Publications

Hope Center Member Publications: April 21, 2024

Treating sex and gender differences as a continuous variable can improve precision cancer treatments” (2024) Biology of Sex Differences

Treating sex and gender differences as a continuous variable can improve precision cancer treatments
(2024) Biology of Sex Differences, 15 (1), art. no. 35, . 

Yang, W.a , Rubin, J.B.b c

a Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, United States
b Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, United States
c Department of Neuroscience, Washington University School of Medicine, St. Louis, MO 63110, United States

Abstract
Background: The significant sex and gender differences that exist in cancer mechanisms, incidence, and survival, have yet to impact clinical practice. One barrier to translation is that cancer phenotypes cannot be segregated into distinct male versus female categories. Instead, within this convenient but contrived dichotomy, male and female cancer phenotypes are highly overlapping and vary between female- and male- skewed extremes. Thus, sex and gender-specific treatments are unrealistic, and our translational goal should be adaptation of treatment to the variable effects of sex and gender on targetable pathways. Methods: To overcome this obstacle, we profiled the similarities in 8370 transcriptomes of 26 different adult and 4 different pediatric cancer types. We calculated the posterior probabilities of predicting patient sex and gender based on the observed sexes of similar samples in this map of transcriptome similarity. Results: Transcriptomic index (TI) values were derived from posterior probabilities and allowed us to identify poles with local enrichments for male or female transcriptomes. TI supported deconvolution of transcriptomes into measures of patient-specific activity in sex and gender-biased, targetable pathways. It identified sex and gender-skewed extremes in mechanistic phenotypes like cell cycle signaling and immunity, and precisely positioned each patient’s whole transcriptome on an axis of continuously varying sex and gender phenotypes. Conclusions: Cancer type, patient sex and gender, and TI value provides a novel and patient- specific mechanistic identifier that can be used for realistic sex and gender-adaptations of precision cancer treatment planning. © The Author(s) 2024.

Author Keywords
Bayesian analyses;  Cancer;  Cell cycle regulation;  Hallmark pathways;  Inflammation/immunity;  Personalized medicine;  Sex and gender differences

Document Type: Article
Publication Stage: Final
Source: Scopus

Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease” (2024) Acta Neuropathologica

Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer’s disease
(2024) Acta Neuropathologica, 147 (1), art. no. 70, . 

Bhattarai, P.a b , Gunasekaran, T.I.a c , Belloy, M.E.d e f , Reyes-Dumeyer, D.a c , Jülich, D.g , Tayran, H.a b , Yilmaz, E.a b , Flaherty, D.b h , Turgutalp, B.a b , Sukumar, G.i , Alba, C.i , McGrath, E.M.i , Hupalo, D.N.i , Bacikova, D.i , Le Guen, Y.d j , Lantigua, R.a b k , Medrano, M.l , Rivera, D.m n , Recio, P.m , Nuriel, T.b h , Ertekin-Taner, N.o p , Teich, A.F.a b h , Dickson, D.W.o , Holley, S.g , Greicius, M.d , Dalgard, C.L.q r , Zody, M.s , Mayeux, R.a b c t u , Kizil, C.a b c , Vardarajan, B.N.a b c

a Department of Neurology, Columbia University Irving Medical Center, Columbia University New York, New York, NY, United States
b Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Irving Medical Center, Columbia University, New York, NY, United States
c Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY, United States
d Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, United States
e NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520, United States
h Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, United States
i Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD 20817, United States
j Quantitative Sciences Unit, Department of Medicine, Stanford University, Stanford, CA, United States
k Department of Medicine, College of Physicians and Surgeons, Columbia University New York, New York, United States
l School of Medicine, Pontificia Universidad Catolica Madre y Maestra, Santiago, Dominican Republic
m Department of Neurology, CEDIMAT, Plaza de la Salud, Santo Domingo, Dominican Republic
n School of Medicine, Universidad Pedro Henriquez Urena (UNPHU), Santo Domingo, Dominican Republic
o Department of Neuroscience, Mayo Clinic Florida, Jacksonville, FL 32224, United States
p Department of Neurology, Mayo Clinic Florida, Jacksonville, FL 32224, United States
q Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, United States
r The American Genome Center, Center for Military Precision Health, Uniformed Services University of the Health Sciences, Bethesda, MD, United States
s New York Genome Center, New York, NY 10013, United States
t Department of Psychiatry, College of Physicians and Surgeons, Columbia University, 1051 Riverside Drive, New York, NY 10032, United States
u Department of Epidemiology, Mailman School of Public Health, Columbia University, 722 W 168th St., New York, NY 10032, United States

Abstract
The risk of developing Alzheimer’s disease (AD) significantly increases in individuals carrying the APOEε4 allele. Elderly cognitively healthy individuals with APOEε4 also exist, suggesting the presence of cellular mechanisms that counteract the pathological effects of APOEε4; however, these mechanisms are unknown. We hypothesized that APOEε4 carriers without dementia might carry genetic variations that could protect them from developing APOEε4-mediated AD pathology. To test this, we leveraged whole-genome sequencing (WGS) data in the National Institute on Aging Alzheimer’s Disease Family Based Study (NIA-AD FBS), Washington Heights/Inwood Columbia Aging Project (WHICAP), and Estudio Familiar de Influencia Genetica en Alzheimer (EFIGA) cohorts and identified potentially protective variants segregating exclusively among unaffected APOEε4 carriers. In homozygous unaffected carriers above 70 years old, we identified 510 rare coding variants. Pathway analysis of the genes harboring these variants showed significant enrichment in extracellular matrix (ECM)-related processes, suggesting protective effects of functional modifications in ECM proteins. We prioritized two genes that were highly represented in the ECM-related gene ontology terms, (FN1) and collagen type VI alpha 2 chain (COL6A2) and are known to be expressed at the blood–brain barrier (BBB), for postmortem validation and in vivo functional studies. An independent analysis in a large cohort of 7185 APOEε4 homozygous carriers found that rs140926439 variant in FN1 was protective of AD (OR = 0.29; 95% CI [0.11, 0.78], P = 0.014) and delayed age at onset of disease by 3.37 years (95% CI [0.42, 6.32], P = 0.025). The FN1 and COL6A2 protein levels were increased at the BBB in APOEε4 carriers with AD. Brain expression of cognitively unaffected homozygous APOEε4 carriers had significantly lower FN1 deposition and less reactive gliosis compared to homozygous APOEε4 carriers with AD, suggesting that FN1 might be a downstream driver of APOEε4-mediated AD-related pathology and cognitive decline. To validate our findings, we used zebrafish models with loss-of-function (LOF) mutations in fn1b—the ortholog for human FN1. We found that fibronectin LOF reduced gliosis, enhanced gliovascular remodeling, and potentiated the microglial response, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Our study suggests that vascular deposition of FN1 is related to the pathogenicity of APOEε4, and LOF variants in FN1 may reduce APOEε4-related AD risk, providing novel clues to potential therapeutic interventions targeting the ECM to mitigate AD risk. © The Author(s) 2024.

Document Type: Article
Publication Stage: Final
Source: Scopus

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer’s disease: a cross-sectional study“(2024) The Lancet Neurology

Comparison of tau spread in people with Down syndrome versus autosomal-dominant Alzheimer’s disease: a cross-sectional study
(2024) The Lancet Neurology, 23 (5), pp. 500-510. Cited 1 time.

Wisch, J.K.a , McKay, N.S.b , Boerwinkle, A.H.f , Kennedy, J.a , Flores, S.b , Handen, B.L.g , Christian, B.T.i , Head, E.k , Mapstone, M.l , Rafii, M.S.n , O’Bryant, S.E.o , Price, J.C.p , Laymon, C.M.h , Krinsky-McHale, S.J.r , Lai, F.q , Rosas, H.D.p q , Hartley, S.L.j , Zaman, S.s ah , Lott, I.T.m , Tudorascu, D.g , Zammit, M.i , Brickman, A.M.t , Lee, J.H.t u , Bird, T.D.v , Cohen, A.g , Chrem, P.w , Daniels, A.a , Chhatwal, J.P.q , Cruchaga, C.c e ai , Ibanez, L.c ai , Jucker, M.y ai , Karch, C.M.a c z , Day, G.S.x , Lee, J.-H.aa ai , Levin, J.ab ac ad ai , Llibre-Guerra, J.e , Li, Y.a d ai , Lopera, F.ae ai , Roh, J.H.af ai , Ringman, J.M.n , Supnet-Bell, C.a ai , van Dyck, C.H.ag , Xiong, C.d , Wang, G.a d ai , Morris, J.C.a , McDade, E.a ai , Bateman, R.J.a , Benzinger, T.L.S.b , Gordon, B.A.b , Ances, B.M.a , Aizenstein, H.J.ah , Andrews, H.F.ah , Bell, K.ah , Birn, R.M.ah , Bulova, P.ah , Cheema, A.ah , Chen, K.ah , Clare, I.ah , Clark, L.ah , Cohen, A.D.ah , Constantino, J.N.ah , Doran, E.W.ah , Feingold, E.ah , Foroud, T.M.ah , Hartley, S.L.ah , Hom, C.ah , Honig, L.ah , Ikonomovic, M.D.ah , Johnson, S.C.ah , Jordan, C.ah , Kamboh, M.I.ah , Keator, D.ah , Klunk, W.E.ah , Kofler, J.K.ah , Kreisl, W.C.ah , Krinsky-McHale, S.J.ah , Lao, P.ah , Laymon, C.ah , Lott, I.T.ah , Lupson, V.ah , Mathis, C.A.ah , Minhas, D.S.ah , Nadkarni, N.ah , Pang, D.ah , Petersen, M.ah , Price, J.C.ah , Pulsifer, M.ah , Reiman, E.ah , Rizvi, B.ah , Sabbagh, M.N.ah , Schupf, N.ah , Tudorascu, D.L.ah , Tumuluru, R.ah , Tycko, B.ah , Varadarajan, B.ah , White, D.A.ah , Yassa, M.A.ah , Zhang, F.ah , Bateman, R.ai , Daniels, A.J.ai , Courtney, L.ai , Llibre-Guerra, J.J.ai , Xiong, C.ai , Xu, X.ai , Lu, R.ai , Gremminger, E.ai , Perrin, R.J.ai , Franklin, E.ai , Jerome, G.ai , Herries, E.ai , Stauber, J.ai , Baker, B.ai , Minton, M.ai , Goate, A.M.ai , Renton, A.E.ai , Picarello, D.M.ai , Benzinger, T.ai , Gordon, B.A.ai , Hornbeck, R.ai , Hassenstab, J.ai , Smith, J.ai , Stout, S.ai , Aschenbrenner, A.J.ai , Karch, C.M.ai , Marsh, J.ai , Morris, J.C.ai , Holtzman, D.M.ai , Barthelemy, N.ai , Xu, J.ai , Noble, J.M.ai , Berman, S.B.ai , Ikonomovic, S.ai , Nadkarni, N.K.ai , Day, G.ai , Graff-Radford, N.R.ai , Farlow, M.ai , Chhatwal, J.P.ai , Ikeuchi, T.ai , Kasuga, K.ai , Niimi, Y.ai , Huey, E.D.ai , Salloway, S.ai , Schofield, P.R.ai , Brooks, W.S.ai , Bechara, J.A.ai , Martins, R.ai , Fox, N.C.ai , Cash, D.M.ai , Ryan, N.S.ai , Laske, C.ai , Hofmann, A.ai , Kuder-Buletta, E.ai , Graber-Sultan, S.ai , Obermueller, U.ai , Roedenbeck, Y.ai , Vöglein, J.ai , Sanchez-Valle, R.ai , Rosa-Neto, P.ai , Allegri, R.F.ai , Chrem Mendez, P.ai , Surace, E.ai , Vazquez, S.ai , Leon, Y.M.ai , Ramirez, L.ai , Aguillon, D.ai , Levey, A.I.ai , Johnson, E.C.B.ai , Seyfried, N.T.ai , Ringman, J.ai , Mori, H.ai , Alzheimer’s Biomarker Consortium-Down syndromeaj ak , Dominantly Inherited Alzheimer Networkaj ak

a Department of Neurology, Washington University in St Louis, St Louis, MO, United States
b Department of Radiology, Washington University in St Louis, St Louis, MO, United States
c Department of Psychiatry, Washington University in St Louis, St Louis, MO, United States
d Department of Biostatistics, Washington University in St Louis, St Louis, MO, United States
e Hope Center for Neurological Disorders, Washington University in St Louis, St Louis, MO, United States
f McGovern Medical School, University of Texas in Houston, Houston, TX, United States
g Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
h Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States
i Department of Medical Physics and Psychiatry, University of Wisconsin–Madison, Madison, WI, United States
j Waisman Center, University of Wisconsin–Madison, Madison, WI, United States
k Department of Pathology, Gillespie Neuroscience Research Facility, University of California, Irvine, CA, United States
l Department of Neurology, University of California Irvine School of Medicine, Irvine, CA, United States
m Department of Pediatrics, University of California Irvine School of Medicine, Irvine, CA, United States
n Alzheimer’s Therapeutic Research Institute, Keck School of Medicine of USC, Los Angeles, CA, United States
o Institute for Translational Research Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, United States
p Department of Radiology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, United States
q Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, United States
r Department of Psychology, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, United States
s Cambridge Intellectual and Developmental Disabilities Research Group, University of Cambridge, Cambridge, United Kingdom
t Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
u Department of Epidemiology, Columbia University Irving Medical Center, New York, NY, United States
v Department of Neurology, University of Washington, Seattle, WA, United States
w Centro de Memoria y Envejecimiento, Buenos Aires, Argentina
x Department of Neurology, Mayo Clinic Florida, Jacksonville, FL, United States
y Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
z German Center for Neurodegenerative Diseases, Tübingen, Germany
aa Department of Neurology, University of Ulsan College of Medicine, Asian Medical Center, Seoul, South Korea
ab Department of Neurology, LMU University Hospital, LMU Munich, Munich, Germany
ac German Center for Neurodegenerative Diseases, site Munich, Munich, Germany
ad Munich Cluster for Systems Neurology, Munich, Germany
ae Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
af Departments of Physiology and Neurology, Korea University College of Medicine, Seoul, South Korea
ag School of Medicine, Yale University, New Haven, CT, United States

Abstract
Background: In people with genetic forms of Alzheimer’s disease, such as in Down syndrome and autosomal-dominant Alzheimer’s disease, pathological changes specific to Alzheimer’s disease (ie, accumulation of amyloid and tau) occur in the brain at a young age, when comorbidities related to ageing are not present. Studies including these cohorts could, therefore, improve our understanding of the early pathogenesis of Alzheimer’s disease and be useful when designing preventive interventions targeted at disease pathology or when planning clinical trials. We compared the magnitude, spatial extent, and temporal ordering of tau spread in people with Down syndrome and autosomal-dominant Alzheimer’s disease. Methods: In this cross-sectional observational study, we included participants (aged ≥25 years) from two cohort studies. First, we collected data from the Dominantly Inherited Alzheimer’s Network studies (DIAN-OBS and DIAN-TU), which include carriers of autosomal-dominant Alzheimer’s disease genetic mutations and non-carrier familial controls recruited in Australia, Europe, and the USA between 2008 and 2022. Second, we collected data from the Alzheimer Biomarkers Consortium–Down Syndrome study, which includes people with Down syndrome and sibling controls recruited from the UK and USA between 2015 and 2021. Controls from the two studies were combined into a single group of familial controls. All participants had completed structural MRI and tau PET (18F-flortaucipir) imaging. We applied Gaussian mixture modelling to identify regions of high tau PET burden and regions with the earliest changes in tau binding for each cohort separately. We estimated regional tau PET burden as a function of cortical amyloid burden for both cohorts. Finally, we compared the temporal pattern of tau PET burden relative to that of amyloid. Findings: We included 137 people with Down syndrome (mean age 38·5 years [SD 8·2], 74 [54%] male, and 63 [46%] female), 49 individuals with autosomal-dominant Alzheimer’s disease (mean age 43·9 years [11·2], 22 [45%] male, and 27 [55%] female), and 85 familial controls, pooled from across both studies (mean age 41·5 years [12·1], 28 [33%] male, and 57 [67%] female), who satisfied the PET quality-control procedure for tau-PET imaging processing. 134 (98%) people with Down syndrome, 44 (90%) with autosomal-dominant Alzheimer’s disease, and 77 (91%) controls also completed an amyloid PET scan within 3 years of tau PET imaging. Spatially, tau PET burden was observed most frequently in subcortical and medial temporal regions in people with Down syndrome, and within the medial temporal lobe in people with autosomal-dominant Alzheimer’s disease. Across the brain, people with Down syndrome had greater concentrations of tau for a given level of amyloid compared with people with autosomal-dominant Alzheimer’s disease. Temporally, increases in tau were more strongly associated with increases in amyloid for people with Down syndrome compared with autosomal-dominant Alzheimer’s disease. Interpretation: Although the general progression of amyloid followed by tau is similar for people Down syndrome and people with autosomal-dominant Alzheimer’s disease, we found subtle differences in the spatial distribution, timing, and magnitude of the tau burden between these two cohorts. These differences might have important implications; differences in the temporal pattern of tau accumulation might influence the timing of drug administration in clinical trials, whereas differences in the spatial pattern and magnitude of tau burden might affect disease progression. Funding: None. © 2024 Elsevier Ltd

Document Type: Article
Publication Stage: Final
Source: Scopus

Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial” (2024) The Lancet Neurology

Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial
(2024) The Lancet Neurology, 23 (5), pp. 477-486. Cited 1 time.

Tawil, R.a , Wagner, K.R.b , Hamel, J.I.a , Leung, D.G.b , Statland, J.M.c , Wang, L.H.d , Genge, A.e , Sacconi, S.f , Lochmüller, H.g h , Reyes-Leiva, D.i , Diaz-Manera, J.i j , Alonso-Perez, J.k l , Muelas, N.m n o p , Vilchez, J.J.n , Pestronk, A.q , Gibson, S.r , Goyal, N.A.s , Hayward, L.J.t , Johnson, N.u , LoRusso, S.v , Freimer, M.v , Shieh, P.B.w , Subramony, S.H.x , van Engelen, B.y , Kools, J.y , Leinhard, O.D.z aa ab , Widholm, P.z aa ab ac , Morabito, C.ad , Moxham, C.M.ad , Cadavid, D.ad , Mellion, M.L.ad , Odueyungbo, A.ad , Tracewell, W.G.ad , Accorsi, A.ad , Ronco, L.ad , Gould, R.J.ad , Shoskes, J.ad , Rojas, L.A.ad , Jiang, J.G.ad

a Department of Neurology, University of Rochester Medical Center, Rochester, NY, United States
b Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD, United States
c University of Kansas, Lawrence, KS, United States
d University of Washington, Seattle, WA, United States
e Montreal Neurological Institute and Hospital, Montreal, QC, Canada
f Peripheral Nervous System and Muscle Department, Nice University Hospital, University of Côte d’Azur, Nice, France
g Children’s Hospital of Eastern Ontario Research Institute, Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, Canada
h Brain and Mind Research Institute, University of Ottawa, Ottawa, ON, Canada
i Institut de Recerca IIB Sant Pau, Hospital Universitari Santa Creu i Sant Pau, Barcelona, Spain
j John Walton Muscular Dystrophy Research Center, Newcastle University, Newcastle, United Kingdom
k Neuromuscular Diseases Unit, Neurology Department, Hospital Universitario Nuestra Señora de Candelaria, Fundación Canaria Instituto de Investigación Sanitaria de Canarias, Tenerife, Santa Cruz de Tenerife, Spain
l Neuromuscular Diseases Unit, Neurology Department, Institut d’Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
m Neuromuscular Diseases Unit, Neurology Department, Hospital Universitari i Politecnic La Fe and Neuromuscular Reference Centre, Valencia, Spain
n Neuromuscular and Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
o Centro de Investigación Biomédica en Red de Enfermedades Raras, Barcelona, Spain
p Department of Medicine, University of Valencia, Valencia, Spain
q Washington University in St Louis, St Louis, MO, United States
r University of Utah, Salt Lake City, UT, United States
s University of California at Irvine, Irvine, CA, United States
t University of Massachusetts, Worcester, MA, United States
u Virginia Commonwealth University, Richmond, VA, United States
v Ohio State University Wexner Medical Center, Columbus, OH, United States
w University of California at Los Angeles, Los Angeles, CA, United States
x University of Florida College of Medicine, Gainesville, FL, United States
y Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands
z AMRA Medical, Linköping, Sweden
aa Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
ab Center for Medical Image Science and Visualization, Linköping University, Linköping, Sweden
ac Department of Radiology, Linköping University, Linköping, Sweden
ad Fulcrum Therapeutics, Cambridge, MA, United States

Abstract
Background: Facioscapulohumeral muscular dystrophy is a hereditary progressive myopathy caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. No approved disease-modifying treatments are available for this disorder. We aimed to assess the safety and efficacy of losmapimod (a small molecule that inhibits p38α MAPK, a regulator of DUX4 expression, and p38β MAPK) for the treatment of facioscapulohumeral muscular dystrophy. Methods: We did a randomised, double-blind, placebo-controlled phase 2b trial at 17 neurology centres in Canada, France, Spain, and the USA. We included adults aged 18–65 years with type 1 facioscapulohumeral muscular dystrophy (ie, with loss of repression of DUX4 expression, as ascertained by genotyping), a Ricci clinical severity score of 2–4, and at least one skeletal muscle judged using MRI to be suitable for biopsy. Participants were randomly allocated (1:1) to either oral losmapimod (15 mg twice a day) or matching placebo for 48 weeks, via an interactive response technology system. The investigator, study staff, participants, sponsor, primary outcome assessors, and study monitor were masked to the treatment allocation until study closure. The primary endpoint was change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples, as measured by quantitative RT-PCR. The primary efficacy analysis was done in all participants who were randomly assigned and who had available data for assessment, according to the modified intention-to-treat principle. Safety and tolerability were assessed as secondary endpoints. This study is registered at ClinicalTrials.gov, number NCT04003974. The phase 2b trial is complete; an open-label extension is ongoing. Findings: Between Aug 27, 2019, and Feb 27, 2020, 80 people were enrolled. 40 were randomly allocated to losmapimod and 40 to placebo. 54 (68%) participants were male and 26 (33%) were female, 70 (88%) were White, and mean age was 45·7 (SD 12·5) years. Least squares mean changes from baseline in DUX4-driven gene expression did not differ significantly between the losmapimod (0·83 [SE 0·61]) and placebo (0·40 [0·65]) groups (difference 0·43 [SE 0·56; 95% CI –1·04 to 1·89]; p=0·56). Losmapimod was well tolerated. 29 treatment-emergent adverse events (nine drug-related) were reported in the losmapimod group compared with 23 (two drug-related) in the placebo group. Two participants in the losmapimod group had serious adverse events that were deemed unrelated to losmapimod by the investigators (alcohol poisoning and suicide attempt; postoperative wound infection) compared with none in the placebo group. No treatment discontinuations due to adverse events occurred and no participants died during the study. Interpretation: Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy. Funding: Fulcrum Therapeutics. © 2024 Elsevier Ltd

Document Type: Article
Publication Stage: Final
Source: Scopus

Perioperative mental health intervention for depression and anxiety symptoms in older adults study protocol: design and methods for three linked randomised controlled trials” (2024) BMJ Open

Perioperative mental health intervention for depression and anxiety symptoms in older adults study protocol: design and methods for three linked randomised controlled trials
(2024) BMJ Open, 14 (4), art. no. e082656, . 

Holzer, K.J.a , Bartosiak, K.A.b , Calfee, R.P.b , Hammill, C.W.c , Haroutounian, S.a , Kozower, B.D.c , Cordner, T.A.a , Lenard, E.M.d , Freedland, K.E.d , Tellor Pennington, B.R.a , Wolfe, R.C.e , Miller, J.P.f , Politi, M.C.c , Zhang, Y.d , Yingling, M.D.d , Baumann, A.A.c , Kannampallil, T.a f , Schweiger, J.A.d , McKinnon, S.L.a , Avidan, M.S.a , Lenze, E.J.d , Abraham, J.a f

a Department of Anesthesiology, Washington University School of Medicine in Saint Louis, St Louis, MO, United States
b Department of Orthopaedics, Washington University School of Medicine in Saint Louis, St Louis, MO, United States
c Department of Surgery, Washington University School of Medicine in Saint Louis, St Louis, MO, United States
d Department of Psychiatry, Washington University School of Medicine in Saint Louis, St Louis, MO, United States
e Department of Pharmacy, Barnes-Jewish Hospital, St Louis, MO, United States
f Institute for Informatics, Data Science and Biostatistics, Washington University School of Medicine in Saint Louis, St. Louis, MO, United States

Abstract
Introduction Preoperative anxiety and depression symptoms among older surgical patients are associated with poor postoperative outcomes, yet evidence-based interventions for anxiety and depression have not been applied within this setting. We present a protocol for randomised controlled trials (RCTs) in three surgical cohorts: cardiac, oncological and orthopaedic, investigating whether a perioperative mental health intervention, with psychological and pharmacological components, reduces perioperative symptoms of depression and anxiety in older surgical patients. Methods and analysis Adults ≥60 years undergoing cardiac, orthopaedic or oncological surgery will be enrolled in one of three-linked type 1 hybrid effectiveness/ implementation RCTs that will be conducted in tandem with similar methods. In each trial, 100 participants will be randomised to a remotely delivered perioperative behavioural treatment incorporating principles of behavioural activation, compassion and care coordination, and medication optimisation, or enhanced usual care with mental health-related resources for this population. The primary outcome is change in depression and anxiety symptoms assessed with the Patient Health Questionnaire-Anxiety Depression Scale from baseline to 3 months post surgery. Other outcomes include quality of life, delirium, length of stay, falls, rehospitalisation, pain and implementation outcomes, including study and intervention reach, acceptability, feasibility and appropriateness, and patient experience with the intervention. Ethics and dissemination The trials have received ethics approval from the Washington University School of Medicine Institutional Review Board. Informed consent is required for participation in the trials. The results will be submitted for publication in peer-reviewed journals, presented at clinical research conferences and disseminated via the Center for Perioperative Mental Health website. © Author(s) (or their employer(s)) 2024.

Document Type: Article
Publication Stage: Final
Source: Scopus

Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model” (2024) Science Translational Medicine

Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model
(2024) Science Translational Medicine, 16 (741), art. no. eadj9052, . 

Hou, J.a , Chen, Y.a b , Cai, Z.a , Heo, G.S.c , Yuede, C.M.d , Wang, Z.a , Lin, K.a , Saadi, F.b , Trsan, T.a , Nguyen, A.T.e , Constantopoulos, E.e , Larsen, R.A.e , Zhu, Y.a , Wagner, N.D.f , McLaughlin, N.f , Kuang, X.C.f , Barrow, A.D.g , Li, D.h , Zhou, Y.a , Wang, S.i , Gilfillan, S.a , Gross, M.L.f , Brioschi, S.a , Liu, Y.c , Holtzman, D.M.b , Colonna, M.a

a department of Pathology and immunology, Washington University in St. louis, St. louis, Mo 63110, United States
b department of neurology, Hope center for neurological disorders, Knight Alzheimer’s disease research center, Washington University in St. louis, St. louis, Mo 63110, United States
c department of radiology, Washington University in St. louis, St. louis, Mo 63110, United States
d department of Psychiatry, Washington University School of Medicine, St. louis, Mo 63110, United States
e department of laboratory Medicine and Pathology, Mayo clinic, rochester, Mn 55905, United States
f department of chemistry, Washington University in St. louis, St. louis, Mo 63110, United States
g depart-ment of Microbiology and immunology, University of Melbourne, Peter doherty institute for infection and immunity, Parkville, Vic 3000, Australia
h division of nephrology, department of Medicine, Washington University, St. louis, Mo 63110, United States
i School of Biomedical Sciences, li Ka Shing Faculty of Medicine, University of Hong Kong, Pok Fu lam, Hong Kong

Abstract
Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia wrapping around Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ load, mitigated some Aβ-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD. copyright © 2024 The Authors, some rights reserved.

Document Type: Article
Publication Stage: Final
Source: Scopus

Association of county-level socioeconomic status with meningioma incidence and outcomes” (2024) Neuro-Oncology

Association of county-level socioeconomic status with meningioma incidence and outcomes
(2024) Neuro-Oncology, 26 (4), pp. 749-763. 

Pugazenthi, S.h , Price, M.a i , De La Vega Gomar, R.b , Kruchko, C.i , Waite, K.A.c i i , Barnholtz-Sloan, J.S.c i d i , Walsh, K.M.a f g , Kim, A.H.e h , Ostrom, Q.T.a i f g i

a Department of Neurosurgery, Duke University School of Medicine, Durham, NC, United States
b Duke Kunshan University, Suzhou, China
c Trans-Divisional Research Program (TDRP), Division of Cancer Epidemiology and Genetics (DCEG), National Cancer Institute, Bethesda, MD, United States
d Center for Biomedical Informatics & Information Technology (CBIIT), National Cancer Institute, Bethesda, MD, United States
e The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, United States
f The Preston Robert Tisch Brain Tumor Center, Duke University School of Medicine, Durham, NC, United States
g Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States
h Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
i Central Brain Tumor Registry of the United States, Hinsdale, IL, United States

Abstract
Background. Prior literature suggests that individual socioeconomic status (SES) may influence incidence, treatments, and survival of brain tumor cases. We aim to conduct the first national study to evaluate the association between US county-level SES and incidence, treatment, and survival in meningioma.

Methods. The Central BrainTumor Registry of the United States analytic dataset, which combines data from CDC’s National Program of Cancer Registries (NPCR) and National Cancer Institute’s Surveillance, Epidemiology, and End Results Program, was used to identify meningioma cases from 2006 to 2019. SES quintiles were created using American Community Survey data. Logistic regression models were used to evaluate associations between SES and meningioma. Cox proportional hazard models were constructed to assess the effect of SES on survival using the NPCR analytic dataset.

Results. A total of 409 681 meningioma cases were identified. Meningioma incidence increased with higher county-level SES with Q5 (highest quintile) having a 12% higher incidence than Q1 (incidence rate ratios (IRR) = 1.12, 95%CI: 1.10–1.14; P < .0001). The Hispanic group was the only racial–ethnic group that had lower SES associated with increased meningioma incidence (Q5: age-adjusted incidence ratio (AAIR) = 9.02, 95%CI: 8.87–9.17 vs. Q1: AAIR = 9.33, 95%CI: 9.08–9.59; IRR = 0.97, 95%CI: 0.94–1.00; P = .0409). Increased likelihood of surgical treatment was associated with Asian or Pacific Islander non-Hispanic individuals (compared to White non-Hispanic (WNH)) (OR = 1.28, 95%CI: 1.23–1.33, P < .001) and males (OR = 1.31, 95%CI: 1.29–1.33, P < .001). Black non-Hispanic individuals (OR = 0.90, 95%CI: 0.88–0.92, P < .001) and those residing in metropolitan areas (OR = 0.96, 95%CI: 0.96–0.96, P < .001) were less likely to receive surgical treatment compared to WNH individuals. Overall median survival was 137 months, and survival was higher in higher SES counties (Q5 median survival = 142 months).

Conclusions. Higher county-level SES was associated with increased meningioma incidence, surgical treatment, and overall survival. Racial–ethnic stratification identified potential disparities within the meningioma population. Further work is needed to understand the underpinnings of socioeconomic and racial disparities for meningioma patients. © 2024 Oxford University Press. All rights reserved.

Author Keywords
Central Brain Tumor Registry of the United States;  disparities;  epidemiology;  meningioma;  socioeconomic status

Document Type: Article
Publication Stage: Final
Source: Scopus

A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus” (2024) Brain

A novel SMARCC1 BAFopathy implicates neural progenitor epigenetic dysregulation in human hydrocephalus
(2024) Brain, 147 (4), pp. 1553-1570. 

Singh, A.K.a b , Allington, G.a b c , Viviano, S.d , McGee, S.e , Kiziltug, E.a b , Ma, S.c f , Zhao, S.b g , Mekbib, K.Y.a b , Shohfi, J.P.a b , Duy, P.Q.a b f , DeSpenza, T., Jr.a b f , Furey, C.G.a , Reeves, B.C.a b , Smith, H.a b , Sousa, A.M.M.h , Cherskov, A.f , Allocco, A.a , Nelson-Williams, C.c , Haider, S.i j , Rizvi, S.R.A.i , Alper, S.L.k l m , Sestan, N.c d , Shimelis, H.n , Walsh, L.K.n , Lifton, R.P.o , Moreno-De-Luca, A.n p , Jin, S.C.g , Kruszka, P.e , Deniz, E.d , Kahle, K.T.b k q

a Department of Neurosurgery, Yale University, New Haven, CT 06510, United States
b Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, United States
c Department of Genetics, Yale University, New Haven, CT 06510, United States
d Department of Pediatrics, Yale University, New Haven, CT 06510, United States
e GeneDx, Gaithersburg, MD 20877, United States
f Department of Neuroscience, Yale University, New Haven, CT 06510, United States
g Departments of Genetics and Pediatrics, Washington University School of Medicine, St Louis, MO 63110, United States
h Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, United States
i Department of Pharmaceutical and Biological Chemistry, University College London School of Pharmacy, London, WC1N 1AX, United Kingdom
j UCL Centre for Advanced Research Computing, University College London, London, WC1H 9RN, United Kingdom
k Division of Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
l Division of Nephrology, Vascular Biology Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, United States
m Department of Medicine, Harvard Medical School, Boston, MA 02115, United States
n Department of Radiology, Neuroradiology section, Kingston Health Sciences Centre, Queen’s University Faculty of Health Sciences, Kingston, ON, Canada
o Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065, United States
p Department of Radiology, Diagnostic Medicine Institute, Geisinger, Danville, PA 17822, United States
q Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA 02115, United States

Abstract
Hydrocephalus, characterized by cerebral ventriculomegaly, is the most common disorder requiring brain surgery in children. Recent studies have implicated SMARCC1, a component of the BRG1-associated factor (BAF) chromatin remodelling complex, as a candidate congenital hydrocephalus gene. However, SMARCC1 variants have not been systematically examined in a large patient cohort or conclusively linked with a human syndrome. Moreover, congenital hydrocephalus-associated SMARCC1 variants have not been functionally validated or mechanistically studied in vivo. Here, we aimed to assess the prevalence of SMARCC1 variants in an expanded patient cohort, describe associated clinical and radiographic phenotypes, and assess the impact of Smarcc1 depletion in a novel Xenopus tropicalis model of congenital hydrocephalus. To do this, we performed a genetic association study using whole-exome sequencing from a cohort consisting of 2697 total ventriculomegalic trios, including patients with neurosurgically-treated congenital hydrocephalus, that total 8091 exomes collected over 7 years (2016–23). A comparison control cohort consisted of 1798 exomes from unaffected siblings of patients with autism spectrum disorder and their unaffected parents were sourced from the Simons Simplex Collection. Enrichment and impact on protein structure were assessed in identified variants. Effects on the human fetal brain transcriptome were examined with RNA-sequencing and Smarcc1 knockdowns were generated in Xenopus and studied using optical coherence tomography imaging, in situ hybridization and immunofluorescence. SMARCC1 surpassed genome-wide significance thresholds, yielding six rare, protein-altering de novo variants localized to highly conserved residues in key functional domains. Patients exhibited hydrocephalus with aqueductal stenosis; corpus callosum abnormalities, developmental delay, and cardiac defects were also common. Xenopus knockdowns recapitulated both aqueductal stenosis and cardiac defects and were rescued by wild-type but not patient-specific variant SMARCC1. Hydrocephalic SMARCC1-variant human fetal brain and Smarcc1-variant Xenopus brain exhibited a similarly altered expression of key genes linked to midgestational neurogenesis, including the transcription factors NEUROD2 and MAB21L2. These results suggest de novo variants in SMARCC1 cause a novel human BAFopathy we term ‘SMARCC1-associated developmental dysgenesis syndrome’, characterized by variable presence of cerebral ventriculomegaly, aqueductal stenosis, developmental delay and a variety of structural brain or cardiac defects. These data underscore the importance of SMARCC1 and the BAF chromatin remodelling complex for human brain morphogenesis and provide evidence for a ‘neural stem cell’ paradigm of congenital hydrocephalus pathogenesis. These results highlight utility of trio-based whole-exome sequencing for identifying pathogenic variants in sporadic congenital structural brain disorders and suggest whole-exome sequencing may be a valuable adjunct in clinical management of congenital hydrocephalus patients. © The Author(s) 2023.

Author Keywords
chromatin;  congenital;  genetics;  genomics;  neurodevelopment;  neurosurgery

Document Type: Article
Publication Stage: Final
Source: Scopus

Impact of Upper Limb Motor Recovery on Functional Independence After Traumatic Low Cervical Spinal Cord Injury” (2024) Journal of Neurotrauma

Impact of Upper Limb Motor Recovery on Functional Independence After Traumatic Low Cervical Spinal Cord Injury
(2024) Journal of Neurotrauma, . 

Javeed, S.a , Zhang, J.K.b , Greenberg, J.K.a , Botterbush, K.a , Benedict, B.a , Plog, B.a , Gupta, V.P.a , Dibble, C.F.a , Khalifeh, J.M.c , Wen, H.d , Chen, Y.d , Park, Y.e , Belzberg, A.c , Tuffaha, S.f , Burks, S.S.g , Levi, A.D.g , Zager, E.L.h , Faraji, A.H.i , Mahan, M.A.b , Midha, R.j , Wilson, T.J.k , Juknis, N.l , Ray, W.Z.a , the Nerve Transfers in Spinal Cord Injury (NT-SCI) Consortiumm

a Department of Neurological Surgery, Washington University, St. Louis, MO, United States
b Department of Neurological Surgery, University of Utah, Salt Lake City, UT, United States
c Department of Neurological Surgery, Johns Hopkins University, Baltimore, MD, United States
d Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham, Birmingham, AL, United States
e Division of Public Health Sciences, Department of Surgery, Washington University, St. Louis, MO, United States
f Department of Plastic and Reconstructive Surgery, Johns Hopkins University, Baltimore, MD, United States
g Department of Neurological Surgery, University of Miami School of Medicine, Miami, FL, United States
h Department of Neurosurgery, Hospital of the University of Pennsylvania, Philadelphia, PA, United States
i Department of Neurological Surgery, Houston Methodist Hospital, Houston, TX, United States
j Department of Clinical Neurosciences, University of Calgary, Foothills Medical Centre, Calgary, AB, Canada
k Department of Neurosurgery, Stanford University, Palo Alto, CA, United States
l Physical Medicine and Rehabilitation, Washington University, St. Louis, MO, United States

Abstract
Cervical spinal cord injury (SCI) causes devastating loss of upper limb function and independence. Restoration of upper limb function can have a profound impact on independence and quality of life. In low-cervical SCI (level C5-C8), upper limb function can be restored via reinnervation strategies such as nerve transfer surgery. The translation of recovered upper limb motor function into functional independence in activities of daily living (ADLs), however, remains unknown in low cervical SCI (i.e., tetraplegia). The objective of this study was to evaluate the association of patterns in upper limb motor recovery with functional independence in ADLs. This will then inform prioritization of reinnervation strategies focused to maximize function in patients with tetraplegia. This retrospective study performed a secondary analysis of patients with low cervical (C5-C8) enrolled in the SCI Model Systems (SCIMS) database. Baseline neurological examinations and their association with functional independence in major ADLs—i.e., eating, bladder management, and transfers (bed/wheelchair/chair)—were evaluated. Motor functional recovery was defined as achieving motor strength, in modified research council (MRC) grade, of ≥ 3 /5 at one year from ≤ 2/5 at baseline. The association of motor function recovery with functional independence at one-year follow-up was compared in patients with recovered elbow flexion (C5), wrist extension (C6), elbow extension (C7), and finger flexion (C8). A multi-variable logistic regression analysis, adjusting for known factors influencing recovery after SCI, was performed to evaluate the impact of motor function at one year on a composite outcome of functional independence in major ADLs. Composite outcome was defined as functional independence measure score of 6 or higher (complete independence) in at least two domains among eating, bladder management, and transfers. Between 1992 and 2016, 1090 patients with low cervical SCI and complete neurological/functional measures were included. At baseline, 67% of patients had complete SCI and 33% had incomplete SCI. The majority of patients were dependent in eating, bladder management, and transfers. At one-year follow-up, the largest proportion of patients who recovered motor function in finger flexion (C8) and elbow extension (C7) gained independence in eating, bladder management, and transfers. In multi-variable analysis, patients who had recovered finger flexion (C8) or elbow extension (C7) had higher odds of gaining independence in a composite of major ADLs (odds ratio [OR] = 3.13 and OR = 2.87, respectively, p < 0.001). Age 60 years (OR = 0.44, p = 0.01), and complete SCI (OR = 0.43, p = 0.002) were associated with reduced odds of gaining independence in ADLs. After cervical SCI, finger flexion (C8) and elbow extension (C7) recovery translate into greater independence in eating, bladder management, and transfers. These results can be used to design individualized reinnervation plans to reanimate upper limb function and maximize independence in patients with low cervical SCI. Copyright 2024, Mary Ann Liebert, Inc., publishers.

Author Keywords
cervical spinal cord injury;  functional independence;  low tetraplegia;  nerve transfer;  spinal cord injury;  upper limb function

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