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dc.contributor.authorNelson, Peter T
dc.contributor.authorDickson, Dennis W
dc.contributor.authorTrojanowski, John Q
dc.contributor.authorJack, Clifford R
dc.contributor.authorBoyle, Patricia A
dc.contributor.authorArfanakis, Konstantinos
dc.contributor.authorRademakers, Rosa
dc.contributor.authorAlafuzoff, Irina
dc.contributor.authorAttems, Johannes
dc.contributor.authorBrayne, Carol
dc.contributor.authorCoyle-Gilchrist, Ian TS
dc.contributor.authorChui, Helena C
dc.contributor.authorFardo, David W
dc.contributor.authorFlanagan, Margaret E
dc.contributor.authorHalliday, Glenda
dc.contributor.authorHokkanen, Suvi
dc.contributor.authorHunter, Sally
dc.contributor.authorJicha, Gregory A
dc.contributor.authorKatsumata, Yuriko
dc.contributor.authorKawas, Claudia H
dc.contributor.authorKeene, C Dirk
dc.contributor.authorKovacs, Gabor G
dc.contributor.authorKukull, Walter A
dc.contributor.authorLevey, Allan I
dc.contributor.authorMakkinejad, Nazanin
dc.contributor.authorMontine, Thomas J
dc.contributor.authorMurayama, Shigeo
dc.contributor.authorMurray, Melissa E
dc.contributor.authorNag, Sukriti
dc.contributor.authorRissman, Robert A
dc.contributor.authorSeeley, William W
dc.contributor.authorSperling, Reisa A
dc.contributor.authorWhite, Charles L
dc.contributor.authorYu, Lei
dc.contributor.authorSchneider, Julie A
dc.date.accessioned2019-03-19T00:30:12Z
dc.date.available2019-03-19T00:30:12Z
dc.date.issued2019-06-01
dc.identifier.issn0006-8950
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/290624
dc.description.abstractWe describe a recently recognized disease entity, limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE neuropathological change (LATE-NC) is defined by a stereotypical TDP-43 proteinopathy in older adults, with or without coexisting hippocampal sclerosis pathology. LATE-NC is a common TDP-43 proteinopathy, associated with an amnestic dementia syndrome that mimicked Alzheimer's-type dementia in retrospective autopsy studies. LATE is distinguished from frontotemporal lobar degeneration with TDP-43 pathology based on its epidemiology (LATE generally affects older subjects), and relatively restricted neuroanatomical distribution of TDP-43 proteinopathy. In community-based autopsy cohorts, ∼25% of brains had sufficient burden of LATE-NC to be associated with discernible cognitive impairment. Many subjects with LATE-NC have comorbid brain pathologies, often including amyloid-β plaques and tauopathy. Given that the 'oldest-old' are at greatest risk for LATE-NC, and subjects of advanced age constitute a rapidly growing demographic group in many countries, LATE has an expanding but under-recognized impact on public health. For these reasons, a working group was convened to develop diagnostic criteria for LATE, aiming both to stimulate research and to promote awareness of this pathway to dementia. We report consensus-based recommendations including guidelines for diagnosis and staging of LATE-NC. For routine autopsy workup of LATE-NC, an anatomically-based preliminary staging scheme is proposed with TDP-43 immunohistochemistry on tissue from three brain areas, reflecting a hierarchical pattern of brain involvement: amygdala, hippocampus, and middle frontal gyrus. LATE-NC appears to affect the medial temporal lobe structures preferentially, but other areas also are impacted. Neuroimaging studies demonstrated that subjects with LATE-NC also had atrophy in the medial temporal lobes, frontal cortex, and other brain regions. Genetic studies have thus far indicated five genes with risk alleles for LATE-NC: GRN, TMEM106B, ABCC9, KCNMB2, and APOE. The discovery of these genetic risk variants indicate that LATE shares pathogenetic mechanisms with both frontotemporal lobar degeneration and Alzheimer's disease, but also suggests disease-specific underlying mechanisms. Large gaps remain in our understanding of LATE. For advances in prevention, diagnosis, and treatment, there is an urgent need for research focused on LATE, including in vitro and animal models. An obstacle to clinical progress is lack of diagnostic tools, such as biofluid or neuroimaging biomarkers, for ante-mortem detection of LATE. Development of a disease biomarker would augment observational studies seeking to further define the risk factors, natural history, and clinical features of LATE, as well as eventual subject recruitment for targeted therapies in clinical trials.
dc.description.sponsorshipSally Hunter and Carol Brayne are supported by funding from the National Institute for Health Research, Senior Investigator Award, awarded to Carol Brayne. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. Sally Hunter is supported by the Addenbrooke’s Charitable Trust, the Paul G. Allen Family Foundation and Alzheimer’s Research, UK. Suvi Hokkanen was supported by Alzheimer’s Research, UK.
dc.format.mediumPrint
dc.languageeng
dc.publisherOxford University Press (OUP)
dc.rightsAttribution-NonCommercial 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/
dc.subjectBrain
dc.subjectHumans
dc.subjectBrain Diseases
dc.subjectAlzheimer Disease
dc.subjectRetrospective Studies
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectFrontotemporal Lobar Degeneration
dc.subjectTDP-43 Proteinopathies
dc.subjectFrontotemporal Dementia
dc.subjectNeuroimaging
dc.titleLimbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report.
dc.typeArticle
prism.endingPage1527
prism.issueIdentifier6
prism.publicationDate2019
prism.publicationNameBrain
prism.startingPage1503
prism.volume142
dc.identifier.doi10.17863/CAM.37842
dcterms.dateAccepted2019-02-25
rioxxterms.versionofrecord10.1093/brain/awz099
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2019-06
dc.contributor.orcidBrayne, Carol [0000-0001-5307-663X]
dc.contributor.orcidHokkanen, Suvi [0000-0001-6520-1274]
dc.contributor.orcidHunter, Sally [0000-0002-8063-6556]
dc.identifier.eissn1460-2156
rioxxterms.typeJournal Article/Review
pubs.funder-project-idPaul G Allen Family Foundation (12076)
cam.issuedOnline2019-04-30
cam.orpheus.successThu Jan 30 10:49:51 GMT 2020 - The item has an open VoR version.
rioxxterms.freetoread.startdate2100-01-01


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Attribution-NonCommercial 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial 4.0 International