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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., 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.

This chapter describes the main neuropathological features of the most common age-associated neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and dementia with Lewy bodies, as well as other less frequent ones such as multiple system atrophy, Pick’s disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, neurofibrillary tangle-dominant dementia, frontotemporal lobar degeneration with TDP-43 pathology, and Huntington’s disease. Likewise, cerebral amyloid angiopathy, hippocampal sclerosis, vascular dementia, and prion diseases are described. A main aim of this chapter is to assist the reader in interpreting neuropathological reports; hence criteria for the neuropathological classifications of the major diseases are provided. One section covers general considerations on neurodegeneration, and basic pathophysiological mechanisms of tau, amyloid-β‎, α‎-synuclein, TDP-43, and prions are briefly described in the sections on the respective diseases. Finally, one section is dedicated to cerebral multimorbidity, and a view on currently emerging neuropathological methods is given.

This chapter describes the main neuropathological features of the most common age associated neurodegenerative diseases including Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies as well as other less frequent ones such as multiple system atrophy, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, argyrophilic grain disease, neurofibrillary tangle dominant dementia, frontotemporal lobar degeneration with TDP-43 pathology and Huntington's disease. Likewise cerebral amyloid angiopathy, hippocampal sclerosis, vascular dementia and prion diseases are described. A main aim of this chapter is to assist the reader in interpreting neuropathological reports, hence criteria for the neuropathological classifications of the major diseases are provided. One section covers general considerations on neurodegeneration and basic pathophysiological mechanisms of tau, amyloid-β, α-synuclein, TDP-43 and prions are briefly described in the sections on the respective diseases. Finally, one section is dedicated to cerebral multimorbidity and we give a view on currently emerging neuropathological methods.

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.