Multisite assessment of NIA‐AA guidelines for the neuropathologic evaluation of Alzheimer's disease

Montine, Thomas J.; Monsell, Sarah E.; Beach, Thomas G.; Bigio, Eileen H.; Bu, Yunqi; Cairns, Nigel J.; Frosch, Matthew P.; Henriksen, Jonathan C.; Kofler, Julia; Kukull, Walter A.; Lee, Edward B.; Nelson, Peter T.; Schantz, Aimee M.; Schneider, Julie A.; Sonnen, Joshua A.; Trojanowski, John Q.; Vinters, Harry V.; Zhou, Xiao Hua; Hyman, Bradley T.

doi:10.1016/j.jalz.2015.07.492

Cited by 89 publications

(107 citation statements)

References 14 publications

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“…2a–b). Semi-quantitative analyses of LBs and GCIs 15,16 stained by Syn7015 or Syn303 on adjacent sections showed that Syn7015 preferentially recognized GCIs over LBs (Fig. 1e), which was also supported by the ratio of total area occupied by Syn7015+ over Syn303+ pathology (Fig.…”

Section: Main Textmentioning

confidence: 57%

Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

Peng

Gathagan

Covell

et al. 2018

Nature

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In Lewy body (LB) diseases, including Parkinson’s disease (PD), without and with dementia (PDD), dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) patients with LB co-pathology1, α-synuclein (α-Syn) aggregates in neurons as LBs and Lewy neurites (LNs)2, while in multiple system atrophy (MSA), α-Syn mainly accumulates in oligodendrocytes as glial cytoplasmic inclusions (GCIs)3. Here, we report that pathological α-Syn in GCIs and LBs (GCI-α-Syn and LB-α-Syn) are conformationally and biologically distinct. GCI-α-Syn forms more compact structures and is ~1,000-fold more potent than LB-α-Syn in seeding α-Syn aggregation, consistent with the highly aggressive nature of MSA. Surprisingly, GCI-α-Syn and LB-α-Syn show no cell type preference in seeding α-Syn pathology, raising the question of why they demonstrate different cell type distributions in LB disease versus MSA. Strikingly, we found that oligodendrocytes but not neurons transform misfolded α-Syn into a GCI-like strain, highlighting that distinct α-Syn strains are generated by different intracellular milieus. Moreover, GCI-α-Syn maintains its high seeding activity when propagated in neurons. Thus, α-Syn strains are determined by both misfolded seeds and intracellular environments.

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Section: Main Textmentioning

confidence: 57%

Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

Peng

Gathagan

Covell

et al. 2018

Nature

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500

547

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“…Replication of our findings in an independent prospective cohort is needed to further interpret the generalizability of results; however, we used a bootstrapped random patient selection procedure to reduce overfitting of our models. Finally, the neuropathological data were collected at autopsy from multiple centers using different staining procedures; however, we used standardized methods—used across >30 NIH/NIA-funded Alzheimer’s centers in the National Alzheimer’s disease Coordinating Center https://www.alz.washington.edu/ —for merging multi-center data which provide reliability across participating institutions to reduce inter-lab variability, 4,13 and the neuropathological methods and criteria used here were recently validated in a large multi-center study 30 .…”

Section: Discussionmentioning

confidence: 99%

Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis

Irwin

Grossman

Weintraub

et al. 2017

The Lancet Neurology

420

413

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Background There exists great heterogeneity in patient survival and the time interval between motor symptom and dementia onset (MDI) across Lewy body spectrum disorders (LBSD). The goal of this study is to identify genetic and pathological findings that have the strongest association with these features of clinical heterogeneity in LBSD. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of LBSD patients with autopsy-confirmed α-synucleinopathy (as of Oct 1, 2015) recruited from 5 clinical research centres in 5 cities in the USA. Using histopathology techniques and markers, we assessed the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathologic changes in cortical regions using averaged ordinal scores and genotyped cases for variants associated with LBSD. We evaluated the time interval from onset of motor symptoms to dementia (MDI) and overall survival in groups with varying levels of co-morbid Alzheimer’s disease pathology (AD) according to current National Institute on Aging–Alzheimer’s Association neuropathological criteria and used multivariate regression to control for age at death and gender. Findings This study included 213 patients who had been followed to autopsy and met inclusion criteria of clinical LBSD with autopsy-confirmed α-synculeinopathy. Patient groups were characterized by no (n=49,23%), low-level (n=56,26%), intermediate-level (n=45,21%) or high-level (n=63,30%) AD neuropathology. Across groups of increasing levels of AD neuropathology, there were higher cerebral α-synuclein scores, shorter MDI, and shorter disease duration (p<0·0001 all). Multivariate regression found independent negative associations of cerebral tau score with MDI (β= −4·0, 95% CI −5·5 to −2·6; p<0·0001) (R2=0·22, p<0·0001) and with survival (β=−2·0, 95% CI −3·2 to −0·8; p<0·0001) (R2=0·15, p<0·0001) in models including age at death, gender, cerebral neuritic plaque scores, cerebral α-synuclein, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation AD neuropathology is common in LBSD and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tau tangle burden, α-synuclein pathology, and amyloid plaque pathology are the strongest pathological predictors of a shorter MDI and survival in LBSD. In the future, clinical diagnostic criteria which use reliable biomarkers for AD neuropathology in LBSD should help identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-beta or α-synuclein, and stratify them by level of AD neuropathology. Funding NIH (NIA/NINDS).

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“…Future studies should also aim to re-evaluate these observations to validate this approach and to develop a concise classification of ARTAG for diagnostic neuropathology. To reach this goal, paradigms will need to be designed for ARTAG along the lines used to standardize evaluation and diagnostic criteria for tau, amyloid and α-synuclein and other major pathologies [2–4, 10, 45]. Subsequently, it will be possible to evaluate inter-rater reliability of the proposed evaluation and eventually to merge clinical and pathologic data from multiple centers to determine practical significance of ARTAG.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2015

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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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Multisite assessment of NIA‐AA guidelines for the neuropathologic evaluation of Alzheimer's disease

Cited by 89 publications

References 14 publications

Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

Cellular milieu imparts distinct pathological α-synuclein strains in α-synucleinopathies

Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis

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

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