Biomarkers.

Background: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a common neuropathologic finding at advanced age that associates with hippocampal sclerosis (HS) and is often comorbid with AD pathology. Neuroimaging measurements of LATE-NC-associated limbic degeneration have been proposed as indirect biomarkers, but molecular-specific biomarkers for LATE-NC are still lacking. Here we used combined ante-mortem blood and MRI data to study TDP-43 levels in plasma-derived small extracellular vesicles (sEV-TDP-43) and hippocampal volume (HV) in relation to LATE-NC and HS at autopsy.

Method: We studied 56 autopsied dementia patients from the Reina Sofia Alzheimer Center (Madrid) who had ante-mortem blood samples and quality-controlled 3T-MRI available. Plasma sEVs were isolated by size exclusion chromatography and TDP-43 was quantified by SIMOA. HV was derived from structural MRI using Freesurfer. Neuropathological examination included assessment of AD neuropathologic change (ADNC), LATE-NC, and presence of HS. Differences in plasma sEV-TDP-43 levels and HV between individuals with (+) and without (-) LATE-NC were assessed using t-tests and ROC curve analysis. Additional analyses stratified cases by presence/absence of HS and limited the sample to those with high ADNC.

Result: Plasma sEV-TDP-43 levels were significantly higher (p=0.02) and HV (p=0.03) was significantly lower in LATE-NC(+)(n=35) vs LATE-NC(-)(n=21), although group separation in ROC analysis was relatively weak (AUC = 0.65; AUC = 0.68). Combining both biomarkers increased group separation to AUC = 0.76. HV was highly sensitive to HS status (p=0.001), whereas sEV-TDP-43 was not (p=0.45). As a consequence, sEV-TDP-43 also distinguished between LATE-NC(-) and LATE-NC(+) without HS (p=0.02, AUC=0.72), whereas HV did not (p=0.17). When limited to cases with high ADNC, sEV-TDP-43 distinguished between those with and without comorbid LATE-NC (p=0.03, AUC=0.64), but HV did not (p=0.37).

Conclusion: Plasma sEV-TDP-43 levels and hippocampal volume provide complementary information as biomarkers of LATE-NC. While hippocampal volume is a sensitive biomarker of LATE-NC-associated neurodegeneration, plasma sEV-TDP-43 levels appear to be more directly linked to the pathology. The relatively low group separation could be partly due to the characteristics of the study sample focused on end-of-life dementia patients with late stage disease and multiple comorbidities.