Browsing by Author "Wisniewski, Thomas"

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    Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy
    (Springer, 2016-01) Kovacs, Gabor G.; Ferrer, Isidro; Alafuzoff, Irina; Attems, Johannes; Budka, Herbert; Cairns, Nigel J.; Crary, John F.; Duyckaerts, Charles; Ghetti, Bernardino; Halliday, Glenda M.; Ironside, James W.; Love, Seth; Mackenzie, Ian R.; Munoz, David G.; Murray, Melissa E.; Nelson, Peter T.; Takahashi, Hitoshi; Trojanowski, John Q.; Ansorge, Olaf; Arzberger, Thomas; Baborie, Atik; Beach, Thomas G.; Bieniek, Kevin F.; Bigio, Eileen H.; Bodi, Istvan; Dugger, Brittany N.; Feany, Mel; Gelpi, Ellen; Gentleman, Stephen M.; Giaccone, Giorgio; Hatanpaa, Kimmo J.; Heale, Richard; Hof, Patrick R.; Hofer, Monika; Hortobágyi, Tibor; Jellinger, Kurt; Jicha, Gregory A.; Ince, Paul; Kofler, Julia; Kövari, Enikö; Kril, Jillian J.; Mann, David M.; Matej, Radoslav; McKee, Ann C.; McLean, Catriona; Milenkovic, Ivan; Montine, Thomas J.; Murayama, Shigeo; Lee, Edward B.; Rahimi, Jasmin; Rodriguez, Roberta D.; Rozemüller, Annemieke; Schneider, Julie A.; Schultz, Christian; Seeley, William; Seilhean, Danielle; Smith, Colin; Tagliavini, Fabrizio; Takao, Masaki; Thal, Dietmar Rudolf; Toledo, Jon B.; Tolnay, Markus; Troncoso, Juan C.; Vinters, Harry V.; Weis, Serge; Wharton, Stephen B.; White III, Charles L.; Wisniewski, Thomas; Woulfe, John M.; Yamada, Masahito; Dicks, Dennis W.; Department of Pathology and Laboratory Medicine, IU School of Medicine
    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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    Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel
    (American Medical Association, 2021-01-01) Kunkle, Brian W.; Schmidt, Michael; Klein, Hans-Ulrich; Naj, Adam C.; Hamilton-Nelson, Kara L.; Larson, Eric B.; Evans, Denis A.; De Jager, Phil L.; Crane, Paul K.; Buxbaum, Joe D.; Ertekin-Taner, Nilufer; Go, Rodney C.P.; Obisesan, Thomas O.; Kamboh, Ilyas; Bennett, David A.; Hall, Kathleen S.; Goate, Alison M.; Foroud, Tatiana M.; Martin, Eden R.; Wang, Li-Sao; Byrd, Goldie S.; Farrer, Lindsay A.; Haines, Jonathan L.; Schellenberg, Gerard D.; Mayeux, Richard; Pericak-Vance, Margaret A.; Reitz, Christiane; Graff-Radford, Neill R.; Martinez, Izri; Ayodele, Temitope; Logue, Mark W.; Cantwell, Laura B.; Jean-Francois, Melissa; Kuzma, Amanda B.; Adams, L.D.; Vance, Jeffery M.; Cuccaro, Michael L.; Chung, Jaeyoon; Mez, Jesse; Lunetta, Kathryn L.; Jun, Gyungah R.; Lopez, Oscar L.; Hendrie, Hugh C.; Reiman, Eric M.; Kowall, Neil W.; Leverenz, James B.; Small, Scott A.; Levey, Allan I.; Golde, Todd E.; Saykin, Andrew J.; Starks, Takiyah D.; Albert, Marilyn S.; Hyman, Bradley T.; Petersen, Ronald C.; Sano, Mary; Wisniewski, Thomas; Vassar, Robert; Kaye, Jeffrey A.; Henderson, Victor W.; DeCarli, Charles; LaFerla, Frank M.; Brewer, James B.; Miller, Bruce L.; Swerdlow, Russell H.; Van Eldik, Linda J.; Paulson, Henry L.; Trojanowski, John Q.; Chui, Helena C.; Rosenberg, Roger N.; Craft, Suzanne; Grabowski, Thomas J.; Asthana, Sanjay; Morris, John C.; Strittmatter, Stephen M.; Kukull, Walter A.; Psychiatry, School of Medicine
    Importance: Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals, ABCA7, TREM2, and an intergenic locus at 5q35 were previously implicated. Objective: To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, setting, and participants: This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main outcomes and measures: Diagnosis of Alzheimer disease. Results: A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (19q13.33; P = 3.5 × 10-7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and relevance: While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.