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Biomarkers.

Michel J Grothe1, Linda Zhang1, Francisco J López-González1

  • 1CIEN Foundation, Reina Sofia Alzheimer Center, ISCIII, Madrid, Madrid, Spain.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
PubMed
Summary

Limbic age-related TDP-43 encephalopathy neuropathologic change with hippocampal sclerosis shows brain-wide atrophy beyond the hippocampus. This MRI signature may aid in diagnosing LATE-NC in living patients.

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Area of Science:

  • Neuropathology
  • Neuroimaging
  • Geriatric Neurology

Background:

  • Limbic age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) often co-occurs with Alzheimer's disease neuropathologic change (ADNC).
  • LATE-NC is associated with hippocampal sclerosis (HS), contributing to memory deficits independently of AD.
  • While FDG-PET and MRI studies have identified temporo-limbic signatures and hippocampal atrophy in HS, the brain-wide atrophy pattern in LATE-NC-associated HS requires further characterization.

Purpose of the Study:

  • To characterize the brain-wide MRI-based atrophy pattern associated with LATE-NC-related hippocampal sclerosis.
  • To compare atrophy patterns between LATE-NC+HS, AD-noHS, and healthy controls.
  • To explore the relationship between HS severity and regional brain volumes.

Main Methods:

  • Studied 84 dementia patients with detailed neuropathologic assessment and ante-mortem 3T-MRI.
  • Assessed ADNC, LATE-NC, and HS using binary and staging schemes.
  • Analyzed MRI data using ROI-based analyses across 52 brain regions, comparing autopsy cases to 1032 healthy controls.

Main Results:

  • Dementia cases with LATE-NC+HS and AD-noHS exhibited similar brain-wide atrophy patterns, most pronounced in medial/anterior temporal and lateral temporo-parietal areas.
  • LATE-NC+HS cases showed significantly greater atrophy in the hippocampus, amygdala, temporal pole, insula, and orbitofrontal cortex compared to AD-noHS.
  • A consistent HS-associated temporo-limbic atrophy pattern correlated with HS severity, with no significant differences between AD-noHS cases with or without comorbid LATE-NC.

Conclusions:

  • LATE-NC-associated HS is linked to an in-vivo MRI atrophy pattern extending beyond the hippocampus.
  • This extended atrophy involves temporo-limbic cortical areas affected by TDP-43 pathology in LATE-NC.
  • The identified MRI signature may improve in-vivo clinical detection of LATE-NC.