Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report

• Type of Material: Article
• Authors: Peter T Nelson, University of Kentucky; Dennis W Dickson, Mayo Clinic in Jacksonville; John Q Trojanowski, University of Pennsylvania; Clifford R Jack, Mayo Clinic; Patricia A Boyle, Rush University Medical Center; Konstantinos Arfanakis, Rush University Medical Center; Rosa Rademakers, Mayo Clinic in Jacksonville; Irina Alafuzoff, Uppsala Universitet; Johannes Attems, Newcastle University; Carol Brayne, University of Cambridge; Ian T S Coyle-Gilchrist, University of Cambridge; Helena C Chui, University of Southern California; David W Fardo, University of Kentucky; Margaret Flanagan, Emory University; Glenda Halliday, University of Sydney; Suvi R K Hokkanen, University of Cambridge; Sally Hunter, University of Cambridge; Gregory A Jicha, University of Kentucky; Yuriko Katsumata, University of Kentucky; Allan Levey, Emory University
• Language: English
• Date: 2019-06-01
• Publisher: Oxford University Press (OUP): Policy B - Oxford Open Option B
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.
• License: Creative Commons Attribution-NonCommercial 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1093/brain/awz099
• Title of Journal or Parent Work: Brain
• ISSN: 0006-8950
• Volume: 142
• Issue: 6
• Start Page: 1503
• End Page: 1527
• Grant/Funding Information: S.R.K.H. is supported by Alzheimer’s Research, UK.; UK grants included ARUK-PhD2014–19, and NIHR Senior Investigators award Ref: 534906 NF-SI-0616–10090 to co-author C.B.; S.H. is supported by the Addenbrooke’s Charitable Trust; the Paul G. Allen Family Foundation and Alzheimer’s Research, UK.; Grant support from U.S. National Institutes of Health included grants P01 AG003949 (D.W.D.); R01 AG037491 (D.W.D.); P50 AG016574 (D.W.D.); R01 AG054449 (M.E.M.); P30 AG028303 (P.T.N. and G.A.J.); P30 AG012300 (C.L.W.); P30 AG049638 (T.J.M.); P30 AG010124 (J.Q.T.); P30 AG010161 (K.A., J.A.S., P.A.B.); P50 AG047366 (T.J.M.); P50 AG025688 (A.I.L.); P50 AG005131 (R.A.R.); R37 AG011378 (C.R.J.); R01 AG041851 (C.R.J.); R01 AG042210 (J.A.S.); R01 AG017917 (J.A.S.); R01 AG034374 (P.A.B.); UF1 AG053983 (T.J.M.); UF1 AG057707 (T.J.M.); Direct support for meeting logistics was provided via a NIA/NACC grant (supplemental to the parent NIH grant U01 AG016976 to W.A.K.).; National Institute for Health Research, Senior Investigator Award, was awarded to C.B. for C.B. and S.H.; Support from the National Health and Medical Research Council of Australia (NHMRC) included NHMRC Senior Principal Research Fellowship (1079679) and other NHMRC grants (1132524, 1095127, 1037746) to G.H.
• Keywords: FTLD; PET; MRI; SNAP; epidemiology
• Research Categories: Biology, Neuroscience; Health Sciences, Epidemiology

Abstract

We 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.