LATE-NC staging in routine neuropathologic diagnosis: an update

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. Supplementary Information The online version contains supplementary material available at 10.1007/s00401-022-02524-2.

sulcus (cs), and the (lateral) occipitotemporal or fusiform gyrus (OTG or FG). In the medial bank of rs is the transentorhinal cortex (TEC or BA 35), also termed perirhinal cortex. Lateral to rs is temporal cortex, including Brodmann area 36 (BA 36) and neocortex of Brodmann area 20 (BA 20). ERC and TEC are part of the periallocortex that surrounds amygdala, and these may have isolated TDP-43-positive NCI pathology even without NCIs in amygdala proper (see text for detail).
The amygdala itself can broadly be divided into four regions, as shown here. These are the cortical-like region (Co), immediately deep to the pial surface of the SLG, the basal nuclei, divided into basomedial (Bm) and basolateral (Bl) nuclear groups, the lateral nuclear group (Lat) including its conspicuous, stripe-like lateral subdivision (Lat-L), and the dorsally located centromedian nuclear group (Me/Ce). The ventral extension of claustrum (Cls) and basal forebrain (not shown) are both closely associated with amygdala and are frequently sampled in this section. The 2 subamygdaloid white matter (wm) is a conspicuous site of TDP-43 positive "processes" in some patients (see text for detail).
Though not shown here, sections taken at a slightly more posterior/ caudal level will demonstrate the temporal horn of the lateral ventricle. This portion of ventricle is variably dilated across patients, depending on the degree of limbic region atrophy. In addition, at these more posterior/ caudal levels, CA1 and subiculum of the anterior hippocampus begin to appear, positioned between amygdala dorsally and the ERC ventrally. As described in the text, in some samples, this anterior hippocampal region may have TDP-43 pathology in the absence of clear amygdala NCIs. As this pathology occurs in standard sections through uncus and amygdala, this pathology is also considered as being within "Amygdala Region" (see text for detail).

Hippocampus Region
The recommended coronal section of hippocampus is shown in the "Hippocampal Region" panel shown below (an LFB/PAS image with accompanying diagram of the same).
The recommended Hippocampus region section is taken at the level of the lateral geniculate nucleus (LGN). Dorsally located structures in this section also include medial geniculate nucleus (MGN), stria terminalis (st), tail of caudate nucleus (Cd) and tapetum (tp).
The hippocampal formation proper comprises the dentate gyrus (DG) and cornu ammonis. The granule cell layer of DG is a frequent site of TDP-43 NCI pathology in LATE-NC (dashed line). Components of cornu ammonis include sectors CA3, CA2, and CA1, as shown. Of these sectors, CA1 is a frequent site of neurite and NCI pathology in LATE-NC.
Medial to CA1 is the subiculum (Sub), the third region of the hippocampal formation.
Like CA1 and DG, subiculum is a frequent site of TDP-43 pathology in LATE-NC. The border of CA1 and subiculum is ill-defined as these structures overlap (and their distinction is not relevant to staging LATE-NC). But at its more lateral extent, subiculum is recognized by being wider than CA1, by its greater neuron numbers, by slightly larger pyramidal cells, and at its medial-most extent, by overlap with clusters of small neurons (indicated by small circles here) that are part of Presubiculum (Prs), a region that also extends medially onto the PHG surface.
Additional landmarks in this region include cs, and OTG (FG), as defined above under "Amygdala Region". Note that ERC (BA 28) is not present in this section. This portion of posterior parahippocampal cortex instead contains Von Economo areas TH and TF (BA 36). The fusiform gyrus lateral to cs contains neocortex of BA 20 (Von Economo area TE).

Middle frontal gyrus
For LATE-NC staging, cortex of middle frontal gyrus is ideally sampled at the level of the genu of corpus callosum and temporal poles. The gyrus is easily distinguished in this section between the superior and inferior frontal sulci (see manuscript Figure 1) and this neocortical region corresponds approximately to Brodmann area 46. Neocortical pathology in this region may be seen in stage 3 LATE-NC (see text for detail).

Note
Images created with BioRender.com. There is interindividual variability in sections through amygdala region and uncus, as well as in terminology applied in various references to both amygdala and hippocampal regions. As such, the labels applied above are based on consensus features in multiple references, in tandem with the features of the specific samples shown.