Multiple Neuropathologies Underly Hippocampal Subfield Atrophy in a Case With a Slowly Progressive Amnestic Syndrome:...

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, marked by abnormal protein buildup (beta-amyloid and tau) resulting in neuronal loss, especially in the medial temporal lobe and other limbic regions. The presence of transactive response DNA binding protein 43 (TDP-43) immunoreactive inclusions in medial temporal lobe regions has also been associated with neuroimaging changes in limbic regions. It has been proposed that hypometabolism in limbic regions on [¹⁸F] fluorodeoxyglucose positron emission tomography (FDG-PET) in a patient with a slowly evolving amnestic syndrome may be a signature of the presence of TDP-43. In this context, we observed an 86-year-old Caucasian female with dementia characterized by a slowly evolving amnestic syndrome, along with focal medial temporal atrophy evident on MRI and hypometabolism in limbic regions on FDG-PET. The patient subsequently died and underwent an autopsy. We performed detailed neuroimaging and digital neuropathological analyses of the hippocampal subfields to better understand the relationship between clinico-imaging findings and histopathology. In addition to TDP-43, we identified three other pathological processes in the medial temporal lobe: sequestosome-1/p62, argyrophilic grain disease (AGD), and primary age-related tauopathy (PART). Hippocampal subfield volumes and rates of atrophy were no different from those of matched healthy controls, except for the atrophy rate in cornu ammonis 1 (CA1). Digital histopathology revealed the relative highest burden of pathology for p62, followed by TDP-43, AGD, and PART in CA1. Multiple pathological processes appear to have contributed to the hippocampal atrophy and hypometabolism in our patient with a slowly progressive amnestic syndrome.