez, M.ay , Giegling, I.az , Goldhardt, O.an , Gobom, J.ac , Grimmer, T.an , Haapasalo, A.ba , Hampel, H.bb bc , Hanon, O.w bd , Hausner, L.ax , Heilmann-Heimbach, S.be , Helisalmi, S.bf , Heneka, M.T.o p , Hernández, I.h i , Herukka, S.-K.bg , Holstege, H.a b d , Jarholm, J.bh , Kern, S.m bi , Knapskog, A.-B.bj , Koivisto, A.M.bg bk bl , Kornhuber, J.bm , Kuulasmaa, T.bn , Lage, C.ay bo , Laske, C.bp bq , Leinonen, V.br bs , Lewczuk, P.bm bt , Lleó, A.i s , de Munain, A.L.i bu bv bw , Lopez-Garcia, S.ay , Maier, W.o , Marquié, M.h i , Mol, M.O.bz , Montrreal, L.h , Moreno, F.i bu bv , Moreno-Grau, S.h i , Nicolas, G.by , Nöthen, M.M.be , Orellana, A.h i , Pålhaugen, L.av aw , Papma, J.M.bz , Pasquier, F.l , Perneczky, R.ae ca cb cc , Peters, O.at cd , Pijnenburg, Y.A.L.a b , Popp, J.ce cf , Posthuma, D.c , Pozueta, A.ay , Priller, J.cd cg ch , Puerta, R.h , Quintela, I.ag , Ramakers, I.ci , Rodriguez-Rodriguez, E.ay , Rujescu, D.az , Saltvedt, I.cj ck , Sanchez-Juan, P.cl , Scheltens, P.a b , Scherbaum, N.cm , Schmid, M.cn , Schneider, A.o p , Selbæk, G.y av bj , Selnes, P.aw , Shadrin, A.v , Skoog, I.m bi , Soininen, H.bg , Tárraga, L.h i , Teipel, S.co cp , Tijms, B.a b , Tsolaki, M.cq , Van Broeckhoven, C.r cr , Van Dongen, J.q r , van Swieten, J.C.bz , Vandenberghe, R.cs ct , Vidal, J.-S.w , Visser, P.J.a b cu cv , Vogelgsang, J.cw cx , Waern, M.m cy , Wagner, M.o p , Wiltfang, J.cw cz da , Wittens, M.M.J.r db , Zetterberg, H.ab ac dc dd de , Zulaica, M.i bu bv , van Duijn, C.M.bx df , Bjerke, M.r db dg , Engelborghs, S.r db dg dh , Jessen, F.p di dj , Teunissen, C.E.b dk , Pastor, P.dl , Hiltunen, M.dm , Ingelsson, M.dn do dp , Andreassen, O.A.v dq , Clarimón, J.i s , Sleegers, K.q r , Ruiz, A.h i , Ramirez, A.j o p dj dr , Cruchaga, C.e f g , Lambert, J.-C.l , van der Flier, W.a b , EADB consortiumds , The GR@ACE study groupds
a Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, Netherlands
b Amsterdam Neuroscience, Neurodegeneration, Amsterdam, Netherlands
c Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU Amsterdam, Amsterdam, Netherlands
d Section Genomics of Neurodegenerative Diseases and Aging, Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, Amsterdam, Netherlands
e Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
f NeuroGenomics and Informatics, Washington University School of Medicine, St Louis, MO, United States
g Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
h Research Center and Memory Clinic, Ace Alzheimer Center Barcelona, Universitat Internacional de Catalunya, Barcelona, Spain
i CIBERNED, Network Center for Biomedical Research in Neurodegenerative Diseases, National Institute of Health Carlos III, Madrid, Spain
j Division of Neurogenetics and Molecular Psychiatry, Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
k Neurosciences and Complex Systems Unit (ENyS), CONICET, Hospital El Cruce, National University A. Jauretche (UNAJ), Florencio Varela, Argentina
l Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 – RID-AGE / Labex DISTALZ – Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement, Lille, F-59000, France
m Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden
n University of Bordeaux, Inserm, Bordeaux Population Health Research Center, Team VINTAGE, UMR 1219, Bordeaux, 33000, France
o Department of Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Medical Faculty, Bonn, Germany
p German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
q Complex Genetics of Alzheimer’s Disease Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
r Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
s Sant Pau Memory Unit, Department of Neurology, Institut d’Investigacions Biomèdiques Sant Pau – Hospital de Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain
t Memory Disorders Unit, Department of Neurology, Hospital Universitari Mutua de Terrassa, Terrassa, Spain
u Fundació per a la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Spain
v NORMENT Centre, Institute of Clinical Medicine, University of Oslo and Division of Mental Health, Oslo, Norway
w Université Paris Cité, EA4468, Maladie d’Alzheimer, F-75013 Paris, France
x The Research-Centre for Age-Related Functional Decline and Disease, Innlandet Hospital Trust, Brumunddal, Norway
y Norwegian National Centre for Ageing and Health, Vestfold Hospital Trust, Tønsberg, Norway
z Lübeck Interdisciplinary Platform for Genome Analytics, University of Lübeck, Lübeck, Germany
aa Department of Neurology, UMC Utrecht Brain Center, Utrecht, Netherlands
ab Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
ac Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
ad Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, Evry, 91057, France
ae German Center for Neurodegenerative Diseases (DZNE, Munich), Munich, Germany
af Institute for Stroke and Dementia Research (ISD), University Hospital, LMU Munich, Munich, Germany
ag Grupo de Medicina Xenómica, Centro Nacional de Genotipado (CEGEN-PRB3-ISCIII), Universidade de Santiago de Compostela, Santiago de Compostela, Spain
ah Fundación Pública Galega de Medicina Xenómica-CIBERER-IDIS, Santiago de Compostela, Spain
ai Department of Neurology, CHU de Bordeaux, Bordeaux, 33000, France
aj Radboudumc Alzheimer Center, Department of Geriatrics, Radboud University Medical Center, Nijmegen, Netherlands
ak Donders Center for Medical Neuroscience, Nijmegen, Netherlands
al Department of Neurology, Boston University School of Medicine, Boston, MA 2115, United States
am Department of Neurology and Alzheimer Center Groningen, University Medical Center Groningen, Groningen, Netherlands
an Center for Cognitive Disorders, Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany
ao kbo-Inn-Salzach-Hospital, Wasserburg am Inn, Germany
ap Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
aq Department of Clinical Science, NORMENT Centre, University of Bergen, Bergen, Norway
ar Pôle de Santé Publique Centre Hospitalier Universitaire (CHU) de Bordeaux, Bordeaux, France
as Univerisité Paris-Saclay. Inserm 1178 MOODS, Paris, France
at German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
au Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, Magdeburg, Germany
av Institute of Clinical Medicine, University of Oslo, Oslo, Norway
aw Department of Neurology, Akershus University Hospital, Lorenskog, Norway
ax Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg, Germany
ay Cognitive Impairment Unit, Neurology Service, “Marqués de Valdecilla” University Hospital, Institute for Research “Marques de Valdecilla” (IDIVAL), University of Cantabria, Santander, Spain, and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
az Division of General Psychiatry, Department of Psychiatry and Psychotherapy, Medical University of Vienna, Vienna, Austria
ba A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
bb Alzheimer Precision Medicine (APM), Sorbonne University, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
bc Neurology Business Group, Eisai Inc, 100 Tice Blvd, Woodcliff Lake, NJ 07677, United States
bd Service gériatrie, Centre Mémoire de Ressources et Recherches Ile de France-Broca, AP-HP, Hôpital Broca, Paris, F-75013, France
be Institute of Human Genetics, University of Bonn, School of Medicine and University Hospital Bonn, Bonn, 53127, Germany
bf Institute of Clinical Medicine, Internal Medicine, University of Eastern Finland, Kuopio, Finland
bg Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
bh Department of Neurology, Akershus University Hospital, Lorenskog, Norway
bi Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Cognition and Old Age Psychiatry Clinic, Gothenburg, Sweden
bj Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway
bk Department of Neurology, Kuopio University Hospital, Kuopio, Finland
bl Department of Neurology, Helsinki University Hospital, Helsinki, Finland
bm Department of Psychiatry and Psychotherapy, Universitätsklinikum Erlangen, and Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
bn Bioinformatics Center, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
bo Atlantic Fellow at the Global Brain Health Institute (GBHI) -, University of California, San Francisco, United States
bp German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
bq Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
br Institute of Clinical Medicine, Neurosurgery, University of Eastern Finland, Kuopio, Finland
bs Department of Neurosurgery, Kuopio University Hospital, Kuopio, Finland
bt Department of Neurodegeneration Diagnostics, Medical University of Białystok, Białystok, Poland
bu Hospital Universitario Donostia-OSAKIDETZA, Donostia, Spain
bv Instituto Biodonostia, San Sebastián, Spain
bw University of The Basque Country, San Sebastian, Spain
bx Department of Epidemiology, ErasmusMC, Rotterdam, Netherlands
by Department of Genetics and CNR-MAJ, Normandie Univ, UNIROUEN, Inserm U1245 and CHU Rouen, Rouen, France
bz Department of Neurology and Alzheimer Center Erasmus MC, Erasmus MC University Medical Center, Rotterdam, Netherlands
ca Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Munich, Germany
cb Munich Cluster for Systems Neurology (SyNergy) Munich, Munich, Germany
cc Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, United Kingdom
cd German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
ce Department of Geriatric Psychiatry, University Hospital of Psychiatry Zürich and University of Zürich, Zurich, Switzerland
cf Old Age Psychiatry, Department of Psychiatry, University Hospital of Lausanne, Lausanne, Switzerland
cg Department of Psychiatry and Psychotherapy, Charité, Charitéplatz 1, Berlin, 10117, Germany
ch Department of Psychiatry and Psychotherapy, Klinikum rechts der isar, Technical University Munich, Munich, 81675, Germany
ci Department of Psychiatry and Neuropsychologie, Alzheimer Center Limburg, Maastricht University, Maastricht, Netherlands
cj Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
ck Department of Geriatrics, St Olav Hospital, University Hospital of Trondheim, Trondheim, Norway
cl Alzheimer’s Centre Reina Sofia-CIEN Foundation-ISCIII, Madrid, 28031, Spain
cm Department of Psychiatry and Psychotherapy, Medical Faculty, LVR-Hospital Essen, University of Duisburg-Essen, Essen, Germany
cn Institute of Medical Biometry, Informatics and Epidemiology, University Hospital of Bonn, Bonn, Germany
co German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany
cp Department of Psychosomatic Medicine, Rostock University Medical Center, Gehlsheimer Str. 20, Rostock, 18147, Germany
cq 1st Department of Neurology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Makedonia, Thessaloniki, Greece
cr Neurodegenerative Brain Diseases Group, VIB Center for Molecular Neurology, VIB, Antwerp, Belgium
cs Neurology, University Hospitals Leuven, Leuven, Belgium
ct Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute, Leuven, Belgium
cu Alzheimer Center Limburg, School for Mental Health and Neuroscience Maastricht University, Maastricht, Netherlands
cv Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics Karolinska Institutet, Stockholm, Sweden
cw Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Göttingen, Germany
cx Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, MA, United States
cy Region Västra Götaland, Sahlgrenska University Hospital, Psychiatry, Psychosis Clinic, Gothenburg, Sweden
cz German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany
da Medical Science Department, iBiMED, Aveiro, Portugal
db Center for Neurosciences (C4N), Vrije Universiteit Brussel, Brussels, Belgium
dc Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom
dd UK Dementia Research Institute at UCL, London, United Kingdom
de Hong Kong Center for Neurodegenerative Diseases, Hong Kong
df Nuffield Department of Population Health, Oxford University, Oxford, United Kingdom
dg Laboratory of Neurochemistry, Universitair Ziekenhuis Brussel, Brussels, Belgium
dh Department of Neurology, Universitair Ziekenhuis Brussel, Brussels, Belgium
di Department of Psychiatry and Psychotherapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
dj Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
dk Neurochemistry Lab, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, Netherlands
dl Unit of Neurodegenerative diseases, Department of Neurology, University Hospital Germans Trias i Pujol and The Germans Trias i Pujol Research Institute (IGTP) Badalona, Barcelona, Spain
dm Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
dn Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden
do Krembil Brain Institute, University Health Network, Toronto, ON, Canada
dp Department of Medicine and Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada
dq Addiction, Oslo University Hospital, Oslo, 0407, Norway
dr Department of Psychiatry, Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, United States
Abstract
Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. © 2022, The Author(s).
Author Keywords
Alzheimer’s disease; Amyloid-beta; Cerebrospinal fluid; GWAS; Tau
Funding details
Fondation pour la Recherche sur Alzheimer
Alzheimer’s AssociationAAZEN-21-848495
JPND2019-466-236
Deutsche ForschungsgemeinschaftDFGRA 1971/8-1, RA 1971/6-1, RA1971/7-1
ALF 716681
European Regional Development FundERDF
Academy of FinlandAKA338182
Chan Zuckerberg InitiativeCZI
PI17/01474, 115975, PI19/01301, 115985, PI19/01240, PI16/01861, PI13/02434
2020-04-13, 2021-04-17
Bundesministerium für Bildung und ForschungBMBF
H2020 Marie Skłodowska-Curie ActionsMSCA860197
VetenskapsrådetVR11267, 2013-8717, 2019-01096, 2017-00639, 2015-02830, 825-2012-5041
AlzheimerfondenAF-939988, AF-646061, AF-741361, AF-930582
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO024.004.012
FO2016-0214, FO2018-0214, FO2019- 0163
UK Dementia Research InstituteUK DRI2017-0243, 2017-00915, -201809-2016615, -742881
National Institutes of HealthNIHRF1AG058501, U01AG058922, R01AG064614, RF1AG053303, R01AG044546, R01AG064877, R01AG058501
National Institutes of HealthNIH1R01AG068398-01
Forskningsrådet om Hälsa, Arbetsliv och VälfärdFORTE2004-0145, 2008-1229, 2006-0596, 2001-2849, 2005-0762, 2013-1202, 2013-2300, 2001-2835, 2010-0870, 2001-2646, 2013-2496, 2008-1111, 2006-0020, 2004-0150, 2008-1210, 2003-0234, 2012-1138
Fonds Wetenschappelijk OnderzoekFWO
01G10102, 01GI0420, 04GI0434, 01GI0711, 01GI0423, 01GI0431, 01GI0422, 01GI0433, 01GI0429
Alzheimer’s AssociationAA2019-02075, IIRG-00-2159, AF-737641, AF-939825, IIRG-09-131338, ZEN-01-3151, ALFGBG-81392, IIRG-03-6168, AF-842471, 2016-01590, ALF GBG-771071
-715986
Centro de Investigación Biomédica en Red sobre Enfermedades NeurodegenerativasCIBERNED
Universiteit Antwerpen
Horizon 2020 Framework ProgrammeH2020
EU Joint Programme – Neurodegenerative Disease ResearchJPND301220
Deutsche ForschungsgemeinschaftDFG
Instituto de Salud Carlos IIIISCIII
European Regional Development FundERDFP30AG066444, P01AG003991, FI20/00215
Bundesministerium für Bildung und ForschungBMBF01ED1619A
Bijzonder Onderzoeksfonds UGentBOFPI12/02288, PI08/0139, PI16/01652, PI11/03028, PI20/01011
ALFGBG-720931
Alzheimer’s Drug Discovery FoundationADDF201809-2016862
Hope Center for Neurological Disorders
European Research CouncilERC2018-02532, ERC-2018-AdG GWAS2FUNC 834057, 681712
Fonds Wetenschappelijk OnderzoekFWO
Siemens Healthineers
Novartis
Eisai
Pfizer
Eisai
Eli Lilly and Company
Health~HollandLSH
Roche
20106
Eli Lilly and Company
Biogen
Servier
ZonMw
Nederlandse Organisatie voor Wetenschappelijk OnderzoekNWO
Seventh Framework ProgrammeFP7
GE Healthcare
Document Type: Article
Publication Stage: Article in Press
Source: Scopus