Scopus list of publications for July 9, 2023
Defining diurnal fluctuations in mouse choroid plexus and CSF at high molecular, spatial, and temporal resolution
(2023) Nature Communications, 14 (1), art. no. 3720, .
Fame, R.M.a l , Kalugin, P.N.a b c , Petrova, B.a , Xu, H.a , Soden, P.A.a , Shipley, F.B.a d , Dani, N.a , Grant, B.a , Pragana, A.a , Head, J.P.a , Gupta, S.a , Shannon, M.L.a , Chifamba, F.F.e f , Hawks-Mayer, H.e f , Vernon, A.g h i , Gao, F.g h i m , Zhang, Y.j , Holtzman, M.J.j , Heiman, M.g h i , Andermann, M.L.b d k , Kanarek, N.a i , Lipton, J.O.e f , Lehtinen, M.K.a b d i
a Department of Pathology, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, United States
b Graduate Program in Neuroscience, Harvard Medical School, Boston, MA 02115, United States
c Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, United States
d Graduate Program in Biophysics, Harvard University, Cambridge, MA 02138, United States
e Department of Neurology and the F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA 02115, United States
f Division of Sleep Medicine, Harvard Medical School, Boston, MA 02115, United States
g Department of Brain and Cognitive Sciences, MIT, Cambridge, MA, United States
h Picower Institute for Learning and Memory, Cambridge, MA, United States
i Broad Institute of MIT and Harvard, Cambridge, MA, United States
j Pulmonary and Critical Care Medicine, Department of Medicine, Washington University, St. Louis, MO 63110, United States
k Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, United States
l Department of Neurosurgery, Stanford University, Stanford, CA 94305, United States
m Lyterian Therapeutics, South San Francisco, CA 94080, United States
Abstract
Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene expression. We achieved real-time tracking of CSF-TTR in awake Ttr mNeonGreen mice via multi-day intracerebroventricular fiber photometry. Diurnal changes in ChP and CSF TTR levels correlated with CSF thyroid hormone levels. These datasets highlight an integrated platform for investigating diurnal control of brain states by the ChP and CSF. © 2023, The Author(s).
Funding details
F30 DK131642, T32 HL007901
National Institutes of HealthNIHT32 HL110852
National Institute of General Medical SciencesNIGMSDoD W81XWH-18-1-0194, R01 HL151368, R01-AI130591, R35-HL145242, T32 GM007753, T32 GM144273
New York Stem Cell FoundationNYSCF1U54HD090255
JPB FoundationJPBFOT2-OD030544, U2C-DK119886
Human Frontier Science ProgramHFSP0063/2018, R01 NS088566, RF1 DA048790
State Key Laboratory of Structural Analysis for Industrial EquipmentSAIL
Document Type: Article
Publication Stage: Final
Source: Scopus
Neurocognitive basis of model-based decision making and its metacontrol in childhood
(2023) Developmental Cognitive Neuroscience, 62, art. no. 101269, .
Smid, C.R.a , Ganesan, K.a , Thompson, A.a , Cañigueral, R.a , Veselic, S.b c , Royer, J.d , Kool, W.e , Hauser, T.U.c f , Bernhardt, B.d , Steinbeis, N.a
a Department of Psychology and Language Sciences, University College London, United Kingdom
b Clinical and Movement Neurosciences, Department of Motor Neuroscience, University College London, United Kingdom
c Wellcome Centre for Human Neuroimaging, University College London, United Kingdom
d McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal, Canada
e Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
f Max Planck University College London Centre for Computational Psychiatry and Ageing Research, United Kingdom
Abstract
Human behavior is supported by both goal-directed (model-based) and habitual (model-free) decision-making, each differing in its flexibility, accuracy, and computational cost. The arbitration between habitual and goal-directed systems is thought to be regulated by a process known as metacontrol. However, how these systems emerge and develop remains poorly understood. Recently, we found that while children between 5 and 11 years displayed robust signatures of model-based decision-making, which increased during this developmental period, there were substantial individual differences in the display of metacontrol. Here, we inspect the neurocognitive basis of model-based decision-making and metacontrol in childhood and focus this investigation on executive functions, fluid reasoning, and brain structure. A total of 69 participants between the ages of 6–13 completed a two-step decision-making task and an extensive behavioral test battery. A subset of 44 participants also completed a structural magnetic resonance imaging scan. We find that individual differences in metacontrol are specifically associated with performance on an inhibition task and individual differences in thickness of dorsolateral prefrontal, temporal, and superior-parietal cortices. These brain regions likely reflect the involvement of cognitive processes crucial to metacontrol, such as cognitive control and contextual processing. © 2023 The Authors
Author Keywords
Childhood; Cortical thickness; Metacontrol; Model-based decision-making; Reinforcement learning
Funding details
NI17-039
Centre Azrieli de recherche sur l’autisme, Institut et Hôpital Neurologiques de MontréalCARA
Canadian Institutes of Health ResearchIRSCFDN-154298, PJT-174995
Natural Sciences and Engineering Research Council of CanadaNSERC1304413
Fonds de Recherche du Québec – SantéFRQS
Economic and Social Research CouncilESRC211155/Z/18/B, 211155/Z/18/Z, 224051/Z/21, ES/V013505/1
Leverhulme TrustPLP-2021-040
European Research CouncilERC715282
Max-Planck-GesellschaftMPG
Horizon 2020946055
Medical Research Foundation
Document Type: Article
Publication Stage: Final
Source: Scopus
Demographic Features and Clinical Course of Patients With Pediatric-Onset Multiple Sclerosis on Newer Disease-Modifying Treatments
(2023) Pediatric Neurology, 145, pp. 125-131.
Malani Shukla, N.a , Casper, T.C.b , Ness, J.c , Wheeler, Y.c , Chitnis, T.d , Lotze, T.a , Gorman, M.e , Benson, L.e , Weinstock-Guttmann, B.f , Aaen, G.g , Rodriguez, M.h , Tillema, J.-M.h , Krupp, L.i , Schreiner, T.j , Mar, S.k , Goyal, M.k , Rensel, M.l , Abrams, A.l , Rose, J.m , Waltz, M.b , Liu, T.n , Manlius, C.n , Waubant, E.o , U.S. Network of Pediatric Multiple Sclerosis Centersp
a Baylor College of Medicine/Texas Children’s Hospital, Neurology and Developmental Neuroscience, Houston, Texas, United States
b Department of Pediatrics, University of Utah, Salt Lake City, Utah, United States
c Center for Pediatric-Onset Demyelinating Disease, Children’s Hospital of Alabama, Birmingham, Alabama, United States
d Mass General Brigham Pediatric MS Center, Massachusetts General Hospital for Children, Yawkey Center for Outpatient Care, Boston, Massachusetts, United States
e Pediatric Multiple Sclerosis and Related Disorders Program, Boston Children’s Hospital, Department of Neurology, Boston, Massachusetts, United States
f Pediatric MS Center of the Jacobs Neurological Institute, Buffalo, New York, United States
g Pediatric Multiple Sclerosis Center at Loma Linda University Children’s Hospital, San Bernardino, California, United States
h Pediatric MS Center, Mayo Clinic, Rochester, Minnesota, United States
i New York University Langone Medical Center, Pediatric Multiple Sclerosis Center, New York, New York, United States
j Rocky Mountain MS Center, University of Colorado, Aurora, Colorado, United States
k Pediatric MS and other Demyelinating Disease Center, Washington University, St. Louis, Missouri, United States
l Cleveland Clinic, Mellen Center for Multiple Sclerosis, Cleveland, Ohio, United States
m Department of Neurology, University of Utah, Salt Lake City, Utah, United States
n F. Hoffmann-La Roche Ltd, Basel, Switzerland
o UCSF, Weill Institute for Neurosciences, San Francisco, California, United States
Abstract
Background: Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Our objective was to describe the demographic features and clinical and radiologic course of patients with POMS treated with the commonly used newer DMTs within the US Network of Pediatric MS Centers (NPMSC). Methods: This is an analysis of prospectively collected data from patients who initiated treatment before age 18 with the DMTs listed below at the 12 regional pediatric MS referral centers participating in the NPMSC. Results: One hundred sixty-eight patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2 to 16.5 years. Disease duration at the time of initiation of index DMT ranged from 1.1 to 1.6 years with treatment duration of 0.9-2.0 years. Mean annualized relapse rate (ARR) in the year prior to initiating index DMT ranged from 0.4 to 1.0. Mean ARR while on index DMT ranged from 0.05 to 0.20. New T2 and enhancing lesions occurred in 75%-88% and 55%-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 0%-46% and 11%-34% patients, respectively. Rates of NEDA-2 (no evidence of disease activity) ranged from 76% to 91% at 6 months of treatment with index DMTs and 66% to 84% at 12 months of treatment with index DMTs. Conclusions: Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit, as well as high rates of NEDA-2, in a large number of POMS patients, which can be used to guide future studies in this population. © 2023 Elsevier Inc.
Author Keywords
Disease-modifying treatment; Multiple sclerosis; Pediatric demyelinating disease; Pediatric multiple sclerosis
Document Type: Article
Publication Stage: Final
Source: Scopus
The relation of food insecurity to eating disorder characteristics and treatment-seeking among adult respondents to the National Eating Disorders Association online screen
(2023) Eating Behaviors, 50, art. no. 101776, .
Laboe, A.A.a , D’Adamo, L.a b , Grammer, A.C.a , McGinnis, C.G.a , Davison, G.M.a , Balantekin, K.N.c , Graham, A.K.d , Smolar, L.e , Taylor, C.B.f g , Wilfley, D.E.a , Fitzsimmons-Craft, E.E.a
a Department of Psychiatry, Washington University School of Medicine, Mailstop 8134-29-2100, 660 S. Euclid Ave., St. Louis, MO 63110, United States
b Department of Psychological and Brain Sciences, Center for Weight, Eating, and Lifestyle Science (WELL Center), Drexel University, 3201 Chestnut St., Philadelphia, PA 19104, United States
c Department of Exercise and Nutrition Sciences, School of Public Health and Health Professions, University at Buffalo, Buffalo, NY 14214, United States
d Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
e National Eating Disorders Association, New York, NY, United States
f Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 401 Quarry Road, Stanford, CA 94305, United States
g Center for m<sup>2</sup>Health, Palo Alto University, 5150 El Camino Real, Los Altos, CA 94022, United States
Abstract
Background: Food insecurity (FI), characterized by limited or uncertain access to adequate food, has been associated with eating disorders (EDs). This study explored whether FI was associated with ED behaviors, ED diagnosis, current treatment status, and treatment-seeking intentions among adults who completed an online ED screen. Methods: Respondents to the National Eating Disorders Association online screening tool self-reported demographics, FI, height and weight, past 3-month ED behaviors, and current treatment status. Respondents were also asked an optional question about treatment-seeking intentions. Hierarchical regressions evaluated relations between FI and ED behaviors, treatment status, and treatment-seeking intentions. Logistic regressions explored differences in probable ED diagnosis by FI status. Results: Of 8714 respondents, 25 % screened at risk for FI. FI was associated with greater binge eating (R2Change = 0.006), laxative use (R2Change = 0.001), and presence of dietary restriction (R2Change = 0.001, OR: 1.32) (ps <.05). Having FI was associated with greater odds of screening positive for a probable ED or as high risk for an ED (ps <.05). FI was not associated with current treatment status or treatment-seeking intentions (ps >.05). Conclusions: Findings add to existing literature supporting a relation between FI and EDs. Implications include a need to disseminate EDs screening and treatment resources to populations affected by FI and to tailor treatments to account for barriers caused by FI. © 2023 Elsevier Ltd
Author Keywords
Eating disorders; Food insecurity; Mental health screening; Treatment-seeking
Funding details
National Institutes of HealthNIHF31 HD106750, F31 HL158000, K01 DK116925, K01 DK120778, K08 MH120341, T32 HL130357
Document Type: Article
Publication Stage: Final
Source: Scopus
Targeting miR-223 enhances myeloid-derived suppressor cell suppressive activities in multiple sclerosis patients
(2023) Multiple Sclerosis and Related Disorders, 76, art. no. 104839, .
Cantoni, C.a , Ghezzi, L.b c d , Choi, J.b , Cross, A.H.b , Piccio, L.b e
a Department of Translational Neuroscience, Barrow Neurological Institute, Phoenix, AZ 85013, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Biomedical, Surgical and Dental Sciences, University of Milan, Milan, 20122, Italy
d Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, 20122, Italy
e Charles Perkins Centre, School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia
Abstract
Background: Multiple sclerosis (MS) is an incurable autoimmune inflammatory demyelinating disease of the central nervous system. Several MS medications can modify disease course through effects on adaptive immune cells, while drugs targeting innate immunity are under investigation. Myeloid-derived suppressor cells (MDSCs) which arise during chronic inflammation, are defined by their T-cell immunosuppressive functions. MiR-223 modulates myeloid cell maturation and expansion, including MDSCs. Methods: MDSCs isolated from healthy controls (HC) and people with MS (pwMS) were co-cultured with CD4+ T-cells to study their immunosuppressive activities in vitro. Cytokines and chemokines concentration were evaluated by Luminex assay in the serum of HC, pwMS, and other neuroinflammatory diseases and correlated with MDSC activities. Results: MDSC suppressive functions are dysregulated in pwMS compared to HC, which was reversed by glucocorticoids (GC). GC specifically downregulated miR-223 levels in MDSCs and increased the expression of STAT3. In vitro assay showed that miR-223 inhibition enhanced MDSC suppressive activity, STAT3 dependently. By multiple linear regression analysis, we demonstrated that MDSC phosphorylated STAT3 was correlated with serum GM-CSF in HC and pwMS. Conclusions: These results suggest that miR-223 could be a therapeutic target for enhancing MDSC’s suppressive activities as an alternative to GC. © 2023
Author Keywords
Glucocorticoids; miR-223; Multiple sclerosis; Myeloid-derived suppressor cells; Neuroinflammation
Funding details
C06RR014513
National Institutes of HealthNIHWLC6313040077
U.S. Department of DefenseDODMS200066
National Cancer InstituteNCI30 CA091842
National Multiple Sclerosis SocietyNMSSTA-1805–31003
Foundation for Barnes-Jewish HospitalFBJH
Associazione Italiana Sclerosi MultiplaAISMFG-1907–34474, FISM 2018/B/1, R01 AG058501, R01 NS102633–01
Barrow Neurological FoundationBNF
Document Type: Article
Publication Stage: Final
Source: Scopus
Demographics and baseline disease characteristics of Black and Hispanic patients with multiple sclerosis in the open-label, single-arm, multicenter, phase IV CHIMES trial
(2023) Multiple Sclerosis and Related Disorders, 76, art. no. 104794, .
Williams, M.J.a , Okai, A.F.b , Cross, A.H.c , Monson, N.L.d , Vartanian, T.e , Thrower, B.W.f , Reder, A.T.g , English, J.B.h , Wu, G.F.c , Bernitsas, E.i , Yap, S.j , Ndrio, J.j , Pei, J.j , Mowry, E.M.k , Magrini, F.j , Acosta, J.j , Amezcua, L.l , CHIMES investigatorsm
a Joi Life Wellness MS Center, 767 Concord Rd SE, Smyrna, GA 30082, United States
b North Texas Institute of Neurology and Headache, 6201 Dallas Pkwy, Plano, TX 75024, United States
c Washington University in St. Louis School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, United States
d University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, United States
e Weill Cornell Medical College, 1305 York Ave, New York, NY 10021, United States
f Andrew C. Carlos MS Institute, Shepherd Center, 2020 Peachtree Road, NW, Atlanta, GA 30309, United States
g University of Chicago Medicine, 5841 S Maryland Ave, Chicago, IL 60637, United States
h Atlanta Neuroscience Institute/Multiple Sclerosis Center of Atlanta, 3200 Downwood Cir NW, Atlanta, GA 30327, United States
i Wayne State University School of Medicine, 540 E Canfield St, Detroit, MI 48201, United States
j Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States
k Johns Hopkins Hospital, 600 N Wolfe St, Pathology 627, Baltimore, MD 21287, United States
l Keck School of Medicine, University of Southern California, 1975 Zonal Ave, Los Angeles, CA 90033, United States
Abstract
Background: Black/African American patients with multiple sclerosis (BpwMS) and Hispanic/Latino patients with multiple sclerosis (HpwMS), who historically have been underrepresented in multiple sclerosis (MS) clinical trials, exhibit greater disease severity and more rapid disease progression than White patients with MS (WpwMS). The lack of diversity and inclusion in clinical trials, which may be due to barriers at the system, patient and study levels, impacts the ability to effectively assess risks, benefits and treatment responses in a generalized patient population. Methods: CHIMES (Characterization of Ocrelizumab in Minorities With Multiple Sclerosis), an open-label, single-arm, multicenter, phase IV study of self-identified BpwMS and HpwMS aged 18–65 years with relapsing MS and an Expanded Disability Status Score (EDSS) of ≤5.5, was developed in collaboration with patients with MS, national advocacy groups and clinical researchers. Patients were enrolled at study centers across the US, including Puerto Rico, and 1 site in Kenya. Results: A total of 182 patients enrolled in CHIMES: 113 (62.1%) were BpwMS, and 69 (37.9%) were HpwMS; the mean (SD) baseline EDSS score was 2.4 (1.4), and 62.6% of patients were treatment naive. Using the pooled non–BpwMS/HpwMS group in the OPERA ocrelizumab trials as a reference population, patients enrolled in CHIMES were younger, had a higher mean body mass and had a greater T2 lesion volume but similar T2 lesion number on MRI. Conclusion: BpwMS and HpwMS have been consistently underrepresented in clinical trials, limiting the understanding of disease biology and response to treatment in this population. Data from the CHIMES study revealed differences in demographics and some baseline disease characteristics and disease burden between BpwMS and HpwMS vs WpwMS. These differences could have an impact when assessing clinical outcomes in BpwMS and HpwMS. Clinicaltrials.gov identifier: NCT04377555 © 2023 The Author(s)
Author Keywords
Disease-modifying therapy; Ethnicity; Ocrelizumab; Race; Relapsing multiple sclerosis
Funding details
F. Hoffmann-La Roche
Document Type: Article
Publication Stage: Final
Source: Scopus
Cardiovascular and metabolic health is associated with functional brain connectivity in middle-aged and older adults: Results from the Human Connectome Project-Aging study
(2023) NeuroImage, 276, art. no. 120192, .
Rashid, B.a b , Glasser, M.F.c , Nichols, T.d , Van Essen, D.c , Juttukonda, M.R.a b , Schwab, N.A.a b , Greve, D.N.a b , Yacoub, E.e , Lovely, A.a b , Terpstra, M.f , Harms, M.P.g , Bookheimer, S.Y.h , Ances, B.M.c g , Salat, D.H.a b , Arnold, S.E.a b
a Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, 149 13th St., Charlestown, MA 02129, United States
b Harvard Medical School, Boston, MA, United States
c Washington University School of Medicine, St. Louis, MO, United States
d University of Oxford, Oxford, United Kingdom
e Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States
f University of Minnesota, Minneapolis, MN, United States
g Washington University in St. Louis, St. Louis, MO, United States
h University of California, Los Angeles, Los Angeles, CA, United States
Abstract
Several cardiovascular and metabolic indicators, such as cholesterol and blood pressure have been associated with altered neural and cognitive health as well as increased risk of dementia and Alzheimer’s disease in later life. In this cross-sectional study, we examined how an aggregate index of cardiovascular and metabolic risk factor measures was associated with correlation-based estimates of resting-state functional connectivity (FC) across a broad adult age-span (36–90+ years) from 930 volunteers in the Human Connectome Project Aging (HCP-A). Increased (i.e., worse) aggregate cardiometabolic scores were associated with reduced FC globally, with especially strong effects in insular, medial frontal, medial parietal, and superior temporal regions. Additionally, at the network-level, FC between core brain networks, such as default-mode and cingulo-opercular, as well as dorsal attention networks, showed strong effects of cardiometabolic risk. These findings highlight the lifespan impact of cardiovascular and metabolic health on whole-brain functional integrity and how these conditions may disrupt higher-order network integrity. © 2023 The Author(s)
Author Keywords
Aging; Alzheimer’s disease; Cardiovascular risk; Functional connectivity; Resting-state fMRI
Funding details
National Institutes of HealthNIHU01AG052564 -S1, U19AG073585
National Institute on AgingNIAAG062421
Document Type: Article
Publication Stage: Final
Source: Scopus
Histidine-rich protein II nanoparticle delivery of heme iron load drives endothelial inflammation in cerebral malaria
(2023) Proceedings of the National Academy of Sciences of the United States of America, 120 (26), pp. e2306318120.
Nguyen, S.T.a b , Du, D.b , Wychrij, D.b , Cain, M.D.b , Wu, Q.b , Klein, R.S.b , Russo, I.b , Goldberg, D.E.b c
a Division of Infectious Diseases, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
b Division of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, United States
Abstract
Histidine-rich protein II (HRPII) is secreted by Plasmodium falciparum during the blood stage of malaria infection. High plasma levels of HRPII are associated with cerebral malaria, a severe and highly fatal complication of malaria. HRPII has been shown to induce vascular leakage, the hallmark of cerebral malaria, in blood-brain barrier (BBB) and animal models. We have discovered an important mechanism for BBB disruption that is driven by unique features of HRPII. By characterizing serum from infected patients and HRPII produced by P. falciparum parasites in culture, we found that HRPII exists in large multimeric particles of 14 polypeptides that are richly laden with up to 700 hemes per particle. Heme loading of HRPII is required for efficient binding and internalization via caveolin-mediated endocytosis in hCMEC/D3 cerebral microvascular endothelial cells. Upon acidification of endolysosomes, two-thirds of the hemes are released from acid-labile binding sites and metabolized by heme oxygenase 1, generating ferric iron and reactive oxygen species. Subsequent activation of the NLRP3 inflammasome and IL-1β secretion resulted in endothelial leakage. Inhibition of these pathways with heme sequestration, iron chelation, or anti-inflammatory drugs protected the integrity of the BBB culture model from HRPII:heme. Increased cerebral vascular permeability was seen after injection of young mice with heme-loaded HRPII (HRPII:heme) but not with heme-depleted HRPII. We propose that during severe malaria infection, HRPII:heme nanoparticles in the bloodstream deliver an overwhelming iron load to endothelial cells to cause vascular inflammation and edema. Disrupting this process is an opportunity for targeted adjunctive therapies to reduce the morbidity and mortality of cerebral malaria.
Author Keywords
blood–brain barrier; heme oxygenase; malaria pathogenesis
Document Type: Article
Publication Stage: Final
Source: Scopus
A comprehensive assay of social motivation reveals sex-specific roles of autism-associated genes and oxytocin
(2023) Cell Reports Methods, 3 (6), art. no. 100504, .
Maloney, S.E.a b , Sarafinovska, S.a c , Weichselbaum, C.a c , McCullough, K.B.a c , Swift, R.G.a c , Liu, Y.a c , Dougherty, J.D.a b c
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Intellectual and Developmental Disabilities Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Social motivation is critical to the development of typical social functioning. Social motivation, specifically one or more of its components (e.g., social reward seeking or social orienting), could be relevant for understanding phenotypes related to autism. We developed a social operant conditioning task to quantify effort to access a social partner and concurrent social orienting in mice. We established that mice will work for access to a social partner, identified sex differences, and observed high test-retest reliability. We then benchmarked the method with two test-case manipulations. Shank3B mutants exhibited reduced social orienting and failed to show social reward seeking. Oxytocin receptor antagonism decreased social motivation, consistent with its role in social reward circuitry. Overall, we believe that this method provides a valuable addition to the assessment of social phenotypes in rodent models of autism and the mapping of potentially sex-specific social motivation neural circuits. © 2023 The Authors
Author Keywords
autism; behavioral assay; CP: Neuroscience; mice; operant conditioning; oxytocin; sex differences; Shank3b; sociability; social motivation
Funding details
National Institute of Mental HealthNIMHR01MH107515-05, R01MH124808
Autism Science FoundationASF22-007
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50HD103525
Document Type: Article
Publication Stage: Final
Source: Scopus
Outcome measures for Alzheimer’s disease: A global inter-societal Delphi consensus
(2023) Alzheimer’s and Dementia, 19 (6), pp. 2707-2729.
Ellison, T.S.a , Cappa, S.F.b c , Garrett, D.d , Georges, J.e , Iwatsubo, T.f g , Kramer, J.H.h , Lehmann, M.i , Lyketsos, C.j , Maier, A.B.k l m n , Merrilees, J.h , Morris, J.C.o , Naismith, S.L.p , Nobili, F.q r , Pahor, M.s , Pond, D.t , Robinson, L.u , Soysal, P.v w , Vandenbulcke, M.x y , Weber, C.J.z , Visser, P.J.aa ab ac , Weiner, M.ad ae , Frisoni, G.B.af ag
a PharmaGenesis London, London, United Kingdom
b Scuola Universitaria Superiore IUSS Pavia, Pavia, Italy
c Dementia Research Center, IRCCS Mondino Foundation, Pavia, Italy
d Royal College of Nursing, London, United Kingdom
e Alzheimer Europe, Luxembourg, Luxembourg
f Unit for Early and Exploratory Clinical Development, The University of Tokyo Hospital, Tokyo, Japan
g Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
h Department of Neurology, Memory and Aging Center, University of California, San Francisco, CA, United States
i World Dementia Council, George, South Africa
j Richman Family Precision Medicine Center of Excellence in Alzheimer’s Disease, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University and Medicine, Baltimore, United States
k Department of Medicine and Aged Care, The Royal Melbourne Hospital, The University of Melbourne, Melbourne, VIC, Australia
l Faculty of Behavioural and Movement Sciences, Department of Human Movement Sciences, Vrije Universiteit, Amsterdam Movement Sciences, Amsterdam, Netherlands
m Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
n Centre for Healthy Longevity, National University Health System, Singapore, Singapore
o Department of Neurology, Washington University, St. Louis, MO, United States
p School of Psychology, The University of Sydney, Sydney, NSW, Australia
q UO Clinica Neurologica, Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Policlinico San Martino, Genova, Italy
r Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Child and Mother Health, University of Genoa, Genova, Italy
s Department of Aging and Geriatric Research, Institute on Aging, University of Florida College of Medicine, Gainesville, FL, United States
t Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
u Population Health Sciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
v Department of Geriatric Medicine, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
w European Society of Geriatric Medicine, Dementia Special Interest Group, Italy
x Neuropsychiatry, Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
y Geriatric Psychiatry, University Psychiatric Centre KU Leuven, Leuven, Belgium
z Alzheimer’s Association, Chicago, IL, United States
aa Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, Netherlands
ab Alzheimer Center, Department of Neurology, Neuroscience Campus Amsterdam, Amsterdam University Medical Center, VU Medical Center, Amsterdam, Netherlands
ac Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institute, Stockholm, Sweden
ad San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
ae Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States
af Laboratory of Neuroimaging of Aging (LANVIE), University of Geneva, Geneva, Switzerland
ag Memory Clinic, Department of Readaptation and Geriatrics, Geneva University and University Hospitals, Geneva, Switzerland
Abstract
Introduction: We aim to provide guidance on outcomes and measures for use in patients with Alzheimer’s clinical syndrome. Methods: A consensus group of 20 voting members nominated by 10 professional societies, and a non-voting chair, used a Delphi approach and modified GRADE criteria. Results: Consensus was reached on priority outcomes (n = 66), measures (n = 49) and statements (n = 37) across nine domains. A number of outcomes and measurement instruments were ranked for: Cognitive abilities; Functional abilities/dependency; Behavioural and neuropsychiatric symptoms; Patient quality of life (QoL); Caregiver QoL; Healthcare and treatment-related outcomes; Medical investigations; Disease-related life events; and Global outcomes. Discussion: This work provides indications on the domains and ideal pertinent measurement instruments that clinicians may wish to use to follow patients with cognitive impairment. More work is needed to develop instruments that are more feasible in the context of the constraints of clinical routine. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; consensus; Delphi; dementia; measures; outcomes
Funding details
F. Hoffmann-La Roche
Document Type: Article
Publication Stage: Final
Source: Scopus
Local and long-distance organization of prefrontal cortex circuits in the marmoset brain
(2023) Neuron, .
Watakabe, A.a b , Skibbe, H.c , Nakae, K.d e , Abe, H.a b , Ichinohe, N.a f , Rachmadi, M.F.c g , Wang, J.a , Takaji, M.a b , Mizukami, H.h , Woodward, A.i , Gong, R.i , Hata, J.j k , Van Essen, D.C.l , Okano, H.j m , Ishii, S.d , Yamamori, T.a b n
a Laboratory for Molecular Analysis of Higher Brain Function, RIKEN Center for Brain Science, Saitama, Wako, 351-0198, Japan
b Laboratory for Haptic Perception and Cognitive Physiology, RIKEN Center for Brain Science, Saitama, Wako, 351-0198, Japan
c Brain Image Analysis Unit, RIKEN Center for Brain Science, Saitama, Wako, 351-0198, Japan
d Integrated Systems Biology Laboratory, Department of Systems Science, Graduate School of Informatics, Kyoto University, Kyoto, Kyoto, 606-8501, Japan
e Exploratory Research Center on Life and Living Systems, National Institutes of Natural Sciences, Aichi, Okazaki, 444-8787, Japan
f Department of Ultrastructural Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Kodaira, 187-0031, Japan
g Faculty of Computer Science, Universitas Indonesia, Jawa Barat, Depok, 16424, Indonesia
h Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Tochigi, Shimotsuke, 329-0498, Japan
i Connectome Analysis Unit, RIKEN Center for Brain Science, Saitama, Wako, 351-0198, Japan
j Laboratory for Marmoset Neural Architecture, RIKEN Center for Brain Science, Saitama, Wako, 351-0198, Japan
k Graduate School of Human Health Sciences, Tokyo Metropolitan University, Tokyo, 116-8551, Japan
l Department of Neuroscience, Washington University School of Medicine, Saint Louis, MO 63110, United States
m Department of Physiology, Keio University School of Medicine, Tokyo, 108-8345, Japan
n Department of Marmoset Biology and Medicine, Central Institute for Experimental Animals, Kanagawa, Kawasaki, 210-0821, Japan
Abstract
The prefrontal cortex (PFC) has dramatically expanded in primates, but its organization and interactions with other brain regions are only partially understood. We performed high-resolution connectomic mapping of the marmoset PFC and found two contrasting corticocortical and corticostriatal projection patterns: “patchy” projections that formed many columns of submillimeter scale in nearby and distant regions and “diffuse” projections that spread widely across the cortex and striatum. Parcellation-free analyses revealed representations of PFC gradients in these projections’ local and global distribution patterns. We also demonstrated column-scale precision of reciprocal corticocortical connectivity, suggesting that PFC contains a mosaic of discrete columns. Diffuse projections showed considerable diversity in the laminar patterns of axonal spread. Altogether, these fine-grained analyses reveal important principles of local and long-distance PFC circuits in marmosets and provide insights into the functional organization of the primate brain. © 2023 The Authors
Author Keywords
AAV; anterograde tracer; association cortex; cortical column; non-human primate; nonnegative matrix factorization; serial two-photon tomography; STPT; topographic connectivity; tractography
Funding details
19-102
JP15dm0207001, JP19dm0207088
National Institutes of HealthNIH1R01EB023947-01, P41 GM103545, R24 GM136986, RO1 MH-060974
National Institute of General Medical SciencesNIGMS
Japan Agency for Medical Research and DevelopmentAMED
Japan Society for the Promotion of ScienceKAKEN22H05163, JP22H05154
Ministry of Education, Culture, Sports, Science and TechnologyMEXT
RIKEN22123009
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Cognitive Motor Dissociation: Gap Analysis and Future Directions
(2023) Neurocritical Care, .
Claassen, J.a , Kondziella, D.b c , Alkhachroum, A.d , Diringer, M.e , Edlow, B.L.f , Fins, J.J.g , Gosseries, O.h i , Hannawi, Y.j , Rohaut, B.k , Schnakers, C.l , Stevens, R.D.m , Thibaut, A.h i , Monti, M.n , the Curing Coma Campaign, and Its Contributing Collaboratorso
a Department of Neurology, Neurological Institute, Columbia University Irving Medical Center, NewYork Presbyterian Hospital, 177 Fort Washington Avenue, MHB 8 Center, Room 300, New York, NY 10032, United States
b Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
c Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
d University of Miami, Miami, FL, United States
e Department of Neurology, Washington University, St. Louis, MO, United States
f Department of Neurology, Center for Neurotechnology and Neurorecovery, Massachusetts General Hospital, Boston, MA 02114, United States
g Division of Medical Ethics, Department of Medicine, Weill Cornell Medical College, NewYork Presbyterian Hospital, New York, NY 10032, United States
h Coma Science Group, GIGA Consciousness, University of Liege, Liege, Belgium
i Centre du Cerveau, University Hospital of Liege, Liege, Belgium
j Division of Cerebrovascular Diseases and Neurocritical Care, Department of Neurology, The Ohio State University, Columbus, OH, United States
k Sorbonne Université, Assistance Publique–Hôpitaux de Paris (AP-HP) – Pitié Salpêtrière, Paris, France
l Casa Colina Hospital and Centers for Healthcare, Pomona, CA, United States
m Department of Anesthesiology and Critical Care Medicine, Neurology, and Radiology, School of Medicine, Secondary Appointment in Biomedical Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, United States
n Department of Psychology, University of California Los Angeles, Los Angeles, CA, United States
Abstract
Background: Patients with disorders of consciousness who are behaviorally unresponsive may demonstrate volitional brain responses to motor imagery or motor commands detectable on functional magnetic resonance imaging or electroencephalography. This state of cognitive motor dissociation (CMD) may have prognostic significance. Methods: The Neurocritical Care Society’s Curing Coma Campaign identified an international group of experts who convened in a series of monthly online meetings between September 2021 and April 2023 to examine the science of CMD and identify key knowledge gaps and unmet needs. Results: The group identified major knowledge gaps in CMD research: (1) lack of information about patient experiences and caregiver accounts of CMD, (2) limited epidemiological data on CMD, (3) uncertainty about underlying mechanisms of CMD, (4) methodological variability that limits testing of CMD as a biomarker for prognostication and treatment trials, (5) educational gaps for health care personnel about the incidence and potential prognostic relevance of CMD, and (6) challenges related to identification of patients with CMD who may be able to communicate using brain–computer interfaces. Conclusions: To improve the management of patients with disorders of consciousness, research efforts should address these mechanistic, epidemiological, bioengineering, and educational gaps to enable large-scale implementation of CMD assessment in clinical practice. © 2023, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.
Author Keywords
Acute brain injury; Cognitive motor dissociation; Coma; Consciousness; Covert consciousness; Curing Coma Campaign; Outcome; Prognostication; Vegetative state
Funding details
945539
K23NS126577, KL2 UL1TR002736
19-610-00060, 21-610-00119
National Institutes of HealthNIHRF1MH12378-01
National Institute of General Medical SciencesNIGMS
National Institute of Neurological Disorders and StrokeNINDSR01NS106014, R03NS112760, R21NS128326
James S. McDonnell FoundationJSMF
Mind Science FoundationMSF
Johns Hopkins UniversityJHU
AstraZeneca Foundation
European CommissionECR33AG071744
Fonds De La Recherche Scientifique – FNRSFNRS
Lundbeck FoundationR349-2020-658
Koning Boudewijnstichtingkbs-frbEU-H2020-MSCA–RISE–778234
Novo Nordisk FondenNNFNNF21OC0067769
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Age-dependent immune and lymphatic responses after spinal cord injury
(2023) Neuron, .
Salvador, A.F.M.a b c , Dykstra, T.a b , Rustenhoven, J.a b d , Gao, W.a b , Blackburn, S.M.a b , Bhasiin, K.a b , Dong, M.Q.e , Guimarães, R.M.a b f , Gonuguntla, S.a b , Smirnov, I.a b , Kipnis, J.a b , Herz, J.a b
a Brain Immunology and Glia (BIG) Center, Washington University in St. Louis, St. Louis, MO 63110, United States
b Department of Pathology and Immunology, Division of Immunobiology, Washington University in St. Louis, St. Louis, MO 63110, United States
c Neuroscience Graduate Program, University of Virginia, Charlottesville, VA 22903, United States
d Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, 1023, New Zealand
e Thomas Jefferson University Hospital, Philadelphia, PA 19107, United States
f Center for Research in Inflammatory Diseases (CRID), Department of Pharmacology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil
Abstract
Spinal cord injury (SCI) causes lifelong debilitating conditions. Previous works demonstrated the essential role of the immune system in recovery after SCI. Here, we explored the temporal changes of the response after SCI in young and aged mice in order to characterize multiple immune populations within the mammalian spinal cord. We revealed substantial infiltration of myeloid cells to the spinal cord in young animals, accompanied by changes in the activation state of microglia. In contrast, both processes were blunted in aged mice. Interestingly, we discovered the formation of meningeal lymphatic structures above the lesion site, and their role has not been examined after contusive injury. Our transcriptomic data predicted lymphangiogenic signaling between myeloid cells in the spinal cord and lymphatic endothelial cells (LECs) in the meninges after SCI. Together, our findings delineate how aging affects the immune response following SCI and highlight the participation of the spinal cord meninges in supporting vascular repair. © 2023 Elsevier Inc.
Author Keywords
immune response to injury; lymphatics; macrophages; meninges; microglia; neuroimmunology; spinal cord injury
Funding details
National Institutes of HealthNIHAG034113, AG057496, AT010416, NS096967
Howard Hughes Medical InstituteHHMI
Washington University School of Medicine in St. LouisWUSM
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer’s Disease Study (LEADS) cohort
(2023) Alzheimer’s and Dementia, .
Polsinelli, A.J.af , Wonderlin, R.J.a , Hammers, D.B.af , Garcia, A.P.a , Eloyan, A.b , Taurone, A.b , Thangarajah, M.b , Beckett, L.c , Gao, S.d , Wang, S.e , Kirby, K.af , Logan, P.E.af , Aisen, P.f , Dage, J.L.g af af , Foroud, T.g , Griffin, P.h , Iaccarino, L.i , Kramer, J.H.i , Koeppe, R.j , Kukull, W.A.k , La Joie, R.i , Mundada, N.S.i , Murray, M.E.l , Nudelman, K.g , Soleimani-Meigooni, D.N.i , Rumbaugh, M.g , Toga, A.W.m , Touroutoglou, A.n , Vemuri, P.o , Atri, A.p , Day, G.S.q , Duara, R.r , Graff-Radford, N.R.q , Honig, L.S.s , Jones, D.T.o t , Masdeu, J.u , Mendez, M.F.v , Womack, K.w , Musiek, E.w , Onyike, C.U.x , Riddle, M.y , Rogalski, E.z , Salloway, S.y , Sha, S.J.aa , Turner, R.S.ab , Wingo, T.S.ac , Wolk, D.A.ad , Carrillo, M.C.h , Dickerson, B.C.n , Rabinovici, G.D.i , Apostolova, L.G.f ae , LEADS Consortiumaf
a Marian University College of Osteopathic Medicine, Indianapolis, IN, United States
b Department of Biostatistics, Center for Statistical Sciences, Brown University, Providence, RI, United States
c Department of Public Health Sciences, University of California – Davis, Davis, CA, United States
d Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, United States
e Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, United States
f Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
g Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
h Medical & Scientific Relations Division, Alzheimer’s Association, Chicago, IL, United States
i Department of Neurology, University of California – San Francisco, San Francisco, CA, United States
j Department of Radiology, University of Michigan, Ann Arbor, MI, United States
k Department of Epidemiology, University of Washington, Seattle, WA, United States
l Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
m Laboratory of Neuro Imaging, USC Stevens Neuroimaging and Informatics Institute, Keck School of Medicine of USC, Los Angeles, CA, United States
n Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
o Department of Radiology, Mayo Clinic, Rochester, MN, United States
p Banner Sun Health Research Institute, Sun City, AZ, United States
q Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
r Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center, Miami, FL, United States
s Taub Institute and Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
t Department of Neurology, Mayo Clinic, Rochester, MN, United States
u Nantz National Alzheimer Center, Houston Methodist and Weill Cornell Medicine, Houston, TX, United States
v Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
w Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
x Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States
y Department of Psychiatry, Alpert Medical School, Brown University, Providence, RI, United States
z Department of Psychiatry and Behavioral Sciences, Mesulam Center for Cognitive Neurology and Alzheimer’s Disease, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
aa Department of Neurology & Neurological Sciences, Stanford University, Palo Alto, CA, United States
ab Department of Neurology, Georgetown University, Washington, DC, United States
ac Department of Neurology and Human Genetics, Emory University School of Medicine, Atlanta, GA, United States
ad Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
ae Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine Indianapolis, Indianapolis, IN, United States
af Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
Abstract
Introduction: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer’s disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer’s Disease Study (LEADS). Methods: Baseline NPS (Neuropsychiatric Inventory – Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups – amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer’s disease (EOnonAD; n = 70). Results: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. Discussion: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
early-onset Alzheimer’s disease; early-onset dementia; mild cognitive impairment; neuropharmacology; neuropsychiatric symptoms; psychotropic medications
Funding details
National Institute on AgingNIAU24 AG072122
Alzheimer’s AssociationAALDRFP‐21‐828356
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Location of pathogenic variants in PSEN1 impacts progression of cognitive, clinical, and neurodegenerative measures in autosomal-dominant Alzheimer’s disease
(2023) Aging Cell, .
Schultz, S.A.a , Shirzadi, Z.a , Schultz, A.P.a , Liu, L.b c , Fitzpatrick, C.D.a , McDade, E.d , Barthelemy, N.R.d , Renton, A.e , Esposito, B.e , Joseph-Mathurin, N.d , Cruchaga, C.d , Chen, C.D.d , Goate, A.e , Allegri, R.F.f , Benzinger, T.L.S.d , Berman, S.g , Chui, H.C.h , Fagan, A.M.d , Farlow, M.R.i , Fox, N.C.j , Gordon, B.A.d , Day, G.S.k , Graff-Radford, N.R.k , Hassenstab, J.J.d , Hanseeuw, B.J.l m , Hofmann, A.n , Jack, C.R., Jr.o , Jucker, M.n , Karch, C.M.d , Koeppe, R.A.p , Lee, J.-H.q , Levey, A.I.r , Levin, J.s t u , Martins, R.N.v , Mori, H.w , Morris, J.C.d , Noble, J.x , Perrin, R.J.d , Rosa-Neto, P.y , Salloway, S.P.z , Sanchez-Valle, R.aa , Schofield, P.R.ab ac , Xiong, C.d , Johnson, K.A.a b , Bateman, R.J.d , Sperling, R.A.a b , Chhatwal, J.P.a b , the Dominantly Inherited Alzheimer Network Investigatorsad
a Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
b Brigham and Women’s Hospital, Boston, MA, United States
c Ann Romney Center for Neurologic Diseases, Boston, MA, United States
d Washington University in St. Louis School of Medicine, St. Louis, MO, United States
e Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
f INEBA, Buenos Aires, Argentina
g University of Pittsburgh, Pittsburgh, PA, United States
h Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
i Indiana Alzheimer’s Disease Research Center, Indianapolis, IN, United States
j Dementia Research Centre & UK Dementia Research Institute, UCL Institute of Neurology, London, United Kingdom
k Mayo Clinic, Jacksonville, FL, United States
l Institute of Neuroscience, UCLouvain, Brussels, Belgium
m Gordon Center for Medical Imaging in the Radiology Department of MGH, Boston, MA, United States
n German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany
o Mayo Clinic, Rochester, MN, United States
p University of Michigan, Ann Arbor, MI, United States
q Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
r Emory Goizueta Alzheimer’s Disease Research Center, Atlanta, GA, United States
s German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
t Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
u Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
v Edith Cowan University, Joondalup, WA, Australia
w Osaka City University Medical School, Osaka, Japan
x Columbia University, New York, NY, United States
y Translational Neuroimaging Laboratory, Le Centre intégré universitaire de santé et de services sociaux (CIUSSS) de l’Ouest-de-l’Île-de-Montréal; Department of Neurology and Neurosurgery, McGill University, Montreal, Canada
z Butler Hospital, Providence, RI, United States
aa Alzheimer’s disease and other cognitive disorders Unit, Neurology Department, Hospital Clínic de Barcelona, Institut d’Investigacions Biomediques, Barcelona, Spain
ab Neuroscience Research Australia, Randwick, NSW, Australia
ac School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
Abstract
Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials. © 2023 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.
Author Keywords
Autosomal dominant Alzheimer disease (ADAD); heterogeneity; neurodegeneration; Presenilin-1; PSEN1
Funding details
National Institute on AgingNIA
Alzheimer’s AssociationAAAARF‐21‐846786
Biogen
Research and Development
AbbVie
Society for Anthropological SciencesSAS
Japan Agency for Medical Research and DevelopmentAMEDR01 AG071865
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Characterization of cerebrospinal fluid (CSF) microbiota at the time of initial surgical intervention for children with hydrocephalus
(2023) PloS One, 18 (6), p. e0280682.
Pandey, S.a , Whitlock, K.B.b , Test, M.R.c , Hodor, P.d , Pope, C.E.c , Limbrick, D.D., Jre f , McDonald, P.J.g h , Hauptman, J.S.d i j , Hoffman, L.R.c d j , Simon, T.D.k l m , Cerebrospinal FLuId MicroBiota in Shunts (CLIMB) Study Groupn
a University of Washington School of Medicine, Seattle, WA, United States
b New Harmony Statistical Consulting, Clinton, WA, United States
c Department of Pediatrics, University of Washington, Seattle, WA, United States
d Seattle Children’s Research Institute, Seattle, WA, United States
e Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO, United States
f St. Louis Children’s Hospital, St. Louis, MO, United States
g Section of Neurosurgery, University of Manitoba, Winnipeg, MB, Canada
h Winnipeg Children’s Hospital, Winnipeg, MB, Canada
i Department of Neurosurgery, University of Washington, Seattle, WA, United States
j Seattle Children’s Hospital, Seattle, WA, United States
k Department of Pediatrics, University of Southern California, Los Angeles, CA, United States
l Saban Research Institute, Los Angeles, CA, United States
m Children’s Hospital Los Angeles, Los Angeles, CA, United States
Abstract
OBJECTIVE: To characterize the microbiota of the cerebrospinal fluid (CSF) from children with hydrocephalus at the time of initial surgical intervention. STUDY DESIGN: CSF was obtained at initial surgical intervention. One aliquot was stored in skim milk-tryptone-glucose-glycerol (STGG) medium and the second was unprocessed; both were then stored at -70°C. Bacterial growth for CSF samples stored in STGG were subsequently characterized using aerobic and anaerobic culture on blood agar and MALDI-TOF sequencing. All unprocessed CSF samples underwent 16S quantitative polymerase chain reaction (qPCR) sequencing, and a subset underwent standard clinical microbiological culture. CSF with culture growth (either after storage in STGG or standard clinical) were further analyzed using whole-genome amplification sequencing (WGAS). RESULTS: 11/66 (17%) samples stored in STGG and 1/36 (3%) that underwent standard clinical microbiological culture demonstrated bacterial growth. Of the organisms present, 8 were common skin flora and 4 were potential pathogens; only 1 was also qPCR positive. WGAS findings and STGG culture findings were concordant for only 1 sample, identifying Staphylococcus epidermidis. No significant difference in time to second surgical intervention was observed between the STGG culture-positive and negative groups. CONCLUSION(S): Using high sensitivity methods, we detected the presence of bacteria in a subset of CSF samples at the time of first surgery. Therefore, the true presence of bacteria in CSF of children with hydrocephalus cannot be ruled out, though our findings may suggest these bacteria are contaminants or false positives of the detection methods. Regardless of origin, the detection of microbiota in the CSF of these children may not have any clinical significance. Copyright: © 2023 Pandey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Document Type: Article
Publication Stage: Final
Source: Scopus
Cognitive impairment in people living with HIV: consensus recommendations for a new approach
(2023) Nature Reviews Neurology, .
Nightingale, S.a , Ances, B.b , Cinque, P.c , Dravid, A.d , Dreyer, A.J.a , Gisslén, M.e f , Joska, J.A.a , Kwasa, J.g , Meyer, A.-C.h , Mpongo, N.i , Nakasujja, N.j , Pebody, R.k , Pozniak, A.l m , Price, R.W.n , Sandford, C.o , Saylor, D.h p , Thomas, K.G.F.q , Underwood, J.r s , Vera, J.H.t , Winston, A.u v
a HIV Mental Health Research Unit, Division of Neuropsychiatry, Department of Psychiatry and Mental Health, Neuroscience Institute, University of Cape Town, Cape Town, South Africa
b Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
c Unit of Infectious Diseases, San Raffaele Institute, Milan, Italy
d Department of Medicine, Poona Hospital and Research Centre and Noble Hospital, Pune, India
e Institute of Biomedicine, Department of Infectious Diseases, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
f Region Västra Götaland, Sahlgrenska University Hospital, Department of Infectious Diseases, Gothenburg, Sweden
g Department of Clinical Medicine and Therapeutics, Faculty of Health Science, University of Nairobi, Nairobi, Kenya
h Department of Neurology, Johns Hopkins University, Baltimore, MD, United States
i Desmond Tutu HIV Centre, Cape Town, South Africa
j Department of Psychiatry, College of Health Sciences, Makerere University, Kampala, Uganda
k NAM, London, United Kingdom
l Department of HIV Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, London, United Kingdom
m Department of Clinical Research, London School of Hygiene & Tropical Medicine, London, United Kingdom
n Department of Neurology, University of California San Francisco, San Francisco, CA, United States
o UK Community Advisory Board (UK-CAB), London, United Kingdom
p University Teaching Hospital, Lusaka, Zambia
q Applied Cognitive Science and Experimental Neuropsychology Team (ACSENT), Department of Psychology, University of Cape Town, Cape Town, South Africa
r Division of Infection and Immunity, Cardiff University, Cardiff, United Kingdom
s Department of Infectious Diseases, Cardiff and Vale University Health Board, Cardiff, United Kingdom
t Department of Global Health and Infection, Brighton and Sussex Medical School, Brighton, United Kingdom
u Department of Infectious Disease, Imperial College London, London, United Kingdom
v HIV Clinical Trials, Winston Churchill Wing, St Mary’s Hospital, London, United Kingdom
Abstract
Current approaches to classifying cognitive impairment in people living with HIV can overestimate disease burden and lead to ambiguity around disease mechanisms. The 2007 criteria for HIV-associated neurocognitive disorders (HAND), sometimes called the Frascati criteria, can falsely classify over 20% of cognitively healthy individuals as having cognitive impairment. Minimum criteria for HAND are met on the basis of performance on cognitive tests alone, which might not be appropriate for populations with diverse educational and socioeconomic backgrounds. Imprecise phenotyping of cognitive impairment can limit mechanistic research, biomarker discovery and treatment trials. Importantly, overestimation of cognitive impairment carries the risk of creating fear among people living with HIV and worsening stigma and discrimination towards these individuals. To address this issue, we established the International HIV-Cognition Working Group, which is globally representative and involves the community of people living with HIV. We reached consensus on six recommendations towards a new approach for diagnosis and classification of cognitive impairment in people living with HIV, intended to focus discussion and debate going forward. We propose the conceptual separation of HIV-associated brain injury — including active or pretreatment legacy damage — from other causes of brain injury occurring in people living with HIV. We suggest moving away from a quantitative neuropsychological approach towards an emphasis on clinical context. Our recommendations are intended to better represent the changing profile of cognitive impairment in people living with HIV in diverse global settings and to provide a clearer framework of classification for clinical management and research studies. © 2023, Springer Nature Limited.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Genomic risk for post-traumatic stress disorder in families densely affected with alcohol use disorders
(2023) Molecular Psychiatry, .
Saenz de Viteri, S.a , Zhang, J.a , Johnson, E.C.b , Barr, P.B.a , Edenberg, H.J.c , Hesselbrock, V.M.d , Nurnberger, J.I., Jrc , Pandey, A.K.a , Kamarajan, C.a , Kinreich, S.a , Tischfield, J.A.e , Plawecki, M.H.c , Kramer, J.R.f , Lai, D.c , Kuperman, S.f , Chan, G.d f f , McCutcheon, V.V.b , Bucholz, K.K.b , Porjesz, B.a , Meyers, J.L.a
a State University of New York Downstate Health Sciences University, Brooklyn, NY, United States
b Washington University School of Medicine in St. Louis, St. Louis, MO, United States
c Indiana University School of Medicine, Indianapolis, IN, United States
d University of Connecticut Health Center, Farmington, CT, United States
e Rutgers University, Piscataway, NJ, United States
f University of Iowa Carver College of Medicine, Iowa City, IA, United States
Abstract
Recent genome-wide association studies (GWAS) have identified genetic markers of post-traumatic stress disorder (PTSD) in civilian and military populations. However, studies have yet to examine the genetics of PTSD while factoring in risk for alcohol dependence, which commonly co-occur. We examined genome-wide associations for DSM-IV PTSD among 4,978 trauma-exposed participants (31% with alcohol dependence, 50% female, 30% African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA). We also examined associations of polygenic risk scores (PRS) derived from the Psychiatric Genomics Consortium (PGC)-PTSD Freeze 2 (N = 3533) and Million Veterans Program GWAS of PTSD (N = 5200) with PTSD and substance dependence in COGA, and moderating effects of sex and alcohol dependence. 7.3% of COGA participants met criteria for PTSD, with higher rates in females (10.1%) and those with alcohol dependence (12.3%). No independent loci met genome-wide significance in the PTSD meta-analysis of European (EA) and African ancestry (AA) participants. The PGC-PTSD PRS was associated with increased risk for PTSD (B = 0.126, p < 0.001), alcohol dependence (B = 0.231, p < 0.001), and cocaine dependence (B = 0.086, p < 0.01) in EA individuals. A significant interaction was observed, such that EA individuals with alcohol dependence and higher polygenic risk for PTSD were more likely to have PTSD (B = 0.090, p < 0.01) than those without alcohol dependence. These results further support the importance of examining substance dependence, specifically alcohol dependence, and PTSD together when investigating genetic influence on these disorders. © 2023, The Author(s).
Funding details
National Institutes of HealthNIHU10AA008401
National Institute on Drug AbuseNIDA
National Institute on Alcohol Abuse and AlcoholismNIAAA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Neonatal exposure to a neuroactive steroid alters low-frequency oscillations in the subiculum
(2023) Experimental Biology and Medicine, .
Fine-Raquet, B.a , Manzella, F.M.a b , Joksimovic, S.M.a , Dietz, R.M.c , Orfila, J.E.a , Sampath, D.d , Tesic, V.e , Atluri, N.f , Covey, D.F.g h , Raol, Y.H.i j , Jevtovic-Todorovic, V.a , Herson, P.S.a b , Todorovic, S.M.a b
a Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
b Neuroscience Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
c Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
d Department of Neuroscience and Experimental Therapeutics, Texas A&M University, College Station, TX 77843, United States
e Department of Neurology, Louisiana State University Health Sciences Center, Shreveport, LA 71103, United States
f Department of Anesthesiology, University of Virginia, Charlottesville, VA 22903, United States
g Department of Developmental Biology, St. Louis School of Medicine, Washington University, St. Louis, MO 63130, United States
h Taylor Family Institute for Innovative Psychiatric Research, St. Louis School of Medicine, Washington University, St. Louis, MO 63130, United States
i Department of Pediatrics, Division of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
j National Institute of Neurological Disorders and Stroke, National Institutes of Health, Rockville, MD 20824, United States
Abstract
Preclinical studies have established that neonatal exposure to contemporary sedative/hypnotic drugs causes neurotoxicity in the developing rodent and primate brains. Our group recently reported that novel neuroactive steroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH) induced effective hypnosis in both neonatal and adult rodents but did not cause significant neurotoxicity in vulnerable brain regions such as subiculum, an output region of hippocampal formation particularly sensitive to commonly used sedatives/hypnotics. Despite significant emphasis on patho-morphological changes, little is known about long-term effects on subicular neurophysiology after neonatal exposure to neuroactive steroids. Hence, we explored the lasting effects of neonatal exposure to 3β-OH on sleep macrostructure as well as subicular neuronal oscillations in vivo and synaptic plasticity ex vivo in adolescent rats. At postnatal day 7, we exposed rat pups to either 10 mg/kg of 3β-OH over a period of 12 h or to volume-matched cyclodextrin vehicle. At weaning age, a cohort of rats was implanted with a cortical electroencephalogram (EEG) and subicular depth electrodes. At postnatal day 30–33, we performed in vivo assessment of sleep macrostructure (divided into wake, non-rapid eye movement, and rapid eye movement sleep) and power spectra in cortex and subiculum. In a second cohort of 3β-OH exposed animals, we conducted ex vivo studies of long-term potentiation (LTP) in adolescent rats. Overall, we found that neonatal exposure to 3β-OH decreased subicular delta and sigma oscillations during non-rapid eye movement sleep without altering sleep macrostructure. Furthermore, we observed no significant changes in subicular synaptic plasticity. Interestingly, our previous study found that neonatal exposure to ketamine increased subicular gamma oscillations during non-rapid eye movement sleep and profoundly suppressed subicular LTP in adolescent rats. Together these results suggest that exposure to different sedative/hypnotic agents during a critical period of brain development may induce distinct functional changes in subiculum circuitry that may persist into adolescent age. © 2023 by the Society for Experimental Biology and Medicine.
Author Keywords
3β-OH; brain development; EEG; hypnosis; long-term potentiation
Funding details
National Institutes of HealthNIH2R01 GM102525, 5R35GM141802-02
National Institute of General Medical SciencesNIGMSR01GM118197
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDF32HD101357, R01HD044517, R01HD097990, R21HD080281
Document Type: Short Survey
Publication Stage: Article in Press
Source: Scopus
Anxiety and Depression Diagnoses and the Cough Severity Index: A Retrospective Study
(2023) Ear, Nose and Throat Journal, .
Hari, G.a , Naunheim, M.b , Kallogjeri, D.a , Huston, M.a
a Department of Otolaryngology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
b Department of Otolaryngology—Head and Neck Surgery, Massachusetts Eye and Ear, Harvard Medical School, Boston, MA, United States
Abstract
Background: As mental health comorbidities can impact patient perception of symptoms, understanding a potential association of anxiety and depression with patients’ perception of their cough may provide insight into preferred treatment plans. Methods: A retrospective cohort study of patients presenting with chronic cough was completed. Demographics, anxiety and depression diagnoses, and patient-reported outcome measures were collected. Patient-reported outcomes between the four groups of patients—anxiety only, depression only, anxiety and depression, and none of these conditions—were compared using Kruskal–Wallis and Mann–Whitney U tests that were used for post-hoc analysis. Results: Cough Severity Index scores were higher in those with both anxiety and depression as compared to neither, with a median score of 26 (range: 5-39) versus 19 (range: 1-38), respectively (P =.041). These results were persistent also after controlling for sex and smoking status in the robust regression analysis. Conclusions: Patients with prior diagnoses of anxiety and depression self-reported more severe symptoms for chronic cough. Adequately understanding the association of mental health with perceived cough severity may help for more individualized, successful treatment plans. © The Author(s) 2023.
Author Keywords
anxiety; Cough; depression; mental health
Document Type: Article
Publication Stage: Article in Press
Source: Scopus