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Jennifer S Yokoyama, Gabe Marx, Jesse A Brown, Luke W Bonham, Dan Wang, Giovanni Coppola, William W Seeley, Howard J Rosen, Bruce L Miller, Joel H Kramer, Dena B Dubal
Cognitive decline is a major biomedical challenge as the global population ages. Elevated levels of the longevity factor klotho suppress aging, enhance cognition, and promote synaptic plasticity and neural resilience against aging and Alzheimer's disease (AD)-related pathogenic proteins. Here, we examined the relationship between human genetic variants of KLOTHO and systemic klotho levels - and assessed neuroanatomic correlates of serum klotho in a cohort of healthy older adults. Serum klotho levels were increased with KL-VS heterozygosity, as anticipated...
October 6, 2016: Brain Imaging and Behavior
Maxime Bertoux, Marie Sarazin, Florence Pasquier, Michel Bottlaender, Leonardo Cruz de Souza, Eneida Mioshi, Michael Hornberger, Kamalini G Ranasinghe, Katherine P Rankin, Iryna V Lobach, Joel H Kramer, Virginia E Sturm, Brianne M Bettcher, Katherine Possin, S Christine You, Amanda K Lamarre, Tal Shany-Ur, Melanie L Stephens, David C Perry, Suzee E Lee, Zachary A Miller, Maria L Gorno-Tempini, Howard J Rosen, Adam Boxer, William W Seeley, Gil D Rabinovici, Keith A Vossel, Bruce L Miller
No abstract text is available yet for this article.
October 4, 2016: Neurology
Jihong Park, W Matt Denning, Jordan D Pitt, Devin Francom, J Ty Hopkins, Matthew K Seeley
CONTEXT: Although knee pain is common, some facets of this pain are unclear. The independent effects (i.e., independent from other knee injury or pathology) of knee pain on neural activation of lower-extremity muscles during landing and jumping have not been observed. OBJECTIVE: To investigate the independent effects of knee pain on lower-extremity muscle (gastrocnemius, vastus medialis, medial hamstrings, gluteus medius, and gluteus maximus) activation amplitude during landing and jumping, performed at two different intensities...
August 24, 2016: Journal of Sport Rehabilitation
Shane C Quinonez, Andrea H Seeley, Cindy Lam, Thomas W Glover, Bruce A Barshop, Catherine E Keegan
Holocarboxylase synthetase (HLCS) deficiency is a rare autosomal recessive disorder that presents with multiple life-threatening metabolic derangements including metabolic acidosis, ketosis, and hyperammonemia. A majority of HLCS deficiency patients respond to biotin therapy; however, some patients show only a partial or no response to biotin therapy. Here, we report a neonatal presentation of HLCS deficiency with partial response to biotin therapy. Sequencing of HLCS showed a novel heterozygous mutation in exon 5, c...
August 13, 2016: JIMD Reports
Panos Theofilas, Alexander J Ehrenberg, Sara Dunlop, Ana T Alho, Austin Nguy, Renata Elaine Paraizo Leite, Roberta Diehl Rodriguez, Maria B Mejia, Claudia K Suemoto, Renata Eloah de Lucena Ferretti-Rebustini, Livia Polichiso, Camila F Nascimento, William W Seeley, Ricardo Nitrini, Carlos Augusto Pasqualucci, Wilson Jacob Filho, Udo Rueb, John Neuhaus, Helmut Heinsen, Lea T Grinberg
INTRODUCTION: Alzheimer's disease (AD) progression follows a specific spreading pattern, emphasizing the need to characterize those brain areas that degenerate first. The brainstem's locus coeruleus (LC) is the first area to develop neurofibrillary changes (neurofibrillary tangles [NFTs]). METHODS: The methods include unbiased stereological analyses in human brainstems to estimate LC volume and neuronal population in controls and individuals across all AD stages...
August 8, 2016: Alzheimer's & Dementia: the Journal of the Alzheimer's Association
Maria Luisa Mandelli, Eduard Vilaplana, Jesse A Brown, H Isabel Hubbard, Richard J Binney, Suneth Attygalle, Miguel A Santos-Santos, Zachary A Miller, Mikhail Pakvasa, Maya L Henry, Howard J Rosen, Roland G Henry, Gil D Rabinovici, Bruce L Miller, William W Seeley, Maria Luisa Gorno-Tempini
Neurodegeneration has been hypothesized to follow predetermined large-scale networks through the trans-synaptic spread of toxic proteins from a syndrome-specific epicentre. To date, no longitudinal neuroimaging study has tested this hypothesis in vivo in frontotemporal dementia spectrum disorders. The aim of this study was to demonstrate that longitudinal progression of atrophy in non-fluent/agrammatic variant primary progressive aphasia spreads over time from a syndrome-specific epicentre to additional regions, based on their connectivity to the epicentre in healthy control subjects...
August 6, 2016: Brain: a Journal of Neurology
Kamalini G Ranasinghe, Katherine P Rankin, Peter S Pressman, David C Perry, Iryna V Lobach, William W Seeley, Giovanni Coppola, Anna M Karydas, Lea T Grinberg, Tal Shany-Ur, Suzee E Lee, Gil D Rabinovici, Howard J Rosen, Maria Luisa Gorno-Tempini, Adam L Boxer, Zachary A Miller, Winston Chiong, Mary DeMay, Joel H Kramer, Katherine L Possin, Virginia E Sturm, Brianne M Bettcher, Michael Neylan, Diana D Zackey, Lauren A Nguyen, Robin Ketelle, Nikolas Block, Teresa Q Wu, Alison Dallich, Natanya Russek, Alyssa Caplan, Daniel H Geschwind, Keith A Vossel, Bruce L Miller
IMPORTANCE: Clearer delineation of the phenotypic heterogeneity within behavioral variant frontotemporal dementia (bvFTD) will help uncover underlying biological mechanisms and improve clinicians' ability to predict disease course and to design targeted management strategies. OBJECTIVE: To identify subtypes of bvFTD syndrome based on distinctive patterns of atrophy defined by selective vulnerability of specific functional networks targeted in bvFTD using statistical classification approaches...
September 1, 2016: JAMA Neurology
Gaël Chételat, Rik Ossenkoppele, Victor L Villemagne, Audrey Perrotin, Brigitte Landeau, Florence Mézenge, William J Jagust, Vincent Dore, Bruce L Miller, Stéphanie Egret, William W Seeley, Wiesje M van der Flier, Renaud La Joie, David Ames, Bart N M van Berckel, Philip Scheltens, Frederik Barkhof, Christopher C Rowe, Colin L Masters, Vincent de La Sayette, Femke Bouwman, Gil D Rabinovici
See O'Sullivan and Vann (doi:10.1093/aww166) for a scientific commentary on this article.About 15% of patients clinically diagnosed with Alzheimer's disease do not show high tracer retention on amyloid positon emission tomography imaging. The present study investigates clinical and demographic features, patterns of brain atrophy and hypometabolism and longitudinal clinical trajectories of these patients. Forty amyloid-negative patients carrying a pre-scan diagnosis of Alzheimer's disease dementia from four centres were included (11/29 females/males; mean age = 67 ± 9)...
September 2016: Brain: a Journal of Neurology
Peter Dongmin Sohn, Tara E Tracy, Hye-In Son, Yungui Zhou, Renata E P Leite, Bruce L Miller, William W Seeley, Lea T Grinberg, Li Gan
BACKGROUND: Neurons are highly polarized cells in which asymmetric axonal-dendritic distribution of proteins is crucial for neuronal function. Loss of polarized distribution of the axonal protein tau is an early sign of Alzheimer's disease (AD) and other neurodegenerative disorders. The cytoskeletal network in the axon initial segment (AIS) forms a barrier between the axon and the somatodentritic compartment, contributing to axonal retention of tau. Although perturbation of the AIS cytoskeleton has been implicated in neurological disorders, the molecular triggers and functional consequence of AIS perturbation are incompletely understood...
2016: Molecular Neurodegeneration
Sebum Lee, Yulei Shang, Stephanie A Redmond, Anatoly Urisman, Amy A Tang, Kathy H Li, Alma L Burlingame, Ryan A Pak, Ana Jovičić, Aaron D Gitler, Jinhua Wang, Nathanael S Gray, William W Seeley, Teepu Siddique, Eileen H Bigio, Virginia M-Y Lee, John Q Trojanowski, Jonah R Chan, Eric J Huang
Persistent accumulation of misfolded proteins causes endoplasmic reticulum (ER) stress, a prominent feature in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Here we report the identification of homeodomain interacting protein kinase 2 (HIPK2) as the essential link that promotes ER-stress-induced cell death via the IRE1α-ASK1-JNK pathway. ER stress, induced by tunicamycin or SOD1(G93A), activates HIPK2 by phosphorylating highly conserved serine and threonine residues (S359/T360) within the activation loop of the HIPK2 kinase domain...
July 6, 2016: Neuron
H Frikke-Schmidt, R W O'Rourke, C N Lumeng, D A Sandoval, R J Seeley
Bariatric surgery is currently the most effective treatment for obesity. Not only do these types of surgeries produce significant weight loss but also they improve insulin sensitivity and whole body metabolic function. The aim of this review is to explore how altered physiology of adipose tissue may contribute to the potent metabolic effects of some of these procedures. This includes specific effects on various fat depots, the function of individual adipocytes and the interaction between adipose tissue and other key metabolic tissues...
September 2016: Obesity Reviews: An Official Journal of the International Association for the Study of Obesity
Sugeerth Murugesan, Kristofer Bouchard, Jesse A Brown, Bernd Hamann, William W Seeley, Andrew Trujillo, Gunther H Weber
We present Brain Modulyzer, an interactive visual exploration tool for functional magnetic resonance imaging (fMRI) brain scans, aimed at analyzing the correlation between different brain regions when resting or when performing mental tasks. Brain Modulyzer combines multiple coordinated views-such as heat maps, node link diagrams and anatomical views-using brushing and linking to provide an anatomical context for brain connectivity data. Integrating methods from graph theory and analysis, e.g., community detection and derived graph measures, makes it possible to explore the modular and hierarchical organization of functional brain networks...
May 9, 2016: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Cora J Kerssens, Welmoed A Krudop, Niels D Prins, Bart N M van Berckel, Annemieke Rozemuller, William W Seeley, Philip Scheltens, Max L Stek, Yolande A L Pijnenburg
Recently, the diagnostic criteria for the behavioral variant of frontotemporal dementia were revised. Although these criteria offer a relatively high sensitivity, their specificity is yet unknown. We describe a 54-year-old woman fulfilling criteria for both late-onset schizophrenia and probable behavioral variant frontotemporal dementia. Following an initial presentation with psychosis, she developed progressive apathy, compulsiveness, and executive dysfunction. Moreover, bilateral frontotemporal hypometabolism was seen on [(18)F]fludeoxyglucose-positron emission tomography...
June 2016: Neurocase
Malathi Narayan, Kent W Seeley, Umesh K Jinwal
AIM: Amyotrophic lateral sclerosis (ALS) is a debilitating fatal neurodegenerative disorder. 90-95% of ALS cases are sporadic with no clear risk factors associated with the disease. Identification of biomarkers associated with ALS may lead to early detection and make it more amenable to therapeutic intervention. MATERIALS & METHODS: SILAC was used to quantitatively analyze the proteomes of ALS and control human fibroblasts. RESULTS: Out of total of 861 proteins identified, 33 were found to be differentially regulated...
May 2016: Biomarkers in Medicine
Hansen Lui, Jiasheng Zhang, Stefanie R Makinson, Michelle K Cahill, Kevin W Kelley, Hsin-Yi Huang, Yulei Shang, Michael C Oldham, Lauren Herl Martens, Fuying Gao, Giovanni Coppola, Steven A Sloan, Christine L Hsieh, Charles C Kim, Eileen H Bigio, Sandra Weintraub, Marek-Marsel Mesulam, Rosa Rademakers, Ian R Mackenzie, William W Seeley, Anna Karydas, Bruce L Miller, Barbara Borroni, Roberta Ghidoni, Robert V Farese, Jeanne T Paz, Ben A Barres, Eric J Huang
Microglia maintain homeostasis in the brain, but whether aberrant microglial activation can cause neurodegeneration remains controversial. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive upregulation of lysosomal and innate immunity genes, increased complement production, and enhanced synaptic pruning in microglia. During aging, Grn(-/-) mice show profound microglia infiltration and preferential elimination of inhibitory synapses in the ventral thalamus, which lead to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors...
May 5, 2016: Cell
Miguel A Santos-Santos, Maria Luisa Mandelli, Richard J Binney, Jennifer Ogar, Stephen M Wilson, Maya L Henry, H Isabel Hubbard, Minerva Meese, Suneth Attygalle, Lynne Rosenberg, Mikhail Pakvasa, John Q Trojanowski, Lea T Grinberg, Howie Rosen, Adam L Boxer, Bruce L Miller, William W Seeley, Maria Luisa Gorno-Tempini
IMPORTANCE: We provide novel evidence of specific clinical and neuroimaging features that may help for the in vivo prediction of underlying pathology in patients with nonfluent/agrammatic primary progressive aphasia (nfvPPA) and progressive supranuclear palsy (PSP) or corticobasal degeneration (CBD) proved by autopsy. OBJECTIVE: To characterize the neurological, cognitive, and neuroimaging features of patients with nfvPPA-in whom either PSP or CBD was eventually confirmed at autopsy-at initial presentation and at 1-year follow-up...
June 1, 2016: JAMA Neurology
Christine C Guo, Virginia E Sturm, Juan Zhou, Efstathios D Gennatas, Andrew J Trujillo, Alice Y Hua, Richard Crawford, Lara Stables, Joel H Kramer, Katherine Rankin, Robert W Levenson, Howard J Rosen, Bruce L Miller, William W Seeley
The brain continuously influences and perceives the physiological condition of the body. Related cortical representations have been proposed to shape emotional experience and guide behavior. Although previous studies have identified brain regions recruited during autonomic processing, neurological lesion studies have yet to delineate the regions critical for maintaining autonomic outflow. Even greater controversy surrounds hemispheric lateralization along the parasympathetic-sympathetic axis. The behavioral variant of frontotemporal dementia (bvFTD), featuring progressive and often asymmetric degeneration that includes the frontoinsular and cingulate cortices, provides a unique lesion model for elucidating brain structures that control autonomic tone...
April 26, 2016: Proceedings of the National Academy of Sciences of the United States of America
Andrea Boman, Samuel Svensson, Adam Boxer, Julio C Rojas, William W Seeley, Anna Karydas, Bruce Miller, Katarina Kågedal, Per Svenningsson
BACKGROUND: Clinical diagnosis of parkinsonian syndromes like Parkinson's disease (PD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) is hampered by overlapping symptomatology and lack of diagnostic biomarkers, and definitive diagnosis is only possible post-mortem. OBJECTIVE: Since impaired protein degradation plays an important role in many neurodegenerative disorders, we hypothesized that profiles of select lysosomal network proteins in cerebrospinal fluid could be differentially expressed in these parkinsonian syndromes...
April 2, 2016: Journal of Parkinson's Disease
Malathi Narayan, Kent W Seeley, Umesh K Jinwal
Mass spectrometry data collected in a study analyzing the effect of withaferin A (WA) on a mouse microglial (N9) cell line is presented in this article. Data was collected from SILAC-based quantitative analysis of lysates from mouse microglial cells treated with either WA or DMSO vehicle control. This article reports all the proteins that were identified in this analysis. The data presented here is related to the published research article on the effect of WA on the differential regulation of proteins in mouse microglial cells [1]...
June 2016: Data in Brief
W Matt Denning, Michael Becker Pardo, Jason G Winward, Iain Hunter, Sarah Ridge, J Ty Hopkins, C Shane Reese, Allen C Parcell, Matthew K Seeley
Because serum cartilage oligomeric matrix protein (COMP) has been used to reflect articular cartilage condition, we aimed to identify walking and running mechanics that are associated with changes in serum COMP. Eighteen subjects (9 male, 9 female; age=23 ± 2 yrs.; mass=68.3 ± 9.6 kg; height=1.70 ± 0.08 m) completed 4000 steps on an instrumented treadmill on three separate days. Each day corresponded to a different ambulation speed: slow (preferred walking speed), medium (+50% of slow), and fast (+100% of slow)...
February 2016: Gait & Posture
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