Publications

Hope Center member publications

List of publications for week of March 21, 2022

Baseline Microglial Activation Correlates With Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease” (2022) Neurology(R) Neuroimmunology & Neuroinflammation

Baseline Microglial Activation Correlates With Brain Amyloidosis and Longitudinal Cognitive Decline in Alzheimer Disease
(2022) Neurology(R) Neuroimmunology & Neuroinflammation, 9 (3), . 

Wang, Q.a , Chen, G.a , Schindler, S.E.a , Christensen, J.a , McKay, N.S.b , Liu, J.a , Wang, S.a , Sun, Z.a , Hassenstab, J.a , Su, Y.a , Flores, S.a , Hornbeck, R.a , Cash, L.a , Cruchaga, C.a , Fagan, A.M.a , Tu, Z.a , Morris, J.C.a , Mintun, M.A.a , Wang, Y.a , Benzinger, T.L.S.a

a From the Mallinckrodt Institute of Radiology (Q.W., G.C., J.C., S.F., R.H., Z.T., Y.W., T.L.S.B.), Washington University School of Medicine; Knight Alzheimer Disease Research Center (Q.W., G.C., S.E.S., J.H., L.C., A.M.F., J.C.M., T.L.S.B.), Washington University School of Medicine; Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Washington University School of Medicine; Department of Surgery (J.L.), Washington University School of Medicine; Department of Electrical and System Engineering (S.W., Y.W.), Washington University School of Med-icine; Department of Biomedical Engineering (Z.S., Y.W.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium (Y.S.), Phoenix, AZ; Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Avid Radiopharmaceuticals (M.A.M.), Philadelphia, PA; Department of Obstetrics and Gynecology (Y.W.), Washington University School of Medicine; and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO
b From the Mallinckrodt Institute of Radiology (Q.W., G.C., J.C., S.F., R.H., Z.T., Y.W., T.L.S.B.), Washington University School of Medicine; Knight Alzheimer Disease Research Center (Q.W., G.C., S.E.S., J.H., L.C., A.M.F., J.C.M., T.L.S.B.), Washington University School of Medicine; Department of Neurology (S.E.S., J.H., C.C., A.M.F., J.C.M.), Washington University School of Medicine; Department of Surgery (J.L.), Washington University School of Medicine; Department of Electrical and System Engineering (S.W., Y.W.), Washington University School of Med-icine; Department of Biomedical Engineering (Z.S., Y.W.), Washington University School of Medicine, St. Louis, MO; Banner Alzheimer’s Institute and Arizona Alzheimer’s Consortium (Y.S.), Phoenix, AZ; Department of Psychiatry (C.C.), Washington University School of Medicine, St. Louis, MO; Avid Radiopharmaceuticals (M.A.M.), Philadelphia, PA; Department of Obstetrics and Gynecology (Y.W.), Washington University School of Medicine; and Department of Neurosurgery (T.L.S.B.), Washington University School of Medicine, St. Louis, MO. wangyong@wustl.edu

Abstract
BACKGROUND AND OBJECTIVES: This study aims to quantify microglial activation in individuals with Alzheimer disease (AD) using the 18-kDa translocator protein (TSPO) PET imaging in the hippocampus and precuneus, the 2 AD-vulnerable regions, and to evaluate the association of baseline neuroinflammation with amyloidosis, tau, and longitudinal cognitive decline. METHODS: Twenty-four participants from the Knight Alzheimer Disease Research Center (Knight ADRC) were enrolled and classified into stable cognitively normal, progressor, and symptomatic AD groups based on clinical dementia rating (CDR) at 2 or more clinical assessments. The baseline TSPO radiotracer [11C]PK11195 was used to image microglial activation. Baseline CSF concentrations of Aβ42, Aβ42/Aβ40 ratio, tau phosphorylated at position 181 (p-tau181), and total tau (t-tau) were measured. Clinical and cognitive decline were examined with longitudinal CDR and cognitive composite scores (Global and Knight ADRC-Preclinical Alzheimer Cognitive Composite [Knight ADRC-PACC] Score). RESULTS: Participants in the progressor and symptomatic AD groups had significantly elevated [11C]PK11195 standard uptake value ratios (SUVRs) in the hippocampus but not in the precuneus region. In the subcohort with CSF biomarkers (16 of the 24), significant negative correlations between CSF Aβ42 or Aβ42/Aβ40 and [11C]PK11195 SUVR were observed in the hippocampus and precuneus. No correlations were observed between [11C]PK11195 SUVR and CSF p-tau181 or t-tau at baseline in those regions. Higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions predicted longitudinal decline on cognitive tests. DISCUSSION: Microglial activation is increased in individuals with brain amyloidosis and predicts worsening cognition in AD. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with AD, higher baseline [11C]PK11195 SUVR averaged in the whole cortical regions was associated with longitudinal decline on cognitive tests. Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Document Type: Article
Publication Stage: Final
Source: Scopus

Targeting IFN-λ Signaling Promotes Recovery from Central Nervous System Autoimmunity” (2022) Journal of immunology (Baltimore, Md. : 1950)

Targeting IFN-λ Signaling Promotes Recovery from Central Nervous System Autoimmunity
(2022) Journal of immunology (Baltimore, Md. : 1950), 208 (6), pp. 1341-1351. 

Manivasagam, S.a , Williams, J.L.b , Vollmer, L.L.a , Bollman, B.c , Bartleson, J.M.d , Ai, S.a , Wu, G.F.c d , Klein, R.S.c d e

a Department of Medicine, Washington University in St. Louis, St. Louis, MO
b Department of Neurosciences, Cleveland Clinic, Cleveland, OH
c Department of Neurology, Washington University in St. Louis, St. Louis, MO; and
d Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO
e Department of Medicine, Washington University in St. Louis, St. Louis, MO;

Abstract
Type III IFNs (IFNLs) are newly discovered cytokines, acting at epithelial and other barriers, that exert immunomodulatory functions in addition to their primary roles in antiviral defense. In this study, we define a role for IFNLs in maintaining autoreactive T cell effector function and limiting recovery in a murine model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis. Genetic or Ab-based neutralization of the IFNL receptor (IFNLR) resulted in lack of disease maintenance during experimental autoimmune encephalomyelitis, with loss of CNS Th1 effector responses and limited axonal injury. Phenotypic effects of IFNLR signaling were traced to increased APC function, with associated increase in T cell production of IFN-γ and GM-CSF. Consistent with this, IFNL levels within lesions of CNS tissues derived from patients with MS were elevated compared with MS normal-appearing white matter. Furthermore, expression of IFNLR was selectively elevated in MS active lesions compared with inactive lesions or normal-appearing white matter. These findings suggest IFNL signaling as a potential therapeutic target to prevent chronic autoimmune neuroinflammation. Copyright © 2022 by The American Association of Immunologists, Inc.

Document Type: Article
Publication Stage: Final
Source: Scopus

COVID-19 Outcomes and Vaccination in People with Relapsing Multiple Sclerosis Treated with Ofatumumab
(2022) Neurology and Therapy

COVID-19 Outcomes and Vaccination in People with Relapsing Multiple Sclerosis Treated with Ofatumumab
(2022) Neurology and Therapy, . 

Cross, A.H.a , Delgado, S.b , Habek, M.c , Davydovskaya, M.d , Ward, B.J.e , Cree, B.A.C.f , Totolyan, N.g , Pingili, R.h , Mancione, L.h , Hu, X.h , Sullivan, R.h , Su, W.h , Zielman, R.i , Gupta, A.D.j , Montalban, X.k , Winthrop, K.l

a Department of Neurology, Washington University, St. Louis, MO, United States
b University of Miami Miller School of Medicine, Miami, FL, United States
c University Hospital Center Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia
d Moscow State Public Healthcare InsCity Clinical Hospital 24, Moscow, Russian Federation
e Infectious Diseases Division, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
f UCSF Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco, CA, United States
g First Saint Petersburg State Medical University, St. Petersburg, Russian Federation
h Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States
i Novartis Pharma B.V., Amsterdam, Netherlands
j Novartis Healthcare Private Limited, Hyderabad, India
k Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Barcelona, Spain
l School of Public Health at Oregon Health and Science University, Portland, OR, United States

Abstract
Introduction: The SARS-CoV-2 pandemic necessitated better understanding of the impact of disease-modifying therapies on COVID-19 outcomes and vaccination. We report characteristics of COVID-19 cases and vaccination status in ofatumumab-treated relapsing multiple sclerosis (RMS) patients. Methods: COVID-19 data analyzed were from the ongoing, open-label, long-term extension phase 3b ALITHIOS study from December 2019 (pandemic start) and post-marketing cases from August 2020 (ofatumumab first approval) up to 25 September 2021. COVID-19 cases, severity, seriousness, outcomes, vaccination status, and breakthrough infection were evaluated. Results: As of 25 September 2021, 245 of 1703 patients (14.3%) enrolled in ALITHIOS receiving ofatumumab (median exposure: 2.45 years) reported COVID-19 (confirmed: 210; suspected: 35). Most COVID-19 was of mild (44.1%) or moderate (46.5%) severity, but 9% had severe/life-threatening COVID-19. There were 24 serious cases (9.8%) with 23 patients were hospitalized; 22 recovered and 2 died. At study cut-off, 241 patients (98.4%) had recovered or were recovering or had recovered with sequelae and 2 (0.8%) had not recovered. Ofatumumab was temporarily interrupted in 39 (15.9%) patients. Before COVID-19 onset, IgG levels were within the normal range in all COVID-19–affected patients, while IgM was < 0.4 g/l in 23 (9.4%) patients. No patient had a reinfection. Overall, 559 patients were vaccinated (full, 476; partial, 74; unspecified, 9). Breakthrough infection was reported in 1.5% (7/476) patients, and 11 reported COVID-19 after partial vaccination. As of 25 September 2021, the Novartis Safety Database (~ 4713 patient-treatment years) recorded 90 confirmed COVID-19 cases receiving ofatumumab. Most cases were non-serious (n = 80), and ten were serious (1 medically significant, 9 hospitalized, 0 deaths). Among 36 of 90 cases with outcomes reported, 30 recovered and 6 did not recover. Conclusion: COVID-19 in RMS patients on ofatumumab was primarily of mild/moderate severity and non-serious in these observational data. Most recovered from COVID-19 without treatment interruption. Two people died with COVID-19. Breakthrough COVID-19 despite being fully/partially vaccinated was uncommon. © 2022, The Author(s).

Author Keywords
ALITHIOS;  Anti-CD20 therapy;  B-cell therapy;  COVID-19;  Ofatumumab;  Post-marketing;  Relapsing multiple sclerosis;  SARS-CoV-2;  Vaccination

Funding details
National Institutes of HealthNIH
U.S. Department of DefenseDOD
National Multiple Sclerosis SocietyNMSS
Conrad N. Hilton FoundationCNHF
Novartis
Roche
Biogen
Novartis Pharma
TG Therapeutics

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

Testing the amyloid cascade hypothesis: Prevention trials in autosomal dominant Alzheimer disease” (2022) Alzheimer’s and Dementia

Testing the amyloid cascade hypothesis: Prevention trials in autosomal dominant Alzheimer disease
(2022) Alzheimer’s and Dementia, . 

Levin, J.a b c , Vöglein, J.a b , Quiroz, Y.T.d e , Bateman, R.J.f , Ghisays, V.g , Lopera, F.e , McDade, E.f , Reiman, E.g , Tariot, P.N.g , Morris, J.C.f

a Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
b German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
c Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
d Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, United States
e Grupo de Neurociencias, Universidad de Antioquia, Antioquia, Colombia
f Washington University School of Medicine, Saint Louis, MO, United States
g Banner Alzheimer’s Institute, Phoenix, AZ, United States

Abstract
Objective: The amyloid cascade hypothesis of Alzheimer disease (AD) has been increasingly challenged. Here, we aim to refocus the amyloid cascade hypothesis on its original premise that the accumulation of amyloid beta (Aβ) peptide is the primary and earliest event in AD pathogenesis as based on current evidence, initiating several pathological events and ultimately leading to AD dementia. Background: An ongoing debate about the validity of the amyloid cascade hypothesis for AD has been triggered by clinical trials with investigational disease-modifying drugs targeting Aβ that have not demonstrated consistent clinically meaningful benefits. Updated Hypothesis: It is an open question if monotherapy targeting Aβ pathology could be markedly beneficial at a stage when the brain has been irreversibly damaged by a cascade of pathological changes. Interventions in cognitively unimpaired individuals at risk for dementia, during amyloid-only and pre-amyloid stages, are more appropriate for proving or refuting the amyloid hypothesis. Our updated hypothesis states that anti-Aβ investigational therapies are likely to be most efficacious when initiated in the preclinical (asymptomatic) stages of AD and specifically when the disease is driven primarily by amyloid pathology. Given the young age at symptom onset and the deterministic nature of the mutations, autosomal dominant AD (ADAD) mutation carriers represent the ideal population to evaluate the efficacy of putative disease-modifying Aβ therapies. Major Challenges for the Hypothesis: Key challenges of the amyloid hypothesis include the recognition that disrupted Aβ homeostasis alone is insufficient to produce the AD pathophysiologic process, poor correlation of Aβ with cognitive impairment, and inconclusive data regarding clinical efficacy of therapies targeting Aβ. Challenges of conducting ADAD research include the rarity of the disease and uncertainty of the generalizability of ADAD findings for the far more common “sporadic” late-onset AD. Linkage to Other Major Theories: The amyloid cascade hypothesis, modified here to pertain to the preclinical stage of AD, still needs to be integrated with the development and effects of tauopathy and other co-pathologies, including neuroinflammation, vascular insults, synucleinopathy, and many others. © 2022 the Alzheimer’s Association

Author Keywords
Alzheimer disease;  amyloid hypothesis;  autosomal dominant Alzheimer disease;  preclinical;  prevention;  therapy

Funding details
R01AG054671
National Institutes of HealthNIHR01NS065667, R1AG046179, U01AG042791‐S1, UF1AG032438
Foundation for the National Institutes of HealthFNIHR01/R56 AG053267
National Institute on AgingNIA
NIH Office of the DirectorODDP5OD019833
Alzheimer’s AssociationAA
Abbott Laboratories
Eli Lilly and Company
Pfizer
Genentech
Novartis
Roche
Massachusetts General HospitalMGH1200‐228010, 1200‐228767
Biogen
BrightFocus FoundationBFF
AbbVie
Departamento Administrativo de Ciencia, Tecnología e Innovación (COLCIENCIAS)
University of RochesterURP01AG003991, P01AG026276, P50AG005681
Janssen Pharmaceuticals
Banner Alzheimer’s Foundation
ACADIA PharmaceuticalsACADIA
GHR FoundationGHR
NOMIS Stiftung

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