Limbic-Predominant Age-Related TDP-43 Encephalopathy: LATE-Breaking Updates in Clinicopathologic Features and Biomarkers

Abstract

Purpose of review: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently defined neurodegenerative disease characterized by amnestic phenotype and pathological inclusions of TAR DNA-binding protein 43 (TDP-43). LATE is distinct from rarer forms of TDP-43 diseases such as frontotemporal lobar degeneration with TDP-43 but is also a common copathology with Alzheimer's disease (AD) and cerebrovascular disease and accelerates cognitive decline. LATE contributes to clinicopathologic heterogeneity in neurodegenerative diseases, so it is imperative to distinguish LATE from other etiologies.

Recent findings: Novel biomarkers for LATE are being developed with magnetic resonance imaging (MRI) and positron emission tomography (PET). When cooccurring with AD, LATE exhibits identifiable patterns of limbic-predominant atrophy on MRI and hypometabolism on ¹⁸F-fluorodeoxyglucose PET that are greater than expected relative to levels of local AD pathology. Efforts are being made to develop TDP-43-specific radiotracers, molecularly specific biofluid measures, and genomic predictors of TDP-43. LATE is a highly prevalent neurodegenerative disease distinct from previously characterized cognitive disorders.

Keywords: Alzheimer’s disease (AD); Biomarkers; Limbic-predominant age-related TDP-43 encephalopathy (LATE); Magnetic resonance imaging (MRI); Positron emission tomography (PET); TAR DNA-binding protein 43 (TDP-43).

Figure 1.

Example clinical vignette of a patient with LATE. A 78-year-old woman presents with several years of subjective memory loss and was clinically diagnosed with AD. (A) At baseline, T1-weighted coronal MRI (top) shows some volume loss in the bilateral hippocampi and medial temporal lobes, with axial FLAIR sequence scan depicting periventricular white matter hyperintensities corresponding to small vessel ischemia. (B) Ten years after baseline scan, coronal (top) computed tomography (CT) shows mild interval change of limbic structures, with some ventricular dilatation and widening of the lateral fissures compared to prior studies. Small vessel disease is redemonstrated as periventricular hypodensities on axial CT (bottom). (C) Psychometric testing over about nine years shows slow, minimal decline in Mini-Mental Status Examination (MMSE), Animal fluency, Word List (WL) delayed recall and Trails B time (natural log transformed). (D) At autopsy, immunohistochemistry of the hippocampus with TDP-43 antibody (1D3, images at 20x and 50x) reveals TDP-43 cytoplasmic inclusions, consistent with a primary neuropathological diagnosis of LATE-NC. Additional staining showed diagnostic evidence of Primary Age-Related Tauopathy and Lewy Body Disease (amygdala-predominant) and did not reflect AD neuropathologic change.

Figure 2.

Limbic PET imaging patterns in susceptible and resilient patients with similar ¹⁸F-FDG standardized uptake value ratio (SUVR 0.87 to 0.89) but different tau load (SUVR 1.41 to 1.75) in the inferior temporal gyrus (ITG). ¹⁸F-Florbetaben (amyloid), ¹⁸F-Flortaucipir (tau) and ¹⁸F-FDG PET scans are shown for a (A) cognitively impaired 84-year-old male with amyloid+/tau+ status and AD Assessment Scale-Cognitive (ADAS-Cog) score of 37.0 (higher is worse) and a (B) cognitively impaired 62-year-old female with A+/T+ status and ADAS-Cog of 14.7. The patient in (A) demonstrates an imaging marker related to LATE seen as the relative sparing of the inferior temporal gyrus (I) relative to medial temporal lobe (MTL) and frontal supraorbital gyrus (FSO), measured by higher I / MTL / FSO than the patient in (B). Hence, the patient in (A) has evidence concerning for both AD and non-AD (TDP-43) pathology potentially contributing to neurodegeneration not accounted for by tau pathology alone (as in “limbic susceptibility”).