Performance of a condensed protocol to assess limbic-predominant age-related TDP-43 encephalopathy neuropathologic change

Abstract

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a dementia-related proteinopathy common in the elderly population. LATE-NC stages 2 or 3 are consistently associated with cognitive impairment. A condensed protocol (CP) for the assessment of Alzheimer disease neuropathologic change and other disorders associated with cognitive impairment, recommended sampling of small brain portions from specific neuroanatomic regions that were consolidated, resulting in significant cost reduction. Formal evaluation of the CP for LATE-NC staging was not previously performed. Here, we determined the ability of the CP to identify LATE-NC stages 2 or 3. Forty brains donated to the University of Washington BioRepository and Integrated Neuropathology laboratory with known LATE-NC status were resampled. Slides containing brain regions required for LATE-NC staging were immunostained for phospho-TDP-43 and reviewed by 6 neuropathologists blinded to original LATE-NC diagnosis. Overall group performance distinguishing between LATE-NC stages 0-1 and 2-3 was 85% (confidence interval [CI]: 75%-92%). We also used the CP to evaluate LATE-NC in a hospital autopsy cohort, in which LATE-NC was more common in individuals with a history of cognitive impairment, older age, and/or comorbid hippocampal sclerosis. This study shows that the CP can effectively discriminate higher stages of LATE-NC from low or no LATE-NC and that it can be successfully applied in clinical practice using a single tissue block and immunostain.

Keywords: Condensed protocol; LATE; LATE-NC; Limbic predominant age-related TDP-43 encephalopathy neuropathologic change.

Figure 1.

(A) For this study, blocks were prepared according to the original condensed protocol for the assessment of neurodegenerative disease in order to assess the use of this condensed blocking scheme for the identification of LATE-NC compared to standard research blocking protocols. Specifically, blocks 2, 3, and 4 from the original protocol contain the brain regions relevant to the assessment of LATE-NC and were the focus of this study. Blocks 1 and 2 in the current study exactly followed the original protocol for blocks 2 and 3, respectively. Block 3 in the current study is a modified version of block 4 from the original protocol that includes bilateral amygdala sampling when available. Immunohistochemistry for pTDP-43 was applied to all 3 blocks. (B) For primary analysis, only block 1 or 2, depending on tissue availability, was included for assessment of unilateral pTDP-43 pathology in the hippocampus and frontal cortex (n = 40). In an exploratory analysis, the 19 cases with bilateral hippocampal tissue available were analyzed to determine if adding a second block significantly improved sensitivity of the CP for detecting clinically relevant LATE-NC. In a secondary analysis, the 38 cases with available amygdala were assessed to determine if the CP amygdala samples were sufficient to accurately identify LATE-NC stage 1.

Figure 2.

Algorithm for NIA-AA condensed protocol work up in clinical autopsy cohort.

Figure 3.

Characteristics of the hospital autopsy subjects. Of the 253 hospital autopsy cohort subjects that underwent complete condensed protocol assessments, 7 with LATE-NC were identified, 6 of which had high Braak stage (Braak V/VI), and 1 of which had intermediate Braak stage (Braak IV). Three of seven subjects with LATE-NC also had HS (42.9%) compared to 2 of 246 subjects without LATE-NC that had HS (0.8%). HS, hippocampal sclerosis.