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1. Multisite Assessment of Aging-Related Tau Astrogliopathy (ARTAG).

Author

Kovacs, Gabor G, Xie, Sharon X, Lee, Edward B, Robinson, John L, Caswell, Carrie, Irwin, David J, Toledo, Jon B, Johnson, Victoria E, Smith, Douglas H, Alafuzoff, Irina, Attems, Johannes, Bencze, Janos, Bieniek, Kevin F, Bigio, Eileen H, Bodi, Istvan, Budka, Herbert, Dickson, Dennis W, Dugger, Brittany N, Duyckaerts, Charles, Ferrer, Isidro, Forrest, Shelley L, Gelpi, Ellen, Gentleman, Stephen M, Giaccone, Giorgio, Grinberg, Lea T, Halliday, Glenda M, Hatanpaa, Kimmo J, Hof, Patrick R, Hofer, Monika, Hortobágyi, Tibor, Ironside, James W, King, Andrew, Kofler, Julia, Kövari, Enikö, Kril, Jillian J, Love, Seth, Mackenzie, Ian R, Mao, Qinwen, Matej, Radoslav, McLean, Catriona, Munoz, David G, Murray, Melissa E, Neltner, Janna, Nelson, Peter T, Ritchie, Diane, Rodriguez, Roberta D, Rohan, Zdenek, Rozemuller, Annemieke, Sakai, Kenji, Schultz, Christian, Seilhean, Danielle, Smith, Vanessa, Tacik, Pawel, Takahashi, Hitoshi, Takao, Masaki, Rudolf Thal, Dietmar, Weis, Serge, Wharton, Stephen B, White, Charles L, Woulfe, John M, Yamada, Masahito, and Trojanowski, John Q

Subjects
Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Frontotemporal Dementia (FTD), Aging, Neurodegenerative, Acquired Cognitive Impairment, Brain Disorders, Alzheimer's Disease, Aged, Aged, 80 and over, Astrocytes, Female, Humans, Male, Middle Aged, Severity of Illness Index, Tauopathies, tau Proteins, ARTAG, Digital pathology, Interrater agreement, Neuropathology, Tau, Tau-astrogliopathy, Clinical Sciences, Neurosciences, Neurology & Neurosurgery
Abstract

Aging-related tau astrogliopathy (ARTAG) is a recently introduced terminology. To facilitate the consistent identification of ARTAG and to distinguish it from astroglial tau pathologies observed in the primary frontotemporal lobar degeneration tauopathies we evaluated how consistently neuropathologists recognize (1) different astroglial tau immunoreactivities, including those of ARTAG and those associated with primary tauopathies (Study 1); (2) ARTAG types (Study 2A); and (3) ARTAG severity (Study 2B). Microphotographs and scanned sections immunostained for phosphorylated tau (AT8) were made available for download and preview. Percentage of agreement and kappa values with 95% confidence interval (CI) were calculated for each evaluation. The overall agreement for Study 1 was >60% with a kappa value of 0.55 (95% CI 0.433-0.645). Moderate agreement (>90%, kappa 0.48, 95% CI 0.457-0.900) was reached in Study 2A for the identification of ARTAG pathology for each ARTAG subtype (kappa 0.37-0.72), whereas fair agreement (kappa 0.40, 95% CI 0.341-0.445) was reached for the evaluation of ARTAG severity. The overall assessment of ARTAG showed moderate agreement (kappa 0.60, 95% CI 0.534-0.653) among raters. Our study supports the application of the current harmonized evaluation strategy for ARTAG with a slight modification of the evaluation of its severity.

Published
2017

2. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy

Author

Kovacs, Gabor G, Ferrer, Isidro, Grinberg, Lea T, 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, Charles L, Wisniewski, Thomas, Woulfe, John M, Yamada, Masahito, and Dickson, Dennis W

Subjects
Biomedical and Clinical Sciences, Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Rare Diseases, Alzheimer's Disease, Aging, Frontotemporal Dementia (FTD), Brain Disorders, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Neurological, Animals, Astrocytes, Brain, Humans, Neuroglia, Tauopathies, tau Proteins, ARTAG, Tau astrogliopathy, Tau, Clinical Sciences, Neurology & Neurosurgery
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.

Published
2016

3. Loss of angiotensin II receptor expression in dopamine neurons in Parkinson's disease correlates with pathological progression and is accompanied by increases in Nox4- and 8-OH guanosine-related nucleic acid oxidation and caspase-3 activation.

Author

Zawada, W Michael, Mrak, Robert E, Biedermann, JoAnn, Palmer, Quinton D, Gentleman, Stephen M, Aboud, Orwa, and Griffin, W Sue T

Subjects
Substantia Nigra, Humans, Parkinson Disease, Disease Progression, Angiotensin II, Receptor, Angiotensin, Type 1, Guanosine, Case-Control Studies, Oxidative Stress, Aged, Aged, 80 and over, Female, Male, Caspase 3, Dopaminergic Neurons, NADPH Oxidases, Neurodegenerative, Parkinson's Disease, Neurosciences, Aging, Brain Disorders, Hypertension, Aetiology, 2.1 Biological and endogenous factors, Neurological, Angiotensin, Dopamine neuron, NADPH oxidase, Nox, Nigrosome, Oxidative stress, Parkinson's, RAS, Substantia nigra, Biochemistry and Cell Biology, Clinical Sciences
Abstract

BackgroundIn rodent models of Parkinson's disease (PD), dopamine neuron loss is accompanied by increased expression of angiotensin II (AngII), its type 1 receptor (AT1), and NADPH oxidase (Nox) in the nigral dopamine neurons and microglia. AT1 blockers (ARBs) stymie such oxidative damage and neuron loss. Whether changes in the AngII/AT1/Nox4 axis contribute to Parkinson neuropathogenesis is unknown. Here, we studied the distribution of AT1 and Nox4 in dopamine neurons in two nigral subregions: the less affected calbindin-rich matrix and the first-affected calbindin-poor nigrosome 1 of three patients, who were clinically asymptomatic, but had nigral dopamine cell loss and Braak stages consistent with a neuropathological diagnosis of PD (prePD). For comparison, five clinically- and neuropathologically-confirmed PD patients and seven age-matched control patients (AMC) were examined.ResultsAT1 and Nox4 immunoreactivity was noted in dopamine neurons in both the matrix and the nigrosome 1. The total cellular levels of AT1 in surviving dopamine neurons in the matrix and nigrosome 1 declined from AMC>prePD>PD, suggesting that an AngII/AT1/Nox4 axis orders neurodegenerative progression. In this vein, the loss of dopamine neurons was paralleled by a decline in total AT1 per surviving dopamine neuron. Similarly, AT1 in the nuclei of surviving neurons in the nigral matrix declined with disease progression, i.e., AMC>prePD>PD. In contrast, in nigrosome 1, the expression of nuclear AT1 was unaffected and similar in all groups. The ratio of nuclear AT1 to total AT1 (nuclear + cytoplasmic + membrane) in dopamine neurons increased stepwise from AMC to prePD to PD. The proportional increase in nuclear AT1 in dopamine neurons in nigrosome 1 of prePD and PD patients was accompanied by elevated nuclear expression of Nox4, oxidative damage to DNA, and caspase-3-mediated cell loss.ConclusionsOur observations are consistent with the idea that AngII/AT1/Nox4 axis-mediated oxidative stress gives rise to the dopamine neuron dysfunction and loss characteristic of the neuropathological and clinical manifestations of PD and suggest that the chance for a neuron to survive increases in association with lower total as well as nuclear AT1 expression. Our results support the need for further evaluation of ARBs as disease-modifying agents in PD.

Published
2015

8. Variation at the TRIM11 locus modifies Progressive Supranuclear Palsy phenotype

Author

Jabbari, Edwin, Woodside, John, Tan, Manueal M X, Shoai, Maryam, Pittman, Alan, Ferrari, Raffaele, Mok, Kin Y, Zhang, David, Reynolds, Regina H, de Silva, Rohan, Grimm, Max-Joseph, Respondek, Gesine, Müller, Ulrich, Al-Sarraj, Safa, Gentleman, Stephen M, Lees, Andrew J, Warner, Thomas T, Hardy, John, Revesz, Tamas, Höglinger, Günter U, Holton, Janice L, Ryten, Mina, Morris, Huw R, Leigh, P Nigel, and PROSPECT-UK consortium

Subjects
RC0346
Abstract

OBJECTIVE\ud \ud The basis for clinical variation related to underlying Progressive Supranuclear Palsy (PSP) pathology is unknown. We performed a genome wide association study (GWAS) to identify genetic determinants of PSP phenotype.\ud \ud METHODS\ud \ud Two independent pathological and clinically diagnosed PSP cohorts were genotyped and phenotyped to create Richardson's syndrome (RS) and non-RS groups. We carried out separate logistic regression GWAS to compare RS and non-RS groups and then combined datasets to carry out a whole cohort analysis (RS=367, non-RS=130). We validated our findings in a third cohort by referring to data from 100 deeply phenotyped cases from a recent GWAS. We assessed the expression/co-expression patterns of our identified genes and used our data to carry out gene-based association testing.\ud \ud RESULTS\ud \ud Our lead single nucleotide polymorphism (SNP), rs564309, showed an association signal in both cohorts, reaching genome wide significance in our whole cohort analysis - OR 5.5 (3.2-10.0), p-value 1.7x10 . rs564309 is an intronic variant of the tripartite motif-containing protein 11 (TRIM11) gene, a component of the ubiquitin proteasome system (UPS). In our third cohort, minor allele frequencies of surrogate SNPs in high linkage disequilibrium with rs564309 replicated our findings. Gene based association testing confirmed an association signal at TRIM11. We found that TRIM11 is predominantly expressed neuronally, in the cerebellum and basal ganglia.\ud \ud INTERPRETATION\ud \ud Our study suggests that the TRIM11 locus is a genetic modifier of PSP phenotype and potentially adds further evidence for the UPS having a key role in tau pathology, therefore representing a target for disease modifying therapies. This article is protected by copyright. All rights reserved.

Published
2019

15. Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Author

Jabbari, Edwin, Woodside, John, Tan, Manuela M. X., Shoai, Maryam, Pittman, Alan, Ferrari, Raffaele, Mok, Kin Y., Zhang, David, Reynolds, Regina H., de Silva, Rohan, Grimm, Max-Joseph, Respondek, Gesine, Müller, Ulrich, Al-Sarraj, Safa, Gentleman, Stephen M., Lees, Andrew J., Warner, Thomas T., Hardy, John, Revesz, Tamas, Höglinger, Günter U., Holton, Janice L., Ryten, Mina, and Morris, Huw R.

Subjects
ddc
Published
2018

19. Variation at the TRIM11 locus modifies progressive supranuclear palsy phenotype

Author

Jabbari, Edwin, primary, Woodside, John, additional, Tan, Manuela M. X., additional, Shoai, Maryam, additional, Pittman, Alan, additional, Ferrari, Raffaele, additional, Mok, Kin Y., additional, Zhang, David, additional, Reynolds, Regina H., additional, de Silva, Rohan, additional, Grimm, Max‐Joseph, additional, Respondek, Gesine, additional, Müller, Ulrich, additional, Al‐Sarraj, Safa, additional, Gentleman, Stephen M., additional, Lees, Andrew J., additional, Warner, Thomas T., additional, Hardy, John, additional, Revesz, Tamas, additional, Höglinger, Günter U., additional, Holton, Janice L., additional, Ryten, Mina, additional, and Morris, Huw R., additional

Published
2018
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22. Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy

Author

Kovacs, Gabor G., primary, Ferrer, Isidro, additional, Grinberg, Lea T., additional, Alafuzoff, Irina, additional, Attems, Johannes, additional, Budka, Herbert, additional, Cairns, Nigel J., additional, Crary, John F., additional, Duyckaerts, Charles, additional, Ghetti, Bernardino, additional, Halliday, Glenda M., additional, Ironside, James W., additional, Love, Seth, additional, Mackenzie, Ian R., additional, Munoz, David G., additional, Murray, Melissa E., additional, Nelson, Peter T., additional, Takahashi, Hitoshi, additional, Trojanowski, John Q., additional, Ansorge, Olaf, additional, Arzberger, Thomas, additional, Baborie, Atik, additional, Beach, Thomas G., additional, Bieniek, Kevin F., additional, Bigio, Eileen H., additional, Bodi, Istvan, additional, Dugger, Brittany N., additional, Feany, Mel, additional, Gelpi, Ellen, additional, Gentleman, Stephen M., additional, Giaccone, Giorgio, additional, Hatanpaa, Kimmo J., additional, Heale, Richard, additional, Hof, Patrick R., additional, Hofer, Monika, additional, Hortobágyi, Tibor, additional, Jellinger, Kurt, additional, Jicha, Gregory A., additional, Ince, Paul, additional, Kofler, Julia, additional, Kövari, Enikö, additional, Kril, Jillian J., additional, Mann, David M., additional, Matej, Radoslav, additional, McKee, Ann C., additional, McLean, Catriona, additional, Milenkovic, Ivan, additional, Montine, Thomas J., additional, Murayama, Shigeo, additional, Lee, Edward B., additional, Rahimi, Jasmin, additional, Rodriguez, Roberta D., additional, Rozemüller, Annemieke, additional, Schneider, Julie A., additional, Schultz, Christian, additional, Seeley, William, additional, Seilhean, Danielle, additional, Smith, Colin, additional, Tagliavini, Fabrizio, additional, Takao, Masaki, additional, Thal, Dietmar Rudolf, additional, Toledo, Jon B., additional, Tolnay, Markus, additional, Troncoso, Juan C., additional, Vinters, Harry V., additional, Weis, Serge, additional, Wharton, Stephen B., additional, White, Charles L., additional, Wisniewski, Thomas, additional, Woulfe, John M., additional, Yamada, Masahito, additional, and Dickson, Dennis W., additional

Published
2015
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26. Tau acts as an independent genetic risk factor in pathologically proven PD

Author

Charlesworth, Gavin, primary, Gandhi, Sonia, additional, Bras, Jose M., additional, Barker, Roger A., additional, Burn, David J., additional, Chinnery, Patrick F., additional, Gentleman, Stephen M., additional, Guerreiro, Rita, additional, Hardy, John, additional, Holton, Janice L., additional, Lees, Andrew, additional, Morrison, Karen, additional, Sheerin, Una-Marie, additional, Williams, Nigel, additional, Morris, Huw, additional, Revesz, Tamas, additional, and Wood, Nicholas W., additional

Published
2012
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46. Microwave Antigen Retrieval in Formaldehyde-Fixed Human Brain Tissue.

Author

Walker, John M., Rayne, Richard C., Newman, Suzanna J., and Gentleman, Stephen M.

Abstract

The use of formaldehyde as a reagent for fixing tissue was first identified over a century ago (1), and because of its efficacy in a broad range of situations, at varying concentrations and with virtually all tissues, it has remained one of the most widely used fixatives. Formaldehyde is a reactive electrophilic species (2,3) that reacts readily with primary amines, amide groups, aromatic rings, and alcoholic hydroxyl groups, crosslinking various biological macromolecules. For histological purposes, this crosslinking is highly desirable in that it allows considerable morphological detail to be maintained, but such fixation invariably results in a corresponding time-dependent loss of antigenicity (4). Consequently, early immunocytochemical protocols used fresh/frozen or alcohol-fixed tissue only (5), retaining tissue antigenicity, but at the expense of morphology. Despite the effects of formalin fixation, however, the loss of antigenicity is neither complete nor irreversible. Indeed, formaldehydefixed tissue has been successfully used for the detection of many different tissue antigens, such as neurotransmitters (6), neuropeptides (7), cell surface markers (8), and enzymes (9). The suitability of formalin-fixed tissue for immunocytochemistry has been further enhanced with the development of sensitive indirect staining methods, such as PAP (peroxidase antiperoxidase) (10) and, more recently, avidin-biotin complex (ABC) methods (11). [ABSTRACT FROM AUTHOR]

Published
1997
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49. Up-regulation of soluble amyloid precursor protein fragment secretion in the rat retina in vivoby metabotropic glutamate receptor stimulation

Author

Croucher, Martin J., Patel, Hemanshu, Walsh, Desmond T., Moncaster, Juliet A., Gentleman, Stephen M., Fazal, Abidali, and Jen, Ling-Sun

Abstract

Using the novel rat retinal-vitreal model we have investigated the effect of metabotropic glutamate receptor activation on amyloid precursor protein (APP) metabolism. The release of low mol. wt fragments of APP, at 15–23 kDa in particular, was markedly up-regulated by the metabotropic glutamate receptor agonist (1S,3R)-1-amino-1,3-cyclopentane dicarboxylic acid ((1S,3R)-ACPD) in a concentration- and time-dependent manner, and this response was blocked by the receptor antagonist (S)--methyl-4-caboxyphenylglycine ((S)-MCPG). These results, together with the observation of a lack of deleterious effects of (1S,3R)-ACPD on the retinal neurons, support a physiological role of metabotropic glutamate receptors in mediating the release of soluble APP fragments, an action which may have important functional and therapeutic implications for Alzheimer's disease.

Published
2003

50. A β42is the predominant form of amyloid b protein in the brains of shortterm survivors of head injury

Author

Gentleman, Stephen M., Greenberg, Barry D., Savage, Mary J., Noori, Muna, Newman, Suzanna J., Roberts, Gareth W., Griffin, W Sue T., and Graham, David I.

Abstract

FATAL head injury results in the formation of diffuse parenchymal deposits of amyloid β-protein (Aβ) in the brains of approximately 30 of individuals. We used carboxyl terminal-specific antisera to examine the exact nature of these deposits in paraffin sections of neocortex from seven head-injured patients. Immunostaining for Aβ42was observed in all parenchymal deposits whereas staining for Aβ40, the form of the protein which predominates in serum and cerebrospinal fluid, was seen in only a small proportion of deposits. The relative paucity of Aβ40suggests that post-traumatic deposits do not arise as a result of passive leakage from damaged cerebral blood vessels but are similar to the early Aβ42parenchymal deposits seen in Down's syndrome and Alzheimer's disease.

Published
1997

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