LATE-NC staging in routine neuropathologic diagnosis: an update

Abstract

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Keywords: Aging; Dementia; FTD; Hippocampal sclerosis; NCI; Neuroanatomy; Processes; Stages; TDP-43.

Fig. 1

Anatomical regions of interest for tissue sampling and typical findings in routine autopsy diagnosis of LATE-NC. At autopsy, tissue portions for sampling include amygdala, mid-level hippocampus, and middle frontal gyrus. The levels of sections are shown in the cartoon form (upper left) with gross photographs of hemi-brains cut in the coronal plane (Panel a). Note that the amygdala is preferably sampled for TDP-43 immunohistochemical staining at the level of the uncus (pink arrowhead, Sect. 1), the hippocampus at the level of the lateral geniculate nucleus (yellow arrowhead, Sect. 2), and the middle frontal gyrus (Sect. 3) is sampled rather than other portions of frontal cortex. Panels b and c are representations of the amygdala region and hippocampal region, showing both the local anatomy and a cursory depiction of the subtypes of TDP-43 pathology that are generally found in those regions with corresponding colored circles in panels d-h. Panel d shows a neuronal TDP-43 + inclusion reminiscent of a neurofibrillary tangle. Panel e depicts a different TDP-43 pathologic appearance with a granular NCI (arrow with red outline), neuronal intranuclear inclusion (arrow with blue outline), and TDP-43 + fibrillary material in the background. This pattern is reminiscent of FTLD-TDP type A. TDP-43 pathology can also be present around vascular components such as capillaries (termed Lin Bodies after Ref. [87]) or in unknown histologic compartments as shown in Panel f. In some regions, the predominant TDP-43 + pathology is fine non-tapering neurite-like processes (Panel g). A different type of TDP-43-immunoreactive cell processes can be seen in the sub-pial region, often near corpora amylacea (arrow in Panel h). Scale bars = 50 microns (d); 30 microns (e); 30 microns (f); 100 microns (g); and, 30 microns (h). Abbreviations: Amyg: amygdala proper; dg: dentate granule layer of hippocampus; ErC: entorhinal cortex; LGN: lateral geniculate nucleus; LV: lateral ventricle; NCI: TDP-43 immunoreactive neuronal cytoplasmic inclusions; NFT: neurofibrillary tangles; TErC: transentorhinal cortex; Unc: uncus