Two cardinal features of ALS, reduced STMN2 and pathogenic TDP-43, synergize to accelerate motor decline in mice
(2025) Experimental Neurology, 384, art. no. 115068, .
Krus, K.L.a , Benitez, A.M.a , Strickland, A.b , Milbrandt, J.b c d , Bloom, A.J.b c , DiAntonio, A.a d
a Department of Developmental Biology, Washington University School of Medicine, St. Louis, 63110, United States
b Department of Genetics, Washington University School of Medicine, St. Louis, 63110, United States
c McDonnell Genome Institute, Washington University School of Medicine, St. Louis, 63110, United States
d Needleman Center for Neurometabolism and Axonal Therapeutics, St. Louis, 63110, United States
Abstract
Pathological TDP-43 loss from the nucleus and cytoplasmic aggregation occurs in almost all cases of ALS and half of frontotemporal dementia patients. Stathmin2 (Stmn2) is a key target of TDP-43 regulation and aberrantly spliced Stmn2 mRNA is found in patients with ALS, frontotemporal dementia, and Alzheimer’s Disease. STMN2 participates in the axon injury response and its depletion in vivo partially replicates ALS-like symptoms including progressive motor deficits and distal NMJ denervation. The interaction between STMN2 loss and TDP-43 dysfunction has not been studied in mice because TDP-43 regulates human but not murine Stmn2 splicing. Therefore, we generated trans-heterozygous mice that lack one functional copy of Stmn2 and express one mutant TDP-43Q331K knock-in allele to investigate whether reduced STMN2 function exacerbates TDP-43-dependent pathology. Indeed, we observe synergy between these two alleles, resulting in an early onset, progressive motor deficit. Surprisingly, this behavioral defect is not accompanied by detectable neuropathology in the brain, spinal cord, peripheral nerves or at neuromuscular junctions (NMJs). However, the trans-heterozygous mice exhibit abnormal mitochondrial morphology in their distal axons and NMJs. As both STMN2 and TDP-43 affect mitochondrial dynamics, and neuronal mitochondrial dysfunction is a cardinal feature of many neurodegenerative diseases, this abnormality likely contributes to the observed motor deficit. These findings demonstrate that partial loss of STMN2 significantly exacerbates TDP-43-associated phenotypes, suggesting that STMN2 restoration could ameliorate TDP-43 related disease before the onset of degeneration. © 2024 The Author(s)
Author Keywords
ALS; FTD; Neurodegeneration; Neuropathy; Stathmin; STMN2; TARDBP; TDP-43
Funding details
Institute of Clinical and Translational SciencesICTS
National Center for Advancing Translational SciencesNCATS
National Institutes of HealthNIHRF1AG013730, R01NS119812, R01NS087632, R37NS065053
Georgia Clinical and Translational Science AllianceGaCTSA#UL1 TR002345
Document Type: Article
Publication Stage: Final
Source: Scopus
International collaboration of neoadjuvant stereotactic radiosurgery for brain metastases: The INTERNEO individual patient data pooled analysis
(2025) Radiotherapy and Oncology, 202, art. no. 110641, .
Udovicich, C.a b , Koo, K.a b c d , Bryant, J.M.e , Bugarini, A.f , Huo, M.g , Kim, K.H.h , Li, Y.D.i , Oliver, D.E.e , Patel, S.j , Rogers, S.k , Chicoine, M.R.i l , Foote, M.C.g , Kim, S.-H.h , Mahadevan, A.m , Pinkham, M.B.g , Sia, J.a b , Haghighi, N.a b n , INTERNEO Investigatorso
a Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
b Sir Peter MacCallum Department of Oncology, The University of MelbourneVIC, Australia
c Radiation Oncology, Alfred Health, Melbourne, Australia
d School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia
e Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States
f Department of Neurosurgery, Geisinger Health, Danville, PA, United States
g Department of Radiation Oncology, Princess Alexandra Hospital, Woolloongabba, QLD, Australia
h Department of Neurosurgery, Chungnam National University Hospital, Chungnam National University School of Medicine, Daejeon, South Korea
i Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
j Division of Radiation Oncology, University of Alberta, Edmonton, AB, Canada
k Radiation Oncology Center Mittelland, Canton Hospital Aarau, Aarau, Switzerland
l Department of Neurosurgery, University of Missouri, Columbia, MO, United States
m Department of Radiation Oncology, Perlmutter Cancer Center at New York, University Grossman School of Medicine, New York, NY, United States
n Department of Radiation Oncology, Icon Cancer Centre, Epworth Centre, Richmond, VIC, Australia
Abstract
Background and Purpose: Neoadjuvant stereotactic radiosurgery (NaSRS) is an emerging treatment option for brain metastases (BrM) planned for resection. The aim of this study was to report on the efficacy and safety of NaSRS in an individual patient data pooled analysis. Materials and Methods: Patients undergoing single- and multi-fraction NaSRS for BrM at nine institutions in five countries (Australia, Canada, South Korea, Switzerland and USA) were included. Eligibility criteria included BrM from any primary malignancy and no prior local therapy. The primary endpoint was a composite of local recurrence (LR), any grade radionecrosis (RN), and/or nodular leptomeningeal disease (nLMD). Secondary endpoints included these endpoints and Grade ≥ 2 RN. Endpoints were evaluated using cumulative incidence functions. Results: NaSRS was delivered to 179 patients with 189 BrM. Median follow-up was 28.4 months. Primary malignancies included non-small cell lung carcinoma (44 %) and melanoma (17 %). The median BrM diameter was 29 mm (IQR 21–36 mm). Single- and multi-fraction NaSRS was utilised in 100 (53 %) and 89 BrM (47 %) respectively. The median single-fraction dose was 18 Gy (IQR 16–20 Gy). Multi-fraction doses included 24 Gy in three fractions (55 %) and 27 Gy in three fractions (25 %). The 12-month incidence for the composite endpoint was 8.0 %. The 12-month incidence of LR was 4.6 %, any grade RN was 3.6 %, Grade ≥ 2 RN was 1.8 % and nLMD was 1.2 %. Conclusion: Neoadjuvant SRS results in favourable rates of LR, RN and nLMD. We provide a global experience of this treatment approach with long-term data and the largest cohort of patients undergoing multi-fraction SRS. © 2024 Elsevier B.V.
Author Keywords
Brain metastases; Neoadjuvant; Pre-operative; Preoperative; SRS; Stereotactic radiosurgery; Stereotactic radiotherapy; Surgery
Document Type: Article
Publication Stage: Final
Source: Scopus
Breaking the cycle between caregiver mental health and child behavioral issues: Does food insecurity matter?
(2025) Social Science and Medicine, 364, art. no. 117488, .
Chen, J.-H.a , Helton, J.J.a , Chiang, C.-J.b , Wu, C.-F.c , Jonson-Reid, M.d , Drake, B.d
a School of Social Work, Saint Louis University, Tegeler Hall, 3550 Lindell Blvd, St. Louis, MO 63103, United States
b Department of Social Work, The University of Texas at San Antonio, One UTSA Circle, Main Building 2.306, San Antonio, TX 78249, United States
c School of Social Work, University of Illinois at Urbana-Champaign, 1010 W Nevada St, Urbana, IL 61801, United States
d George Warren Brown School of Social Work, Washington University in St. Louis, 1 Brookings Dr, St. Louis, MO 63130, United States
Abstract
Food insecurity is a key determinant of not only caregiver’s mental health but also children’s emotional problems and hyperactivity symptoms. Although substantial studies have explored such a relationship, it is unclear to us whether this relation would vary when considering that caregiver’s mental health and aforementioned children’s behavioral issues can be the cause and effect of each other. Addressing this research gap is a key to advancing our understanding of how to promote a healthier family dynamic, especially for those facing material needs. This research applies the family stress model to explore how food insecurity affects caregiver psychological distress and child emotional problems and hyperactivity symptoms, while considering the reciprocal relationships between caregiver mental health and these child behavioral issues. Utilizing data from the 2019 Panel Study of Income Dynamic and 2019–2020 Child Development Supplements, this study conducts path analyses applied with propensity score weighting to support causal inference. Results support the family stress model framework, where food insecurity significantly predicts an increase in psychological distress in caregivers, which in turn leads to more severe child emotional problems and hyperactivity symptoms. This study also shows that food insecurity is a risk factor resulting in a reciprocal association between caregiver psychological distress and child emotional problems, where the strength of both directions is similarly harmful to each other. These findings underscore the need to address food insecurity, not only to meet material needs but also to break the harmful cycle of mental health and behavioral issues within families. © 2024 Elsevier Ltd
Author Keywords
Caregiver psychological distress; Child emotional problems; Child hyperactivity symptoms; Family stress model; Food insecurity; Propensity score weight
Document Type: Article
Publication Stage: Final
Source: Scopus
Cerebral Oxygen Metabolic Stress in Children and Adults With Large Vessel Vasculopathy Due to Sickle Cell Disease
(2024) Neurology, 103 (11), p. e210032.
Wang, Y., Fellah, S., Reis, M., Guilliams, K.P., Fields, M.E., Steger-May, K., Mirro, A.E., Lewis, J.B., Ying, C., Cohen, R.A., Hulbert, M.L., King, A.A., Chen, Y., Lee, J.-M., An, H., Ford, A.L.
From the Department of Neurology (Y.W., S.F., K.G., M.E.F., J.B.L., Y.C., J.-M.L.), Mallinckrodt Institute of Radiology (M.R., K.G., M.E.F., C.Y., J.-M.L., H.A.), and Division of Pediatrics (K.G., A.E.M., M.L.H.), Center for Biostatistics and Data Science (K.S.-M.), Washington University School of Medicine; Washington University in St. Louis (R.A.C.); and Division of Hematology/Oncology (A.A.K., A.L.F.), Department of Medicine, Washington University School of Medicine, St. Louis, MO
Abstract
BACKGROUND AND OBJECTIVES: Large vessel vasculopathy (LVV), or moyamoya syndrome, increases the risk of stroke in patients with sickle cell disease (SCD), yet effective treatments are lacking. In atherosclerotic carotid disease, previous studies demonstrated elevated oxygen extraction fraction (OEF) as a predictor of ipsilateral stroke. In a SCD cohort, we examined hemispheric hemodynamic and oxygen metabolic dysfunction as tissue-based biomarkers of cerebral ischemic risk in patients with LVV. METHODS: Children and adults with SCD were recruited from a SCD clinic associated with a tertiary medical center and underwent prospective brain MRI and MR angiography. LVV was defined as ≥75% stenosis in a major anterior circulation artery, excluding occlusion or previous revascularization surgery. Baseline characteristics, cerebral blood flow (CBF), normalized OEF (nOEF), infarct volume, white matter microstructure, and brain volume were compared in hemispheres with vs without LVV. In a cross-sectional analysis, mixed-effects linear multivariable models examined the effect of LVV on: (1) CBF and nOEF, as tissue markers of hemodynamic and oxygen metabolic stress, respectively, and (2) endpoints of cerebral ischemic injury including infarct volume, white matter microstructure, and brain volume. RESULTS: Of 155 patients (22 [12-31] years, 57% female), 33 (21%) had ≥25% stenosis, 22 (14%) had ≥50% stenosis, 14 (9%) had 75%-99% stenosis, and 5 (3%) had 100% occlusion. After excluding hemispheres with previous revascularization surgery, LVV was present in 16 hemispheres from 11 patients. Hemispheres with (N = 16) vs without (N = 283) LVV had lower CBF (25.2 vs 32.1 mL/100 g/min, p = 0.01) and higher nOEF (0.99 vs 0.95, p = 0.02). On multivariable analysis, CBF was nonsignificantly lower (β = -0.16, p = 0.07) while nOEF remained higher in hemispheres with LVV (β = 0.04, p = 0.03). Moreover, LVV was associated with greater hemispheric infarct volume, microstructural disruption, and atrophy. DISCUSSION: Beyond greater infarct burden, LVV was associated with hemispheric atrophy and white matter microstructural injury. As an indicator of active hypoxia, elevated nOEF likely represents a compensatory response to flow-limiting stenosis in hemispheres with LVV. The study is limited by a small number of patients with severe stenosis. Future studies are needed to evaluate the potential of tissue-based CBF and nOEF in assessing stroke risk and guide timely treatment of vasculopathy in SCD.
Document Type: Article
Publication Stage: Final
Source: Scopus
Child Neurology: Five-Year Update on Siblings With Riboflavin Transporter Deficiency: Stable Visual and Neurologic Status With Continued Riboflavin Therapy
(2024) Neurology, 103 (11), p. e209969.
O’Brien, M.A., Culican, S.M., Shinawi, M.S., Zaidman, C.M.
From the Department of Ophthalmology and Visual Sciences (M.A.O.), Division of Genetics and Genomic Medicine (M.S.S.), and Division of Pediatric and Developmental Neurology (C.M.Z.), Washington University School of Medicine, St. Louis, MO; Graduate Medical Education Office (S.M.C.) and Department of Ophthalmology and Visual Neurosciences (S.M.C.), University of Minnesota Medical School, Minneapolis
Abstract
Riboflavin transporter deficiency (RTD), previously referred to as Brown-Vialetto-Van Laere syndrome, is caused by pathogenic variants in the SLC52A1, SLC52A2, or SLC52A3 genes, resulting in RTD types 1, 2, and 3, respectively. Researchers estimate an occurrence of approximately 1 in 1,000,000. There is only one case of type 1 described in medical literature. Type 2 is characterized by muscle weakness in the arms and neck, vision loss, hearing impairment, and sensory ataxia. In type 3, vocal cord paralysis is more common and muscle weakness is more generalized. In 2018, we described a case of a 6-year-old girl with RTD type 2 who made remarkable visual recovery after initiation of treatment with oral riboflavin and coenzyme Q10 supplementation. The patient’s younger brother began the same treatment regimen after genetic testing confirmed that he carried the same genetic variant. In this report, we update the visual and neurologic status in these siblings 5 years after our initial report and 7.5 years after initiation of riboflavin treatment.
Document Type: Article
Publication Stage: Final
Source: Scopus
Comparative neurofilament light chain trajectories in CSF and plasma in autosomal dominant Alzheimer’s disease
(2024) Nature Communications, 15 (1), art. no. 9982, .
Hofmann, A.a b , Häsler, L.M.a b , Lambert, M.a b , Kaeser, S.A.a b , Gräber-Sultan, S.a , Obermüller, U.a b , Kuder-Buletta, E.a , la Fougere, C.a c , Laske, C.a b d , Vöglein, J.e f g , Levin, J.e f g , Fox, N.C.h , Ryan, N.S.h , Zetterberg, H.i j , Llibre-Guerra, J.J.k , Perrin, R.J.k l , Ibanez, L.k m n , Schofield, P.R.o p , Brooks, W.S.o q , Day, G.S.r , Farlow, M.R.s , Allegri, R.F.t , Chrem Mendez, P.t , Ikeuchi, T.u , Kasuga, K.u , Lee, J.-H.v , Roh, J.H.w , Mori, H.x , Lopera, F.y , Bateman, R.J.k , McDade, E.k , Gordon, B.A.z , Chhatwal, J.P.aa ab ac , Jucker, M.a b , Schultz, S.A.aa ab , Xu, J.z , Xu, X.ae , Xiong, C.ae , Wang, Q.z , Wang, G.ae , Vöglein, J.e f g , Vazquez, S.t , Surace, E.t , Supnet-Bell, C.ae , Stout, S.k , Stauber, J.k , Smith, H.ae , Smith, J.k , Simmons, A.ae , Seyfried, N.T.ah , Scott, J.ae , Sanchez-Valle, R.ao , Salloway, S.ag , Sabaredzovic, E.ae , Rosa-Neto, P.an , Roedenbeck, Y.e f g , Rizzo, J.ae , Ringman, J.am , Renton, A.E.af , Ramirez, L.y , Pulizos, C.ae , Picarello, D.M.af , Obermueller, U.a b , Noble, J.M.al , Niimi, Y.ak , Nicklaus, J.z , Nadkarni, N.K.ad , Morris, J.C.ae , Minton, M.ae , McKay, N.z , McCullough, A.z , Masters, C.aj , Massoumzadeh, P.ae , Martins, R.ai , Marsh, J.ae , Lu, R.ae , Li, Y.af , Levey, A.I.ah , Leon, Y.M.y , Koudelis, D.ae , Keefe, S.z , Karch, C.M.m , Joseph-Mathurin, N.z , Johnson, E.C.B.ah , Jerome, G.ae , Jarman, S.ae , Jackson, K.ae , Ikonomovic, S.ad , Huey, E.D.ag , Hornbeck, R.z , Holtzman, D.M.k , Herries, E.k , Hassenstab, J.k , Gremminger, E.ae , Graff-Radford, N.R.r , Graber-Sultan, S.ae , Goate, A.M.af , Franklin, E.l , Flores, S.z , Farlow, M.g , Fagan, A.M.k , Day, G.S.r , Daniels, A.J.ae , Cruchaga, C.m , Courtney, L.ae , Mendez, P.C.t , Chhatwal Chhatwal, J.P.aa ab ac , Chen, C.z , Chen, A.z , Cash, D.M.h , Berman, S.B.ad , Benzinger, T.z , Bechara, J.A.o , Bateman, R.k , Barthelemy, N.k , Baker, B.k , Aschenbrenner, A.J.k , Aguillon, D.y , Dominantly Inherited Alzheimer Networkap
a German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
b Department of Cellular Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
c Nuclear Medicine and Clinical Molecular Imaging, University Hospital Tübingen, Tübingen, Germany
d Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
e German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
f Department of Neurology, Ludwig Maximilians-Universität München, Munich, Germany
g Munich Cluster of Systems Neurology (SyNergy), Munich, Germany
h Dementia Research Centre, UCL Queen Square Institute of Neurology, London, United Kingdom
i Department Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
j Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
k Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
l Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, United States
m Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
n NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
o Neuroscience Research Australia, Randwick, NSW, Australia
p School of Biomedical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, Australia
q School of Clinical Medicine, Faculty of Medicine and Health Sydney, University of New South Wales, Sydney, Australia
r Department of Neurology, Mayo Clinic in Florida, Jacksonville, FL, United States
s Indiana Alzheimer Disease Center and Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
t Instituto Neurológico FLENI, Buenos Aires, Argentina
u Brain Research Institute, Niigata University, Niigata, Japan
v Department of Neurology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
w Departments of Neurology and Physiology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea
x Faculty of Medicine, Osaka Metropolitan University, Nagaoka Sutoku University, Osaka, Japan
y Grupo de Neurociencias de Antioquia (GNA), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
z Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
aa Department of Neurology, Harvard Medical School, Boston, MA, United States
ab Massachusetts General Hospital, Boston, MA, United States
ac Brigham and Women’s Hospital Boston, Boston, MA, United States
ad University of Pittsburgh, Pittsburgh, PA, United States
ae Washington University in St. Louis, School of Medicine, St. Louis, MO, United States
af Dept. of Genetics & amp; Genomic Sciences, Dept. of Neuroscience, Ronald M. Loeb Center for Alzheimer’s disease, Icahn School of Medicine at Mount Sinai, Mount Sinai, NY, United States
ag Memory and Aging Program, Butler Hospital, Departments of Psychiatry and Human Behavior and Neurology, Alpert Medical School, Brown University, Providence, RI, United States
ah Goizueta Alzheimer’s Disease Research Center, Emory University, Atlanta, GA, United States
ai Edith Cowan University, Joondalup, Australia
aj Florey Institute, The University of Melbourne, Melbourne, Australia
ak Specially appointed lecturer, Unit for Early and Exploratory Clinical Development, The University of Tokyo, Tokyo, Japan
al Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, G.H. Sergievsky Center, Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
am Department of Neurology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, United States
an McGill University, Montreal, Canada
ao Hospital Clínic de Barcelona. FRCB-IDIBAPS. University of Barcelona, Barcelona, Spain
Abstract
Disease-modifying therapies for Alzheimer’s disease (AD) are likely to be most beneficial when initiated in the presymptomatic phase. To track the benefit of such interventions, fluid biomarkers are of great importance, with neurofilament light chain protein (NfL) showing promise for monitoring neurodegeneration and predicting cognitive outcomes. Here, we update and complement previous findings from the Dominantly Inherited Alzheimer Network Observational Study by using matched cross-sectional and longitudinal cerebrospinal fluid (CSF) and plasma samples from 567 individuals, allowing timely comparative analyses of CSF and blood trajectories across the entire disease spectrum. CSF and plasma trajectories were similar at presymptomatic stages, discriminating mutation carriers from non-carrier controls 10-20 years before the estimated onset of clinical symptoms, depending on the statistical model used. However, after symptom onset the rate of change in CSF NfL continued to increase steadily, whereas the rate of change in plasma NfL leveled off. Both plasma and CSF NfL changes were associated with grey-matter atrophy, but not with Aβ-PET changes, supporting a temporal decoupling of Aβ deposition and neurodegeneration. These observations support NfL in both CSF and blood as an early marker of neurodegeneration but suggest that NfL measured in the CSF may be better suited for monitoring clinical trial outcomes in symptomatic AD patients. © The Author(s) 2024.
Funding details
Deutsches Zentrum für Neurodegenerative ErkrankungenDZNE
Fleni
Ministry of Health and WelfareMOHW
Korea Dementia Research CenterKDRC
National Institute on AgingNIA
Korea Health Industry Development InstituteKHIDI
National Institutes of HealthNIHK01AG084816
National Institutes of HealthNIH
RS-2024-00344521
Alzheimer’s AssociationAASG-20-690363-DIAN
Alzheimer’s AssociationAA
Instituto de Salud Carlos IIIISCIIIAARF-21-846786
Instituto de Salud Carlos IIIISCIII
U19AG032438
Japan Agency for Medical Research and DevelopmentAMEDAMED JP23dk0207066, JP22dk0207049
Japan Agency for Medical Research and DevelopmentAMED
Document Type: Article
Publication Stage: Final
Source: Scopus
Polygenic score analyses on antidepressant response in late-life depression, results from the IRL-GRey study
(2024) Pharmacogenomics Journal, 24 (6), art. no. 38, .
Elsheikh, S.S.M.a , Marshe, V.S.b , Men, X.a c , Islam, F.a c , Gonçalves, V.F.a c d e , Paré, G.f g h i , Felsky, D.a d e j , Kennedy, J.L.a d e , Mulsant, B.H.a d e , Reynolds, C.F., 3rdk , Lenze, E.J.l , Müller, D.J.a c d e m
a Campbell Family Mental Health Research Institute, Center for Addiction and Mental Health, Toronto, ON, Canada
b Columbia University Irving Medical Center, New York, NY, United States
c Department of Pharmacology & amp; Toxicology, University of Toronto, Toronto, ON, Canada
d Department of Psychiatry, University of Toronto, Toronto, ON, Canada
e Institute of Medical Science, University of Toronto, Toronto, ON, Canada
f Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, Canada
g Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, 237 Barton Street East, Hamilton, ON, Canada
h Department of Pathology and Molecular Medicine, Michael G. DeGroote School of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON, Canada
i Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
j Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
k Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, United States
l Healthy Mind Lab, Department of Psychiatry, Washington University, St. Louis, MO, United States
m Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
Abstract
Late-life depression (LLD) is often accompanied by medical comorbidities such as psychiatric disorders and cardiovascular diseases, posing challenges to antidepressant treatment. Recent studies highlighted significant associations between treatment-resistant depression (TRD) and polygenic risk score (PRS) for attention deficit hyperactivity disorder (ADHD) in adults as well as a negative association between antidepressant symptom improvement with both schizophrenia and bipolar. Here, we sought to validate these findings with symptom remission in LLD. We analyzed the Incomplete Response in Late Life Depression: Getting to Remission (IRL-GRey) sample consisting of adults aged 60+ with major depression (N = 342) treated with venlafaxine for 12 weeks. We constructed PRSs for ADHD, depression, schizophrenia, bipolar disorder, neuroticism, general intelligence, antidepressant symptom remission and antidepressant percentage symptom improvement using summary statistics from the Psychiatric Genomics Consortium and the GWAS Catalog. Logistic regression was used to test the association of PRSs with venlafaxine symptom remission and percentage symptom improvement, co-varying for the genomic principal components, age, sex and depressive symptoms severity at baseline. We found a nominal (i.e., p value ≤ 0.05) association between symptom remission and both PRS for ADHD and (OR = 1.36 [1.07, 1.73], p = 0.011) and PRS for bipolar disorder (OR = 0.75 [0.58, 0.97], p = 0.031), as well as between percentage symptom improvement and PRS for general intelligence (beta = 6.81 (SE = 3.122), p = 0.03). However, the ADHD association was in the opposite direction as expected, and both associations did not survive multiple testing corrections. Altogether, these findings suggest that previous findings regarding ADHD PRS and antidepressant response (measured with various outcomes) do not replicate in older adults. © The Author(s), under exclusive licence to Springer Nature Limited 2024.
Funding details
Canada Foundation for InnovationCFI
Centre for Addiction and Mental Health FoundationCAMH
Canadian Statistical Sciences InstituteCANSSI
Canadian Institutes of Health ResearchCIHR
Document Type: Article
Publication Stage: Final
Source: Scopus
Sertraline modulates hippocampal plasticity via sigma 1 receptors, cellular stress and neurosteroids
(2024) Translational Psychiatry, 14 (1), art. no. 474, .
Izumi, Y.a b , Reiersen, A.M.a b , Lenze, E.J.a b , Mennerick, S.J.a b , Zorumski, C.F.a b
a Department of Psychiatry & amp; Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, MO, United States
b Center for Brain Research in Mood Disorders, Washington University School of Medicine, St. Louis, MO, United States
Abstract
In addition to modulating serotonin transport, selective serotonin reuptake inhibitors (SSRIs) have multiple other mechanisms that may contribute to clinical effects, and some of these latter actions prompt repurposing of SSRIs for non-psychiatric indications. In a recent study of the SSRIs fluvoxamine, fluoxetine and sertraline we found that, unlike the other two SSRIs, sertraline acutely inhibited LTP at a low micromolar concentration through inverse agonism of sigma 1 receptors (S1Rs). In the present studies, we pursued mechanisms contributing to sertraline modulation of LTP in rat hippocampal slices. We found that sertraline partially inhibits synaptic responses mediated by N-methyl-D-aspartate receptors (NMDARs) via effects on NMDARs that contain GluN2B subunits. A selective S1R antagonist (NE-100), but not an S1R agonist (PRE-084) blocked effects on NMDARs, even though both S1R ligands were previously shown to prevent LTP inhibition. Both NE-100 and PRE-084, however, prevented adverse effects of sertraline on one-trial learning. Because of the important role that S1Rs play in modulating endoplasmic reticulum stress, we examined whether inhibitors of cellular stress alter effects of sertraline. We found that two stress inhibitors, ISRIB and quercetin, prevented LTP inhibition, as did inhibitors of the synthesis of endogenous neurosteroids, which are homeostatic regulators of cellular stress. These studies highlight complex effects of sertraline, S1Rs and neurosteroids on hippocampal function and have relevance for understanding therapeutic and adverse drug actions. © The Author(s) 2024.
Document Type: Article
Publication Stage: Final
Source: Scopus
Lymphocytic choriomeningitis arenavirus utilises intercellular connections for cell to cell spread
(2024) Scientific Reports, 14 (1), art. no. 28961, .
Byford, O.a b , Shaw, A.B.a b , Tse, H.N.a b , Moon-Walker, A.c d e g , Saphire, E.O.c , Whelan, S.P.J.d , Stacey, M.a , Hewson, R.f , Fontana, J.a b , Barr, J.N.a b
a School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, United Kingdom
b Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
c Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology, La Jolla, CA 92037, United States
d Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO 63110, United States
e Program in Virology, Harvard Medical School, Boston, MA 02115, United States
f Virology and Pathogenesis Group, National Infection Service, Public Health England, Porton Down, SP4 0JG, United Kingdom
g Merck Research Laboratories, Merck & amp; Co, Cambridge, MA 02141, United States
Abstract
The Arenaviridae family of segmented RNA viruses contains nearly 70 species with several associated with fatal haemorrhagic fevers, including Lassa, Lujo and Junin viruses. Lymphocytic choriomeningitis arenavirus (LCMV) is associated with fatal neurologic disease in humans and additionally represents a tractable model for studying arenavirus biology. Within cultured cells, a high proportion of LCMV spread is between directly neighbouring cells, suggesting infectivity may pass through intercellular connections, bypassing the canonical extracellular route involving egress from the plasma membrane. Consistent with this, we visualized abundant actin- and tubulin-rich connections conjoining LCMV-infected and uninfected cells within cultures, resembling tunnelling nanotubes (TNTs). Within these TNT-like connections, confocal and STED microscopy identified puncta containing the major structural components of LCMV virions alongside genomic RNA, consistent with intercellular transit of assembled virions or ribonucleoprotein genome segments. Blocking the extracellular route of infection by adding potent LCMV neutralising antibody M28 to supernatants during infection revealed around 50% of LCMV transmission was via intercellular connections. These results show arenaviruses transmission is more complex than previously thought involving both extracellular and intercellular routes. © The Author(s) 2024.
Author Keywords
Arenavirus; Intercellular transmission; LCMV; Tunnelling nanotubes
Funding details
Biotechnology and Biological Sciences Research CouncilBBSRC
Medical Research CouncilMRCMR/T016159/1
Medical Research CouncilMRC
Wellcome TrustWTWT104918MA, BB/S019464/1, 221538/Z/20/Z
Wellcome TrustWT
Document Type: Article
Publication Stage: Final
Source: Scopus
Overexpression of enhanced yellow fluorescent protein fused with Channelrhodopsin-2 causes contractile dysfunction in skeletal muscle
(2024) FASEB Journal, 38 (22), art. no. e70185, .
Lamia, S.N.a b c , Davis, C.S.a , Macpherson, P.C.D.a , Willingham, T.B.d , Zhang, Y.d , Liu, C.d , Iannucci, L.e , Ganji, E.a f , Harden, D.a , Bhattacharya, I.f , Abraham, A.C.a , Brooks, S.V.a , Glancy, B.d g , Killian, M.L.a b f
a Michigan Medicine, University of Michigan, Ann Arbor, MI, United States
b College of Engineering, University of Michigan, Ann Arbor, MI, United States
c School of Medicine, Washington University, St Louis, MO, United States
d National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
e Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD, United States
f College of Engineering, University of Delaware, Newark, DE, United States
g National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, United States
Abstract
Skeletal muscle activation using optogenetics has emerged as a promising technique for inducing noninvasive muscle contraction and assessing muscle function both in vivo and in vitro. Transgenic mice overexpressing the optogenetic fusion protein, Channelrhodopsin 2-EYFP (ChR2-EYFP) in skeletal muscle are widely used; however, overexpression of fluorescent proteins can negatively impact the functionality of activable tissues. In this study, we characterized the contractile properties of ChR2-EYFP skeletal muscle and introduced the ChR2-only mouse model that expresses light-responsive ChR2 without the fluorescent EYFP in their skeletal muscles. We found a significant reduction in the contractile ability of ChR2-EYFP muscles compared with ChR2-only and WT mice, observed under both electrical and optogenetic stimulation paradigms. Bulk RNAseq identified the downregulation of genes associated with transmembrane transport and metabolism in ChR2-EYFP muscle, while the ChR2-only muscle did not demonstrate any notable deviations from WT muscle. The RNAseq results were further corroborated by a reduced protein-level expression of ion channel-related HCN2 in ChR2-EYFP muscles and gluconeogenesis-modulating FBP2 in both ChR2-EYFP and ChR2-only muscles. Overall, this study reveals an intrinsic skeletal dysfunction in the widely used ChR2-EYFP mice model and underscores the importance of considering alternative optogenetic models, such as the ChR2-only, for future research in skeletal muscle optogenetics. © 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.
Author Keywords
Channelrhodopsin-2; function; optogenetics; skeletal muscle; structure
Funding details
National Heart, Lung, and Blood InstituteNHLBI
1ZIAHL006221, R03HD094594, K12HD073945, P30AR069620
National Institutes of HealthNIHR01AR079367
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Mitochondrial pyruvate transport regulates presynaptic metabolism and neurotransmission
(2024) Science Advances, 10 (46), art. no. eadp7423, .
Tiwari, A.a , Myeong, J.a , Hashemiaghdam, A.a , Stunault, M.I.a , Zhang, H.b , Niu, X.b , Laramie, M.A.a , Sponagel, J.a , Shriver, L.P.b , Patti, G.J.b , Klyachko, V.A.a , Ashrafi, G.a c
a Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, United States
b Department of Chemistry, Department of Medicine, Center for Mass Spectrometry and Metabolic Tracing, Washington University in St. Louis, St. Louis, MO, United States
c Needleman Centerfor Neurometabolism and Axonal Therapeutics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Glucose has long been considered the primary fuel source for the brain. However, glucose levels fluctuate in the brain during sleep or circuit activity, posing major metabolic stress. Here, we demonstrate that the mammalian brain uses pyruvate as a fuel source, and pyruvate can support neuronal viability in the absence of glucose. Nerve terminals are sites of metabolic vulnerability, and we show that mitochondrial pyruvate uptake is a critical step in oxidative ATP production in hippocampal terminals. We find that the mitochondrial pyruvate carrier is post-translationally modified by lysine acetylation, which, in turn, modulates mitochondrial pyruvate uptake. Our data reveal that the mitochondrial pyruvate carrier regulates distinct steps in neurotransmission, namely, the spatiotemporal pattern of synaptic vesicle release and the efficiency of vesicle retrieval—functions that have profound implications for synaptic plasticity. In summary, we identify pyruvate as a potent neuronal fuel and mitochondrial pyruvate uptake as a critical node for the metabolic control of neurotransmission in hippocampal terminals. © 2024 The Authors, some rights reserved;
Funding details
Center for Cellular Imaging, Washington UniversityWUCCI
Institute of Clinical and Translational SciencesICTS
Whitehall Foundation
Alvin J. Siteman Cancer CenterSCC
National Institute of Neurological Disorders and StrokeNINDS
Office of Research Infrastructure ProgramsORIP, NIH
Genome Technology Access CenterGTAC
National Center for Research ResourcesNCRR
National Center for Advancing Translational SciencesNCATS
University of WashingtonUW
Ul1TR002345
National Cancer InstituteNCI#P30 CA91842
Georgia Clinical and Translational Science AllianceGaCTSAUL1TR002345
National Institute of General Medical SciencesNIGMSR35 NS111596, R35GM147222
National Institutes of HealthNIHOD021629
Document Type: Article
Publication Stage: Final
Source: Scopus
Thalamic spindles and Up states coordinate cortical and hippocampal co-ripples in humans
(2024) PLoS Biology, 22 (11), art. no. e3002855, .
Dickey, C.W.a b c , Verzhbinsky, I.A.a b , Kajfez, S.d , Rosen, B.Q.a e , Gonzalez, C.E.a , Chauvel, P.Y.f g h , Cash, S.S.i , Pati, S.j , Halgren, E.c k
a Neurosciences Graduate Program, University of California San Diego, La JollaCA, United States
b Medical Scientist Training Program, University of California San Diego, La JollaCA, United States
c Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, United States
d Department of Radiology, University of California San Diego, La JollaCA, United States
e Department of Neuroscience, Washington University in St. Louis, St. Louis, MO, United States
f Aix-Marseille Université, Marseille, France
g INSERM, Institut de Neurosciences des Systèmes UMR 1106, Marseille, France
h APHM (Assistance Publique–Hôpitaux de Marseille), Timone Hospital, Marseille, France
i Department of Neurology, Massachusetts General Hospital, Boston, MA, United States
j Department of Neurology, University of Texas Health Science Center at Houston, Houston, TX, United States
k Department of Neurosciences, University of California San Diego, La JollaCA, United States
Abstract
In the neocortex, ~90 Hz ripples couple to ~12 Hz sleep spindles on the ~1 Hz Down-to-Up state transition during non-rapid eye movement sleep. This conjunction of sleep waves is critical for the consolidation of memories into long-term storage. The widespread co-occurrences of ripples (“co-ripples”) may integrate information across the neocortex and hippocampus to facilitate consolidation. While the thalamus synchronizes spindles and Up states in the cortex for memory, it is not known whether it may also organize co-ripples. Using human intracranial recordings during NREM sleep, we investigated whether cortico-cortical co-ripples and hippocampo-cortical co-ripples are either: (1) driven by directly projected thalamic ripples; or (2) coordinated by propagating thalamic spindles or Up states. We found ripples in the anterior and posterior thalamus, with similar characteristics as hippocampal and cortical ripples, including having a center frequency of ~90 Hz and coupling to local spindles on the Down-to-Up state transition. However, thalamic ripples rarely co-occur or phase-lock with cortical or hippocampal ripples. By contrast, spindles and Up states that propagate from the thalamus strongly coordinate co-ripples in the cortex and hippocampus. Thus, thalamo-cortical spindles and Up states, rather than thalamic ripples, may provide input facilitating spatially distributed co-rippling that integrates information for memory consolidation during sleep in humans. © 2024 Dickey et al.
Funding details
National Institute of Mental HealthNIMH1RF1MH117155-01, T32 MH020002
National Institute of Mental HealthNIMH
N00014-16-1-2829
Document Type: Article
Publication Stage: Final
Source: Scopus
Development, usability, and preliminary efficacy of a virtual reality experience to promote healthy lifestyle behaviors in children: pilot randomized controlled trial
(2024) mHealth, 10, art. no. 29, .
Fowler, L.A.a , Vázquez, M.M.b , DePietro, B.b , Wilfley, D.E.b , Fitzsimmons-Craft, E.E.b c
a Department of Health Promotion, Education, and Behavior, University of South Carolina, Columbia, SC, United States
b Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
c Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background: Virtual reality (VR) shows promise for supporting behavior change in children. This study used user-centered design to translate key tenets of behavioral health interventions into VR for children aged 6–12 years and their caregivers and examined the feasibility, acceptability, and preliminary efficacy of the VR experience in a pilot parallel, two-group randomized controlled trial (RCT). Methods: The VR experience incorporates psychoeducational content from evidence-based behavioral health interventions using voiceover and an interactive go-kart game related to the concepts of “food as fuel” and nutrition guidelines. Study 1 involved usability testing with n=5 child-caregiver dyads, which informed technical and content refinements to the experience. Study 2 involved children aged 6–12 years with body mass index (BMI) ≥85th percentile for age and sex who were comfortable speaking English and their caregivers with BMI ≥25 kg/m2. After participants completed baseline assessments in lab on eating-related behavioral cognitions and behaviors, participants were randomly assigned to the 10-minute VR experience or a control condition (i.e., nutrition education video and mobile phone food game), and were unblinded to condition. Child and caregivers completed assessments immediately post-intervention (eating-related behavioral cognitions) and at 2-week follow-up (behaviors, caregiver readiness to change). The objectives were to evaluate the feasibility, usability, and acceptability of the VR experience, and examine the preliminary efficacy of VR compared to the control condition on the primary outcomes of child behavioral cognitions and behaviors. Non-parametric tests examined differences in change scores across conditions as well as overall and within-group changes in outcomes. Results: Twenty-seven child-caregiver dyads (14 in VR, 13 in control) were enrolled (child mean age =10.4 years; 14 girls). Caregivers reported good usability and excellent immersion in the virtual environment. Children reported significantly greater acceptability of VR compared to control (P=0.02). Child self-efficacy for healthy eating, self-efficacy for physical activity, attitudes toward healthy eating, and behavioral intentions for healthy eating increased from pre- to post-test in both conditions. From baseline to 2-week follow-up, all children reported greater weekly vegetable servings and more active days in the past week. Children in the VR condition had greater change in attitudes towards healthy eating from pre- to post-test compared to children in the control condition [effect size r=0.44, 95% confidence interval (CI): 0.03–0.72]. Readiness to help child change significantly increased for caregivers in the VR condition from pre- to 2-week follow-up, but did not change for caregivers in the control condition. No adverse events were reported. Conclusions: A VR program to promote healthy eating among children shows high feasibility and acceptability, and high potential for improving child and caregiver behavioral cognitions in this pilot RCT. Future work should examine the impact of repeated exposure to the experience over time, and examine long-term effects. © AME Publishing Company.
Author Keywords
behavioral cognitions; child eating behavior; gamification; user-centered design; Virtual reality (VR)
Funding details
National Institutes of HealthNIHK01 MD017630, R01 MH115128-02S1, K08 MH120341
National Institutes of HealthNIH
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKP30 DK092950
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDK
Document Type: Article
Publication Stage: Final
Source: Scopus
Hippocampal volumes in UK Biobank are associated with APOE only in older adults
(2024) Alzheimer’s and Dementia: Diagnosis, Assessment and Disease Monitoring, 16 (4), art. no. e70024, .
Chaloemtoem, A.a , Thornton, V.a , Chang, Y.a , Anokhin, A.P.a , Belloy, M.E.b c , Bijsterbosch, J.d , Gordon, B.A.b d , Hartz, S.M.a , Bierut, L.J.a
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
d Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
INTRODUCTION: The hippocampus atrophies with age and is implicated in neurodegenerative disorders including Alzheimer’s disease (AD). We examined the interplay between age and apolipoprotein E (APOE) genotype on total hippocampal volume. METHODS: Using neuroimaging data from 37,463 UK Biobank participants, we applied linear regression to quantify the association of age and APOE with hippocampal volume and identified the age when volumes of ε2/ε3, ε3/ε4, and ε4/ε4 carriers significantly deviated from ε3/ε3 using generalized additive modeling. RESULTS: Total hippocampal volume declined with age, with significant differences by APOE genotype emerging after age 60. ε3/ε4 and ε4/ε4 carriers displayed reduced volumes from ages 69 and 61, respectively, while ε2/ε3 showed delayed decline starting at the age of 76. DISCUSSION: The association of APOE and hippocampal volume is age-dependent, with differences in volumes of ε4/ε4 carriers detected as early as age 61. This work underscores the importance of APOE genotype in determining when to begin screening for AD. Highlights: Apolipoprotein E (APOE) genotype shows an age-dependent association with total hippocampal volume. No association between APOE and total hippocampal volume was detected before age 60. Accelerated decline was observed in ε4/ε4 carriers at age 61 and ε3/ε4 at age 69. Delayed decline was evident in ε2/ε3 carriers starting at age 76. © 2024 The Author(s). Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
age; Alzheimer’s disease; apolipoprotein E; hippocampus; neurodegeneration; UK Biobank
Funding details
National Institutes of HealthNIH
National Institute on Alcohol Abuse and AlcoholismNIAAAU10AA008401, R01AA027049, R01AA029308
National Institute on Alcohol Abuse and AlcoholismNIAAA
National Institute of Child Health and Human DevelopmentNICHDR21HD112910, R01AA025646
National Institute of Child Health and Human DevelopmentNICHD
Institute of Clinical and Translational SciencesICTS47267, 48123, TL1TR002344
Institute of Clinical and Translational SciencesICTS
National Institute on AgingNIARF1AG079569, R01AG065234, RF1AG082030, U19AG032438, R01AG070139, P01AG026276, RF1AG073424, R01AG073267
National Institute on AgingNIA
National Institute on Drug AbuseNIDAR01DA058114
National Institute on Drug AbuseNIDA
National Institute of Mental HealthNIMHR01MH132962, R01MH128286, R00AG075238
National Institute of Mental HealthNIMH
Document Type: Article
Publication Stage: Final
Source: Scopus
Chronic pain and complex regional pain syndrome are associated with alterations to the intestinal microbiota in both humans and mice. An observational cross-sectional study
(2024) Neurobiology of Pain, 16, art. no. 100173, .
Crock, L.W.a , Rodgers, R.b , Huck, N.A.c , Schriefer, L.A.b , Lawrence, D.b , Wang, L.b , Muwanga, G.P.B.c , Tawfik, V.L.c , Baldridge, M.T.b d
a Department of Anesthesiology and Pain Medicine, Washington University in St. Louis, St. Louis, MO, United States
b Division of Infectious Diseases, Department of Medicine, Edison Family Center for Genome Sciences & Systems Biology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA, United States
d Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: This study aimed to evaluate pain metrics and gut microbiota differences from human subjects with complex regional pain syndrome (CRPS) compared to cohabitants (HHC) and non-cohabitating (biobank) controls. In addition, we aimed evaluate longitudinal changes of gut microbiota using a mouse model of acute and chronic CRPS. Methods: In an observational, cross-sectional study, 25 patients with CRPS and 24 household controls (HHC) were recruited, completed pain questionnaires, and submitted stool samples. 23 biobank stool samples were matched to the CRPS group. Additionally, longitudinal stool samples were collected from a mouse model of acute and chronic CRPS. 16S rRNA gene sequencing analysis was performed on all samples. Results: A diagnosis of CRPS is associated with higher pain, increased pain interference, and decreased physical and social function when compared to HHC. Interestingly, 46% of HHC reported significant daily pain. In the households where HHC were also suffering from pain, there was decreased bacterial richness and diversity when compared to households wherein only the participant with CRPS suffered from pain. Furthermore, when comparing households where the HHC had significant pain, CRPS was clinically more severe. In the mouse model of CRPS, we observed decreased bacterial richness and diversity when compared to non-cohabitating littermate controls. Conclusions: Both humans living in chronic pain households and mice shared distinct taxa over the time course of disease and pain chronicity. These findings suggest that microbiota changes seen in CRPS as well as in a mouse model of CRPS may reflect pain chronicity and may indicate that pain alone can contribute to microbiota dysbiosis. The trial was registered at ClinicalTrials.gov (NCT03612193). © 2024 The Author(s)
Author Keywords
Chronic pain; Complex regional pain syndrome; Gut microbiota; Injury; Microbiome
Funding details
International Anesthesia Research SocietyIARS
National Institute of Diabetes and Digestive and Kidney DiseasesNIDDKP30 DK052574
National Institutes of HealthNIHR35 GM137906
Document Type: Article
Publication Stage: Final
Source: Scopus
Unlocking Cognitive Analysis Potential in Alzheimer’s Disease Clinical Trials: Investigating Hierarchical Linear Models for Analyzing Novel Measurement Burst Design Data
(2024) Statistics in Medicine, .
Wang, G.a b , Hassenstab, J.a , Li, Y.a , Aschenbrenner, A.J.a , McDade, E.M.a , Llibre-Guerra, J.a , Bateman, R.J.a , Xiong, C.b
a Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
b Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Measurement burst designs typically administer brief cognitive tests four times per day for 1 week, resulting in a maximum of 28 data points per week per test for every 6 months. In Alzheimer’s disease clinical trials, utilizing measurement burst designs holds great promise for boosting statistical power by collecting huge amount of data. However, appropriate methods for analyzing these complex datasets are not well investigated. Furthermore, the large amount of burst design data also poses tremendous challenges for traditional computational procedures such as SAS mixed or Nlmixed. We propose to analyze burst design data using novel hierarchical linear mixed effects models or hierarchical mixed models for repeated measures. Through simulations and real-world data applications using the novel SAS procedure Hpmixed, we demonstrate these hierarchical models’ efficiency over traditional models. Our sample simulation and analysis code can serve as a catalyst to facilitate the methodology development for burst design data. © 2024 John Wiley & Sons Ltd.
Author Keywords
Alzheimer’s disease; hierarchical linear mixed effects model; hierarchical mixed models for repeated measures; measurement burst design data; SAS
Funding details
National Institute on AgingNIAR01 AG059798, R01AG057840
National Institute on AgingNIA
GHR FoundationGHRR01AG057840
GHR FoundationGHR
National Institutes of HealthNIHU19 AG032438, U01 AG042791‐01A1
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Plasma pTau217 ratio predicts continuous regional brain tau accumulation in amyloid-positive early Alzheimer’s disease
(2024) Alzheimer’s and Dementia, .
Devanarayan, V.a b , Charil, A.a , Horie, K.a c d , Doherty, T.e , Llano, D.A.f g h , Andreozzi, E.a , Sachdev, P.a , Ye, Y.a , Murali, L.K.a , Zhou, J.a , Reyderman, L.a , Hampel, H.a , Kramer, L.D.a , Dhadda, S.a , Irizarry, M.C.a , for the Alzheimer’s Disease Neuroimaging Initiative (ADNI)i
a Clinical Evidence Generation, Eisai Inc., Nutley, NJ, United States
b Department of Mathematics, Statistics and Computer Science, University of Illinois Chicago, Chicago, IL, United States
c The Tracy Family SILQ Center, Washington University School of Medicine, St Louis, MO, United States
d Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
e Clinical Evidence Generation, Eisai Ltd., Hatfield, United Kingdom
f Biomedical and Translational Sciences, Carle Illinois College of Medicine, Urbana, IL, United States
g Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, United States
h Intelligent Systems, Beckman Institute for Advanced Science and Technology, Urbana, IL, United States
Abstract
BACKGROUND: This study examines whether phosphorylated plasma Tau217 ratio (pTau217R) can predict tau accumulation in different brain regions, as measured by positron emission tomography (PET) standardized uptake value ratio (SUVR), for staging Alzheimer’s disease (AD). METHODS: Plasma pTau217R was measured using immunoprecipitation-mass spectrometry. Models for predicting tau PET SUVR, developed with 144 early AD individuals using [18F]MK6240, were validated in two validation sets, VS1 (98 early AD) and VS2 (47 preclinical/early AD with a different tracer, flortaucipir (Tauvid)), all amyloid-beta positive (Aβ+). RESULTS: The pTau217R-based model predicted tau levels up to an SUVR of 2 in multiple brain regions, effectively assessing tau status at different tau levels with receiver operating characteristic (ROC) curve areas of 0.84–0.95 in VS1 and 0.71–0.88 in VS2 (using a different tracer). It reduced PET scan needs by 65% while maintaining 95% sensitivity. DISCUSSION: PTau217R reliably predicts regional tau accumulation in early AD, reducing reliance on tau PET scans and broadening its clinical application. CLINICAL TRIAL REGISTRATION NUMBER: NCT03887455 (ClarityAD). Highlights: Developed a model using plasma pTau217R to predict tau levels across brain regions. pTau217R model outperformed models based on clinical, MRI, and other blood biomarkers. The model reliably predicted tau levels exceeding tau positivity and higher thresholds. Screening with pTau217R could reduce tau PET scans by 65% at 95% sensitivity. pTau217R model aids in disease staging and monitoring in early AD. © 2024 Eisai Inc. Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
blood–based biomarkers; diagnosis; disease continuum; disease staging; patient monitoring; patient screening; prediction; Tau PET
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Depression, sleep and pain affect instrumental activities of daily living through cognitive functioning in adults with sickle cell disease: A report from the Sickle Cell Disease Implementation Consortium
(2024) British Journal of Haematology, .
Longoria, J.N.a , Howell, K.E.b , Porter, J.S.a , Treadwell, M.c , King, A.A.d , Gordeuk, V.e , Shah, N.f , Abrams, C.M.g , McCuskee, S.h , Gollan, S.i , Hankins, J.S.j , Heitzer, A.M.a , the Sickle Cell Disease Implementation Consortiumk
a Department of Psychology and Biobehavioral Sciences, St. Jude Children’s Research Hospital, Memphis, TN, United States
b Epidemiology and Biostatistics, Texas A&M University, College Station, TX, United States
c Department of Pediatrics, Division of Hematology, University of California San Francisco, Oakland, CA, United States
d Department of Pediatrics and Medicine, Washington University, St. Louis, MO, United States
e Department of Medicine, University of Illinois at Chicago, Chicago, IL, United States
f Department of Medicine, Duke University, Durham, NC, United States
g Department of Pediatrics, Medical University of South Carolina, Charleston, SC, United States
h Department of Emergency Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
i Augusta University, Augusta, GA, United States
j Hematology and Global Pediatric Medicine, St. Jude Children’s Research Hospital, Memphis, TN, United States
Abstract
Depression, disrupted sleep and pain are common comorbidities in sickle cell disease. We tested (1) if these comorbidities are associated with attention/executive functioning, processing speed and instrumental activities of daily living (IADLs), which describe complex skills that support independence, and (2) if cognitive symptoms mediate the relationship between comorbidities and IADLs. Participants (n = 2417) completed patient-reported outcome measures through the Sickle Cell Disease Implementation Consortium. Mean age of participants was 28 years and HbSS/Sβ0 genotypes were prevalent (73%). Comorbidities of depression, pain frequency and disrupted sleep were associated with processing speed and attention/executive functioning (all p < 0.01) when controlling for stroke and demographics. IADLs were associated with depression, pain, sleep, attention/executive functioning, income (<$25 000) (all p < 0.001) and genotype (p = 0.0025) after controlling for covariates. The indirect effects of attention/executive functioning and processing speed were both significant (p < 0.001) in mediation models that examined pathways between comorbidities and IADLs. Attention/executive functioning accounted for 17.5% of the relationship between depression and IADLs and sleep and IADLs. Processing speed explained 10% of the relationship between sleep and IADLs and 8% of the relationship between depression and IADLs. Managing comorbidities should be prioritized to mitigate cognitive symptoms and improve complex daily living skills. © 2024 British Society for Haematology and John Wiley & Sons Ltd.
Author Keywords
cognitive; depression; instrumental activities of daily living; pain; sickle cell disease; sleep
Funding details
National Heart, Lung, and Blood InstituteNHLBI
National Institute on Minority Health and Health DisparitiesNIMHDK23HL166697
National Institute on Minority Health and Health DisparitiesNIMHD
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Role of Cardiovascular Risk in Associations of Brain-Derived Neurotrophic Factor with Longitudinal Brain and Cognitive Trajectories in Older Adults
(2024) Experimental Aging Research, .
Shearon, J.a , Jackson, J.a , Head, D.a b c , for the Alzheimer’s Disease Neuroimaging Initiatived
a Department of Psychological and Brain Sciences, Washington University, St. Louis, MO, United States
b Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
c Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Background: Higher levels of brain-derived neurotrophic factor (BDNF) have been associated with better neurocognitive outcomes. BDNF is present in cardiovascular tissue, and some evidence suggests it may benefit cardiovascular function. The current study assessed whether there is a mediating and/or moderating role of cardiovascular health in the relationship between BDNF and brain and cognitive outcomes. Method: We examined longitudinal data from 397 older adults (aged 54–89;164 females, 233 males) enrolled in the Alzheimer’s Disease Neuroimaging Initiative with available plasma BDNF, medical, neuroimaging, and cognitive assessments. We used path analysis and linear regression to estimate the mediating and moderating roles of two measures of cardiovascular health, the Framingham Risk Score (FRS) and pulse pressure, in the relationships between BDNF and longitudinal changes in brain structure (white matter hyperintensity volume, hippocampal volume, and primary visual cortex volume) and cognitive function (executive function, episodic memory, and language). Results: There was no significant association of plasma BDNF with FRS or pulse pressure (ps > 0.31), precluding mediation. There were no robust associations between BDNF and longitudinal change in any brain structural or cognitive measures (ps >.12). Higher FRS was significantly associated with greater increases in WMH volume (ps <.01). FRS and pulse pressure were not associated with any other brain structural or cognitive outcomes (ps >.07). Conclusion: These results suggest that cardiovascular health may not play an important role in the influence of BDNF on neurocognitive health in older adults. © 2024 Taylor & Francis Group, LLC.
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
A Comparison of two Maps of the Human Neocortex: the multimodal MRI-based parcellation of Glasser et al. (2016a), and the myeloarchitectonic parcellation of Nieuwenhuys and Broere (2023), as a first step toward a unified, canonical map
(2024) Brain Structure and Function, .
Nieuwenhuys, R.a b , Glasser, M.F.c
a The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, Amsterdam, 1105 BA, Netherlands
b Department of Medical Imaging, Anatomy, Radboud University Medical Center, P.O. Box 9101, Nijmegen, 6500 HB, Netherlands
c Departments of Radiology, Neuroscience, and Biomedical Engineering, Washington University Medical School, St. Louis, MO, United States
Abstract
The first, introductory part of this paper presents an overview of the long quest for a universal map of the human cortex, useful as a standard reference for all remaining studies on this brain part. It is pointed out that such a map does still not exist, but that systematic comparison of some recently produced 3D maps may well be conducive toward this important goal. Hence, the second part of this article is devoted to a detailed comparison of two of such maps, the multimodal MRI-based parcellation of Glasser et al. (Nature 536:171–178, 2016) and the myeloarchitectonic parcellation presented by Nieuwenhuys and Broere (Brain Struct Funct 228:1549–1559, 2023), with the specific aim to detect areal concordances between these two maps. In the search for these concordances, the following three criteria were used: (1) the relative or topological position of the various areas, (2) the relation of the areas to particular invariant sulci, and (3) the overall myelin content of the areas. In total 61 concordances were detected, most of which were located in the frontal and parietal lobes. These concordances were recorded in standard views of the two maps compared (Figs. 5, 6, 7, 8), as well as in Table 1. We consider these findings as a first step towards the creation of a unified, consensus (canonical) parcellation of the human neocortex. © The Author(s) 2024.
Author Keywords
Architectonics; Canonical map; Cerebral cortex; Cortical areas; Cytoarchitectonics; Myeloarchitectonics; Neuroimaging
Funding details
National Institute of Mental HealthNIMHR01MH60974
National Institute of Mental HealthNIMH
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Benchmarking of a multi-biomarker low-volume panel for Alzheimer’s disease and related dementia research
(2024) Alzheimer’s and Dementia, .
Ibanez, L.a b c , Liu, M.a c , Beric, A.a c , Timsina, J.a c , Kohlfeld, P.a c , Bergmann, K.a c , Lowery, J.a c , Sykora, N.a c , Sanchez-Montejo, B.a c , Brock, W.a c , Budde, J.P.a c , Bateman, R.J.b d e f , Barthelemy, N.b e , Schindler, S.E.b d f , Holtzman, D.M.b d f , Benzinger, T.L.S.d f g , Xiong, C.h , Tarawneh, R.i , Moulder, K.b f , Morris, J.C.b f , Sung, Y.J.a c , Cruchaga, C.a b c d f j
a Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c NeuroGenomics and Informatics Center, Washington University School of Medicine, St. Louis, MO, United States
d Hope Center for Neurologic Diseases, Washington University School of Medicine, St. Louis, MO, United States
e The Tracy Family SILQ Center, Washington University School of Medicine, St. Louis, MO, United States
f Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, United States
g Department of Radiology, Washington University School of Medicine, St. Louis, MO, United States
h Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
i Department of Neurology, University of New Mexico School of Medicine, Albuquerque, NM, United States
j Department of Genetics, Washington University School of Medicine, St. Louis, MO, United States
Abstract
INTRODUCTION: In the research setting, obtaining accurate established biomarker measurements and maximizing use of the precious samples is key. Accurate technologies are available for Alzheimer’s disease (AD), but no platform can measure all the established and emerging biomarkers in one run. The NUcleic acid Linked Immuno-Sandwich Assay (NULISA) is a technology that requires 15 µL of sample to measure more than 100 analytes. METHODS: We compared AD-relevant biomarkers included in the NULISA against validated assays in cerebrospinal fluid (CSF) and plasma. RESULTS: CSF measures of amyloid beta 42/40, and phosphorylated tau (p-tau)217 are highly correlated when measured by immunoassay, mass spectrometry, or NULISA. In plasma, p-tau217 performance is similar to that reported with other technologies when predicting amyloidosis. Other biomarkers show a wide range of correlation values depending on the fluid and the platform. DISCUSSION: The NULISA multiplexed platform produces reliable results for established biomarkers in CSF that are useful in research settings, with the advantage of measuring additional biomarkers using minimal sample volume. Highlights: We tested the novel technology NUcleic acid Linked Immuno-Sandwich Assay (NULISA) in the dementia research setting. NULISA multiplexed platform produces reliable results for established and emerging biomarkers using minimal sample volume. Cerebrospinal fluid measures of amyloid beta 42/40, and phosphorylated tau (p-tau)217 are highly correlated when measured by immunoassay, mass spectrometry, or NULISA. In plasma, p-tau217 performance is similar to that reported with other technologies when predicting amyloidosis. NULISA measures are useful in research settings, with the advantage of measuring additional biomarkers using minimal sample volume. © 2024 The Author(s). Alzheimer’s & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer’s Association.
Author Keywords
amyloidosis biomarkers; biomarkers; multiplex; NUcleic acid Linked Immuno-Sandwich Assay
Funding details
Hope Center for Neurological Disorders, Washington University in St. Louis
Chan Zuckerberg InitiativeCZI
Michael J. Fox Foundation for Parkinson’s ResearchMJFF
Alzheimer’s Drug Discovery FoundationADDF
National Institutes of HealthNIHRF1AG053303, P01AG003991, U01AG058922, R01AG044546, RF1AG074007, R01AG070941, RF1AG058501, K99/R00‐AG062723
National Institutes of HealthNIH
Alzheimer’s AssociationAAZEN‐22‐848604
Alzheimer’s AssociationAA
Division of Social and Economic SciencesSESRF1AG083744
Division of Social and Economic SciencesSES
U.S. Department of DefenseDODW81XWH2010849
U.S. Department of DefenseDOD
P30AG066444, P01AG03991, P01AG026276
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Stereospecific Properties and Intracellular Transport of Novel Intrinsically Fluorescent Neurosteroids
(2024) ACS Chemical Neuroscience, .
Akkerman, V.a , Reinholdt, P.b , Schnoor-Madsen, R.a , Lauritsen, L.a , Bader, J.c , Qian, M.d , Xu, Y.d , Akk, G.c , Scheidt, H.A.e , Müller, P.f , Covey, D.F.g , Evers, A.S.g , Kongsted, J.b , Wüstner, D.a
a Department of Biochemistry and Molecular Biology, University of Southern Denmark, Campusvej 55, Odense M, DK-5230, Denmark
b Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, Odense M, DK-5230, Denmark
c Department of Anesthesiology, Washington University in St. Louis, St. Louis, MO 63110, United States
d Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO 63110, United States
e Institute for Medical Physics and Biophysics, Leipzig University, Härtelstr. 16-18, Leipzig, 04107, Germany
f Department of Biology, Humboldt University Berlin, Invalidenstr. 42, Berlin, 10115, Germany
g Department of Developmental Biology, Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis, St. Louis, MO 63110, United States
Abstract
Allopregnanolone (AlloP) is an example of neuroactive steroids (NAS), which is a potent allosteric activator of the γ-aminobutyric acid A (GABAA) receptor. The mechanisms underlying the biological activity of AlloP and other NAS are only partially understood. Here, we present intrinsically fluorescent analogs of AlloP (MQ-323) and its 3β-epimer, epi-allopregnanolone (E-AlloP) (YX-11), and show, by a combination of spectroscopic and computational studies, that these analogs mimic the membrane properties of AlloP and E-AlloP very well. We found stereospecific differences in the orientation and dynamics of the NAS as well as in their impact on membrane permeability. However, all NAS are unable to condense the lipid bilayer, in stark contrast to cholesterol. Using Förster resonance energy transfer (FRET) and electrophysiological measurements, we show that MQ-323 but not YX-11 binds at the intersubunit site of the ELICα1GABAA receptor and potentiates GABA-induced receptor currents. In aqueous solvents, YX-11 forms aggregates at much lower concentrations than MQ-323, and loading both analogs onto cyclodextrin allows for their uptake by human astrocytes, where they become enriched in lipid droplets (LDs), as shown by quantitative fluorescence microscopy. Trafficking of the NAS analogs is stereospecific, as uptake and lipid droplet targeting is more pronounced for YX-11 compared to MQ-323. In summary, we present novel minimally modified analogs of AlloP and E-AlloP, which enable us to reveal stereospecific membrane properties, allosteric receptor activation, and intracellular transport of these neurosteroids. Our fluorescence design strategy will be very useful for the analysis of other NAS in the future. © 2024 American Chemical Society.
Author Keywords
allopregnanolone; astrocytes; fluorescence; microscopy; probes; trafficking
Funding details
National Institutes of HealthNIH
National Institute of General Medical SciencesNIGMSR35GM149287, R35GM140947, 1 P50 MH122379
National Institute of General Medical SciencesNIGMS
Deutsche ForschungsgemeinschaftDFGMU 1017/14-1
Deutsche ForschungsgemeinschaftDFG
Lundbeck FoundationR366-2021-226
Lundbeck Foundation
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
The associations between well-being and Cloninger’s personality dimensions in a Korean community sample
(2024) PeerJ, 12 (11), art. no. e18379, .
Lee, S.J.a , Cloninger, R.b c , Chae, H.d
a Department of Psychology, Kyungsung University, Busan, South Korea
b Department of Psychiatry, Washington University in St. Louis, St. Louis, MO, United States
c Anthropedia Foundation, St. Louis, MO, United States
d School of Korean Medicine, Pusan National University, Busan, South Korea
Abstract
Background. Well-being is a multidimensional construct comprising affective and non-affective components. Previous research has consistently linked personality traits to well-being, yet cultural variations in this association remain underexplored, particularly in collectivistic cultures such as Korea. Therefore, this study aims to identify universal and culture-specific characteristics of personality in relation to well-being. Methods. A sample of 527 Korean university students participated, providing data through the Korean version of the Temperament and Character Inventory-RS (TCI-RS), self-rated health (SRH), social support (SS), Satisfaction With Life Scale (SWLS), and positive and negative affect schedule (PANAS). Pearson correlation analysis and ANCOVA, with sex and age as covariates, were employed to examine linear associations. Multidimensional personality profiles were utilized to investigate nonlinear associations among character dimensions on different aspects of well-being. All analysis was performed using jamovi 2.3.12. Results. Self-directedness and cooperativeness exhibited positive linear associations with both affective (positive and negative affect) and non-affective (SRH, SS, SWLS) components of well-being. Self-directedness emerged as a key predictor across various well-being aspects. Cooperativeness was strongly associated with perception of social support. Self-transcendence showed positive associations with both positive and negative affect, considering interactions with other character dimensions. Discussion. While self-directedness played a pivotal role universally, the impact of cooperativeness and self-transcendence appeared to be influenced by cultural factors, enhancing perception of social support and affecting both positive and negative affect in a collectivistic culture. This study illustrates the importance of considering cultural nuances in the relationship between personality and well-being. Future research should delve deeper into cultural differences, emphasizing the need for subtle interpretations of specific personality traits within diverse cultural contexts. Copyright 2024 Lee et al.
Author Keywords
negative affect schedule; Positive; Satisfaction with life scale; Self-rated health; Social support; Temperament and character; Well-being
Document Type: Article
Publication Stage: Final
Source: Scopus
Design and In Vivo Testing of an Anatomic 3D-Printed Peripheral Nerve Conduit in a Rat Sciatic Nerve Model
(2024) HSS Journal, .
Chang, P.S.a , Lee, T.Y.b , Kneiber, D.c , Dy, C.J.d , Ward, P.M.e , Kazarian, G.f , Apostolakos, J.g , Brogan, D.M.d
a Department of Orthopaedic Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
b School of Medicine, Saint Louis University, St. Louis, MO, United States
c Department of Anesthesiology, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, United States
d Department of Orthopaedic Surgery, School of Medicine, Washington University, St. Louis, MO, United States
e Department of Orthopaedic Surgery, University of Chicago, Chicago, IL, United States
f Hospital for Special Surgery, New York, NY, United States
g Department of Orthopaedic Surgery, Case Western Reserve University, Cleveland, OH, United States
Abstract
Background: Three-dimensional (3D) printer technology has seen a surge in use in medicine, particularly in orthopedics. A recent area of research is its use in peripheral nerve repair, which often requires a graft or conduit to bridge segmental defects. Currently, nerve gaps are bridged using autografts, allografts, or synthetic conduits. Purpose: We sought to improve upon the current design of simple hollow, cylindrical conduits that often result in poor nerve regeneration. Previous attempts were made at reducing axonal dispersion with the use of multichanneled conduits. To our knowledge, none has attempted to mimic and test the anatomical topography of the nerve. Methods: Using serial histology sections, 3D reconstruction software, and computer-aided design, a scaffold was created based on the fascicular topography of a rat sciatic nerve. A 3D printer produced both cylindrical conduits and topography-based scaffolds. These were implanted in 12 Lewis rats: 6 rats with the topographical scaffold and 6 rats with the cylindrical conduit. Each rodent’s uninjured contralateral limb was used as a control for comparison of functional and histologic outcomes. Walking track analysis was performed, and the Sciatic Functional Index (SFI) was calculated with the Image J software. After 6 weeks, rats were sacrificed and analyses performed on the regenerated nerve tissue. Primary outcomes measured included nerve (fiber) density, nerve fiber width, total number of nerve fibers, G-ratio (ratio of axon width to total fiber width), and percent debris. Secondary outcomes measured included electrophysiology studies of electromyography (EMG) latency and EMG amplitude and isometric force output by the gastrocnemius and tibialis anterior. Results: There were no differences observed between the cylindrical conduit and topographical scaffold in terms of histological outcomes, muscle force, EMG, or SFI. Conclusion: This study of regeneration of the sciatic nerve in a rat model suggests the feasibility of 3D-printed topographical scaffolds. More research is required to quantify the functional outcomes of this technology for peripheral nerve regeneration. © The Author(s) 2024.
Author Keywords
conduit; nerve conduit; nerve injury; nerve surgery; peripheral nerve conduit; peripheral nerve injuryDocument Type: Article
Publication Stage: Article in Press
Source: Scopus
Family income and polygenic scores are independently but not interactively associated with cognitive performance among youth genetically similar to European reference populations
(2024) Development and Psychopathology, .
Paul, S.E.a , Elsayed, N.M.a , Colbert, S.M.C.b , Bogdan, R.a , Hatoum, A.S.a , Barch, D.M.a b c
a Department of Psychological and Brain Sciences, Washington University in St. Louis, St. Louis, United States
b Department of Psychiatry, Washington University, School of Medicine, St. Louis, United States
c Department of Radiology, Washington University, School of Medicine, St. Louis, United States
Abstract
Cognitive abilities are heritable and influenced by socioeconomic status (SES). It is critical to understand the association between SES and cognition beyond genetic propensity to inform potential benefits of SES-based interventions and to determine if such associations vary across (i) cognitive domains, (ii) facets of SES, and/or (iii) genetic propensity for different aspects of cognition. We examined the contributions of neighborhood socioeconomic advantage, family income, and polygenic scores (PGS) for domains of cognition (i.e., general cognitive ability, executive function, learning and memory, fluid reasoning) in a sample of children (ages 9-10; n = 5549) most genetically similar to reference populations from Europe. With some variability across cognitive outcomes, family income and PGS were independently significantly associated with cognitive performance. Within-sibling analyses revealed that cognitive PGS associations were predominantly driven by between-family effects suggestive of non-direct genetic mechanisms. These findings provide evidence that SES and genetic propensity to cognition have unique associations with cognitive performance in middle childhood. These results underscore the importance of environmental factors and genetic influences in the development of cognitive abilities and caution against overinterpreting associations with PGS of cognitive and educational outcomes as predominantly direct genetic effects. © The Author(s), 2024.
Author Keywords
cognitive ability; familial income; gene-environment interaction; neighborhood advantage; polygenic risk scores
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
ReNeu: A Pivotal, Phase IIb Trial of Mirdametinib in Adults and Children with Symptomatic Neurofibromatosis Type 1-Associated Plexiform Neurofibroma
(2024) Journal of Clinical Oncology, art. no. JCO.24.01034, .
Moertel, C.L.a , Hirbe, A.C.b , Shuhaiber, H.H.c , Bielamowicz, K.d , Sidhu, A.e , Viskochil, D.f , Weber, M.D.g , Lokku, A.g , Smith, L.M.g , Foreman, N.K.h , Hajjar, F.M.i , McNall-Knapp, R.Y.j , Weintraub, L.k , Antony, R.l , Franson, A.T.m , Meade, J.n , Schiff, D.o , Walbert, T.p , Ambady, P.q , Bota, D.A.r , Campen, C.J.s , Kaur, G.t , Klesse, L.J.u , Maraka, S.v , Moots, P.L.w , Nevel, K.x , Bornhorst, M.y , Aguilar-Bonilla, A.z , Chagnon, S.aa , Dalvi, N.ab , Gupta, P.ac , Khatib, Z.ad , Metrock, L.K.ae , Nghiemphu, P.L.af , Roberts, R.D.ag , Robison, N.J.ah , Sadighi, Z.ai , Stapleton, S.aj , Babovic-Vuksanovic, D.ak , Gershon, T.R.al , Raslan, A.am , Tine, B.V.an , Koschmann, C.m , Capal, J.K.ao , Slopis, J.ap , Gill, J.ap , Kilburn, L.aq , Mrugala, M.M.ar , Dhamija, R.ar , Merrell, R.as , ReNeu Trial Investigatorsat
a Department of Pediatrics, University of Minnesota, Minneapolis, MN, United States
b Washington University, School of Medicine in St Louis, St Louis, MO, United States
c University of Florida Clinical Research Center, Gainesville, FL, United States
d The University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, AR, United States
e University of Iowa Hospitals and Clinics, Iowa City, IA, United States
f University of Utah, Salt Lake City, UT, United States
g SpringWorks Therapeutics, Inc, Stamford, CT, United States
h Children’s Hospital Colorado, Aurora, CO, United States
i AdventHealth for Children, Orlando, FL, United States
j University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States
k Albany Medical Center, Albany, NY, United States
l University of California Davis, Sacramento, CA, United States
m University of Michigan, Ann Arbor, MI, United States
n University of Pittsburgh School of Medicine, Pittsburgh, PA, United States
o University of Virginia Medical Center, Charlottesville, VA, United States
p Wayne State University, Michigan State University, Henry Ford Health, Detroit, MI, United States
q Oregon Health and Science University, Portland, OR, United States
r University of California, Irvine, CA, United States
s Stanford/Lucile Packard Children’s Hospital and Stanford Children’s Health, Palo Alto, CA, United States
t Columbia University Medical Center, New York Presbyterian Morgan Stanley Children’s Hospital, New York, NY, United States
u University of Texas Southwestern/Children’s Health, Dallas, TX, United States
v University of Illinois at Chicago, Chicago, IL, United States
w Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, TN, United States
x Indiana University Health, Indiana University School of Medicine, Indianapolis, IN, United States
y Children’s National Hospital, Washington, DC, United States
z Orlando Health, Inc, Orlando, FL, United States
aa Children’s Hospital of the Kings Daughters, Norfolk, VA, United States
ab Montefiore Medical Center, Children’s Hospital at Montefiore, New York City, NY, United States
ac St Joseph’s Regional Medical Center, Paterson, NJ, United States
ad Nicklaus Children’s Hospital, Miami, FL, United States
ae University of Alabama at Birmingham, Birmingham, AL, United States
af University of CaliforniaLos Angeles (UCLA), Los Angeles, CA, United States
ag Nationwide Children’s Hospital, Columbus, OH, United States
ah Children’s Hospital Los Angeles, Los Angeles, CA, United States
ai University of Texas Md Anderson Cancer Center, Houston, TX, United States
aj Johns Hopkins All Children’s Hospital, St Petersburg, FL, United States
ak Mayo Clinic, Rochester, MN, United States
al Department of Pediatrics, Emory University, Atlanta, GA, United States
am Oregon Health and Science University (OHSU), Portland, OR, United States
an Washington University School of Medicine- Siteman Cancer Center, St Louis, MO, United States
ao Unc Neurology Clinical Trials Unit, Chapel Hill, NC, United States
ap The University of Texas Md Anderson Cancer Center, Houston, TX, United States
aq Children’s National Medical Center, Washington, DC, United States
ar Mayo Clinic Hospital, Phoenix, AZ, United States
as Henry-Joyce Cancer Clinic, Nashville, TN, United States
Abstract
PURPOSE Pharmacologic therapies for neurofibromatosis type 1-associated plexiform neurofibromas (NF1-PNs) are limited; currently, none are US Food and Drug Administration-approved for adults.METHODSReNeu is an open-label, multicenter, pivotal, phase IIb trial of mirdametinib in 58 adults (≥18 years of age) and 56 children (2 to 17 years of age) with NF1-PN causing significant morbidities. Patients received mirdametinib capsules or tablets for oral suspension (2 mg/m2 twice daily, maximum 4 mg twice daily), regardless of food intake, in 3 weeks on/1 week off 28-day cycles. The primary end point was confirmed objective response rate (ORR; proportion of patients with a ≥20% reduction of target PN volume from baseline on consecutive scans during the 24-cycle treatment phase) assessed by blinded independent central review (BICR) of volumetric magnetic resonance imaging.RESULTSTwenty-four of 58 adults (41%) and 29 of 56 children (52%) had a BICR-confirmed objective response during the 24-cycle treatment phase; in addition, two adults and one child had confirmed responses during long-term follow-up. Median (range) target PN volumetric best response was -41% (-90 to 13) in adults and -42% (-91 to 48) in children. Both cohorts reported significant and clinically meaningful improvement in patient- or parent proxy-reported outcome measures of worst tumor pain severity, pain interference, and health-related quality of life (HRQOL) that began early and were sustained during treatment. The most commonly reported treatment-related adverse events were dermatitis acneiform, diarrhea, and nausea in adults and dermatitis acneiform, diarrhea, and paronychia in children.CONCLUSIONIn ReNeu, the largest multicenter NF1-PN trial reported to date, mirdametinib treatment demonstrated significant confirmed ORRs by BICR, deep and durable PN volume reductions, and early, sustained, and clinically meaningful improvement in pain and HRQOL. Mirdametinib was well-tolerated in adults and children. © American Society of Clinical Oncology.
Funding details
Springworks Therapeutics
Document Type: Article
Publication Stage: Article in Press
Source: Scopus