64 Works

Data from: Nusinersen in later-onset spinal muscular atrophy: long-term results from the phase 1/2 studies

Basil T. Darras, Claudia A. Chiriboga, Susan T. Iannaccone, Kathryn J. Swoboda, Jacqueline Montes, Laurence Mignon, Shuting Xia, C. Frank Bennett, Kathie M. Bishop, Jeremy M. Shefner, Allison M. Green, Peng Sun, Ishir Bhan, Sarah Gheuens, Eugene Schneider, Wildon Farwell & Darryl C. De Vivo
Objective: Report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA). Methods: Analyses included children from the phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2 to 15 years. The extension study...

Data from: Histopathology of diffusion imaging abnormalities in cerebral amyloid angiopathy

Susanne J. Van Veluw, Yael D. Reijmer, Andre J. Van Der Kouwe, Andreas Charidimou, Grace A. Riley, Alexander Leemans, Brian J. Bacskai, Matthew P. Frosch, Anand Viswanathan & Steven M. Greenberg
Objective: we sought to determine the underlying mechanism for altered white matter diffusion tensor imaging (DTI) measures at the histopathologic level in patients with cerebral amyloid angiopathy (CAA). Methods: formalin-fixed intact hemispheres from nine CAA cases and two elderly controls were scanned at 3 tesla MRI, including a diffusion-weighted sequence. DTI measures (i.e. fractional anisotropy (FA) and mean diffusivity (MD)) and histopathology measures were obtained from two tracts: the anterior thalamic radiation (ATR) and inferior...

Data from: A quantitative electrophysiological biomarker of duplication 15q11.2-q13.1 syndrome

Joel Frohlich, Damla Senturk, Vidya Saravanapandian, Peyman Golshani, Lawrence T. Reiter, Raman Sankar, Ronald Thibert, Charlotte Distefano, Scott Huberty, Edwin H. Cook & Shafali S. Jeste
Background: Duplications of 15q11.2-q13.1 (Dup15q syndrome) are highly penetrant for autism spectrum disorder (ASD). A distinct electrophysiological (EEG) pattern characterized by excessive activity in the beta band has been noted in clinical reports. We asked whether EEG power in the beta band, as well as in other frequency bands, distinguished children with Dup15q syndrome from those with non-syndromic ASD and then examined the clinical correlates of this electrophysiological biomarker in Dup15q syndrome. Methods: In the...

The STARS phase 2 study: a randomized controlled trial of gaboxadol in Angelman syndrome

Lynne Bird, Cesar Ochoa-Lubinoff, Wen-Hann Tan, Gali Heimer, Raun Melmed, Amit Rakhit, Jeannie Visootsak, Matthew During, Rebecca Burdine, Christina Holcroft, Alexander Kolevzon & Ronald Thibert
Objective: To evaluate safety and tolerability and exploratory efficacy endpoints for gaboxadol (OV101) compared with placebo in individuals with Angelman syndrome (AS). Methods: Gaboxadol is a highly selective orthosteric agonist that activates γ-subunit–containing extrasynaptic γ-aminobutyric acid type A (GABAA) receptors. In a multicenter, double-blind, placebo-controlled, parallel-group trial, adolescent and adult individuals with a molecular diagnosis of AS were randomized (1:1:1) to 1 of 3 dosing regimens for a duration of 12 weeks: placebo morning dose...

Data from: Clinical EEG slowing correlates with delirium severity and predicts poor clinical outcomes

Eyal Y Kimchi, Anudeepthi Neelagiri, Wade Whitt, Avinash Rao Sagi, Sophia L Ryan, Greta Gadbois, Daniël Groothuysen, Michael B Westover & Eyal Kimchi
Objective To determine which findings on routine clinical EEGs correlate with delirium severity across various presentations, and to determine whether EEG findings independently predict important clinical outcomes. Methods We prospectively studied a cohort of non-intubated inpatients undergoing EEG for evaluation of altered mental status. Patients were assessed for delirium within one hour of EEG using the 3-Minute Diagnostic Interview for Confusion Assessment Method (3D-CAM) and 3D-CAM severity score (3D-CAM-S). EEGs were interpreted clinically by neurophysiologists,...

Enhancing U.S. Surveillance of Laboratory Confirmed SARS-CoV-2, Influenza, and other Respiratory Viruses through a Network of Emergency Departments

Jeffrey Kline
This emergency department (ED) surveillance network comprises 24 nodes represented by site investigators at hospital systems in 21 states and the District of Columbia. This work is funded by a contract from the Centers for Disease Control with Wayne State as the prime. The goal of the network is to identify patients who present with acute respiratory illness (e.g. cough or fever). The network report demographic data, vaccination status as identified in the medical record,...

Data from: Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer

Luigi Formisano, Yao Lu, Alberto Servetto, Ariella B. Hanker, Valerie M. Jansen, Joshua A. Bauer, Dhivya R. Sudhan, Angel L. Guerrero-Zotano, Sarah Croessmann, Yan Guo, Paula Gonzalez, Kyung-Min Lee, Melissa J. Nixon, Luis J. Schwarz, Melinda E. Sanders, Teresa C. Dugger, Marcelo Rocha Cruz, Amir Behdad, Massimo Cristofanilli, Aditya Bardia, Joyce O'Shaughnessy, Rebecca J. Nagy, Richard B. Lanman, Nadia Solovieff, Wei He … & Carlos L. Arteaga
Using an ORF kinome screen in MCF-7 cells treated with the CDK4/6 inhibitor ribociclib plus fulvestrant, we identified FGFR1 as a mechanism of drug resistance. FGFR1-amplified/ER+ breast cancer cells and MCF-7 cells transduced with FGFR1 were resistant to fulvestrant ± ribociclib or palbociclib. This resistance was abrogated by treatment with the FGFR tyrosine kinase inhibitor (TKI) lucitanib. Addition of the FGFR TKI erdafitinib to palbociclib/fulvestrant induced complete responses of FGFR1-amplified/ER+ patient-derived-xenografts. Next generation sequencing of...

Data from: Cholinergic modulation of hippocampal calcium activity across the sleep-wake cycle

Heng Zhou, Kevin R Neville, Nitsan Goldstein, Shushi Kabu, Naila Kausar, Rong Ye, Thuan Tinh Nguyen, Noah Gelwan, Bradley T Hyman & Stephen N Gomperts
Calcium is a critical second messenger in neurons that contributes to learning and memory, but how the coordination of action potentials of neuronal ensembles with the hippocampal local field potential (LFP) is reflected in dynamic calcium activity remains unclear. Here, we recorded hippocampal calcium activity with endoscopic imaging of the genetically encoded fluorophore GCaMP6 with concomitant LFP in freely behaving mice. Dynamic calcium activity was greater in exploratory behavior and REM sleep than in quiet...

Data from: The Golgi-localized γ-ear-containing ARF-binding (GGA) proteins alter amyloid-β precursor protein (APP) processing through interaction of their GAE domain with the beta-site APP cleaving enzyme 1 (BACE1)

Bjoern Von Einem, Anke Wahler, Tobias Schips, Alberto Serrano-Pozo, Christian Proepper, Tobias M. Boeckers, Angelika Rueck, Thomas Wirth, Bradley T. Hyman, Karin M. Danzer, Dietmar R. Thal & Christine A. F. Von Arnim
Proteolytic processing of amyloid-β precursor protein (APP) by beta-site APP cleaving enzyme 1 (BACE1) is the initial step in the production of amyloid beta (Aβ), which accumulates in senile plaques in Alzheimer’s disease (AD). Essential for this cleavage is the transport and sorting of both proteins through endosomal/Golgi compartments. Golgi-localized γ-ear-containing ARF-binding (GGA) proteins have striking cargo-sorting functions in these pathways. Recently, GGA1 and GGA3 were shown to interact with BACE1, to be expressed in...

Data from: Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease

Eric McDade, Guoqiao Wang, Brian Andrew Gordon, Jason Hassenstab, Tammie L.S. Benzinger, Virginia Buckles, Anne M. Fagan, David M. Holtzman, Nigel J. Cairns, Alison M. Goate, Daniel S. Marcus, John C. Morris, Katrina Paumier, Chengjie Xiong, Ricardo Allegri, Sarah B. Berman, William Klunk, James Nobel, John Ringman, Bernardino Ghetti, Martin Farlow, Reisa Anne Sperling, Jasmeer Chhatwal, Stephen Salloway, Neil R. Graff-Radford … & Randall J. Bateman
Objective: To assess the onset, sequence and rate of progression of comprehensive biomarker and clinical measures across the spectrum of Alzheimer disease using the Dominantly Inherited Alzheimer Network (DIAN) study and compare these to cross-sectional estimates. Methods: We conducted longitudinal clinical, cognitive, cerebrospinal fluid (CSF) and neuroimaging assessments (mean of 2.7 (+/- 1.1) visits) in 217 DIAN participants. Linear mixed effects models were used to assess changes in each measure relative to individuals’ estimated years...

Cerebrovascular disease progression in patients with ACTA2 Arg179 pathogenic variants supplementary materials

Arne Lauer, Samantha Speroni, Jay Patel, Ellen Regalado, Myoung Choi, Edward Smith, Jayashree Kalpathy-Kramer, Paul Caruso, Dianna Milewicz & Patricia Musolino
Our study entitled “Cerebrovascular disease progression in patients with ACTA2 Arg179 Pathogenic Variants” examines progression of imaging biomarkers of stroke, arterial steno-occlusive disease and white matter injury in patients with smooth muscle dysfunction syndrome caused by mutations in the ACTA2 gene (ACTA2 Arg179 pathogenic variants). We found characteristic patterns of acute white matter ischemic injury and progressive internal carotid artery stenosis on MRI. Longitudinal analysis showed both stable and progressive lesion entities. The data was...

Data from: Clinical presentation and management of SMART syndrome

Sebastian F. Winter, Joshua P. Klein, Eugene J. Vaios, Philipp Karschnia, Eudocia Q. Lee, Helen A. Shih, Franziska Loebel & Jorg Dietrich
Stroke-like migraine attacks after radiation therapy (SMART) syndrome represents a rare but serious condition manifesting years after cranial radiation therapy (RT). Characterized by migraine-type headaches, stroke-like deficits and/or seizures and MR imaging abnormalities, including cortical gyriform enhancement in irradiated brain regions, SMART remains diagnostically and therapeutically challenging. Distinction from tumor progression is difficult and treatment options are limited. Although frequently reversible, SMART episodes can recur and effectuate persistent neurologic and/or imaging sequelae.

Data from: In vivo human whole-brain Connectom diffusion MRI dataset at 760 µm isotropic resolution (PART II)

Fuyixue Wang, Zijing Dong, Qiyuan Tian, Congyu Liao, Qiuyun Fan, W. Scott Hoge, Boris Keil, Jonathan R. Polimeni, Lawrence L. Wald, Susie Y. Huang & Kawin Setsompop
This whole-brain in vivo diffusion MRI dataset was acquired at 760 µm isotropic resolution and sampled at 1260 q-space points across 9 two-hour sessions on a single healthy subject. It was acquired using state-of-the-art acquisition hardware and advanced reconstruction to achieve high SNR at such resolution, including a high-gradient-strength Connectom scanner, a custom-built 64-channel phased-array coil, a personalized motion-robust head stabilizer, a recently developed SNR-efficient dMRI acquisition, and parallel imaging reconstruction with advanced ghost reduction...

Data from: Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials

Leonard H Van Den Berg, Eric Sorenson, Gary Gronseth, Eric A. Macklin, Jinsy Andrews, Robert H. Baloh, Michael Benatar, James D. Berry, Adriano Chio, Philippe Corcia, Angela Genge, Amelie K. Gubitz, Catherine Lomen-Hoerth, Christopher J. McDermott, Erik P. Pioro, Jeffrey Rosenfeld, Vincenzo Silani, Martin R. Turner, Markus Weber, Benjamin Rix Brooks, Robert G. Miller & Hiroshi Mitsumoto
Objective: To revise the 1999 Airlie House consensus guidelines for the design and implementation of preclinical therapeutic studies and clinical trials in amyotrophic lateral sclerosis (ALS). Methods: A consensus committee comprising 140 key members of the international ALS community (ALS researchers, clinicians, patient representatives, research funding representatives, industry and regulatory agencies) addressed nine areas of need within ALS research: 1. Pre-clinical studies; 2. Biological and phenotypic heterogeneity; 3. Outcome measures; 4. Disease-modifying and symptomatic interventions;...

Data from: Phased whole-genome genetic risk in a family quartet using a major allele reference sequence

Frederick E. Dewey, Rong Chen, Sergio P. Cordero, Kelly E. Ormond, Colleen Caleshu, Konrad J. Karczewski, Michelle Whirl-Carrillo, Matthew T. Wheeler, Joel T. Dudley, Jake T. Byrnes, Omar E. Cornejo, Joshua W. Knowles, Mark Woon, Katrin Sangkuhl, Li Gong, Caroline F. Thorn, Joan M. Hebert, Emidio Capriotti, Sean P. David, Aleksandra Pavlovic, Anne West, Joseph V. Thakuria, Madeline P. Ball, Alexander W. Zaranek, Heidi L. Rehm … & Jake K. Byrnes
Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date...

Data from: Association between aspirin dose and subarachnoid hemorrhage from saccular aneurysms: a case-control study

Anil Can, Robert F. Rudy, Victor M. Castro, Sheng Yu, Dmitriy Dligach, Sean Finan, Vivian Gainer, Nancy A. Shadick, Guergana Savova, Shawn Murphy, Tianxi Cai, Scott T. Weiss & Rose Du
Objective: We aimed to determine the association between ruptured saccular aneurysms and aspirin use/aspirin dose. Methods: 4,701 patients who were diagnosed at the Massachusetts General Hospital and Brigham and Women’s Hospital between 1990 and 2016 with 6,411 unruptured and ruptured saccular intracranial aneurysms were evaluated. Univariable and multivariable logistic regression analyses were performed to determine the association between aSAH and aspirin use, including aspirin dose. Inverse probability weighting using propensity scores was used to adjust...

Data from: Vision fine-tunes preparation for landing in the cane toad, Rhinella marina

Laura J. Ekstrom, Christopher Panzini, Gary B. Gillis & Chris Panzini
In toad hopping, the hindlimbs generate the propulsive force for takeoff while the forelimbs resist the impact forces associated with landing. Preparing to perform a safe landing, in which impact forces are managed appropriately, likely involves the integration of multiple types of sensory feedback. In toads, vestibular and/or proprioceptive feedback are critical for coordinated landing, however, the role of vision remains unclear. To clarify this role, this study compares pre-landing forelimb muscle activation patterns in...

Data from: 7 Tesla MRI of the ex vivo human brain at 100 micron resolution

Brian L. Edlow, Azma Mareyam, Andreas Horn, Jonathan R. Polimeni, Thomas Witzel, M. Dylan Tisdall, Jean Augustinack, Jason P. Stockmann, Bram R. Diamond, Allison Stevens, Lee S. Tirrell, Rebecca D. Folkerth, Lawrence L. Wald, Bruce Fischl & Andre Van Der Kouwe
We present an ultra-high resolution MRI dataset of an ex vivo human brain specimen. The brain specimen was donated by a 58-year-old woman who had no history of neurological disease and died of non-neurological causes. After fixation in 10% formalin, the specimen was imaged on a 7 Tesla MRI scanner at 100 µm isotropic resolution using a custom-built 31-channel receive array coil. Single-echo multi-flip Fast Low-Angle SHot (FLASH) data were acquired over 100 hours of...

Data from: Developmental loss of neurofibromin across distributed neuronal circuits drives excessive grooming in Drosophila

Seth Tomchik, Lanikea King, Tamara Boto, Valentina Botero, Ari Aviles, Breanna Jomsky, Chevara Joseph & James Walker
Neurofibromatosis type 1 is a monogenetic disorder that predisposes individuals to tumor formation and cognitive and behavioral symptoms. The neuronal circuitry and developmental events underlying these neurological symptoms are unknown. To better understand how mutations of the underlying gene (NF1) drive behavioral alterations, we have examined grooming in the Drosophila neurofibromatosis 1 model. Mutations of the fly NF1 ortholog drive excessive grooming, and increased grooming was observed in adults when Nf1 was knocked down during...

Association of caffeine and related analytes with resistance to Parkinson’s disease among LRRK2 mutation carriers: a metabolomic study

Grace F Crotty, Romeo Maciuca, Eric A Macklin, Junhua Wang, Manuel Montalban, Sonnet S. Davis, Jamal I Alkabsh, Rachit Bakshi, Xiqun Chen, Alberto Ascherio, Giuseppe Astarita, Sarah Huntwork-Rodriguez & Michael A Schwarzschild
Objective: To identify markers of resistance to developing Parkinson’s disease (PD) among LRRK2 mutation (LRRK2+) carriers, we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the LRRK2 mutation. Methods: Plasma from 368 PD and UC subjects in the LRRK2 Cohort Consortium (LCC), comprising 118 LRRK2+/PD+, 115 LRRK2+/UC, 70 LRRK2-/PD+ and 65 LRRK2-/UC, and CSF available from 68 of them were analyzed by liquid chromatography with mass spectrometry. For...

Ligand-dependent effects of methionine-8 oxidation in parathyroid hormone peptide analogs

Thomas Gardella, Vsevolod Katritch, Saheem Zaidi, Eileen Daley, Ashok Khatri & Jean-Pierre Vilardaga
LA-PTH is a long-acting parathyroid hormone (PTH) peptide analog in pre-clinical development for hypoparathyroidism (HP). Like native PTH, LA-PTH contains a methionine at position 8 that is predicted to be critical for function. We assessed the impact of methionine oxidation on the functional properties of LA-PTH and control PTH ligands. Oxidation of PTH(1-34) resulted in marked (~20-fold) reductions in binding affinity on the PTH receptor-1 (PTHR1) in cell membranes, similarly diminished potency for cAMP signaling...

Thalamic encoding of lexical status is lateralized during reading aloud

Dengyu Wang, Witold J. Lipski, Alan Bush, Anna Chrabaszcz, Christina Dastolfo-Hromack, Michael W. Dickey, Julie A. Fiez & R. Mark Richardson
To explore whether the thalamus participates in lexical status encoding, local field potentials were recorded in patients undergoing deep brain stimulation lead implantation while they read aloud single-syllable words and nonwords. Bilateral decreases in thalamic beta (12-30Hz) activity were preferentially locked to stimulus presentation, and these decreases were greater when nonwords were read. Increased broadband gamma (70-150Hz) activity also was locked preferentially to speech onset bilaterally, but greater nonword-related increases in this activity were observed...

Data from: Telemedicine in neurology: telemedicine work group of the American Academy of Neurology update

Jaime M. Hatcher-Martin, Jamie Lynn Adams, Eric R Anderson, Riley Bove, Tamika M. Burrus, Mahan Chehrenama, Mary Dolan O'Brien, Dawn S. Eliashiv, Deniz Erten-Lyons, Barbara S. Giesser, Lauren Moo, Pushpa Narayanaswami, Marvin A. Rossi, Madhu Soni, Nauman Tariq, Jack W. Tsao, Bert Vargas, Scott Vota, Scott Wessels, Hannah Planalp & Raghav Govindarajan
ABSTRACT Purpose: While there is strong evidence supporting the importance of telemedicine in stroke, its role in other areas of neurology is not as clear. The goal of this review is to provide an overview of evidence-based data regarding the role of teleneurology in the care of patients with neurologic disorders other than stroke. Recent findings: Studies across multiple specialties report noninferiority of evaluations by telemedicine compared with traditional, in-person evaluations in terms of patient...

Fine particulate matter and neuroanatomic risk for Alzheimer’s disease in older women

Diana Younan, Xinhui Wang, Ramon Casanova, Ryan Barnard, Sarah Gaussoin, Santiago Saldana, Andrew Petkus, Daniel Beavers, Susan Resnick, JoAnn Manson, Marc Serre, William Vizuete, Victor Henderson, Bonnie Sachs, Joel Salinas, Margaret Gatz, Mark Espeland, Helena Chui, Sally Shumaker, Stephen Rapp & Jiu-Chiuan Chen
Objective: To examine whether late-life exposure to PM2.5 (particulate matter with aerodynamic diameters <2.5-µm) contributes to progressive brain atrophy predictive of Alzheimer’s disease (AD) using a community-dwelling cohort of women (aged 71-89) with up to two brain MRI scans (MRI-1: 2005-6; MRI-2: 2010-11). Methods: AD pattern similarity (AD-PS) scores, developed by supervised machine learning and validated with MRI data from the AD Neuroimaging Initiative, was used to capture high-dimensional gray matter atrophy in brain areas...

Continuous glucose monitoring in cystic fibrosis: glycemic relationships, clinical correlations, and implications for CFRD diagnosis

Melissa Putman & Scully Kevin
Context: The clinical utility and implications of continuous glucose monitoring (CGM) in cystic fibrosis (CF) are unclear. Objective: We examined the correlation between CGM measures and clinical outcomes in adults with CF, investigated the relationship between hemoglobin A1c (HbA1c) and CGM-derived average glucose (AG), and explored CGM measures that distinguish cystic fibrosis–related diabetes (CFRD) from normal and abnormal glucose tolerance. Methods: This prospective observational study included 77 adults with CF who had CGM and HbA1c...

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  • Massachusetts General Hospital
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