Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy

Abstract

Limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is highly prevalent in late life and a common co-pathology with Alzheimer's disease neuropathologic change (ADNC). LATE-NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE-NC is associated with a more rapid course. With the emergence of anti-amyloid therapeutics, discrimination of LATE-NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co-pathology with LATE-NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE-NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). HIGHLIGHTS: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a highly prevalent driver of neuropathologic memory loss in late life. LATE neuropathologic change (LATE-NC) is a common co-pathology with Alzheimer's disease neuropathologic change (ADNC) and may influence outcomes with emerging disease-modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE-NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

Keywords: Alzheimer's disease; dementia; limbic predominant age‐related TDP‐43 encephalopathy; mild cognitive impairment; multi‐etiology dementia.

FIGURE 1

Flow for decisions about diagnosis of of LATE. A‐ , amyloid negative biomarker; A+ , amyloid positive biomarker; T‐ , tau negative biomarker; T+, tau positive biomarker; LATE.

FIGURE 2

(A) MRI scans of a ≈90‐year‐old man with more than 8 years of a slowly progressive amnestic syndrome with more mild decline in category fluency. He had a negative amyloid PET scan and MRI with severe atrophy of the (left) head and (right) body of the hippocampus (see arrows). Autopsy revealed Stage 3 limbic‐predominant, age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC), hippocampal sclerosis, and low Alzheimer's Disease neuropathologic change (ADNC; A1, B2, C0). (B) MRI scan of an 86‐year‐old with a – to 3‐year isolated progressive amnestic syndrome and a negative amyloid PET scan, who would qualify as “Probable LATE” based on proposed criteria. Coronal slices demonstrate (left) severe hippocampal atrophy and (right) severe cortical thinning in entorhinal cortex (arrow) with widening of the collateral sulcus. (C) FDG‐PET pattern of hypometabolism in LATE‐NC with arrows pointing to severe hypometabolism of the medial temporal lobe (MTL) and relative sparing of the inferolateral temporal cortex (left). This can be contrasted with the FDG‐PET pattern of hypometabolism in typical ADNC (right), with more mild MTL hypometabolism and more significant hypometabolism in the inferolateral temporal cortex.