Hope Center member publications

Regional age-related atrophy after screening for preclinical alzheimer disease
(2022) Neurobiology of Aging, 109, pp. 43-51. 

Koenig, L.N.^a , LaMontagne, P.^a , Glasser, M.F.^a b , Bateman, R.^c d , Holtzman, D.^c d e , Yakushev, I.^f , Chhatwal, J.^g , Day, G.S.^h , Jack, C.ⁱ , Mummery, C.^j , Perrin, R.J.^d e g k , Gordon, B.A.^c d l , Morris, J.C.^c d , Shimony, J.S.^a , Benzinger, T.L.S.^a d , Dominantly Inherited Alzheimer Network (DIAN)^m

^a Department of Radiology, Washington University, St Louis, MO, United States
^b Department of Neuroscience, Washington University School of Medicine, St Louis, MO, United States
^c Department of Neurology, Washington University, St. Louis, MO, United States
^d Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University, School of Medicine, St. Louis, MO, United States
^e Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, United States
^f Department of Nuclear Medicine, Technical University of MunichMunich, Germany
^g Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
^h Department of Neurology, Mayo Clinic, Jacksonville, FL, United States
ⁱ Department of Radiology, Mayo Clinic, Rochester, MN, United States
^j Dementia Research Center, UCL Queen Square Institute of Neurology, London, United Kingdom
^k Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
^l Department of Psychological & Brain Sciences, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Brain atrophy occurs in aging even in the absence of dementia, but it is unclear to what extent this is due to undetected preclinical Alzheimer disease. Here we examine a cross-sectional cohort (ages 18-88) free from confounding influence of preclinical Alzheimer disease, as determined by amyloid PET scans and three years of clinical evaluation post-imaging. We determine the regional strength of age-related atrophy using linear modeling of brain volumes and cortical thicknesses with age. Age-related atrophy was seen in nearly all regions, with greatest effects in the temporal lobe and subcortical regions. When modeling age with the estimated derivative of smoothed aging curves, we found that the temporal lobe declined linearly with age, subcortical regions declined faster at later ages, and frontal regions declined slower at later ages than during midlife. This age-derivative pattern was distinct from the linear measure of age-related atrophy and significantly associated with a measure of myelin. Atrophy did not detectably differ from a preclinical Alzheimer disease cohort when age ranges were matched. © 2021

Author Keywords
Magnetic Resonance Imaging (MRI);  Normal Aging;  Preclinical Alzheimer disease;  Volumetrics

Document Type: Article
Publication Stage: Final
Source: Scopus

White matter microstructure associations to amyloid burden in adults with Down syndrome
(2022) NeuroImage: Clinical, 33, art. no. 102908, . 

Bazydlo, A.M.^a , Zammit, M.D.^a , Wu, M.^c , Lao, P.J.^a , Dean, D.C., III^a b , Johnson, S.C.^a , Tudorascu, D.L.^c , Cohen, A.^c , Cody, K.A.^a , Ances, B.^d , Laymon, C.M.^c , Klunk, W.E.^c , Zaman, S.^e , Handen, B.L.^c , Hartley, S.L.^b , Alexander, A.L.^a b , Christian, B.T.^a b

^a School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
^b Waisman Center, Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, United States
^c University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
^d Washington University, St. Louis, MO, United States
^e Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, United Kingdom

Abstract
Introduction: Individuals with Down syndrome (DS) are at an increased risk of developing Alzheimer’s Disease (AD). One of the early underlying mechanisms in AD pathology is the accumulation of amyloid protein plaques, which are deposited in extracellular gray matter and signify the first stage in the cascade of neurodegenerative events. AD-related neurodegeneration is also evidenced as microstructural changes in white matter. In this work, we explored the correlation of white matter microstructure with amyloid load to assess amyloid-related neurodegeneration in a cohort of adults with DS. Methods: In this study of 96 adults with DS, the relation of white matter microstructure using diffusion tensor imaging (DTI) and amyloid plaque burden using [11C]PiB PET were examined. The amyloid load (AβL) derived from [11C]PiB was used as a global measure of amyloid burden. AβL and DTI measures were compared using tract-based spatial statistics (TBSS) and corrected for imaging site and chronological age. Results: TBSS of the DTI maps showed widespread age-by-amyloid interaction with both fractional anisotropy (FA) and mean diffusivity (MD). Further, diffuse negative association of FA and positive association of MD with amyloid were observed. Discussion: These findings are consistent with the white matter microstructural changes associated with AD disease progression in late onset AD in non-DS populations. © 2021

Author Keywords
Alzheimer’s Disease;  Amyloid-β;  Down syndrome;  DTI;  PET

Funding details
National Institutes of HealthNIHR01AG031110, T32CA009206, U01AG0514
Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentNICHDU54 HD090256

Document Type: Article
Publication Stage: Final
Source: Scopus

Asthma reduces glioma formation by T cell decorin-mediated inhibition of microglia
(2021) Nature Communications, 12 (1), art. no. 7122, . 

Chatterjee, J.^a , Sanapala, S.^a , Cobb, O.^a , Bewley, A.^a , Goldstein, A.K.^a , Cordell, E.^a , Ge, X.^b , Garbow, J.R.^b , Holtzman, M.J.^c , Gutmann, D.H.^a

^a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
^b Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, United States
^c Department of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, MO, United States

Abstract
To elucidate the mechanisms underlying the reduced incidence of brain tumors in children with Neurofibromatosis type 1 (NF1) and asthma, we leverage Nf1 optic pathway glioma (Nf1OPG) mice, human and mouse RNAseq data, and two different experimental asthma models. Following ovalbumin or house dust mite asthma induction at 4–6 weeks of age (WOA), Nf1OPG mouse optic nerve volumes and proliferation are decreased at 12 and 24 WOA, indicating no tumor development. This inhibition is accompanied by reduced expression of the microglia-produced optic glioma mitogen, Ccl5. Human and murine T cell transcriptome analyses reveal that inhibition of microglia Ccl5 production results from increased T cell expression of decorin, which blocks Ccl4-mediated microglia Ccl5 expression through reduced microglia NFκB signaling. Decorin or NFκB inhibitor treatment of Nf1OPG mice at 4–6 WOA inhibits tumor formation at 12 WOA, thus establishing a potential mechanistic etiology for the attenuated glioma incidence observed in children with asthma. © 2021, The Author(s).

Funding details
5-T35-HL007815
CDI-CORE-2015-505, CDI-CORE-2019-813
National Institutes of HealthNIH
National Heart, Lung, and Blood InstituteNHLBIR35-HL145242
National Eye InstituteNEIP30EY002687
National Cancer InstituteNCIP30-CA091842
National Institute of Neurological Disorders and StrokeNINDS1-R35-NS07211-01
National Center for Research ResourcesNCRR
Alex’s Lemonade Stand Foundation for Childhood CancerALSF
Foundation for Barnes-Jewish Hospital3770, 4642
Institute of Clinical and Translational SciencesICTS
Center for Cellular Imaging, Washington UniversityWUCCI
Georgia Clinical and Translational Science AllianceGaCTSAUL1TR002345

Document Type: Article
Publication Stage: Final
Source: Scopus

Neuropathology of murine Sanfilippo D syndrome
(2021) Molecular Genetics and Metabolism, 134 (4), pp. 323-329. 

Takahashi, K.^a , Le, S.Q.^a , Kan, S.-H.^b , Jansen, M.J.^a , Dickson, P.I.^a , Cooper, J.D.^a

^a Department of Pediatrics, Washington University in St. Louis, St. Louis, MO 63110, United States
^b Children’s Hospital Orange County Research Institute, Orange, CA 92868, United States

Abstract
Sanfilippo D syndrome (mucopolysaccharidosis type IIID) is a lysosomal storage disorder caused by the deficiency of N-acetylglucosamine-6-sulfatase (GNS). A mouse model was generated by constitutive knockout of the Gns gene. We studied affected mice and controls at 12, 24, 36, and 48 weeks of age for neuropathological markers of disease in the somatosensory cortex, primary motor cortex, ventral posterior nuclei of the thalamus, striatum, hippocampus, and lateral and medial entorhinal cortex. We found significantly increased immunostaining for glial fibrillary associated protein (GFAP), CD68 (a marker of activated microglia), and lysosomal-associated membrane protein-1 (LAMP-1) in Sanfilippo D mice compared to controls at 12 weeks of age in all brain regions. Intergroup differences were marked for GFAP and CD68 staining, with levels in Sanfilippo D mice consistently above controls at all age groups. Intergroup differences in LAMP-1 staining were more pronounced in 12- and 24-week age groups compared to 36- and 48-week groups, as control animals showed some LAMP-1 staining at later timepoints in some brain regions. We also evaluated the somatosensory cortex, medial entorhinal cortex, reticular nucleus of the thalamus, medial amygdala, and hippocampal hilus for subunit c of mitochondrial ATP synthase (SCMAS). We found a progressive accumulation of SCMAS in most brain regions of Sanfilippo D mice compared to controls by 24 weeks of age. Cataloging the regional neuropathology of Sanfilippo D mice may aid in understanding the disease pathogenesis and designing preclinical studies to test brain-directed treatments. © 2021 Elsevier Inc.

Author Keywords
Glycosaminoglycan;  Lysosomal storage disease;  Mucopolysaccharidosis

Funding details
National Institutes of HealthNIH1R01NS088766, 2R44NS089061
Genzyme

Document Type: Article
Publication Stage: Final
Source: Scopus

Live imaging reveals the cellular events downstream of sarm1 activation
(2021) eLife, 10, art. no. e71148, . 

Ko, K.W.^a , Devault, L.^a , Sasaki, Y.^b , Milbrandt, J.^c , Diantonio, A.^d

^a Washington University School of Medicine, St Louis, United States
^b Genetics Washington University School of Medicine, St Louis, United States
^c Genetics Hope Center for Neurological Disorders, Washington University School of Medicine, St Louis, United States
^d Developmental Biology, Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St Louis, United States

Abstract
SARM1 is an inducible NAD+ hydrolase that triggers axon loss and neuronal cell death in the injured and diseased nervous system. While SARM1 activation and enzyme function are well defined, the cellular events downstream of SARM1 activity but prior to axonal demise are much less well understood. Defects in calcium, mitochondria, ATP, and membrane homeostasis occur in injured axons, but the relationships among these events have been difficult to disentangle because prior studies analyzed large collections of axons in which cellular events occur asynchronously. Here, we used live imaging of mouse sensory neurons with single axon resolution to investigate the cellular events downstream of SARM1 activity. Our studies support a model in which SARM1 NADase activity leads to an ordered sequence of events from loss of cellular ATP, to defects in mitochondrial movement and depolarization, followed by calcium influx, externalization of phosphatidylserine, and loss of membrane permeability prior to catastrophic axonal self-destruction. © Ko et al.

Funding details
National Institutes of HealthNIHF32NS117784, R01CA219866, RF1-AG013730, RO1NS087632

Document Type: Article
Publication Stage: Final
Source: Scopus

PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans
(2021) Nature Medicine, . 

Barak, T.^a b c d , Ristori, E.^b e , Ercan-Sencicek, A.G.^a b c d , Miyagishima, D.F.^a b c d , Nelson-Williams, C.^b , Dong, W.^b f , Jin, S.C.^b f g , Prendergast, A.^e , Armero, W.^b e , Henegariu, O.^a b c d , Erson-Omay, E.Z.^a b c d , Harmancı, A.S.^a b c d , Guy, M.^h , Gültekin, B.^a , Kilic, D.^a , Rai, D.K.^a b c d , Goc, N.^a , Aguilera, S.M.^a , Gülez, B.^a , Altinok, S.^a , Ozcan, K.^a , Yarman, Y.^a , Coskun, S.^a b c d , Sempou, E.ⁱ , Deniz, E.ⁱ , Hintzen, J.^e , Cox, A.^b , Fomchenko, E.^a , Jung, S.W.^j , Ozturk, A.K.^k , Louvi, A.^a d , Bilgüvar, K.^b d l , Connolly, E.S., Jr.^m , Khokha, M.K.^b i , Kahle, K.T.^a n o p , Yasuno, K.^a b c d , Lifton, R.P.^b f , Mishra-Gorur, K.^a b c d , Nicoli, S.^b e q , Günel, M.^a b c d

^a Department of Neurosurgery, Yale School of Medicine, New Haven, CT, United States
^b Department of Genetics, Yale School of Medicine, New Haven, CT, United States
^c Department of Neuroscience, Yale School of Medicine, New Haven, CT, United States
^d Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT, United States
^e Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiology, Yale School of Medicine, New Haven, CT, United States
^f Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, United States
^g Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
^h Yale Center for Research Computing, Yale University, New Haven, CT, United States
ⁱ Department of Pediatrics, Yale School of Medicine, New Haven, CT, United States
^j Division of Nephrology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Seoul, South Korea
^k Department of Neurosurgery, Pennsylvania Hospital, University of Pennsylvania Health System, Philadelphia, PA, United States
^l Yale Center for Genome Analysis, Yale University, New Haven, CT, United States
^m Department of Neurosurgery, Columbia University College of Physicians and Surgeons, New York, NY, United States
ⁿ Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States
^o Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA, United States
^p Broad Institute of MIT and Harvard, Massachusetts Institute of Technology, Cambridge, MA, United States
^q Department of Pharmacology, Yale School of Medicine, New Haven, CT, United States

Abstract
Intracranial aneurysm (IA) rupture leads to subarachnoid hemorrhage, a sudden-onset disease that often causes death or severe disability. Although genome-wide association studies have identified common genetic variants that increase IA risk moderately, the contribution of variants with large effect remains poorly defined. Using whole-exome sequencing, we identified significant enrichment of rare, deleterious mutations in PPIL4, encoding peptidyl-prolyl cis-trans isomerase-like 4, in both familial and index IA cases. Ppil4 depletion in vertebrate models causes intracerebral hemorrhage, defects in cerebrovascular morphology and impaired Wnt signaling. Wild-type, but not IA-mutant, PPIL4 potentiates Wnt signaling by binding JMJD6, a known angiogenesis regulator and Wnt activator. These findings identify a novel PPIL4-dependent Wnt signaling mechanism involved in brain-specific angiogenesis and maintenance of cerebrovascular integrity and implicate PPIL4 gene mutations in the pathogenesis of IA. © 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIH4R01NS057756-10
Yale University

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