Scopus list of publications for September 3, 2023
Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice
(2023) Nature Communications, 14 (1), art. no. 5197, .
Lee, J.a , Dimitry, J.M.a , Song, J.H.b , Son, M.b , Sheehan, P.W.a , King, M.W.a , Travis Tabor, G.c , Goo, Y.A.b , Lazar, M.A.d , Petrucelli, L.e , Musiek, E.S.a
a Department of Neurology and Center On Biological Rhythms And Sleep, Washington University School of Medicine, St. Louis, MO, United States
b Mass Spectrometry Technology Access Center at McDonnell Genome Institute (MTAC@MGI) at Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
d Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
e Department of Neuroscience, Mayo Clinic, Jacksonville, FL, United States
Abstract
Alzheimer’s disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy. © 2023, Springer Nature Limited.
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAU19AG060909
National Cancer InstituteNCI30 CA91842
National Center for Research ResourcesNCRR
Foundation for Barnes-Jewish HospitalFBJH
Cure Alzheimer’s FundCAF
University of WashingtonUW
Washington University School of Medicine in St. LouisWUSM
Center for Cellular Imaging, Washington UniversityWUCCI
St. Louis Children’s HospitalSLCHCDI-CORE-2015-505, CDI-CORE-2019-813
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis586 R35NS097273, P01NS084974-01, R01DK45586, R35NS097273, RF1AG062077, RF1AG062171
Document Type: Article
Publication Stage: Final
Source: Scopus
AT(N) biomarker profiles and Alzheimer’s disease symptomology in Down syndrome
(2023) Alzheimer’s and Dementia, .
Hartley, S.L.a b , Handen, B.c , Tudorascu, D.c , Lee, L.c , Cohen, A.c , Schworer, E.K.a , Peven, J.C.c , Zammit, M.a d , Klunk, W.c , Laymon, C.e f , Minhas, D.e , Luo, W.e , Zaman, S.g , Ances, B.h , Preboske, G.i , Christian, B.T.a d
a Waisman Center, University of Wisconsin–Madison, Madison, WI, United States
b School of Human Ecology, University of Wisconsin–Madison, Madison, WI, United States
c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Medical Physics, University of Wisconsin–Madison, Madison, WI, United States
e Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
f Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
g Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
h Department of Neurology, Washington University at St. Louis, St. Louis, MO, United States
i Mayo Clinic, Rochester, MN, United States
Abstract
INTRODUCTION: Down syndrome (DS) is a genetic cause of early-onset Alzheimer’s disease (AD). The National Institute on Aging–Alzheimer’s Association AT(N) Research Framework is a staging model for AD biomarkers but has not been assessed in DS. METHOD: Data are from the Alzheimer’s Biomarker Consortium–Down Syndrome. Positron emission tomography (PET) amyloid beta (Aβ; 15 mCi of [11C]Pittsburgh compound B) and tau (10 mCi of [18F]AV-1451) were used to classify amyloid (A) –/+ and tau (T) +/–. Hippocampal volume classified neurodegeneration (N) –/+. The modified Cued Recall Test assessed episodic memory. RESULTS: Analyses included 162 adults with DS (aged M = 38.84 years, standard deviation = 8.41). Overall, 69.8% of participants were classified as A–/T–/(N)–, 11.1% were A+/T–/(N)–, 5.6% were A+/T+/(N)–, and 9.3% were A+/T+/(N)+. Participants deemed cognitively stable were most likely to be A–T–(N)– and A+T–(N)–. Tau PET (T+) most closely aligning with memory impairment and AD clinical status. DISCUSSION: Findings add to understanding of AT(N) biomarker profiles in DS. HIGHLIGHTS: Overall, 69.8% of adults with Down syndrome (DS) aged 25 to 61 years were classified as amyloid (A)–/tau (T)–/neurodegeneration (N)–, 11.1% were A+/T–/(N)–, 5.6% were A+/T+/(N)–, and 9.3% were A+/T+/(N)+. The AT(N) profiles were associated with clinical Alzheimer’s disease (AD) status and with memory performance, with the presence of T+ aligned with AD clinical symptomology. Findings inform models for predicting the transition to the prodromal stage of AD in DS. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
adults; Alzheimer’s; amyloid; ATN; biomarker; cognitive; dementia; Down syndrome; hippocampal; imaging; magnetic resonance imaging; memory; positron emission tomography; tau
Funding details
National Institute on AgingNIA
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDP50HD105353, R01AG031110, UO1 AG051406, UO1 AG051412
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Characterizing the emergence of amyloid and tau burden in Down syndrome
(2023) Alzheimer’s and Dementia, .
Zammit, M.D.a , Betthauser, T.J.b c , McVea, A.K.a , Laymon, C.M.d , Tudorascu, D.L.e , Johnson, S.C.b c , Hartley, S.L.a , Converse, A.K.a , Minhas, D.S.d , Zaman, S.H.f , Ances, B.M.g , Stone, C.K.c , Mathis, C.A.e , Cohen, A.D.e , Klunk, W.E.e , Handen, B.L.e , Christian, B.T.a h
a University of Wisconsin-Madison Waisman Center, Madison, WI, United States
b University of Wisconsin-Madison Alzheimer’s Disease Research Center, Madison, WI, United States
c Department of Medicine, University of Wisconsin-Madison, Madison, WI, United States
d Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
e Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
f Cambridge Intellectual Disability Research Group, University of Cambridge, Cambridge, United Kingdom
g Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
h Department of Medical Physics, University of Wisconsin-Madison, Madison, WI, United States
Abstract
INTRODUCTION: Almost all individuals with Down syndrome (DS) will develop neuropathological features of Alzheimer’s disease (AD). Understanding AD biomarker trajectories is necessary for DS-specific clinical interventions and interpretation of drug-related changes in the disease trajectory. METHODS: A total of 177 adults with DS from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) underwent positron emission tomography (PET) and MR imaging. Amyloid-beta (Aβ) trajectories were modeled to provide individual-level estimates of Aβ-positive (A+) chronicity, which were compared against longitudinal tau change. RESULTS: Elevated tau was observed in all NFT regions following A+ and longitudinal tau increased with respect to A+ chronicity. Tau increases in NFT regions I-III was observed 0–2.5 years following A+. Nearly all A+ individuals had tau increases in the medial temporal lobe. DISCUSSION: These findings highlight the rapid accumulation of amyloid and early onset of tau relative to amyloid in DS and provide a strategy for temporally characterizing AD neuropathology progression that is specific to the DS population and independent of chronological age. Highlights: Longitudinal amyloid trajectories reveal rapid Aβ accumulation in Down syndrome NFT stage tau was strongly associated with A+ chronicity Early longitudinal tau increases were observed 2.5–5 years after reaching A+. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amyloid; amyloid chronicity; Down syndrome; longitudinal; PET; Tau; trajectory modeling
Funding details
P50 HD105353, U54 HD087011, U54 HD090256
U24 AG21886
National Institutes of HealthNIHP30 AG062421, P30 AG062715, P30 AG066519, P50 AG005133, P50 AG005681, P50 AG008702, P50 AG16537
National Institute on AgingNIA
National Institute of Child Health and Human DevelopmentNICHDU01 AG051406, U01 AG051412, U19 AG068054
National Center for Advancing Translational SciencesNCATSUL1 TR001414, UL1 TR001857, UL1 TR001873, UL1 TR002345, UL1 TR002373
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
NIHR Cambridge Biomedical Research Centre
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology
(2023) European Journal of Human Genetics, .
Oppermann, H.a , Marcos-Grañeda, E.b , Weiss, L.A.b , Gurnett, C.A.c , Jelsig, A.M.d , Vineke, S.H.d , Isidor, B.e , Mercier, S.e f , Magnussen, K.g , Zacher, P.h , Hashim, M.i , Pagnamenta, A.T.i , Race, S.j , Srivastava, S.k , Frazier, Z.k , Maiwald, R.l , Pergande, M.m , Milani, D.n , Rinelli, M.o p , Levy, J.q , Krey, I.a , Fontana, P.r , Lonardo, F.r , Riley, S.s , Kretzer, J.s , Rankin, J.t , Reis, L.M.u , Semina, E.V.u , Reuter, M.S.v w , Scherer, S.W.v w , Iascone, M.x , Weis, D.y , Fagerberg, C.R.z , Brasch-Andersen, C.z , Hansen, L.K.aa , Kuechler, A.ab , Noble, N.ac , Gardham, A.ad , Tenney, J.ae , Rathore, G.af , Beck-Woedl, S.ag , Haack, T.B.ag , Pavlidou, D.C.ah , Atallah, I.ah , Vodopiutz, J.ai aj , Janecke, A.R.ak al , Hsieh, T.-C.am , Lesmann, H.am an , Klinkhammer, H.am ao , Krawitz, P.M.am , Lemke, J.R.a ap , Jamra, R.A.a , Nieto, M.b , Tümer, Z.aq ar , Platzer, K.a
a Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
b Department of Cellular and Molecular Biology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas (CNB-CSIC), Campus de Cantoblanco, Madrid, Spain
c Department of Neurology, Washington University in St Louis, St Louis, MO, United States
d Dpt. of Clinical Genetics, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
e Service de Génétique Médicale, CHU de Nantes, Nantes, France
f L’institut du thorax, Inserm, Cnrs, Univ Nantes, Nantes, France
g Randall Children’s Hospital at Legacy Emanuel, Portland, OR, United States
h Epilepsy Center Kleinwachau, Radeberg, Germany
i NIHR Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
j BC Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
k Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
l MVZ for Coagulation Diagnostics and Medical Genetics Cologne, ÜBAG Zotz/Klimas, Cologne, Germany
m MVZ Düsseldorf Zentrum, ÜBAG Zotz/Klimas, Düsseldorf, Germany
n Fondazione IRCCS Ca’Granda Ospedale Maggiore Policlinico, Milan, Italy
o Laboratory of Medical Genetics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
p Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
q Genetics Department, CHU Robert-Debré, AP-HP, Paris, France
r Medical Genetics Unit, A.O.R.N. San Pio, Benevento, Italy
s Department of Pediatrics, University of Maryland School of Medicine, Baltimore, MD, United States
t Department of Clinical Genetics, Royal Devon University Healthcare NHS Trust, Exeter, United Kingdom
u Department of Pediatrics and Children’s Research Institute, Medical College of Wisconsin and Children’s Hospital of Wisconsin, Milwaukee, WI, United States
v The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada
w Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
x Laboratory of Medical Genetics, ASST Papa Giovanni XXIII, Bergamo, Italy
y Department of Medical Genetics, Kepler University Hospital Med Campus IV, Johannes Kepler University, Linz, Austria
z Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
aa HC Andersen Childrens Hospital, Odense University Hospital, Odense, Denmark
ab Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
ac Blank Children’s Developmental Center, Unity Point Health, Des Moines, IA, United States
ad North West Thames Regional Genetic Service, North West London Hospitals, London, United Kingdom
ae Division of Medical Genetics, University of California, San Francisco, CA, United States
af Dvision of Pediatric Neurology, University of Nebraska Medical Center, Omaha, NE, United States
ag Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
ah Division of Genetic Medicine, Lausanne Universitary Hospital and University of Lausanne, Lausanne, Switzerland
ai Department of Pediatrics and Adolescent Medicine, Division of Pediatric Pulmonology, Allergology and Endocrinology, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria
aj Vienna Bone and Growth Center, Vienna, Austria
ak Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria
al Institute of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria
am Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
an Institut für Humangenetik, Universitätsklinikum Bonn, Universität Bonn, Bonn, Germany
ao Institute for Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany
ap Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany
aq Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark
ar Department of Clinical Medicin, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Abstract
Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1 +/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1 +/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1 +/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1 +/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course. © 2023, The Author(s).
Funding details
National Institutes of HealthNIHP50 HD103525, PID2020-112831GB-I00 AEI /10.13039/501100011033
National Institute of Neurological Disorders and StrokeNINDSK23NS119666
Autism SpeaksAS
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Ministerio de Ciencia, Innovación y UniversidadesMCIUEY025718, FPU18/06240
Sick Kids Foundation
McLaughlin Centre, University of Toronto
Region Syddanmark
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A pilot phase Ib study to evaluate tadalafil to overcome immunosuppression during chemoradiotherapy for IDH-wild-Type glioblastoma
(2023) Neuro-Oncology Advances, 5 (1), art. no. vdad088, .
Ghosh, S.a b , Johanns, T.M.b d , Chheda, M.G.b d , Liu, E.a , Butt, O.b d , Abraham, C.a d d , Badiyan, S.a d d , Huang, Y.a d d , Denardo, D.b , Kim, A.H.b d c d , Hallahan, D.d , Thotala, D.a b , Huang, J.a d d
a Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, 4921 Parkview Place, Campus Box 8224, St. Louis, MI 63110, United States
b Department of Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
c Department of Medicine, Division of Medical Oncology, Washington University School of Medicine, St. Louis, MI, United States
d Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, 4511 Forest Park Ave, St. Louis, MO 63108, United States
Abstract
Background: Myeloid-derived suppressor cells (MDSCs) are critical regulators of immunosuppression and radioresistance in glioblastoma (GBM). The primary objective of this pilot phase Ib study was to validate the on-Target effect of tadalafil on inhibiting MDSCs in peripheral blood and its safety when combined with chemoradiotherapy in GBM patients. Methods: Patients with newly diagnosed IDH-wild-Type GBM received radiation therapy (RT) and temozolomide (TMZ) combined with oral tadalafil for 2 months. A historical cohort of 12 GBM patients treated with RT and TMZ was used as the comparison group. The ratio of MDSCs, T cells, and cytokines at week 6 of RT compared to baseline were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: Tadalafil was well tolerated with no dose-limiting toxicity among 16 evaluable patients. The tadalafil cohort had a significantly lower ratio of circulating MDSCs than the control: granulocytic-MDSCs (mean 0.78 versus 3.21, respectively, P=0.01) and monocytic-MDSCs (1.02 versus 1.96, respectively, P=0.006). Tadalafil increased the CD8 ratio compared to the control (1.99 versus 0.70, respectively, P<0.001), especially the PD-1-CD8 T cells expressing Ki-67, CD38, HLA-DR, CD28, and granzyme B. Proinflammatory cytokine IL-1β was also significantly increased after tadalafil compared to the control. The tadalafil cohort did not have significantly different PFS and OS than the historical control. Conclusions: Concurrent tadalafil is well tolerated during chemoradiotherapy for GBM. Tadalafil is associated with a reduction of peripheral MDSCs after chemoradiotherapy and increased CD8 T-cell proliferation and activation. © 2023 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
Author Keywords
glioblastoma; immunosuppression; MDSC; radiotherapy; tadalafil
Funding details
National Cancer InstituteNCI30 CA091842
Document Type: Article
Publication Stage: Final
Source: Scopus
Mapping sleep’s oscillatory events as a biomarker of Alzheimer’s disease
(2023) Alzheimer’s and Dementia, .
Pulver, R.L.a b , Kronberg, E.a , Medenblik, L.M.a b , Kheyfets, V.O.c , Ramos, A.R.d , Holtzman, D.M.e f g , Morris, J.C.e f g , Toedebusch, C.D.e , Sillau, S.H.a b , Bettcher, B.M.a b , Lucey, B.P.e f g , McConnell, B.V.a b
a Department of Neurology, University of Colorado School of Medicine, Aurora, CO, United States
b University of Colorado Alzheimer’s and Cognition Center, University of Colorado School of Medicine, Aurora, CO, United States
c Department of Pediatric Critical Care Medicine, University of Colorado School of Medicine, Aurora, CO, United States
d Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, United States
e Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
f Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, MO, United States
g Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, MO, United States
Abstract
INTRODUCTION: Memory-associated neural circuits produce oscillatory events including theta bursts (TBs), sleep spindles (SPs), and slow waves (SWs) in sleep electroencephalography (EEG). Changes in the “coupling” of these events may indicate early Alzheimer’s disease (AD) pathogenesis. METHODS: We analyzed 205 aging adults using single-channel sleep EEG, cerebrospinal fluid (CSF) AD biomarkers, and Clinical Dementia Rating® (CDR®) scale. We mapped SW-TB and SW-SP neural circuit coupling precision to amyloid positivity, cognitive impairment, and CSF AD biomarkers. RESULTS: Cognitive impairment correlated with lower TB spectral power in SW-TB coupling. Cognitively unimpaired, amyloid positive individuals demonstrated lower precision in SW-TB and SW-SP coupling compared to amyloid negative individuals. Significant biomarker correlations were found in oscillatory event coupling with CSF Aβ42/Aβ40, phosphorylated- tau181, and total-tau. DISCUSSION: Sleep-dependent memory processing integrity in neural circuits can be measured for both SW-TB and SW-SP coupling. This breakdown associates with amyloid positivity, increased AD pathology, and cognitive impairment. Highlights: At-home sleep EEG is a potential biomarker of neural circuits linked to memory. Circuit precision is associated with amyloid positivity in asymptomatic aging adults. Levels of CSF amyloid and tau also correlate with circuit precision in sleep EEG. Theta burst EEG power is decreased in very early mild cognitive impairment. This technique may enable inexpensive wearable EEGs for monitoring brain health. © 2023 The Authors. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amyloid; EEG; memory; mild cognitive impairment; slow wave; tau
Funding details
National Institutes of HealthNIHP01AG003991, P01AG026276, P30 AG066444, R01AG058772, R03AG080427, U19 AG032438
Document Type: Article
Publication Stage: Article in Press
Source: Scopus