“Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons” (2021) Nature Communications
Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons
(2021) Nature Communications, 12 (1), art. no. 4251, .
Pearson, T.S.a b , Gupta, N.a , San Sebastian, W.a , Imamura-Ching, J.a , Viehoever, A.c , Grijalvo-Perez, A.c , Fay, A.J.c , Seth, N.d , Lundy, S.M.e , Seo, Y.f , Pampaloni, M.f , Hyland, K.g , Smith, E.h , de Oliveira Barbosa, G.i , Heathcock, J.C.i , Minnema, A.j , Lonser, R.j , Elder, J.B.j , Leonard, J.j k , Larson, P.a , Bankiewicz, K.S.a j
a Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurology, University of California San Francisco, San Francisco, CA, United States
d Department of Rehabilitative Services, University of California San Francisco, San Francisco, CA, United States
e Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
f Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, United States
g Medical Neurogenetics Laboratories, Atlanta, GA, United States
h Therapy Services, St. Louis Children’s Hospital, St. Louis, MO, United States
i School of Health and Rehabilitation Sciences, The Ohio State University, Columbus, OH, United States
j Department of Neurological Surgery, The Ohio State University, Columbus, OH, United States
k Department of Neurological Surgery, Nationwide Children’s Hospital, Columbus, OH, United States
Abstract
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4–9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function. © 2021, The Author(s).
Funding details
National Institutes of HealthNIH1 × 01 NS073514-01, R01NS094292
National Institute of Neurological Disorders and StrokeNINDS
Ohio State UniversityOSU
AADC Research Trust
Pediatric Neurotransmitter Diseases Association
Document Type: Article
Publication Stage: Final
Source: Scopus
“Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism” (2021) Human Genomics
Coding and noncoding variants in EBF3 are involved in HADDS and simplex autism
(2021) Human Genomics, 15 (1), art. no. 44, .
Padhi, E.M.a , Hayeck, T.J.b c , Cheng, Z.d , Chatterjee, S.e , Mannion, B.J.f , Byrska-Bishop, M.g , Willems, M.h , Pinson, L.h , Redon, S.i , Benech, C.i , Uguen, K.i , Audebert-Bellanger, S.j , Le Marechal, C.i , Férec, C.i , Efthymiou, S.k , Rahman, F.l , Maqbool, S.k l , Maroofian, R.k , Houlden, H.k , Musunuri, R.g , Narzisi, G.g , Abhyankar, A.g , Hunter, R.D.f , Akiyama, J.f , Fries, L.E.e , Ng, J.K.a , Mehinovic, E.a , Stong, N.m , Allen, A.S.n o p , Dickel, D.E.f , Bernier, R.A.q , Gorkin, D.U.d r , Pennacchio, L.A.f s , Zody, M.C.g , Turner, T.N.a
a Department of Genetics, Washington University School of Medicine, 4523 Clayton Avenue, Campus Box 8232, St. Louis, MO 63110, United States
b Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
c Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, United States
d Center for Epigenomics, University of California San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, United States
e Center for Human Genetics and Genomics, NYU School of Medicine, New York, NY 10016, United States
f Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, United States
g New York Genome Center, New York, NY 10013, United States
h University of Montpellier, département de Génétique, maladies rares médecine personnalisée, U 1298, CHU Montpellier, University of Montpellier, Montpellier, France
i CHU Brest, Inserm, Univ Brest, EFS,UMR 1078, GGB, Brest, F-29200, France
j Service de Génétique Médicale, CHRU de Brest, Brest, France
k Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom
l Development and Behavioral Pediatrics Department, Institute of Child Health and Children Hospital, Lahore, Pakistan
m Institute for Genomic Medicine, Columbia University, New York, NY 10027, United States
n Center for Statistical Genetics and Genomics, Duke University, Durham, NC 27708, United States
o Division of Integrative Genomics, Duke University, Durham, NC 27708, United States
p Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 27708, United States
q Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98195, United States
r Department of Biology, Emory University, Atlanta, GA 30322, United States
s U.S. Department of Energy Joint Genome Institute, Walnut Creek, CA 94598, United States
Abstract
Background: Previous research in autism and other neurodevelopmental disorders (NDDs) has indicated an important contribution of protein-coding (coding) de novo variants (DNVs) within specific genes. The role of de novo noncoding variation has been observable as a general increase in genetic burden but has yet to be resolved to individual functional elements. In this study, we assessed whole-genome sequencing data in 2671 families with autism (discovery cohort of 516 families, replication cohort of 2155 families). We focused on DNVs in enhancers with characterized in vivo activity in the brain and identified an excess of DNVs in an enhancer named hs737. Results: We adapted the fitDNM statistical model to work in noncoding regions and tested enhancers for excess of DNVs in families with autism. We found only one enhancer (hs737) with nominal significance in the discovery (p = 0.0172), replication (p = 2.5 × 10−3), and combined dataset (p = 1.1 × 10−4). Each individual with a DNV in hs737 had shared phenotypes including being male, intact cognitive function, and hypotonia or motor delay. Our in vitro assessment of the DNVs showed they all reduce enhancer activity in a neuronal cell line. By epigenomic analyses, we found that hs737 is brain-specific and targets the transcription factor gene EBF3 in human fetal brain. EBF3 is genome-wide significant for coding DNVs in NDDs (missense p = 8.12 × 10−35, loss-of-function p = 2.26 × 10−13) and is widely expressed in the body. Through characterization of promoters bound by EBF3 in neuronal cells, we saw enrichment for binding to NDD genes (p = 7.43 × 10−6, OR = 1.87) involved in gene regulation. Individuals with coding DNVs have greater phenotypic severity (hypotonia, ataxia, and delayed development syndrome [HADDS]) in comparison to individuals with noncoding DNVs that have autism and hypotonia. Conclusions: In this study, we identify DNVs in the hs737 enhancer in individuals with autism. Through multiple approaches, we find hs737 targets the gene EBF3 that is genome-wide significant in NDDs. By assessment of noncoding variation and the genes they affect, we are beginning to understand their impact on gene regulatory networks in NDDs. © 2021, The Author(s).
Author Keywords
Autism; De novo; EBF3; Enhancer; Gene regulatory network; Genome; hs737; Neurodevelopmental disorder; Variant
Funding details
National Institutes of HealthNIHR00MH117165, R01HG003988, UM1HG008901
U.S. Department of EnergyUSDOEDE-AC02-05CH11231
National Heart, Lung, and Blood InstituteNHLBIU24HG008956
National Human Genome Research InstituteNHGRI
University of CaliforniaUC
Document Type: Article
Publication Stage: Final
Source: Scopus
“EEG/ERP as a pragmatic method to expand the reach of infant-toddler neuroimaging in HBCD: Promises and challenges” (2021) Developmental Cognitive Neuroscience
EEG/ERP as a pragmatic method to expand the reach of infant-toddler neuroimaging in HBCD: Promises and challenges
(2021) Developmental Cognitive Neuroscience, 51, art. no. 100988, .
Norton, E.S.a b c , MacNeill, L.A.b c , Harriott, E.M.b , Allen, N.c d , Krogh-Jespersen, S.b c , Smyser, C.D.e f , Rogers, C.E.f , Smyser, T.A.f , Luby, J.f , Wakschlag, L.b c
a Roxelyn and Richard Pepper Department of Communication Sciences and Disorders, Northwestern University, United States
b Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, United States
c Institute for Innovations in Developmental Sciences, Northwestern University, United States
d Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, United States
e Departments of Neurology, Pediatrics, and Radiology, Washington University School of Medicine, United States
f Department of Psychiatry, Washington University School of Medicine, United States
Abstract
Though electrophysiological measures (EEG and ERP) offer complementary information to MRI and a variety of advantages for studying infants and young children, these measures have not yet been included in large cohort studies of neurodevelopment. This review summarizes the types of EEG and ERP measures that could be used in the HEALthy Brain and Cognitive Development (HBCD) study, and the promises and challenges in doing so. First, we provide brief overview of the use of EEG/ERP for studying the developing brain and discuss exemplar findings, using resting or baseline EEG measures as well as the ERP mismatch negativity (MMN) as exemplars. We then discuss the promises of EEG/ERP such as feasibility, while balancing challenges such as ensuring good signal quality in diverse children with different hair types. We then describe an ongoing multi-site EEG data harmonization from our groups. We discuss the process of alignment and provide preliminary usability data for both resting state EEG data and auditory ERP MMN in diverse samples including over 300 infants and toddlers. Finally, we provide recommendations and considerations for the HBCD study and other studies of neurodevelopment. © 2021 The Author(s)
Author Keywords
EEG; ERP; HBCD; Mismatch negativity; Neurodevelopment
Funding details
National Institutes of HealthNIHR01DC016273, R01MH107652, R01MH113883, R01MH121877, R34DA050266
Document Type: Review
Publication Stage: Final
Source: Scopus
“Withdrawal of antiepileptic drugs after stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy” (2021) Epilepsy Research
Withdrawal of antiepileptic drugs after stereotactic laser amygdalohippocampotomy for mesial temporal lobe epilepsy
(2021) Epilepsy Research, 176, art. no. 106721, .
Athreya, A.a , Fasano, R.E.a , Drane, D.L.a b c , Millis, S.R.d , Willie, J.T.e f , Gross, R.E.f , Karakis, I.a
a Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States
b Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
c Department of Neurology, University of Washington, Seattle, WA, United States
d Department of Neurology, Physical Medicine & Rehabilitation, Wayne State University School of Medicine, Detroit, MI, United States
e Department of Neurosurgery, Washington University School of Medicine, St. Louis, MO, United States
f Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States
Abstract
Objective: This retrospective study investigated the success rate of withdrawal of antiepileptic drugs (AEDs) following stereotactic laser amygdalohippocampotomy (SLAH) for mesial temporal lobe epilepsy (MTLE), and identified predictors of seizure recurrence. Materials and methods: We retrospectively assessed 65 patients who underwent SLAH for MTLE (59 lesional). Patients’ demographics, disease characteristics and post-surgical outcomes were evaluated for their potential to predict seizure recurrence associated with withdrawal of AEDs. Results: The mean period of observation post SLAH was 51 months (range 12–96 months) and the mean period to initial reduction of AEDs was 21 months (range 12–60 months). Reduction of AEDs was attempted in 37 patients (57 %) who were seizure free post SLAH and it was successful in approximately 2/3 of them. From the remainder 1/3 who relapsed, nearly all regained seizure control after reinstitution of their AEDs. The likelihood of relapse after reduction of AEDs was predicted only by pre-operative seizure frequency. At the end of the observation period, approximately 14 % of all SLAH patients were seizure free without AEDs and approximately 54 % remained seizure free on AEDs. Compared with preoperative status, the number of AEDs were reduced in 37 % of patients, unchanged in 51 % of them and increased in 12 % of them. Conclusions: Successful SLAH for MTLE allows for reduction of AEDs in a significant portion of patients and complete withdrawal of AEDs in a subset of them. Patients with higher pre-operative seizure frequency exhibit a greater chance of relapse post reduction of AEDs. © 2021 Elsevier B.V.
Author Keywords
Antiepileptic drugs; Epilepsy; Epilepsy surgery; Laser ablation; Stereotactic laser amygdalohippocampotomy
Funding details
Medtronic
Boston Scientific CorporationBSC
Document Type: Article
Publication Stage: Final
Source: Scopus
“Neurocognition in Kenyan youth at clinical high risk for psychosis” (2021) Schizophrenia Research: Cognition
Neurocognition in Kenyan youth at clinical high risk for psychosis
(2021) Schizophrenia Research: Cognition, 25, art. no. 100198, .
Mamah, D.a , Mutiso, V.N.b , Ndetei, D.M.b c
a Department of Psychiatry, Washington University Medical School, St. Louis, MO, United States
b Africa Mental Health Research and Training Foundation, Nairobi, Kenya
c Department of Psychiatry, University of Nairobi, Kenya
Abstract
Introduction: Cognitive deficits are typically seen in schizophrenia and in the prodrome, and are a major predictor of functional outcomes in patients. In Africa, few studies have investigated neurocognition in psychosis, which presents a gap in our understanding of the heterogeneity of the illness. In this study, we assessed neurocognition among the largest sample of psychosis-risk participants recruited in the continent to date. Methods: The study was conducted in Kenya, and involved 295 psychiatric medication-naïve participants at clinical high-risk (CHR) for psychosis and healthy controls, aged 15–25 yrs. Psychosis-risk status was determined separately using the Structured Interview of Psychosis-Risk Syndromes (i.e. CHR) and by self-report with the Washington Early Recognition Center Affectivity and Psychosis Screen. Eleven tests were administered using the University of Pennsylvania Computerized Neurocognitive Battery. Test performance across groups were investigated, as well as demographic and clinical effects. Results: Fewer participants were designated as being at psychosis-risk with structured interview (n = 47; CHR) than with self-report (n = 155). A MANOVA of cognitive test performance was significant only when groups were ascertained based on self-report (p = 0.03), with decreased performance in the risk group on verbal intelligence (p = 0.003; d = 0.39), emotion recognition (p = 0.003; d = 0.36), sensorimotor processing (p = 0.01; d = 0.31) and verbal memory (p = 0.035; d = 0.21). Only verbal intelligence was significantly worse in the CHR group compared to controls (p = 0.036; d = 0.45). There were no significant age and gender relationships. Conclusion: Deficits across multiple cognitive domains are present in Kenyan psychosis-risk youth, most significantly in verbal intelligence. The pattern of cognitive deficits and an absence of gender effects may represent ethnicity-specific phenotypes of the psychosis-risk state. Longitudinal studies of neurocognition in Kenyan patients who convert to psychosis may enhance risk prediction in this population, and facilitate targeted interventions. © 2021
Author Keywords
Africa; Cognition; Kenya; Neurocognition; Psychosis; Risk; SIPS; WERCAP
Funding details
National Institute of Mental HealthNIMHR56 MH111300
Document Type: Article
Publication Stage: Final
Source: Scopus
“C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation (2021) Neuron
C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation
(2021) Neuron, 109 (14), pp. 2275-2291.e8. Cited 1 time.
Lall, D.a b , Lorenzini, I.d , Mota, T.A.a b , Bell, S.a b , Mahan, T.E.e , Ulrich, J.D.e , Davtyan, H.f , Rexach, J.E.g , Muhammad, A.K.M.G.a b , Shelest, O.b , Landeros, J.a b , Vazquez, M.a b , Kim, J.d , Ghaffari, L.d , O’Rourke, J.G.a b , Geschwind, D.H.g , Blurton-Jones, M.f , Holtzman, D.M.e , Sattler, R.d , Baloh, R.H.a b c
a Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, United States
b Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, United States
c Department of Neurology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, United States
d Department of Neurobiology, Barrow Neurological Institute, 350 W. Thomas Road, Phoenix, AZ 85013, United States
e 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
f Institute for Memory Impairments and Neurological Disorders, Sue & Bill Gross Stem Cell Research Center, University of California, 3200 Gross Hall, 845 Health Sciences Road, Irvine, Irvine, CA 92697, United States
g Program in Neurogenetics, Department of Neurology, Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, United States
Abstract
C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer’s disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities. © 2021 Elsevier Inc.
Author Keywords
Alzheimer’s disease; amyotrophic lateral sclerosis; C9orf72; frontotemporal dementia; microglia; neurodegeneration
Funding details
AG047644, NS090934
National Institutes of HealthNIHNS097545
Howard Hughes Medical InstituteHHMI
ALS AssociationALSA
Genentech
Merck
Muscular Dystrophy AssociationMDA
JPB FoundationRO1NS085207
University of WashingtonUW
Barrow Neurological FoundationBNF
Rainwater Charitable FoundationRCF5R25 NS065723, AG055524, AG061895
Document Type: Article
Publication Stage: Final
Source: Scopus
“Neuronal VCP loss of function recapitulates FTLD-TDP pathology” (2021) Cell Reports
Neuronal VCP loss of function recapitulates FTLD-TDP pathology
(2021) Cell Reports, 36 (3), art. no. 109399, .
Wani, A.a , Zhu, J.a , Ulrich, J.D.a , Eteleeb, A.b , Sauerbeck, A.D.a , Reitz, S.J.a , Arhzaouy, K.a , Ikenaga, C.a , Yuede, C.M.a b , Pittman, S.K.a , Wang, F.c , Li, S.c , Benitez, B.A.b , Cruchaga, C.b , Kummer, T.T.a , Harari, O.b , Chou, T.-F.c , Schröder, R.d , Clemen, C.S.e f , Weihl, C.C.a
a Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St. Louis, MO, United States
b Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
c Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, United States
d Institute of Neuropathology, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nürnberg, Erlangen, Germany
e Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany
f Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany
Abstract
The pathogenic mechanism by which dominant mutations in VCP cause multisystem proteinopathy (MSP), a rare neurodegenerative disease that presents as fronto-temporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), remains unclear. To explore this, we inactivate VCP in murine postnatal forebrain neurons (VCP conditional knockout [cKO]). VCP cKO mice have cortical brain atrophy, neuronal loss, autophago-lysosomal dysfunction, and TDP-43 inclusions resembling FTLD-TDP pathology. Conditional expression of a single disease-associated mutation, VCP-R155C, in a VCP null background similarly recapitulates features of VCP inactivation and FTLD-TDP, suggesting that this MSP mutation is hypomorphic. Comparison of transcriptomic and proteomic datasets from genetically defined patients with FTLD-TDP reveal that progranulin deficiency and VCP insufficiency result in similar profiles. These data identify a loss of VCP-dependent functions as a mediator of FTLD-TDP and reveal an unexpected biochemical similarity with progranulin deficiency. © 2021 The Author(s)
Author Keywords
autophagy; FTD; FTLD; multisystem proteinopathy; neurodegeneration; progranulin; TDP-43; VCP
Funding details
National Institutes of HealthNIHI01BX005204, K24AR073317, P01AG003991, P30AG066444, R01AG031867, R01AG044546, R01AG057777, R01NS102279, R01NS118146, RF1AG053303, RF1AG058501, U01AG058922
Document Type: Article
Publication Stage: Final
Source: Scopus
“Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors” (2021) Frontiers in Synaptic Neuroscience
Reducing Auditory Nerve Excitability by Acute Antagonism of Ca2+-Permeable AMPA Receptors
(2021) Frontiers in Synaptic Neuroscience, 13, art. no. 680621, .
Walia, A.a , Lee, C.a d , Hartsock, J.a , Goodman, S.S.b , Dolle, R.c , Salt, A.N.a , Lichtenhan, J.T.a , Rutherford, M.A.a
a Department of Otolaryngology, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
b Department of Communication Sciences and Disorders, University of Iowa, Iowa City, IA, United States
c Department of Biochemistry and Molecular Biophysics, Washington University, Center for Drug Discovery, Washington University in St. Louis School of Medicine, St. Louis, MO, United States
d ‡Choongheon Lee, Department of Otolaryngology, University of Rochester, New York, NY, United States
Abstract
Hearing depends on glutamatergic synaptic transmission mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). AMPARs are tetramers, where inclusion of the GluA2 subunit reduces overall channel conductance and Ca2+ permeability. Cochlear afferent synapses between inner hair cells (IHCs) and auditory nerve fibers (ANFs) contain the AMPAR subunits GluA2, 3, and 4. However, the tetrameric complement of cochlear AMPAR subunits is not known. It was recently shown in mice that chronic intracochlear delivery of IEM-1460, an antagonist selective for GluA2-lacking AMPARs [also known as Ca2+-permeable AMPARs (CP-AMPARs)], before, during, and after acoustic overexposure prevented both the trauma to ANF synapses and the ensuing reduction of cochlear nerve activity in response to sound. Surprisingly, baseline measurements of cochlear function before exposure were unaffected by chronic intracochlear delivery of IEM-1460. This suggested that cochlear afferent synapses contain GluA2-lacking CP-AMPARs alongside GluA2-containing Ca2+-impermeable AMPA receptors (CI-AMPARs), and that the former can be antagonized for protection while the latter remain conductive. Here, we investigated hearing function in the guinea pig during acute local or systemic delivery of CP-AMPAR antagonists. Acute intracochlear delivery of IEM-1460 or systemic delivery of IEM-1460 or IEM-1925 reduced the amplitude of the ANF compound action potential (CAP) significantly, for all tone levels and frequencies, by > 50% without affecting CAP thresholds or distortion product otoacoustic emissions (DPOAE). Following systemic dosing, IEM-1460 levels in cochlear perilymph were ~ 30% of blood levels, on average, consistent with pharmacokinetic properties predicting permeation of the compounds into the brain and ear. Both compounds were metabolically stable with half-lives >5 h in vitro, and elimination half-lives in vivo of 118 min (IEM-1460) and 68 min (IEM-1925). Heart rate monitoring and off-target binding assays suggest an enhanced safety profile for IEM-1925 over IEM-1460. Compound potency on CAP reduction (IC50 ~ 73 μM IEM-1460) was consistent with a mixture of GluA2-lacking and GluA2-containing AMPARs. These data strongly imply that cochlear afferent synapses of the guinea pig contain GluA2-lacking CP-AMPARs. We propose these CP-AMPARs may be acutely antagonized with systemic dosing, to protect from glutamate excitotoxicity, while transmission at GluA2-containing AMPARs persists to mediate hearing during the protection. © Copyright © 2021 Walia, Lee, Hartsock, Goodman, Dolle, Salt, Lichtenhan and Rutherford.
Author Keywords
auditory nerve fiber; blood labyrinth barrier; Ca2+-permeable AMPA receptor; cochlear synapse; hearing protection; IEM-1460 and IEM-1925; intracochlear drug; non-competitive open-channel block
Funding details
1071
National Institutes of HealthNIH
National Institute on Deafness and Other Communication DisordersNIDCDR01DC014712, R01DC014997, T32DC000022
National Center for Advancing Translational SciencesNCATSUL1TR002345
University of WashingtonUW
Institute of Clinical and Translational SciencesICTS
Document Type: Article
Publication Stage: Final
Source: Scopus
“Intrasubunit and intersubunit steroid binding sites independently and additively mediate a1b2c2L GABAA receptor potentiation by the endogenous neurosteroid allopregnanolone” (2021) Molecular Pharmacology
Intrasubunit and intersubunit steroid binding sites independently and additively mediate a1b2c2L GABAA receptor potentiation by the endogenous neurosteroid allopregnanolone
(2021) Molecular Pharmacology, 100 (1), pp. 19-31.
Germann, A.L.a , Pierce, S.R.a , Tateiwa, H.a , Sugasawa, Y.d , Reichert, D.E.b c , Evers, A.S.a c , Steinbach, J.H.a c , Akk, G.a c
a Department of Anesthesiology, Washington University, School of Medicine, St. Louis, MO, United States
b Department of Radiology, Washington University, School of Medicine, St. Louis, MO, United States
c The Taylor Family Institute for Innovative Psychiatric Research, Washington University, School of Medicine, St. Louis, MO, United States
d Department of Anesthesiology and Pain Medicine, Juntendo University, School of Medicine, Tokyo, Japan
Abstract
Prior work employing functional analysis, photolabeling, and X-ray crystallography have identified three distinct binding sites for potentiating steroids in the heteromeric GABAA receptor. The sites are located in the membrane-spanning domains of the receptor at the b-a subunit interface (site I) and within the a (site II) and b subunits (site III). Here, we have investigated the effects of mutations to these sites on potentiation of the rat a1b2c2L GABAA receptor by the endogenous neurosteroid allopregnanolone (3a5aP). The mutations were introduced alone or in combination to probe the additivity of effects. We show that the effects of amino acid substitutions in sites I and II are energetically additive, indicating independence of the actions of the two steroid binding sites. In site III, none of the mutations tested reduced potentiation by 3a5aP, nor did a mutation in site III modify the effects of mutations in sites I or II. We infer that the binding sites for 3a5aP act independently. The independence of steroid action at each site is supported by photolabeling data showing that mutations in either site I or site II selectively change steroid orientation in the mutated site without affecting labeling at the unmutated site. The findings are discussed in the context of linking energetic additivity to empirical changes in receptor function and ligand binding. SIGNIFICANCE STATEMENT Prior work has identified three distinct binding sites for potentiating steroids in the heteromeric c-aminobutyric acid type A receptor. This study shows that the sites act independently and additively in the presence of the steroid allopregnanolone and provide estimates of energetic contributions made by steroid binding to each site. Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics
Funding details
National Institute of General Medical SciencesNIGMSR01GM108580, R01GM108799
Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine in St. Louis
Document Type: Article
Publication Stage: Final
Source: Scopus
“Cohort study protocol to characterize the incidence and severity of neuropathic pain in patients with severe acute respiratory syndrome coronavirus 2 infection” (2021) Pain Reports
Cohort study protocol to characterize the incidence and severity of neuropathic pain in patients with severe acute respiratory syndrome coronavirus 2 infection
(2021) Pain Reports, 6 (1), art. no. e925, .
Odozor, C.U.a , Roles, K.b , Burk, C.b , Kannampallil, T.b c , Clifford, D.B.d , Piccirillo, J.F.e , Haroutounian, S.d
a Washington University School of Medicine, St. Louis, MO, United States
b Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, United States
c Institute for Informatics, 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 Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Introduction and Objectives: The coronavirus disease 2019 (COVID-19) pandemic has resulted in patients experiencing symptoms that include neurological dysfunction. As many viral infections are associated with neuropathy, the aim of the study is to characterize the incidence and severity of neuropathic pain in patients with COVID-19. Methods: A cohort study will be conducted in adult ($18 years) patients who were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at Washington University/Barnes-Jewish Hospital. Participants who are deceased, with incomplete test results, or who cannot be contacted will be excluded. Approximately 1320 participants will be recruited in a 1:2 ratio of thosewith a positiveto- negative SARS-CoV-2 test result. Each participant will be invited to complete a survey to assess their symptoms related to neuropathy, 30 to 90 days after their initial SARS-CoV-2 test. Survey responses, demographics, and clinical data from the electronic health record will be used for analysis. The primary outcome is the incidence of new symptoms of neuropathic pain. The self-reported DN4 and Neuropathic Pain Symptom Inventory questionnaires (Appendix 1, http://links.lww.com/PR9/A103) will be used for neuropathic pain screening and severity assessment, respectively. Exploratory analyses will be performed to investigate other potential clinical endpoints and trends. Results/Conclusion: Similar to previous coronavirus infections, an increased incidence of new-onset neuropathic pain after COVID-19 disease is expected, along with an increase in the severity experienced by patients with COVID-19 with pre-existing chronic pain. Comprehensive understanding of howCOVID-19 affects the nervous system can provide a better framework formanaging pain in this disease. Copyright © 2021 The Author(s).
Author Keywords
Coronavirus; Covid-19; Neuropathic pain; Neuropathy; Sars-cov-2
Funding details
National Cancer InstituteNCIP30 CA091842
Washington University School of Medicine in St. Louis
Alvin J. Siteman Cancer Center
Document Type: Article
Publication Stage: Final
Source: Scopus
“Isofurans and Isoprostanes as Potential Markers of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Study” (2021) Neurocritical Care
Isofurans and Isoprostanes as Potential Markers of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Study
(2021) Neurocritical Care, .
Gomes, J.A.a , Milne, G.b , Kallianpur, A.c , Shriver, L.d
a Cerebrovascular Center, Cleveland Clinic Lerner College of Medicine, 9500 Euclid Ave., Mail code S-80, Cleveland, OH 44195, United States
b Department of Medicine, Vanderbilt University, Nashville, TN, United States
c Genomic Medicine Institute, Cleveland Clinic Lerner College of Medicine, Cleveland, OH, United States
d Department of Chemistry, Washington University in St. Louis, St. Louis, MO, United States
Abstract
Background: F2-Isoprostanes (F2-IsoPs) and Isofurans (IsoF), specific markers of lipid peroxidation in vivo, have been reported to be elevated and have prognostic implications following subarachnoid hemorrhage (SAH). Platelet activation and vasoconstriction are attributed to these compounds. Elevated IsoF to F2-IsoPs ratios have been proposed as in vivo biomarkers of mitochondrial dysfunction. In this pilot study, we examined their performance as specific biomarkers for delayed cerebral ischemia (DCI) development following SAH. Methods: Eighteen patients with SAH and six controls with normal neuroimaging and cerebrospinal fluid (CSF) analysis results underwent CSF sampling and abstraction of clinical, demographic, and laboratory data. Samples (two) of CSF were collected on day 1 and once on days 5–8 post bleed. F2-IsoP and IsoF assays were performed by gas chromatography/mass spectroscopy methods. Levels are expressed in median (interquartile range) for nonnormally distributed data. Repeated sample measurements were compared using the Wilcoxon signed-rank test, whereas the Mann–Whitney U-test was used for other nonnormally distributed data. Results: Mean age was 61 ± 15.7 (SAH cases) versus 48 ± 10 (controls) years, and 80% of patients with SAH were women. Median Hunt and Hess score was 3 (2–4), and modified Fisher scale was 3 (3–4). Thirty nine percent of patients developed DCI. F2-IsoP were significantly higher in SAH cases than in controls [47.5 (30.2–53.5) vs. 26.0 (21.2–34.5) pg/mL]. No significant differences were observed in patients with or without DCI [41 (33.5–52) vs. 44 (28.5–55.5) pg/mL]. IsoF were elevated in the second CSF sample in nine patients but were undetectable in the remainder cases and all controls. Patients who developed DCI had significantly higher IsoF than those who did not [57 (34–72) vs. 0 (0–34) pg/mL]. Patients who met criteria for DCI had a significantly higher IsoF to F2IsoPs ratio on the late CSF sample [1.03 (1–1.38) vs. 0 (0–0.52)]. Conclusions: Preliminary findings from this study suggest that IsoF may represent a specific biomarker predicting DCI following SAH. Future studies to further explore the value of IsoF as biomarkers of secondary brain injury following SAH seem warranted. © 2021, Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society.
Author Keywords
Isofurans; Isoprostanes; Oxidative stress; Subarachnoid hemorrhage
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Short-term deceleration capacity of heart rate: a sensitive marker of cardiac autonomic dysfunction in idiopathic Parkinson’s disease” (2021) Clinical Autonomic Research
Short-term deceleration capacity of heart rate: a sensitive marker of cardiac autonomic dysfunction in idiopathic Parkinson’s disease
(2021) Clinical Autonomic Research, .
Carricarte Naranjo, C.a , Marras, C.b , Visanji, N.P.b , Cornforth, D.J.c , Sanchez‑Rodriguez, L.d , Schüle, B.e , Goldman, S.M.f , Estévez, M.g , Stein, P.K.h , Lang, A.E.b , Jelinek, H.F.i , Machado, A.a
a Facultad de Biología, Universidad de La Habana, Havana, Cuba
b Edmond J Safra Program in Parkinson’s Disease and the Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, Toronto, ON, Canada
c Member of the National Coalition of Independent Scholars (NCIS), Battleboro, VT, United States
d Department of Radiology, University of Calgary, Calgary, AB, Canada
e Department of Pathology, Stanford School of Medicine, Stanford, CA, United States
f Department of Neurology, University of California, San Francisco, CA, United States
g Departamento de Neurofisiología Clínica, Instituto de Neurología y Neurocirugía, La Habana, Cuba
h School of Medicine, Washington University, St. Louis, MO, United States
i Khalifa University, Abu Dhabi, United Arab Emirates
Abstract
Purpose: Cardiac autonomic dysfunction in idiopathic Parkinson’s disease (PD) manifests as reduced heart rate variability (HRV). In the present study, we explored the deceleration capacity of heart rate (DC) in patients with idiopathic PD, an advanced HRV marker that has proven clinical utility. Methods: Standard and advanced HRV measures derived from 7-min electrocardiograms in 20 idiopathic PD patients and 27 healthy controls were analyzed. HRV measures were compared using regression analysis, controlling for age, sex, and mean heart rate. Results: Significantly reduced HRV was found only in the subcohort of PD patients older than 60 years. Low- frequency power and global HRV measures were lower in patients than in controls, but standard beat-to-beat HRV markers (i.e., rMSSD and high-frequency power) were not significantly different between groups. DC was significantly reduced in the subcohort of PD patients older than 60 years compared to controls. Conclusions: Deceleration-related oscillations of HRV were significantly reduced in the older PD patients compared to healthy controls, suggesting that short-term DC may be a sensitive marker of cardiac autonomic dysfunction in PD. DC may be complementary to traditional markers of short-term HRV for the evaluation of autonomic modulation in PD. Further study to examine the association between DC and cardiac adverse events in PD is needed to clarify the clinical relevance of DC in this population. © 2021, Springer-Verlag GmbH Germany, part of Springer Nature.
Author Keywords
Cardiac autonomic modulation; Deceleration capacity of heart rate; Heart rate variability; Idiopathic Parkinson’s disease
Funding details
National Institutes of HealthNIH
Michael J. Fox Foundation for Parkinson’s ResearchMJFFMJFF 6896
International Parkinson and Movement Disorder SocietyMDS
Canadian Institutes of Health ResearchCIHR
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic–Ischemic Encephalopathy” (2021) Journal of Pediatrics
Acute and Chronic Placental Abnormalities in a Multicenter Cohort of Newborn Infants with Hypoxic–Ischemic Encephalopathy
(2021) Journal of Pediatrics, .
Chalak, L.a , Redline, R.W.b , Goodman, A.M.c , Juul, S.E.d , Chang, T.e , Yanowitz, T.D.f , Maitre, N.g , Mayock, D.E.d , Lampland, A.L.h , Bendel-Stenzel, E.i , Riley, D.j , Mathur, A.M.k , Rao, R.l , Van Meurs, K.P.m , Wu, T.-W.n o , Gonzalez, F.F.p , Flibotte, J.q r , Mietzsch, U.d s , Sokol, G.M.s , Ahmad, K.A.t , Baserga, M.u , Weitkamp, J.-H.v , Poindexter, B.B.w , Comstock, B.A.x , Wu, Y.W.c
a Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, United States
b Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, OH, United States
c Department of Neurology, University of California San Francisco, San Francisco, CA, United States
d Division of Neonatology, Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States
e Department of Neurology, Children’s National Hospital, George Washington School of Medicine, Washington, DC, United States
f Division of Newborn Medicine, Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh of UPMC and Magee Womens Hospital of UPMC, Pittsburgh, PA, United States
g Department of Pediatrics and Research Institute, Nationwide Children’s Hospital, Columbus, OH, United States
h Department of Neonatology, Children’s Minnesota, St Paul, MN, United States
i Division of Neonatal Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, United States
j Department of Pediatrics, Cook Children’s Medical Center, Texas Christian University and University of North Texas Health Science Center School of Medicine, Fort Worth, TX, United States
k Department of Pediatrics/Neonatal-Perinatal Medicine, Saint Louis University School of Medicine, St Louis, MO, United States
l Division of Newborn-Medicine, Department of Pediatrics, Washington University School of Medicine, St Louis, MO, United States
m Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Palo Alto, CA, United States
n Division of Neonatology, Fetal and Neonatal Institute, Children’s Hospital Los Angeles, Los Angeles, CA, United States
o Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
p Department of Pediatrics, University of California San Francisco, San Francisco, CA, United States
q Division of Neonatology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
r Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States
s Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, United States
t Pediatrix Medical Group of San Antonio, San Antonio, TX, United States
u Division of Neonatology, Department of Pediatrics, University of Utah, Salt Lake City, UT, United States
v Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, United States
w Division of Neonatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, GA, United States
x Department of Biostatistics, University of Washington, Seattle, WA, United States
Abstract
Objective: To examine the frequency of placental abnormalities in a multicenter cohort of newborn infants with hypoxic–ischemic encephalopathy (HIE) and to determine the association between acuity of placental abnormalities and clinical characteristics of HIE. Study design: Infants born at ≥36 weeks of gestation (n = 500) with moderate or severe HIE were enrolled in the High-dose Erythropoietin for Asphyxia and Encephalopathy Trial. A placental pathologist blinded to clinical information reviewed clinical pathology reports to determine the presence of acute and chronic placental abnormalities using a standard classification system. Results: Complete placental pathologic examination was available for 321 of 500 (64%) trial participants. Placental abnormalities were identified in 273 of 321 (85%) and were more common in infants ≥40 weeks of gestation (93% vs 81%, P = .01). A combination of acute and chronic placental abnormalities (43%) was more common than either acute (20%) or chronic (21%) abnormalities alone. Acute abnormalities included meconium staining of the placenta (41%) and histologic chorioamnionitis (39%). Chronic abnormalities included maternal vascular malperfusion (25%), villitis of unknown etiology (8%), and fetal vascular malperfusion (6%). Infants with chronic placental abnormalities exhibited a greater mean base deficit at birth (−15.9 vs −14.3, P = .049) than those without such abnormalities. Patients with HIE and acute placental lesions had older mean gestational ages (39.1 vs 38.0, P < .001) and greater rates of clinically diagnosed chorioamnionitis (25% vs 2%, P < .001) than those without acute abnormalities. Conclusions: Combined acute and chronic placental abnormalities were common in this cohort of infants with HIE, underscoring the complex causal pathways of HIE. Trial registration: ClinicalTrials.gov: NCT02811263 © 2021
Author Keywords
encephalopathy; HIE; neonate; placenta
Funding details
National Institute of Neurological Disorders and StrokeNINDS1U01NS092764-01
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Trends in mechanical thrombectomy and decompressive hemicraniectomy for stroke: A multicenter study” (2021) Neuroradiology Journal
Trends in mechanical thrombectomy and decompressive hemicraniectomy for stroke: A multicenter study
(2021) Neuroradiology Journal, .
Oravec, C.S.a , Tschoe, C.a , Fargen, K.M.a , Kittel, C.A.b , Spiotta, A.c , Almallouhi, E.c , Starke, R.M.d , McCarthy, D.J.d , Simon, S.e , Zyck, S.f , Gould, G.C.f , De Leacy, R.g , Mocco, J.g , Siddiqui, A.h , Vaziri, S.i , Fox, W.C.i , Fraser, J.F.j , Chitale, R.k , Zipfel, G.l , Huguenard, A.l , Wolfe, S.Q.a
a Department of Neurosurgery, Wake Forest Baptist Medical Center, United States
b Department of Biostatistics and Data Science, Wake Forest University School of Medicine, United States
c Medical University of South Carolina, United States
d Miami University, United States
e Pennsylvania State University, United States
f State University of New York, United States
g Mount Sinai Hospital, United States
h University at Buffalo, United States
i University of Florida, United States
j Departments of Neurological Surgery, Neurology, Radiology, and Neuroscience, University of Kentucky, United States
k Vanderbilt University, United States
l Washington University of Saint Louis, United States
Abstract
Background and purpose: Acute ischemic stroke has increasingly become a procedural disease following the demonstrated benefit of mechanical thrombectomy (MT) for emergent large vessel occlusion (ELVO) on clinical outcomes and tissue salvage in randomized trials. Given these data and anecdotal experience of decreased numbers of decompressive hemicraniectomies (DHCs) performed for malignant cerebral edema, we sought to correlate the numbers of strokes, thrombectomies, and DHCs performed over the timeline of the 2013 failed thrombolysis/thrombectomy trials, to the 2015 modern randomized MT trials, to post-DAWN and DEFUSE 3. Materials and methods: This is a multicenter retrospective compilation of patients who presented with ELVO in 11 US high-volume comprehensive stroke centers. Rates of tissue plasminogen activator (tPA), thrombectomy, and DHC were determined by current procedural terminology code, and specificity to acute ischemic stroke confirmed by each institution. Endpoints included the incidence of stroke, thrombectomy, and DHC and rates of change over time. Results: Between 2013 and 2018, there were 55,247 stroke admissions across 11 participating centers. Of these, 6145 received tPA, 4122 underwent thrombectomy, and 662 patients underwent hemicraniectomy. The trajectories of procedure rates over time were modeled and there was a significant change in MT rate (p = 0.002) without a concomitant change in the total number of stroke admissions, tPA administration rate, or rate of DHC. Conclusions: This real-world study confirms an increase in thrombectomy performed for ELVO while demonstrating stable rates of stroke admission, tPA administration and DHC. Unlike prior studies, increasing thrombectomy rates were not associated with decreased utilization of hemicraniectomy. © The Author(s) 2021.
Author Keywords
acute ischemic stroke; Decompressive craniectomy; endovascular therapy; hemicraniectomy; malignant cerebral edema; mechanical thrombectomy
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Hydroxyurea treatment and neurocognitive functioning in sickle cell disease from school age to young adulthood” (2021) British Journal of Haematology
Hydroxyurea treatment and neurocognitive functioning in sickle cell disease from school age to young adulthood
(2021) British Journal of Haematology, .
Heitzer, A.M.a , Longoria, J.a , Okhomina, V.b , Wang, W.C.c , Raches, D.a , Potter, B.a , Jacola, L.M.a , Porter, J.a , Schreiber, J.E.d , King, A.A.e , Kang, G.b , Hankins, J.S.c
a Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, United States
b Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States
c Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN, United States
d Department of Psychology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
e Program in Occupational Therapy and Departments of Pediatrics and Medicine, Washington University, St. Louis, MO, United States
Abstract
Neurocognitive impairment is common in sickle cell disease (SCD) and is associated with significant functional limitations. In a cross-sectional analysis, we examined the association between hydroxyurea (HU) treatment and neurocognitive functioning from school-age to young adulthood in individuals with SCD. A total of 215 patients with HbSS/HbSβ0-thalassaemia (71% HU treated) and 149 patients with HbSC/HbSβ+-thalassaemia (20% HU treated) completed neurocognitive measures at one of four developmental stages: school-age (age 8–9 years), early adolescence (age 12–13 years), late adolescence (age 16–17 years) and young adulthood (ages 19–24 years). For participants with multiple assessments, only the most recent evaluation was included. In multivariable analysis adjusted for social vulnerability, HU treatment and sex, older age was associated with a reduction in overall intelligence quotient (IQ) of 0·55 points per year of life [standard error (SE) = 0·18, false discovery rate adjusted P value (PFDR) = 0.01] for patients with HbSS/HbSβ0-thalassaemia. Earlier initiation of HU (n = 152) in HbSS/HbSβ0-thalassaemia was associated with higher scores on neurocognitive measures across most domains, including IQ [estimate (SE) 0·77 (0·25)/year, PFDR = 0·01], after adjusting for social vulnerability, sex and treatment duration. These results support the early use of HU to limit the detrimental neurocognitive effects of SCD, while highlighting the need for additional measures to further mitigate neurocognitive deterioration. © 2021 British Society for Haematology and John Wiley & Sons Ltd.
Author Keywords
aging; fetal haemoglobin; hydroxyurea; neurocognition; sickle cell disease
Funding details
American Lebanese Syrian Associated CharitiesALSAC
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
“Prescription and acceptance of durable medical equipment in FORTITUDE-ALS, a study of reldesemtiv in ALS: post hoc analyses of a randomized, double-blind, placebo-controlled clinical trial” (2021) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Prescription and acceptance of durable medical equipment in FORTITUDE-ALS, a study of reldesemtiv in ALS: post hoc analyses of a randomized, double-blind, placebo-controlled clinical trial
(2021) Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, .
Rudnicki, S.A.a , Andrews, J.A.b , Genge, A.c , Jackson, C.d , Lechtzin, N.e , Miller, T.M.f , Cockroft, B.M.a , Malik, F.I.a , Meng, L.a , Wei, J.a , Wolff, A.A.a , Shefner, J.M.g , ON BEHALF OF THE FORTITUDE-ALS STUDY GROUPh
a Cytokinetics, Incorporated, South San Francisco, CA, United States
b The Neurological Institute, Columbia University, New York, NY, United States
c Montreal Neurological Institute, Montreal, QC, Canada
d Departments of Neurology and Otolaryngology, University of Texas Health Science Center, San Antonio, TX, United States
e Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, United States
f Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
g Department of Neurology, Barrow Neurological Institute, Phoenix, AZ, United States
Abstract
Objective: To evaluate the possible effect of reldesemtiv, a fast skeletal muscle troponin activator, on prescription and acceptance of durable medical equipment (DME) in the FORTITUDE-ALS trial. Methods: Health economic outcome information was collected in FORTITUDE-ALS (NCT03160898); sites recorded if and when DME, specifically manual or power wheelchairs, gastrostomy tubes, noninvasive ventilators, or augmentative language devices, was prescribed by a physician and accepted by the patient (DME-PAP) during the trial. Acceptance was defined as the patient agreeing the item was needed. Cox regression analysis compared time to DME-PAP for each reldesemtiv dose with placebo. Post hoc analyses evaluated all reldesemtiv doses compared with placebo. Results: At least one DME item was prescribed and accepted by 33/114 (28.9%) of placebo patients, 19/112 (17.0%) of patients receiving reldesemtiv 150 mg bid, 24/113 (21.2%) receiving 300 mg bid, and 29/117 (24.8%) receiving 450 mg bid. The proportion of new DME-PAP was significantly lower in patients receiving reldesemtiv 150 mg bid vs placebo (17.0% vs 28.9%, p = 0.032). The hazard ratio versus placebo for accepting at least one DME item for all reldesemtiv doses combined was 0.61 (confidence interval: 0.39, 0.96, p = 0.032). 25% of placebo patients were prescribed and agreed to obtain a DME item by 84 days; this threshold was met for reldesemtiv-treated patients at 120 days. Conclusions: Results suggest ALS patients receiving reldesemtiv may have lower risk of and delayed need for DME related to impaired mobility, breathing, swallowing, or speaking; this delay is consistent with other measures indicating delay in disease progression. © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
Author Keywords
clinical trial; Disease burden; FORTITUDE-ALS; health outcomes research; reldesemtiv
Funding details
CytokineticsCYTK
Document Type: Article
Publication Stage: Article in Press
Source: Scopus