Hope Center Member Publications

The CELLO trial: Protocol of a planned phase 4 study to assess the efficacy of Ocrelizumab in patients with radiologically isolated syndrome
(2022) Multiple Sclerosis and Related Disorders, 68, art. no. 104143, . 

Longbrake, E.E.^a , Hua, L.H.^b , Mowry, E.M.^c , Gauthier, S.A.^d , Alvarez, E.^e , Cross, A.H.^f , Pei, J.^g , Priest, J.^g , Raposo, C.^g , Hafler, D.A.^a , Winger, R.C.^g

^a Department of Neurology, Yale School of Medicine, New Haven, CT, United States
^b Lou Ruvo Center for Brain Health, Cleveland Clinic, Las Vegas, NV, United States
^c The Johns Hopkins University School of Medicine, Baltimore, MD, United States
^d Weill Cornell Medical College, New York, NY, United States
^e Rocky Mountain Multiple Sclerosis Center at Anschutz Medical Campus, University of Colorado, Aurora, CO, United States
^f Washington University School of Medicine, St Louis, MO, United States
^g Genentech, Inc., South San Francisco, CA, United States

Abstract
Background: Patients with radiologically isolated syndrome (RIS) exhibit CNS lesions suggestive of multiple sclerosis (MS) in the absence of overt neurological symptoms characteristic of the disease. They may have concurrent brain atrophy, subtle cognitive impairment, and intrathecal inflammation. At least half ultimately develop MS, cementing RIS as preclinical MS for many. However, high-quality data, including immunologic biomarkers, to guide treatment decisions in this population are lacking. Early intervention with ocrelizumab, a humanized monoclonal antibody approved for relapsing and primary progressive MS that targets CD20+ B-cells, may affect disease course and improve long-term outcomes. The objective of this study is to describe the protocol for CELLO, a clinical trial assessing the effect of ocrelizumab on RIS. Methods: The CELLO clinical trial, a phase 4, multicenter, randomized, double-blind, placebo-controlled study conducted as an academic-industry collaboration, aims to (1) assess the efficacy of ocrelizumab in patients with RIS and (2) identify biomarkers indicative of emerging autoimmunity as well as immune recovery after transient B-cell depletion. The study will enroll 100 participants across ≥15 sites. Participants will be aged 18 to 40 years, have RIS (defined as meeting 2017 revised McDonald criteria for dissemination in space), and have either been diagnosed with RIS within the last 5 years or have had new brain lesions identified within 5 years of study entry. A screening program of first-degree relatives of patients with MS will be used to boost recruitment. Eligible patients will be randomized 1:1 to receive 3 courses of ocrelizumab or placebo at baseline, week 24, and week 48. Patients will subsequently be followed up for ≥3 years. The primary outcome is time to development of new radiological or clinical evidence of MS. Secondary and exploratory objectives will investigate neuroimaging, serological and immunologic biomarkers, cognitive function, and patient-reported outcomes. A substudy using single-cell RNA sequencing to characterize blood and CSF immune cells will assess markers associated with conversion to clinical MS. Conclusion: The CELLO study will improve the understanding of B-cell biology in early MS disease pathophysiology, characterize the emergence of CNS autoimmunity, and provide evidence to inform treatment decision-making for individuals with RIS. ClinicalTrials.gov: NCT04877457 © 2022 Elsevier B.V.

Author Keywords
Biomarker;  Clinical trial;  Multiple sclerosis;  Radiologically isolated syndrome

Funding details
UL1 TR001863
National Institutes of HealthNIHK23 NS107624, K23107624, KL2 TR001862
National Multiple Sclerosis SocietyNMSS
Conrad N. Hilton FoundationCNHF
Genentech
Yale University
Biogen
Patient-Centered Outcomes Research InstitutePCORI
National Center for Advancing Translational SciencesNCATS
F. Hoffmann-La Roche
TG Therapeutics
Horizon Pharmaceuticals

Document Type: Article
Publication Stage: Final
Source: Scopus

Sequence grammar underlying the unfolding and phase separation of globular proteins
(2022) Molecular Cell, 82 (17), pp. 3193-3208.e8. 

Ruff, K.M.^a , Choi, Y.H.^b , Cox, D.^b , Ormsby, A.R.^b , Myung, Y.^c d e , Ascher, D.B.^c d e , Radford, S.E.^f , Pappu, R.V.^a , Hatters, D.M.^b

^a Department of Biomedical Engineering, Center for Science & Engineering of Living Systems, Washington University in St. Louis, St. Louis, MO 63130, United States
^b Department of Biochemistry and Pharmacology and Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3010, Australia
^c Computational Biology and Clinical Informatics, Baker Heart and Diabetes Institute, Melbourne, VIC 3004, Australia
^d Structural Biology and Bioinformatics, Department of Biochemistry and Pharmacology, The University of Melbourne, Melbourne, VIC 3010, Australia
^e Systems and Computational Biology, Bio21 Institute, The University of Melbourne, Melbourne, VIC 3010, Australia
^f Astbury Centre for Structural and Molecular Biology, School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom

Abstract
Aberrant phase separation of globular proteins is associated with many diseases. Here, we use a model protein system to understand how the unfolded states of globular proteins drive phase separation and the formation of unfolded protein deposits (UPODs). We find that for UPODs to form, the concentrations of unfolded molecules must be above a threshold value. Additionally, unfolded molecules must possess appropriate sequence grammars to drive phase separation. While UPODs recruit molecular chaperones, their compositional profiles are also influenced by synergistic physicochemical interactions governed by the sequence grammars of unfolded proteins and cellular proteins. Overall, the driving forces for phase separation and the compositional profiles of UPODs are governed by the sequence grammars of unfolded proteins. Our studies highlight the need for uncovering the sequence grammars of unfolded proteins that drive UPOD formation and cause gain-of-function interactions whereby proteins are aberrantly recruited into UPODs. © 2022 The Authors

Author Keywords
barnase;  chaperonin-containing T-complex;  Cry2;  molecular condensate;  protein deposit;  protein folding;  protein misfolding;  protein quality control;  proteostasis;  SOD1;  superoxide dismutase 1;  TRiC

Funding details
National Institutes of HealthNIH5R01NS056114
Air Force Office of Scientific ResearchAFOSRFA9550-20-1-0241
Wellcome TrustWT204963
Australian Research CouncilARC
National Health and Medical Research CouncilNHMRCDP170103093

Document Type: Article
Publication Stage: Final
Source: Scopus

Silent Infarcts, White Matter Integrity, and Oxygen Metabolic Stress in Young Adults With and Without Sickle Cell Trait
(2022) Stroke, 53 (9), pp. 2887-2895. 

Wang, Y.^a , Guilliams, K.P.^b , Fields, M.E.^c , Fellah, S.^a , Binkley, M.M.^a , Reis, M.^d , Vo, K.D.^d , Chen, Y.^a , Ying, C.^d , Blinder, M.^e , King, A.A.^f , Hulbert, M.L.^c , An, H.^a , Lee, J.-M.^a , Ford, A.L.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Division of Pediatric Neurology, Washington University School of Medicine, St. Louis, MO, United States
^c Division of Pediatric Hematology/Oncology, Washington University School of Medicine, St. Louis, MO, United States
^d Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^e Division of Hematology/Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United States
^f Program in Occupational Therapy and Departments of Pediatrics and Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background: Individuals with sickle cell anemia have heightened risk of stroke and cognitive dysfunction. Given its high prevalence globally, whether sickle cell trait (SCT) is a risk factor for neurological injury has been of interest; however, data have been limited. We hypothesized that young, healthy adults with SCT would show normal cerebrovascular structure and hemodynamic function. Methods: As a case-control study, young adults with (N=25, cases) and without SCT (N=24, controls) underwent brain magnetic resonance imaging to quantify brain volume, microstructural integrity (fractional anisotropy), silent cerebral infarcts (SCI), intracranial stenosis, and aneurysms. Pseudocontinuous arterial spin labeling and asymmetric spin echo sequences measured cerebral blood flow and oxygen extraction fraction, respectively, from which cerebral metabolic oxygen demand was calculated. Imaging metrics were compared between SCT cases and controls. SCI volume was correlated with baseline characteristics. Results: Compared with controls, adults with SCT demonstrated similar normalized brain volumes (SCT 0.80 versus control 0.81, P=0.41), white matter fractional anisotropy (SCT 0.41 versus control 0.43, P=0.37), cerebral blood flow (SCT 62.04 versus control, 61.16 mL/min/100 g, P=0.67), oxygen extraction fraction (SCT 0.27 versus control 0.27, P=0.31), and cerebral metabolic oxygen demand (SCT 2.71 versus control 2.70 mL/min/100 g, P=0.96). One per cohort had an intracranial aneurysm. None had intracranial stenosis. The SCT cases and controls showed similar prevalence and volume of SCIs; however, in the subset of participants with SCIs, the SCT cases had greater SCI volume versus controls (0.29 versus 0.07 mL, P=0.008). Of baseline characteristics, creatinine was mildly elevated in the SCT cohort (0.9 versus 0.8 mg/dL, P=0.053) and correlated with SCI volume (ρ=0.49, P=0.032). In the SCT cohort, SCI distribution was similar to that of young adults with sickle cell anemia. Conclusions: Adults with SCT showed normal cerebrovascular structure and hemodynamic function. These findings suggest that healthy individuals with SCT are unlikely to be at increased risk for early or accelerated ischemic brain injury. © 2022 Lippincott Williams and Wilkins. All rights reserved.

Author Keywords
hemodynamics;  ischemia;  neuroimaging;  oxygen;  sickle cell trait

Funding details
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBIK23HL136904, R01 HL129241
National Institute of Neurological Disorders and StrokeNINDS1K23NS099472-01

Document Type: Article
Publication Stage: Final
Source: Scopus

Association between antidepressant use and ED or hospital visits in outpatients with SARS-CoV-2
(2022) Translational Psychiatry, 12 (1), p. 341. 

Fritz, B.A.^a , Hoertel, N.^b c d , Lenze, E.J.^e , Jalali, F.^f , Reiersen, A.M.^e

^a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
^b Hôpital Corentin-Celton, Issy-les-Moulineaux, Assistance Publique-Hôpitaux de Paris92130, France
^c Paris, France
^d Institut de psychiatrie et neurosciences de Paris (IPNP), INSERM, Paris, France
^e Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Gastroenterology, Saddleback Medical Group, Laguna HillsCA, United States

Abstract
Antidepressants have previously been associated with better outcomes in patients hospitalized with COVID-19, but their effect on clinical deterioration among ambulatory patients has not been fully explored. The objective of this study was to assess whether antidepressant exposure was associated with reduced emergency department (ED) or hospital visits among ambulatory patients with SARS-CoV-2 infection. This retrospective cohort study included adult patients (N = 25 034) with a positive SARS-CoV-2 test performed in a non-hospital setting. Logistic regression analyses tested associations between home use of antidepressant medications and a composite outcome of ED visitation or hospital admission within 30 days. Secondary exposures included individual antidepressants and antidepressants with functional inhibition of acid sphingomyelinase (FIASMA) activity. Patients with antidepressant exposure were less likely to experience the primary composite outcome compared to patients without antidepressant exposure (adjusted odds ratio [aOR] 0.89, 95% CI 0.79-0.99, p = 0.04). This association was only observed with daily doses of at least 20 mg fluoxetine-equivalent (aOR 0.87, 95% CI 0.77-0.99, p = 0.04), but not with daily doses lower than 20 mg fluoxetine-equivalent (aOR 0.94, 95% CI 0.80-1.11, p = 0.48). In exploratory secondary analyses, the outcome incidence was also reduced with exposure to selective serotonin reuptake inhibitors (aOR 0.87, 95% CI 0.75-0.99, p = 0.04), bupropion (aOR 0.70, 95% CI 0.55-0.90, p = 0.005), and FIASMA antidepressant drugs (aOR 0.87, 95% CI 0.77-0.99, p = 0.03). Antidepressant exposure was associated with a reduced incidence of emergency department visitation or hospital admission among SARS-CoV-2 positive patients, in a dose-dependent manner. These data support the FIASMA model of antidepressants’ effects against COVID-19. © 2022. The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Natural locus coeruleus dynamics during feeding
(2022) Science Advances, 8 (33), p. eabn9134. 

Sciolino, N.R.^a , Hsiang, M.^a , Mazzone, C.M.^a , Wilson, L.R.^a , Plummer, N.W.^a , Amin, J.^a , Smith, K.G.^a , McGee, C.A.^b , Fry, S.A.^a , Yang, C.X.^a , Powell, J.M.^a , Bruchas, M.R.^c , Kravitz, A.V.^d , Cushman, J.D.^a , Krashes, M.J.^e , Cui, G.^a , Jensen, P.^a

^a Neurobiology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle ParkNC, United States
^b Comparative Medicine, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle ParkNC, United States
^c Departments of Anesthesiology and Pharmacology, Center for the Neurobiology of Addiction, Pain, Emotion, University of Washington, Seattle, WA, United States
^d Department of Psychiatry, Washington University, St. Louis, MO, United States
^e National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States

Abstract
Recent data demonstrate that noradrenergic neurons of the locus coeruleus (LC-NE) are required for fear-induced suppression of feeding, but the role of endogenous LC-NE activity in natural, homeostatic feeding remains unclear. Here, we found that LC-NE activity was suppressed during food consumption, and the magnitude of this neural response was attenuated as mice consumed more pellets throughout the session, suggesting that LC responses to food are modulated by satiety state. Visual-evoked LC-NE activity was also attenuated in sated mice, suggesting that satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Last, we found that activation of the LC to the lateral hypothalamus pathway suppresses feeding and enhances avoidance and anxiety-like responding. Our findings suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., satiety).

Document Type: Article
Publication Stage: Final
Source: Scopus

Machine Learning Quantifies Accelerated White-Matter Aging in Persons With HIV
(2022) The Journal of Infectious Diseases, 226 (1), pp. 49-58. 

Petersen, K.J.^a , Strain, J.^a , Cooley, S.^a , Vaida, F.^b , Ances, B.M.^a

^a Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^b Department of Family and Preventive Medicine, University of California, San Diego, CA, United States

Abstract
BACKGROUND: Persons with HIV (PWH) undergo white matter changes, which can be quantified using the brain-age gap (BAG), the difference between chronological age and neuroimaging-based brain-predicted age. Accumulation of microstructural damage may be accelerated in PWH, especially with detectable viral load (VL). METHODS: In total, 290 PWH (85% with undetectable VL) and 165 HIV-negative controls participated in neuroimaging and cognitive testing. BAG was measured using a Gaussian process regression model trained to predict age from diffusion magnetic resonance imaging in publicly available normative controls. To test for accelerated aging, BAG was modeled as an age × VL interaction. The relationship between BAG and global neuropsychological performance was examined. Other potential predictors of pathological aging were investigated in an exploratory analysis. RESULTS: Age and detectable VL had a significant interactive effect: PWH with detectable VL accumulated +1.5 years BAG/decade versus HIV-negative controls (P = .018). PWH with undetectable VL accumulated +0.86 years BAG/decade, although this did not reach statistical significance (P = .052). BAG was associated with poorer global cognition only in PWH with detectable VL (P < .001). Exploratory analysis identified Framingham cardiovascular risk as an additional predictor of pathological aging (P = .027). CONCLUSIONS: Aging with detectable HIV and cardiovascular disease may lead to white matter pathology and contribute to cognitive impairment. © The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Author Keywords
aging;  brain age;  diffusion tensor imaging;  HIV;  machine learning;  MRI;  white matter

Document Type: Article
Publication Stage: Final
Source: Scopus

A multidisciplinary Prematurity Research Cohort Study
(2022) PloS One, 17 (8), p. e0272155. 

Stout, M.J.^a , Chubiz, J.^b , Raghuraman, N.^b , Zhao, P.^b , Tuuli, M.G.^c , Wang, L.V.^d , Cahill, A.G.^e , Cuculich, P.S.^f , Wang, Y.^b , Jungheim, E.S.^g , Herzog, E.D.^h , Fay, J.ⁱ , Schwartz, A.L.^j , Macones, G.A.^e , England, S.K.^b

^a Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, United States
^b Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, United States
^c Department of Obstetrics and Gynecology, Brown University, Providence, RI, United States
^d Department of Medical Engineering, California Institute of Technology, Pasadena, CA, United States
^e Department of Women’s Health, University of Texas at Austin, Austin, TX, United States
^f Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, United States
^g Department of Obstetrics and Gynecology, Northwestern University, Chicago, IL, United States
^h Department of Biology, Washington University in St. Louis, St. Louis, MO, United States
ⁱ Department of Biology, University of Rochester, Rochester, NY, United States
^j Department of Pediatrics, Washington University in St. Louis, St. Louis, MO, United States

Abstract
BACKGROUND: Worldwide, 10% of babies are born preterm, defined as a live birth before 37 weeks of gestation. Preterm birth is the leading cause of neonatal death, and survivors face lifelong risks of adverse outcomes. New approaches with large sample sizes are needed to identify strategies to predict and prevent preterm birth. The primary aims of the Washington University Prematurity Research Cohort Study were to conduct three prospective projects addressing possible causes of preterm birth and provide data and samples for future research. STUDY DESIGN: Pregnant patients were recruited into the cohort between January 2017 and January 2020. Consenting patients were enrolled into the study before 20 weeks’ gestation and followed through delivery. Participants completed demographic and lifestyle surveys; provided maternal blood, placenta samples, and cord blood; and participated in up to three projects focused on underlying physiology of preterm birth: cervical imaging (Project 1), circadian rhythms (Project 2), and uterine magnetic resonance imaging and electromyometrial imaging (Project 3). RESULTS: A total of 1260 participants were enrolled and delivered during the study period. Of the participants, 706 (56%) were Black/African American, 494 (39%) were nulliparous, and 185 (15%) had a previous preterm birth. Of the 1260 participants, 1220 (97%) delivered a live infant. Of the 1220 with a live birth, 163 (14.1%) had preterm birth, of which 74 (6.1%) were spontaneous preterm birth. Of the 1220 participants with a live birth, 841 participated in cervical imaging, 1047 contributed data and/or samples on circadian rhythms, and 39 underwent uterine magnetic resonance imaging. Of the 39, 25 underwent electromyometrial imaging. CONCLUSION: We demonstrate feasibility of recruiting and retaining a diverse cohort in a complex prospective, longitudinal study throughout pregnancy. The extensive clinical, imaging, survey, and biologic data obtained will be used to explore cervical, uterine, and endocrine physiology of preterm birth and can be used to develop novel approaches to predict and prevent preterm birth.

Document Type: Article
Publication Stage: Final
Source: Scopus

Differentiating amyloid beta spread in autosomal dominant and sporadic Alzheimer’s disease
(2022) Brain Communications, 4 (3), art. no. fcac085, . 

Levitis, E.^a , Vogel, J.W.^a , Funck, T.^a , Hachinski, V.^b , Gauthier, S.^c , Vöglein, J.^d e f , Levin, J.^d , Gordon, B.A.^g , Benzinger, T.^g , Iturria-Medina, Y.^a , Evans, A.C.^a

^a Montreal Neurological Institute, McGill University, Montreal, QC, Canada
^b Western University, London, ON, Canada
^c McGill Centre for Studies in Aging, McGill University, Montreal, QC, Canada
^d German Center for Neurodegenerative Diseases, Munich, Germany
^e Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
^f Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
^g Department of Radiology, Washington University School of Medicine in Saint Louis, St Louis, MO, United States

Abstract
Amyloid-beta deposition is one of the hallmark pathologies in both sporadic Alzheimer’s disease and autosomal-dominant Alzheimer’s disease, the latter of which is caused by mutations in genes involved in amyloid-beta processing. Despite amyloid-beta deposition being a centrepiece to both sporadic Alzheimer’s disease and autosomal-dominant Alzheimer’s disease, some differences between these Alzheimer’s disease subtypes have been observed with respect to the spatial pattern of amyloid-beta. Previous work has shown that the spatial pattern of amyloid-beta in individuals spanning the sporadic Alzheimer’s disease spectrum can be reproduced with high accuracy using an epidemic spreading model which simulates the diffusion of amyloid-beta across neuronal connections and is constrained by individual rates of amyloid-beta production and clearance. However, it has not been investigated whether amyloid-beta deposition in the rarer autosomal-dominant Alzheimer’s disease can be modelled in the same way, and if so, how congruent the spreading patterns of amyloid-beta across sporadic Alzheimer’s disease and autosomal-dominant Alzheimer’s disease are. We leverage the epidemic spreading model as a data-driven approach to probe individual-level variation in the spreading patterns of amyloid-beta across three different large-scale imaging datasets (2 sporadic Alzheimer’s disease, 1 autosomal-dominant Alzheimer’s disease). We applied the epidemic spreading model separately to the Alzheimer’s Disease Neuroimaging initiative (n = 737), the Open Access Series of Imaging Studies (n = 510) and the Dominantly Inherited Alzheimer’s Network (n = 249), the latter two of which were processed using an identical pipeline. We assessed inter-and intra-individual model performance in each dataset separately and further identified the most likely subject-specific epicentre of amyloid-beta spread. Using epicentres defined in previous work in sporadic Alzheimer’s disease, the epidemic spreading model provided moderate prediction of the regional pattern of amyloid-beta deposition across all three datasets. We further find that, whilst the most likely epicentre for most amyloid-beta-positive subjects overlaps with the default mode network, 13% of autosomal-dominant Alzheimer’s disease individuals were best characterized by a striatal origin of amyloid-beta spread. These subjects were also distinguished by being younger than autosomal-dominant Alzheimer’s disease subjects with a default mode network amyloid-beta origin, despite having a similar estimated age of symptom onset. Together, our results suggest that most autosomal-dominant Alzheimer’s disease patients express amyloid-beta spreading patterns similar to those of sporadic Alzheimer’s disease, but that there may be a subset of autosomal-dominant Alzheimer’s disease patients with a separate, striatal phenotype. © 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
Alzheimer’s disease;  amyloid beta;  brain networks;  diffusion models

Document Type: Article
Publication Stage: Final
Source: Scopus

Detection of β-amyloid positivity in Alzheimer’s Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers
(2021) Brain Communications, 3 (2), art. no. fcab008, . Cited 13 times.

Tosun, D.^a b , Veitch, D.^b , Aisen, P.^c , Jack, C.R.^d , Jagust, W.J.^e , Petersen, R.C.^f g , Saykin, A.J.^h i j , Bollinger, J.^k l , Ovod, V.^k l , Mawuenyega, K.G.^k l , Bateman, R.J.^k l m , Shaw, L.M.ⁿ , Trojanowski, J.Q.^o , Blennow, K.^a p , Zetterberg, H.^a p q r , Weiner, M.W.^a b

^a San Francisco Veterans Affairs Medical Center, San Francisco, CA, United States
^b Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
^c Alzheimer’s Therapeutic Research Institute (ATRI), Keck School of Medicine, University of Southern California, San Diego, CA, United States
^d Department of Radiology, Mayo Clinic, Rochester, MN, United States
^e School of Public Health, Helen Wills Neuroscience Institute, University of California, Berkeley, CA, United States
^f Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, United States
^g Department of Neurology, Mayo Clinic, Rochester, MN, United States
^h Department of Radiology and Imaging Sciences, Center for Neuroimaging, Indiana University School of Medicine, Indianapolis, IN, United States
ⁱ Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, United States
^j Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
^k Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^l Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^m Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
ⁿ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
^o Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
^p Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
^q Department of Neurodegenerative Disease, Ucl Institute of Neurology, London, United Kingdom
^r Uk Dementia Research Institute at Ucl, London, United Kingdom

Abstract
In vivo gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid42 or the β-amyloid42/β-amyloid40 ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer’s disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer’s disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer’s Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid42/β-amyloid40, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, APOE genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid42/β-amyloid40 as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly APOE ϵ4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 0.21-0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04-0.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify β-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, APOE, global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid42/β-amyloid40 may be improved by age and APOE genotype. © 2021 The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Author Keywords
Alzheimer’s;  MRI;  PET;  plasma;  β-amyloid

Document Type: Article
Publication Stage: Final
Source: Scopus