“Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains” (2022) Molecular Neurodegeneration
Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains(2022) Molecular Neurodegeneration, 17 (1), art. no. 10, .
Bigley, T.M.a , Xiong, M.b c d , Ali, M.f , Chen, Y.b c e , Wang, C.b , Serrano, J.R.b , Eteleeb, A.f g , Harari, O.b f g , Yang, L.h , Patel, S.J.h , Cruchaga, C.b f g , Yokoyama, W.M.h , Holtzman, D.M.b
a Division of Rheumatology, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United Statesb Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United Statesc Division of Biology and Biomedical Sciences (DBBS), Washington University School of Medicine, St. Louis, MO 63110, United Statesd Present address: Genentech, 1 DNA Way, South San Francisco, CA 94080, United Statese Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, MO 63110, United Statesf Department Psychiatry, Washington University School of Medicine (WUSM), 660 S. Euclid Ave. B8134, St. Louis, MO 63110, United Statesg NeuroGenomics and Informatics, Washington University School of Medicine, St. Louis, MO, United Statesh Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States
AbstractBackground: The role of viral infection in Alzheimer Disease (AD) pathogenesis is an area of great interest in recent years. Several studies have suggested an association between the human roseoloviruses, HHV-6 and HHV-7, and AD. Amyloid-β (Aβ) plaques are a hallmark neuropathological finding of AD and were recently proposed to have an antimicrobial function in response to infection. Identifying a causative and mechanistic role of human roseoloviruses in AD has been confounded by limitations in performing in vivo studies. Recent -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Murine roseolovirus (MRV) is a natural murine pathogen that is highly-related to the human roseoloviruses, providing an opportunity to perform well-controlled studies of the impact of roseolovirus on Aβ deposition. Methods: We utilized the 5XFAD mouse model to test whether MRV induces Aβ deposition in vivo. We also evaluated viral load and neuropathogenesis of MRV infection. To evaluate Aβ interaction with MRV, we performed electron microscopy. RNA-sequencing of a cohort of AD brains compared to control was used to investigate the association between human roseolovirus and AD. Results: We found that 5XFAD mice were susceptible to MRV infection and developed neuroinflammation. Moreover, we demonstrated that Aβ interacts with viral particles in vitro and, subsequent to this interaction, can disrupt infection. Despite this, neither peripheral nor brain infection with MRV increased or accelerated Aβ plaque formation. Moreover, −omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Our RNA-sequencing analysis of a cohort of AD brains compared to controls did not show an association between roseolovirus infection and AD. Conclusion: Although MRV does infect the brain and cause transient neuroinflammation, our data do not support a role for murine or human roseoloviruses in the development of Aβ plaque formation and AD. © 2022, The Author(s).
Author KeywordsAlzheimer’s disease; Amyloid-beta; Human roseolovirus; Murine roseolovirus; Neuroinflammation
Funding detailsCDI-CORE-2015-505, CDI-CORE-2019-813National Institutes of HealthNIHT32AI106688–07, T32AR007279–40National Institute on AgingNIAAG062027, P01AG003991, P30AG066444, R01AG044546, R01AG057777, RF1AG053303, RF1AG058501, U01AG058922Foundation for Barnes-Jewish Hospital3770, 4642, R01AG047644, R01NS090934JPB FoundationCure Alzheimer’s FundCAFWashington University School of Medicine in St. LouisWUSMCenter for Cellular Imaging, Washington UniversityWUCCITau Consortium
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Resting state functional connectivity provides mechanistic predictions of future changes in sedentary behavior” (2022) Scientific Reports
Resting state functional connectivity provides mechanistic predictions of future changes in sedentary behavior(2022) Scientific Reports, 12 (1), art. no. 940, .
Morris, T.P.a , Kucyi, A.a , Anteraper, S.A.a , Geddes, M.R.b c , Nieto-Castañon, A.a , Burzynska, A.d , Gothe, N.P.e f , Fanning, J.g , Salerno, E.A.h , Whitfield-Gabrieli, S.a i , Hillman, C.H.a j , McAuley, E.e f , Kramer, A.F.a e
a Department of Psychology, Northeastern University, 435 ISEC, 360 Huntington Avenue, Boston, 02115, United Statesb Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Canadac Brigham and Women’s Hospital, Harvard Medical School, Cambridge, United Statesd Department of Human Development and Family Studies, Colorado State University, Fort Collins, United Statese Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana Champaign, Urbana, United Statesf Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign, Urbana, IL, United Statesg Department of Health and Exercise Sciences, Wake Forrest University, Winston-Salem, NC, United Statesh Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St. Louis, St. Louis, MO, United Statesi McGovern Institute for Brain Research, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United Statesj Department of Physical Therapy, Movement, and Rehabilitation Sciences, Northeastern University, Boston, MA, United States
AbstractSedentary behaviors are increasing at the cost of millions of dollars spent in health care and productivity losses due to physical inactivity-related deaths worldwide. Understanding the mechanistic predictors of sedentary behaviors will improve future intervention development and precision medicine approaches. It has been posited that humans have an innate attraction towards effort minimization and that inhibitory control is required to overcome this prepotent disposition. Consequently, we hypothesized that individual differences in the functional connectivity of brain regions implicated in inhibitory control and physical effort decision making at the beginning of an exercise intervention in older adults would predict the change in time spent sedentary over the course of that intervention. In 143 healthy, low-active older adults participating in a 6-month aerobic exercise intervention (with three conditions: walking, dance, stretching), we aimed to use baseline neuroimaging (resting state functional connectivity of two a priori defined seed regions), and baseline accelerometer measures of time spent sedentary to predict future pre-post changes in objectively measured time spent sedentary in daily life over the 6-month intervention. Our results demonstrated that functional connectivity between (1) the anterior cingulate cortex and the supplementary motor area and (2) the right anterior insula and the left temporoparietal/temporooccipital junction, predicted changes in time spent sedentary in the walking group. Functional connectivity of these brain regions did not predict changes in time spent sedentary in the dance nor stretch and tone conditions, but baseline time spent sedentary was predictive in these conditions. Our results add important knowledge toward understanding mechanistic associations underlying complex out-of-session sedentary behaviors within a walking intervention setting in older adults. © 2022, The Author(s).
Funding detailsNational Institutes of HealthNIHNational Institute on AgingNIAR37 AG025667
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Prediction of Individual Analgesic Response to Intravenous Lidocaine in Painful Diabetic Peripheral Neuropathy” (2022) Clinical Journal of Pain
Prediction of Individual Analgesic Response to Intravenous Lidocaine in Painful Diabetic Peripheral Neuropathy(2022) Clinical Journal of Pain, 38 (2), pp. 65-76.
Todorovic, M.S.a , Frey, K.b , Swarm, R.A.b c , Bottros, M.e , Rao, L.b c , Tallchief, D.b , Kraus, K.b , Meacham, K.b c , Bakos, K.d , Zang, X.f , Lee, J.B.f , Kagan, L.f g , Haroutounian, S.b c
a Department of Anesthesiology, Virginia Mason Medical Center, Seattle, WA, United Statesb Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United Statesc Washington University, Pain Center, Saint Louis, MO, United Statesd Investigational Drug Service, Department of Pharmacy, Barnes-Jewish Hospital, Saint Louis, MO, United Statese Department of Anesthesiology, Keck School of Medicine of USC, Los Angeles, CA, United Statesf Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers The State University of New Jersey, Piscataway, NJ, United Statesg Center of Excellence for Pharmaceutical Translational Research and Education, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, NJ, United States
AbstractObjectives: Intravenous lidocaine can alleviate painful diabetic peripheral neuropathy (DPN) in some patients. Whether quantitative sensory testing (QST) can identify treatment responders has not been prospectively tested. Materials and Methods: This was a prospective, randomized, double- blind, crossover, placebo-controlled trial comparing intravenous lidocaine to normal saline (placebo) for painful DPN. Thirty-four participants with painful DPN were enrolled and administered intravenous lidocaine (5 mg/kg ideal body weight) or placebo as a 40-minute infusion, after a battery of QST parameters were tested on the dorsal foot, with a 3-week washout period between infusions. Results: Thirty-one participants completed both study sessions and were included in the final analysis. Lidocaine resulted in a 51% pain reduction 60 to 120 minutes after infusion initiation, as assessed on a 0 to 10 numerical rating scale, while placebo resulted in a 33.5% pain reduction (difference=17.6%, 95% confidence interval [CI], 1.9%-33.3%, P=0.03). Neither mechanical pain threshold, heat pain threshold, or any of the other measured QST parameters predicted the response to treatment. Lidocaine administration reduced mean Neuropathic Pain Symptom Inventory paresthesia/ dysesthesia scores when compared with placebo by 1.29 points (95% CI, -2.03 to -0.55, P=0.001), and paroxysmal pain scores by 0.84 points (95% CI, -1.62 to -0.56, P=0.04), without significant changes in burning, pressing or evoked pain subscores. Discussion: While some participants reported therapeutic benefit from lidocaine administration, QST measures alone were not predictive of response to treatment. Further studies, powered to test more complex phenotypic interactions, are required to identify reliable predictors of response to pharmacotherapy in patients with DPN. © 2021 Wolters Kluwer Health, Inc.
Author KeywordsChronic pain; Diabetic peripheral neuropathy; DPN; Lidocaine; Neuropathic pain
Funding detailsNational Institutes of HealthNIHUL1 TR002345National Center for Advancing Translational SciencesNCATSDiabetes Research Center, University of WashingtonDRC, UW
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Variant-dependent heterogeneity in amyloid β burden in autosomal dominant Alzheimer’s disease: cross-sectional and longitudinal analyses of an observational study” (2022) The Lancet Neurology
Variant-dependent heterogeneity in amyloid β burden in autosomal dominant Alzheimer’s disease: cross-sectional and longitudinal analyses of an observational study(2022) The Lancet Neurology, 21 (2), pp. 140-152. Cited 1 time.
Chhatwal, J.P.a b c , Schultz, S.A.a b , McDade, E.d , Schultz, A.P.a b , Liu, L.a c , Hanseeuw, B.J.a b i , Joseph-Mathurin, N.e , Feldman, R.e , Fitzpatrick, C.D.b c , Sparks, K.P.b , Levin, J.j k n , Berman, S.B.l , Renton, A.E.aa , Esposito, B.T.aa , Fernandez, M.V.f , Sung, Y.J.f , Lee, J.H.p , Klunk, W.E.l m , Hofmann, A.o , Noble, J.M.q , Graff-Radford, N.r , Mori, H.s , Salloway, S.M.u , Masters, C.L.v w , Martins, R.x , Karch, C.M.d , Xiong, C.g , Cruchaga, C.f , Perrin, R.J.h , Gordon, B.A.e , Benzinger, T.L.S.e , Fox, N.C.t , Schofield, P.R.y z , Fagan, A.M.d , Goate, A.M.aa , Morris, J.C.d , Bateman, R.J.d , Johnson, K.A.a b c , Sperling, R.A.a b c , Dominantly Inherited Alzheimer’s Network Investigatorsab
a Department of Neurology, Harvard Medical School, Boston, MA, United Statesb Massachusetts General Hospital, Boston, MA, United Statesc Brigham and Women’s Hospital, Boston, MA, United Statesd Department of Neurology, Washington University in St Louis, St Louis, MO, United Statese Mallinckrodt Institute of Radiology, Washington University in St Louis, St Louis, MO, United Statesf Department of Psychiatry, Washington University in St Louis, St Louis, MO, United Statesg Division of Biostatistics, Washington University in St Louis, St Louis, MO, United Statesh Department of Pathology, Washington University in St Louis, St Louis, MO, United Statesi Université Catholique de Louvain, Brussels, Belgiumj Department of Neurology, Ludwig-Maximilians Universität München, Munich, Germanyk Munich Cluster for Systems Neurology (SyNergy), Munich, Germanyl Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United Statesm Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United Statesn German Center for Neurodegenerative Diseases, Munich, Germanyo German Center for Neurodegenerative Disease, Tübingen, Germanyp Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Koreaq Columbia University Irving Medical Center, Department of Neurology, New York, NY, United Statesr Mayo Clinic, Department of Neurology, Jacksonville, FL, United Statess Osaka City University, Sumiyoshi Ward, Osaka, Japant UCL Queen Square Institute of Neurology, Dementia Research Centre, London, UK, United Kingdomu Butler Hospital, Memory and Aging Program, Brown University Alpert Medical School, Providence, RI, United Statesv The University of Melbourne, Melbourne, VIC, Australiaw Florey Institute, Melbourne, VIC, Australiax Department of Biomedical Sciences, Macquarie University, Sydney, NSW, Australiay Neuroscience Research Australia, Sydney, NSW, Australiaz School of Medical Sciences, University of New South Wales, Sydney, NSW, Australiaaa Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, United States
AbstractBackground: Insights gained from studying individuals with autosomal dominant Alzheimer’s disease have broadly influenced mechanistic hypotheses, biomarker development, and clinical trials in both sporadic and dominantly inherited Alzheimer’s disease. Although pathogenic variants causing autosomal dominant Alzheimer’s disease are highly penetrant, there is substantial heterogeneity in levels of amyloid β (Aβ) between individuals. We aimed to examine whether this heterogeneity is related to disease progression and to investigate the association with mutation location within PSEN1, PSEN2, or APP. Methods: We did cross-sectional and longitudinal analyses of data from the Dominantly Inherited Alzheimer’s Network (DIAN) observational study, which enrols individuals from families affected by autosomal dominant Alzheimer’s disease. 340 participants in the DIAN study who were aged 18 years or older, had a history of autosomal dominant Alzheimer’s disease in their family, and who were enrolled between September, 2008, and June, 2019, were included in our analysis. 206 participants were carriers of pathogenic mutations in PSEN1, PSEN2, or APP, and 134 were non-carriers. 62 unique pathogenic variants were identified in the cohort and were grouped in two ways. First, we sorted variants in PSEN1, PSEN2, or APP by the affected protein domain. Second, we divided PSEN1 variants according to position before or after codon 200. We examined variant-dependent variability in Aβ biomarkers, specifically Pittsburgh-Compound-B PET (PiB-PET) signal, levels of CSF Aβ1-42 (Aβ42), and levels of Aβ1-40 (Aβ40). Findings: Cortical and striatal PiB-PET signal showed striking variant-dependent variability using both grouping approaches (p<0·0001), despite similar progression on the clinical dementia rating (p>0·7), and CSF Aβ42 levels (codon-based grouping: p=0·49; domain-based grouping: p=0·095). Longitudinal PiB-PET signal also varied across codon-based groups, mirroring cross-sectional analyses. Interpretation: Autosomal dominant Alzheimer’s disease pathogenic variants showed highly differential temporal and regional patterns of PiB-PET signal, despite similar functional progression. These findings suggest that although increased PiB-PET signal is generally seen in autosomal dominant Alzheimer’s disease, higher levels of PiB-PET signal at an individual level might not reflect more severe or more advanced disease. Our results have high relevance for ongoing clinical trials in autosomal dominant Alzheimer’s disease, including those using Aβ PET as a surrogate marker of disease progression. Additionally, and pertinent to both sporadic and autosomal dominant Alzheimer’s disease, our results suggest that CSF and PET measures of Aβ levels are not interchangeable and might reflect different Aβ-driven pathobiological processes. Funding: National Institute on Aging, Doris Duke Charitable Foundation, German Center for Neurodegenerative Diseases, Japanese Agency for Medical Research and Development. © 2022 Elsevier Ltd
Funding detailsNational Institutes of HealthNIHNational Institute on AgingNIAAlzheimer’s AssociationAABiogenJapan Agency for Medical Research and DevelopmentAMEDDeutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction” (2022) JCI Insight
Astrocytic 4R tau expression drives astrocyte reactivity and dysfunction(2022) JCI Insight, 7 (1), art. no. 152012, .
Ezerskiy, L.A.a , Schoch, K.M.a , Sato, C.a , Beltcheva, M.b , Horie, K.a , Rigo, F.c , Martynowicz, R.a , Karch, C.M.d , Bateman, R.J.a , Miller, T.M.a
a Department of Neurology, Washington University, School of Medicine, St. Louis, MO, United Statesb Center of Regenerative Medicine, Washington University, School of Medicine, St. Louis, MO, United Statesc Ionis Pharmaceuticals, Carlsbad, CA, United Statesd Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, United States
AbstractThe protein tau and its isoforms are associated with several neurodegenerative diseases, many of which are characterized by greater deposition of the 4-repeat (4R) tau isoform; however, the role of 4R tau in disease pathogenesis remains unclear. We created antisense oligonucleotides (ASOs) that alter the ratio of 3R to 4R tau to investigate the role of specific tau isoforms in disease. Preferential expression of 4R tau in human tau-expressing (hTau-expressing) mice was previously shown to increase seizure severity and phosphorylated tau deposition without neuronal or synaptic loss. In this study, we observed strong colocalization of 4R tau within reactive astrocytes and increased expression of pan-reactive and neurotoxic genes following 3R to 4R tau splicing ASO treatment in hTau mice. Increasing 4R tau levels in primary astrocytes provoked a similar response, including a neurotoxic genetic profile and diminished homeostatic function, which was replicated in human induced pluripotent stem cell-derived (iPSC-derived) astrocytes harboring a mutation that exhibits greater 4R tau. Healthy neurons cultured with 4R tau-expressing human iPSC-derived astrocytes exhibited a higher firing frequency and hypersynchrony, which could be prevented by lowering tau expression. These findings support a potentially novel pathway by which astrocytic 4R tau mediates reactivity and dysfunction and suggest that astrocyte-targeted therapeutics against 4R tau may mitigate neurodegenerative disease progression. © 2022, Ezerskiy et al.
Funding detailsCDI-CORE-2015-505, CDI-CORE-2019-813National Institutes of HealthNIHNS110890National Institute on AgingNIAK01AG062796Foundation for Barnes-Jewish Hospital3770, 4642Rainwater Charitable FoundationRCF
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Brain ventricles as windows into brain development and disease” (2022) Neuron
Brain ventricles as windows into brain development and disease(2022) Neuron, 110 (1), pp. 12-15.
Duy, P.Q.a , Rakic, P.b , Alper, S.L.c , Butler, W.E.d , Walsh, C.A.e , Sestan, N.b , Geschwind, D.H.f , Jin, S.C.g , Kahle, K.T.h
a Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USAb Department of Neuroscience, Yale University School of Medicine, CT, New Haven, United Statesc Division of Nephrology and Vascular Biology Research Center, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, MA, Boston, United Statesd Department of Neurosurgery, Massachusetts General Hospital, MA, Boston, United Statese Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USAf Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USAg Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USAh Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA; Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; MGH Hydrocephalus and Neurodevelopmental Disorders Program, Massachusetts General Hospital, Boston, MA, USA
AbstractDilation of the fluid-filled cerebral ventricles (ventriculomegaly) characterizes hydrocephalus and is frequently seen in autism and schizophrenia. Recent work suggests that the genomic study of congenital hydrocephalus may be unexpectedly fertile ground for revealing insights into neural stem cell regulation, human cerebrocortical development, and pathogenesis of neuropsychiatric disease. Copyright © 2021 Elsevier Inc. All rights reserved.
Author Keywordsbrain ventricle; cerebrospinal fluid; CH; congenital hydrocephalus; CSF; genomics; neural development; neural stem cell; neurodevelopmental disorders; NSC
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model” (2022) Frontiers in Molecular Neuroscience
Disrupted Association of Sensory Neurons With Enveloping Satellite Glial Cells in Fragile X Mouse Model(2022) Frontiers in Molecular Neuroscience, 14, art. no. 796070, .
Avraham, O.a , Deng, P.-Y.b , Maschi, D.b , Klyachko, V.A.b c , Cavalli, V.a c d
a Department of Neuroscience, Washington University School of Medicine, St. LouisMO, United Statesb Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United Statesc Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United Statesd Center of Regenerative Medicine, Washington University School of Medicine, St. Louis, MO, United States
AbstractAmong most prevalent deficits in individuals with Fragile X syndrome (FXS) is hypersensitivity to sensory stimuli and somatosensory alterations. Whether dysfunction in peripheral sensory system contributes to these deficits remains poorly understood. Satellite glial cells (SGCs), which envelop sensory neuron soma, play critical roles in regulating neuronal function and excitability. The potential contributions of SGCs to sensory deficits in FXS remain unexplored. Here we found major structural defects in sensory neuron-SGC association in the dorsal root ganglia (DRG), manifested by aberrant covering of the neuron and gaps between SGCs and the neuron along their contact surface. Single-cell RNAseq analyses demonstrated transcriptional changes in both neurons and SGCs, indicative of defects in neuronal maturation and altered SGC vesicular secretion. We validated these changes using fluorescence microscopy, qPCR, and high-resolution transmission electron microscopy (TEM) in combination with computational analyses using deep learning networks. These results revealed a disrupted neuron-glia association at the structural and functional levels. Given the well-established role for SGCs in regulating sensory neuron function, altered neuron-glia association may contribute to sensory deficits in FXS. Copyright © 2022 Avraham, Deng, Maschi, Klyachko and Cavalli.
Author Keywordsfragile X syndrome; hyperexcitability; neuron-glia communication; satellite glial cells; sensory neuron
Funding detailsCDI-CORE-2015-505, CDI-CORE-2019-813National Institutes of HealthNIHNS111596, R01 NS111719, R35 NS122260Foundation for Barnes-Jewish HospitalFBJHWashington University School of Medicine in St. LouisWUSMCenter for Cellular Imaging, Washington UniversityWUCCI
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Glitter in the Darkness? Nonfibrillar β-Amyloid Plaque Components Significantly Impact the β-Amyloid PET Signal in Mouse Models of Alzheimer Disease” (2022) Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Glitter in the Darkness? Nonfibrillar β-Amyloid Plaque Components Significantly Impact the β-Amyloid PET Signal in Mouse Models of Alzheimer Disease(2022) Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine, 63 (1), pp. 117-124.
Biechele, G.a , Monasor, L.S.b c , Wind, K.a , Blume, T.a b , Parhizkar, S.d , Arzberger, T.b , Sacher, C.a , Beyer, L.a , Eckenweber, F.a , Gildehaus, F.-J.a , von Ungern-Sternberg, B.a , Willem, M.e , Bartenstein, P.a f , Cumming, P.g h , Rominger, A.a g , Herms, J.b f i , Lichtenthaler, S.F.b f j , Haass, C.b e f , Tahirovic, S.b , Brendel, M.f k
a Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germanyb German Center for Neurodegenerative Diseases Munich, Munich, Germanyc Graduate School of Systemic Neuroscience, Ludwig-Maximilians-University Munich, Munich, Germanyd Department of Neurology, Washington University, St. Louis, MO, United Statese Chair of Metabolic Biochemistry, Biomedical Center, Faculty of Medicine, LMU Munich, Munich, Germanyf Munich Cluster for Systems Neurology, Munich, Germanyg Department of Nuclear Medicine, Inselspital, University Hospital BernBern, Switzerlandh School of Psychology and Counselling and IHBI, Queensland University of Technology, Brisbane, Australiai Center of Neuropathology and Prion Research, University of Munich, Munich, Germany; andj Neuroproteomics, School of Medicine, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germanyk Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich, Germany;
Abstractβ-amyloid (Aβ) PET is an important tool for quantification of amyloidosis in the brain of suspected Alzheimer disease (AD) patients and transgenic AD mouse models. Despite the excellent correlation of Aβ PET with gold standard immunohistochemical assessments, the relative contributions of fibrillar and nonfibrillar Aβ components to the in vivo Aβ PET signal remain unclear. Thus, we obtained 2 murine cerebral amyloidosis models that present with distinct Aβ plaque compositions and performed regression analysis between immunohistochemistry and Aβ PET to determine the biochemical contributions to Aβ PET signal in vivo. Methods: We investigated groups of AppNL-G-F and APPPS1 mice at 3, 6, and 12 mo of age by longitudinal 18F-florbetaben Aβ PET and with immunohistochemical analysis of the fibrillar and total Aβ burdens. We then applied group-level intermodality regression models using age- and genotype-matched sets of fibrillar and nonfibrillar Aβ data (predictors) and Aβ PET results (outcome) for both Aβ mouse models. An independent group of double-hit APPPS1 mice with dysfunctional microglia due to knockout of triggering receptor expression on myeloid cells 2 (Trem2-/-) served for validation and evaluation of translational impact. Results: Neither fibrillar nor nonfibrillar Aβ content alone sufficed to explain the Aβ PET findings in either AD model. However, a regression model compiling fibrillar and nonfibrillar Aβ together with the estimate of individual heterogeneity and age at scanning could explain a 93% of variance of the Aβ PET signal (P < 0.001). Fibrillar Aβ burden had a 16-fold higher contribution to the Aβ PET signal than nonfibrillar Aβ. However, given the relatively greater abundance of nonfibrillar Aβ, we estimate that nonfibrillar Aβ produced 79% ± 25% of the net in vivo Aβ PET signal in AppNL-G-F mice and 25% ± 12% in APPPS1 mice. Corresponding results in separate groups of APPPS1/Trem2-/- and APPPS1/Trem2+/+ mice validated the calculated regression factors and revealed that the altered fibrillarity due to Trem2 knockout impacts the Aβ PET signal. Conclusion: Taken together, the in vivo Aβ PET signal derives from the composite of fibrillar and nonfibrillar Aβ plaque components. Although fibrillar Aβ has inherently higher PET tracer binding, the greater abundance of nonfibrillar Aβ plaque in AD-model mice contributes importantly to the PET signal. © 2022 by the Society of Nuclear Medicine and Molecular Imaging.
Author Keywordsamyloid; fibrillar; mouse; nonfibrillar; PET signal
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Quantitative Gradient Echo MRI Identifies Dark Matter as a New Imaging Biomarker of Neurodegeneration that Precedes Tisssue Atrophy in Early Alzheimer’s Disease” (2022) Journal of Alzheimer’s Disease
Quantitative Gradient Echo MRI Identifies Dark Matter as a New Imaging Biomarker of Neurodegeneration that Precedes Tisssue Atrophy in Early Alzheimer’s Disease(2022) Journal of Alzheimer’s Disease, 85 (2), pp. 901-920.
Kothapalli, S.V.V.N.a , Benzinger, T.L.a b , Aschenbrenner, A.J.b c , Perrin, R.J.b c d e , Hildebolt, C.F.a , Goyal, M.S.a c , Fagan, A.M.b c e , Raichle, M.E.a c e , Morris, J.C.b c , Yablonskiy, D.A.a b e
a Department of Radiology, Washington University in St. Louis, St. Louis, MO, United Statesb Knight Alzheimer Disease Research Center, Washington University in St. Louis, St. Louis, MO, United Statesc Department of Neurology, Washington University in St. Louis, St. Louis, MO, United Statesd Department of Pathology and Immunology, Washington University in St. Louis, St. Louis, MO, United Statese The Hope Center for Neurological Disorders, Washington University in St. Louis, St. Louis, MO, United States
AbstractBackground: Currently, brain tissue atrophy serves as an in vivo MRI biomarker of neurodegeneration in Alzheimer’s disease (AD). However, postmortem histopathological studies show that neuronal loss in AD exceeds volumetric loss of tissue and that loss of memory in AD begins when neurons and synapses are lost. Therefore, in vivo detection of neuronal loss prior to detectable atrophy in MRI is essential for early AD diagnosis. Objective: To apply a recently developed quantitative Gradient Recalled Echo (qGRE) MRI technique for in vivo evaluation of neuronal loss in human hippocampus. Methods: Seventy participants were recruited from the Knight Alzheimer Disease Research Center, representing three groups: Healthy controls [Clinical Dementia Rating® (CDR®) = 0, amyloid β (Aβ)-negative, n = 34]; Preclinical AD (CDR = 0, Aβ-positive, n = 19); and mild AD (CDR = 0.5 or 1, Aβ-positive, n = 17). Results: In hippocampal tissue, qGRE identified two types of regions: one, practically devoid of neurons, we designate as ‘Dark Matter’, and the other, with relatively preserved neurons, ‘Viable Tissue’. Data showed a greater loss of neurons than defined by atrophy in the mild AD group compared with the healthy control group; neuronal loss ranged between 31% and 43%, while volume loss ranged only between 10% and 19%. The concept of Dark Matter was confirmed with histopathological study of one participant who underwent in vivo qGRE 14 months prior to expiration. Conclusion: In vivo qGRE method identifies neuronal loss that is associated with impaired AD-related cognition but is not recognized by MRI measurements of tissue atrophy, therefore providing new biomarkers for early AD detection. © 2022 – The authors. Published by IOS Press.
Author KeywordsAlzheimer’s disease; brain atrophy; cognitive impairment; hippocampal subfields; hippocampus; magnetic resonance imaging; neurodegeneration; quantitative Gradient Recalled Echo
Funding detailsNational Institutes of HealthNIHP50 AG0581, R01 AG054513
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Quantifying regional α -synuclein, amyloid β, and tau accumulation in lewy body dementia” (2022) Annals of Clinical and Translational Neurology
Quantifying regional α -synuclein, amyloid β, and tau accumulation in lewy body dementia(2022) Annals of Clinical and Translational Neurology, .
Miller, R.L.a b , Dhavale, D.D.a b , O’Shea, J.Y.a b , Andruska, K.M.a b , Liu, J.a b , Franklin, E.E.b c , Buddhala, C.a b , Loftin, S.K.a d , Cirrito, J.R.a b , Perrin, R.J.a b c , Cairns, N.J.a b c e , Campbell, M.C.a b d , Perlmutter, J.S.a d f g h , Kotzbauer, P.T.a b i
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United Statesb Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United Statesc Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United Statesd Department of Radiology, Washington University School of Medicine, St. Louis, MO, United Statese College of Medicine and Health, University of Exeter, Exeter, United Kingdomf Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United Statesg Program in Occupational Therapy, Washington University School of Medicine, St. Louis, MO, United Statesh Program in Physical Therapy, Washington University School of Medicine, St. Louis, MO, United Statesi Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
AbstractObjective: Parkinson disease (PD) is defined by the accumulation of misfolded α-synuclein (α-syn) in Lewy bodies and Lewy neurites. It affects multiple cortical and subcortical neuronal populations. The majority of people with PD develop dementia, which is associated with Lewy bodies in neocortex and referred to as Lewy body dementia (LBD). Other neuropathologic changes, including amyloid β (Aβ) and tau accumulation, occur in some LBD cases. We sought to quantify α-syn, Aβ, and tau accumulation in neocortical, limbic, and basal ganglia regions. Methods: We isolated insoluble protein from fresh frozen postmortem brain tissue samples for eight brains regions from 15 LBD, seven Alzheimer disease (AD), and six control cases. We measured insoluble α-syn, Aβ, and tau with recently developed sandwich ELISAs. Results: We detected a wide range of insoluble α-syn accumulation in LBD cases. The majority had substantial α-syn accumulation in most regions, and dementia severity correlated with neocortical α-syn. However, three cases had low neocortical levels that were indistinguishable from controls. Eight LBD cases had substantial Aβ accumulation, although the mean Aβ level in LBD was lower than in AD. The presence of Aβ was associated with greater α-syn accumulation. Tau accumulation accompanied Aβ in only one LBD case. Interpretation: LBD is associated with insoluble α-syn accumulation in neocortical regions, but the relatively low neocortical levels in some cases suggest that other changes contribute to impaired function, such as loss of neocortical innervation from subcortical regions. The correlation between Aβ and α-syn accumulation suggests a pathophysiologic relationship between these two processes. © 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association
Funding detailsNational Institutes of HealthNIHNS075321, NS097437, NS097799, NS110436National Institute on AgingNIANational Institute of Neurological Disorders and StrokeNINDSAG003991, AG026276, AG066444Michael J. Fox Foundation for Parkinson’s ResearchMJFFAmerican Parkinson Disease AssociationAPDAWashington University in St. LouisWUSTLFoundation for Barnes-Jewish Hospital
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Cerebral Palsy in Child Neurology and Neurodevelopmental Disabilities Training: An Unmet Need” (2022) Journal of Child Neurology
Cerebral Palsy in Child Neurology and Neurodevelopmental Disabilities Training: An Unmet Need(2022) Journal of Child Neurology, .
Wilson, J.L.a , Kim, Y.-M.b , O’Malley, J.A.c , Gelineau-Morel, R.d , Gilbert, L.e , Bain, J.M.f , Aravamuthan, B.R.e
a Division of Pediatric Neurology, Oregon Health Science University, Portland, OR, United Statesb Division of Pediatric Neurology, Department of Pediatrics, Loma Linda University School of Medicine, Loma Linda, CA, United Statesc Division of Child Neurology, Department of Neurology, Stanford University School of Medicine, Palo Alto, CA, United Statesd Division of Neurology, Department of Pediatrics, University of Missouri Kansas City, Kansas City, MO, United Statese Division of Pediatric Neurology, Department of Neurology, School of Medicine, Washington University in St Louis and St Louis Children’s Hospital, St Louis, MO, United Statesf Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
AbstractBackground: Cerebral palsy (CP) is the most common cause of childhood motor disability. However, there is limited guidance on training of child neurologists and neurodevelopmental disability specialists in the care of individuals with cerebral palsy. We sought to determine training program directors’ impressions of the importance and adequacy of training in the diagnosis and management of cerebral palsy. Methods: In this cross-sectional study, all 82 child neurology and neurodevelopmental disability program directors were asked to complete a survey querying program characteristics, aspects of training in cerebral palsy, importance of cerebral palsy training, and perceived competence at graduation in cerebral palsy care. Results: There were 35 responses (43% response rate). Nearly all program directors (91%) reported “learning to diagnose cerebral palsy” as very important, and most (71%) felt that “learning to manage cerebral palsy” was very important. Although most program directors reported trainees to be very or extremely competent in cerebral palsy diagnosis (77%), only 43% of program directors felt that trainees were very or extremely competent in cerebral palsy management. Time spent with cerebral palsy faculty was associated with higher reported competence in cerebral palsy diagnosis (P =.03) and management (P <.01). The presence of a cerebral palsy clinic was associated with higher reported competence in cerebral palsy management (P =.03). Conclusions: Child neurology and neurodevelopmental disability program directors reported that training in cerebral palsy is important for residents; however, a significant proportion felt that residents were not very well prepared to manage cerebral palsy. The development of cerebral palsy curricula and exposure to cerebral palsy clinics may improve training, translating to better care of individuals with cerebral palsy. © The Author(s) 2022.
Author Keywordscerebral palsy; children; developmental delay; developmental disability; neurodevelopment; spasticity
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Comparison of Demographic and Clinical Features of Bipolar Disorder in Persons of African and European Ancestry” (2022) Journal of Racial and Ethnic Health Disparities
Comparison of Demographic and Clinical Features of Bipolar Disorder in Persons of African and European Ancestry(2022) Journal of Racial and Ethnic Health Disparities, .
Taylor-Desir, M.J.a , Balls-Berry, J.E.b , McElroy, S.L.c , Bond, D.J.d , Vallender, E.J.e , Ladner, M.e , Coombes, B.J.f , Jackson, L.g , Arceo, D.h , Caples, F.V.i , Colby, C.f , Patten, C.A.a , Biernacka, J.M.a f , Frye, M.A.a
a Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United Statesb Department of Neurology, Washington University, St. Louis, MO, United Statesc Lindner Center of HOPE &, University of Cincinnati College of Medicine, Cincinnati, OH, United Statesd Department of Psychiatry, University of Minnesota, Minneapolis, MN, United Statese Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, United Statesf Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, United Statesg Division of Gastroenterology, Mayo Clinic, Rochester, MN, United Statesh Kirk Kerkorian School of Medicine, University of Nevada, Las Vegas, NV, United Statesi Department of Health Policy and Management, College of Health Sciences, Jackson State University, Jackson, MS, United States
AbstractAim: This study quantified and compared demographic and clinical features of bipolar disorder (BD) in persons of African ancestry (AA) and European ancestry (EUR). Methods: Participants enrolled in the Mayo Clinic Bipolar Biobank from 2009 to 2015. The structured clinical interview for DSM-IV was used to confirm the diagnosis of BD, and a questionnaire was developed to collect data on the clinical course of illness. Descriptive statistics and bivariate analyses were completed to compare AA versus EUR participants. Subsequently, clinical outcomes were compared between AA and EUR participants using linear regression for continuous outcomes or logistic regression for binary outcomes while controlling for differences in age, sex, and recruitment site. Results: Of 1865 participants enrolled in the bipolar biobank, 65 (3.5%) self-identified as AA. The clinical phenotype for AA participants, in comparison to EUR participants, was more likely to include a history of PTSD (39.7% vs. 26.2%), cocaine use disorder (24.2% vs. 11.9%), and tardive dyskinesia (7.1% vs. 3%). Conclusion: The low rate of AA enrollment is consistent with other genetic studies. While clinical features of bipolar disorder are largely similar, this study identified differences in rates of trauma, substance use, and tardive dyskinesia that may represent health disparities in bipolar patients of African ancestry. Future bipolar biomarker studies with larger sample sizes focused on underrepresented populations will provide greater ancestry diversity in genomic medicine with greater applicability to diverse patient populations, serving to inform health care policies to address disparities in bipolar disorder. © 2022, W. Montague Cobb-NMA Health Institute.
Author KeywordsBipolar disorder; Health/racial disparities; Psychiatric genetics
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Caregiver Socialization of Reappraisal and Children’s Cognitive Flexibility Jointly Predict Latinx Children’s Anxiety” (2022) Journal of Child and Family Studies
Caregiver Socialization of Reappraisal and Children’s Cognitive Flexibility Jointly Predict Latinx Children’s Anxiety(2022) Journal of Child and Family Studies, .
Quiñones-Camacho, L.E.a b , Davis, E.L.c
a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United Statesb Department of Educational Psychology, The University of Texas at Austin, Austin, TX, United Statesc Department of Psychology, University of California Riverside, Riverside, CA, United States
AbstractAnxiety disorders are among the most common forms of psychopathology in childhood and represent a particularly concerning issue for Latinx children. Research on adults and children with anxiety suggests that the effective regulation of emotion is associated with fewer symptoms. The current study used data from 78 Latinx (predominantly Mexican American) 8- to 11-year-old children (M = 9.91; SD = 1.14; 50% girls) and one caregiver to explore regulatory processes that may characterize emerging psychopathology in Latinx families. Caregivers reported on their use of reappraisal and their child’s anxiety symptoms. Children completed a cognitive flexibility task and self-reported their anxiety symptoms. More extensive caregiver use of reappraisal was associated with fewer child anxiety symptoms (an average of caregiver- and child-report). As expected, this effect was qualified by children’s cognitive flexibility. Caregiver reappraisal was associated with anxiety symptoms only for children with greater cognitive flexibility, highlighting the importance of individual differences in cognitive skills underlying children’s mastery of sophisticated cognitive strategies. Findings suggest the importance of considering both caregiver and child regulatory processes to improve understanding of anxiety symptoms among Latinx children. © 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Author KeywordsAnxiety symptoms; Cognitive flexibility; Latinx; Reappraisal; Self-regulation
Funding detailsNational Science FoundationNSFDGE-1326120National Institute of Mental HealthNIMHT32 MH0100019-06
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“What is Operative? Conceptualizing Neuralgia: Neuroma, Compression Neuropathy, Painful Hyperalgesia, and Phantom Nerve Pain” (2022) Journal of Hand Surgery Global Online
What is Operative? Conceptualizing Neuralgia: Neuroma, Compression Neuropathy, Painful Hyperalgesia, and Phantom Nerve Pain(2022) Journal of Hand Surgery Global Online, .
Hill, E.J.R.a , Patterson, J.M.M.b , Yee, A.c , Crock, L.W.d , Mackinnon, S.E.c
a Department of Orthopedic Surgery, Division of Hand and Microsurgery, Washington University in St. Louis School of Medicine, St. Louis, MOb Department of Orthopedic Surgery, University of North Carolina, Chapel Hill, NC, United Statesc Division of Plastic and Reconstructive Surgery, Washington University in St. Louis School of Medicine, St. Louis, MOd Division of Pain Management, Washington University in St. Louis School of Medicine, St. Louis, MO
AbstractNeuralgia, or nerve pain, is a common presenting complaint for the hand surgeon. When the nerve at play is easily localized, and the cause of the pain is clear (eg, carpal tunnel syndrome), the patient may be easily treated with excellent results. However, in more complex cases, the underlying pathophysiology and cause of neuralgia can be more difficult to interpret; if incorrectly managed, this leads to frustration for both the patient and surgeon. Here we offer a way to conceptualize neuralgia into 4 categories—compression neuropathy, neuroma, painful hyperalgesia, and phantom nerve pain—and offer an illustrative clinical vignette and strategies for optimal management of each. Further, we delineate the reasons why compression neuropathy and neuroma are amenable to surgery, while painful hyperalgesia and phantom nerve pain are not. © 2022 The Authors
Author KeywordsNerve pain; Nerve surgery; Neuralgia; Neuroma; Neuropathy
Document Type: ArticlePublication Stage: Article in PressSource: Scopus
“Task Modulation of Single-Neuron Activity in the Human Amygdala and Hippocampus” (2022) eNeuro
Task Modulation of Single-Neuron Activity in the Human Amygdala and Hippocampus(2022) eNeuro, 9 (1), art. no. ENEURO.0398-21.2021, .
Cao, R.a , Todorov, A.b , Brandmeir, N.J.c , Wang, S.a d
a Lane Department of Computer Science and Electrical Engineering, West Virginia University, Morgantown, WV 26506, United Statesb Booth School of Business, University of Chicago, Chicago, IL 60637, United Statesc Department of Neurosurgery, West Virginia University, Morgantown, WV 26506, United Statesd Department of Radiology, Washington University in St. Louis, St. Louis, MO 63110, United States
AbstractThe human amygdala and hippocampus are critically involved in various processes in face perception. However, it remains unclear how task demands or evaluative contexts modulate processes underlying face perception. In this study, we employed two task instructions when participants viewed the same faces and recorded single-neuron activity from the human amygdala and hippocampus. We comprehensively analyzed task modulation for three key aspects of face processing and we found that neurons in the amygdala and hippocampus (1) encoded high-level social traits such as perceived facial trustworthiness and dominance and this response was modulated by task instructions; (2) encoded low-level facial features and demonstrated region-based feature coding, which was not modulated by task instructions; and (3) encoded fixations on salient face parts such as the eyes and mouth, which was not modulated by task instructions. Together, our results provide a comprehensive survey of task modulation of neural processes underlying face perception at the single-neuron level in the human amygdala and hippocampus. © 2022 Cao et al.
Author KeywordsAmygdala and hippocampus; Dominance; Face; Human single-neuron recordings; Task modulation; Trustworthiness
Funding detailsFA9550-21-1-0088National Science FoundationNSFBCS-1945230, IIS-2114644Dana FoundationOak Ridge Associated UniversitiesORAU
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Seizures in Fragile X Syndrome: Associations and Longitudinal Analysis of a Large Clinic-Based Cohort” (2021) Frontiers in Pediatrics
Seizures in Fragile X Syndrome: Associations and Longitudinal Analysis of a Large Clinic-Based Cohort(2021) Frontiers in Pediatrics, 9, art. no. 736255, .
Berry-Kravis, E.a b , Filipink, R.A.c , Frye, R.E.d e , Golla, S.f , Morris, S.M.g , Andrews, H.h , Choo, T.-H.i , Kaufmann, W.E.j , The FORWARD Consortiumk
a Department of Pediatrics, Rush University Medical Center, Chicago, IL, United Statesb Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, United Statesc Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, United Statesd Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, United Statese Department of Child Health, University of Arizona College of Medicine–Phoenix, Phoenix, AZ, United Statesf Division of Neurodevelopmental Medicine, Department of Neurology, Thompson Autism Center, Children’s Hospital of California, University of Irvine, Orange, CA, United Statesg Division of Pediatric and Developmental Neurology, Department of Neurology, Washington University in St. Louis, St. Louis, MO, United Statesh Department of Biostatistics, Mailman School of Public Health, Columbia University Medical Center, New York, NY, United Statesi Department of Psychiatry, New York State Psychiatric Institute, Columbia University Medical Center, New York, NY, United Statesj Emory University School of Medicine, Atlanta, GA, United States
AbstractFragile X syndrome (FXS), the most common inherited cause of intellectual disability, learning disability, and autism spectrum disorder, is associated with an increased prevalence of certain medical conditions including seizures. The goal of this study was to better understand seizures in individuals with FXS using the Fragile X Online Registry with Accessible Research Database, a multisite observational study initiated in 2012 involving FXS clinics in the Fragile X Clinic and Research Consortium. Seizure data were available for 1,607 participants, mostly male (77%) and white (74.5%). The overall prevalence of at least one seizure was 12%, with this rate being significantly higher in males than females (13.7 vs. 6.2%, p < 0.001). As compared to individuals with FXS without seizures, those with seizures were more likely to have autism spectrum disorder, current sleep apnea, later acquisition of expressive language, more severe intellectual disability, hyperactivity, irritability, and stereotyped movements. The mean age of seizure onset was 6.4 (SD 6.1) years of age with the great majority (>80%) having onset of seizures which was before 10. For those with epilepsy, about half (52%) had seizures for more than 3 years. This group was found to have greater cognitive and language impairment, but not behavioral disruptions, compared with those with seizures for <3 years. Antiepileptic drugs were more often used in males (60.6%) than females (34.8%), and females more often required more than one medication. The most commonly used anticonvulsants were oxcarbazepine, valproic acid, lamotrigine, and levetiracetam. The current study is the largest and first longitudinal study ever conducted to describe seizures in FXS. Overall, this study confirms previous reports of seizures in FXS and extends previous findings by further defining the cognitive and behavioral phenotype of those with epilepsy in FXS. Future studies should further investigate the natural history of seizures in FXS and the characteristics of seizures in FXS in adulthood. Copyright © 2021 Berry-Kravis, Filipink, Frye, Golla, Morris, Andrews, Choo, Kaufmann and the FORWARD Consortium.
Author Keywordsautism spectrum disorder; epilepsy; Fragile X syndrome; longitudinal; seizures
Funding detailsCenters for Disease Control and PreventionCDC
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Functional characterization of hiPSCs-derived glial cells and neurons from patients harboring a TREM2 loss of function mutation” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association
Functional characterization of hiPSCs-derived glial cells and neurons from patients harboring a TREM2 loss of function mutation(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e058712.
Filipello, F.a , You, S.-F.b , Martinez, R.a , Korvatska, O.c , Raskind, W.H.c , Mahali, S.b , Ghezzi, L.b , Wandy, B.b , Cella, M.d , Piccio, L.e f , Karch, C.M.g h i
a Washington University, MO, Saint Louis, United Statesb Washington University, St Louis, MO, USAc University of Washington, Seattle, WA, USAd Washington University in St. Louis, St. Louis, MO, USAe Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, USAf Department of Neurology, Washington University School of Medicine, St. Louis, MO, USAg Hope Center for Neurological Disorders, St. Louis, MO, USAh Washington University in St. Louis, St Louis, MO, USAi Washington University School of Medicine, St. Louis, MO, USA
AbstractBACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed by microglia in the adult brain. Homozygous loss of function TREM2 variants cause a rare leukodystrophy characterized by bone cysts and early-onset dementia, Nasu-Hakola disease (NHD). However, despite intense investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. METHOD: Here, we investigated the mechanisms by which a homozygous stop-gain TREM2 variant (Q33X), which leads to a truncated TREM2 transcript, contributes to disease pathology in NHD. Human induced pluripotent stem cells (hiPSCs)-derived microglia (iMGLs), neurons and astrocytes were obtained from two siblings homozygous for the TREM2 Q33X mutation and one non-carrier sibling. RESULT: Transcriptomic analysis and biochemical assays revealed that iMGLs from NHD patients display decreased activation, reduced lipid droplet content and defects in lysosomal function compared to related and unrelated controls. These in vitro findings were validated in brain tissues from NHD patients carrying loss of function TREM2 mutations. Strikingly, we observed defects beyond iMGLs. iPSCs-derived neurons and astrocytes from NHD siblings displayed downregulation of pathways involved in synaptic activation, neuronal development and interferon response compared to the unaffected sibling. These pathways were also observed to be similarly altered in NHD brains. This could be due to the presence of low levels of mutant TREM2 transcripts in iPSC and neural progenitor cells, which may initiate a cascade of events that drives cellular dysfunction beyond microglia. CONCLUSION: These finding open a new scenario on TREM2 function and reveal that NHD is a complex pathology affecting glial cells and neurons at multiple levels. © 2021 the Alzheimer’s Association.
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Defining the role of PLD3 in Alzheimer’s disease pathology” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association
Defining the role of PLD3 in Alzheimer’s disease pathology(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e058730.
Rosene, M.J.a , Hsu, S.b , Martinez, R.c , Norton, J.a b d e , Yan, P.a , Cirrito, J.R.f , Lee, J.-M.g , Cuervo, A.M.h , Goate, A.M.i j , Cruchaga, C.d k l m n , Karch, C.M.c d k o
a Washington University School of Medicine, St. Louis, MO, USAb Washington University in St Louis, St Louis, MO, USAc Washington University, MO, Saint Louis, United Statesd Hope Center for Neurological Disorders, St. Louis, MO, USAe Knight Alzheimer Disease Research Center, St Louis, MO, USAf Washington University School of Medicine, MO, Saint Louis, United Statesg Washington University School of Medicine, St Louis, MO, USAh Albert Einstein College of Medicine, Bronx, NY, USAi Ronald M. Loeb Center for Alzheimer’s disease, NY, NY, United Statesj Icahn School of Medicine at Mount Sinai, NY, NY, United Statesk NeuroGenomics and Informatics Center, St. Louis, MO, USAl Washington University, St. Louis, MO, USAm Knight Alzheimer Disease Research Center, MO, Saint Louis, United Statesn Washington University in St. Louis, MO, Saint Louis, United Stateso Washington University in St. Louis, St Louis, MO, USA
AbstractBACKGROUND: Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) in the brain. We recently identified coding variants in the phospholipase D3 (PLD3) gene that double the risk for late onset AD. METHOD: We examined the impact of PLD3 risk variants on PLD3 and Aβ metabolism using CRISPR/Cas9 in induced pluripotent stem cells (iPSC). We then modeled the PLD3 expression patterns observed in AD brains in immortalized cell and AD mouse models. Lysosomal function was assessed in human brain tissue. RESULT: PLD3 A442A disrupts a splicing enhancer binding site and reduces PLD3 splicing in human brains. Differentiation of PLD3 A442A and isogenic control iPSCs into cortical neurons produced cells that were morphologically similar. At the molecular level, PLD3 A442A neurons displayed a similar defect in PLD3 splicing as was observed in human brains and a significant increase in Aβ42/Aβ40 compared with isogenic control lines. Thus, PLD3 A442A is sufficient to alter PLD3 splicing and Aβ metabolism. PLD3 expression was significantly lower in AD brains compared with controls, and PLD3 expression was highly correlated with expression of lysosomal genes. Thus, we sought to determine whether PLD3 contributes to Aβ accumulation in AD via disrupted Aβ metabolism. We found that overexpression of PLD3 in immortalized cells decreased Aβ levels while shRNA silencing of Pld3 increased Aβ levels. In an AD mouse model, overexpression of PLD3 in hippocampal neurons produced decreased interstitial fluid (ISF) Aβ levels and accelerated Aβ turnover. Conversely, knocking out Pld3 increased ISF Aβ, reduced Aβ turnover, and increased APP protein levels. Knocking out Pld3 overtime lead to altered amyloid morphology. To begin to determine whether PLD3 influences Aβ turnover via the lysosome, we isolated lysosomal fractions from human AD and control brains. PLD3 was enriched in lysosomal subfractions and PLD3 distribution in these subfractions was altered in AD. Furthermore, PLD3 stability in the lysosomal fractions was disrupted in AD brains. CONCLUSION: Together, our findings demonstrate that PLD3 promotes Aβ clearance through pathways involving lysosomal degradation. © 2021 the Alzheimer’s Association.
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Astrocytic BMAL1 regulates protein aggregation in mouse models of alpha-synuclein and tau pathology” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association
Astrocytic BMAL1 regulates protein aggregation in mouse models of alpha-synuclein and tau pathology(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e058631.
Sheehan, P.W.a , Kanan, M.a , Benitez, B.A.a b c d e , Harari, O.b c d e f , Davis, A.A.c , Musiek, E.S.a e
a Washington University in St. Louis, St. Louis, MO, USAb Hope Center for Neurological Disorders, St. Louis, MO, USAc Washington University School of Medicine, St. Louis, MO, USAd NeuroGenomics and Informatics Center, St. Louis, MO, USAe Knight Alzheimer Disease Research Center, St. Louis, MO, USAf Washington University, MO, Saint Louis, United States
AbstractBACKGROUND: The circadian clock regulates inflammatory responses in the peripheral immune system, though its function in neuroinflammation is poorly understood. Deletion of the master circadian clock transcription factor BMAL1 abrogates cellular circadian clock function and can be used to probe cell-type specific functions of the clock. Our lab has previously shown that Bmal1 deletion induces oxidative stress, astrocyte activation, and increased β-amyloid plaque deposition in mice. We hypothesized that deletion of Bmal1 would increase pathology in other protein aggregation models. METHODS: We generated global inducible Bmal1 knock out mice expressing human P301S mutant tau. Pathology, aggregation state, and gliosis were quantified at nine months of age. We induced synuclein aggregation in global Bmal1 knock out mice using an alpha-synuclein preformed fibril injection (PFF) model. Three months post-PFF injection, mice were analyzed for synuclein pathology and gliosis. To determine a cell-type specific effect, we generated astrocyte- and microglia-specific Bmal1 knock out mice and used these for PFF injections. Pathology and gliosis were analyzed from these mice three months post-PFF injection. We then generated astrocyte-specific Bmal1 knock out mice expressing human P301S mutant tau to test the effect of Bmal1 deletion in astrocytes on tau aggregation. RESULTS: Global Bmal1 deletion in the P301S model resulted in a significant decrease in aggregated tau and microglia activation. Global Bmal1 knock out mice injected with PFFs had significantly decreased synuclein pathology and a decrease in microgliosis. Bmal1 deletion specifically in astrocytes was sufficient to reduce both tau and synuclein pathology. Using bioinformatics methods, we discovered an astrocytic candidate gene, Bag3, which may play a role in reducing pathology in our models. We used an in vitro PFF uptake assay and found that Bmal1 knockdown resulted in increased PFF uptake, which was reduced to baseline after simultaneous knockdown of Bag3. CONCLUSION: Bmal1 deletion in astrocytes is sufficient to reduce tau and synuclein pathologies and attenuate microglia activation. This effect may be driven by the upregulation of the macroautophagy chaperone protein, Bag3. Our data suggests that targeting astrocytic protein degradation machinery may be a therapeutic strategy for reducing intra-neuronal protein aggregates, such as tau and synuclein. © 2021 the Alzheimer’s Association.
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient-derived pluripotent cell models” (2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association
Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient-derived pluripotent cell models(2021) Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, 17, p. e058313.
Minaya, M.a , Martinez, R.b , Eteleeb, A.c , Cruchaga, C.d , Harari, O.b , Karch, C.M.d
a Washington University, MO, Saint Louis, United Statesb Washington University, MO, Saint Louis, United Statesc Washington University School of Medicine, MO, Saint Louis, United Statesd Washington University School of Medicine, St. Louis, MO, USA
AbstractBACKGROUND: Mutations in the microtubule-associated protein tau (MAPT) cause heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD-tau). Yet the pathogenic events linked to disease remain poorly understood. This study aimed to identify genes and pathways that lead to FTLD-tau. METHOD: To identify the earliest genes and pathways that are dysregulated in FTLD-tau, we identified differentially expressed genes in RNA-seq data generated from induced pluripotent stem cell (iPSC)-derived cortical neurons carrying MAPT R406W, MAPT P301L, and MAPT IVS10+16 and isogenic, controls and brain tissue samples from progressive supranuclear palsy (PSP) and control brains. We then identified pathological pathways and drug targets that were enriched among the differentially expressed genes. RESULTS: We identified 275 genes that were differentially expressed in iPSC-derived cortical neurons from MAPT R406W carriers compared to isogenic controls, MAPT IVS10+16 carriers compared to isogenic controls, and MAPT P301L carriers compared with isogenic controls. These commonly dysregulated genes were enriched for pathways involving synaptic function, neuronal development, and endolysosomal function. A subset of these genes were also changed in brains from human subjects with PSP compared to normal control brains. Finally, a subset of genes, enriched in glutamate receptor signaling, were altered across the mutant neurons and significantly changed with tau accumulation in a mouse model of tauopathy (Tau-P301L mice). CONCLUSION: The results from this study demonstrate that iPSC-derived neurons capture molecular processes that occur in human brains and can be used to model disease and point to common molecular pathways driven by 3 distinct MAPT mutations. © 2021 the Alzheimer’s Association.
Document Type: ArticlePublication Stage: FinalSource: Scopus
“Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes” (2021) Annals of Neurology
Variants in Mitochondrial ATP Synthase Cause Variable Neurologic Phenotypes(2021) Annals of Neurology, .
Zech, M.a b , Kopajtich, R.a b , Steinbrücker, K.c , Bris, C.d e , Gueguen, N.d e , Feichtinger, R.G.c , Achleitner, M.T.c , Duzkale, N.f , Périvier, M.g , Koch, J.c , Engelhardt, H.h , Freisinger, P.i , Wagner, M.a b , Brunet, T.a b , Berutti, R.a b , Smirnov, D.a b , Navaratnarajah, T.j , Rodenburg, R.J.T.k , Pais, L.S.l , Austin-Tse, C.m , O’Leary, M.n , Boesch, S.o , Jech, R.p , Bakhtiari, S.q r , Jin, S.C.s t , Wilbert, F.u , Kruer, M.C.q r , Wortmann, S.B.c v , Eckenweiler, M.u , Mayr, J.A.c , Distelmaier, F.j , Steinfeld, R.w , Winkelmann, J.a b x y , Prokisch, H.a b
a Technical University of Munich, School of Medicine, Institute of Human Genetics, Munich, Germanyb Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germanyc University Children’s Hospital, Paracelsus Medical University (PMU), Salzburg, Austriad Unité Mixte de Recherche MITOVASC, CNRS 6015/INSERM 1083, Université d’Angers, Angers, Francee Département de Biochimie et Génétique, Centre Hospitalier Universitaire d’Angers, Angers, Francef Department of Medical Genetic, Diskapi Yildirim Beyazit Training and Research Hospital, Ankara, Turkeyg Pediatric Neurology Department, CHU Clocheville, Tours, Franceh Kinderkrankenhaus St. Marien gGmbH, Zentrum für Kinder- und Jugendmedizin, Landshut, Germanyi Children’s Hospital Kreiskliniken, Reutlingen, Germanyj Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children’s Hospital, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germanyk Radboud Centre for Mitochondrial Medicine, Department of Paediatrics Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen Medical Centre Nijmegen, Nijmegen, Netherlandsl Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, United Statesm Harvard Medical School & Center for Genomic Medicine, Massachusetts General Hospital, Boston & Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, MA, United Statesn Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, Cambridge, MA, United Stateso Department of Neurology, Medical University of Innsbruck, Innsbruck, Austriap Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republicq Pediatric Movement Disorders Program, Division of Pediatric Neurology, Barrow Neurological Institute, Phoenix Children’s Hospital, Phoenix, AZ, United Statesr Departments of Child Health, Neurology, and Cellular & Molecular Medicine, and Program in Genetics, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, United Statess Department of Genetics, Washington University School of Medicine, St. Louis, MO, United Statest Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United Statesu Department of Neuropediatrics and Muscle Disorders, University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germanyv Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Amalia Children’s Hospital, Radboud UMC, Nijmegen, Netherlandsw Department of Pediatric Neurology, University Children’s Hospital Zurich, University of Zurich, Zurich, Switzerlandx Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germanyy Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
AbstractObjective: ATP synthase (ATPase) is responsible for the majority of ATP production. Nevertheless, disease phenotypes associated with mutations in ATPase subunits are extremely rare. We aimed at expanding the spectrum of ATPase-related diseases. Methods: Whole-exome sequencing in cohorts with 2,962 patients diagnosed with mitochondrial disease and/or dystonia and international collaboration were used to identify deleterious variants in ATPase-encoding genes. Findings were complemented by transcriptional and proteomic profiling of patient fibroblasts. ATPase integrity and activity were assayed using cells and tissues from 5 patients. Results: We present 10 total individuals with biallelic or de novo monoallelic variants in nuclear ATPase subunit genes. Three unrelated patients showed the same homozygous missense ATP5F1E mutation (including one published case). An intronic splice-disrupting alteration in compound heterozygosity with a nonsense variant in ATP5PO was found in one patient. Three patients had de novo heterozygous missense variants in ATP5F1A, whereas another 3 were heterozygous for ATP5MC3 de novo missense changes. Bioinformatics methods and populational data supported the variants’ pathogenicity. Immunohistochemistry, proteomics, and/or immunoblotting revealed significantly reduced ATPase amounts in association to ATP5F1E and ATP5PO mutations. Diminished activity and/or defective assembly of ATPase was demonstrated by enzymatic assays and/or immunoblotting in patient samples bearing ATP5F1A-p.Arg207His, ATP5MC3-p.Gly79Val, and ATP5MC3-p.Asn106Lys. The associated clinical profiles were heterogeneous, ranging from hypotonia with spontaneous resolution (1/10) to epilepsy with early death (1/10) or variable persistent abnormalities, including movement disorders, developmental delay, intellectual disability, hyperlactatemia, and other neurologic and systemic features. Although potentially reflecting an ascertainment bias, dystonia was common (7/10). Interpretation: Our results establish evidence for a previously unrecognized role of ATPase nuclear-gene defects in phenotypes characterized by neurodevelopmental and neurodegenerative features. ANN NEUROL 2022. © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details01GM1920A, 01KU2016ANational Heart, Lung, and Blood InstituteNHLBI2020‐224274, R01 HG009141, U01 HG0011755National Human Genome Research InstituteNHGRIUM1 HG008900National Eye InstituteNEINational Institute of Neurological Disorders and StrokeNINDS1R01 NS106298Silicon Valley Community FoundationSVCF701900167, DI 1731/2‐2Univerzita Karlova v PrazeUKBroad InstituteChan Zuckerberg InitiativeCZIDeutsche ForschungsgemeinschaftDFGDFG 458949627, WI 1820/14‐1, ZE 1213/2‐1Ministerstvo Školství, Mládeže a TělovýchovyMŠMT825575, NV19‐04‐00233Bundesministerium für Bildung und ForschungBMBF01GM1906AAustrian Science FundFWFElse Kröner-Fresenius-StiftungEKFSTechnische Universität MünchenTUM
Document Type: ArticlePublication Stage: Article in PressSource: Scopus