Publications

Hope Center member publications

List of publications for the week of September 27, 2021

Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk” (2021) Journal of Neurodevelopmental Disorders

Genetic counseling as preventive intervention: toward individual specification of transgenerational autism risk
(2021) Journal of Neurodevelopmental Disorders, 13 (1), art. no. 39, . 

Marrus, N.a , Turner, T.N.b , Forsen, E.a , Bolster, D.a , Marvin, A.c , Whitehouse, A.d , Klinger, L.e , Gurnett, C.A.f , Constantino, J.N.a

a Department of Psychiatry, Washington University School of Medicine, 660 S. Euclid Ave; Box 8504, St. Louis, MO 63110, United States
b Department of Genetics, Washington University School of Medicine, 660 S. Euclid Ave; Box 8108, St. Louis, MO 63110, United States
c Maryland Center for Developmental Disabilities, Kennedy Krieger Institute, PACT Building/Office 121B; 7000 Tudsbury Road, Baltimore, MD 21244, United States
d Telethon Kids Institute, Perth Children’s Hospital, 15 Hospital Avenue, Nedlands, WA 6009, United States
e TEACCH Autism Program, Department of Psychiatry, University of North Carolina at Chapel Hill, Campus Box #7180, Chapel Hill, NC 27599-7180, United States
f Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave; Box 8111, St. Louis, MO 63110, United States

Abstract
Background: Although autism spectrum disorders (ASD) are among the most heritable of all neuropsychiatric syndromes, most affected children are born to unaffected parents. Recently, we reported an average increase of 3–5% over general population risk of ASD among offspring of adults who have first-degree relatives with ASD in a large epidemiologic family sample. A next essential step is to investigate whether there are measurable characteristics of individual parents placing them at higher or lower recurrence risk, as this information could allow more personalized genetic counseling. Methods: We assembled what is to our knowledge the largest collection of data on the ability of four measurable characteristics of unaffected prospective parents to specify risk for autism among their offspring: (1) sub clinical autistic trait burden, (2) parental history of a sibling with ASD, (3) transmitted autosomal molecular genetic abnormalities, and (4) parental age. Leveraging phenotypic and genetic data in curated family cohorts, we evaluate the respective associations between these factors and child outcome when autism is present in the family in the parental generation. Results: All four characteristics were associated with elevation in offspring risk; however, the magnitude of their predictive power—with the exception of isolated rare inherited pathogenic variants —does not yet reach a threshold that would typically be considered actionable for reproductive decision-making. Conclusions: Individual specification of risk to offspring of adults in ASD-affected families is not straightforwardly improved by ascertainment of parental phenotype, and it is not yet clear whether genomic screening of prospective parents in families affected by idiopathic ASD is warranted as a clinical standard. Systematic screening of affected family members for heritable pathogenic variants, including rare sex-linked mutations, will identify a subset of families with substantially elevated transmission risk. Polygenic risk scores are only weakly predictive at this time but steadily improving and ultimately may enable more robust prediction either singly or when combined with the risk variables examined in this study. © 2021, The Author(s).

Author Keywords
Early detection;  Family studies;  Genetic counseling;  Personalized medicine;  Reproductive health planning

Funding details
National Institutes of HealthNIH
National Institute of Mental HealthNIMHK08 MH112891, R00MH117165
National Cancer InstituteNCI30 CA91842
National Institute of Child Health and Human DevelopmentNICHD1P50HD103525
National Center for Research ResourcesNCRR
Institute of Clinical and Translational SciencesICTS
Autism Science FoundationASF
Georgia Clinical and Translational Science AllianceGaCTSA1TR000448

Document Type: Article
Publication Stage: Final
Source: Scopus

Falls: A marker of preclinical Alzheimer disease: A cohort study protocol” (2021) BMJ Open

Falls: A marker of preclinical Alzheimer disease: A cohort study protocol
(2021) BMJ Open, 11 (9), art. no. e050820, . 

Bollinger, R.M.a , Keleman, A.a , Thompson, R.b , Westerhaus, E.b , Fagan, A.M.b , Benzinger, T.L.S.c , Schindler, S.E.b , Xiong, C.d , Balota, D.b e , Morris, J.C.b , Ances, B.M.b , Stark, S.L.a

a Program in Occupational Therapy, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
d Division of Biostatistics, Washington University, School of Medicine, St. Louis, MO, United States
e Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Introduction Progression to symptomatic Alzheimer disease (AD) occurs slowly over a series of preclinical stages. Declining functional mobility may be an early indicator of loss of brain network integration and may lead to an increased risk of experiencing falls. It is unknown whether measures of functional mobility and falls are preclinical markers of AD. The purpose of this study is to examine (1) the relationship between falls and functional mobility with AD biomarkers to determine when falls occur within the temporal progression to symptomatic Alzheimer disease, and (2) the attentional compared with perceptual/motor systems that underlie falls and functional mobility changes seen with AD. Methods and analysis This longitudinal cohort study will be conducted at the Knight Alzheimer Disease Research Center. Approximately 350 cognitively normal participants (with and without preclinical AD) will complete an in-home visit every year for 4 years. During each yearly assessment, functional mobility will be assessed using the Performance Oriented Mobility Assessment, Timed Up and Go, and Timed Up and Go dual task. Data regarding falls (including number and severity) will be collected monthly by self-report and confirmed through interviews. This study will leverage ongoing neuropsychological assessments and neuroimaging (including molecular imaging using positron emission tomography and MRI) performed by the Knight Alzheimer Disease Research Center. Relationships between falls and biomarkers of amyloid, tau and neurodegeneration will be evaluated. Ethics and dissemination This study was approved by the Washington University in St. Louis Institutional Review Board (reference number 201807135). Written informed consent will be obtained in the home prior to the collection of any study data. Results will be published in peer-reviewed publications and presented at national and international conferences. Trial registration number NCT04949529; Pre-results. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Author Keywords
adult neurology;  dementia;  neurological injury;  neuropathology;  neurophysiology

Funding details
P01 AG03991
P01 AG026276, P30 AG066444
National Institute on AgingNIA1 R01 AG057680-01A1

Document Type: Article
Publication Stage: Final
Source: Scopus

COVID-19 in Patients With Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody Disease in North America: From the COViMS Registry” (2021) Neurology(R) Neuroimmunology & Neuroinflammation

COVID-19 in Patients With Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody Disease in North America: From the COViMS Registry
(2021) Neurology(R) Neuroimmunology & Neuroinflammation, 8 (5), . 

Newsome, S.D.a , Cross, A.H.b , Fox, R.J.b , Halper, J.b , Kanellis, P.b , Bebo, B.b , Li, D.b , Cutter, G.R.b , Rammohan, K.W.b , Salter, A.b

a From the Johns Hopkins University School of Medicine (S.D.N.), Baltimore, MD; Washington University in St. Louis School of Medicine (A.H.C., A.S.), MO; Mellen Center for MS (R.J.F.), Cleveland Clinic, OH; Consortium of MS Centers (J.H.), Hackensack, NJ; MS Society of Canada (P.K.), Toronto, Ontario, Canada; National Multiple Sclerosis Society (B.B.) New York, NY; University of British Columbia (D.L.), Vancouver, British Columbia, Canada; The University of Alabama at Birmingham (G.R.C.); and University of Miami School of Medicine (K.W.R.), FL. snewsom2@jhmi.edu
b From the Johns Hopkins University School of Medicine (S.D.N.), Baltimore, MD; Washington University in St. Louis School of Medicine (A.H.C., A.S.), MO; Mellen Center for MS (R.J.F.), Cleveland Clinic, OH; Consortium of MS Centers (J.H.), Hackensack, NJ; MS Society of Canada (P.K.), Toronto, Ontario, Canada; National Multiple Sclerosis Society (B.B.) New York, NY; University of British Columbia (D.L.), Vancouver, British Columbia, Canada; The University of Alabama at Birmingham (G.R.C.); and University of Miami School of Medicine (K.W.R.), FL

Abstract
BACKGROUND AND OBJECTIVE: To describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). METHODS: The COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using t-tests, Pearson χ2 tests, or Fisher exact tests for categorical variables. Univariate logistic regression models examined effects of risk factors and COVID-19 clinical severity. RESULTS: As of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were laboratory positive for SARS-CoV-2 and taking rituximab at the time of COVID-19 diagnosis. Most patients with NMOSD were not hospitalized (64.9% [95% CI: 53.2%-75.5%]), whereas 15.6% (95% CI: 8.3%-25.6%) were hospitalized only, 9.1% (95% CI: 3.7%-17.8%) were admitted to the ICU and/or ventilated, and 10.4% (95% CI: 4.6%-19.5%) died. In patients with NMOSD, having a comorbidity was the sole factor identified for poorer COVID-19 outcome (OR = 6.0, 95% CI: 1.79-19.98). Most patients with MOGAD were laboratory positive for SARS-CoV-2, and almost half were taking rituximab. Among patients with MOGAD, 75.0% were not hospitalized, and no deaths were recorded; no factors were different between those not hospitalized and those hospitalized, admitted to the ICU, or ventilated. DISCUSSION: Among the reported patients with NMOSD, a high mortality rate was observed, and the presence of comorbid conditions was associated with worse COVID-19 outcome. There were no deaths reported in the patients with MOGAD, although these observations are limited due to small sample size. Copyright © 2021 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

Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease” (2021) JAMA Neurology

Head-to-Head Comparison of 8 Plasma Amyloid-β 42/40 Assays in Alzheimer Disease
(2021) JAMA Neurology, . 

Janelidze, S.a , Teunissen, C.E.b , Zetterberg, H.c d e f , Allué, J.A.g , Sarasa, L.g , Eichenlaub, U.h , Bittner, T.i , Ovod, V.j , Verberk, I.M.W.b , Toba, K.k l , Nakamura, A.m , Bateman, R.J.j , Blennow, K.d n , Hansson, O.a o

a Clinical Memory Research Unit, Department of Clinical Sciences Malmo, Lund University, Solvegatan 19, BMC B11, Lund, 221 84, Sweden
b Neurochemistry Laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam University Medical Center, Amsterdam, Netherlands
c Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
d Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
e Department of Neurodegenerative Disease, University College London, Institute of Neurology, London, United Kingdom
f United Kingdom Dementia Research Institute, University College London, London, United Kingdom
g Mass Spectrometry Laboratory, Araclon Biotech, Zaragoza, Spain
h Roche Diagnostics, Penzberg, Germany
i F. Hoffmann-La Roche, Basel, Switzerland
j Department of Neurology, Washington University, School of Medicine, St Louis, MO, United States
k National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
l Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
m Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Aichi, Japan
n Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden
o Memory Clinic, Skåne University Hospital, S:t Johannesgatan 8, Malmö, SE-20502, Sweden

Abstract
Importance: Blood-based tests for brain amyloid-β (Aβ) pathology are needed for widespread implementation of Alzheimer disease (AD) biomarkers in clinical care and to facilitate patient screening and monitoring of treatment responses in clinical trials. Objective: To compare the performance of plasma Aβ42/40 measured using 8 different Aβ assays when detecting abnormal brain Aβ status in patients with early AD. Design, Setting, and Participants: This study included 182 cognitively unimpaired participants and 104 patients with mild cognitive impairment from the BioFINDER cohort who were enrolled at 3 different hospitals in Sweden and underwent Aβ positron emission tomography (PET) imaging and cerebrospinal fluid (CSF) and plasma collection from 2010 to 2014. Plasma Aβ42/40 was measured using an immunoprecipitation-coupled mass spectrometry developed at Washington University (IP-MS-WashU), antibody-free liquid chromatography MS developed by Araclon (LC-MS-Arc), and immunoassays from Roche Diagnostics (IA-Elc); Euroimmun (IA-EI); and Amsterdam University Medical Center, ADx Neurosciences, and Quanterix (IA-N4PE). Plasma Aβ42/40 was also measured using an IP-MS-based method from Shimadzu in 200 participants (IP-MS-Shim) and an IP-MS-based method from the University of Gothenburg (IP-MS-UGOT) and another immunoassay from Quanterix (IA-Quan) among 227 participants. For validation, 122 participants (51 cognitively normal, 51 with mild cognitive impairment, and 20 with AD dementia) were included from the Alzheimer Disease Neuroimaging Initiative who underwent Aβ-PET and plasma Aβ assessments using IP-MS-WashU, IP-MS-Shim, IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays. Main Outcomes and Measures: Discriminative accuracy of plasma Aβ42/40 quantified using 8 different assays for abnormal CSF Aβ42/40 and Aβ-PET status. Results: A total of 408 participants were included in this study. In the BioFINDER cohort, the mean (SD) age was 71.6 (5.6) years and 49.3% of the cohort were women. When identifying participants with abnormal CSF Aβ42/40 in the whole cohort, plasma IP-MS-WashU Aβ42/40 showed significantly higher accuracy (area under the receiver operating characteristic curve [AUC], 0.86; 95% CI, 0.81-0.90) than LC-MS-Arc Aβ42/40, IA-Elc Aβ42/40, IA-EI Aβ42/40, and IA-N4PE Aβ42/40 (AUC range, 0.69-0.78; P <.05). Plasma IP-MS-WashU Aβ42/40 performed significantly better than IP-MS-UGOT Aβ42/40 and IA-Quan Aβ42/40 (AUC, 0.84 vs 0.68 and 0.64, respectively; P <.001), while there was no difference in the AUCs between IP-MS-WashU Aβ42/40 and IP-MS-Shim Aβ42/40 (0.87 vs 0.83; P =.16) in the 2 subcohorts where these biomarkers were available. The results were similar when using Aβ-PET as outcome. Plasma IPMS-WashU Aβ42/40 and IPMS-Shim Aβ42/40 showed highest coefficients for correlations with CSF Aβ42/40 (r range, 0.56-0.65). The BioFINDER results were replicated in the Alzheimer Disease Neuroimaging Initiative cohort (mean [SD] age, 72.4 [5.4] years; 43.4% women), where the IP-MS-WashU assay performed significantly better than the IP-MS-UGOT, IA-Elc, IA-N4PE, and IA-Quan assays but not the IP-MS-Shim assay. Conclusions and Relevance: The results from 2 independent cohorts indicate that certain MS-based methods performed better than most of the immunoassays for plasma Aβ42/40 when detecting brain Aβ pathology. © 2021 American Medical Association. All rights reserved.

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

Sex Differences in the Role of CNIH3 on Spatial Memory and Synaptic Plasticity” (2021) Biological Psychiatry

Sex Differences in the Role of CNIH3 on Spatial Memory and Synaptic Plasticity
(2021) Biological Psychiatry, . 

Frye, H.E.a b h , Izumi, Y.c d e , Harris, A.N.f , Williams, S.B.a b , Trousdale, C.R.a b , Sun, M.-Y.c , Sauerbeck, A.D.g , Kummer, T.T.g , Mennerick, S.c d e , Zorumski, C.F.c d e , Nelson, E.C.c , Dougherty, J.D.c f , Morón, J.A.a b c d

a Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
b Pain Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
e Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
f Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
g Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
h Program in Neuroscience, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Background: CNIH3 is an AMPA receptor (AMPAR) auxiliary protein prominently expressed in the dorsal hippocampus (dHPC), a region that plays a critical role in spatial memory and synaptic plasticity. However, the effects of CNIH3 on AMPAR-dependent synaptic function and behavior have not been investigated. Methods: We assessed a gain-of-function model of Cnih3 overexpression in the dHPC and generated and characterized a line of Cnih3−/− C57BL/6 mice. We assessed spatial memory through behavioral assays, protein levels of AMPAR subunits and synaptic proteins by immunoblotting, and long-term potentiation in electrophysiological recordings. We also utilized a super-resolution imaging workflow, SEQUIN (Synaptic Evaluation and Quantification by Imaging of Nanostructure), for analysis of nanoscale synaptic connectivity in the dHPC. Results: Overexpression of Cnih3 in the dHPC improved short-term spatial memory in female mice but not in male mice. Cnih3−/− female mice exhibited weakened short-term spatial memory, reduced dHPC synapse density, enhanced expression of calcium-impermeable AMPAR (GluA2-containing) subunits in synaptosomes, and attenuated long-term potentiation maintenance compared with Cnih3+/+ control mice; Cnih3−/− males were unaffected. Further investigation revealed that deficiencies in spatial memory and changes in AMPAR composition and synaptic plasticity were most pronounced during the metestrus phase of the estrous cycle in female Cnih3−/− mice. Conclusions: This study identified a novel effect of sex and estrous on CNIH3’s role in spatial memory and synaptic plasticity. Manipulation of CNIH3 unmasked sexually dimorphic effects on spatial memory, synaptic function, AMPAR composition, and hippocampal plasticity. These findings reinforce the importance of considering sex as a biological variable in studies of memory and hippocampal synaptic function. © 2021 Society of Biological Psychiatry

Author Keywords
AMPA receptors;  Hippocampus;  Memory;  Sex differences;  Super-resolution microscopy;  Synaptic plasticity

Funding details
CDI-CORE-2015-505, CDI-CORE-2019-813
National Institutes of HealthNIHDA041781, DA041883, DA042499, DA042581, DA042620, DA045463, DA046436, GM008151, I01BX005204
Brain Research FoundationBRFBRFSG-2017-05
BrightFocus FoundationBFFA2017084S
Foundation for Barnes-Jewish Hospital3770, 4642
Washington University School of Medicine in St. LouisWUSM

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