Publications

Hope Center member publications

List of publications for week of March 28, 2022

Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer’s disease: a longitudinal observational study” (2022) The Lancet Neurology

Soluble TREM2 in CSF and its association with other biomarkers and cognition in autosomal-dominant Alzheimer’s disease: a longitudinal observational study
(2022) The Lancet Neurology, 21 (4), pp. 329-341. 

Morenas-Rodríguez, E.a b , Li, Y.e , Nuscher, B.a b x , Franzmeier, N.c , Xiong, C.e , Suárez-Calvet, M.i j k , Fagan, A.M.f , Schultz, S.g , Gordon, B.A.g , Benzinger, T.L.S.g , Hassenstab, J.f , McDade, E.f , Feederle, R.a l m n , Karch, C.M.h , Schlepckow, K.a b , Morris, J.C.f , Kleinberger, G.a b , Nellgard, B.o p , Vöglein, J.a d , Blennow, K.q r , Zetterberg, H.q r s t u , Ewers, M.a c , Jucker, M.v w , Levin, J.a d l , Bateman, R.J.f , Haass, C.a b l , Adams, S.x , Allegri, R.x , Araki, A.x , Barthelemy, N.x , Bechara, J.x , Berman, S.x , Bodge, C.x , Brandon, S.x , Brooks, W.B.x , Brosch, J.x , Buck, J.x , Buckles, V.x , Carter, K.x , Cash, L.x , Chen, C.x , Chhatwal, J.x , Chrem, P.x , Chua, J.x , Chui, H.x , Cruchaga, C.x , Day, G.S.x , De La Cruz, C.x , Denner, D.x , Diffenbacher, A.x , Dincer, A.x , Donahue, T.x , Douglas, J.x , Duong, D.x , Egido, N.x , Esposito, B.x , Farlow, M.x , Feldman, B.x , Fitzpatrick, C.x , Flores, S.x , Fox, N.x , Franklin, E.x , Friedrichsen, N.x , Fujii, H.x , Gardener, S.x , Ghetti, B.x , Goate, A.x , Goldberg, S.x , Goldman, J.x , Gonzalez, A.x , Gräber-Sultan, S.x , Graff-Radford, N.x , Graham, M.x , Gray, J.x , Gremminger, E.x , Grilo, M.x , Groves, A.x , Häsler, L.x , Hellm, C.x , Herries, E.x , Hoechst-Swisher, L.x , Hofmann, A.x , Holtzman, D.x , Hornbeck, R.x , Igor, Y.x , Ihara, R.x , Ikeuchi, T.x , Ikonomovic, S.x , Ishii, K.x , Jack, C.x , Jerome, G.x , Johnson, E.x , Käser, S.x , Kasuga, K.x , Keefe, S.x , Klunk, W.B.x , Koeppe, R.x , Koudelis, D.x , Kuder-Buletta, E.x , Laske, C.x , Levey, A.x , Lopez, O.x , Marsh, J.x , Martinez, R.x , Martins, R.x , Mason, N.S.x , Masters, C.x , Mawuenyega, K.x , McCullough, A.x , Mejia, A.x , MountzMD, J.x , Mummery, C.x , Nadkarni, N.x , Nagamatsu, A.x , Neimeyer, K.x , Niimi, Y.x , Noble, J.x , Norton, J.x , O’Connor, A.x , Obermüller, U.x , Patira, R.x , Perrin, R.x , Ping, L.x , Preische, O.x , Renton, A.x , Ringman, J.x , Salloway, S.x , Schofield, P.x , Senda, M.x , Seyfried, N.x , Shady, K.x , Shimada, H.x , Sigurdson, W.x , Smith, J.x , Smith, L.x , Snitz, B.x , Sohrabi, H.x , Stephens, S.x , Taddei, K.x , Thompson, S.x , Wang, P.x , Wang, Q.x , Weamer, E.x , Xu, J.x , Xu, X.x , Dominantly Inherited Alzheimer Networky

a German Center for Neurodegenerative Diseases, Munich, Germany
b Metabolic Biochemistry, Biomedical Center, Faculty of Medicine, Ludwig-Maximilians University, Munich, Germany
c Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians University, Munich, Germany
d Department of Neurology, University Hospital of Munich, Ludwig-Maximilians University, Munich, Germany
e Division of Biostatistics, 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 Mallinckrodt Institute of Radiology, Washington University School of Medicine, St Louis, MO, United States
h Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
i Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
j Servei de Neurologia, Hospital del Mar Medical Research Institute, Barcelona, Spain
k Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, Madrid, Spain
l Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
m Institute for Diabetes and Obesity, Monoclonal Antibody Core Facility, Helmholtz Center, Munich, Germany
n German Research Center for Environmental Health, Neuherberg, Germany
o Department of Anesthesiology and Intensive Care, Sahlgrenska University Hospital, Mölndal, Sweden
p Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
q Department of Psychiatry and Neurochemistry, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
r Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
s Department of Neurodegenerative Disease, UCL Queens Square Institute of Neurology, University College London, UK, London, United Kingdom
t UK Dementia Research Institute, University College London, UK, London, United Kingdom
u Hong Kong Center for Neurodegenerative Diseases, Hong Kong Special Administrative Region, China
v German Center for Neurodegenerative Diseases, Tübingen, Germany
w Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, Tübingen, Germany

Abstract
Background: Therapeutic modulation of TREM2-dependent microglial function might provide an additional strategy to slow the progression of Alzheimer’s disease. Although studies in animal models suggest that TREM2 is protective against Alzheimer’s pathology, its effect on tau pathology and its potential beneficial role in people with Alzheimer’s disease is still unclear. Our aim was to study associations between the dynamics of soluble TREM2, as a biomarker of TREM2 signalling, and amyloid β (Aβ) deposition, tau-related pathology, neuroimaging markers, and cognitive decline, during the progression of autosomal dominant Alzheimer’s disease. Methods: We did a longitudinal analysis of data from the Dominantly Inherited Alzheimer Network (DIAN) observational study, which includes families with a history of autosomal dominant Alzheimer’s disease. Participants aged over 18 years who were enrolled in DIAN between Jan 1, 2009, and July 31, 2019, were categorised as either carriers of pathogenic variants in PSEN1, PSEN2, and APP genes (n=155) or non-carriers (n=93). We measured amounts of cleaved soluble TREM2 using a novel immunoassay in CSF samples obtained every 2 years from participants who were asymptomatic (Clinical Dementia Rating [CDR]=0) and annually for those who were symptomatic (CDR>0). CSF concentrations of Aβ40, Aβ42, total tau (t-tau), and tau phosphorylated on threonine 181 (p-tau) were measured by validated immunoassays. Predefined neuroimaging measurements were total cortical uptake of Pittsburgh compound B PET (PiB-PET), cortical thickness in the precuneus ascertained by MRI, and hippocampal volume determined by MRI. Cognition was measured using a validated cognitive composite (including DIAN word list test, logical memory delayed recall, digit symbol coding test [total score], and minimental status examination). We based our statistical analysis on univariate and bivariate linear mixed effects models. Findings: In carriers of pathogenic variants, a high amyloid burden at baseline, represented by low CSF Aβ42 (β=–4·28 × 10–2 [SE 0·013], p=0·0012), but not high cortical uptake in PiB-PET (β=–5·51 × 10–3 [0·011], p=0·63), was the only predictor of an augmented annual rate of subsequent increase in soluble TREM2. Augmented annual rates of increase in soluble TREM2 were associated with a diminished rate of decrease in amyloid deposition, as measured by Aβ42 in CSF (r=0·56 [0·22], p=0·011), in presymptomatic carriers of pathogenic variants, and with diminished annual rate of increase in PiB-PET (r=–0·67 [0·25], p=0·0060) in symptomatic carriers of pathogenic variants. Presymptomatic carriers of pathogenic variants with annual rates of increase in soluble TREM2 lower than the median showed a correlation between enhanced annual rates of increase in p-tau in CSF and augmented annual rates of increase in PiB-PET signal (r=0·45 [0·21], p=0·035), that was not observed in those with rates of increase in soluble TREM2 higher than the median. Furthermore, presymptomatic carriers of pathogenic variants with rates of increase in soluble TREM2 above or below the median had opposite associations between Aβ42 in CSF and PiB-PET uptake when assessed longitudinally. Augmented annual rates of increase in soluble TREM2 in presymptomatic carriers of pathogenic variants correlated with decreased cortical shrinkage in the precuneus (r=0·46 [0·22]), p=0·040) and diminished cognitive decline (r=0·67 [0·22], p=0·0020). Interpretation: Our findings in autosomal dominant Alzheimer’s disease position the TREM2 response within the amyloid cascade immediately after the first pathological changes in Aβ aggregation and further support the role of TREM2 on Aβ plaque deposition and compaction. Furthermore, these findings underpin a beneficial effect of TREM2 on Aβ deposition, Aβ-dependent tau pathology, cortical shrinkage, and cognitive decline. Soluble TREM2 could, therefore, be a key marker for clinical trial design and interpretation. Efforts to develop TREM2-boosting therapies are ongoing. Funding: German Research Foundation, US National Institutes of Health. © 2022 Elsevier Ltd

Funding details
ALFGBG-715986
JPND2019-466-236
ALFGBG-720931
National Institutes of HealthNIH1R01AG068398-01
National Institute on AgingNIA
Alzheimer’s AssociationAAZEN-21-848495
Alzheimer’s Drug Discovery FoundationADDFRDAPB-201809-2016615
Genentech
Biogen
F. Hoffmann-La Roche
Janssen Pharmaceuticals
Japan Agency for Medical Research and DevelopmentAMED
Ministerio de Ciencia, Innovación y UniversidadesMCIU2017-00915, IJC2018-037478-I
GHR FoundationGHR
European Research CouncilERC681712
Deutsche ForschungsgemeinschaftDFG390857198
Korea Health Industry Development InstituteKHIDIHA1737/16-1
Eisai
VetenskapsrådetVR2018-02532
Instituto de Salud Carlos IIIISCIIIPI19/00155
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Horizon 2020948677
AlzheimerfondenAF-742881, FO2017-0243

Document Type: Article
Publication Stage: Final
Source: Scopus

Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models” (2022) Clinical Cancer Research: An Official Journal of the American Association for Cancer Research

Long-Acting Recombinant Human Interleukin-7, NT-I7, Increases Cytotoxic CD8 T Cells and Enhances Survival in Mouse Glioma Models
(2022) Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 28 (6), pp. 1229-1239. Cited 1 time.

Campian, J.L.a , Ghosh, S.b , Kapoor, V.b , Yan, R.a , Thotala, S.b , Jash, A.a , Hu, T.a c , Mahadevan, A.b , Rifai, K.b , Page, L.b , Lee, B.H.d , Ferrando-Martinez, S.d , Wolfarth, A.A.d , Yang, S.H.d , Hallahan, D.a e , Chheda, M.G.a c , Thotala, D.b e

a Department of Medicine, Division of Oncology, Washington University in St. Louis, St. Louis, MO, United States
b Department of Radiation Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
c Department of Neurology, School of Medicine, Washington University in St. Louis, St. Louis, MO, United States
d Rockville, MD, United States
e Siteman Cancer Center, Washington University in St. Louis, St. Louis, MO, United States

Abstract
PURPOSE: Patients with glioblastoma (GBM) are treated with radiotherapy (RT) and temozolomide (TMZ). These treatments may cause prolonged systemic lymphopenia, which itself is associated with poor outcomes. NT-I7 is a long-acting IL7 that expands CD4 and CD8 T-cell numbers in humans and mice. We tested whether NT-I7 prevents systemic lymphopenia and improves survival in mouse models of GBM. EXPERIMENTAL DESIGN: C57BL/6 mice bearing intracranial tumors (GL261 or CT2A) were treated with RT (1.8 Gy/day × 5 days), TMZ (33 mg/kg/day × 5 days), and/or NT-I7 (10 mg/kg on the final day of RT). We followed the mice for survival while serially analyzing levels of circulating T lymphocytes. We assessed regulatory T cells (Treg) and cytotoxic T lymphocytes in the tumor microenvironment, cervical lymph nodes, spleen, and thymus, and hematopoietic stem and progenitor cells in the bone marrow. RESULTS: GBM tumor-bearing mice treated with RT+NT-I7 increased T lymphocytes in the lymph nodes, thymus, and spleen, enhanced IFNγ production, and decreased Tregs in the tumor which was associated with a significant increase in survival. NT-I7 also enhanced central memory and effector memory CD8 T cells in lymphoid organs and tumor. Depleting CD8 T cells abrogated the effects of NT-I7. Furthermore, NT-I7 treatment decreased progenitor cells in the bone marrow. CONCLUSIONS: In orthotopic glioma-bearing mice, NT-I7 mitigates RT-related lymphopenia, increases cytotoxic CD8 T lymphocytes systemically and in the tumor, and improves survival. A phase I/II trial to evaluate NT-I7 in patients with high-grade gliomas is ongoing (NCT03687957). ©2022 American Association for Cancer Research.

Document Type: Article
Publication Stage: Final
Source: Scopus

Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation” (2022) Cells

Mitochondrial Phenotypes in Genetically Diverse Neurodegenerative Diseases and Their Response to Mitofusin Activation
(2022) Cells, 11 (6), art. no. 1053, . Cited 1 time.

Dang, X.a , Walton, E.K.a , Zablocka, B.b , Baloh, R.H.c , Shy, M.E.d , Dorn, G.W., IIa

a Center for Pharmacogenomics, Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Ave, St. Louis, MO 63110, United States
b Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, 02-106, Poland
c Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
d Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, United States

Abstract
Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot–Marie– Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson’s and Alzheimer’s disease patients, implicating addressable mitochondrial dysdynamism in these illnesses. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Author Keywords
Mitochondrial dynamics;  Mitofusin;  Neurodegenerative diseases

Funding details
National Institutes of HealthNIH628906, R35135736, R42NS115184
Muscular Dystrophy AssociationMDA

Document Type: Article
Publication Stage: Final
Source: Scopus

Association of a Perioperative Multicomponent Fall Prevention Intervention With Falls and Quality of Life After Elective Inpatient Surgical Procedures” (2022) JAMA Network Open

Association of a Perioperative Multicomponent Fall Prevention Intervention With Falls and Quality of Life After Elective Inpatient Surgical Procedures
(2022) JAMA Network Open, 5 (3), p. e221938. 

Fritz, B.A.a , King, C.R.a , Mehta, D.a , Somerville, E.b , Kronzer, A.a , Ben Abdallah, A.a , Wildes, T.a , Avidan, M.S.a , Lenze, E.J.c , Stark, S.b , ENGAGES Research Groupd

a Department of Anesthesiology, Washington University School of Medicine in St Louis, St Louis, MO, United States
b Program in Occupational Therapy, 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

Abstract
Importance: Falls after elective inpatient surgical procedures are common and have physical, emotional, and financial consequences. Close interactions between patients and health care teams before and after surgical procedures may offer opportunities to address modifiable risk factors associated with falls. Objective: To assess whether a multicomponent intervention that incorporates education, home medication review, and home safety assessment is associated with reductions in the incidence of falls after elective inpatient surgical procedures. Design, Setting, and Participants: This prospective propensity score-matched cohort study was a prespecified secondary analysis of data from the Electroencephalography Guidance of Anesthesia to Alleviate Geriatric Syndromes (ENGAGES) randomized clinical trial, which was conducted at a single academic medical center between January 16, 2015, and May 7, 2018. Patients in the intervention group of the present study were enrolled in either arm of the ENGAGES clinical trial. Patients in the control group were selected from the Systematic Assessment and Targeted Improvement of Services Following Yearly Surgical Outcomes Surveys prospective observational cohort study, which created a registry of patient-reported postoperative outcomes at the same single center. The propensity score-matched cohort in the present study included 1396 patients (698 pairs) selected from a pool of 2013 eligible patients. All patients underwent elective surgical procedures with general anesthesia and had a hospital stay of 2 or more days. Data were analyzed from January 2, 2020, to January 11, 2022. Interventions: The multicomponent safety intervention (offered to all patients in the ENGAGES clinical trial) included patient education on fall prevention techniques, home medication review by a geriatric psychiatrist (with communication of recommended changes to the surgeon), a self-administered home safety assessment, and targeted occupational therapy home visits with home hazard removal (offered to patients with a preoperative history of falls). Main Outcomes and Measures: The primary outcome was patient-reported falls within 1 year after an elective inpatient surgical procedure. The secondary outcome was quality of life 1 year after an elective surgical procedure, which was measured using the physical and mental composite summary scores on the Veterans RAND 12-item health survey (score range, 0-100 points, with 0 indicating lowest quality of life and 100 indicating highest quality of life). Results: Among 1396 patients, the median age was 69 years (IQR, 64-75 years), and 739 patients (52.9%) were male. With regard to race, 5 patients (0.4%) were Asian, 97 (6.9%) were Black or African American, 2 (0.1%) were Native Hawaiian or Pacific Islander, 1237 (88.6%) were White, 3 (0.2%) were of other race, and 52 (3.7%) were of unknown race; with regard to ethnicity, 12 patients (0.9%) were Hispanic or Latino, 1335 (95.6%) were non-Hispanic or non-Latino, and 49 (3.5%) were of unknown ethnicity. Adherence to individual intervention components was modest (from 22.9% for completion of the self-administered home safety assessment to 28.2% for implementation of the geriatric psychiatrist’s recommended medication changes). Falls within 1 year after surgical procedures were reported by 228 of 698 patients (32.7%) in the intervention group and 225 of 698 patients (32.2%) in the control group. No significant difference was found in falls between the 2 groups (standardized risk difference, 0.4%; 95% CI, -4.5% to 5.3%). After adjusting for preoperative quality of life, patients in the intervention group had higher physical composite summary scores (3.8 points; 95% CI, 2.4-5.1 points) and higher mental composite summary scores (5.7 points; 95% CI, 4.7-6.7 points) at 1 year compared with patients in the control group. Conclusions and Relevance: In this cohort study, a multicomponent safety intervention was not associated with reductions in falls within the first year after an elective surgical procedure; however, an increase in quality of life at 1 year was observed. These results suggest a need for other interventions, such as those designed to increase adherence, to lower the incidence of falls after surgical procedures.

Document Type: Article
Publication Stage: Final
Source: Scopus

Partial Ablation of Postsynaptic Dopamine D2 Receptors in the Central Nucleus of the Amygdala Increases Risk Avoidance in Exploratory Tasks” (2022) eNeuro

Partial Ablation of Postsynaptic Dopamine D2 Receptors in the Central Nucleus of the Amygdala Increases Risk Avoidance in Exploratory Tasks
(2022) eNeuro, 9 (2), art. no. ENEURO.0528-21.2022, . 

Casey, E.a d , Avale, M.E.a b , Kravitz, A.c d e , Rubinstein, M.a b

a Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, 1428, Argentina
b Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, 1428, Argentina
c Department of Anesthesiology, Washington University St. Louis, St. Louis, MO 63108, United States
d Department of Psychiatry, Washington University St. Louis, St. Louis, MO 63108, United States
e Department of Neuroscience and Biomedical Engineering, Washington University St. Louis, St. Louis, MO 63108, United States

Abstract
The central nucleus of the amygdala (CeA) is involved in the expression of fear and has been implicated in several anxiety disorders. This structure is densely innervated by DAergic projections that impinge on amygdalar neurons expressing various dopamine (DA) receptor subtypes, including D2 receptors (D2Rs). Although various pharmacological approaches have assessed the role of D2Rs in the CeA, the actual participation of postsynaptic D2Rs in the CeA to defensive behaviors remains unclear. Here, we investigated the distribution of D2Rs in the CeA and their role in modifying neuronal activity and fear related behaviors in mice. First, using the mouse reporter strain D2R-EGFP, we verified that D2Rs are present both in neurons of the CeA and in A10 dorsocaudal (A10dc) DAergic neurons that innervate the CeA. Moreover, we showed that pharmacological stimulation of D2Rs increases the activity of protein kinase C (PKC)δ cells present in the CeA, a type of neuron previously associated with reduced defensive behaviors. Finally, using a molecular genetics approach that discriminates postsynaptic D2Rs from presynaptic D2 autoreceptors, we demonstrated that mice carrying targeted deletions of postsynaptic D2Rs in the CeA display increased risk avoidance in exploratory tasks. Together, our results indicate that postsynaptic D2Rs in the CeA attenuate behavioral reactions to potential environmental threats. © 2022 Casey et al.

Funding details
Consejo Nacional de Investigaciones Científicas y TécnicasCONICET
Agencia Nacional de Promoción Científica y TecnológicaANPCyT

Document Type: Article
Publication Stage: Final
Source: Scopus

Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels” (2022) Nature Neuroscience

Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels
(2022) Nature Neuroscience, . 

Mazzitelli, J.A.a b c d , Smyth, L.C.D.a b , Cross, K.A.b e , Dykstra, T.a b , Sun, J.c , Du, S.a b f , Mamuladze, T.a b f , Smirnov, I.a b , Rustenhoven, J.a b g , Kipnis, J.a b c d e f

a Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
b Center for Brain Immunology and Glia (BIG), Washington University School of Medicine, St. Louis, MO, United States
c Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, United States
d Neuroscience Graduate Program, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
f Immunology Graduate Program, Washington University School of Medicine, St. Louis, MO, United States
g Department of Pharmacology and Clinical Pharmacology, The University of Auckland, Auckland, New Zealand

Abstract
It remains unclear how immune cells from skull bone marrow niches are recruited to the meninges. Here we report that cerebrospinal fluid (CSF) accesses skull bone marrow via dura–skull channels, and CSF proteins signal onto diverse cell types within the niches. After spinal cord injury, CSF-borne cues promote myelopoiesis and egress of myeloid cells into meninges. This reveals a mechanism of CNS-to-bone-marrow communication via CSF that regulates CNS immune responses. © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

Funding details
National Institutes of HealthNIHAT010416, NS096967
Cure Alzheimer’s FundCAFT32NS121881

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

Reproducible brain-wide association studies require thousands of individuals” (2022) Nature

Reproducible brain-wide association studies require thousands of individuals
(2022) Nature, . 

Marek, S.a , Tervo-Clemmens, B.b c , Calabro, F.J.d e , Montez, D.F.f , Kay, B.P.f , Hatoum, A.S.a , Donohue, M.R.a , Foran, W.d , Miller, R.L.a f , Hendrickson, T.J.g , Malone, S.M.h , Kandala, S.a , Feczko, E.i j , Miranda-Dominguez, O.i j , Graham, A.M.k , Earl, E.A.i k , Perrone, A.J.i k , Cordova, M.k , Doyle, O.k , Moore, L.A.k , Conan, G.M.i k , Uriarte, J.k , Snider, K.k , Lynch, B.J.i l , Wilgenbusch, J.C.i l , Pengo, T.g , Tam, A.m n o p , Chen, J.m n o p , Newbold, D.J.f , Zheng, A.f , Seider, N.A.f , Van, A.N.f q , Metoki, A.f , Chauvin, R.J.f , Laumann, T.O.a , Greene, D.J.r , Petersen, S.E.f q s t u , Garavan, H.v , Thompson, W.K.w , Nichols, T.E.x , Yeo, B.T.T.m n o p y z , Barch, D.M.a u , Luna, B.c d , Fair, D.A.i j aa , Dosenbach, N.U.F.f q s ab ac

a Department of Psychiatry, Washington University School of Medicine, St Louis, MO, United States
b Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
c Department of Psychology, University of Pittsburgh, Pittsburgh, PA, United States
d Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
e Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, United States
f Department of Neurology, Washington University School of Medicine, St Louis, MO, United States
g University of Minnesota Informatics Institute, University of Minnesota, Minneapolis, MN, United States
h Department of Psychology, University of Minnesota, Minneapolis, MN, United States
i Masonic Institute for the Developing Brain, University of Minnesota Medical School, Minneapolis, MN, United States
j Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, United States
k Department of Psychiatry, Oregon Health and Science University, Portland, OR, United States
l Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN, United States
m Department of Electrical and Computer Engineering, National University of Singapore, Singapore, Singapore
n Centre for Sleep and Cognition, National University of Singapore, Singapore, Singapore
o Centre for Translational MR Research, National University of Singapore, Singapore, Singapore
p N.1 Institute for Health, Institute for Digital Medicine, National University of Singapore, Singapore, Singapore
q Department of Biomedical Engineering, Washington University in St Louis, St Louis, MO, United States
r Department of Cognitive Science, University of California San Diego, La Jolla, CA, United States
s Department of Radiology, Washington University School of Medicine, St Louis, MO, United States
t Department of Neurological Surgery, Washington University School of Medicine, St Louis, MO, United States
u Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
v Department of Psychiatry, University of Vermont, Burlington, VT, United States
w Division of Biostatistics, University of California San Diego, La Jolla, CA, United States
x Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
y Integrative Sciences and Engineering Programme, National University of Singapore, Singapore, Singapore
z Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States
aa Institute of Child Development, University of Minnesota Medical School, Minneapolis, MN, United States
ab Program in Occupational Therapy, Washington University School of Medicine, St Louis, MO, United States
ac Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States

Abstract
Magnetic resonance imaging (MRI) has transformed our understanding of the human brain through well-replicated mapping of abilities to specific structures (for example, lesion studies) and functions1–3 (for example, task functional MRI (fMRI)). Mental health research and care have yet to realize similar advances from MRI. A primary challenge has been replicating associations between inter-individual differences in brain structure or function and complex cognitive or mental health phenotypes (brain-wide association studies (BWAS)). Such BWAS have typically relied on sample sizes appropriate for classical brain mapping4 (the median neuroimaging study sample size is about 25), but potentially too small for capturing reproducible brain–behavioural phenotype associations5,6. Here we used three of the largest neuroimaging datasets currently available—with a total sample size of around 50,000 individuals—to quantify BWAS effect sizes and reproducibility as a function of sample size. BWAS associations were smaller than previously thought, resulting in statistically underpowered studies, inflated effect sizes and replication failures at typical sample sizes. As sample sizes grew into the thousands, replication rates began to improve and effect size inflation decreased. More robust BWAS effects were detected for functional MRI (versus structural), cognitive tests (versus mental health questionnaires) and multivariate methods (versus univariate). Smaller than expected brain–phenotype associations and variability across population subsamples can explain widespread BWAS replication failures. In contrast to non-BWAS approaches with larger effects (for example, lesions, interventions and within-person), BWAS reproducibility requires samples with thousands of individuals. © 2022, The Author(s), under exclusive licence to Springer Nature Limited.

Funding details
PSC TG-IBN200009
1U54MH091657, U54 MH091657
National Science FoundationNSFACI-1445606, ACI-1548562
National Institutes of HealthNIHAA02969, DA007261, DA04112, DA041148, MH096773, MH100019, MH104592, MH112473, MH115357, MH121276, MH121518, MH122066, MH124567, MH125023, NS088590, NS090978, NS110332, NS115672, U01DA041022, U01DA041025, U01DA041028, U01DA041048, U01DA041089, U01DA041093, U01DA041106, U01DA041117, U01DA041120, U01DA041134, U01DA041156, U01DA041174, U24DA041123, U24DA041147
NIH Blueprint for Neuroscience Research
Minnesota Department of HealthMDH
University of WashingtonUW
Intellectual and Developmental Disabilities Research CenterIDDRCP50 HD103525
Institute of Clinical and Translational SciencesICTSUL1 TR002345
College of Health, Education, and Human Development, Clemson UniversityHEHD
McDonnell Center for Systems Neuroscience
Scottish Government
Medical Research CouncilMRC
British Heart FoundationBHF
Cancer Research UKCRUK
Jacobs Foundation2016121703
Northwest Regional Development AgencyNWDA

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

Therapeutic Targets for Alzheimer’s Disease: Amyloid Vs. Non-Amyloid. Where Does Consensus Lie Today? An CTAD Task Force Report” (2022) Journal of Prevention of Alzheimer’s Disease

Therapeutic Targets for Alzheimer’s Disease: Amyloid Vs. Non-Amyloid. Where Does Consensus Lie Today? An CTAD Task Force Report
(2022) Journal of Prevention of Alzheimer’s Disease, . 

Gauthier, S.a , Boxer, A.b , Knopman, D.c , Sims, J.d , Doody, R.e , Aisen, P.f , Iwatsubo, T.g , Bateman, R.h , Vellas, B.i

a McGill Center for Studies in Aging, Montreal, Canada
b Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, United States
c Department of Neurology, Mayo Clinic, Rochester, MN, United States
d Eli Lilly and Company, Indianapolis, IN, United States
e Genentech and F. Hoffman LaRoche, Basel, Switzerland
f Keck Scholl of Medicine of USC, San Diego, CA, United States
g Department of Neuropathology, The University of Tokyo, Tokyo, Japan
h Department of Neurology, Washington University, St-Louis, MO, United States
i Toulouse University Hospital, Inserm 1295, University of Toulouse, UPS, Toulouse, France

Abstract
There was consensus that both amyloid and tau pathologies should be targeted in Alzheimer’s disease, as well as additional pathophysiological mechanisms such as neuroinflammation. The selection of one or both of these targets may depend upon a personalized approach that takes into account the genetic and acquired factors that cause AD in any given person as well as their stage of disease as reflected in a biomarker profile. The validation of this therapeutic approach will be made possible by new methodologies for subdividing into predominant pathology, by efficient methods for identifying people in the earliest stages of disease, and by combination studies. © 2022, The Author(s).

Author Keywords
Alzheimer disease;  Amyloid;  tau;  therapeutic targets

Funding details
National Institutes of HealthNIH
Foundation for the National Institutes of HealthFNIH
National Institute on AgingNIA
Alzheimer’s AssociationAA
Alzheimer’s Drug Discovery FoundationADDFR01AG038791, U01AG045390, U19AG063911, U54NS092089
Eli Lilly and Company
GlaxoSmithKlineGSK
Merck
Roche
Biogen
AbbVie
University of California, San FranciscoUCSF
Janssen Pharmaceuticals
Applied Genetic Technologies CorporationAGTC
GHR FoundationGHR
Eisai
H. Lundbeck A/S

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

Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II” (2022) Multiple Sclerosis Journal

Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: Results from ASCLEPIOS I and II
(2022) Multiple Sclerosis Journal, . 

Gärtner, J.a , Hauser, S.L.b , Bar-Or, A.c , Montalban, X.d , Cohen, J.A.e , Cross, A.H.f , Deiva, K.g , Ganjgahi, H.h l , Häring, D.A.i , Li, B.j , Pingili, R.j , Ramanathan, K.i , Su, W.j , Willi, R.i , Kieseier, B.i , Kappos, L.k

a Department of Paediatrics and Adolescent Medicine, Division of Paediatric Neurology, University Medical Centre Göttingen, Georg August University Göttingen, Göttingen, Germany
b UCSF Weill Institute for Neurosciences, Department of Neurology, University of California – San Francisco, San Francisco, CA, United States
c Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
d Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, Barcelona, Spain
e Department of Neurology, Mellen MS Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, United States
f Department of Neurology, Section of Neuroimmunology, Washington University School of Medicine, St Louis, MO, United States
g Department of Pediatric Neurology, University Hospitals Paris Saclay, Hôpital Bicêtre, National Reference Center for Rare Inflammatory Brain and Spinal Diseases, Le Kremlin-Bicêtre, France
h Oxford Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom
i Novartis Pharma AG, Basel, Switzerland
j Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States
k Research Center for Clinical Neuroimmunology and Neuroscience Basel, RC2NB) and MS Center, and Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital of Basel, University of Basel, Basel, Switzerland
l Statistics Department, University of Oxford, Oxford, United Kingdom

Abstract
Background: In the phase III ASCLEPIOS I and II trials, participants with relapsing multiple sclerosis receiving ofatumumab had significantly better clinical and magnetic resonance imaging (MRI) outcomes than those receiving teriflunomide. Objectives: To assess the efficacy and safety of ofatumumab versus teriflunomide in recently diagnosed, treatment-naive (RDTN) participants from ASCLEPIOS. Methods: Participants were randomized to receive ofatumumab (20 mg subcutaneously every 4 weeks) or teriflunomide (14 mg orally once daily) for up to 30 months. Endpoints analysed post hoc in the protocol-defined RDTN population included annualized relapse rate (ARR), confirmed disability worsening (CDW), progression independent of relapse activity (PIRA) and adverse events. Results: Data were analysed from 615 RDTN participants (ofatumumab: n = 314; teriflunomide: n = 301). Compared with teriflunomide, ofatumumab reduced ARR by 50% (rate ratio (95% confidence interval (CI)): 0.50 (0.33, 0.74); p < 0.001), and delayed 6-month CDW by 46% (hazard ratio (HR; 95% CI): 0.54 (0.30, 0.98); p = 0.044) and 6-month PIRA by 56% (HR: 0.44 (0.20, 1.00); p = 0.049). Safety findings were manageable and consistent with those of the overall ASCLEPIOS population. Conclusion: The favourable benefit–risk profile of ofatumumab versus teriflunomide supports its consideration as a first-line therapy in RDTN patients. ASCLEPIOS I and II are registered at ClinicalTrials.gov (NCT02792218 and NCT02792231). © The Author(s), 2022.

Author Keywords
neurofilament light chain;  no evidence of disease activity;  progression independent of relapse activity;  recently diagnosed;  Relapsing multiple sclerosis;  treatment-naive

Funding details
Bayer
Novartis
Biogen
European CommissionEC
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen ForschungSNF
MedImmune
Schweizerische Multiple Sklerose Gesellschaft

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

Analysis workflow to assess de novo genetic variants from human whole-exome sequencing” (2021) STAR Protocols

Analysis workflow to assess de novo genetic variants from human whole-exome sequencing
(2021) STAR Protocols, 2 (1), p. 100383.

Diab, N.S.a , King, S.b c , Dong, W.a d , Allington, G.a , Sheth, A.e , Peters, S.T.b , Kahle, K.T.e f g , Jin, S.C.b

a Department of Genetics, Yale School of Medicine, CT, New Haven, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA
c Department of Computer Science & Engineering, Washington University in St. Louis, St. Louis, MO, USA
d Laboratory of Human Genetics and Genomics, Rockefeller University, NY, NY, United States
e Department of Neurosurgery, Yale School of Medicine, CT, New Haven, United States
f Department of Pediatrics, Yale School of Medicine, CT, New Haven, United States
g Department of Cellular & Molecular Physiology, Yale School of Medicine, CT, New Haven, United States

Abstract
Here, we present a protocol to analyze de novo genetic variants derived from the whole-exome sequencing (WES) of proband-parent trios. We provide stepwise instructions for using existing pipelines to call de novo mutations (DNMs) and determine whether the observed number of such mutations is enriched relative to the expected number. This protocol may be extended to any human disease trio-based cohort. Cohort size is a limiting determinant to the discovery of high-confidence pathogenic DNMs. For complete details on the use and execution of this protocol, please refer to Dong et al. (2020). © 2021 The Author(s).

Author Keywords
Bioinformatics;  Genetics;  Genomics;  High-throughput screening;  Sequence analysis;  Sequencing

Document Type: Article
Publication Stage: Final
Source: Scopus

Immune cell analysis of pilocytic astrocytomas reveals sexually dimorphic brain region-specific differences in T-cell content” (2021) Neuro-Oncology Advances

Immune cell analysis of pilocytic astrocytomas reveals sexually dimorphic brain region-specific differences in T-cell content
(2021) Neuro-Oncology Advances, 3 (1), art. no. vdab068, . 

Chen, J.a b , Sinha, N.a c , Cobb, O.d , Liu, C.e , Ersen, A.f , Phillips, J.J.g h , Tihan, T.g , Gutmann, D.H.d , Dahiya, S.a

a Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
c Department of Pathology, Health Sciences Center, University of Manitoba, Winnipeg, MB, Canada
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Department of Neurological Surgery, University of Nebraska Medical Center, Omaha, NE, United States
f Department of Pathology, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey
g Department of Pathology, University of California, San Francisco, San Francisco, CA, United States
h Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, United States

Funding details
National Institute of Neurological Disorders and StrokeNINDS1-R35-NS097211-01

Document Type: Article
Publication Stage: Final
Source: Scopus

Salvage therapies for radiation-relapsed isocitrate dehydrogenase-mutant astrocytoma and 1p/19q codeleted oligodendroglioma” (2021) Neuro-Oncology Advances

Salvage therapies for radiation-relapsed isocitrate dehydrogenase-mutant astrocytoma and 1p/19q codeleted oligodendroglioma
(2021) Neuro-Oncology Advances, 3 (1), art. no. vdab081, . 

Ma, S.a , Rudra, S.b , Campian, J.L.c e , Chheda, M.G.c e , Johanns, T.M.c e , Ansstas, G.c e , Abraham, C.D.a e e , Chicoine, M.R.d e e , Leuthardt, E.C.d e e , Dowling, J.L.d e e , Dunn, G.P.d e e , Kim, A.H.d e e , Huang, J.a

a Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States
c Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, MO, United States
d Department of Neurological Surgery, Washington University School of Medicine, St. Louis, MO, United States
e Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States

Abstract
Background. Optimal management for recurrent IDH-mutant glioma after radiation therapy (RT) is not well-defined. This study assesses practice patterns for managing recurrent IDH-mutant astrocytoma (Astro) and 1p/19q codeleted oligodendroglioma (Oligo) after RT and surveys their clinical outcomes after different salvage approaches. Methods. Ninety-four recurrent Astro or Oligo patients after RT who received salvage systemic therapy (SST) between 2001 and 2019 at a tertiary cancer center were retrospectively analyzed. SST was defined as either alkylating chemotherapy (AC) or nonalkylating therapy (non-AC). Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method from the start of SST. Multivariable analysis (MVA) was conducted using Cox regression analysis. Results. Recurrent Oligo (n = 35) had significantly higher PFS (median: 3.1 vs 0.8 years, respectively, P = .002) and OS (median: 6.3 vs 1.5 years, respectively, P < .001) than Astro (n = 59). Overall, 90% of recurrences were local. Eight-three percent received AC as the first-line SST; 50% received salvage surgery before SST; approximately 50% with local failure >2 years after prior RT received reirradiation. On MVA, non-AC was associated with worse OS for both Oligo and Astro; salvage surgery was associated with improved PFS and OS for Astro; early reirradiation was associated with improved PFS for Astro. Conclusions. Recurrent radiation-relapsed IDH-mutant gliomas represent a heterogeneous group with variable treatment approaches. Surgery, AC, and reirradiation remain the mainstay of salvage options for retreatment. © The Author(s) 2021.

Author Keywords
Chemotherapy;  IDH-mutant glioma;  recurrence;  reirradiation;  salvage therapy;  surgery

Funding details
Intel Corporation

Document Type: Article
Publication Stage: Final
Source: Scopus