Force and energy transmission at the brain-skull interface of the minipig in vivo and post-mortem
(2025) Journal of the Mechanical Behavior of Biomedical Materials, 161, art. no. 106775, .
Wang, S.a , Eckstein, K.N.a , Okamoto, R.J.a , McGarry, M.D.J.b , Johnson, C.L.c , Bayly, P.V.a d
a Washington University in St. Louis, Mechanical Engineering and Material Science, United States
b Dartmouth College, Thayer School of Engineering, United States
c University of Delaware, Biomedical Engineering, United States
d Washington University in St. Louis, Biomedical Engineering, United States
Abstract
The brain-skull interface plays an important role in the mechano-pathology of traumatic brain injury (TBI). A comprehensive understanding of the mechanical behavior of the brain-skull interface in vivo is significant for understanding the mechanisms of TBI and creating accurate computational models. Here we investigate the force and energy transmission at the minipig brain-skull interface by non-invasive methods in the live (in vivo) and dead animal (in situ). Displacement fields in the brain and skull were measured in four female minipigs by magnetic resonance elastography (MRE), and the relative displacements between the brain and skull were estimated. Surface maps of deviatoric stress, the apparent mechanical properties of the brain-skull interface, and the net energy flux were generated for each animal when alive and at specific times post-mortem. After death, these maps reveal increases in relative motion between brain and skull, brain surface stress, stiffness of brain-skull interface, and net energy flux from skull to brain. These results illustrate the ability to study both skull and brain mechanics by MRE; the observed post-mortem decrease in the protective capability of the brain-skull interface emphasizes the importance of measuring its behavior in vivo. © 2024 Elsevier Ltd
Author Keywords
Brain-skull interface; Magnetic resonance elastography; Post-mortem changes; Traumatic brain injury
Funding details
National Institutes of HealthNIHR01 EB027577
Office of Naval ResearchONRN00014-22-1-2198
Document Type: Article
Publication Stage: Final
Source: Scopus
Targeting TREM2 signaling shows limited impact on cerebrovascular calcification
(2025) Life Science Alliance, 8 (1), .
Sridhar, S.a b , Zhou, Y.c , Ibrahim, A.d , Bertazzo, S.e , Wyss, T.f , Swain, A.c , Maheshwari, U.a , Huang, S.-F.a , Colonna, M.c , Keller, A.a b
a https://ror.org/02crff812 Department of Neurosurgery, Clinical Neuroscience Center, University Hospital Zurich, University of ZurichZurich, Switzerland
b https://ror.org/02crff812 Neuroscience Centre Zurich, University of Zurich and ETH ZurichZurich, Switzerland
c Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, United States
d South San Francisco, CA, United States
e https://ror.org/02jx3x895 Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom
f AGORA Cancer Research Center, Swiss Institute of Bioinformatics, Lausanne, Switzerland
Abstract
Brain calcification, the ectopic mineral deposits of calcium phosphate, is a frequent radiological finding and a diagnostic criterion for primary familial brain calcification. We previously showed that microglia curtail the growth of small vessel calcification via the triggering receptor expressed in myeloid 2 (TREM2) in the Pdgfbret/ret mouse model of primary familial brain calcification. Because boosting TREM2 function using activating antibodies has been shown to be beneficial in other disease conditions by aiding in microglial clearance of diverse pathologies, we investigated whether administration of a TREM2-activating antibody could mitigate vascular calcification in Pdgfbret/ret mice. Single-nucleus RNA-sequencing analysis showed that calcification-associated microglia share transcriptional similarities to disease-associated microglia and exhibited activated TREM2 and TGFβ signaling. Administration of a TREM2-activating antibody increased TREM2-dependent microglial deposition of cathepsin K, a collagen-degrading protease, onto calcifications. However, this did not ameliorate the calcification load or alter the mineral composition and the microglial phenotype around calcification. We therefore conclude that targeting microglia with TREM2 agonistic antibodies is insufficient to demineralize and clear vascular calcifications. © 2024 Sridhar et al.
Document Type: Article
Publication Stage: Final
Source: Scopus
Genotype‒phenotype correlation in recessive DNAJB4 myopathy
(2024) Acta Neuropathologica Communications, 12 (1), art. no. 171, .
Inoue, M.a , Jayaraman, D.b c , Bengoechea, R.a , Bhadra, A.d , Genetti, C.A.b , Aldeeri, A.A.b e , Turan, B.f , Pacheco-Orozco, R.A.g h , Al-Maawali, A.i , Al Hashmi, N.j , Zamani, A.G.f , Göktaş, E.f , Pekcan, S.k , Çağlar, H.T.k , True, H.d , Beggs, A.H.b , Weihl, C.C.a
a Department of Neurology, Washington University School of Medicine, Box 8111, 4523 Clayton Avenue, Saint Louis, MO 63110, United States
b Division of Genetics and Genomics, Boston Children’s Hospital, The Manton Center for Orphan Disease Research, Harvard Medical School, Boston, United States
c Department of Neurology, Division of Neuromuscular Medicine, Massachusetts General Hospital and Brigham and Women’s Hospital, Boston, United States
d Department of Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, United States
e Department of Internal Medicine, King Saud University, Riyadh, Saudi Arabia
f Department of Medical Genetics, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
g Organización Clinica General del Norte, Barranquilla, Colombia
h Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
i Department of Genetics, Sultan Qaboos University Hospital, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
j Royal Hospital, National Genetic Center, Ministry of Health, Muscat, Oman
k Department of Pediatric Pulmonology, Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey
Abstract
Protein aggregate myopathies can result from pathogenic variants in genes encoding protein chaperones. DNAJB4 is a cochaperone belonging to the heat shock protein-40 (HSP40) family and plays a vital role in cellular proteostasis. Recessive loss-of-function variants in DNAJB4 cause myopathy with early respiratory failure and spinal rigidity, presenting from infancy to adulthood. This study investigated the broader clinical and genetic spectrum of DNAJB4 myopathy. In this study, we performed whole-exome sequencing on seven patients with early respiratory failure of unknown genetic etiology. We identified five distinct pathogenic variants in DNAJB4 in five unrelated families of diverse ethnic backgrounds: three loss-of-function variants (c.547 C > T, p.R183*; c.775 C > T, p.R259*; an exon 2 deletion) and two missense variants (c.105G > C, p.K35N; c.181 A > G, p.R61G). All patients were homozygous. Most affected individuals exhibited early respiratory failure, and patients from three families had rigid spine syndrome with axial weakness in proportion to appendicular weakness. Additional symptoms included dysphagia, ankle contractures, scoliosis, neck stiffness, and cardiac dysfunction. Notably, J-domain missense variants were associated with a more severe phenotype, including an earlier age of onset and a higher mortality rate, suggesting a strong genotype‒phenotype correlation. Consistent with a loss of function, the nonsense variants presented decreased stability. In contrast, the missense variants exhibited normal or increased stability but behaved as loss-of-function variants in yeast complementation and TDP-43 disaggregation assays. Our findings suggest that DNAJB4 is an emerging cause of myopathy with rigid spine syndrome of variable age of onset and severity. This diagnosis should be considered in individuals presenting with suggestive symptoms, particularly if they exhibit neck stiffness during infancy or experience respiratory failure in adults without significant limb muscle weakness. Missense variants in the J domain may predict a more severe phenotype. © The Author(s) 2024.
Author Keywords
Chaperonopathy; DNAJB4; Heat shock proteins; Protein aggregate myopathy; Respiratory failure; Rigid spine syndrome
Funding details
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMSMDA961862
National Institute of Arthritis and Musculoskeletal and Skin DiseasesNIAMS
Muscular Dystrophy AssociationMDAR25NS070682
Muscular Dystrophy AssociationMDA
National Institute of Neurological Disorders and StrokeNINDSP50HD105351
National Institute of Neurological Disorders and StrokeNINDS
Document Type: Article
Publication Stage: Final
Source: Scopus
The effects of mosaicism on biological and clinical markers of Alzheimer’s disease in adults with Down syndrome
(2024) eBioMedicine, 110, art. no. 105433, .
Xicota, L.a , Dang, L.-H.T.a b , Lee, A.c , Krinsky-McHale, S.d , Pang, D.d n , Melilli, L.a , O’Bryant, S.e , Henson, R.L.f , Laymon, C.g n , Lai, F.h n , Rosas, H.D.h n , Ances, B.f , Lott, I.i , Hom, C.i n , Christian, B.j , Hartley, S.j , Zaman, S.k n , Head, E.l n , Mapstone, M.i n , Jin, Z.m , Silverman, W.i , Schupf, N.a b n , Handen, B.c , Lee, J.H.a b n , Aizenstein, H.J.n , Ances, B.M.n , Andrews, H.F.n , Bell, K.n , Birn, R.n , Brickman, A.M.n , Bulova, P.n , Cheema, A.n , Chen, K.n , Christian, B.T.n , Clare, I.n , Clark, L.n , Cohen, A.D.n , Constantino, J.N.n , Doran, E.W.n , Fagan, A.n , Feingold, E.n , Foroud, T.M.n , Handen, B.L.n , Harp, J.n , Hartley, S.L.n , Henson, R.n , Honig, L.n , Ikonomovic, M.D.n , Johnson, S.C.n , Jordan, C.n , Kamboh, M.I.n , Keator, D.n , Klunk, W.E.n , Kofler, J.K.n , Kreisl, W.C.n , Krinsky-McHale, S.J.n , Lao, P.n , Lott, I.T.n , Lupson, V.n , Mathis, C.A.n , Minhas, D.S.n , Nadkarni, N.n , O’Bryant, S.n , Parisi, M.n , Pettersen, M.n , Price, J.C.n , Pulsifer, M.n , Rafii, M.S.n , Reiman, E.n , Rizvi, B.n , Ryan, L.n , Schmitt, F.n , Silverman, W.P.n , Tudorascu, D.L.n , Tumuluru, R.n , Tycko, B.n , Varadarajan, B.n , White, D.A.n , Yassa, M.A.n , Zhang, F.n , Alzheimer’s Biomarker Consortium – Down Syndrome (ABC-DS)o
a Sergievsky Center, Taub Institute, Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, United States
b Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States
c Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Psychology, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, United States
e Institute of Translational Research, University of North Texas Health Sciences Center, Fort Worth, TX, United States
f Department of Neurology, Washington University in St. Louis, St. Louis, MO, United States
g Departments of Radiology and Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
h Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States
i Department of Neurology, UC Irvine, Irvine, CA, United States
j Waisman Center and Department of Human Development and Family Studies, University of Wisconsin–Madison, Madison, WI, United States
k Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
l Department of Pathology & Laboratory Medicine and Department of Neurology, UC Irvine, Irvine, CA, United States
m Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY, United States
Abstract
Background: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer’s disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21. Methods: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium–Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data. Findings: For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ40 and Aβ42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia. Interpretation: Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted. Funding: National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873). © 2024 The Author(s)
Author Keywords
Alzheimer’s disease; CSF; Down syndrome; Mosaicism; PET; Plasma biomarkers
Document Type: Article
Publication Stage: Final
Source: Scopus
Failure in a population: Tauopathy disrupts homeostatic set-points in emergent dynamics despite stability in the constituent neurons
(2024) Neuron, 112 (21), pp. 3567-3584.e5.
McGregor, J.N.a , Farris, C.A.a , Ensley, S.a , Schneider, A.a , Fosque, L.J.a , Wang, C.b c , Tilden, E.I.d , Liu, Y.a , Tu, J.a , Elmore, H.a , Ronayne, K.D.a , Wessel, R.e , Dyer, E.L.f , Bhaskaran-Nair, K.a , Holtzman, D.M.b , Hengen, K.B.a
a Department of Biology, Washington University in Saint Louis, St. Louis, MO, United States
b Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University in Saint Louis, St. Louis, MO, United States
c Institute for Brain Science and Disease, Chongqing Medical University, Chongqing, 400016, China
d Department of Neuroscience, Washington University in Saint Louis, St. Louis, MO, United States
e Department of Physics, Washington University in Saint Louis, St. Louis, MO, United States
f Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
Abstract
Homeostatic regulation of neuronal activity is essential for robust computation; set-points, such as firing rate, are actively stabilized to compensate for perturbations. The disruption of brain function central to neurodegenerative disease likely arises from impairments of computationally essential set-points. Here, we systematically investigated the effects of tau-mediated neurodegeneration on all known set-points in neuronal activity. We continuously tracked hippocampal neuronal activity across the lifetime of a mouse model of tauopathy. We were unable to detect effects of disease in measures of single-neuron firing activity. By contrast, as tauopathy progressed, there was disruption of network-level neuronal activity, quantified by measuring neuronal pairwise interactions and criticality, a homeostatically controlled, ideal computational regime. Deviations in criticality correlated with symptoms, predicted underlying anatomical pathology, occurred in a sleep-wake-dependent manner, and could be used to reliably classify an animal’s genotype. This work illustrates how neurodegeneration may disrupt the computational capacity of neurobiological systems. © 2024 The Author(s)
Author Keywords
behavior; criticality; hippocampus; homeostasis; neurodegeneration; neurophysiology; sleep; tau
Funding details
National Institutes of HealthNIH29225, 1R01NS118442-01, RF1AG047644, RF1NS090934
National Institutes of HealthNIH
National Science FoundationNSFIIS-2146072
National Science FoundationNSF
JPB FoundationJPBF1R01EB029852
JPB FoundationJPBF
Document Type: Article
Publication Stage: Final
Source: Scopus
Multiomic and clinical analysis of multiply recurrent meningiomas reveals risk factors, underlying biology, and insights into evolution
(2024) Science Advances, 10 (43), art. no. eadn4419, .
Pugazenthi, S.a , Patel, B.a b , English, C.W.c , Leidig, W.A.a , McGeehan, K.P.a d , McCornack, C.R.a d , Mok, S.a , Anzaldua-Campos, M.a , Nouri, S.H.c , Roberts, K.e , Chatrath, A.a , Khan, A.B.c , Gadot, R.c , Yano, H.a b f g , Klisch, T.J.h i , Harmanci, A.S.b j , Patel, A.J.b i j k , Kim, A.H.a b f g l
a Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
b The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurosurgery, Baylor College of Medicine, Houston, TX, United States
d Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neuropathology, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
h Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
i Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX, United States
j Center for Cancer Neuroscience, Baylor College of Medicine, Houston, TX, United States
k Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, United States
l Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
An important subset of meningiomas behaves aggressively and is characterized by multiple recurrences. We identify clinical, genetic, and epigenetic predictors of multiply recurrent meningiomas (MRMs) and evaluate the evolution of these meningiomas in patient-matched samples. On multivariable binomial logistic regression, MRMs were significantly associated with male sex (P = 0.012), subtotal resection (P = 0.001), higher number of meningiomas on presentation (P = 0.017), and histopathological sheeting (P = 0.002). Multiomic analysis of primary meningiomas revealed that MRMs have greater copy number losses (P = 0.0313) and increased DNA methylation (P = 0.0155). In meningioma cells with knockdown of EDNRB, a locus with greater promoter methylation and decreased gene expression in MRMs had increased proliferation (P < 0.0001). MRM recurrences were found to be similar to primaries but have a greater burden of copy number gains (P < 0.0001) and increased methylation (P = 0.0045). This clinical and multiomic investigation of MRMs harbors implications for the future development of biomarkers and therapeutic agents for these challenging tumors. Copyright © 2024 The Authors, some rights reserved;
Document Type: Article
Publication Stage: Final
Source: Scopus
An autonomous implantable device for the prevention of death from opioid overdose
(2024) Science Advances, 10 (43), art. no. eadr3567, .
Ciatti, J.L.a b , Vázquez-Guardado, A.b c , Brings, V.E.d e , Park, J.b , Ruyle, B.d e f , Ober, R.A.g h , McLuckie, A.J.g , Talcott, M.R.i , Carter, E.A.g , Burrell, A.R.g , Sponenburg, R.A.j , Trueb, J.b , Gupta, P.d e , Kim, J.b , Avila, R.k , Seong, M.b , Slivicki, R.A.d e , Kaplan, M.A.b k , Villalpando-Hernandez, B.a b , Massaly, N.d e , Montana, M.C.d , Pet, M.l , Huang, Y.a k m , Morón, J.A.d e f , Gereau, R.W., IVd e f n , Rogers, J.A.a b o p
a Department of Materials Science and Engineering, Northwestern University, Evanston, IL 60208, United States
b Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL 60208, United States
c Department of Electrical and Computer Engineering, North Carolina State University, Raleigh, NC 27606, United States
d Depart-ment of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, United States
e Washington University Pain Center, Washington University School of Medicine, St. Louis, MO 63110, United States
f Department of Neuroscience, Washington University, St. Louis, MO 63110, United States
g Center for Comparative Medicine, Northwestern University, Evanston, IL 60208, United States
h Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
i Division of Cardiology, Washington University School of Medicine, St. Louis, MO 63110, United States
j Chemistry of Life Processes Institute (Quantitative Bio-element Imaging Center), Northwestern University, Evanston, IL 60208, United States
k Department of Mechanical Engineering, Northwestern University, Evanston, IL 60208, United States
l Division of Plastic and Reconstructive Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States
m Department of Civil and Environmental Engineering, Northwestern University, Evanston, IL 60208, United States
n Department of Biomedical Engineering, Washington University, St. Louis, MO 63110, United States
o Department of Biomedical Engineering, Northwestern University, Evanston, IL 60208, United States
p Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
Abstract
Opioid overdose accounts for nearly 75,000 deaths per year in the United States, now a leading cause of mortality among young people aged 18 to 45 years. At overdose levels, opioid-induced respiratory depression becomes fatal without the administration of naloxone within minutes. Currently, overdose survival relies on bystander intervention, requiring a nearby person to find the overdosed individual and have immediate access to naloxone to administer. To circumvent the bystander requirement, we developed the Naloximeter: a class of life-saving implantable devices that autonomously detect and treat overdose while simultaneously contacting first responders. We present three Naloximeter platforms, for fundamental research and clinical translation, all equipped with optical sensors, drug delivery mechanisms, and a supporting ecosystem of technology to counteract opioid-induced respiratory depression. In small and large animal studies, the Naloximeter rescues from otherwise fatal opioid overdose within minutes. This work introduces life-changing, clinically translatable technologies that can broadly benefit a susceptible population recovering from opioid use disorder. Copyright © 2024 The Authors, some rights reserved;
Document Type: Article
Publication Stage: Final
Source: Scopus
Individual-level metabolic connectivity from dynamic [18F]FDG PET reveals glioma-induced impairments in brain architecture and offers novel insights beyond the SUVR clinical standard
(2024) European Journal of Nuclear Medicine and Molecular Imaging, .
Vallini, G.a , Silvestri, E.a , Volpi, T.b c , Lee, J.J.d , Vlassenko, A.G.d , Goyal, M.S.d , Cecchin, D.b e , Corbetta, M.b f , Bertoldo, A.a b
a Department of Information Engineering, University of Padova, Padova, Italy
b Padova Neuroscience Center, University of Padova, Padova, Italy
c Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, United States
d Neuroimaging Laboratories, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
e Department of Medicine, Unit of Nuclear Medicine, University of Padova, Padova, Italy
f Department of Neuroscience, University of Padova, Padova, Italy
Abstract
Purpose: This study evaluates the potential of within-individual Metabolic Connectivity (wi-MC), from dynamic [18F]FDG PET data, based on the Euclidean Similarity method. This approach leverages the biological information of the tracer’s full temporal dynamics, enabling the direct extraction of individual metabolic connectomes. Specifically, the proposed framework, applied to glioma pathology, seeks to assess sensitivity to metabolic dysfunctions in the whole brain, while simultaneously providing further insights into the pathophysiological mechanisms regulating glioma progression. Methods: We designed an index (Distance from Healthy Group, DfHG) based on the alteration of wi-MC in each patient (n = 44) compared to a healthy reference (from 57 healthy controls), to individually quantify metabolic connectivity abnormalities, resulting in an Impairment Map highlighting significantly compromised areas. We then assessed whether our measure of metabolic network alteration is associated with well-established markers of disease severity (tumor grade and volume, with and without edema). Subsequently, we investigated disruptions in wi-MC homotopic connectivity, assessing both affected and seemingly healthy tissue to deepen the pathology’s impact on neural communication. Finally, we compared network impairments with local metabolic alterations determined from SUVR, a validated diagnostic tool in clinical practice. Results: Our framework revealed how gliomas cause extensive alterations in the topography of brain networks, even in structurally unaffected regions outside the lesion area, with a significant reduction in connectivity between contralateral homologous regions. High-grade gliomas have a stronger impact on brain networks, and edema plays a mediating role in global metabolic alterations. As compared to the conventional SUVR-based analysis, our approach offers a more holistic view of the disease burden in individual patients, providing interesting additional insights into glioma-related alterations. Conclusion: Considering our results, individual PET connectivity estimates could hold significant clinical value, potentially allowing the identification of new prognostic factors and personalized treatment in gliomas or other focal pathologies. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.
Author Keywords
Brain network alterations; Cancer neuroscience; Glioma; Individual-level metabolic connectivity; SUVR; [18F]FDG dynamic PET
Funding details
National Institutes of HealthNIH
McDonnell Center for Systems Neuroscience
National Institute on AgingNIAR01AG053503, R01AG057536
National Institute on AgingNIA
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model
(2024) Neuron, .
Carling, G.K.a b , Fan, L.a , Foxe, N.R.a b , Norman, K.a , Wong, M.Y.a , Zhu, D.a , Corona, C.c , Razzoli, A.d e , Yu, F.a , Yarahmady, A.f , Ye, P.a , Chen, H.a , Huang, Y.a g , Amin, S.a , Sereda, R.h , Lopez-Lee, C.a b , Zacharioudakis, E.i , Chen, X.j , Xu, J.k , Cheng, F.k , Gavathiotis, E.i , Cuervo, A.M.h , Holtzman, D.M.j , Mok, S.-A.f , Sinha, S.C.a , Sidoli, S.i , Ratan, R.R.c , Luo, W.a , Gong, S.a , Gan, L.a
a Helen and Robert Appel Alzheimer’s Disease Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, United States
b Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY 10065, United States
c Burke Neurological Institute, Weill Cornell Medicine, White Plains, NY 10605, United States
d Transfusion Medicine Unit, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, 42122, Italy
e Clinical and Experimental PhD Program, University of Modena and Reggio Emilia, Modena, 41121, Italy
f Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
g Biochemistry, Structural Biology, Cell Biology, Developmental Biology, and Molecular Biology Graduate Program, Weill Cornell Medicine, New York, NY 10065, United States
h Department of Developmental and Molecular Biology, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, New York, NY 10461, United States
i Department of Biochemistry, Department of Medicine, Montefiore Einstein Comprehensive Cancer Center, Institute for Aging Research, Albert Einstein College of Medicine, New York, NY 10461, United States
j Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO 63110, United States
k Cleveland Clinic Genome Center and Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, United States
Abstract
The strongest risk factors for late-onset sporadic Alzheimer’s disease (AD) include the ε4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting detrimental disease mechanisms. We find that R47H induces neurodegeneration in 9- to 10-month-old female APOE4 tauopathy mice. The combination of APOE4 and R47H (APOE4-R47H) worsened hyperphosphorylated tau pathology in the frontal cortex and amplified tauopathy-induced microglial cyclic guanosine monophosphate (GMP)-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling and downstream interferon response. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk. © 2024 The Author(s)
Author Keywords
Alzheimer’s disease; APOE; cGAS; inflammation; interferon; microglia; R47H; senescence; tau; TREM2
Funding details
Rainwater Charitable FoundationRCF
JPB FoundationJPBF
Cure Alzheimer’s FundCAF
BrightFocus FoundationBFF
Tau Consortium
National Institutes of HealthNIH1R01AG079291-01A1, R01AG079557-01, R01AG064239, R01AG076448, F31AG079560, R01AG072758, R01AG074541, K99AG078493, R01AG054214
NIH Office of the DirectorODS10OD030286
A20201312F
Document Type: Article
Publication Stage: Article in Press
Source: Scopus