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
Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges
(2024) Nature Communications, 15 (1), art. no. 3156, .
Blanpain, L.T.a b c , Cole, E.R.a c , Chen, E.a , Park, J.K.a , Walelign, M.Y.d , Gross, R.E.a e , Cabaniss, B.T.f , Willie, J.T.g , Singer, A.C.b c
a Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States
b Neuroscience Graduate Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA, United States
c Coulter Department of Biomedical Engineering, Georgia Institute of Technology & amp; Emory University, Atlanta, GA, United States
d Department of Electrical and Computer Engineering, Georgia Institute of Technology, Atlanta, GA, United States
e Departments of Neurosurgery and Neuroscience and Cell Biology, Rutgers Robert Wood Johnson Medical School, New Brunswick and New Jersey Medical School, Newark, NJ, United States
f Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
g Departments of Neurological Surgery, Neurology, Psychiatry, and Biomedical Engineering, Washington University, St. Louis, MO, United States
Abstract
Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Mechanism of antagonist ligand binding to REV-ERBα
(2024) Scientific Reports, 14 (1), art. no. 8401, .
Rahman, M.H.a b , Hegazy, L.a b
a Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences and Pharmacy, St. Louis, MO, United States
b Department of Pharmaceutical and Administrative Sciences, University of Health Sciences and Pharmacy, St. Louis, MO, United States
Abstract
REV-ERBα, a therapeutically promising nuclear hormone receptor, plays a crucial role in regulating various physiological processes such as the circadian clock, inflammation, and metabolism. However, the availability of chemical probes to investigate the pharmacology of this receptor is limited, with SR8278 being the only identified synthetic antagonist. Moreover, no X-ray crystal structures are currently available that demonstrate the binding of REV-ERBα to antagonist ligands. This lack of structural information impedes the development of targeted therapeutics. To address this issue, we employed Gaussian accelerated molecular dynamics (GaMD) simulations to investigate the binding pathway of SR8278 to REV-ERBα. For comparison, we also used GaMD to observe the ligand binding process of STL1267, for which an X-ray structure is available. GaMD simulations successfully captured the binding of both ligands to the receptor’s orthosteric site and predicted the ligand binding pathway and important amino acid residues involved in the antagonist SR8278 binding. This study highlights the effectiveness of GaMD in investigating protein–ligand interactions, particularly in the context of drug recognition for nuclear hormone receptors. © The Author(s) 2024.
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, 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
Olfactory tract/bulb metal concentration in Manganese-exposed mineworkers
(2024) NeuroToxicology, 102, pp. 96-105.
Gonzalez-Cuyar, L.F.a , Nelson, G.b c , Nielsen, S.S.d , Dlamini, W.W.d e , Keyser-Gibson, A.a , Keene, C.D.a , Paulsen, M.f , Criswell, S.R.c d , Senini, N.c , Sheppard, L.f g , Samy, S.f , Simpson, C.D.f , Baker, M.G.f , Racette, B.A.b c d
a University of Washington, School of Medicine and Department of Laboratory Medicine and Pathology, Division of Neuropathology, 325 9th Ave, Seattle, WA 98104, United States
b School of Public Health, Faculty of Health Sciences, University of the Witwatersrand, 27 St Andrews Rd, Parktown, 2193, South Africa
c Department of Neurology, Barrow Neurological Institute, 240 W Thomas Rd, Phoenix, AZ 85013, United States
d Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States
e Department of Epidemiology, School of Public Health, University of Washington, 3980 15th Ave NE, Seattle, WA 98195, United States
f Department of Environmental and Occupational Health Sciences, School of Public Health, University of Washington, 1959 NE Pacific St, Seattle, WA 98195, United States
g Department of Biostatistics, School of Public Health, University of Washington, 3980 15th Ave NE, Seattle, WA 98195, United States
Abstract
Background: Manganese (Mn) is an essential micronutrient as well as a well-established neurotoxicant. Occupational and environmental exposures may bypass homeostatic regulation and lead to increased systemic Mn levels. Translocation of ultrafine ambient airborne particles via nasal neuronal pathway to olfactory bulb and tract may be an important pathway by which Mn enters the central nervous system. Objective: To measure olfactory tract/bulb tissue metal concentrations in Mn-exposed and non-exposed mineworkers. Methods: Using inductively coupled plasma-mass spectrometry (ICP-MS), we measured and compared tissue metal concentrations in unilateral olfactory tracts/bulbs of 24 Mn-exposed and 17 non-exposed South African mineworkers. We used linear regression to investigate the association between cumulative Mn exposures and olfactory tract/bulb Mn concentration. Results: The difference in mean olfactory tract/bulb Mn concentrations between Mn-exposed and non-Mn exposed mineworkers was 0.16 µg/g (95% CI −0.11, 0.42); but decreased to 0.09 µg/g (95% CI 0.004, 0.18) after exclusion of one influential observation. Olfactory tract/bulb metal concentration and cumulative Mn exposure suggested there may be a positive association; for each mg Mn/m3-year there was a 0.05 µg/g (95% CI 0.01, 0.08) greater olfactory tract/bulb Mn concentration overall, but −0.003 (95% CI −0.02, 0.02) when excluding the three influential observations. Recency of Mn exposure was not associated with olfactory tract/bulb Mn concentration. Conclusions: Our findings suggest that Mn-exposed mineworkers might have higher olfactory tract/bulb tissue Mn concentrations than non-Mn exposed mineworkers, and that concentrations might depend more on cumulative dose than recency of exposure. © 2024 Elsevier B.V.
Author Keywords
ICP-MS; Manganese; Metals exposure; Mineworkers; MRI; Olfactory; South Africa
Document Type: Article
Publication Stage: Final
Source: Scopus
Exploring phenotypic overlap across schizotypy and autism spectrum conditions in American and Chinese young adults
(2024) Schizophrenia Research, 267, pp. 359-366.
Chirica, M.G.a , Zhu, Y.b , Mu, W.c , Zhou, H.d , Gong, J.e , Chan, R.C.K.f g , Kwapil, T.R.h , Berenbaum, H.h
a Department of Psychological and Brain Sciences, Indiana University Bloomington, Bloomington, IN, United States
b Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, MO, United States
c Department of Psychology, Tsinghua University, Beijing, China
d School of Psychology and Cognitive Science, East China Normal University, Shanghai, China
e Shanghai Changning Mental Health Center, Shanghai, China
f Neuropsychology and Applied Cognitive Neuroscience Laboratory, CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
g Department of Psychology, University of Chinese Academy of Sciences, Beijing, China
h Department of Psychology, University of Illinois at Urbana Champaign, Champaign, IL, United States
Abstract
Competing theories have been proposed to explain the considerable overlap in social-cognitive features and risk factors across schizotypy and autism spectrum conditions (ASCs). Six previous factor analyses have been reported in the literature, yet all have major limitations; evidence for the clear superiority of any of the competing theories is insufficient and warrants further investigation. The primary aim of the present research was to identify dimensions that cut across schizotypy and ASCs while addressing limitations of past research. Data were collected from three independent samples (n = 1006, 544, and 2469) in the U.S. and China using the Autism-Spectrum Quotient, the Schizotypal Personality Questionnaire, and the Wisconsin Schizotypy Scales. Exploratory factor analyses in Sample 1 identified an interpretable three-factor structure, which was replicated in Samples 2 and 3 using confirmatory factor analyses. We found consistent evidence for three dimensions (Aberrant Salience, Asociality, and Concrete Thinking) underlying schizotypy and ASCs. This three-dimension model is consistent with a common vulnerability model of schizotypy and ASCs. Implications of these findings for the schizotypy and ASCs literature are discussed. © 2024 Elsevier B.V.
Author Keywords
Affect; Common vulnerability model; Diametrical continuum model; Factor analysis
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, 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, 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
Tabernanthalog and ibogainalog inhibit the α7 and α9α10 nicotinic acetylcholine receptors via different mechanisms and with higher potency than the GABAA receptor and CaV2.2 channel
(2024) Biochemical Pharmacology, 223, art. no. 116183, .
Tae, H.-S.a , Ortells, M.O.b , Yousuf, A.a , Xu, S.Q.c , Akk, G.c d , Adams, D.J.a , Arias, H.R.e
a Molecular Horizons/Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW 2522, Australia
b Facultad de Medicina, Universidad de Morón, CONICET, Morón, Argentina
c Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
d The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
e Department of Pharmacology and Physiology, Oklahoma State University College of Osteopathic Medicine, Tahlequah, OK, United States
Abstract
In this study, we have investigated the pharmacological activity and structural interaction of two novel psychoplastogens, tabernanthalog (TBG) and ibogainalog (IBG) at heterologously-expressed rat (r) and human (h) nicotinic acetylcholine receptors (nAChRs), the rα1β2γ2L γ-aminobutyric acid type A receptor (GABAAR), and the human voltage-gated N-type calcium channel (CaV2.2 channel). Both compounds inhibited the nAChRs with the following receptor selectivity: α9α10 > α7 > α3β2 ≅ α3β4, indicating that β2/β4 subunits are relatively less important for their activity. The potencies of TBG and IBG were comparable at hα7 and hα9α10 subtypes, and comparable to their rat counterparts. TBG- and IBG-induced inhibition of rα7 was ACh concentration-independent and voltage-dependent, whereas rα9α10 inhibition was ACh concentration-dependent and voltage-independent, suggesting that they interact with the α7 ion channel pore and α9α10 orthosteric ligand binding site, respectively. These results were supported by molecular docking studies showing that at the α7 model TBG forms stable interactions with luminal rings at 9′, 13′, and 16′, whereas IBG mostly interacts with the extracellular-transmembrane junction. In the α9α10 model, however, these compounds interacted with several residues from the principal (+) and complementary (–) sides in the transmitter binding site. Ibogaminalog (DM506) also interacted with a non-luminal site at α7, and one α9α10 orthosteric site. TBG and IBG inhibited the GABAAR and CaV2.2 channels with 10 to 30-fold lower potencies. In sum, we show that TBG and IBG inhibit the α7 and α9α10 nAChRs by noncompetitive and competitive mechanisms, respectively, and with higher potency than the GABAAR and CaV2.2 channel. © 2024 The Author(s)
Author Keywords
CaV2.2 channel; GABAA receptor; Ibogainalog; Nicotinic acetylcholine receptor; Psychoplastogens; Tabernanthalog
Document Type: Article
Publication Stage: Final
Source: Scopus
The MATRICS consensus cognitive battery for the assessment of cognitive impairment in schizotypal personality disorder
(2024) Schizophrenia Research, 267, pp. 308-312.
Challman, K.N.a b , Rosell, D.R.b , Barch, D.c , Koenigsberg, H.W.a b , Harvey, P.D.d , Hazlett, E.A.a b , Perez-Rodriguez, M.M.b , New, A.S.b , McClure, M.M.a b e
a Mental Illness Research, Education, Clinical Center (MIRECC VISN 2), James J. Peters VA Medical Center, 130 W. Kingsbridge Road, Bronx, NY 10468, United States
b Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY 10029, United States
c Washington University in St. Louis, One Brookings Drive St. LouisMO 63130, United States
d University of Miami Health System, 1120 NW 14th St, Miami, FL 33136, United States
e Department of Psychological and Brain Sciences, Fairfield University, 1073 North Benson Road FairfieldCT 06824, United States
Abstract
Cognitive deficits are a core impairment across the range of schizophrenia (SZ) spectrum disorders, including schizotypal personality disorder (SPD). The MATRICS Consensus Cognitive Battery (MCCB) was developed to be a robust, specific, and valid cognitive assessment battery to assess cognition in clinical trials for treating cognitive impairments in SZ. Despite the similarity of cognitive impairments shown in SPD and SZ and the clear relevance of uniform assessment across a diagnostic spectrum, the MCCB has yet to be validated in SPD. As such, this is the first study to evaluate the sensitivity of the MCCB for the assessment of cognitive function in individuals with SPD. Participants were 30 individuals with SPD and 54 healthy controls (HC) assessed with the MCCB and supplemental neurocognitive assessments (Trails B, DOT test, Paced Auditory Serial Addition Test (PASAT), AX Continuous Performance Task (AX-CPT), and N-back). Individuals with SPD performed worse than HC participants on all MCCB subtests, as well as on converging supplemental tasks including Trails B, DOT test, PASAT, AX-CPT, and N-back. These results indicate that the MCCB was sensitive to cognitive impairment in SPD compared to controls. SPD participants demonstrate impairments similar to data of SZ participants within the literature, although to a slightly lesser degree of severity. Taken together, these results highlight the generalizability of using the MCCB across SZ spectrum diagnostic groups to assess cognition. Such findings allow for further comparison across disorders, greater understanding of the cognitive characteristics in the spectrum, and use of uniform assessment within cognitive intervention research. © 2024
Author Keywords
Cognition; Functioning; MATRICS; Schizophrenia-spectrum; Schizotypal personality disorder
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, 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, 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
Social relationships, amyloid burden, and dementia: The ARIC-PET study
(2024) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 16 (2), art. no. e12560, .
Groechel, R.C.a , Liu, A.C.b , Liu, C.c , Knopman, D.S.d , Koton, S.e f , Kucharska-Newton, A.M.b , Lutsey, P.L.g , Mosley, T.H., Jr.h , Palta, P.i , Sharrett, A.R.f , Walker, K.A.j , Wong, D.F.k , Gottesman, R.F.a
a National Institute of Neurological Disorders & Stroke Intramural Research Program, National Institutes of Health, Bethesda, MD, United States
b Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, Chapel Hill, NC, United States
c Department of Epidemiology, George Washington University-Milken Institute School of Public Health, Washington, DC, United States
d Department of Neurology, Mayo Clinic, Rochester, MN, United States
e Department of Nursing, The Stanley Steyer School of Health Professions, Tel Aviv University, Tel Aviv, Israel
f Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, United States
g Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, MN, United States
h Department of Medicine, University of Mississippi Medical Center, Jackson, MS, United States
i Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
j National Institute on Aging Intramural Research Program, National Institutes of Health, Bethesda, MD, United States
k Mallinckrodt Institute of Radiology, Washington University, St. Louis, MO, United States
Abstract
INTRODUCTION: This study aimed to assess whether social relationships in mid-life reduce the risk of dementia related to amyloid burden. METHODS: Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990–1992). A composite measure, “social relationships,” was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012–2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid-life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models. RESULTS: Among 310 participants without dementia, strong mid-life social relationships were associated independently with lower dementia risk. Elevated late-life brain amyloid was associated with greater dementia risk. DISCUSSION: Although mid-life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia. © 2024 The Authors. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer’s Association. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Author Keywords
amyloid beta; Atherosclerosis Risk in Communities study; dementia; mid-life; positron emission tomography; social relationships
Document Type: Article
Publication Stage: Final
Source: Scopus
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, 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
Clinical characteristics and treatment exposure of patients with marked treatment-resistant unipolar major depressive disorder: A RECOVER trial report
(2024) Brain Stimulation, 17 (2), pp. 448-459.
Conway, C.R.a , Aaronson, S.T.b , Sackeim, H.A.c , Duffy, W.d , Stedman, M.e , Quevedo, J.f , Allen, R.M.g , Riva-Posse, P.h , Berger, M.A.i , Alva, G.j , Malik, M.A.k , Dunner, D.L.l , Cichowicz, I.m , Luing, H.n , Zajecka, J.o v , Nahas, Z.p , Mickey, B.J.q , Kablinger, A.S.r , Kriedt, C.L.a , Bunker, M.T.s , Lee, Y.-C.L.s , Shy, O.s , Majewski, S.s , Olin, B.s , Tran, Q.s , Rush, A.J.t u
a Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
b Department of Clinical Research, Sheppard Pratt Health System, Baltimore, MD, United States
c Departments of Psychiatry and Radiology, Columbia University, New York, NY, United States
d Alivation Research, Lincoln, NE, United States
e Stedman Clinical Trials, Tampa, FL, United States
f Center for Interventional Psychiatry, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston (UTHealth Houston), Houston, TX, United States
g Seattle Neuropsychiatric Treatment Center, Seattle, WA, United States
h Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, United States
i Scranton Medical Institutes, Moosic, PA, United States
j ATP Clinical Research, Senior Brain Health, Hoag Hospital, Newport Beach, CA and Department of Psychiatry and Neuroscience, University of California, Riverside, CA, United States
k PsychCare Consultants Research, St. Louis, MO, United States
l Center for Anxiety and Depression, Mercer Island, WA, United States
m Mindful Behavioral Health, Boca Raton, FL, United States
n Florida Center for TMS, St. Augustine, FL, United States
o Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, United States
p Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, MN, United States
q Department of Psychiatry, Huntsman Mental Health Institute, University of Utah, Salt Lake City, UT, United States
r Department of Psychiatry and Behavioral Medicine, Virginia Tech Carilion School of Medicine, Roanoke, VA, United States
s LivaNova PLC (or a Subsidiary), Great Britain, London, United Kingdom
t Duke-NUS Medical School, Singapore
u Department of Psychiatry and Behavioral Sciences, Duke University, Durham, NC, United States
v Psychiatric Medicine Associates, LLC, Skokie, IL, United States
Abstract
Background: RECOVER is a randomized sham-controlled trial of vagus nerve stimulation and the largest such trial conducted with a psychiatric neuromodulation intervention. Objective: To describe pre-implantation baseline clinical characteristics and treatment history of patients with unipolar, major depressive disorder (MDD), overall and as a function of exposure to interventional psychiatric treatments (INTs), including electroconvulsive therapy, transcranial magnetic stimulation, and esketamine. Methods: Medical, psychiatric, and treatment records were reviewed by study investigators and an independent Study Eligibility Committee prior to study qualification. Clinical characteristics and treatment history (using Antidepressant Treatment History [Short] Form) were compared in those qualified (N = 493) versus not qualified (N = 228) for RECOVER, and among the qualified group as a function of exposure to INTs during the current major depressive episode (MDE). Results: Unipolar MDD patients who qualified for RECOVER had marked TRD (median of 11.0 lifetime failed antidepressant treatments), severe disability (median WHODAS score of 50.0), and high rate of baseline suicidality (77% suicidal ideation, 40% previous suicide attempts). Overall, 71% had received at least one INT. Compared to the no INT group, INT recipients were younger and more severely depressed (QIDS-C, QIDS-SR), had greater suicidal ideation, earlier diagnosis of MDD, and failed more antidepressant medication trials. Conclusions: RECOVER-qualified unipolar patients had marked TRD and marked treatment resistance with most failing one or more prior INTs. Treatment with ≥1 INTs in the current MDE was associated with earlier age of MDD onset, more severe clinical presentation, and greater treatment resistance relative to patients without a history of INT. Trial registration: ClinicalTrials.gov Identifier NCT03887715. © 2024 The Authors
Author Keywords
Electroconvulsive therapy; Esketamine; RECOVER trial; Transcranial magnetic stimulation (TMS); Treatment-resistant depression (TRD); Vagus nerve stimulation (VNS)
Document Type: Article
Publication Stage: Final
Source: Scopus
Does vibrotactile stimulation of the auricular vagus nerve enhance working memory? A behavioral and physiological investigation
(2024) Brain Stimulation, 17 (2), pp. 460-468.
Tan, G.a b e , Adams, J.c , Donovan, K.a b e , Demarest, P.a b e , Willie, J.T.a b d e , Brunner, P.a b e , Gorlewicz, J.L.c , Leuthardt, E.C.a b d e
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
b Department of Biomedical Engineering, Washington University in St. LouisMO, United States
c Department of Aerospace and Mechanical Engineering, Saint Louis UniversityMO, United States
d Department of Neuroscience, Washington University in St. LouisMO, United States
e Division of Neurotechnology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Working memory is essential to a wide range of cognitive functions and activities. Transcutaneous auricular vagus nerve stimulation (taVNS) is a promising method to improve working memory performance. However, the feasibility and scalability of electrical stimulation are constrained by several limitations, such as auricular discomfort and inconsistent electrical contact. Objective: We aimed to develop a novel and practical method, vibrotactile taVNS, to improve working memory. Further, we investigated its effects on arousal, measured by skin conductance and pupil diameter. Method: This study included 20 healthy participants. Behavioral response, skin conductance, and eye tracking data were concurrently recorded while the participants performed N-back tasks under three conditions: vibrotactile taVNS delivered to the cymba concha, earlobe (sham control), and no stimulation (baseline control). Results: In 4-back tasks, which demand maximal working memory capacity, active vibrotactile taVNS significantly improved the performance metric d′ compared to the baseline but not to the sham. Moreover, we found that the reduction rate of d′ with increasing task difficulty was significantly smaller during vibrotactile taVNS sessions than in both baseline and sham conditions. Arousal, measured as skin conductance and pupil diameter, declined over the course of the tasks. Vibrotactile taVNS rescued this arousal decline, leading to arousal levels corresponding to optimal working memory levels. Moreover, pupil diameter and skin conductance level were higher during high-cognitive-load tasks when vibrotactile taVNS was delivered to the concha compared to baseline and sham. Conclusion: Our findings suggest that vibrotactile taVNS modulates the arousal pathway and could be a potential intervention for enhancing working memory. © 2024 The Authors
Document Type: Article
Publication Stage: Final
Source: Scopus
Motivational context and neurocomputation of stop expectation moderate early attention responses supporting proactive inhibitory control
(2024) Frontiers in Human Neuroscience, 18, art. no. 1357868, .
Gupta, R.S.a , Simmons, A.N.b c , Dugas, N.N.c , Stout, D.M.b c c , Harlé, K.M.b c c
a Department of Psychological & Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
b Center of Excellence for Stress and Mental Health, VA San Diego Healthcare System, San Diego, CA, United States
c Department of Psychiatry, University of California, San Diego, La JollaCA, United States
Abstract
Alterations in attention to cues signaling the need for inhibitory control play a significant role in a wide range of psychopathology. However, the degree to which motivational and attentional factors shape the neurocomputations of proactive inhibitory control remains poorly understood. The present study investigated how variation in monetary incentive valence and stake modulate the neurocomputational signatures of proactive inhibitory control. Adults (N = 46) completed a Stop-Signal Task (SST) with concurrent EEG recording under four conditions associated with stop performance feedback: low and high punishment (following unsuccessful stops) and low and high reward (following successful stops). A Bayesian learning model was used to infer individual’s probabilistic expectations of the need to stop on each trial: P(stop). Linear mixed effects models were used to examine whether interactions between motivational valence, stake, and P(stop) parameters predicted P1 and N1 attention-related event-related potentials (ERPs) time-locked to the go-onset stimulus. We found that P1 amplitudes increased at higher levels of P(stop) in punished but not rewarded conditions, although P1 amplitude differences between punished and rewarded blocks were maximal on trials when the need to inhibit was least expected. N1 amplitudes were positively related to P(stop) in the high punishment condition (low N1 amplitude), but negatively related to P(stop) in the high reward condition (high N1 amplitude). Critically, high P(stop)-related N1 amplitude to the go-stimulus predicted behavioral stop success during the high reward block, providing evidence for the role of motivationally relevant context and inhibitory control expectations in modulating the proactive allocation of attentional resources that affect inhibitory control. These findings provide novel insights into the neurocomputational mechanisms underlying proactive inhibitory control under valence-dependent motivational contexts, setting the stage for developing motivation-based interventions that boost inhibitory control. Copyright © 2024 Gupta, Simmons, Dugas, Stout and Harlé.
Author Keywords
attention; event-related potentials; inhibitory control; motivation; proactive control; punishment; reward; stop signal task
Document Type: Article
Publication Stage: Final
Source: Scopus
Priorities for HIV and chronic pain research: results from a survey of individuals with lived experience
(2024) AIDS Care – Psychological and Socio-Medical Aspects of AIDS/HIV, .
Robinson-Papp, J.a , Lawrence, S.b , Wadley, A.c , Scott, W.d e , George, M.C.a , Josh, J.f , O’Brien, K.K.g h i , Price, C.j , Uebelacker, L.k , Edelman, E.J.l , Evangeli, M.m , Goodin, B.R.n , Harding, R.o , Nkhoma, K.o , Parker, R.p , Sabin, C.q , Slawek, D.r , Tsui, J.I.s , Merlin, J.S.t
a Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
b Vilcek Institute of Graduate Biomedical Sciences, NYU Grossman School of Medicine, New York, NY, United States
c Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
d Health Psychology Section, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
e INPUT Pain Unit, Guy’s & St Thomas’ NHS Foundation Trust, United Kingdom
f British HIV Association (BHIVA), London, United Kingdom
g Department of Physical Therapy, Temerty Faculty of Medicine, University of Toronto, Canada
h Rehabilitation Sciences Institute (RSI), University of Toronto, Canada
i Institute of Health Policy, Management and Evaluation (IHPME), Dalla Lana School of Public Health University of Toronto, Toronto, Canada
j Canadian HIV/AIDS and Chronic Pain Society, Ottawa, Canada
k Brown University School of Medicine, Providence, RI, United States
l Yale Schools of Medicine and Public Health, New Haven, CT, United States
m Department of Psychology, Royal Holloway University of London, Egham, United Kingdom
n Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
o Florence Nightingale Faculty of Nursing, Midwifery and Palliative Care, Cicely Saunders Institute, King’s College London, London, United Kingdom
p Department of Anaesthesia and Perioperative Medicine, Faculty of Health Sciences, University of Cape Town, South Africa
q Institute for Global Health, University College London, London, United Kingdom
r Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, United States
s University of Washington School of Medicine, Seattle, WA, United States
t CHAllenges in Managing and Preventing Pain (CHAMPP) Clinical Research Center, Division of General Internal Medicine, Department of Medicine, University of Pittsburgh, United States
Abstract
The Global Task Force on Chronic Pain in HIV published seven research priorities in the field of HIV-associated chronic pain in 2019: (1) causes; (2) management; (3) treatment individualization and integration with addiction treatment; (4) mental and social health factors; (5) prevalence; (6) treatment cost effectiveness; and (7) prevention. The current study used a web-based survey to determine whether the research topics were aligned with the priorities of adults with lived experiences of HIV and chronic pain. We also collected information about respondents’ own pain and treatment experiences. We received 311 survey responses from mostly US-based respondents. Most respondents reported longstanding, moderate to severe, multisite pain, commonly accompanied by symptoms of anxiety and/or depression. The median number of pain treatments tried was 10 (IQR = 8, 13), with medications and exercise being the most common modalities, and opioids being viewed as the most helpful. Over 80% of respondents considered all research topics either “extremely important” or “very important”. Research topic #2, which focused on optimizing management of pain in people with HIV, was accorded the greatest importance by respondents. These findings suggest good alignment between the priorities of researchers and US-based people with lived experience of HIV-associated chronic pain. © 2024 Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
chronic pain; HIV; pain treatment; patient engagement; research priorities
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
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
Ligand efficacy modulates conformational dynamics of the µ-opioid receptor
(2024) Nature, .
Zhao, J.a b c , Elgeti, M.d e , O’Brien, E.S.f , Sár, C.P.g , EI Daibani, A.h , Heng, J.a b , Sun, X.a b , White, E.f , Che, T.h , Hubbell, W.L.d , Kobilka, B.K.f , Chen, C.a c
a State Key Laboratory of Membrane Biology, Beijing Frontier Research Center for Biological Structure, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, China
b Tsinghua–Peking Joint Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China
c School of Life Sciences, Tsinghua University, Beijing, China
d Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, CA, United States
e Institute for Drug Discovery, University of Leipzig Medical Center, Leipzig, Germany
f Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, United States
g Institute of Organic and Medicinal Chemistry, School of Pharmaceutical Sciences, University of Pécs, Pécs, Hungary
h Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, United States
Abstract
The µ-opioid receptor (µOR) is an important target for pain management1 and molecular understanding of drug action on µOR will facilitate the development of better therapeutics. Here we show, using double electron–electron resonance and single-molecule fluorescence resonance energy transfer, how ligand-specific conformational changes of µOR translate into a broad range of intrinsic efficacies at the transducer level. We identify several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation that is capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex. Interaction of β-arrestin-1 with the μOR core binding site appears less specific and occurs with much lower affinity than binding of Gi. © The Author(s) 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Emotional dysregulation moderates the relation between perceived stress and emotional eating in adolescent military dependents
(2024) International Journal of Eating Disorders, .
Spinner, H.a b , Thompson, K.A.a b , Bauman, V.a b , Lavender, J.M.a b c , Thorstad, I.a b , Schrag, R.a b , Sbrocco, T.d , Schvey, N.A.d e , Ford, B.f , Ford, C.g , Wilfley, D.E.h , Jorgensen, S.i , Klein, D.A.f j , Quinlan, J.i , Yanovski, J.A.e , Haigney, M.a c , Tanofsky-Kraff, M.a d e
a Military Cardiovascular Outcomes Research (MiCOR) Program, USU, Bethesda, MD, United States
b The Metis Foundation, San Antonio, TX, United States
c Department of Medicine, Uniformed Services University of the Health Sciences (USU), Bethesda, MD, United States
d Department of Medical and Clinical Psychology, USU, Bethesda, MD, United States
e Section on Growth and Obesity, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
f Department of Family Medicine, USU, Bethesda, MD, United States
g Department of Family Medicine, Fort Belvoir Community Hospital, Fort Belvoir, VA, United States
h Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
i Department of Family Medicine, University of Iowa Hospitals & Clinics, Iowa City, IA, United States
j Department of Pediatrics, USU, Bethesda, MD, United States
Abstract
Objective: Adolescent children of US service members (i.e., military-dependent youth) face unique stressors that increase risk for various forms of disinhibited eating, including emotional eating. Difficulties with adaptively responding to stress and aversive emotions may play an important role in emotional eating. This study examined emotion dysregulation as a potential moderator of the association between perceived stress and emotional eating in adolescent military dependents. Method: Participants were military-dependent youth (N = 163, 57.7% female, Mage = 14.5 ± 1.6, MBMI-z = 1.9 ± 0.4) at risk for adult binge-eating disorder and high weight enrolled in a randomized controlled prevention trial. Prior to intervention, participants completed questionnaires assessing perceived stress and emotional eating. Parents completed a questionnaire assessing their adolescent’s emotion dysregulation. Moderation analyses were conducted using the PROCESS macro in SPSS and adjusted for theoretically relevant sociodemographic covariates. Results: The interaction between adolescent perceived stress and emotion dysregulation (parent-reported about the adolescent) in relation to adolescent emotional eating was found to be significant, such that higher emotion dysregulation magnified the association between perceived stress and emotional eating (p =.010). Examination of simple slopes indicated that associations between perceived stress and emotional eating were strongest for youth with above-average emotion dysregulation, and non-significant for youth with average or below-average emotion dysregulation. Discussion: Findings suggest that greater emotion dysregulation may increase risk for emotional eating in response to stress among military-dependent youth at risk for binge-eating disorder or high weight. Improving emotion regulation skills may be a useful target for eating disorder prevention among youth who are at risk for emotional eating. Public Significance: Prior research has shown that adolescent military dependents are at increased risk for eating disorders and high weight. The current study found that emotion dysregulation moderated the relationship between perceived stress and emotional eating among military-dependent youth. There may be clinical utility in intervening on emotion regulation for adolescent dependents at particular risk for emotional eating and subsequent eating disorders. © 2024 The Authors. International Journal of Eating Disorders published by Wiley Periodicals LLC.
Author Keywords
adolescents; emotion dysregulation; emotional eating; military dependents; perceived stress
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Oral Delta-9-Tetrahydrocannabinol (THC) Increases Parasympathetic Activity and Supraspinal Conditioned Pain Modulation in Chronic Neuropathic Pain Male Patients: A Crossover, Double-Blind, Placebo-Controlled Trial
(2024) CNS Drugs, .
Weizman, L.a , Sharon, H.a b c d , Dayan, L.d , Espaniol, J.e f , Brill, S.d , Nahman-Averbuch, H.g , Hendler, T.a b c h , Jacob, G.b c e f
a Sagol Brain Institute, Wohl Institute for Advanced Imaging, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
b Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
c School of Medicine, Tel Aviv University, Tel Aviv, Israel
d Department of Anesthesiology and Critical Care Medicine, Institute of Pain Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
e Department of Internal Medicine F, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
f Recanati Autonomic Dysfunction Center, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
g Division of Clinical and Translational Research, Department of Anesthesiology, Washington University Pain Center, Washington University in St Louis School of Medicine, St Louis, MO, United States
h School of Psychological Sciences, Tel Aviv University, Tel-Aviv, Israel
Abstract
Background: Disordered autonomic nervous system regulation and supraspinal pain inhibition have been repeatedly described in chronic pain. We aimed to explore the effects of δ-9-tetrahydrocannabinol (THC), an emerging treatment option, on autonomic nervous system and central pain modulation measures in patients with chronic pain. Methods: Twelve male patients with chronic radicular neuropathic pain participated in a randomized, double-blind, crossover, placebo-controlled, single-administration trial. Low/high frequency (LF/HF) heart rate variability (HRV) ratio and conditioned pain modulation (CPM) response were measured and resting-state functional magnetic resonance imaging (MRI) was performed at baseline and after sublingual administration of either 0.2 mg/kg oral THC or placebo. Results: THC significantly reduced the LF/HF ratio compared with placebo (interaction effect F(1,11) = 20.5; p < 0.005) and significantly improved CPM responses (interaction effect F(1,9) = 5.2; p = 0.048). The THC-induced reduction in LF/HF ratio correlated with increased functional connectivity between the rostral ventrolateral medulla and the dorsolateral prefrontal cortex [T(10) = 6.4, cluster p-FDR < 0.005]. Conclusions: THC shifts the autonomic balance towards increased parasympathetic tone and improves inhibitory pain mechanisms in chronic pain. The increase in vagal tone correlates with connectivity changes in higher-order regulatory brain regions, suggesting THC exerts top-down effects. These changes may reflect a normalizing effect of THC on multiple domains of supraspinal pain dysregulation. Clinical Trial Registry Number: NCT02560545. © The Author(s) 2024.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus