Hope Center Member Publications

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

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 investigators^m

^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

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

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 Consortium^af

^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 Investigators^ad

^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., Jr^e 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