Genetic and multi-omic resources for Alzheimer disease and related dementia from the Knight Alzheimer Disease Research Center
(2024) Scientific Data, 11 (1), art. no. 768, .
Fernandez, M.V.a b c , Liu, M.a b , Beric, A.a b , Johnson, M.a b , Cetin, A.a b , Patel, M.a b , Budde, J.a b , Kohlfeld, P.a b , Bergmann, K.a b , Lowery, J.a b , Flynn, A.a b , Brock, W.a b , Sanchez Montejo, B.a b , Gentsch, J.a b , Sykora, N.a b , Norton, J.a b , Gentsch, J.a b , Valdez, O.a b , Gorijala, P.a b , Sanford, J.a b , Sun, Y.a b , Wang, C.a b , Western, D.a b , Timsina, J.a b , Mangetti Goncalves, T.d , Do, A.N.a b e , Sung, Y.J.a b , Zhao, G.d f g , Morris, J.C.f h , Moulder, K.f h , Holtzman, D.M.f h i , Bateman, R.J.f h i j , Karch, C.a h i j , Hassenstab, J.f h , Xiong, C.e f h j , Schindler, S.E.f h , Balls-Berry, J.f h , Benzinger, T.L.S.f h j k , Perrin, R.J.g h j , Denny, A.f h , Snider, B.J.f h i , Stark, S.L.h l , Ibanez, L.a b f j , Cruchaga, C.a b d f h i j
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO 63110, United States
c Research Center and Memory Clinic, ACE Alzheimer Center, Barcelona, Spain
d Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
e Division of Biostatistics, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
g Pathology and Immunology Department, Washington University School of Medicine, St. Louis, MO 63110, United States
h Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
i Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
j Dominantly Inherited Alzheimer Disease Network (DIAN), St. Louis, United States
k Radiology Department, Washington University School of Medicine, St. Louis, MO 63110, United States
l Occupational Therapy, Neurology and Social Work, St. Louis, United States
Abstract
The Knight-Alzheimer Disease Research Center (Knight-ADRC) at Washington University in St. Louis has pioneered and led worldwide seminal studies that have expanded our clinical, social, pathological, and molecular understanding of Alzheimer Disease. Over more than 40 years, research volunteers have been recruited to participate in cognitive, neuropsychologic, imaging, fluid biomarkers, genomic and multi-omic studies. Tissue and longitudinal data collected to foster, facilitate, and support research on dementia and aging. The Genetics and high throughput -omics core (GHTO) have collected of more than 26,000 biological samples from 6,625 Knight-ADRC participants. Samples available include longitudinal DNA, RNA, non-fasted plasma, cerebrospinal fluid pellets, and peripheral blood mononuclear cells. The GHTO has performed deep molecular profiling (genomic, transcriptomic, epigenomic, proteomic, and metabolomic) from large number of brain (n = 2,117), CSF (n = 2,012) and blood/plasma (n = 8,265) samples with the goal of identifying novel risk and protective variants, identify novel molecular biomarkers and causal and druggable targets. Overall, the resources available at GHTO support the increase of our understanding of Alzheimer Disease. © The Author(s) 2024.
Document Type: Data Paper
Publication Stage: Final
Source: Scopus
Plasma galectin-9 relates to cognitive performance and inflammation among adolescents with vertically acquired HIV
(2024) AIDS, 38 (10), pp. 1460-1467. Cited 1 time.
Moar, P.a , Linn, K.b , Premeaux, T.A.a , Bowler, S.a , Sardarni, U.K.c , Gopalan, B.P.d e , Shwe, E.E.f , San, T.f , Han, H.b , Clements, D.g , Hlaing, C.S.b , Kyu, E.H.b , Thair, C.b , Mar, Y.Y.b , Nway, N.b , Mannarino, J.h , Bolzenius, J.h , Mar, S.i , Aye, A.M.M.b , Tandon, R.j , Paul, R.h , Ndhlovu, L.C.a
a Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine, New York, United States
b Department of Pediatrics, Yangon Children’s Hospital, University of Medicine 1, Yangon, Myanmar
c Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, United States
d Division of infectious diseases, St. John’s Research Institute, Bengaluru, India
e Sickle Thrombosis and Vascular Biology Lab, Sickle Cell Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, United States
f Department of Pathology, Yangon Children’s Hospital, University of Medicine 1, Yangon, Myanmar
g Department of Tropical Medicine, Medical Microbiology & Pharmacology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, United States
h Missouri Institute of Mental Health, University of Missouri-St. Louis, Missouri, United States
i Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
j Laboratory of AIDS Research and Immunology, School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
Abstract
Objective: Adolescents with perinatally acquired HIV (AWH) are at an increased risk of poor cognitive development yet the underlying mechanisms remain unclear. Circulating galectin-9 (Gal-9) has been associated with increased inflammation and multimorbidity in adults with HIV despite antiretroviral therapy (ART); however, the relationship between Gal-9 in AWH and cognition remain unexplored. Design: A cross-sectional study of two independent age-matched cohorts from India [AWH on ART (n = 15), ART-naive (n = 15), and adolescents without HIV (AWOH; n = 10)] and Myanmar [AWH on ART (n = 54) and AWOH (n = 22)] were studied. Adolescents from Myanmar underwent standardized cognitive tests. Methods: Plasma Gal-9 and soluble mediators were measured by immunoassays and cellular immune markers by flow cytometry. We used Mann – Whitney U tests to determine group-wise differences, Spearman’s correlation for associations and machine learning to identify a classifier of cognitive status (impaired vs. unimpaired) built from clinical (age, sex, HIV status) and immunological markers. Results: Gal-9 levels were elevated in ART-treated AWH compared with AWOH in both cohorts (all P < 0.05). Higher Gal-9 in AWH correlated with increased levels of inflammatory mediators (sCD14, TNFa, MCP-1, IP-10, IL-10) and activated CD8+ T cells (all P < 0.05). Irrespective of HIV status, higher Gal-9 levels correlated with lower cognitive test scores in multiple domains [verbal learning, visuospatial learning, memory, motor skills (all P < 0.05)]. ML classification identified Gal-9, CTLA-4, HVEM, and TIM-3 as significant predictors of cognitive deficits in adolescents [mean area under the curve (AUC) = 0.837]. Conclusion: Our results highlight a potential role of Gal-9 as a biomarker of inflammation and cognitive health among adolescents with perinatally acquired HIV. Copyright © 2024 The Author(s).
Author Keywords
antiretroviral therapy; galectin-9; inflammation; neurocognition; perinatal HIV
Document Type: Article
Publication Stage: Final
Source: Scopus
Increased intraindividual variability (IIV) in reaction time is the earliest indicator of cognitive change in MS: A two-year observational study
(2024) International Journal of Clinical and Health Psychology, 24 (3), art. no. 100486, .
Pilloni, G.a b , Casper, T.C.c , Mar, S.d , Ness, J.e , Schreiner, T.f , Waltz, M.c , Waubant, E.g , Weinstock-Guttman, B.h , Wheeler, Y.e , Krupp, L.a b , Charvet, L.a b
a Department of Neurology, NYU Grossman School of Medicine, New York, NY, United States
b Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, United States
c University of Utah, Salt Lake City, UT, United States
d Washington University, St. Louis, MO, United States
e University of Alabama, Birmingham, AL, United States
f Children’s Hospital Colorado, Broomfield, CO, United States
g University of California – San Francisco, San Francisco, CA, United States
h University of Buffalo, Williamsville, NY, United States
Abstract
Background: Cognitive decline in multiple sclerosis (MS) is common, but unpredictable, and increases with disease duration. As such, early detection of cognitive decline may improve the effectiveness of interventions. To that end, the Symbol Digit Modalities Test (SDMT) is effective in detecting slow processing speed as it relates to cognitive impairment, and intraindividual variability (IIV) observed in trials assessing continuous reaction time (RT) may be a useful indicator of early cognitive changes. Here, we will assess cognitive IIV changes in adults with early MS. Methods: Adults with relapsing-remitting MS (RRMS), <11 years since diagnosis, were recruited nationally. Baseline and two-year follow-up assessments included Brief International Cognitive Assessment in MS (BICAMS) and Cogstate computerized tests. Intraindividual variability in RT was calculated from psychomotor tasks and data were age-normalized. Results: A total of 44 of the 66 participants completed follow-up (mean age, 34.0 ± 5.5 years; 66 % female; mean disease duration, 4.1 ± 2.9 years; median Expanded Disability Status Scale (EDSS) score, 1.5 [0 to 6.0]). Participants were grouped by SDMT z-score median split. Groups did not differ in demographics or clinical features. The higher baseline SDMT group was faster (p = 0.05) in RT and less variable (lower IIV, p = 0.001). At the two-year follow-up, the higher SDMT group showed increased variability (p = 0.05) compared to the lower SDMT group, with no significant RT or BICAMS changes. Conclusions: In early MS, higher SDMT performance at baseline is associated with less cognitive variability but may indicate susceptibility to increased variability over time, highlighting the importance of monitoring IIV for early cognitive changes. © 2024 The Authors
Author Keywords
Cognitive dysfunction; Computer-assisted testing; Intraindividual variability; Multiple sclerosis; Reaction time; Relapsing remitting
Document Type: Article
Publication Stage: Final
Source: Scopus
Integrating Multisector Molecular Characterization into Personalized Peptide Vaccine Design for Patients with Newly Diagnosed Glioblastoma
(2024) Clinical Cancer Research, 30 (13), pp. 2729-2742.
Johanns, T.M.a b c , Garfinkle, E.A.R.d , Miller, K.E.d , Livingstone, A.J.a , Roberts, K.F.e , Venkata, L.P.R.d , Dowling, J.L.c f , Chicoine, M.R.g , Dacey, R.G.f , Zipfel, G.J.c f , Kim, A.H.c f , Mardis, E.R.d h , Dunn, G.P.i j
a Division of Medical Oncology, Washington University, School of Medicine, St. Louis, MO, United States
b Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University, School of Medicine, St. Louis, MO, United States
c The Brain Tumor Center, Siteman Cancer Center, Washington University, School of Medicine, St. Louis, MO, United States
d The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH, United States
e Department of Pathology and Immunology, Washington University, School of Medicine, St. Louis, MO, United States
f Department of Neurological Surgery, Washington University, School of Medicine, St Louis, MO, United States
g Department of Neurosurgery, University of Missouri in Columbia, Columbia, MO, United States
h Department of Pediatrics, Ohio State University, College of Medicine, Columbus, OH, United States
i Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
j Brain Tumor Immunology and Immunotherapy Program, Department of Neurosurgery, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States
Abstract
Purpose: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. Patients and Methods: In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209). Results: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post- NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. Conclusions: Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM. © 2024 The Authors.
Document Type: Article
Publication Stage: Final
Source: Scopus
Predictors of a relapsing course in myelin oligodendrocyte glycoprotein antibody-associated disease
(2024) Journal of Neurology, Neurosurgery and Psychiatry, art. no. jnnp-2024-333464, .
Virupakshaiah, A.a , Schoeps, V.A.a , Race, J.b , Waltz, M.b , Sharayah, S.c , Nasr, Z.a , Moseley, C.E.a , Zamvil, S.S.a d , Gaudioso, C.c , Schuette, A.b , Casper, T.C.b , Rose, J.b , Flanagan, E.P.e , Rodriguez, M.e , Tillema, J.-M.e , Chitnis, T.f , Gorman, M.P.g , Graves, J.S.h , Benson, L.A.g , Rensel, M.i , Abrams, A.i , Krupp, L.j , Lotze, T.E.k , Aaen, G.l , Wheeler, Y.m , Schreiner, T.n , Waldman, A.o , Chong, J.a , Mar, S.c , Waubant, E.a
a Neurology, UCSF Weill Institute for Neurosciences, San Francisco, CA, United States
b The University of Utah, Salt Lake City, UT, United States
c Department of Neurology, Washington University in St Louis, St Louis, MO, United States
d Program in Immunology, UCSF, San Francisco, CA, United States
e Neurology, Mayo Clinic Rochester, Rochester, MN, United States
f Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
g Boston Children’s Hospital, Boston, MA, United States
h Department of Neurology, University of California San Diego, San Diego, CA, United States
i Cleveland Clinic, Cleveland, OH, United States
j Pediatric MS Center, NYU Langone Health, New York, NY, United States
k Texas Children’s Hospital, Houston, TX, United States
l Loma Linda University Medical Center, Loma Linda, CA, United States
m University of Alabama at Birmingham, Birmingham, AL, United States
n Children’s Hospital Colorado, Aurora, CO, United States
o The Children’s Hospital of Philadelphia, Philadelphia, PA, United States
Abstract
Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described demyelinating disorder, and children represent about 50% of all cases. Almost half of the patients experience relapses, but very few studies have evaluated predictors of relapse risk, challenging clinical management. The study aimed to identify predictors at MOGAD onset that are associated with a relapsing course. Methods: Prospectively collected data from paediatric patients with MOGAD seen by the US Network of Paediatric MS Centres were leveraged. Univariable and adjusted multivariable models were used to predict recurrent disease. Results: We identified 326 MOGAD cases (mean age at first event 8.9 years [SD 4.3], 57% female, 77% white and 74% non-Hispanic) and 46% relapsed during a mean follow-up of 3.9 years (SD 4.1). In the adjusted multivariable model, female sex (HR 1.66, 95% CI 1.17 to 2.36, p=0.004) and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19 to 2.64, p=0.005) were associated with a higher risk of relapsing MOGAD. Maintenance treatment initiated before a second event with rituximab (HR 0.25, 95% CI 0.07 to 0.92, p=0.037) or intravenous immunoglobulin (IVIG) (HR 0.35, 95% CI 0.14 to 0.88, p=0.026) was associated with lower risk of a second event in multivariable analyses. Conversely, maintenance steroids were associated with a higher estimated relapse risk (HR 1.76, 95% CI 0.90 to 3.45, p=0.097). Conclusion: Sex and ethnicity are associated with relapsing MOGAD. Use of rituximab or IVIG therapy shortly after onset is associated with a lower risk of the second event. Preventive treatment after a first event could be considered for those with a higher relapse risk. © Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.
Author Keywords
MULTIPLE SCLEROSIS; NEUROIMMUNOLOGY
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A maternal brain hormone that builds bone
(2024) Nature, .
Babey, M.E.a , Krause, W.C.b , Chen, K.c , Herber, C.B.b i , Torok, Z.b , Nikkanen, J.b j , Rodriguez, R.b k , Zhang, X.d , Castro-Navarro, F.b , Wang, Y.e , Wheeler, E.E.c f , Villeda, S.g , Leach, J.K.c f , Lane, N.E.h , Scheller, E.L.d , Chan, C.K.F.e , Ambrosi, T.H.c , Ingraham, H.A.b
a Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Francisco, San Francisco, CA, United States
b Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, United States
c Department of Orthopaedic Surgery, University of California, Davis, Sacramento, CA, United States
d Department of Medicine, Washington University, St Louis, MO, United States
e Institute for Stem Cell Biology and Regenerative Medicine and Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States
f Department of Biomedical Engineering, University of California, Davis, Davis, CA, United States
g Department of Anatomy, University of California, San Francisco, San Francisco, CA, United States
h Department of Medicine, Division of Rheumatology, University of California, Davis, Sacramento, CA, United States
i Denali Therapeutics, South San Francisco, CA, United States
j Department of Integrative Biology, University of California, Berkeley, Berkeley, CA, United States
k Carmot Therapeutics, Berkeley, CA, United States
Abstract
In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals. © The Author(s) 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Unexpected Low Rate of Amyloid-β Pathology in Multiple Sclerosis Patients
(2024) Annals of Neurology, .
Brier, M.R.a b , Schindler, S.E.a , Salter, A.c , Perantie, D.a , Shelley, N.a , Judge, B.a , Keefe, S.b , Kirmess, K.M.d , Verghese, P.B.d , Yarasheski, K.E.d , Venkatesh, V.d , Raji, C.A.b , Gordon, B.A.b , Bateman, R.J.a , Morris, J.C.a , Naismith, R.T.a , Holtzman, D.M.a , Benzinger, T.L.S.b , Cross, A.H.a
a Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, United States
d C2N Diagnostics, St. Louis, MO, United States
Abstract
The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-β plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-β pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024. © 2024 American Neurological Association.
Funding details
National Institute on AgingNIAR01AG070941, K23AG053426, P01AG026276, CA2016636, P30AG066444, R44 AG059489, P01AG003991
National Institute on AgingNIA
K23NS128325
Alzheimer’s Drug Discovery FoundationADDFGC‐201711‐2013978
Alzheimer’s Drug Discovery FoundationADDF
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Forecasting the Future of Antiphospholipid Syndrome: Prospects and Challenges
(2023) Missouri medicine, Volume 120, Issue 5, Pages 359 – 3661 September 2023
Taylor, A., Kumar, S., Pozzi, N.
a Edward A. Doisy Department of Biochemistry & Molecular Biology, Saint Louis University School of Medicine, St. Louis, MO, United States
Abstract
Antiphospholipid syndrome (APS) is an autoimmune condition affecting young patients, primarily women, negatively impacting their quality of life. APS is under-recognized and underdiagnosed and can have devastating results if untreated, mainly due to uncontrolled thrombosis. Research in the past decades has led to several breakthroughs with important implications for clinical practice. Here, we summarize the state of APS diagnosis, treatment, pathophysiology, and research directions that hold promise for advancing diagnosis and treatment. Copyright 2023 by the Missouri State Medical Association.© This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine