List of publications for week of March 7, 2022
Beta-amyloid moderates the relationship between cortical thickness and attentional control in middle- and older-aged adults
(2022) Neurobiology of Aging, 112, pp. 181-190.
McKay, N.S.a b , Dincer, A.a b , Mehrotra, V.e , Aschenbrenner, A.J.b c , Balota, D.b d , Hornbeck, R.C.a b , Hassenstab, J.b c d , Morris, J.C.b c , Benzinger, T.L.S.a b , Gordon, B.A.a b d
a Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
b Knight Alzheimer’s Disease Research Center, Washington University in St. LouisMO, United States
c Department of Neurology, Washington School of Medicine, St. Louis, MO, United States
d Department of Psychological and Brain Sciences, Washington University in St. LouisMO, United States
e Case Western School of Medicine, Cleveland, OH, United States
Abstract
Although often unmeasured in studies of cognition, many older adults possess Alzheimer disease (AD) pathologies such as beta-amyloid (Aβ) deposition, despite being asymptomatic. We were interested in examining whether the behavior-structure relationship observed in later life was altered by the presence of preclinical AD pathology. A total of 511 cognitively unimpaired adults completed magnetic resonance imaging and three attentional control tasks; a subset (n = 396) also underwent Aβ-positron emissions tomography. A vertex-wise model was conducted to spatially represent the relationship between cortical thickness and average attentional control accuracy, while moderation analysis examined whether Aβ deposition impacted this relationship. First, we found that reduced cortical thickness in temporal, medial- and lateral-parietal, and dorsolateral prefrontal cortex, predicted worse performance on the attention task composite. Subsequent moderation analyses observed that levels of Aβ significantly influence the relationship between cortical thickness and attentional control. Our results support the hypothesis that preclinical AD, as measured by Aβ deposition, is partially driving what would otherwise be considered general aging in a cognitively normal adult population. © 2022 Elsevier Inc.
Author Keywords
Alzheimer disease; Amyloid; Attention; Cognition; Control; Free surfer; Moderation
Funding details
National Institutes of HealthNIH1S10OD018091-01, 1S10RR022984-01A1, K01AG053474, P01AG003991, P01AG026276, P30 AG066444, P30NS098577, P50AG005681, R01EB009352, U19 AG024904, U19 AG032438
Alzheimer’s AssociationAA
Foundation for Barnes-Jewish HospitalFBJH
Document Type: Article
Publication Stage: Final
Source: Scopus
Inhibition of MEK-ERK signaling reduces seizures in two mouse models of tuberous sclerosis complex
(2022) Epilepsy Research, 181, art. no. 106890, .
Nguyen, L.H.a b , Leiser, S.C.c , Song, D.c , Brunner, D.d , Roberds, S.L.d , Wong, M.e , Bordey, A.a b
a Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, United States
b Department of Cellular & Molecular Physiology, Yale University School of Medicine, New Haven, CT, United States
c Department of Translational EEG, PsychoGenics, Inc, Paramus, NJ, United States
d Tuberous Sclerosis Alliance, Silver Spring, MD, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Tuberous sclerosis complex (TSC) is a monogenic disorder characterized by hyperactivation of the mTOR signaling pathway and developmental brain malformations leading to intractable epilepsy. Although treatment with the recently approved mTOR inhibitor, everolimus, results in clinically relevant seizure suppression in up to 40% of TSC patients, seizures remain uncontrolled in a large number of cases, underscoring the need to identify novel treatment targets. The MEK-ERK signaling pathway has been found to be aberrantly activated in TSC and inhibition of MEK-ERK activity independently of mTOR rescued neuronal dendrite overgrowth in mice modeling TSC neuropathology. Here, we evaluated the efficacy of MEK-ERK inhibition on seizures in two mouse models of TSC. We found that treatment with the MEK inhibitor PD0325901 (mirdametinib) significantly reduced seizure activity in both TSC mouse models. These findings support inhibiting MEK-ERK activity as a potential alternative strategy to treat seizures in TSC. © 2022 Elsevier B.V.
Author Keywords
Epilepsy; MAPK; MEK inhibitor; MEK-ERK signaling; Seizures; Tuberous sclerosis complex
Funding details
National Institute of Neurological Disorders and StrokeNINDSR01 NS056872, R01 NS086329
American Epilepsy SocietyAES
Tuberous Sclerosis AllianceTSA
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDF32 HD095567
Document Type: Article
Publication Stage: Final
Source: Scopus
Effect of obstructive sleep apnea on glucose metabolism
(2022) European Journal of Endocrinology, 186 (4), pp. 457-467.
Koh, H.-C.E.a , van Vliet, S.a , Cao, C.a , Patterson, B.W.a , Reeds, D.N.a , Laforest, R.b , Gropler, R.J.b , Ju, Y.-E.S.c d , Mittendorfer, B.a
a Center for Human Nutrition, St. Louis, MO, United States
b Mallinckrodt Institute of Radiology, St. Louis, MO, United States
c Department of Neurology, St. Louis, MO, United States
d Hope Center for Neurological Disorders at Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Obstructive sleep apnea (OSA) is prevalent in people with obesity and is a major risk factor for type 2 diabetes (T2D). The effect of OSA on metabolic function and the precise mechanisms (insulin resistance, β-cell dysfunction, or both) responsible for the increased T2D risk in people with OSA are unknown. Design and methods: We used a two-stage hyperinsulinemic-euglycemic clamp procedure in conjunction with stable isotopically labeled glucose and palmitate tracer infusions and 18F-fluorodeoxyglucose injection and positron emission tomography to quantify multi-organ insulin action and oral and intravenous tolerance tests to evaluate glucose-stimulated insulin secretion in fifteen people with obesity and OSA and thirteen people with obesity without OSA. Results: OSA was associated with marked insulin resistance of adipose tissue triglyceride lipolysis and glucose uptake into both skeletal muscles and adipose tissue, whereas there was no significant difference between the OSA and control groups in insulin action on endogenous glucose production, basal insulin secretion, and glucose-stimulated insulin secretion during both intravenous and oral glucose tolerance tests. Conclusions: These data demonstrate that OSA is a key determinant of insulin sensitivity in people with obesity and underscore the importance of taking OSA status into account when evaluating metabolic function in people with obesity. These findings may also have important clinical implications because disease progression and the risk of diabetes-related complications vary by T2D subtype (i.e. severe insulin resistance vs insulin deficiency). People with OSA may benefit most from the targeted treatment of peripheral insulin resistance and early screening for complications associated with peripheral insulin resistance.
Document Type: Article
Publication Stage: Final
Source: Scopus
Acquired hydrocephalus is associated with neuroinflammation, progenitor loss, and cellular changes in the subventricular zone and periventricular white matter
(2022) Fluids and Barriers of the CNS, 19 (1), p. 17.
Garcia-Bonilla, M.a , Castaneyra-Ruiz, L.a , Zwick, S.a , Talcott, M.a b , Otun, A.a , Isaacs, A.M.c , Morales, D.M.a , Limbrick, D.D., Jra , McAllister, J.P., 2nda
a Department of Neurosurgery, Washington University in St. Louis School of Medicine, St. Louis, MO, 63110, USA
b Division of Comparative Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, 63110, USA
c Division of Neurosurgery, Department of Clinical Neurosciences, University of CalgaryAB T2N 2T9, Canada
Abstract
BACKGROUND: Hydrocephalus is a neurological disease with an incidence of 80-125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants. METHODS: Hydrocephalus was induced by intracisternal kaolin injections in 35-day old female pigs (n = 7 for tissue analysis, n = 10 for CSF analysis). Age-matched sham controls received saline injections (n = 6). After 19-40 days, MRI scanning was performed to measure the ventricular volume. Stem cell proliferation was studied in the Subventricular Zone (SVZ), and cell death and oligodendrocytes were examined in the PVWM. The neuroinflammatory reaction was studied by quantifying astrocytes and microglial cells in the PVWM, and inflammatory cytokines in the CSF. RESULTS: The expansion of the ventricles was especially pronounced in the body of the lateral ventricle, where ependymal disruption occurred. PVWM showed a 44% increase in cell death and a 67% reduction of oligodendrocytes. In the SVZ, the number of proliferative cells and oligodendrocyte decreased by 75% and 57% respectively. The decrease of the SVZ area correlated significantly with ventricular volume increase. Neuroinflammation occurred in the hydrocephalic pigs with a significant increase of astrocytes and microglia in the PVWM, and high levels of inflammatory interleukins IL-6 and IL-8 in the CSF. CONCLUSION: The induction of acquired hydrocephalus produced alterations in the PVWM, reduced cell proliferation in the SVZ, and neuroinflammation. © 2022. The Author(s).
Author Keywords
Kaolin-induced hydrocephalus; Neuroinflammation; Pig model; Subventricular zone reduction; Ventriculomegaly; White matter alteration
Document Type: Article
Publication Stage: Final
Source: Scopus
Isolation of Cardiac and Vascular Smooth Muscle Cells from Adult, Juvenile, Larval and Embryonic Zebrafish for Electrophysiological Studies
(2022) Journal of Visualized Experiments, 2022 (180), art. no. e63225, .
Singareddy, S.S.a , McClenaghan, C.a , Roessler, H.I.b , Tryon, R.a , Nichols, C.G.a
a Department of Cell Biology and Physiology and Center for the Investigation of Membrane Excitability Diseases, Washington University in St. Louis, United States
b Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Netherlands
Abstract
Zebrafish have long been used as a model vertebrate organism in cardiovascular research. The technical difficulties of isolating individual cells from the zebrafish cardiovascular tissues have been limiting in studying their electrophysiological properties. Previous methods have been described for dissection of zebrafish hearts and isolation of ventricular cardiac myocytes. However, the isolation of zebrafish atrial and vascular myocytes for electrophysiological characterization was not detailed. This work describes new and modified enzymatic protocols that routinely provide isolated juvenile and adult zebrafish ventricular and atrial cardiomyocytes, as well as vascular smooth muscle (VSM) cells from the bulbous arteriosus, suitable for patch-clamp experiments. There has been no literary evidence of electrophysiological studies on zebrafish cardiovascular tissues isolated at embryonic and larval stages of development. Partial dissociation techniques that allow patch-clamp experiments on individual cells from larval and embryonic hearts are demonstrated. © 2022 JoVE Journal of Visualized Experiments.
Funding details
National Institutes of HealthNIHHL140024, HL150277
Document Type: Article
Publication Stage: Final
Source: Scopus
Racial differences in longitudinal Alzheimer’s disease biomarkers among cognitively normal adults
(2022) Alzheimer’s and Dementia, .
Xiong, C.a b , Luo, J.a c d , Schindler, S.E.b e , Fagan, A.M.b e , Benzinger, T.b f , Hassenstab, J.b e , Balls-Berry, J.E.b e , Agboola, F.a b , Grant, E.a b , Moulder, K.L.b e , Morris, J.C.b e g
a Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
b Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, MO, United States
d Siteman Cancer Center Biostatistics Core, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
g Departments of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Introduction: Longitudinal changes in Alzheimer’s disease (AD) biomarkers, including cerebrospinal fluid (CSF) analytes, amyloid uptakes from positron emission tomography (PET), structural outcomes from magnetic resonance imaging (MRI), and cognition, have not been compared between Blacks and Whites. Methods: A total of 179 Blacks and 1180 Whites who were cognitively normal at baseline and had longitudinal data from at least one biomarker modality were analyzed for the annual rates of change. Results: CSF amyloid beta (Aβ)42/Aβ40 declined more slowly (P =.0390), and amyloid (PET) accumulated more slowly (P =.0157), in Blacks than Whites. CSF Aβ42 changed in opposite directions over time between Blacks and Whites (P =.0039). The annual increase in CSF total tau and phosphorylated tau181 for Blacks was about half of that for Whites. Discussion: Longitudinal racial differences in amyloid biomarkers are observed. It will be important to comprehensively and prospectively examine the effects of apolipoprotein E genotype and sociocultural factors on these differences. © 2022 the Alzheimer’s Association
Author Keywords
Alzheimer’s disease; cerebrospinal fluid biomarkers; imaging biomarkers; longitudinal; racial difference
Funding details
National Institutes of HealthNIH
National Institute on AgingNIAP01 AG003991, P01AG026276, P30AG066444, R01 AG053550, R01 AG067505
Biogen
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The Worldwide Alzheimer’s Disease Neuroimaging Initiative: ADNI-3 updates and global perspectives
(2021) Alzheimer’s and Dementia: Translational Research and Clinical Interventions, 7 (1), art. no. e12226, .
Weber, C.J.a , Carrillo, M.C.a , Jagust, W.b , Jack, C.R., Jr.c , Shaw, L.M.d , Trojanowski, J.Q.e , Saykin, A.J.f , Beckett, L.A.g , Sur, C.h , Rao, N.P.i , Mendez, P.C.j , Black, S.E.k , Li, K.l , Iwatsubo, T.m , Chang, C.-C.n , Sosa, A.L.o , Rowe, C.C.p , Perrin, R.J.q , Morris, J.C.r , Healan, A.M.B.s , Hall, S.E.a , Weiner, M.W.t
a Alzheimer’s Association, Chicago, IL, United States
b School of Public Health and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, United States
c Department of Radiology, Mayo Clinic, Rochester, MN, United States
d Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
e Department of Pathology and Laboratory Medicine, Perelman School of Medicine, Institute on Aging, Perelman School of Medicine, Alzheimer’s Disease Core Center, Perelman School of Medicine, Udall Parkinson’s Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
f Department of Radiology and Imaging Sciences and the Indiana Alzheimer’s Disease Research Center, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, United States
g Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, CA, United States
h Merck Research Laboratories, Merck, Kenilworth, NJ, United States
i Department of Psychiatry, National Institute of Mental Health and Neurosciences, Karnataka, Bengaluru, India
j Centro de Memoria, FLENI, Montañeses, 2325 (C1428AQK), Bs As, Buenos Aires, Argentina
k Department of Medicine (Neurology), Hurvitz Brain Sciences Program, Canadian Partnership for Stroke Recovery, and LC Campbell Cognitive Neurology Research Unit, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada
l Department of Radiology, Xuanwu Hospital of Capital Medical University, Beijing, China
m Department of Neuropathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
n Department of General Neurology and Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan
o National Institute of Neurology and Neurosurgery of Mexico, Mexico City, Mexico
p Department of Molecular Imaging and Therapy, Austin Health and Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, VIC, Australia
q Charles F. and Joanne Knight Alzheimer Disease Research Center, Department of Pathology and Immunology, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
r Charles F. and Joanne Knight Alzheimer Disease Research Center, Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
s Independent Science Writer and Editor, Nashville, TN, United States
t Department of Veterans Affairs Medical Center, Center for Imaging of Neurodegenerative Diseases, Department of Radiology, Department of Medicine, Department of Psychiatry, Department of Neurology, University of California, San Francisco, CA, United States
Abstract
The Worldwide Alzheimer’s Disease Neuroimaging Initiative (WW-ADNI) is a collaborative effort to investigate imaging and biofluid markers that can inform Alzheimer’s disease treatment trials. It is a public-private partnership that spans North America, Argentina, Australia, Canada, China, Japan, Korea, Mexico, and Taiwan. In 2004, ADNI researchers began a naturalistic, longitudinal study that continues today around the globe. Through several successive phases (ADNI-1, ADNI-GO, ADNI-2, and ADNI-3), the study has fueled amyloid and tau phenotyping and refined neuroimaging methodologies. WW-ADNI researchers have successfully standardized analyses and openly share data without embargo, providing a rich data set for other investigators. On August 26, 2020, the Alzheimer’s Association convened WW-ADNI researchers who shared updates from ADNI-3 and their vision for ADNI-4. © 2021 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer’s Association.
Author Keywords
Alzheimer’s disease; amyloid; biomarkers; cerebrospinal fluid; cognitive impairment; MRI; neuroimaging; PET; Tau
Funding details
005441
U24 AG021886
National Institutes of HealthNIH
Mayo Clinic
Roche
Biogen
AbbVie
Alzheimer’s Disease Research Center, Emory UniversityADRCP30AG010124
Alzheimer’s Disease Neuroimaging InitiativeADNIP30 AG010133, R01 AG019771, R01 AG057739, R01 AG068193, R01 LM013463, U01 AG024904, U01 AG068057
Campbell Foundation
Cosmetic Surgery FoundationCSFU19AG024904
GHR FoundationGHR
Canadian Institutes of Health ResearchIRSC112246, 142381, 159910
National Health and Medical Research CouncilNHMRC
Eisai
Document Type: Article
Publication Stage: Final
Source: Scopus