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

      review-article
      1 , 2 , 3 , 4 , 5 , 5 , 6 , 2 , 7 , 8 , 9 , 9 , 10 , 1 , 11 , 12 , 9 , 9 , 1 , 1 , 13 , 14 , 15 , 14 , 16 , 6 , 17 , 18 , 2 , 5 , 19 , 20 , 21 , 22 , 5 , 5
      Brain
      Oxford University Press
      PET, MRI, FTLD, epidemiology, SNAP

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          Abstract

          Nelson et al. describe a recently recognized brain disorder that mimics the clinical features of Alzheimer’s disease: Limbic-predominant Age-related TDP-43 Encephalopathy (LATE). They review the literature and present consensus-based recommendations of an international, multidisciplinary working group, providing guidelines for diagnosis and staging of LATE neuropathological changes.

          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.

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          Most cited references210

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          National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach.

          We present a practical guide for the implementation of recently revised National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease (AD). Major revisions from previous consensus criteria are: (1) recognition that AD neuropathologic changes may occur in the apparent absence of cognitive impairment, (2) an "ABC" score for AD neuropathologic change that incorporates histopathologic assessments of amyloid β deposits (A), staging of neurofibrillary tangles (B), and scoring of neuritic plaques (C), and (3) more detailed approaches for assessing commonly co-morbid conditions such as Lewy body disease, vascular brain injury, hippocampal sclerosis, and TAR DNA binding protein (TDP)-43 immunoreactive inclusions. Recommendations also are made for the minimum sampling of brain, preferred staining methods with acceptable alternatives, reporting of results, and clinico-pathologic correlations.
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            Primary age-related tauopathy (PART): a common pathology associated with human aging.

            We recommend a new term, "primary age-related tauopathy" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (Aβ) plaques. For these "NFT+/Aβ-" brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as "tangle-only dementia" and "tangle-predominant senile dementia", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of Aβ accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
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              Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease.

              Apolipoprotein E, type epsilon 4 allele (APOE epsilon 4), is associated with late-onset familial Alzheimer's disease (AD). There is high avidity and specific binding of amyloid beta-peptide with the protein ApoE. To test the hypothesis that late-onset familial AD may represent the clustering of sporadic AD in families large enough to be studied, we extended the analyses of APOE alleles to several series of sporadic AD patients. APOE epsilon 4 is significantly associated with a series of probable sporadic AD patients (0.36 +/- 0.042, AD, versus 0.16 +/- 0.027, controls [allele frequency estimate +/- standard error], p = 0.00031). Spouse controls did not differ from CEPH grandparent controls from the Centre d'Etude du Polymorphisme Humain (CEPH) or from literature controls. A large combined series of autopsy-documented sporadic AD patients also demonstrated highly significant association with the APOE epsilon 4 allele (0.40 +/- 0.026, p < or = 0.00001). These data support the involvement of ApoE epsilon 4 in the pathogenesis of late-onset familial and sporadic AD. ApoE isoforms may play an important role in the metabolism of beta-peptide, and APOE epsilon 4 may operate as a susceptibility gene (risk factor) for the clinical expression of AD.
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                Author and article information

                Journal
                Brain
                Brain
                brainj
                Brain
                Oxford University Press
                0006-8950
                1460-2156
                June 2019
                30 April 2019
                30 April 2019
                : 142
                : 6
                : 1503-1527
                Affiliations
                [1 ] University of Kentucky, Lexington, KY, USA
                [2 ] Mayo Clinic, Jacksonville, FL, USA
                [3 ] University of Pennsylvania, Philadelphia, PA, USA
                [4 ] Mayo Clinic, Rochester, MN, USA
                [5 ] Rush University Medical Center, Chicago, IL, USA
                [6 ] Illinois Institute of Technology, Chicago, IL, USA
                [7 ] Uppsala University, Uppsala, Sweden
                [8 ] Newcastle University, Newcastle upon Tyne, UK
                [9 ] University of Cambridge, Cambridge, UK
                [10 ] University of Southern California, Los Angeles, CA, USA
                [11 ] University of Minnesota, Minneapolis, MN, USA
                [12 ] The University of Sydney Brain and Mind Centre and Central Clinical School Faculty of Medicine and Health, Sydney, Australia
                [13 ] University of California, Irvine, CA, USA
                [14 ] University of Washington, Seattle, WA, USA
                [15 ] Institute of Neurology Medical University of Vienna, Vienna, Austria
                [16 ] Emory University, Atlanta, GA, USA
                [17 ] Stanford University, Stanford, CA, USA
                [18 ] Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
                [19 ] University of California, San Diego, CA, USA
                [20 ] University of California, San Francisco, CA, USA
                [21 ] Harvard University, Cambridge, MA, USA
                [22 ] University of Texas Southwestern Medical Center, Dallas, TX, USA
                Author notes
                Correspondence to: Peter T. Nelson 311 Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA E-mail: peter.nelson@ 123456uky.edu
                Author information
                http://orcid.org/0000-0001-7189-7917
                http://orcid.org/0000-0003-1410-2027
                Article
                awz099
                10.1093/brain/awz099
                6536849
                31039256
                afa4e070-d63a-4222-8713-f25b83417701
                © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                : 7 January 2019
                : 10 February 2019
                : 25 February 2019
                Page count
                Pages: 25
                Funding
                Funded by: NIA 10.13039/100000049
                Funded by: NACC 10.13039/501100000298
                Funded by: NIH 10.13039/100000002
                Award ID: U01 AG016976
                Funded by: National Health and Medical Research Council 10.13039/501100000925
                Funded by: NHMRC 10.13039/501100000925
                Funded by: NHMRC 10.13039/501100000925
                Funded by: Senior Principal Research Fellowship
                Award ID: 1079679
                Funded by: NHMRC 10.13039/501100000925
                Award ID: 1132524
                Award ID: 1095127
                Award ID: 1037746
                Funded by: National Institutes of Health 10.13039/100000002
                Award ID: P01 AG003949
                Award ID: R01 AG037491
                Award ID: P50 AG016574
                Award ID: R01 AG054449
                Award ID: P30 AG028303
                Award ID: P30 AG012300
                Award ID: P30 AG049638
                Award ID: P30 AG010124
                Award ID: P30 AG010161
                Award ID: P50 AG047366
                Award ID: P50 AG025688
                Award ID: P50 AG005131
                Award ID: R37 AG011378
                Award ID: R01 AG041851
                Award ID: R01 AG042210
                Award ID: R01 AG017917
                Award ID: R01 AG034374
                Award ID: UF1 AG053983
                Award ID: UF1 AG057707
                Funded by: NIHR 10.13039/100006662
                Award ID: 534906
                Award ID: NF-SI-0616–10090
                Funded by: National Institute for Health Research 10.13039/501100000272
                Funded by: NHS
                Funded by: NIHR 10.13039/100006662
                Funded by: Department of Health and Social Care
                Funded by: Addenbrooke’s Charitable Trust
                Funded by: Paul G. Allen Family Foundation and Alzheimer’s Research
                Categories
                Review Article
                Editor's Choice

                Neurosciences
                pet,mri,ftld,epidemiology,snap
                Neurosciences
                pet, mri, ftld, epidemiology, snap

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