65 Works

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...

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...

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: 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: 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.

PAM-altering SNP-based allele-specific CRISPR-Cas9 therapeutic strategies for Huntington's disease

Jong-Min Lee
Huntington's disease (HD) is caused by an expanded CAG repeat in huntingtin (HTT). Since HD is dominant, and loss of HTT leads to neurological abnormalities, safe therapeutic strategies require selective inactivation of mutant HTT. Previously, we proposed a concept of CRISPR-Cas9 using mutant-specific PAM sites generated by SNPs to selectively inactivate mutant HTT. Aiming at revealing suitable targets for clinical development, we analyzed the largest HD genotype dataset to reveal target PAM-altering SNPs (PAS) and...

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...

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: 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: 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,...

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...

Complete allele-specific silencing of the gain-of-function mutation of Huntington's disease

Jong-Min Lee
Dominant gain-of-function mechanism in Huntington's disease (HD) suggests selective inactivation of mutant HTT produces the biggest therapeutic benefit. Here, we developed a complete allele-specific CRISPR/Cas9 strategy to permanently silence mutant HTT through nonsense-mediated decay (NMD), capitalizing on an exonic PAM (protospacer adjacent motif)-Altering SNP (PAS). Comprehensive sequence/haplotype analysis identified PAS-generated NGG PAM sites on exons of common HTT haplotypes in HD patients, revealing a single clinically meaningful PAS-based mutant-specific NMD-CRISPR/Cas9 strategy. The alternative allele of...

Data from: Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012

Jennifer E. Miller, David Korn & Joseph S. Ross
Objective: To evaluate clinical trial registration, reporting and publication rates for new drugs by: (1) legal requirements and (2) the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge. Design: Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration (FDA) for drugs approved in 2012, sponsored by large biopharmaceutical companies. Data sources: Information from Drugs@FDA, ClinicalTrials.gov, MEDLINE-indexed journals and drug company communications. Main outcome...

Data from: Multi-contrast submillimetric 3-Tesla hippocampal subfield segmentation protocol and dataset

Jessie Kulaga-Yoskovitz, Boris C. Bernhardt, Seok-Jun Hong, Tommaso Mansi, Kevin E. Liang, Andre J. W. Van Der Kouwe, Jonathan Smallwood, Andrea Bernasconi & Neda Bernasconi
The hippocampus is composed of distinct anatomical subregions that participate in multiple cognitive processes and are differentially affected in prevalent neurological and psychiatric conditions. Advances in high-field MRI allow for the non-invasive identification of hippocampal substructure. These approaches, however, demand time-consuming manual segmentation that relies heavily on anatomical expertise. Here, we share manual labels and associated high-resolution MRI data (MNI-HISUB25; submillimetric T1- and T2-weighted images, detailed sequence information, and stereotaxic probabilistic anatomical maps) based on...

Data from: The NBS-LRR architectures of plant R-proteins and metazoan NLRs evolved in independent events

Jonathan M. Urbach & Frederick M. Ausubel
There are intriguing parallels between plants and animals, with respect to the structures of their innate immune receptors, that suggest universal principles of innate immunity. The cytosolic nucleotide binding site–leucine rich repeat (NBS-LRR) resistance proteins of plants (R-proteins) and the so-called NOD-like receptors of animals (NLRs) share a domain architecture that includes a STAND (signal transduction ATPases with numerous domains) family NTPase followed by a series of LRRs, suggesting inheritance from a common ancestor with...

Data from: Population-specific genetic modification of Huntington's disease in Venezuela

Michael J. Chao, Kyung-Hee Kim, Jun Wan Shin, Diane Lucente, Vanessa C. Wheeler, Hong Li, Jared C. Roach, Leroy Hood, Nancy S. Wexler, Laura B. Jardim, Peter Holmans, Lesley Jones, Michael Orth, Seung Kwak, James F. Gusella, Marcy E. MacDonald & Jong-Min Lee
Modifiers of Mendelian disorders can provide insights into disease mechanisms and guide therapeutic strategies. A recent genome-wide association (GWA) study discovered genetic modifiers of Huntington's disease (HD) onset in Europeans. Here, we performed whole genome sequencing and GWA analysis of a Venezuelan HD cluster whose families were crucial for the original mapping of the HD gene defect. The Venezuelan HD subjects develop motor symptoms earlier than their European counterparts, implying the potential for population-specific modifiers....

Data from: Succinate links atrial dysfunction and cardioembolic stroke

Sarah E. Nelson, Zsuzsanna Ament, Zoe Wolcott, Robert E. Gerszten & W. Taylor Kimberly
Objective: To determine whether altered metabolic profiles represent a link between atrial dysfunction and cardioembolic (CE) stroke, and thus whether underlying dysfunctional atrial substrate may contribute to thromboembolism risk in CE stroke. Methods: One hundred forty-four metabolites were measured using liquid chromatography-tandem mass spectrometry in plasma samples collected within 9 hours of stroke onset in 367 acute stroke patients. Stroke subtype was assigned using the causative classification of stroke, and CE stroke (n=181) was compared...

Data from: Quantification of motor speech impairment and its anatomic basis in primary progressive aphasia

Claire Cordella, Megan Quimby, Alexandra Touroutoglou, Michael Brickhouse, Bradford Clark Dickerson & Jordan R. Green
Objective: To evaluate whether a quantitative speech measure is effective in identifying and monitoring motor speech impairment (MSI) in patients with primary progressive aphasia (PPA), and to investigate the neuroanatomical basis of MSI in PPA. Methods: Sixty-four patients with PPA were evaluated at baseline, with a subset (N=39) evaluated longitudinally. Articulation rate (AR), a quantitative measure derived from spontaneous speech, was measured at each timepoint. MRI was collected at baseline. Differences in baseline AR were...

Data from: Alcoholism gender differences in brain responsivity to emotional stimuli

Kayle S Sawyer, Nasim Maleki, Trinity Urban, Marinkovic Ksenija, Karson Steven, Susan Mosher Ruiz, Gordon J Harris & Marlene Oscar-Berman
Men and women may use alcohol to regulate emotions differently, with corresponding differences in neural responses. We explored how the viewing of different types of emotionally salient stimuli impacted brain activity observed through functional magnetic resonance imaging (fMRI) from 42 long-term abstinent alcoholic (25 women) and 46 nonalcoholic (24 women) participants. Analyses revealed blunted brain responsivity in alcoholic compared to nonalcoholic groups, as well as gender differences in those activation patterns. Brain activation in alcoholic...

Data from: Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP Trial

W. Taylor Kimberly, Matthew B. Bevers, Rüdiger Von Kummer, Andrew M. Demchuk, Javier M. Romero, Jordan J. Elm, Holly E. Hinson, Bradley J. Molyneaux, J. Marc Simard & Kevin Navin Sheth
Objective: In this secondary analysis of the GAMES-RP trial, we report the effect of IV glyburide on adjudicated, edema-related endpoints. Methods: Blinded adjudicators assigned designations for hemorrhagic transformation, neurological deterioration, malignant edema and edema-related death to patients from the GAMES-RP Phase II randomized controlled trial of IV glyburide for large hemispheric infarct. Rates of these endpoints were compared between treatment arms in the per-protocol sample. In those participants with malignant edema, the effects of treatment...

Data from: Revisiting protein aggregation as pathogenic in sporadic Parkinson’s and Alzheimer’s diseases

Alberto J. Espay, Joaquin A. Vizcarra, Luca Marsili, Anthony E. Lang, David K. Simon, Aristide Merola, Keith A. Josephs, Alfonso Fasano, Francesca Morgante, Rodolfo Savica, J. Timothy Greenamyre, Franca Cambi, Tritia R. Yamasaki, Caroline M. Tanner, Ziv Gan-Or, Irene Litvan, Ignacio F. Mata, Cyrus P. Zabetian, Patrik Brundin, Hubert H. Fernandez, David G. Standaert, Marcelo A. Kauffman, Michael A. Schwarzschild, S. Pablo Sardi, Todd Sherer … & James B. Leverenz
The gold standard for a definitive diagnosis of Parkinson’s disease (PD) is the pathologic finding of aggregated alpha-synuclein into Lewy bodies and for Alzheimer’s disease (AD) aggregated amyloid into plaques and hyperphosphorylated tau into tangles. Implicit in this clinico-pathologic-based nosology is the assumption that pathological protein aggregation at autopsy reflect pathogenesis at disease onset. While these aggregates may in exceptional cases be on a causal pathway in humans (e.g., aggregated alpha-synuclein in SNCA gene multiplication...

Data from: Neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors

Bhaskar Roy, Avash Das, Kumar Ashish, Dhrubajyoti Bandyopadhyay, Abhishek Maiti, Sandipan Chakraborty, Martha E. Stone, Lisa Liang Philpotts, Richard J. Nowak & Huned S. Patwa
Objective: To explore the association of peripheral neuropathy with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) use in cancer patients. Methods: Published data search up to November 2018 reporting peripheral neuropathy in cancer patients treated with VEGFR-TKIs was performed. The primary outcome was presence of peripheral neuropathy at the end of the trial. Random-effects meta-analysis was performed to estimate Relative Risk (RR) of individual treatment. Results: Thirty Randomized Clinical Trials (RCTs) including 12,490...

Genetic overlap and causal inferences between kidney function and cerebrovascular disease

Sandro Marini, Marios Georgakis, Jaeyoon Chung, Jonathan Henry, Martin Dichgans, Jonathan Rosand, Christopher Anderson & Rainer Malik
Objective: Leveraging large-scale genetic data, we aimed to identify shared pathogenic mechanisms and causal relationships between impaired kidney function and cerebrovascular disease phenotypes. Methods: We used summary statistics from genome-wide association studies (GWAS) of kidney function traits (chronic kidney disease (CKD) diagnosis, estimated glomerular filtration rate (eGFR), and Urinary Albumin-to-Creatinine Ratio (UACR)), and of cerebrovascular disease phenotypes: ischemic stroke and its subtypes, intracerebral hemorrhage (ICH), white matter hyperintensities (WMH) on brain MRI. We (i) tested...

Registration Year

  • 2022
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  • 2011

Resource Types

  • Dataset


  • Massachusetts General Hospital
  • Brigham and Women's Hospital
  • Stanford University
  • University of Pittsburgh
  • Boston Children's Hospital
  • Columbia University
  • University of Virginia
  • McGill University
  • University of Southern California
  • University of Tennessee Health Science Center