Publications

Hope Center Member Publications

List of publications for October 30, 2022

Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading” (2023) The Journal of Experimental Medicine

Chronic TREM2 activation exacerbates Aβ-associated tau seeding and spreading
(2023) The Journal of Experimental Medicine, 220 (1), . 

Jain, N.a b c , Lewis, C.A.a b c , Ulrich, J.D.a b c , Holtzman, D.M.a b c

a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
c Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are associated with increased risk for late-onset AD. Genetic loss of or decreased TREM2 function impairs the microglial response to amyloid-β (Aβ) plaques, resulting in more diffuse Aβ plaques and increased peri-plaque neuritic dystrophy and AD-tau seeding. Thus, microglia and TREM2 are at a critical intersection of Aβ and tau pathologies in AD. Since genetically decreasing TREM2 function increases Aβ-induced tau seeding, we hypothesized that chronically increasing TREM2 signaling would decrease amyloid-induced tau-seeding and spreading. Using a mouse model of amyloidosis in which AD-tau is injected into the brain to induce Aβ-dependent tau seeding/spreading, we found that chronic administration of an activating TREM2 antibody increases peri-plaque microglial activation but surprisingly increases peri-plaque NP-tau pathology and neuritic dystrophy, without altering Aβ plaque burden. Our data suggest that sustained microglial activation through TREM2 that does not result in strong amyloid removal may exacerbate Aβ-induced tau pathology, which may have important clinical implications. © 2022 Jain et al.

Document Type: Article
Publication Stage: Final
Source: Scopus

Neuropsychological Correlates of Changes in Driving Behavior Among Clinically Healthy Older Adults” (2022) The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences

Neuropsychological Correlates of Changes in Driving Behavior Among Clinically Healthy Older Adults
(2022) The Journals of Gerontology. Series B, Psychological Sciences and Social Sciences, 77 (10), pp. 1769-1778. 

Aschenbrenner, A.J.a , Murphy, S.A.a , Doherty, J.M.a , Johnson, A.M.b , Bayat, S.c d e , Walker, A.a , Peña, Y.a , Hassenstab, J.a , Morris, J.C.a , Babulal, G.M.a f g h

a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Center for Clinical Studies, Washington University in St. Louis, St. Louis, MO, United States
c Department of Biomedical Engineering, University of Calgary, Calgary, AB, Canada
d Department of Geomatics Engineering, University of Calgary, Calgary, AB, Canada
e Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
f Institute of Public Health, Washington University in St. Louis, St. Louis, MO, United States
g Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
h Department of Clinical Research and Leadership, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA

Abstract
OBJECTIVES: To determine the extent to which cognitive domain scores moderate change in driving behavior in cognitively healthy older adults using naturalistic (Global Positioning System-based) driving outcomes and to compare against self-reported outcomes using an established driving questionnaire. METHODS: We analyzed longitudinal naturalistic driving behavior from a sample (N = 161, 45% female, mean age = 74.7 years, mean education = 16.5 years) of cognitively healthy, nondemented older adults. Composite driving variables were formed that indexed “driving space” and “driving performance.” All participants completed a baseline comprehensive cognitive assessment that measured multiple domains as well as an annual self-reported driving outcomes questionnaire. RESULTS: Across an average of 24 months of naturalistic driving, our results showed that attentional control, broadly defined as the ability to focus on relevant aspects of the environment and ignore distracting or competing information as measured behaviorally with tasks such as the Stroop color naming test, moderated change in driving space scores over time. Specifically, individuals with lower attentional control scores drove fewer trips per month, drove less at night, visited fewer unique locations, and drove in smaller spaces than those with higher attentional control scores. No cognitive domain predicted driving performance such as hard braking or sudden acceleration. DISCUSSION: Attentional control is a key moderator of change over time in driving space but not driving performance in older adults. We speculate on mechanisms that may relate attentional control ability to modifications of driving behaviors. © The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
Attentional control;  Naturalistic driving;  Self-regulation

Document Type: Article
Publication Stage: Final
Source: Scopus

Infantile-onset Pompe disease complicated by sickle cell anemia: Case report and management considerations” (2022) Frontiers in Pediatrics

Infantile-onset Pompe disease complicated by sickle cell anemia: Case report and management considerations
(2022) Frontiers in Pediatrics, 10, art. no. 944178, . 

Starosta, R.T.a , Hou, Y.-C.C.b , Leestma, K.a , Singh, P.a , Viehl, L.c , Manwaring, L.a , Granadillo, J.L.a , Schroeder, M.C.b , Colombo, J.N.d , Whitehead, H.c , Dickson, P.I.a , Hulbert, M.L.e , Nguyen, H.T.a

a Division of Clinical Genetics and Genomics, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
c Division of Newborn Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
d Division of Pediatric Cardiology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
e Division of Pediatric Hematology and Oncology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Infantile-onset Pompe disease (IOPD) is a rare, severe disorder of lysosomal storage of glycogen that leads to progressive cardiac and skeletal myopathy. IOPD is a fatal disease in childhood unless treated with enzyme replacement therapy (ERT) from an early age. Sickle cell anemia (SCA) is a relatively common hemoglobinopathy caused by a specific variant in the hemoglobin beta-chain. Here we report a case of a male newborn of African ancestry diagnosed and treated for IOPD and SCA. Molecular testing confirmed two GAA variants, NM_000152.5: c.842G>C, p.(Arg281Pro) and NM_000152.5: c.2560C>T, p.(Arg854*) in trans, and homozygosity for the HBB variant causative of SCA, consistent with his diagnosis. An acute neonatal presentation of hypotonia and cardiomyopathy required ERT with alglucosidase alfa infusions preceded by immune tolerance induction (ITI), as well as chronic red blood cell transfusions and penicillin V potassium prophylaxis for treatment of IOPD and SCA. Clinical course was further complicated by multiple respiratory infections. We review the current guidelines and interventions taken to optimize his care and the pitfalls of those guidelines when treating patients with concomitant conditions. To the best of our knowledge, no other case reports of the concomitance of these two disorders was found. This report emphasizes the importance of newborn screening, early intervention, and treatment considerations for this complex patient presentation of IOPD and SCA. Copyright © 2022 Starosta, Hou, Leestma, Singh, Viehl, Manwaring, Granadillo, Schroeder, Colombo, Whitehead, Dickson, Hulbert and Nguyen.

Author Keywords
alpha-glucosidase;  enzyme replacement therapy;  glycogen storage disorder type II;  immune tolerance induction;  methotrexate;  newborn screening;  sickle cell anemia

Funding details
St. Louis Children’s HospitalSLCH

Document Type: Article
Publication Stage: Final
Source: Scopus

Weakly activated core neuroinflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer’s disease“(2022) Frontiers in Aging Neuroscience

Weakly activated core neuroinflammation pathways were identified as a central signaling mechanism contributing to the chronic neurodegeneration in Alzheimer’s disease
(2022) Frontiers in Aging Neuroscience, 14, art. no. 935279, . 

Li, F.a b c , Eteleeb, A.M.c d e , Buchser, W.f , Sohn, C.c d e , Wang, G.g , Xiong, C.g , Payne, P.R.a , McDade, E.h , Karch, C.M.c d e , Harari, O.c d e , Cruchaga, C.c d e

a Institute for Informatics (I2), Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Pediatrics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c NeuroGenomics and Informatics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
d Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
f Department of Neuroscience, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
g Division of Biostatistics, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
h Department of Neurology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States

Abstract
Objectives: Neuroinflammation signaling has been identified as an important hallmark of Alzheimer’s disease (AD) in addition to amyloid β plaques (Aβ) and neurofibrillary tangles (NFTs). However, the molecular mechanisms and biological processes of neuroinflammation remain unclear and have not well delineated using transcriptomics data available. Our objectives are to uncover the core neuroinflammation signaling pathways in AD using integrative network analysis on the transcriptomics data. Materials and methods: From a novel perspective, i.e., investigating weakly activated molecular signals (rather than the strongly activated molecular signals), we developed integrative and systems biology network analysis to uncover potential core neuroinflammation signaling targets and pathways in AD using the two large-scale transcriptomics datasets, i.e., Mayo Clinic (77 controls and 81 AD samples) and ROSMAP (97 controls and 260 AD samples). Results: Our analysis identified interesting core neuroinflammation signaling pathways, which are not systematically reported in the previous studies of AD. Specifically, we identified 7 categories of signaling pathways implicated on AD and related to virus infection: immune response, x-core signaling, apoptosis, lipid dysfunctional, biosynthesis and metabolism, and mineral absorption signaling pathways. More interestingly, most of the genes in the virus infection, immune response, and x-core signaling pathways are associated with inflammation molecular functions. The x-core signaling pathways were defined as a group of 9 signaling proteins: MAPK, Rap1, NF-kappa B, HIF-1, PI3K-Akt, Wnt, TGF-beta, Hippo, and TNF, which indicated the core neuroinflammation signaling pathways responding to the low-level and weakly activated inflammation and hypoxia and leading to the chronic neurodegeneration. It is interesting to investigate the detailed signaling cascades of these weakly activated neuroinflammation signaling pathways causing neurodegeneration in a chronic process, and consequently uncover novel therapeutic targets for effective AD treatment and prevention. Conclusions: The potential core neuroinflammation and associated signaling targets and pathways were identified using integrative network analysis on two large-scale transcriptomics datasets of AD. Copyright © 2022 Li, Eteleeb, Buchser, Sohn, Wang, Xiong, Payne, McDade, Karch, Harari and Cruchaga.

Author Keywords
Alzheimer’s disease;  molecular mechanism;  neuroinflammation;  signaling network;  signaling targets

Funding details
National Institutes of HealthNIHP01AG003991, R01AG044546, RF1AG053303, RF1AG058501, U01AG058922
National Institute on AgingNIAR56AG065352
Biogen
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZI

Document Type: Article
Publication Stage: Final
Source: Scopus

Functional neuropathology of neonatal hypoxia-ischemia by single-mouse longitudinal electroencephalography” (2022) Epilepsia

Functional neuropathology of neonatal hypoxia-ischemia by single-mouse longitudinal electroencephalography
(2022) Epilepsia, . 

Johnson, K.J., Moy, B., Rensing, N., Robinson, A., Ly, M., Chengalvala, R., Wong, M., Galindo, R.

Department of Neurology, Division of Pediatric & Developmental Neurology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Objective: Neonatal cerebral hypoxia-ischemia (HI) results in symptomatic seizures and long-term neurodevelopmental disability. The Rice-Vannucci model of rodent neonatal HI has been used extensively to examine and translate the functional consequences of acute and chronic HI-induced encephalopathy. Yet, longitudinal electrophysiological characterization of this brain injury model has been limited by the size of the neonatal mouse’s head and postnatal maternal dependency. We overcome this challenge by employing a novel method of longitudinal single-mouse electroencephalography (EEG) using chronically implanted subcranial electrodes in the term-equivalent mouse pup. We characterize the neurophysiological disturbances occurring during awake and sleep states in the acute and chronic phases following newborn brain injury. Methods: C57BL/6 mice underwent long-term bilateral subcranial EEG and electromyographic electrode placement at postnatal day 9 followed by unilateral carotid cauterization and exposure to 40 minutes of hypoxia the following day. EEG recordings were obtained prior, during, and intermittently after the HI procedure from postnatal day 10 to weaning age. Quantitative EEG and fast Fourier transform analysis were used to evaluate seizures, cortical cerebral dysfunction, and disturbances in vigilance states. Results: We observed neonatal HI-provoked electrographic focal and bilateral seizures during or immediately following global hypoxia and most commonly contralateral to the ischemic injury. Spontaneous chronic seizures were not seen. Injured mice developed long-term asymmetric EEG background attenuation in all frequencies and most prominently during non–rapid eye movement (NREM) sleep. HI mice also showed transient impairments in vigilance state duration and transitions during the first 2 days following injury. Significance: The functional burden of mouse neonatal HI recorded by EEG resembles closely that of the injured human newborn. The use of single-mouse longitudinal EEG in this immature model can advance our understanding of the developmental and pathophysiological mechanisms of neonatal cerebral injury and help translate novel therapeutic strategies against this devastating condition. © 2022 International League Against Epilepsy.

Author Keywords
brain injury;  development;  EEG;  neonatal encephalopathy;  newborn;  seizures;  sleep

Funding details
National Institutes of HealthNIHR01 NS112234

Document Type: Article
Publication Stage: Article in Press
Source: Scopus

Increasing participant diversity in AD research: Plans for digital screening, blood testing, and a community-engaged approach in the Alzheimer’s Disease Neuroimaging Initiative 4” (2022) Alzheimer’s and Dementia

Increasing participant diversity in AD research: Plans for digital screening, blood testing, and a community-engaged approach in the Alzheimer’s Disease Neuroimaging Initiative 4
(2022) Alzheimer’s and Dementia, . 

Weiner, M.W.a b c d e , Veitch, D.P.a f , Miller, M.J.a f , Aisen, P.S.g , Albala, B.h , Beckett, L.A.i , Green, R.C.j , Harvey, D.i , Jack, C.R., Jr.k , Jagust, W.l , Landau, S.M.l , Morris, J.C.m n o , Nosheny, R.a d , Okonkwo, O.C.p , Perrin, R.J.m n o , Petersen, R.C.q , Rivera-Mindt, M.r s , Saykin, A.J.t u , Shaw, L.M.v , Toga, A.W.w , Tosun, D.a b , Trojanowski, J.Q.v , Alzheimer’s Disease Neuroimaging Initiativex

a Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, San Francisco, CA, United States
b Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA, United States
c Department of Medicine, University of California, San Francisco, CA, United States
d Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, CA, United States
e Department of Neurology, University of California, San Francisco, CA, United States
f Northern California Institute for Research and Education (NCIRE), Department of Veterans Affairs Medical Center, San Francisco, CA, United States
g Alzheimer’s Therapeutic Research Institute, University of Southern California, San Diego, CA, United States
h Department of Neurology, University of California Irvine School of Medicine, Irvine, CA, United States
i Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, United States
j Division of Genetics, Department of Medicine, Brigham and Women’s Hospital, Broad Institute Ariadne Labs and Harvard Medical School, Boston, MA, United States
k Department of Radiology, Mayo Clinic, Rochester, MN, United States
l Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, United States
m Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, Saint Louis, MO, United States
n Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
o Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States
p Wisconsin Alzheimer’s Disease Research Center and Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States
q Department of Neurology, Mayo Clinic, Rochester, MN, United States
r Department of Psychology, Latin American and Latino Studies Institute, & African and African American Studies, Fordham University, New York, NY, United States
s Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
t Department of Radiology and Imaging Sciences and the Indiana Alzheimer’s Disease Research Center, Indiana University School of Medicine, Indianapolis, IN, United States
u Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
v Department of Pathology and Laboratory Medicine and the PENN Alzheimer’s Disease Research Center, Center for Neurodegenerative Research, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
w Laboratory of Neuro Imaging, Institute of Neuroimaging and Informatics, Keck School of Medicine of University of Southern California, Los Angeles, CA, United States

Abstract
Introduction: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) aims to validate biomarkers for Alzheimer’s disease (AD) clinical trials. To improve generalizability, ADNI4 aims to enroll 50-60% of its new participants from underrepresented populations (URPs) using new biofluid and digital technologies. ADNI4 has received funding from the National Institute on Aging beginning September 2022. Methods: ADNI4 will recruit URPs using community-engaged approaches. An online portal will screen 20,000 participants, 4000 of whom (50-60% URPs) will be tested for plasma biomarkers and APOE. From this, 500 new participants will undergo in-clinic assessment joining 500 ADNI3 rollover participants. Remaining participants (∼3500) will undergo longitudinal plasma and digital cognitive testing. ADNI4 will add MRI sequences and new PET tracers. Project 1 will optimize biomarkers in AD clinical trials. Results and Discussion: ADNI4 will improve generalizability of results, use remote digital and blood screening, and continue providing longitudinal clinical, biomarker, and autopsy data to investigators. © 2022 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.

Author Keywords
Alzheimer’s disease;  amyloid;  cerebrovascular disease;  digital biomarkers;  generalizability;  mild cognitive impairment;  plasma biomarkers;  tau;  underrepresented populations

Funding details
G‐89294
National Institutes of HealthNIH1910611‐0, 5U19AG024904, AG034570, AG062542, AG067418, B639943, HD090019, HG008685, HG009922, HL143295, P01AG003991, P01AG026276, P30 AG010133, P30 AG066444, P30 AG072976, P30 AG072979, P30AG072972, P50HD103526, R01 AG019771, R01 AG052550, R01 AG053267, R01 AG057739, R01 AG068193, R01 AG070883, R01 LM013463, R01 NS075321, R01AG051618, R01AG054513, R01AG054567, R01AG062240, R01AG062517, R01AG062689, R01AG064688, R01AG065110‐01A1, R01AG066471‐01A1, R01AG066748, R01AG067541, R01AG068319, R01HD076189, R01HD093654, R01MH117114, R01NS092865, R01NS097799, R13 AG071313‐01, SC3GM141996, T32 AG071444, TR003201, U01 AG068057, U01 AG072177, U19 AG032438, U54NS079202
U.S. Department of DefenseDODW81XWH‐12‐2‐0012, W81XWH‐13‐1‐0259, W81XWH‐14‐1‐0462
Foundation for the National Institutes of HealthFNIH
National Institute on AgingNIA
Division of Information and Intelligent SystemsIIS
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Mayo Clinic
Alzheimer’s AssociationAA
Merck
Roche
National Institute of JusticeNIJ2014‐R2‐CX‐0012
Biogen
AbbVie
GHR FoundationGHR
Anglo-Israel AssociationAIA
Eisai
Shionogi

Document Type: Review
Publication Stage: Article in Press
Source: Scopus