WashU weekly Neuroscience publications

De novo variants in GATAD2A in individuals with a neurodevelopmental disorder: GATAD2A-related neurodevelopmental disorder
(2023) Human Genetics and Genomics Advances, 4 (3), art. no. 100198, . 

Werren, E.A.^a , Guxholli, A.^a b , Jones, N.^c , Wagner, M.^d , Hannibal, I.^d , Granadillo, J.L.^e , Tyndall, A.V.^f , Moccia, A.^a , Kuehl, R.^g , Levandoski, K.M.^g , Day-Salvatore, D.L.^g , Wheeler, M.^h , Chong, J.X.^i j , Bamshad, M.J.^i j , Innes, A.M.^f k , Pierson, T.M.^l m n o , Mackay, J.P.^c , Bielas, S.L.^a b , Martin, D.M.^a b , University of Washington Center for Mendelian Genomics^p

^a Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, United States
^b Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, United States
^c School of Life and Environmental Sciences, University of Sydney, Sydney, NSW 2006, Australia
^d Institute of Human Genetics, Technical University of Munich, Munich, 80333, Germany
^e Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
^f Department of Medical Genetics, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
^g Saint Peter’s University Hospital, New Brunswick, NJ 08901, United States
^h Department of Genome Sciences, University of Washington, Seattle, WA 98195, United States
ⁱ Department of Pediatrics, University of Washington, Seattle, WA 98195, United States
^j Brotman Baty Institute, Seattle, WA 98195, United States
^k Department of Pediatrics, Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
^l Division of Pediatric Neurology, Department of Pediatrics, Guerin Children’s, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
^m Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
ⁿ Center for the Undiagnosed Patient, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
^o Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States

Abstract
GATA zinc finger domain containing 2A (GATAD2A) is a subunit of the nucleosome remodeling and deacetylase (NuRD) complex. NuRD is known to regulate gene expression during neural development and other processes. The NuRD complex modulates chromatin status through histone deacetylation and ATP-dependent chromatin remodeling activities. Several neurodevelopmental disorders (NDDs) have been previously linked to variants in other components of NuRD’s chromatin remodeling subcomplex (NuRDopathies). We identified five individuals with features of an NDD that possessed de novo autosomal dominant variants in GATAD2A. Core features in affected individuals include global developmental delay, structural brain defects, and craniofacial dysmorphology. These GATAD2A variants are predicted to affect protein dosage and/or interactions with other NuRD chromatin remodeling subunits. We provide evidence that a GATAD2A missense variant disrupts interactions of GATAD2A with CHD3, CHD4, and CHD5. Our findings expand the list of NuRDopathies and provide evidence that GATAD2A variants are the genetic basis of a previously uncharacterized developmental disorder. © 2023 The Author(s)

Author Keywords
GATAD2A;  neurodevelopmental disorder;  NuRD complex;  NuRDopathies

Funding details
National Institutes of HealthNIHR01 DC018404
National Heart, Lung, and Blood InstituteNHLBIU24 HG008956, UM1 HG006493
National Human Genome Research InstituteNHGRI
University of WashingtonUW
Genome CanadaGC
Ontario Research FoundationORF
Cedars-Sinai Medical CenterCS
Génome QuébecGQ
Children’s Hospital of Eastern Ontario Foundation
Center for Mendelian Genomics, University of WashingtonUWCMG
Canadian Institutes of Health ResearchIRSC
Ontario Genomics InstituteOGI
Genome British Columbia
Alberta Children’s Hospital Foundation
Genome Alberta

Document Type: Article
Publication Stage: Final
Source: Scopus

Apolipoprotein E O-glycosylation is associated with amyloid plaques and APOE genotype
(2023) Analytical Biochemistry, 672, art. no. 115156, . 

Lawler, P.E.^a b , Bollinger, J.G.^a b , Schindler, S.E.^a d , Hodge, C.R.^a b , Iglesias, N.J.^e , Krishnan, V.^a , Coulton, J.B.^a b , Li, Y.^a b , Holtzman, D.M.^a c d , Bateman, R.J.^a b c d

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b The Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, United States
^c Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^d Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^e School of Medicine, University of Texas Medical Branch, Galveston, TX, United States

Abstract
Although the APOE ε4 allele is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), the relationship between apolipoprotein (apoE) and AD pathophysiology is not yet fully understood. Relatively little is known about the apoE protein species, including post-translational modifications, that exist in the human periphery and CNS. To better understand these apoE species, we developed a LC-MS/MS assay that simultaneously quantifies both unmodified and O-glycosylated apoE peptides. The study cohort included 47 older individuals (age 75.6 ± 5.7 years [mean ± standard deviation]), including 23 individuals (49%) with cognitive impairment. Paired plasma and cerebrospinal fluid samples underwent analysis. We quantified O-glycosylation of two apoE protein residues – one in the hinge region and one in the C-terminal region – and found that glycosylation occupancy of the hinge region in the plasma was significantly correlated with plasma total apoE levels, APOE genotype and amyloid status as determined by CSF Aβ42/Aβ40. A model with plasma glycosylation occupancy, plasma total apoE concentration, and APOE genotype distinguished amyloid status with an AUROC of 0.89. These results suggest that plasma apoE glycosylation levels could be a marker of brain amyloidosis, and that apoE glycosylation may play a role in the pathophysiology of AD. © 2023

Author Keywords
Alzheimer’s disease;  Apolipoprotein E;  Glycosylation;  Mass spectrometry;  Proteomics

Funding details
Novartis
Cure Alzheimer’s FundCAF
University of WashingtonUW

Document Type: Article
Publication Stage: Final
Source: Scopus

Conditional deletion of LRRC8A in the brain reduces stroke damage independently of swelling-activated glutamate release
(2023) iScience, 26 (5), art. no. 106669, . 

Balkaya, M.^a , Dohare, P.^a , Chen, S.^a , Schober, A.L.^a , Fidaleo, A.M.^a , Nalwalk, J.W.^a , Sah, R.^b , Mongin, A.A.^a

^a Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, United States
^b Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
The ubiquitous volume-regulated anion channels (VRACs) facilitate cell volume control and contribute to many other physiological processes. Treatment with non-specific VRAC blockers or brain-specific deletion of the essential VRAC subunit LRRC8A is highly protective in rodent models of stroke. Here, we tested the widely accepted idea that the harmful effects of VRACs are mediated by release of the excitatory neurotransmitter glutamate. We produced conditional LRRC8A knockout either exclusively in astrocytes or in the majority of brain cells. Genetically modified mice were subjected to an experimental stroke (middle cerebral artery occlusion). The astrocytic LRRC8A knockout yielded no protection. Conversely, the brain-wide LRRC8A deletion strongly reduced cerebral infarction in both heterozygous (Het) and full KO mice. Yet, despite identical protection, Het mice had full swelling-activated glutamate release, whereas KO animals showed its virtual absence. These findings suggest that LRRC8A contributes to ischemic brain injury via a mechanism other than VRAC-mediated glutamate release. © 2023 The Author(s)

Author Keywords
Cell biology;  Molecular biology;  Molecular neuroscience

Funding details
National Institutes of HealthNIH
National Institute of Neurological Disorders and StrokeNINDSR01 NS111943

Document Type: Article
Publication Stage: Final
Source: Scopus

Bi-allelic variants in INTS11 are associated with a complex neurological disorder
(2023) American Journal of Human Genetics, 110 (5), pp. 774-789. 

Tepe, B.^a b , Macke, E.L.^c , Niceta, M.^d , Weisz Hubshman, M.^a , Kanca, O.^a b , Schultz-Rogers, L.^c , Zarate, Y.A.^e , Schaefer, G.B.^f , Granadillo De Luque, J.L.^g , Wegner, D.J.^h , Cogne, B.ⁱ , Gilbert-Dussardier, B.^j , Le Guillou, X.^j , Wagner, E.J.^k , Pais, L.S.^l m , Neil, J.E.^l , Mochida, G.H.^l n , Walsh, C.A.^l , Magal, N.^o , Drasinover, V.^o , Shohat, M.^p q , Schwab, T.^c , Schmitz, C.^c , Clark, K.^c , Fine, A.^r , Lanpher, B.^s , Gavrilova, R.^s , Blanc, P.^t , Burglen, L.^t , Afenjar, A.^u , Steel, D.^v w , Kurian, M.A.^v w , Prabhakar, P.^w , Gößwein, S.^x , Di Donato, N.^x , Bertini, E.S.^y , Acosta, M.T.^aa , Adam, M.^aa , Adams, D.R.^aa , Alvey, J.^aa , Amendola, L.^aa , Andrews, A.^aa , Ashley, E.A.^aa , Azamian, M.S.^aa , Bacino, C.A.^aa , Bademci, G.^aa , Balasubramanyam, A.^aa , Baldridge, D.^aa , Bale, J.^aa , Bamshad, M.^aa , Barbouth, D.^aa , Bayrak-Toydemir, P.^aa , Beck, A.^aa , Beggs, A.H.^aa , Behrens, E.^aa , Bejerano, G.^aa , Bellen, H.J.^a b z aa , Bennet, J.^aa , Berg-Rood, B.^aa , Bernstein, J.A.^aa , Berry, G.T.^aa , Bican, A.^aa , Bivona, S.^aa , Blue, E.^aa , Bohnsack, J.^aa , Bonner, D.^aa , Botto, L.^aa , Boyd, B.^aa , Briere, L.C.^aa , Brokamp, E.^aa , Brown, G.^aa , Burke, E.A.^aa , Burrage, L.C.^aa , Butte, M.J.^aa , Byers, P.^aa , Byrd, W.E.^aa , Carey, J.^aa , Carrasquillo, O.^aa , Cassini, T.^aa , Peter Chang, T.C.^aa , Chanprasert, S.^aa , Chao, H.-T.^aa , Clark, G.D.^aa , Coakley, T.R.^aa , Cobban, L.A.^aa , Cogan, J.D.^aa , Coggins, M.^aa , Cole, F.S.^aa , Colley, H.A.^aa , Cooper, C.M.^aa , Cope, H.^aa , Craigen, W.J.^aa , Crouse, A.B.^aa , Cunningham, M.^aa , D’Souza, P.^aa , Dai, H.^aa , Dasari, S.^aa , Davis, J.^aa , Dayal, J.G.^aa , Deardorff, M.^aa , Dell’Angelica, E.C.^aa , Dipple, K.^aa , Doherty, D.^aa , Dorrani, N.^aa , Doss, A.L.^aa , Douine, E.D.^aa , Duncan, L.^aa , Earl, D.^aa , Eckstein, D.J.^aa , Emrick, L.T.^aa , Eng, C.M.^aa , Esteves, C.^aa , Falk, M.^aa , Fernandez, L.^aa , Fieg, E.L.^aa , Fisher, P.G.^aa , Fogel, B.L.^aa , Forghani, I.^aa , Gahl, W.A.^aa , Glass, I.^aa , Gochuico, B.^aa , Godfrey, R.A.^aa , Golden-Grant, K.^aa , Goldrich, M.P.^aa , Grajewski, A.^aa , Gutierrez, I.^aa , Hadley, D.^aa , Hahn, S.^aa , Hamid, R.^aa , Hassey, K.^aa , Hayes, N.^aa , High, F.^aa , Hing, A.^aa , Hisama, F.M.^aa , Holm, I.A.^aa , Hom, J.^aa , Horike-Pyne, M.^aa , Huang, A.^aa , Huang, Y.^aa , Introne, W.^aa , Isasi, R.^aa , Izumi, K.^aa , Jamal, F.^aa , Jarvik, G.P.^aa , Jarvik, J.^aa , Jayadev, S.^aa , Jean-Marie, O.^aa , Jobanputra, V.^aa , Karaviti, L.^aa , Kennedy, J.^aa , Ketkar, S.^aa , Kiley, D.^aa , Kilich, G.^aa , Kobren, S.N.^aa , Kohane, I.S.^aa , Kohler, J.N.^aa , Krakow, D.^aa , Krasnewich, D.M.^aa , Kravets, E.^aa , Korrick, S.^aa , Koziura, M.^aa , Lalani, S.R.^aa , Lam, B.^aa , Lam, C.^aa , LaMoure, G.L.^aa , Lanpher, B.C.^aa , Lanza, I.R.^aa , LeBlanc, K.^aa , Lee, B.H.^aa , Levitt, R.^aa , Lewis, R.A.^aa , Liu, P.^aa , Liu, X.Z.^aa , Longo, N.^aa , Loo, S.K.^aa , Loscalzo, J.^aa , Maas, R.L.^aa , Macnamara, E.F.^aa , MacRae, C.A.^aa , Maduro, V.V.^aa , Mahoney, R.^aa , Mak, B.C.^aa , Malicdan, M.C.V.^aa , Mamounas, L.A.^aa , Manolio, T.A.^aa , Mao, R.^aa , Maravilla, K.^aa , Marom, R.^aa , Marth, G.^aa , Martin, B.A.^aa , Martin, M.G.^aa , Martínez-Agosto, J.A.^aa , Marwaha, S.^aa , McCauley, J.^aa , McConkie-Rosell, A.^aa , McCray, A.T.^aa , McGee, E.^aa , Mefford, H.^aa , Merritt, J.L.^aa , Might, M.^aa , Mirzaa, G.^aa , Morava, E.^aa , Moretti, P.M.^aa , Nakano-Okuno, M.^aa , Nelson, S.F.^aa , Newman, J.H.^aa , Nicholas, S.K.^aa , Nickerson, D.^aa , Nieves-Rodriguez, S.^aa , Novacic, D.^aa , Oglesbee, D.^aa , Orengo, J.P.^aa , Pace, L.^aa , Pak, S.^aa , Pallais, J.C.^aa , Palmer, C.G.^aa , Papp, J.C.^aa , Parker, N.H.^aa , Phillips, J.A., III^aa , Posey, J.E.^aa , Potocki, L.^aa , Pusey, B.N.^aa , Quinlan, A.^aa , Raskind, W.^aa , Raja, A.N.^aa , Rao, D.A.^aa , Raper, A.^aa , Renteria, G.^aa , Reuter, C.M.^aa , Rives, L.^aa , Robertson, A.K.^aa , Rodan, L.H.^aa , Rosenfeld, J.A.^aa , Rosenwasser, N.^aa , Rossignol, F.^aa , Ruzhnikov, M.^aa , Sacco, R.^aa , Sampson, J.B.^aa , Saporta, M.^aa , Schaechter, J.^aa , Schedl, T.^aa , Schoch, K.^aa , Scott, C.R.^aa , Scott, D.A.^aa , Shashi, V.^aa , Shin, J.^aa , Silverman, E.K.^aa , Sinsheimer, J.S.^aa , Sisco, K.^aa , Smith, E.C.^aa , Smith, K.S.^aa , Solem, E.^aa , Krezel, L.S.^aa , Solomon, B.^aa , Spillmann, R.C.^aa , Stoler, J.M.^aa , Sullivan, J.A.^aa , Sullivan, K.^aa , Sun, A.^aa , Sutton, S.^aa , Sweetser, D.A.^aa , Sybert, V.^aa , Tabor, H.K.^aa , Tan, A.L.M.^aa , Tan, Q.K.-G.^aa , Tekin, M.^aa , Telischi, F.^aa , Thorson, W.^aa , Tifft, C.J.^aa , Toro, C.^aa , Tran, A.A.^aa , Tucker, B.M.^aa , Urv, T.K.^aa , Vanderver, A.^aa , Velinder, M.^aa , Viskochil, D.^aa , Vogel, T.P.^aa , Wahl, C.E.^aa , Walker, M.^aa , Wallace, S.^aa , Walley, N.M.^aa , Wambach, J.^aa , Wan, J.^aa , Wang, L.-K.^aa , Wangler, M.F.^a b aa , Ward, P.A.^aa , Wegner, D.^aa , Weisz-Hubshman, M.^aa , Wener, M.^aa , Wenger, T.^aa , Perry, K.W.^aa , Westerfield, M.^aa , Wheeler, M.T.^aa , Whitlock, J.^aa , Wolfe, L.A.^aa , Worley, K.^aa , Xiao, C.^aa , Yamamoto, S.^a b z aa , Yang, J.^aa , Zastrow, D.B.^aa , Zhang, Z.^aa , Zhao, C.^aa , Zuchner, S.^aa , Tartaglia, M.^d , Klee, E.W.^c s , Undiagnosed Diseases Network^ab

^a Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, United States
^b Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, United States
^c Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, United States
^d Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
^e Division of Genetics and Metabolism, University of Kentucky, Lexington, KY, United States
^f Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, United States
^g Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, United States
^h Edward Mallinckrodt Department of Pediatrics, Washington University in St. Louis School of Medicine and St. Louis Children’s Hospital, St. Louis, MO, United States
ⁱ Laboratory of Molecular Genetics, CHU de Nantes, Nantes, France
^j Department of Medical Genetics, CHU de Poitiers, Poitiers, France
^k Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine, Rochester, NY 14642, United States
^l Division of Genetics and Genomics, and Howard Hughes Medical Institute, Boston Children’s Hospital, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, United States
^m Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
ⁿ Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^o The Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel
^p Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel
^q Medical Genetics, nstitute of Maccabi HMO, Rechovot, Israel
^r Department of Neurology, Mayo Clinic, Rochester, MN 55905, United States
^s Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, United States
^t APHP, Département de génétique, Sorbonne Université, GRC n°19, ConCer-LD, Centre de Référence déficiences intellectuelles de causes rares, Hôpital Armand Trousseau, Paris, 75012, France
^u APHP. SU, Centre de Référence Malformations et maladies congénitales du cervelet, département de génétique et embryologie médicale, Hôpital Trousseau, Paris, 75012, France
^v Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
^w Department of Neurology, Great Ormond Street Hospital for Children, London, United Kingdom
^x Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Fetscherstrasse 74, Dresden, 01307, Germany
^y Unit of Neuromuscular and Neurodegenerative Disorders, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy
^z Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, United States

Abstract
The Integrator complex is a multi-subunit protein complex that regulates the processing of nascent RNAs transcribed by RNA polymerase II (RNAPII), including small nuclear RNAs, enhancer RNAs, telomeric RNAs, viral RNAs, and protein-coding mRNAs. Integrator subunit 11 (INTS11) is the catalytic subunit that cleaves nascent RNAs, but, to date, mutations in this subunit have not been linked to human disease. Here, we describe 15 individuals from 10 unrelated families with bi-allelic variants in INTS11 who present with global developmental and language delay, intellectual disability, impaired motor development, and brain atrophy. Consistent with human observations, we find that the fly ortholog of INTS11, dIntS11, is essential and expressed in the central nervous systems in a subset of neurons and most glia in larval and adult stages. Using Drosophila as a model, we investigated the effect of seven variants. We found that two (p.Arg17Leu and p.His414Tyr) fail to rescue the lethality of null mutants, indicating that they are strong loss-of-function variants. Furthermore, we found that five variants (p.Gly55Ser, p.Leu138Phe, p.Lys396Glu, p.Val517Met, and p.Ile553Glu) rescue lethality but cause a shortened lifespan and bang sensitivity and affect locomotor activity, indicating that they are partial loss-of-function variants. Altogether, our results provide compelling evidence that integrity of the Integrator RNA endonuclease is critical for brain development. © 2023 American Society of Human Genetics

Author Keywords
brain atrophy;  CPSF3L;  delayed language development;  developmental delay;  dIntS11;  Drosophila;  impaired motor development;  intellectual disability;  INTS11

Funding details
17JTA
U54 NS093793
National Institutes of HealthNIHR01 AG073260, R24 OD022005, R24 OD031447
Howard Hughes Medical InstituteHHMI
National Heart, Lung, and Blood InstituteNHLBIR01 HG009141, R01 NS035129, UM1 HG008900
National Human Genome Research InstituteNHGRI
National Eye InstituteNEI
National Institute of Neurological Disorders and StrokeNINDS
Texas Children’s Hospital
Baylor College of MedicineP50HD103555
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD
Broad Institute
Huffington Foundation
Rosetrees Trust
Ministero della Salute5x1000_2019, R01GM134539, RCR-2021-23671215

Document Type: Article
Publication Stage: Final
Source: Scopus

NSD1 deposits histone H3 lysine 36 dimethylation to pattern non-CG DNA methylation in neurons
(2023) Molecular Cell, 83 (9), pp. 1412-1428.e7. 

Hamagami, N., Wu, D.Y., Clemens, A.W., Nettles, S.A., Li, A., Gabel, H.W.

Department of Neuroscience, Washington University School of Medicine, St Louis, MO 63110-1093, United States

Abstract
During postnatal development, the DNA methyltransferase DNMT3A deposits high levels of non-CG cytosine methylation in neurons. This methylation is critical for transcriptional regulation, and loss of this mark is implicated in DNMT3A-associated neurodevelopmental disorders (NDDs). Here, we show in mice that genome topology and gene expression converge to shape histone H3 lysine 36 dimethylation (H3K36me2) profiles, which in turn recruit DNMT3A and pattern neuronal non-CG methylation. We show that NSD1, an H3K36 methyltransferase mutated in NDD, is required for the patterning of megabase-scale H3K36me2 and non-CG methylation in neurons. We find that brain-specific deletion of NSD1 causes altered DNA methylation that overlaps with DNMT3A disorder models to drive convergent dysregulation of key neuronal genes that may underlie shared phenotypes in NSD1- and DNMT3A-associated NDDs. Our findings indicate that H3K36me2 deposited by NSD1 is important for neuronal non-CG DNA methylation and suggest that the H3K36me2-DNMT3A-non-CG-methylation pathway is likely disrupted in NSD1-associated NDDs. © 2023 Elsevier Inc.

Author Keywords
DNA methylation;  DNMT3A;  genome topology;  histone methylation;  neurodevelopmental disease;  non-CG methylation;  NSD1;  Sotos syndrome

Funding details
National Institute of Mental HealthNIMHR01MH117405
National Institute of Neurological Disorders and StrokeNINDSR01NS041021
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD1F30HD110156-01

Document Type: Article
Publication Stage: Final
Source: Scopus

De novo variants implicate chromatin modification, transcriptional regulation, and retinoic acid signaling in syndromic craniosynostosis
(2023) American Journal of Human Genetics, 110 (5), pp. 846-862. 

Timberlake, A.T.^a , McGee, S.^b , Allington, G.^c , Kiziltug, E.^c , Wolfe, E.M.^d , Stiegler, A.L.^e , Boggon, T.J.^f , Sanyoura, M.^b , Morrow, M.^b , Wenger, T.L.^g , Fernandes, E.M.^h , Caluseriu, O.ⁱ , Persing, J.A.^j , Jin, S.C.^k , Lifton, R.P.^l , Kahle, K.T.^m n o , Kruszka, P.^b

^a Hansjörg Wyss Department of Plastic Surgery, NYU Langone Medical Center, New York, NY, United States
^b GeneDx, Gaithersburg, MD, United States
^c Department of Pathology, Yale University School of Medicine, New Haven, CT, United States
^d Division of Plastic and Reconstructive Surgery, University of Miami Hospital, Miami, FL, United States
^e Department of Pharmacology, Yale University, New Haven, CT, United States
^f Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, United States
^g Division of Genetic Medicine, University of Washington, Seattle, WA, United States
^h Nemours Children’s Health, Wilmington, DE, United States
ⁱ Department of Medical Genetics, University of AlbertaAB, Canada
^j Section of Plastic and Reconstructive Surgery, Yale University School of Medicine, New Haven, CT, United States
^k Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^l Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
^m Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
ⁿ Broad Institute of Harvard and Massachusetts Institute of Technology, Boston, MA, United States
^o Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States

Abstract
Craniosynostosis (CS) is the most common congenital cranial anomaly. Several Mendelian forms of syndromic CS are well described, but a genetic etiology remains elusive in a substantial fraction of probands. Analysis of exome sequence data from 526 proband-parent trios with syndromic CS identified a marked excess (observed 98, expected 33, p = 4.83 × 10−20) of damaging de novo variants (DNVs) in genes highly intolerant to loss-of-function variation (probability of LoF intolerance > 0.9). 30 probands harbored damaging DNVs in 21 genes that were not previously implicated in CS but are involved in chromatin modification and remodeling (4.7-fold enrichment, p = 1.1 × 10−11). 17 genes had multiple damaging DNVs, and 13 genes (CDK13, NFIX, ADNP, KMT5B, SON, ARID1B, CASK, CHD7, MED13L, PSMD12, POLR2A, CHD3, and SETBP1) surpassed thresholds for genome-wide significance. A recurrent gain-of-function DNV in the retinoic acid receptor alpha (RARA; c.865G>A [p.Gly289Arg]) was identified in two probands with similar CS phenotypes. CS risk genes overlap with those identified for autism and other neurodevelopmental disorders, are highly expressed in cranial neural crest cells, and converge in networks that regulate chromatin modification, gene transcription, and osteoblast differentiation. Our results identify several CS loci and have major implications for genetic testing and counseling. © 2023 American Society of Human Genetics

Author Keywords
chromatin modifiers;  cranial neural crest;  craniofacial syndromes;  de novo mutation;  neurodevelopmental disorders;  RARA;  retinoic acid signaling;  syndromic craniosynostosis

Funding details
Wellcome TrustWT

Document Type: Article
Publication Stage: Final
Source: Scopus

Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease
(2023) Acta Neuropathologica Communications, 11 (1), p. 68. 

Ali, M.^a b , Archer, D.B.^c , Gorijala, P.^a b , Western, D.^a b , Timsina, J.^a b , Fernández, M.V.^a b , Wang, T.-C.^c , Satizabal, C.L.^d e f , Yang, Q.^g , Beiser, A.S.^e f g , Wang, R.^h , Chen, G.^i j , Gordon, B.^i j , Benzinger, T.L.S.^i j , Xiong, C.ⁱ , Morris, J.C.^i k , Bateman, R.J.^i k l , Karch, C.M.^a , McDade, E.^k , Goate, A.^m , Seshadri, S.^f n , Mayeux, R.P.^o , Sperling, R.A.^p q , Buckley, R.F.^q r , Johnson, K.A.^s , Won, H.-H.^t , Jung, S.-H.^t , Kim, H.-R.^u , Seo, S.W.^v , Kim, H.J.^t v , Mormino, E.^l , Laws, S.M.^w , Fan, K.-H.^x , Kamboh, M.I.^x , Vemuri, P.^y , Ramanan, V.K.^z , Yang, H.-S.^{aa ab ac ad} , Wenzel, A.^ae , Rajula, H.S.R.^af , Mishra, A.^af , Dufouil, C.^af , Debette, S.^af ag ah , Lopez, O.L.^ai , DeKosky, S.T.^aj , Tao, F.^ak , Nagle, M.W.^ak , Hohman, T.J.^c , Sung, Y.J.^a b , Dumitrescu, L.^c , Cruchaga, C.^{a b i al am} , Knight Alzheimer Disease Research Center (Knight ADRC)^an , Dominantly Inherited Alzheimer Network (DIAN)^ao , Alzheimer’s Disease Neuroimaging Initiative (ADNI)^ap , ADNI-DOD, A4 Study Team^aq , Australian Imaging Biomarkers, Lifestyle (AIBL) Study^ar

^a Department of Psychiatry, Washington University, St. Louis, MO 63110, United States
^b Washington University, St. Louis, MO 63110, United States
^c Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine, Nashville, TN, United States
^d Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, UT Health, San Antonio, TX 78229, United States
^e Department of Neurology, Boston University School of Medicine, Boston, MA, United States
^f Framingham Heart Study, Framingham, MA, United States
^g Department of Biostatistics, Boston University School of Public Health, Boston, MA, United States
^h Boston University, Boston, MA, United States
ⁱ Knight Alzheimer’s Disease Research Center, Washington University, St Louis, MO, United States
^j Mallinckrodt Institute of Radiology, Washington University, St Louis, MO, United States
^k Department of Neurology, Washington University, St Louis, MO, United States
^l Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
^m Department of Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, Icahn School of Medicine at Mount Sinai, New York, NY, USA
ⁿ Boston University School of Medicine, Boston, MA, United States
^o The Department of Neurology, Columbia University, New York, NY, USA
^p Department of Neurology, Harvard Medical School, Boston, MA, United States
^q Brigham and Women’s Hospital and Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^r Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, United States
^s Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^t Department of Digital Health, Samsung Medical Center, SAIHST, Sungkyunkwan UniversitySeoul, South Korea
^u Department of Neurology, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, South Korea
^v Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of MedicineSeoul, South Korea
^w Centre for Precision Health, Edith Cowan University, 270 Joondalup Dr, Joondalup, WA 6027, Australia
^x Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA, United States
^y Department of Radiology, Rochester, MN 55905, United States
^z Department of Neurology, Rochester, MN 55905, United States
^aa Department of Neurology, Brigham and Women’s Hospital, Boston, MA, United States
^ab Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
^ac Harvard Medical School, Boston, MA, United States
^ad Broad Institute of Harvard and MIT, Cambridge, United States
^ae Wisconsin Alzheimer’s Institute, Madison, WI, United States
^af University of Bordeaux, INSERM, Bordeaux Population Health Research Centre, Bordeaux, 33000, France
^ag Department of Neurology, Boston University School of Medicine, Boston, MA 2115, United States
^ah Department of Neurology, CHU de Bordeaux, Bordeaux, 33000, France
^ai Department of Neurology, University of Pittsburgh, Pittsburgh, PA, United States
^aj Department of Neurology and McKnight Brain Institute, University of Florida, Gainesville, FL, United States
^ak Neurogenomics, Genetics-Guided Dementia Discovery, Eisai, Inc, Cambridge, MA, United States
^al Hope Center for Neurologic Diseases, Washington University, St. Louis, MO 63110, United States
^am Department of Genetics, Washington University School of Medicine, St Louis, MO 63110, United States

Abstract
Amyloid PET imaging has been crucial for detecting the accumulation of amyloid beta (Aβ) deposits in the brain and to study Alzheimer’s disease (AD). We performed a genome-wide association study on the largest collection of amyloid imaging data (N = 13,409) to date, across multiple ethnicities from multicenter cohorts to identify variants associated with brain amyloidosis and AD risk. We found a strong APOE signal on chr19q.13.32 (top SNP: APOE ɛ4; rs429358; β = 0.35, SE = 0.01, P = 6.2 × 10-311, MAF = 0.19), driven by APOE ɛ4, and five additional novel associations (APOE ε2/rs7412; rs73052335/rs5117, rs1081105, rs438811, and rs4420638) independent of APOE ɛ4. APOE ɛ4 and ε2 showed race specific effect with stronger association in Non-Hispanic Whites, with the lowest association in Asians. Besides the APOE, we also identified three other genome-wide loci: ABCA7 (rs12151021/chr19p.13.3; β = 0.07, SE = 0.01, P = 9.2 × 10-09, MAF = 0.32), CR1 (rs6656401/chr1q.32.2; β = 0.1, SE = 0.02, P = 2.4 × 10-10, MAF = 0.18) and FERMT2 locus (rs117834516/chr14q.22.1; β = 0.16, SE = 0.03, P = 1.1 × 10-09, MAF = 0.06) that all colocalized with AD risk. Sex-stratified analyses identified two novel female-specific signals on chr5p.14.1 (rs529007143, β = 0.79, SE = 0.14, P = 1.4 × 10-08, MAF = 0.006, sex-interaction P = 9.8 × 10-07) and chr11p.15.2 (rs192346166, β = 0.94, SE = 0.17, P = 3.7 × 10-08, MAF = 0.004, sex-interaction P = 1.3 × 10-03). We also demonstrated that the overall genetic architecture of brain amyloidosis overlaps with that of AD, Frontotemporal Dementia, stroke, and brain structure-related complex human traits. Overall, our results have important implications when estimating the individual risk to a population level, as race and sex will needed to be taken into account. This may affect participant selection for future clinical trials and therapies. © 2023. The Author(s).

Author Keywords
Alzheimer’s disease;  Amyloid PET;  Brain amyloidosis;  GWAS;  Meta-analysis;  Multi-ethnic

Document Type: Article
Publication Stage: Final
Source: Scopus

Sleep deprivation exacerbates microglial reactivity and Aβ deposition in a TREM2-dependent manner in mice
(2023) Science Translational Medicine, 15 (693), p. eade6285. 

Parhizkar, S.^a , Gent, G.^a , Chen, Y.^a b , Rensing, N.^a , Gratuze, M.^a , Strout, G.^c , Sviben, S.^c , Tycksen, E.^d , Zhang, Q.^e , Gilmore, P.E.^e , Sprung, R.^e , Malone, J.^e , Chen, W.^a , Remolina Serrano, J.^a , Bao, X.^a , Lee, C.^a , Wang, C.^a , Landsness, E.^a , Fitzpatrick, J.^c f g h , Wong, M.^a , Townsend, R.^e , Colonna, M.^b , Schmidt, R.E.^b , Holtzman, D.M.^a

^a Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
^b Department of Pathology and Immunology, Washington University, St. Louis, MO, United States
^c Washington University Center for Cellular Imaging, Washington University School of Medicine, St. Louis, MO, United States
^d Genome Technology Access Center, Washington University School of Medicine, St. Louis, MO, United States
^e Department of Medicine, Washington University Medical School, St. Louis, MO, United States
^f Department of Neuroscience, Washington University School of Medicine, St. Louis, MO, United States
^g Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Biomedical Engineering, McKelvey School of Engineering, Washington University in St. Louis, St. Louis, MO, United States

Abstract
Sleep loss is associated with cognitive decline in the aging population and is a risk factor for Alzheimer’s disease (AD). Considering the crucial role of immunomodulating genes such as that encoding the triggering receptor expressed on myeloid cells type 2 (TREM2) in removing pathogenic amyloid-β (Aβ) plaques and regulating neurodegeneration in the brain, our aim was to investigate whether and how sleep loss influences microglial function in mice. We chronically sleep-deprived wild-type mice and the 5xFAD mouse model of cerebral amyloidosis, expressing either the humanized TREM2 common variant, the loss-of-function R47H AD-associated risk variant, or without TREM2 expression. Sleep deprivation not only enhanced TREM2-dependent Aβ plaque deposition compared with 5xFAD mice with normal sleeping patterns but also induced microglial reactivity that was independent of the presence of parenchymal Aβ plaques. We investigated lysosomal morphology using transmission electron microscopy and found abnormalities particularly in mice without Aβ plaques and also observed lysosomal maturation impairments in a TREM2-dependent manner in both microglia and neurons, suggesting that changes in sleep modified neuro-immune cross-talk. Unbiased transcriptome and proteome profiling provided mechanistic insights into functional pathways triggered by sleep deprivation that were unique to TREM2 and Aβ pathology and that converged on metabolic dyshomeostasis. Our findings highlight that sleep deprivation directly affects microglial reactivity, for which TREM2 is required, by altering the metabolic ability to cope with the energy demands of prolonged wakefulness, leading to further Aβ deposition, and underlines the importance of sleep modulation as a promising future therapeutic approach.

Document Type: Article
Publication Stage: Final
Source: Scopus

Single-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
(2023) Nature Communications, 14 (1), p. 2314. 

Brase, L.^a b c , You, S.-F.^a b c , D’Oliveira Albanus, R.^a b c , Del-Aguila, J.L.^d , Dai, Y.^e , Novotny, B.C.^a b c , Soriano-Tarraga, C.^a b c , Dykstra, T.^f g , Fernandez, M.V.^a b c , Budde, J.P.^a b c , Bergmann, K.^a b c , Morris, J.C.^b h i , Bateman, R.J.^b h i , Perrin, R.J.^b f h i , McDade, E.^a , Xiong, C.^h j , Goate, A.M.^k , Farlow, M.^l , Sutherland, G.T.^m , Kipnis, J.^f g , Karch, C.M.^a b c , Benitez, B.A.ⁿ , Harari, O.^a b c , Dominantly Inherited Alzheimer Network (DIAN)^o

^a Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Hope Center for Neurological Disorders, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Merck & Co., Inc., Boston, MA, United States
^e Baylor College of Medicine, Houston, TX, United States
^f Department of Pathology and Immunology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^g Center for Brain Immunology and Glia (BIG), Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^h Knight Alzheimer Disease Research Center, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
ⁱ Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^j Division of Biostatistics, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^k Ronald M. Loeb Center for Alzheimer’s Disease, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
^l Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, United States
^m School of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, NSW, Sydney, Australia
ⁿ Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Abstract
Genetic studies of Alzheimer disease (AD) have prioritized variants in genes related to the amyloid cascade, lipid metabolism, and neuroimmune modulation. However, the cell-specific effect of variants in these genes is not fully understood. Here, we perform single-nucleus RNA-sequencing (snRNA-seq) on nearly 300,000 nuclei from the parietal cortex of AD autosomal dominant (APP and PSEN1) and risk-modifying variant (APOE, TREM2 and MS4A) carriers. Within individual cell types, we capture genes commonly dysregulated across variant groups. However, specific transcriptional states are more prevalent within variant carriers. TREM2 oligodendrocytes show a dysregulated autophagy-lysosomal pathway, MS4A microglia have dysregulated complement cascade genes, and APOEε4 inhibitory neurons display signs of ferroptosis. All cell types have enriched states in autosomal dominant carriers. We leverage differential expression and single-nucleus ATAC-seq to map GWAS signals to effector cell types including the NCK2 signal to neurons in addition to the initially proposed microglia. Overall, our results provide insights into the transcriptional diversity resulting from AD genetic architecture and cellular heterogeneity. The data can be explored on the online browser ( http://web.hararilab.org/SNARE/ ). © 2023. The Author(s).

Document Type: Article
Publication Stage: Final
Source: Scopus

Schwann cells and myelin in human peripheral nerve: Major protein components vary with age, axon size and pathology
(2023) Neuropathology and Applied Neurobiology, 49 (2), art. no. e12898, . 

Pestronk, A.^a b , Schmidt, R.E.^b , Bucelli, R.^a b b , Sim, J.^a

^a Departments of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^b Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO, United States

Abstract
Aims: We examined major protein components of Schwann cells (SCs) and myelin in normal and diseased human peripheral nerves. Methods: We evaluated distributions of neural cell adhesion molecule (NCAM), P0 protein (P0) and myelin basic protein (MBP) in frozen sections of 98 sural nerves. Results: Non-myelinating SC in normal adults contained NCAM, but not P0 or MBP. With chronic axon loss, SC without associated axons (Büngner band cells) often co-stained for both NCAM and P0. Onion bulb cells also co-stained for both P0 and NCAM. Infants had many SC with MBP but no P0. All myelin sheaths contained P0. Myelin around large, and some intermediate-sized, axons co-stained for both MBP and P0. Myelin on other intermediate-sized axons had P0, but no MBP. Regenerated axons often had sheaths with MBP, P0 and some NCAM. During active axon degeneration, myelin ovoids often co-stained for MBP, P0 and NCAM. Demyelinating neuropathy patterns included SC (NCAM) loss, and myelin with abnormally distributed, or reduced, P0. Conclusions: Peripheral nerve SC and myelin have varied molecular phenotypes, related to age, axon size and nerve pathology. In normal adult peripheral nerve, myelin has two different patterns of molecular composition. MBP is mostly absent from myelin around a population of intermediate-sized axons, whereas P0 is present in myelin around all axons. Denervated SCs have a molecular signature that differs from normal SC types. With acute denervation, SCs may stain for both NCAM and MBP. Chronically denervated SCs often stain for both NCAM and P0. © 2023 British Neuropathological Society.

Author Keywords
axon;  myelin;  nerve;  neuropathy;  Schwann cells

Document Type: Article
Publication Stage: Final
Source: Scopus

Isoflurane Conditioning Provides Protection against Subarachnoid Hemorrhage Induced Delayed Cerebral Ischemia through NF-kB Inhibition
(2023) Biomedicines, 11 (4), art. no. 1163, . 

Liu, M.^a , Jayaraman, K.^a , Mehla, J.^a , Diwan, D.^a , Nelson, J.W.^a , Hussein, A.E.^a , Vellimana, A.K.^a , Abu-Amer, Y.^b , Zipfel, G.J.^a , Athiraman, U.^a

^a Department of Anesthesiology, Department of Neurosurgery, Washington University in St. Louis, St. Louis, MO 63110, United States
^b Department of Orthopedic Surgery and Cell Biology & Physiology, Shriners Hospital for Children, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Delayed cerebral ischemia (DCI) is the largest treatable cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). Nuclear Factor Kappa-light-chain-enhancer of Activated B cells (NF-kB), a transcription factor known to function as a pivotal mediator of inflammation, is upregulated in SAH and is pathologically associated with vasospasm. We previously showed that a brief exposure to isoflurane, an inhalational anesthetic, provided multifaceted protection against DCI after SAH. The aim of our current study is to investigate the role of NF-kB in isoflurane-conditioning-induced neurovascular protection against SAH-induced DCI. Twelve-week-old wild type male mice (C57BL/6) were divided into five groups: sham, SAH, SAH + Pyrrolidine dithiocarbamate (PDTC, a selective NF-kB inhibitor), SAH + isoflurane conditioning, and SAH + PDTC with isoflurane conditioning. Experimental SAH was performed via endovascular perforation. Anesthetic conditioning was performed with isoflurane 2% for 1 h, 1 h after SAH. Three doses of PDTC (100 mg/kg) were injected intraperitoneally. NF-kB and microglial activation and the cellular source of NF-kB after SAH were assessed by immunofluorescence staining. Vasospasm, microvessel thrombosis, and neuroscore were assessed. NF-kB was activated after SAH; it was attenuated by isoflurane conditioning. Microglia was activated and found to be a major source of NF-kB expression after SAH. Isoflurane conditioning attenuated microglial activation and NF-kB expression in microglia after SAH. Isoflurane conditioning and PDTC individually attenuated large artery vasospasm and microvessel thrombosis, leading to improved neurological deficits after SAH. The addition of isoflurane to the PDTC group did not provide any additional DCI protection. These data indicate isoflurane-conditioning-induced DCI protection after SAH is mediated, at least in part, via downregulating the NF-kB pathway. © 2023 by the authors.

Author Keywords
aneurysmal subarachnoid hemorrhage;  delayed cerebral ischemia;  isoflurane;  neuroprotection;  NF-kB

Funding details
Brain Aneurysm FoundationBAFGR0026849, NS091603

Document Type: Article
Publication Stage: Final
Source: Scopus

Regulation of astrocyte lipid metabolism and ApoE secretionby the microglial oxysterol, 25-hydroxycholesterol
(2023) Journal of Lipid Research, 64 (4), p. 100350. 

Cashikar, A.G.^a , Toral-Rios, D.^b , Timm, D.^b , Romero, J.^b , Strickland, M.^c , Long, J.M.^d , Han, X.^e , Holtzman, D.M.^d , Paul, S.M.^a

^a Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri, USA; Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St Louis, Missouri, USA; Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA
^b Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
^c Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
^d Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, Missouri, USA; Department of Neurology, Washington University School of Medicine, St Louis, Missouri, USA; Knight Alzheimer Disease Research Center, Washington University School of Medicine, St Louis, Missouri, USA
^e Barshop Institute for Longevity and Aging Studies, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, United States

Abstract
Neuroinflammation, a major hallmark of Alzheimer’s disease and several other neurological and psychiatric disorders, is often associated with dysregulated cholesterol metabolism. Relative to homeostatic microglia, activated microglia express higher levels of Ch25h, an enzyme that hydroxylates cholesterol to produce 25-hydroxycholesterol (25HC). 25HC is an oxysterol with interesting immune roles stemming from its ability to regulate cholesterol metabolism. Since astrocytes synthesize cholesterol in the brain and transport it to other cells via ApoE-containing lipoproteins, we hypothesized that secreted 25HC from microglia may influence lipid metabolism as well as extracellular ApoE derived from astrocytes. Here, we show that astrocytes take up externally added 25HC and respond with altered lipid metabolism. Extracellular levels of ApoE lipoprotein particles increased after treatment of astrocytes with 25HC without an increase in Apoe mRNA expression. In mouse astrocytes-expressing human ApoE3 or ApoE4, 25HC promoted extracellular ApoE3 better than ApoE4. Increased extracellular ApoE was due to elevated efflux from increased Abca1 expression via LXRs as well as decreased lipoprotein reuptake from suppressed Ldlr expression via inhibition of SREBP. 25HC also suppressed expression of Srebf2, but not Srebf1, leading to reduced cholesterol synthesis in astrocytes without affecting fatty acid levels. We further show that 25HC promoted the activity of sterol-o-acyl transferase that led to a doubling of the amount of cholesteryl esters and their concomitant storage in lipid droplets. Our results demonstrate an important role for 25HC in regulating astrocyte lipid metabolism. Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Author Keywords
25-hydroxycholesterol;  Alzheimer disease;  apolipoprotein E;  astrocyte;  cholesterol metabolism;  microglia;  neuroinflammation;  oxysterols

Document Type: Article
Publication Stage: Final
Source: Scopus

Associations Between Preterm Birth, Inhibitory Control-Implicated Brain Regions and Tracts, and Inhibitory Control Task Performance in Children: Consideration of Socioeconomic Context
(2023) Child Psychiatry and Human Development, . 

Taylor, R.L.^a , Rogers, C.E.^b c , Smyser, C.D.^c d e , Barch, D.M.^a b e

^a Department of Psychological and Brain Sciences, Washington University, One Brookings Drive, Box 1125, St. Louis, MO 63130, United States
^b Department of Psychiatry, Washington University, St. Louis, MO, United States
^c Department of Pediatrics, Washington University, St. Louis, MO, United States
^d Department of Neurology, Washington University, St. Louis, MO, United States
^e Department of Radiology, Washington University, St. Louis, MO, United States

Abstract
Preterm birth (PTB) is associated with increased risk for unfavorable outcomes such as deficits in attentional control and related brain structure alterations. Crucially, PTB is more likely to occur within the context of poverty. The current study examined associations between PTB and inhibitory control (IC) implicated brain regions/tracts and task performance, as well as the moderating role of early life poverty on the relation between PTB and IC-implicated regions/tracts/task performance. 2,899 children from the ABCD study were sampled for this study. Mixed effects models examined the relation between PTB and subsequent IC performance as well as prefrontal gray matter volume, white matter fractional anisotropy (FA), and mean diffusivity (MD). Household income was examined as a moderator. PTB was significantly associated with less improvement in IC task performance over time and decreased FA in left uncinate fasciculus (UF) and cingulum bundle (CB). Early life poverty moderated the relation between PTB and both CB FA and UF MD. © 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Author Keywords
Early life poverty;  Inhibitory control;  Neuroimaging;  Preterm birth

Funding details
National Science FoundationNSFDGE-1745038, DGE-2139839
National Institutes of HealthNIHGR0026407, U01 DA041120, U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041134, U01DA041148, U01DA041156, U01DA041174, U01DA050987, U01DA050988, U01DA050989, U01DA051016, U01DA051018, U01DA051037, U01DA051038, U01DA051039, U24DA041123, U24DA041147

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

Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation
(2023) Acta Neuropathologica, . 

Filipello, F.^a , You, S.-F.^a , Mirfakhar, F.S.^a , Mahali, S.^a , Bollman, B.^d , Acquarone, M.^a , Korvatska, O.^b , Marsh, J.A.^a , Sivaraman, A.^a , Martinez, R.^a , Cantoni, C.^d , De Feo, L.^d , Ghezzi, L.^d , Minaya, M.A.^a , Renganathan, A.^a , Cashikar, A.G.^a , Satoh, J.-I.^e , Beatty, W.^f , Iyer, A.K.^a , Cella, M.^g , Raskind, W.H.^b c , Piccio, L.^d h i , Karch, C.M.^a

^a Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
^b Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, United States
^c Department of Medicine, Division of Medical Genetics, University of Washington, Seattle, WA, United States
^d Department of Neurology, Washington University in St Louis, St Louis, MO, United States
^e Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan
^f Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, United States
^g Department Of Pathology and Immunology, Washington University in St Louis, St Louis, MO, United States
^h Charles Perkins Centre and Brain and Mind Centre, School of Medical Sciences (Neuroscience), University of Sydney, Sydney, NSW, Australia
ⁱ School of Medical Sciences, Brain and Mind Centre, University of Sydney, 94 Mallett St, Camperdown, Sydney, NSW 2050, Australia

Abstract
TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer’s disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases. © 2023, The Author(s).

Author Keywords
Induced pluripotent stem cells;  Lysosome;  Microglia;  Nasu-Hakola disease;  Transcriptomics;  TREM2

Funding details
A167463
101 CX001702
National Institutes of HealthNIHP30 AG066444, R01 AG058501, R01 AG062734, R01 NS069719, U01 AG052411, UL1 TR002345
Washington University in St. LouisWUSTL
Office of Research Infrastructure Programs, National Institutes of HealthORIP, NIHOD021629, P01 AG026276
McDonnell Center for Cellular and Molecular Neurobiology, Washington University in St. Louis

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

Cortical stimulation leads to shortened myelin sheaths and increased axonal branching in spared axons after cervical spinal cord injury
(2023) GLIA, . 

Kondiles, B.R.^a b c , Murphy, R.L.^a , Widman, A.J.^a d , Perlmutter, S.I.^a , Horner, P.J.^b

^a Department of Physiology and Biophysics, University of Washington, Seattle, WA, United States
^b Center for Neuroregeneration, Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, United States
^c International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada
^d Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Neural activity and learning lead to myelin sheath plasticity in the intact central nervous system (CNS), but this plasticity has not been well-studied after CNS injury. In the context of spinal cord injury (SCI), demyelination occurs at the lesion site and natural remyelination of surviving axons can take months. To determine if neural activity modulates myelin and axon plasticity in the injured, adult CNS, we electrically stimulated the contralesional motor cortex at 10 Hz to drive neural activity in the corticospinal tract of rats with sub-chronic spinal contusion injuries. We quantified myelin and axonal characteristics by tracing corticospinal axons rostral to and at the lesion epicenter and identifying nodes of Ranvier by immunohistochemistry. Three weeks of daily stimulation induced very short myelin sheaths, axon branching, and thinner axons outside of the lesion zone, where remodeling has not previously been reported. Surprisingly, remodeling was particularly robust rostral to the injury which suggests that electrical stimulation can promote white matter plasticity even in areas not directly demyelinated by the contusion. Stimulation did not alter myelin or axons at the lesion site, which suggests that neuronal activity does not contribute to myelin remodeling near the injury in the sub-chronic period. These data are the first to demonstrate wide-scale remodeling of nodal and myelin structures of a mature, long-tract motor pathway in response to electrical stimulation. This finding suggests that neuromodulation promotes white matter plasticity in intact regions of pathways after injury and raises intriguing questions regarding the interplay between axonal and myelin plasticity. © 2023 The Authors. GLIA published by Wiley Periodicals LLC.

Author Keywords
myelin;  neural activity;  neuromodulation;  spinal cord injury;  white matter plasticity

Funding details
National Science FoundationNSFDGE‐1762114, GRFP DGE‐1256082
National Institute of Neurological Disorders and StrokeNINDSR01NS099872

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

Targeting Slow Wave Sleep Deficiency in Late-Life Depression: A Case Series With Propofol
(2023) American Journal of Geriatric Psychiatry, . 

Rios, R.L.^a , Kafashan, M.^a , Hyche, O.^a , Lenard, E.^b , Lucey, B.P.^c d , Lenze, E.J.^a b , Palanca, B.J.A.^{a b c e f}

^a Department of Anesthesiology, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^b Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^c Center on Biological Rhythms and Sleep, Washington University School of Medicine in St. Louis, St. Louis, MO, United States
^d Department of Neurology, Washington University in St. LouisMO, United States
^e Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States
^f Division of Biology and Biomedical Sciences, Washington University School of Medicine in St. Louis, St. Louis, MO, United States

Abstract
Slow wave sleep (SWS), characterized by large electroencephalographic oscillations, facilitates crucial physiologic processes that maintain synaptic plasticity and overall brain health. Deficiency in older adults is associated with depression and cognitive dysfunction, such that enhancing sleep slow waves has emerged as a promising target for novel therapies. Enhancement of SWS has been noted after infusions of propofol, a commonly used anesthetic that induces electroencephalographic patterns resembling non-rapid eye movement sleep. This paper 1) reviews the scientific premise underlying the hypothesis that sleep slow waves are a novel therapeutic target for improving cognitive and psychiatric outcomes in older adults, and 2) presents a case series of two patients with late-life depression who each received two propofol infusions. One participant, a 71-year-old woman, had a mean of 2.8 minutes of evening SWS prior to infusions (0.7% of total sleep time). SWS increased on the night after each infusion, to 12.5 minutes (5.3% of total sleep time) and 24 minutes (10.6% of total sleep time), respectively. Her depression symptoms improved, reflected by a reduction in her Montgomery-Asberg Depression Rating Scale (MADRS) score from 26 to 7. In contrast, the other participant, a 77-year-old man, exhibited no SWS at baseline and only modest enhancement after the second infusion (3 minutes, 1.3% of total sleep time). His MADRS score increased from 13 to 19, indicating a lack of improvement in his depression. These cases provide proof-of-concept that propofol can enhance SWS and improve depression for some individuals, motivating an ongoing clinical trial (ClinicalTrials.gov NCT04680910). © 2023 American Association for Geriatric Psychiatry

Author Keywords
anesthesia;  cognition;  depression;  electroencephalography;  Older adults;  propofol;  sleep;  slow wave sleep

Funding details
P50 MH122351
National Institutes of HealthNIHK01 MH128663, U01 MH128483, UL1TR002345
National Institute of Mental HealthNIMH

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

Imaging biomarkers of cerebral edema automatically extracted from routine CT scans of large vessel occlusion strokes
(2023) Journal of Neuroimaging, . 

Dhar, R.^a , Kumar, A.^a , Chen, Y.^a , Begunova, Y.^b , Olexa, M.^b , Prasad, A.^b , Carey, G.^a , Gonzalez, I.^a , Bhatia, K.^a , Hamed, M.^c , Heitsch, L.^d , Mainali, S.^e , Petersen, N.^b , Lee, J.-M.^a

^a Department of Neurology, Washington University School of Medicine, Saint Louis, MO, United States
^b Department of Neurology, Yale School of Medicine, New Haven, CT, United States
^c Department of Neurology, The Ohio State University, Columbus, OH, United States
^d Department of Emergency Medicine, Washington University School of Medicine, Saint Louis, MO, United States
^e Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States

Abstract
Background and Purpose: Volumetric and densitometric biomarkers have been proposed to better quantify cerebral edema after stroke, but their relative performance has not been rigorously evaluated. Methods: Patients with large vessel occlusion stroke from three institutions were analyzed. An automated pipeline extracted brain, cerebrospinal fluid (CSF), and infarct volumes from serial CTs. Several biomarkers were measured: change in global CSF volume from baseline (ΔCSF); ratio of CSF volumes between hemispheres (CSF ratio); and relative density of infarct region compared with mirrored contralateral region (net water uptake [NWU]). These were compared to radiographic standards, midline shift and relative hemispheric volume (RHV) and malignant edema, defined as deterioration resulting in need for osmotic therapy, decompressive surgery, or death. Results: We analyzed 255 patients with 210 baseline CTs, 255 24-hour CTs, and 81 72-hour CTs. Of these, 35 (14%) developed malignant edema and 63 (27%) midline shift. CSF metrics could be calculated for 310 (92%), while NWU could only be obtained from 193 (57%). Peak midline shift was correlated with baseline CSF ratio (ρ = –.22) and with CSF ratio and ΔCSF at 24 hours (ρ = –.55/.63) and 72 hours (ρ = –.66/.69), but not with NWU (ρ =.15/.25). Similarly, CSF ratio was correlated with RHV (ρ = –.69/–.78), while NWU was not. Adjusting for age, National Institutes of Health Stroke Scale, tissue plasminogen activator treatment, and Alberta Stroke Program Early CT Score, CSF ratio (odds ratio [OR]: 1.95 per 0.1, 95% confidence interval [CI]: 1.52-2.59) and ΔCSF at 24 hours (OR: 1.87 per 10%, 95% CI: 1.47-2.49) were associated with malignant edema. Conclusion: CSF volumetric biomarkers can be automatically measured from almost all routine CTs and correlate better with standard edema endpoints than net water uptake. © 2023 American Society of Neuroimaging.

Author Keywords
biomarkers;  brain water;  cerebral edema;  cerebrospinal fluid;  computed tomography;  midline shift;  stroke

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

Everyday Driving and Plasma Biomarkers in Alzheimer’s Disease: Leveraging Artificial Intelligence to Expand Our Diagnostic Toolkit
(2023) Journal of Alzheimer’s Disease: JAD, 92 (4), pp. 1487-1497. 

Bayat, S.^a b c , Roe, C.M.^d , Schindler, S.^e , Murphy, S.A.^e , Doherty, J.M.^e , Johnson, A.M.^f , Walker, A.^e , Ances, B.M.^e , Morris, J.C.^e , Babulal, G.M.^e g h i

^a Department of Biomedical Engineering, University of Calgary, Calgary, AB, Canada
^b Department of Geomatics Engineering, University of Calgary, Calgary, AB, Canada
^c Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
^d Roe Consulting LLC, St. Louis, MO, United States
^e Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^f Center for Clinical Studies, Washington University School of Medicine, St. Louis, MO, United States
^g Institute of Public Health, Washington University School of Medicine, St. Louis, MO, United States
^h Department of Psychology, Faculty of Humanities, University of Johannesburg, Johannesburg, South Africa
ⁱ Department of Clinical Research and Leadership, George Washington University School of Medicine and Health SciencesWA, United States

Abstract
BACKGROUND: Driving behavior as a digital marker and recent developments in blood-based biomarkers show promise as a widespread solution for the early identification of Alzheimer’s disease (AD). OBJECTIVE: This study used artificial intelligence methods to evaluate the association between naturalistic driving behavior and blood-based biomarkers of AD. METHODS: We employed an artificial neural network (ANN) to examine the relationship between everyday driving behavior and plasma biomarker of AD. The primary outcome was plasma Aβ42/Aβ40, where Aβ42/Aβ40 < 0.1013 was used to define amyloid positivity. Two ANN models were trained and tested for predicting the outcome. The first model architecture only includes driving variables as input, whereas the second architecture includes the combination of age, APOE ɛ4 status, and driving variables. RESULTS: All 142 participants (mean [SD] age 73.9 [5.2] years; 76 [53.5%] men; 80 participants [56.3% ] with amyloid positivity based on plasma Aβ42/Aβ40) were cognitively normal. The six driving features, included in the ANN models, were the number of trips during rush hour, the median and standard deviation of jerk, the number of hard braking incidents and night trips, and the standard deviation of speed. The F1 score of the model with driving variables alone was 0.75 [0.023] for predicting plasma Aβ42/Aβ40. Incorporating age and APOE ɛ4 carrier status improved the diagnostic performance of the model to 0.80 [>0.051]. CONCLUSION: Blood-based AD biomarkers offer a novel opportunity to establish the efficacy of naturalistic driving as an accessible digital marker for AD pathology in driving research.

Author Keywords
Alzheimer’s disease;  amyloid;  artificial intelligence;  naturalistic;  plasma biomarkers

Document Type: Article
Publication Stage: Final
Source: Scopus

Enhancement of taste by retronasal odors in patients with Wolfram syndrome and decreased olfactory function
(2023) Chemical Senses, 48, art. no. bjad004, . 

Alfaro, R.^a , Nicanor-Carreón, J.G.^b , Doty, T.^c , Lugar, H.^c , Hershey, T.^c d , Pepino, M.^a b e

^a Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, United States
^b Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, United States
^c Department of Psychiatry, School of Medicine, Washington University, St. Louis, MO, United States
^d Department of Radiology, School of Medicine, Washington University, St. Louis, MO, United States
^e Department of Biomedical and Translational Sciences, Carle Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL, United States

Abstract
Wolfram syndrome is a rare disease characterized by diabetes, neurodegeneration, loss of vision, and audition. We recently found, in a young sample of participants (mean age 15 years), that Wolfram syndrome was associated with impairment in smell identification with normal smell sensitivity and whole-mouth taste function. However, these senses were assessed separately, and it is unknown whether smell–taste interactions are altered in Wolfram syndrome, which was the focus of this study. Participants with Wolfram syndrome (n = 36; 18.2 ± 6.8 years) and sex–age-equivalent healthy controls (n = 34) were assessed with a battery of sensory tests. Using sip-and-spit methods, participants tasted solutions containing gustatory and olfactory stimuli (sucrose with strawberry extract, citric acid with lemon extract, sodium chloride in vegetable broth, and coffee) with and without nose clips, and rated perceived taste and retronasal smell intensities using the generalized Labeled Magnitude Scale. Participants also completed n-butanol detection thresholds and the University of Pennsylvania Smell Identification Test (UPSIT). Retronasal smell increased taste intensity of sucrose, sodium chloride, and coffee solutions similarly in both groups (P values <0.03). Compared with the control group, participants in the Wolfram group had lower UPSIT scores and reduced smell sensitivity, retronasal intensity, and saltiness (P values <0.03), but rated other taste intensities similarly when wearing the nose clip. Despite impairments in orthonasal smell identification, odor-induced taste enhancement was preserved in participants with Wolfram syndrome who still had some peripheral olfactory function. This finding suggests that odor-induced taste enhancement may be preserved in the presence of reduced olfactory intensity. © The Author(s) 2023. Published by Oxford University Press. All rights reserved.

Author Keywords
DIDMOAD;  gustation;  olfaction;  orthonasal;  retronasal;  UPSIT

Funding details
National Institutes of HealthNIH
National Institute of Food and AgricultureNIFA698-991, HD070855
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHD

Document Type: Article
Publication Stage: Final
Source: Scopus

Suvorexant Acutely Decreases Tau Phosphorylation and Aβ in the Human CNS
(2023) Annals of Neurology, . Cited 1 time.

Lucey, B.P.^a b c , Liu, H.^a , Toedebusch, C.D.^a , Freund, D.^a , Redrick, T.^a , Chahin, S.L.^a b , Mawuenyega, K.G.^d , Bollinger, J.G.^a b , Ovod, V.^a b , Barthélemy, N.R.^a b , Bateman, R.J.^a b

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, United States
^c Center on Biological Rhythms and Sleep, Washington University School of Medicine, St. Louis, MO, United States
^d Biomolecular Analytical Research and Development, MilliporeSigma, St. Louis, MO, United States

Abstract
Objective: In Alzheimer’s disease, hyperphosphorylated tau is associated with formation of insoluble paired helical filaments that aggregate as neurofibrillary tau tangles and are associated with neuronal loss and cognitive symptoms. Dual orexin receptor antagonists decrease soluble amyloid-β levels and amyloid plaques in mouse models overexpressing amyloid-β, but have not been reported to affect tau phosphorylation. In this randomized controlled trial, we tested the acute effect of suvorexant, a dual orexin receptor antagonist, on amyloid-β, tau, and phospho-tau. Methods: Thirty-eight cognitively unimpaired participants aged 45 to 65 years were randomized to placebo (N = 13), suvorexant 10 mg (N = 13), and suvorexant 20 mg (N = 12). Six milliliters of cerebrospinal fluid were collected via an indwelling lumbar catheter every 2 hours for 36 hours starting at 20:00. Participants received placebo or suvorexant at 21:00. All samples were processed and measured for multiple forms of amyloid-β, tau, and phospho-tau via immunoprecipitation and liquid chromatography-mass spectrometry. Results: The ratio of phosphorylated-tau-threonine-181 to unphosphorylated-tau-threonine-181, a measure of phosphorylation at this tau phosphosite, decreased ~10% to 15% in participants treated with suvorexant 20 mg compared to placebo. However, phosphorylation at tau-serine-202 and tau-threonine-217 were not decreased by suvorexant. Suvorexant decreased amyloid-β ~10% to 20% compared to placebo starting 5 hours after drug administration. Interpretation: In this study, suvorexant acutely decreased tau phosphorylation and amyloid-β concentrations in the central nervous system. Suvorexant is approved by the US Food and Drug Administration to treatment insomnia and may have potential as a repurposed drug for the prevention of Alzheimer’s disease, however, future studies with chronic treatment are needed. ANN NEUROL 2023. © 2023 American Neurological Association.

Funding details
National Institutes of HealthNIHK76 AG054863
BrightFocus FoundationBFFA2016180S

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