Search

Your search keyword '"Mccluskey, Leo"' showing total 512 results
Start Over Author "Mccluskey, Leo"
512 results on '"Mccluskey, Leo"'

1. Machine learning suggests polygenic risk for cognitive dysfunction in amyotrophic lateral sclerosis.

Author

Placek, Katerina, Benatar, Michael, Wuu, Joanne, Rampersaud, Evadnie, Hennessy, Laura, Van Deerlin, Vivianna, Grossman, Murray, Irwin, David, Elman, Lauren, McCluskey, Leo, Quinn, Colin, Granit, Volkan, Statland, Jeffrey, Burns, Ted, Ravits, John, Swenson, Andrea, Katz, Jon, Pioro, Erik, Jackson, Carlayne, Caress, James, So, Yuen, Maiser, Samuel, Walk, David, Lee, Edward, Trojanowski, John, Cook, Philip, Gee, James, Sha, Jin, Naj, Adam, Rademakers, Rosa, Chen, Wenan, Wu, Gang, Paul Taylor, J, and McMillan, Corey

Subjects
amyotrophic lateral sclerosis, cognition, frontotemporal dementia, machine learning, polygenic score, Amyotrophic Lateral Sclerosis, Cognitive Dysfunction, Frontotemporal Dementia, Humans, Machine Learning, Neurodegenerative Diseases
Abstract

Amyotrophic lateral sclerosis (ALS) is a multi-system disease characterized primarily by progressive muscle weakness. Cognitive dysfunction is commonly observed in patients; however, factors influencing risk for cognitive dysfunction remain elusive. Using sparse canonical correlation analysis (sCCA), an unsupervised machine-learning technique, we observed that single nucleotide polymorphisms collectively associate with baseline cognitive performance in a large ALS patient cohort (N = 327) from the multicenter Clinical Research in ALS and Related Disorders for Therapeutic Development (CReATe) Consortium. We demonstrate that a polygenic risk score derived using sCCA relates to longitudinal cognitive decline in the same cohort and also to in vivo cortical thinning in the orbital frontal cortex, anterior cingulate cortex, lateral temporal cortex, premotor cortex, and hippocampus (N = 90) as well as post-mortem motor cortical neuronal loss (N = 87) in independent ALS cohorts from the University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Our findings suggest that common genetic polymorphisms may exert a polygenic contribution to the risk of cortical disease vulnerability and cognitive dysfunction in ALS.

Published
2021

2. Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated.

Author

Robinson, John L, Lee, Edward B, Xie, Sharon X, Rennert, Lior, Suh, EunRan, Bredenberg, Colin, Caswell, Carrie, Van Deerlin, Vivianna M, Yan, Ning, Yousef, Ahmed, Hurtig, Howard I, Siderowf, Andrew, Grossman, Murray, McMillan, Corey T, Miller, Bruce, Duda, John E, Irwin, David J, Wolk, David, Elman, Lauren, McCluskey, Leo, Chen-Plotkin, Alice, Weintraub, Daniel, Arnold, Steven E, Brettschneider, Johannes, Lee, Virginia M-Y, and Trojanowski, John Q

Subjects
Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Aging, Acquired Cognitive Impairment, Frontotemporal Dementia (FTD), Neurodegenerative, Dementia, Rare Diseases, Alzheimer's Disease, Aetiology, 2.1 Biological and endogenous factors, Neurological, Aged, Alzheimer Disease, Amyotrophic Lateral Sclerosis, Apolipoprotein E4, DNA-Binding Proteins, Female, Humans, Inclusion Bodies, Lewy Bodies, Lewy Body Disease, Male, Middle Aged, Multiple System Atrophy, Neurodegenerative Diseases, Pick Disease of the Brain, Prevalence, Supranuclear Palsy, Progressive, TDP-43 Proteinopathies, Tauopathies, alpha-Synuclein, tau Proteins, Alzheimer's disease, co-pathology, neurodegenerative disease, pathology, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery
Abstract

Lewy bodies commonly occur in Alzheimer's disease, and Alzheimer's disease pathology is frequent in Lewy body diseases, but the burden of co-pathologies across neurodegenerative diseases is unknown. We assessed the extent of tau, amyloid-β, α-synuclein and TDP-43 proteinopathies in 766 autopsied individuals representing a broad spectrum of clinical neurodegenerative disease. We interrogated pathological Alzheimer's disease (n = 247); other tauopathies (n = 95) including Pick's disease, corticobasal disease and progressive supranuclear palsy; the synucleinopathies (n = 164) including multiple system atrophy and Lewy body disease; the TDP-43 proteinopathies (n = 188) including frontotemporal lobar degeneration with TDP-43 inclusions and amyotrophic lateral sclerosis; and a minimal pathology group (n = 72). Each group was divided into subgroups without or with co-pathologies. Age and sex matched logistic regression models compared co-pathology prevalence between groups. Co-pathology prevalence was similar between the minimal pathology group and most neurodegenerative diseases for each proteinopathy: tau was nearly universal (92-100%), amyloid-β common (20-57%); α-synuclein less common (4-16%); and TDP-43 the rarest (0-16%). In several neurodegenerative diseases, co-pathology increased: in Alzheimer's disease, α-synuclein (41-55%) and TDP-43 (33-40%) increased; in progressive supranuclear palsy, α-synuclein increased (22%); in corticobasal disease, TDP-43 increased (24%); and in neocortical Lewy body disease, amyloid-β (80%) and TDP-43 (22%) increased. Total co-pathology prevalence varied across groups (27-68%), and was increased in high Alzheimer's disease, progressive supranuclear palsy, and neocortical Lewy body disease (70-81%). Increased age at death was observed in the minimal pathology group, amyotrophic lateral sclerosis, and multiple system atrophy cases with co-pathologies. In amyotrophic lateral sclerosis and neocortical Lewy body disease, co-pathologies associated with APOE ɛ4. Lewy body disease cases with Alzheimer's disease co-pathology had substantially lower Mini-Mental State Examination scores than pure Lewy body disease. Our data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenerative disease severity influences co-pathology as evidenced by the prevalence of co-pathology in high Alzheimer's disease and neocortical Lewy body disease, but not intermediate Alzheimer's disease or limbic Lewy body disease; and that tau and α-synuclein strains may also modify co-pathologies since tauopathies and synucleinopathies had differing co-pathologies and burdens. These findings have implications for clinical trials that focus on monotherapies targeting tau, amyloid-β, α-synuclein and TDP-43.

Published
2018

3. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial

Author

Kiernan, Matthew, Mathers, Susan, Henderson, Robert, Needham, Merrilee, Schultz, David, Löscher, Wolfgang, Mitrovic, Nenad, Rath, Jakob, Damme, Philip Van, De Bleecker, Jan L., Delstanche, Stéphanie, Johnston, Wendy, Zinman, Lorne, O'Connell, Colleen, Matte, Genevieve, Dionne, Annie, Korngut, Lawrence, Turnbull, John, Laaksovirta, Hannu, Jokela, Manu, Tapiola, Tero, Soriani, Marie-Hélène, Couratier, Philippe, Camu, William, Corcia, Philippe, Ludolph, Albert, Großkreutz, Julian, Meyer, Thomas, Boentert, Matthias, Schrank, Berthold, Prudlo, Johannes, Untucht, Robert, Hardiman, Orla, Siciliano, Gabriele, Chio', Adriano, Mazzini, Letizia, Inghilleri, Maurizio, Caponnetto, Claudia, Mora, Gabriele, Mora Pardina, Jesús S, Farrero Munoz, Eva, Vázquez Costa, Juan F, Aguera Morales, Eduardo, Varona, Luis, Andersen, Peter, Ingre, Caroline, Johansson, Rune, Radunovic, Aleksandar, Young, Carolyn, Babu, Suma, Shaibani, Aziz, Staff, Nathan, Vu, Tuan, Rivner, Michael, Scelsa, Stephen, Sivakumar, Kumaraswamy, Waheed, Waqar, Heitzman, Daragh, Rana, Sandeep, Pattee, Gary, Ajroud-Driss, Senda, Bayat, Elham, Kasarskis, Edward, Lange, Dale J, Elliott, Michael, Harris, Brent, Felice, Kevin, Pulley, Michael T, Kwan, Justin, Brown, Martin, Ravits, John, Burford, Matthew, Karam, Chafic, Miller, Timothy, Andrews, Jinsy, Levine, Todd, Locatelli, Eduardo, Wymer, James, Bedlack, Richard, Fee, Dominic, Goyal, Namita, Oskarsson, Bjorn, McCluskey, Leo, Caress, James, Weiss, Michael, Quick, Adam, Bromberg, Mark, Lacomis, David, Goutman, Stephen, Rezania, Kourosh, Guliani, Gaurav, Goslin, Kimberly, Katz, Jonathan S, Cudkowicz, Merit, Genge, Angela, Maragakis, Nicholas, Petri, Susanne, van den Berg, Leonard, Aho, Valtteri V, Sarapohja, Toni, Kuoppamäki, Mikko, Garratt, Chris, and Al-Chalabi, Ammar

Published
2021
Full Text
View/download PDF

4. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis

Author

Gendron, Tania F, Chew, Jeannie, Stankowski, Jeannette N, Hayes, Lindsey R, Zhang, Yong-Jie, Prudencio, Mercedes, Carlomagno, Yari, Daughrity, Lillian M, Jansen-West, Karen, Perkerson, Emilie A, O'Raw, Aliesha, Cook, Casey, Pregent, Luc, Belzil, Veronique, van Blitterswijk, Marka, Tabassian, Lilia J, Lee, Chris W, Yue, Mei, Tong, Jimei, Song, Yuping, Castanedes-Casey, Monica, Rousseau, Linda, Phillips, Virginia, Dickson, Dennis W, Rademakers, Rosa, Fryer, John D, Rush, Beth K, Pedraza, Otto, Caputo, Ana M, Desaro, Pamela, Palmucci, Carla, Robertson, Amelia, Heckman, Michael G, Diehl, Nancy N, Wiggs, Edythe, Tierney, Michael, Braun, Laura, Farren, Jennifer, Lacomis, David, Ladha, Shafeeq, Fournier, Christina N, McCluskey, Leo F, Elman, Lauren B, Toledo, Jon B, McBride, Jennifer D, Tiloca, Cinzia, Morelli, Claudia, Poletti, Barbara, Solca, Federica, Prelle, Alessandro, Wuu, Joanne, Jockel-Balsarotti, Jennifer, Rigo, Frank, Ambrose, Christine, Datta, Abhishek, Yang, Weixing, Raitcheva, Denitza, Antognetti, Giovanna, McCampbell, Alexander, Van Swieten, John C, Miller, Bruce L, Boxer, Adam L, Brown, Robert H, Bowser, Robert, Miller, Timothy M, Trojanowski, John Q, Grossman, Murray, Berry, James D, Hu, William T, Ratti, Antonia, Traynor, Bryan J, Disney, Matthew D, Benatar, Michael, Silani, Vincenzo, Glass, Jonathan D, Floeter, Mary Kay, Rothstein, Jeffrey D, Boylan, Kevin B, and Petrucelli, Leonard

Subjects
Clinical Research, Neurodegenerative, Brain Disorders, Acquired Cognitive Impairment, Dementia, Neurosciences, ALS, Rare Diseases, Clinical Trials and Supportive Activities, Genetics, Neurological, Adult, Aged, Amyotrophic Lateral Sclerosis, Animals, Biomarkers, Brain, C9orf72 Protein, Cell Line, Dinucleotide Repeats, Humans, Induced Pluripotent Stem Cells, Leukocytes, Mononuclear, Longitudinal Studies, Mice, Middle Aged, Neurons, Oligonucleotides, Antisense, Prognosis, RNA, Biological Sciences, Medical and Health Sciences
Abstract

There is no effective treatment for amyotrophic lateral sclerosis (ALS), a devastating motor neuron disease. However, discovery of a G4C2 repeat expansion in the C9ORF72 gene as the most common genetic cause of ALS has opened up new avenues for therapeutic intervention for this form of ALS. G4C2 repeat expansion RNAs and proteins of repeating dipeptides synthesized from these transcripts are believed to play a key role in C9ORF72-associated ALS (c9ALS). Therapeutics that target G4C2 RNA, such as antisense oligonucleotides (ASOs) and small molecules, are thus being actively investigated. A limitation in moving such treatments from bench to bedside is a lack of pharmacodynamic markers for use in clinical trials. We explored whether poly(GP) proteins translated from G4C2 RNA could serve such a purpose. Poly(GP) proteins were detected in cerebrospinal fluid (CSF) and in peripheral blood mononuclear cells from c9ALS patients and, notably, from asymptomatic C9ORF72 mutation carriers. Moreover, CSF poly(GP) proteins remained relatively constant over time, boding well for their use in gauging biochemical responses to potential treatments. Treating c9ALS patient cells or a mouse model of c9ALS with ASOs that target G4C2 RNA resulted in decreased intracellular and extracellular poly(GP) proteins. This decrease paralleled reductions in G4C2 RNA and downstream G4C2 RNA-mediated events. These findings indicate that tracking poly(GP) proteins in CSF could provide a means to assess target engagement of G4C2 RNA-based therapies in symptomatic C9ORF72 repeat expansion carriers and presymptomatic individuals who are expected to benefit from early therapeutic intervention.

Published
2017

5. Defining SOD1 ALS natural history to guide therapeutic clinical trial design

Author

Bali, Taha, Self, Wade, Liu, Jingxia, Siddique, Teepu, Wang, Leo H, Bird, Thomas D, Ratti, Elena, Atassi, Nazem, Boylan, Kevin B, Glass, Jonathan D, Maragakis, Nicholas J, Caress, James B, McCluskey, Leo F, Appel, Stanley H, Wymer, James P, Gibson, Summer, Zinman, Lorne, Mozaffar, Tahseen, Callaghan, Brian, McVey, April L, Jockel-Balsarotti, Jennifer, Allred, Peggy, Fisher, Elena R, Lopate, Glenn, Pestronk, Alan, Cudkowicz, Merit E, and Miller, Timothy M

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Brain Disorders, Neurosciences, ALS, Rare Diseases, Clinical Research, Neurodegenerative, Clinical Trials and Supportive Activities, Adult, Age of Onset, Amyotrophic Lateral Sclerosis, Clinical Trials as Topic, Disease Progression, Humans, Middle Aged, Mutation, Research Design, Retrospective Studies, Superoxide Dismutase, Vital Capacity, Medical and Health Sciences, Psychology and Cognitive Sciences, Neurology & Neurosurgery, Clinical sciences
Abstract

ImportanceUnderstanding the natural history of familial amyotrophic lateral sclerosis (ALS) caused by SOD1 mutations (ALSSOD1) will provide key information for optimising clinical trials in this patient population.ObjectiveTo establish an updated natural history of ALSSOD1.Design, setting and participantsRetrospective cohort study from 15 medical centres in North America evaluated records from 175 patients with ALS with genetically confirmed SOD1 mutations, cared for after the year 2000.Main outcomes and measuresAge of onset, survival, ALS Functional Rating Scale (ALS-FRS) scores and respiratory function were analysed. Patients with the A4V (Ala-Val) SOD1 mutation (SOD1A4V), the largest mutation population in North America with an aggressive disease progression, were distinguished from other SOD1 mutation patients (SOD1non-A4V) for analysis.ResultsMean age of disease onset was 49.7±12.3 years (mean±SD) for all SOD1 patients, with no statistical significance between SOD1A4V and SOD1non-A4V (p=0.72, Kruskal-Wallis). Total SOD1 patient median survival was 2.7 years. Mean disease duration for all SOD1 was 4.6±6.0 and 1.4±0.7 years for SOD1A4V. SOD1A4V survival probability (median survival 1.2 years) was significantly decreased compared with SOD1non-A4V (median survival 6.8 years; p

Published
2017

6. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Author

van Rheenen, Wouter, Shatunov, Aleksey, Dekker, Annelot M, McLaughlin, Russell L, Diekstra, Frank P, Pulit, Sara L, van der Spek, Rick AA, Võsa, Urmo, de Jong, Simone, Robinson, Matthew R, Yang, Jian, Fogh, Isabella, van Doormaal, Perry Tc, Tazelaar, Gijs HP, Koppers, Max, Blokhuis, Anna M, Sproviero, William, Jones, Ashley R, Kenna, Kevin P, van Eijk, Kristel R, Harschnitz, Oliver, Schellevis, Raymond D, Brands, William J, Medic, Jelena, Menelaou, Androniki, Vajda, Alice, Ticozzi, Nicola, Lin, Kuang, Rogelj, Boris, Vrabec, Katarina, Ravnik-Glavač, Metka, Koritnik, Blaž, Zidar, Janez, Leonardis, Lea, Grošelj, Leja Dolenc, Millecamps, Stéphanie, Salachas, François, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S, Rojas-García, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E, Shaw, Pamela J, Hardy, John, Orrell, Richard W, Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Topp, Simon, Petri, Susanne, Abdulla, Susanne, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Ophoff, Roel A, Staats, Kim A, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M, Trojanowski, John Q, Elman, Lauren, McCluskey, Leo, Basak, A Nazli, Tunca, Ceren, Hamzeiy, Hamid, Parman, Yesim, Meitinger, Thomas, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Andres, Christian R, Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine AM, Saker-Delye, Safaa, Dürr, Alexandra, Wood, Nicholas W, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-François, Uitterlinden, Andre G, Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, and Blauw, Hylke M

Subjects
PARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group, Humans, Amyotrophic Lateral Sclerosis, Genetic Predisposition to Disease, Proteins, Cytoskeletal Proteins, Myelin Proteins, Case-Control Studies, Cohort Studies, Mutation, Netherlands, Munc18 Proteins, Genome-Wide Association Study, Neurosciences, Rare Diseases, Brain Disorders, Biotechnology, Prevention, Human Genome, Neurodegenerative, Genetics, ALS, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Published
2016

7. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways.

Author

Cirulli, Elizabeth, Lasseigne, Brittany, Petrovski, Slavé, Sapp, Peter, Dion, Patrick, Leblond, Claire, Couthouis, Julien, Lu, Yi-Fan, Wang, Quanli, Krueger, Brian, Ren, Zhong, Keebler, Jonathan, Han, Yujun, Levy, Shawn, Boone, Braden, Wimbish, Jack, Waite, Lindsay, Jones, Angela, Carulli, John, Day-Williams, Aaron, Staropoli, John, Xin, Winnie, Chesi, Alessandra, Raphael, Alya, McKenna-Yasek, Diane, Cady, Janet, Vianney de Jong, J, Kenna, Kevin, Smith, Bradley, Topp, Simon, Miller, Jack, Gkazi, Athina, Al-Chalabi, Ammar, van den Berg, Leonard, Veldink, Jan, Silani, Vincenzo, Ticozzi, Nicola, Shaw, Christopher, Baloh, Robert, Appel, Stanley, Simpson, Ericka, Lagier-Tourenne, Clotilde, Pulst, Stefan, Gibson, Summer, Trojanowski, John, Elman, Lauren, McCluskey, Leo, Grossman, Murray, Shneider, Neil, Chung, Wendy, Ravits, John, Glass, Jonathan, Sims, Katherine, Van Deerlin, Vivianna, Maniatis, Tom, Hayes, Sebastian, Ordureau, Alban, Swarup, Sharan, Landers, John, Baas, Frank, Allen, Andrew, Bedlack, Richard, Harper, J, Gitler, Aaron, Rouleau, Guy, Brown, Robert, Harms, Matthew, Cooper, Gregory, Harris, Tim, Myers, Richard, and Goldstein, David

Subjects
Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Aged, 80 and over, Amyotrophic Lateral Sclerosis, Autophagy, Cell Cycle Proteins, Exome, Female, Genes, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Male, Membrane Transport Proteins, Middle Aged, Protein Binding, Protein Serine-Threonine Kinases, Risk, Sequence Analysis, DNA, Sequestosome-1 Protein, Transcription Factor TFIIIA, Young Adult
Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease with no effective treatment. We report the results of a moderate-scale sequencing study aimed at increasing the number of genes known to contribute to predisposition for ALS. We performed whole-exome sequencing of 2869 ALS patients and 6405 controls. Several known ALS genes were found to be associated, and TBK1 (the gene encoding TANK-binding kinase 1) was identified as an ALS gene. TBK1 is known to bind to and phosphorylate a number of proteins involved in innate immunity and autophagy, including optineurin (OPTN) and p62 (SQSTM1/sequestosome), both of which have also been implicated in ALS. These observations reveal a key role of the autophagic pathway in ALS and suggest specific targets for therapeutic intervention.

Published
2015

8. Elevated CSF GAP-43 is Alzheimer's disease specific and associated with tau and amyloid pathology

Author

Sandelius, Åsa, Portelius, Erik, Källén, Åsa, Zetterberg, Henrik, Rot, Uros, Olsson, Bob, Toledo, Jon B., Shaw, Leslie M., Lee, Virginia M.Y., Irwin, David J., Grossman, Murray, Weintraub, Daniel, Chen-Plotkin, Alice, Wolk, David A., McCluskey, Leo, Elman, Lauren, Kostanjevecki, Vesna, Vandijck, Manu, McBride, Jennifer, Trojanowski, John Q., and Blennow, Kaj

Published
2019
Full Text
View/download PDF

12. TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions.

Author

Gallagher, Michael D, Suh, Eunran, Grossman, Murray, Elman, Lauren, McCluskey, Leo, Van Swieten, John C, Al-Sarraj, Safa, Neumann, Manuela, Gelpi, Ellen, Ghetti, Bernardino, Rohrer, Jonathan D, Halliday, Glenda, Van Broeckhoven, Christine, Seilhean, Danielle, Shaw, Pamela J, Frosch, Matthew P, Alafuzoff, Irina, Antonell, Anna, Bogdanovic, Nenad, Brooks, William, Cairns, Nigel J, Cooper-Knock, Johnathan, Cotman, Carl, Cras, Patrick, Cruts, Marc, De Deyn, Peter P, DeCarli, Charles, Dobson-Stone, Carol, Engelborghs, Sebastiaan, Fox, Nick, Galasko, Douglas, Gearing, Marla, Gijselinck, Ilse, Grafman, Jordan, Hartikainen, Päivi, Hatanpaa, Kimmo J, Highley, J Robin, Hodges, John, Hulette, Christine, Ince, Paul G, Jin, Lee-Way, Kirby, Janine, Kofler, Julia, Kril, Jillian, Kwok, John BJ, Levey, Allan, Lieberman, Andrew, Llado, Albert, Martin, Jean-Jacques, Masliah, Eliezer, McDermott, Christopher J, McKee, Ann, McLean, Catriona, Mead, Simon, Miller, Carol A, Miller, Josh, Munoz, David G, Murrell, Jill, Paulson, Henry, Piguet, Olivier, Rossor, Martin, Sanchez-Valle, Raquel, Sano, Mary, Schneider, Julie, Silbert, Lisa C, Spina, Salvatore, van der Zee, Julie, Van Langenhove, Tim, Warren, Jason, Wharton, Stephen B, White, Charles L, Woltjer, Randall L, Trojanowski, John Q, Lee, Virginia MY, Van Deerlin, Vivianna, and Chen-Plotkin, Alice S

Subjects
Humans, Amyotrophic Lateral Sclerosis, Genetic Predisposition to Disease, Intercellular Signaling Peptides and Proteins, Proteins, Membrane Proteins, Nerve Tissue Proteins, Cohort Studies, Age Factors, Age of Onset, DNA Repeat Expansion, Genotype, Heterozygote, Polymorphism, Single Nucleotide, Alleles, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Frontotemporal Lobar Degeneration, C9orf72 Protein, Progranulins, Rare Diseases, Aging, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Brain Disorders, Neurodegenerative, Prevention, Genetics, Dementia, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Aetiology, 2.1 Biological and endogenous factors, Neurological, TMEM106B, C9orf72, Frontotemporal dementia, Frontotemporal lobar degeneration, Amyotrophic lateral sclerosis, Genetic modifier, Clinical Sciences, Neurology & Neurosurgery
Abstract

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.

Published
2014

13. Topography of FUS pathology distinguishes late-onset BIBD from aFTLD-U

Author

Lee, Edward B, Russ, Jenny, Jung, Hyunjoo, Elman, Lauren B, Chahine, Lama M, Kremens, Daniel, Miller, Bruce L, Coslett, H, Trojanowski, John Q, Van Deerlin, Vivianna M, and McCluskey, Leo F

Abstract

Abstract Background Multiple neurodegenerative diseases are characterized by the abnormal accumulation of FUS protein including various subtypes of frontotemporal lobar degeneration with FUS inclusions (FTLD-FUS). These subtypes include atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U), basophilic inclusion body disease (BIBD) and neuronal intermediate filament inclusion disease (NIFID). Despite considerable overlap, certain pathologic features including differences in inclusion morphology, the subcellular localization of inclusions, and the relative paucity of subcortical FUS pathology in aFTLD-U indicate that these three entities represent related but distinct diseases. In this study, we report the clinical and pathologic features of three cases of aFTLD-U and two cases of late-onset BIBD with an emphasis on the anatomic distribution of FUS inclusions. Results The aFTLD-U cases demonstrated FUS inclusions in cerebral cortex, subcortical grey matter and brainstem with a predilection for anterior forebrain and rostral brainstem. In contrast, the distribution of FUS pathology in late-onset BIBD cases demonstrated a predilection for pyramidal and extrapyramidal motor regions with relative sparing of cerebral cortex and limbic regions. Conclusions The topography of FUS pathology in these cases demonstrate the diversity of sporadic FUS inclusion body diseases and raises the possibility that late-onset motor neuron disease with BIBD neuropathology may exhibit unique clinical and pathologic features.

Published
2013

14. Deciphering amyotrophic lateral sclerosis: What phenotype, neuropathology and genetics are telling us about pathogenesis

Author

Ravits, John, Appel, Stanley, Baloh, Robert H, Barohn, Richard, Brooks, Benjamin Rix, Elman, Lauren, Floeter, Mary Kay, Henderson, Christopher, Lomen-Hoerth, Catherine, Macklis, Jeffrey D, McCluskey, Leo, Mitsumoto, Hiroshi, Przedborski, Serge, Rothstein, Jeffrey, Trojanowski, John Q, van den Berg, Leonard H, and Ringel, Steven

Subjects
Biomedical and Clinical Sciences, Neurosciences, Genetics, Neurodegenerative, Orphan Drug, Brain Disorders, ALS, Rare Diseases, Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Amyotrophic Lateral Sclerosis, DNA-Binding Proteins, Disease Progression, Extremities, Humans, Motor Neurons, Mutation, Phenotype, PLS, PMA, motor neuron disease, FTD, Clinical Sciences
Abstract

Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS - and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease - a goal that seems increasingly achievable.

Published
2013

16. Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology

Author

Portelius, Erik, Olsson, Bob, Höglund, Kina, Cullen, Nicholas C., Kvartsberg, Hlin, Andreasson, Ulf, Zetterberg, Henrik, Sandelius, Åsa, Shaw, Leslie M., Lee, Virginia M. Y., Irwin, David J., Grossman, Murray, Weintraub, Daniel, Chen-Plotkin, Alice, Wolk, David A., McCluskey, Leo, Elman, Lauren, McBride, Jennifer, Toledo, Jon B., Trojanowski, John Q., and Blennow, Kaj

Published
2018
Full Text
View/download PDF

19. A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank

Author

Toledo, Jon B., Van Deerlin, Vivianna M., Lee, Edward B., Suh, EunRan, Baek, Young, Robinson, John L., Xie, Sharon X., McBride, Jennifer, Wood, Elisabeth M., Schuck, Theresa, Irwin, David J., Gross, Rachel G., Hurtig, Howard, McCluskey, Leo, Elman, Lauren, Karlawish, Jason, Schellenberg, Gerard, Chen-Plotkin, Alice, Wolk, David, Grossman, Murray, Arnold, Steven E., Shaw, Leslie M., Lee, Virginia M.-Y., and Trojanowski, John Q.

Published
2014
Full Text
View/download PDF

21. Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Author

FALS Sequencing Consortium, Cirulli, Elizabeth T., Lasseigne, Brittany N., Petrovski, Slavé, Sapp, Peter C., Dion, Patrick A., Leblond, Claire S., Couthouis, Julien, Lu, Yi-Fan, Wang, Quanli, Krueger, Brian J., Ren, Zhong, Keebler, Jonathan, Han, Yujun, Levy, Shawn E., Boone, Braden E., Wimbish, Jack R., Waite, Lindsay L., Jones, Angela L., Carulli, John P., Day-Williams, Aaron G., Staropoli, John F., Xin, Winnie W., Chesi, Alessandra, Raphael, Alya R., McKenna-Yasek, Diane, Cady, Janet, de Jong, J. M. B. Vianney, Kenna, Kevin P., Smith, Bradley N., Topp, Simon, Miller, Jack, Gkazi, Athina, Al-Chalabi, Ammar, van den Berg, Leonard H., Veldink, Jan, Silani, Vincenzo, Ticozzi, Nicola, Shaw, Christopher E., Baloh, Robert H., Appel, Stanley, Simpson, Ericka, Lagier-Tourenne, Clotilde, Pulst, Stefan M., Gibson, Summer, Trojanowski, John Q., Elman, Lauren, McCluskey, Leo, Grossman, Murray, Shneider, Neil A., Chung, Wendy K., Ravits, John M., Glass, Jonathan D., Sims, Katherine B., Van Deerlin, Vivianna M., Maniatis, Tom, Hayes, Sebastian D., Ordureau, Alban, Swarup, Sharan, Landers, John, Baas, Frank, Allen, Andrew S., Bedlack, Richard S., Harper, J. Wade, Gitler, Aaron D., Rouleau, Guy A., Brown, Robert, Harms, Matthew B., Cooper, Gregory M., Harris, Tim, Myers, Richard M., and Goldstein, David B.

Published
2015

22. Characterization of Parkinson's disease using blood-based biomarkers: A multicohort proteomic analysis

Author

Posavi, Marijan, Diaz-Ortiz, Maria, Liu, Benjamine, Swanson, Christine R., Skrinak, R. Tyler, Hernandez-Con, Pilar, Amado, Defne A., Fullard, Michelle, Rick, Jacqueline, Siderowf, Andrew, Weintraub, Daniel, McCluskey, Leo, Trojanowski, John Q., Dewey, Richard B., Huang, Xuemei, and Chen-Plotkin, Alice S.

Subjects
United States. National Institute of Neurological Disorders and Stroke, University of Pennsylvania, Rankings, Development and progression, Somatotropin -- Rankings, Medical research, Proteins, Biological markers, Fluorescence, Hormones, L-dopa, Amyotrophic lateral sclerosis
Abstract

Author(s): Marijan Posavi 1, Maria Diaz-Ortiz 1, Benjamine Liu 1, Christine R. Swanson 1,2, R. Tyler Skrinak 1, Pilar Hernandez-Con 1, Defne A. Amado 1, Michelle Fullard 1, Jacqueline Rick [...], Background Parkinson's disease (PD) is a progressive neurodegenerative disease affecting about 5 million people worldwide with no disease-modifying therapies. We sought blood-based biomarkers in order to provide molecular characterization of individuals with PD for diagnostic confirmation and prediction of progression. Methods and findings In 141 plasma samples (96 PD, 45 neurologically normal control [NC] individuals; 45.4% female, mean age 70.0 years) from a longitudinally followed Discovery Cohort based at the University of Pennsylvania (UPenn), we measured levels of 1,129 proteins using an aptamer-based platform. We modeled protein plasma concentration (log.sub.10 of relative fluorescence units [RFUs]) as the effect of treatment group (PD versus NC), age at plasma collection, sex, and the levodopa equivalent daily dose (LEDD), deriving first-pass candidate protein biomarkers based on p-value for PD versus NC. These candidate proteins were then ranked by Stability Selection. We confirmed findings from our Discovery Cohort in a Replication Cohort of 317 individuals (215 PD, 102 NC; 47.9% female, mean age 66.7 years) from the multisite, longitudinally followed National Institute of Neurological Disorders and Stroke Parkinson's Disease Biomarker Program (PDBP) Cohort. Analytical approach in the Replication Cohort mirrored the approach in the Discovery Cohort: each protein plasma concentration (log.sub.10 of RFU) was modeled as the effect of group (PD versus NC), age at plasma collection, sex, clinical site, and batch. Of the top 10 proteins from the Discovery Cohort ranked by Stability Selection, four associations were replicated in the Replication Cohort. These blood-based biomarkers were bone sialoprotein (BSP, Discovery false discovery rate [FDR]-corrected p = 2.82 x 10.sup.-2, Replication FDR-corrected p = 1.03 x 10.sup.-4 ), osteomodulin (OMD, Discovery FDR-corrected p = 2.14 x 10.sup.-2, Replication FDR-corrected p = 9.14 x 10.sup.-5 ), aminoacylase-1 (ACY1, Discovery FDR-corrected p = 1.86 x 10.sup.-3, Replication FDR-corrected p = 2.18 x 10.sup.-2 ), and growth hormone receptor (GHR, Discovery FDR-corrected p = 3.49 x 10.sup.-4, Replication FDR-corrected p = 2.97 x 10.sup.-3). Measures of these proteins were not significantly affected by differences in sample handling, and they did not change comparing plasma samples from 10 PD participants sampled both on versus off dopaminergic medication. Plasma measures of OMD, ACY1, and GHR differed in PD versus NC but did not differ between individuals with amyotrophic lateral sclerosis (ALS, n = 59) versus NC. In the Discovery Cohort, individuals with baseline levels of GHR and ACY1 in the lowest tertile were more likely to progress to mild cognitive impairment (MCI) or dementia in Cox proportional hazards analyses adjusting for age, sex, and disease duration (hazard ratio [HR] 2.27 [95% CI 1.04-5.0, p = 0.04] for GHR, and HR 3.0 [95% CI 1.24-7.0, p = 0.014] for ACY1). GHR's association with cognitive decline was confirmed in the Replication Cohort (HR 3.6 [95% CI 1.20-11.1, p = 0.02]). The main limitations of this study were its reliance on the aptamer-based platform for protein measurement and limited follow-up time available for some cohorts. Conclusions In this study, we found that the blood-based biomarkers BSP, OMD, ACY1, and GHR robustly associated with PD across multiple clinical sites. Our findings suggest that biomarkers based on a peripheral blood sample may be developed for both disease characterization and prediction of future disease progression in PD.

Published
2019
Full Text
View/download PDF

24. Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study

Author

Majounie, Elisa, Renton, Alan E, Mok, Kin, Dopper, Elise GP, Waite, Adrian, Rollinson, Sara, Chiò, Adriano, Restagno, Gabriella, Nicolaou, Nayia, Simon-Sanchez, Javier, van Swieten, John C, Abramzon, Yevgeniya, Johnson, Janel O, Sendtner, Michael, Pamphlett, Roger, Orrell, Richard W, Mead, Simon, Sidle, Katie C, Houlden, Henry, Rohrer, Jonathan D, Morrison, Karen E, Pall, Hardev, Talbot, Kevin, Ansorge, Olaf, Hernandez, Dena G, Arepalli, Sampath, Sabatelli, Mario, Mora, Gabriele, Corbo, Massimo, Giannini, Fabio, Calvo, Andrea, Englund, Elisabet, Borghero, Giuseppe, Floris, Gian Luca, Remes, Anne M, Laaksovirta, Hannu, McCluskey, Leo, Trojanowski, John Q, Van Deerlin, Vivianna M, Schellenberg, Gerard D, Nalls, Michael A, Drory, Vivian E, Lu, Chin-Song, Yeh, Tu-Hsueh, Ishiura, Hiroyuki, Takahashi, Yuji, Tsuji, Shoji, Le Ber, Isabelle, Brice, Alexis, Drepper, Carsten, Williams, Nigel, Kirby, Janine, Shaw, Pamela, Hardy, John, Tienari, Pentti J, Heutink, Peter, Morris, Huw R, Pickering-Brown, Stuart, and Traynor, Bryan J

Published
2012
Full Text
View/download PDF

26. A yeast functional screen predicts new candidate ALS disease genes

Author

Couthouis, Julien, Hart, Michael P., Shorter, James, DeJesus-Hernandez, Mariely, Erion, Renske, Oristano, Rachel, Liu, Annie X., Ramos, Daniel, Jethava, Niti, Hosangadi, Divya, Epstein, James, Chiang, Ashley, Diaz, Zamia, Nakaya, Tadashi, Ibrahim, Fadia, Kim, Hyung-Jun, Solski, Jennifer A., Williams, Kelly L., Mojsilovic-Petrovic, Jelena, Ingre, Caroline, Boylan, Kevin, Graff-Radford, Neill R., W. Dickson, Dennis, Clay-Falcone, Dana, Elman, Lauren, McCluskey, Leo, Greene, Robert, Kalb, Robert G., Lee, Virginia M.-Y., Trojanowski, John Q., Ludolph, Albert, Robberecht, Wim, Andersen, Peter M., Nicholson, Garth A., Blair, Ian P., King, Oliver D., Bonini, Nancy M., Van Deerlin, Vivianna, Rademakers, Rosa, Mourelatos, Zissimos, and Gitler, Aaron D.

Published
2011

28. Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Author

Neumann, Manuela, Sampathu, Deepak M., Kwong, Linda K., Truax, Adam C., Micsenyi, Matthew C., Chou, Thomas T., Bruce, Jennifer, Schuck, Theresa, Grossman, Murray, Clark, Christopher M., McCluskey, Leo F., Miller, Bruce L., Masliah, Eliezer, Mackenzie, Ian R., Feldman, Howard, Feiden, Wolfgang, Kretzschmar, Hans A., Trojanowski, John Q., and Lee, Virginia M.-Y.

Published
2006
Full Text
View/download PDF

32. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial

Author

Cudkowicz, Merit, primary, Genge, Angela, additional, Maragakis, Nicholas, additional, Petri, Susanne, additional, van den Berg, Leonard, additional, Aho, Valtteri V, additional, Sarapohja, Toni, additional, Kuoppamäki, Mikko, additional, Garratt, Chris, additional, Al-Chalabi, Ammar, additional, Kiernan, Matthew, additional, Mathers, Susan, additional, Henderson, Robert, additional, Needham, Merrilee, additional, Schultz, David, additional, Löscher, Wolfgang, additional, Mitrovic, Nenad, additional, Rath, Jakob, additional, Damme, Philip Van, additional, De Bleecker, Jan L., additional, Delstanche, Stéphanie, additional, Johnston, Wendy, additional, Zinman, Lorne, additional, O'Connell, Colleen, additional, Matte, Genevieve, additional, Dionne, Annie, additional, Korngut, Lawrence, additional, Turnbull, John, additional, Laaksovirta, Hannu, additional, Jokela, Manu, additional, Tapiola, Tero, additional, Soriani, Marie-Hélène, additional, Couratier, Philippe, additional, Camu, William, additional, Corcia, Philippe, additional, Ludolph, Albert, additional, Großkreutz, Julian, additional, Meyer, Thomas, additional, Boentert, Matthias, additional, Schrank, Berthold, additional, Prudlo, Johannes, additional, Untucht, Robert, additional, Hardiman, Orla, additional, Siciliano, Gabriele, additional, Chio', Adriano, additional, Mazzini, Letizia, additional, Inghilleri, Maurizio, additional, Caponnetto, Claudia, additional, Mora, Gabriele, additional, Mora Pardina, Jesús S, additional, Farrero Munoz, Eva, additional, Vázquez Costa, Juan F, additional, Aguera Morales, Eduardo, additional, Varona, Luis, additional, Andersen, Peter, additional, Ingre, Caroline, additional, Johansson, Rune, additional, Radunovic, Aleksandar, additional, Young, Carolyn, additional, Babu, Suma, additional, Shaibani, Aziz, additional, Staff, Nathan, additional, Vu, Tuan, additional, Rivner, Michael, additional, Scelsa, Stephen, additional, Sivakumar, Kumaraswamy, additional, Waheed, Waqar, additional, Heitzman, Daragh, additional, Rana, Sandeep, additional, Pattee, Gary, additional, Ajroud-Driss, Senda, additional, Bayat, Elham, additional, Kasarskis, Edward, additional, Lange, Dale J, additional, Elliott, Michael, additional, Harris, Brent, additional, Felice, Kevin, additional, Pulley, Michael T, additional, Kwan, Justin, additional, Brown, Martin, additional, Ravits, John, additional, Burford, Matthew, additional, Karam, Chafic, additional, Miller, Timothy, additional, Andrews, Jinsy, additional, Levine, Todd, additional, Locatelli, Eduardo, additional, Wymer, James, additional, Bedlack, Richard, additional, Fee, Dominic, additional, Goyal, Namita, additional, Oskarsson, Bjorn, additional, McCluskey, Leo, additional, Caress, James, additional, Weiss, Michael, additional, Quick, Adam, additional, Bromberg, Mark, additional, Lacomis, David, additional, Goutman, Stephen, additional, Rezania, Kourosh, additional, Guliani, Gaurav, additional, Goslin, Kimberly, additional, and Katz, Jonathan S, additional

Published
2021
Full Text
View/download PDF

38. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

Author

Van Deerlin, Vivianna M, Leverenz, James B, Bekris, Lynn M, Bird, Thomas D, Yuan, Wuxing, Elman, Lauren B, Clay, Dana, Wood, Elisabeth McCarty, Chen-Plotkin, Alice S, Martinez-Lage, Maria, Steinbart, Ellen, McCluskey, Leo, Grossman, Murray, Neumann, Manuela, Wu, I-Lin, Yang, Wei-Shiung, Kalb, Robert, Galasko, Douglas R, Montine, Thomas J, Trojanowski, John Q, Lee, Virginia M-Y, Schellenberg, Gerard D, and Yu, Chang-En

Published
2008
Full Text
View/download PDF

40. ALS GENES: Exome sequencing in amyotrophic lateral sclerosis identifies risk genes and pathways

Author

Cirulli, Elizabeth T., Lasseigne, Brittany N., Petrovski, Slavé, Sapp, Peter C., Dion, Patrick A., Leblond, Claire S., Couthouis, Julien, Lu, Yi-Fan, Wang, Quanli, Krueger, Brian J., Ren, Zhong, Keebler, Jonathan, Han, Yujun, Levy, Shawn E., Boone, Braden E., Wimbish, Jack R., Waite, Lindsay L., Jones, Angela L., Carulli, John P., Day-Williams, Aaron G., Staropoli, John F., Xin, Winnie W., Chesi, Alessandra, Raphael, Alya R., McKenna-Yasek, Diane, Cady, Janet, Vianney de Jong, J. M. B., Kenna, Kevin P., Smith, Bradley N., Topp, Simon, Miller, Jack, Gkazi, Athina, Sequencing Consortium, FALS, Al-Chalabi, Ammar, van den Berg, Leonard H., Veldink, Jan, Silani, Vincenzo, Ticozzi, Nicola, Shaw, Christopher E., Baloh, Robert H., Appel, Stanley, Simpson, Ericka, Lagier-Tourenne, Clotilde, Pulst, Stefan M., Gibson, Summer, Trojanowski, John Q., Elman, Lauren, McCluskey, Leo, Grossman, Murray, Shneider, Neil A., Chung, Wendy K., Ravits, John M., Glass, Jonathan D., Sims, Katherine B., Van Deerlin, Vivianna M., Maniatis, Tom, Hayes, Sebastian D., Ordureau, Alban, Swarup, Sharan, Landers, John, Baas, Frank, Allen, Andrew S., Bedlack, Richard S., Wade Harper, J., Gitler, Aaron D., Rouleau, Guy A., Brown, Robert, Harms, Matthew B., Cooper, Gregory M., Harris, Tim, Myers, Richard M., and Goldstein, David B.

Published
2015

47. High-dimensional spatial normalization of diffusion tensor images improves the detection of white matter differences: an example study using amyotrophic lateral sclerosis

Author

Zhang, Hui, Avants, Brian B., Yushkevich, Paul A., Woo, John H., Wang, Sumei, McCluskey, Leo F., Elman, Lauren B., Melhem, Elias R., and Gee, James C.

Subjects
Amyotrophic lateral sclerosis -- Diagnosis, Diagnostic imaging -- Methods, Business, Electronics, Electronics and electrical industries, Health care industry
Abstract

Spatial normalization of diffusion tensor images plays a key role in voxel-based analysis of white matter (WM) group differences. Currently, it has been achieved using low-dimensional registration methods in the large majority of clinical studies. This paper aims to motivate the use of high-dimensional normalization approaches by generating evidence of their impact on the findings of such studies. Using an ongoing amyotrophic lateral sclerosis (ALS) study, we evaluated three normalization methods representing the current range of available approaches: low-dimensional normalization using the fractional anisotropy (FA), high-dimensional normalization using the FA, and high-dimensional normalization using full tensor information. Each method was assessed in terms of its ability to detect significant differences between ALS patients and controls. Our findings suggest that inadequate normalization with low-dimensional approaches can result in insufficient removal of shape differences which in turn can confound FA differences in a complex manner, and that utilizing high-dimensional normalization can both significantly minimize the confounding effect of shape differences to FA differences and provide a more complete description of WM differences in terms of both size and tissue architecture differences. We also found that high-dimensional approaches, by leveraging full tensor features instead of tensor-derived indices, can further improve the alignment of WM tracts. Index Terms--Diffusion tensor images, spatial normalization.

Published
2007

48. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial

Author

Gordon, Paul H, Moore, Dan H, Miller, Robert G, Florence, Julaine M, Verheijde, Joseph L, Doorish, Carolyn, Hilton, Joan F, Spitalny, G Mark, MacArthur, Robert B, Mitsumoto, Hiroshi, Neville, Hans E, Boylan, Kevin, Mozaffar, Tahseen, Belsh, Jerry M, Ravits, John, Bedlack, Richard S, Graves, Michael C, McCluskey, Leo F, Barohn, Richard J, and Tandan, Rup

Published
2007
Full Text
View/download PDF

50. Stages of pTDP-43 pathology in amyotrophic lateral sclerosis

Author

Brettschneider, Johannes, Del Tredici, Kelly, Toledo, Jon B., Robinson, John L., Irwin, David J., Grossman, Murray, Suh, EunRan, Van Deerlin, Vivianna M., Wood, Elisabeth M., Baek, Young, Kwong, Linda, Lee, Edward B., Elman, Lauren, McCluskey, Leo, Fang, Lubin, Feldengut, Simone, Ludolph, Albert C., Lee, Virginia M.-Y., Braak, Heiko, and Trojanowski, John Q.

Published
2013
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results