Molecular imaging of Limbic-predominant age-related TDP-43 encephalopathy (LATE)

Introduction: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a recently defined neurodegenerative disorder presenting as an amnestic dementia syndrome, typically affecting individuals above 80 years of age. The main point of distinction from Alzheimer’s disease lies in the neuropathology. In this educational abstract, our aim is to review the role of molecular imaging in Limbic-predominant age-related TDP-43 encephalopathy.

Methods: A literature review was conducted using PubMed databases and the Google Scholar search engine on molecular imaging and Limbic-predominant age-related TDP-43. Additionally, we summarized a literature review on the epidemiology and pathogenesis of LATE, along with correlative imaging findings.

Results: In 2019, a consensus working group report described it as a TDP-43 proteinopathy present in older adults, with or without coexisting hippocampal sclerosis pathology. TDP-43 proteinopathy consists of mislocalized and phosphorylated TDP-43, serving as a hallmark of FTLD-TDP, ALS, and LATE. The older age of presentation and specific areas of distribution, including the amygdala, hippocampus, and middle frontal gyrus, characterize LATE. Anatomically, MRI has been utilized to evaluate associated medial temporal lobe atrophy. Currently, there are limited imaging modalities to diagnose LATE, with no approved biomarker specifically targeting TDP-43. 18F-FDG PET can be employed to differentiate LATE from other neurodegenerative diseases. A prior study described hypometabolism in the medial temporal and frontal regions on 18-F FDG PET in Alzheimer's disease patients with postmortem TDP-43. Given the limited biomarkers, the National Institute on Aging and Alzheimer's Association (NIA-AA) classification system, known as the "ATN system (amyloid, tau, neurodegeneration)," can be utilized to assist in evaluating for LATE. By assessing amyloid, tau, and neurodegeneration, it is possible to narrow down the differential diagnosis. For instance, in patients with A+T-N+ and patients with A-T-N+ where N is related to medial temporal atrophy or hypometabolism, LATE should be considered. The discovery of a TDP-43 specific radiotracer is an active area of research. Difficulties faced in creating the biomarker include the intracellular location and limited neuropathologic load. In the meantime, multimodal non-specific approaches, including MR, 18-F FDG, TAU, and amyloid imaging, can be considered in evaluating for LATE.

Conclusions: LATE is a newly defined neurodegenerative disease affecting elderly patients. Currently, there are limited imaging modalities available to evaluate for LATE, with no specific biomarker targeting TDP-43. Additional research is needed to develop targeted imaging and therapy.