Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine
David J. Irwin,Nigel J. Cairns,Murray Grossman,Corey T. McMillan,Edward B. Lee,Vivianna M. Van Deerlin,Virginia M.-Y. Lee,John Q. Trojanowski +7 more
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It is proposed that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach and enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies.Abstract:
Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (i.e., proteinopathies) including tauopathies (i.e., FTLD-Tau) and TDP-43 proteinopathies (i.e., FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presentations of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with specific proteinopathies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD-TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD diseases. Moreover, in view of current limitations to reliably diagnose specific FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, biofluid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies and work toward the goal of defining clinical endophenotypes of FTD.read more
Citations
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Journal ArticleDOI
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis.
TL;DR: The roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS, its amyloid-like in vitro aggregation, its physiological vs. pathological oligomerization in vivo, liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP -43 inclusions are discussed.
Journal ArticleDOI
Neurodegenerative disease concomitant proteinopathies are prevalent, age-related and APOE4-associated
John L. Robinson,Edward B. Lee,Sharon X. Xie,Lior Rennert,EunRan Suh,Colin Bredenberg,Carrie Caswell,Vivianna M. Van Deerlin,Ning Yan,Ahmed Yousef,Howard I. Hurtig,Andrew Siderowf,Murray Grossman,Corey T. McMillan,Bruce L. Miller,John E. Duda,John E. Duda,David J. Irwin,David A. Wolk,Lauren Elman,Leo McCluskey,Alice Chen-Plotkin,Daniel Weintraub,Steven E. Arnold,Johannes Brettschneider,Virginia M.-Y. Lee,John Q. Trojanowski +26 more
TL;DR: The data imply that increased age and APOE ɛ4 status are risk factors for co-pathologies independent of neurodegenerative disease; that neurodegenersative 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 LewyBody disease.
Journal ArticleDOI
Stress granules and neurodegeneration
Benjamin Wolozin,Pavel Ivanov +1 more
TL;DR: A model describing how intrinsic vulnerabilities within the cellular RNA metabolism might lead to the pathological aggregation of RBPs when SGs become persistent is suggested, which might accelerate the pathophysiology of many neurodegenerative diseases and myopathies.
Journal ArticleDOI
Neuroinflammation as a Common Feature of Neurodegenerative Disorders.
Leonardo Guzmán-Martínez,Ricardo B. Maccioni,Víctor Andrade,Leonardo P Navarrete,Maria Gabriela Pastor,Maria Gabriela Pastor,Nicolas Ramos-Escobar +6 more
TL;DR: The model for Alzheimer’s disease involves damage signals that promote glial activation, followed by nuclear factor NF-kβ activation, synthesis, and release of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6, and IL-12 that affect neuronal receptors with an overactivation of protein kinases.
Journal ArticleDOI
Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy
Gabor G. Kovacs,Isidro Ferrer,Lea T. Grinberg,Lea T. Grinberg,Irina Alafuzoff,Johannes Attems,Herbert Budka,Nigel J. Cairns,John F. Crary,Charles Duyckaerts,Bernardino Ghetti,Glenda M. Halliday,James W. Ironside,Seth Love,Ian R. A. Mackenzie,David G. Munoz,Melissa E. Murray,Peter T. Nelson,Hitoshi Takahashi,John Q. Trojanowski,Olaf Ansorge,Thomas Arzberger,Atik Baborie,Thomas G. Beach,Kevin F. Bieniek,Eileen H. Bigio,Istvan Bodi,Brittany N. Dugger,Mel B. Feany,Ellen Gelpi,Stephen M. Gentleman,Giorgio Giaccone,Kimmo J. Hatanpaa,Richard Heale,Patrick R. Hof,Monika Hofer,Tibor Hortobágyi,Kurt A. Jellinger,Gregory A. Jicha,Paul G. Ince,Julia Kofler,Eniko Veronika Kovari,Jillian J. Kril,David M. A. Mann,Radoslav Matej,Ann C. McKee,Catriona McLean,Ivan Milenkovic,Thomas J. Montine,Shigeo Murayama,Edward B. Lee,Jasmin Rahimi,Roberta Diehl Rodriguez,Annemieke J.M. Rozemuller,Julie A. Schneider,Christian Schultz,William W. Seeley,Danielle Seilhean,Colin Smith,Fabrizio Tagliavini,Masaki Takao,Dietmar Rudolf Thal,Dietmar Rudolf Thal,Jon B. Toledo,Markus Tolnay,Juan C. Troncoso,Harry V. Vinters,Serge Weis,Stephen B. Wharton,Charles L. White,Thomas Wisniewski,John Woulfe,Masahito Yamada,Dennis W. Dickson +73 more
Abstract: Pathological accumulation of abnormally phosphorylated tau protein in astrocytes is a frequent, but poorly characterized feature of the aging brain. Its etiology is uncertain, but its presence is sufficiently ubiquitous to merit further characterization and classification, which may stimulate clinicopathological studies and research into its pathobiology. This paper aims to harmonize evaluation and nomenclature of aging-related tau astrogliopathy (ARTAG), a term that refers to a morphological spectrum of astroglial pathology detected by tau immunohistochemistry, especially with phosphorylation-dependent and 4R isoform-specific antibodies. ARTAG occurs mainly, but not exclusively, in individuals over 60 years of age. Tau-immunoreactive astrocytes in ARTAG include thorn-shaped astrocytes at the glia limitans and in white matter, as well as solitary or clustered astrocytes with perinuclear cytoplasmic tau immunoreactivity that extends into the astroglial processes as fine fibrillar or granular immunopositivity, typically in gray matter. Various forms of ARTAG may coexist in the same brain and might reflect different pathogenic processes. Based on morphology and anatomical distribution, ARTAG can be distinguished from primary tauopathies, but may be concurrent with primary tauopathies or other disorders. We recommend four steps for evaluation of ARTAG: (1) identification of five types based on the location of either morphologies of tau astrogliopathy: subpial, subependymal, perivascular, white matter, gray matter; (2) documentation of the regional involvement: medial temporal lobe, lobar (frontal, parietal, occipital, lateral temporal), subcortical, brainstem; (3) documentation of the severity of tau astrogliopathy; and (4) description of subregional involvement. Some types of ARTAG may underlie neurological symptoms; however, the clinical significance of ARTAG is currently uncertain and awaits further studies. The goal of this proposal is to raise awareness of astroglial tau pathology in the aged brain, facilitating communication among neuropathologists and researchers, and informing interpretation of clinical biomarkers and imaging studies that focus on tau-related indicators.
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A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD
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TL;DR: The chromosome 9p21 amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD) locus contains one of the last major unidentified autosomal-dominant genes underlying these common neurodegenerative diseases, and a large hexanucleotide repeat expansion in the first intron of C9ORF72 is shown.
Journal ArticleDOI
Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia.
Katya Rascovsky,John R. Hodges,David S. Knopman,Mario F. Mendez,Joel H. Kramer,John Neuhaus,John C. van Swieten,Harro Seelaar,Elise G.P. Dopper,Chiadi U. Onyike,Argye E. Hillis,Keith A. Josephs,Bradley F. Boeve,Andrew Kertesz,William W. Seeley,Katherine P. Rankin,Julene K. Johnson,Maria Luisa Gorno-Tempini,Howard J. Rosen,Caroline E. Prioleau-Latham,Albert Lee,Christopher M. Kipps,Christopher M. Kipps,Patricia Lillo,Olivier Piguet,Jonathan D. Rohrer,Martin N. Rossor,Jason D. Warren,Nick C. Fox,Douglas Galasko,David P. Salmon,Sandra E. Black,M.-Marsel Mesulam,Sandra Weintraub,Brad C. Dickerson,Janine Diehl-Schmid,Florence Pasquier,Vincent Deramecourt,Florence Lebert,Yolande A.L. Pijnenburg,Tiffany W. Chow,Facundo Manes,Jordan Grafman,Stefano F. Cappa,Morris Freedman,Murray Grossman,Bruce L. Miller +46 more
TL;DR: The revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotmporal lobar degeneration and reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations.
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