Basic Science and Pathogenesis.

Background: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) denotes TDP-43 deposition in older age and is consequential for cognitive function. Currently there is no way to identify LATE-NC during life. Some forms of TDP-43 deposition in younger age, related to frontotemporal dementia (FTD), are associated with pronounced asymmetrical atrophy of the temporal lobe. Given the similar underlying proteinopathy of TDP-43 in both LATE-NC and FTD, we hypothesized LATE-NC would be associated with asymmetrical hippocampal atrophy.

Methods: We included participants from The 90+ Study with both MRI and autopsy data. All participants were assessed for LATE-NC, Alzheimer's disease neuropathologic change (ADNC), and hippocampal sclerosis of aging (HS-A). 3D-T1w MRIs were segmented using FreeSurfer. We examined hippocampal asymmetry, and minimum and average hippocampal volumes (across left and right), in relation to LATE-NC stages. We defined asymmetry as asym = log(100*abs(left. hipp. vol.-right. hipp.vol)/(ave. hipp. vol)). We fit multiple linear regression models for each outcome, accounting for HS-A presence and ADNC severity. Lastly, we examined prediction performance using area under the curve (AUC) for LATE-NC stage 2 or higher, considering dementia status alone or including asymmetry, minimum, or average hippocampal volume. All models were adjusted for age at death, sex, education, and intracranial volume.

Results: Table-1 displays participant characteristics (N = 104), with N = 37 (36%) having LATE-NC. Increasing LATE-NC stage was associated with increasing hippocampal asymmetry and decreasing minimum and average hippocampal volumes (Figure-1). LATE-NC stages 2 and 3 showed significant associations with hippocampal asymmetry (Figure-2). HS-A trended towards an association with, but ADNC was not associated with, hippocampal asymmetry (Figure-2). Both asymmetry and minimum hippocampal volume appeared to be more strongly related to LATE-NC compared to average hippocampal volume (Figure-2). AUC analysis indicated that, for predicting LATE-NC stage 2 or greater, the model which included asymmetry (AUC = 0.79) outperformed both the model with dementia status alone (AUC = 0.64, P = 0.005) and the models with average (AUC = 0.65, P = 0.007) and minimum (AUC = 0.69, P = 0.014) hippocampal volumes.

Conclusion: LATE-NC is associated with asymmetrical hippocampal atrophy in a stage-dependent fashion, independent of HS-A and ADNC. Using measures of hippocampal asymmetry may lead to better identification of LATE-NC during life.