Limbic-predominant age-related TDP-43 encephalopathy (LATE)

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a common neurodegenerative disorder of elderly adults (usually >80 years old), manifest clinically as amnestic dementia and pathologically as TDP-43 proteinopathy in limbic system structures such as the hippocampus.

Terminology 

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is the preferred term (and convenient initialism) according to a 2019 consensus working group report ¹. The term encompasses several previously used terms for TDP-43-related cognitive impairment, including hippocampal sclerosis ² (not to be confused with mesial temporal lobe epilepsy with hippocampal sclerosis), hippocampal sclerosis dementia ³, hippocampal sclerosis of aging ⁴, and cerebral age-related TDP-43 with sclerosis (CARTS) ⁵.

While LATE represents the clinical disorder, the term limbic-predominant age-related TDP-43 encephalopathy-neuropathological changes (LATE-NC) refers to the pathologic findings regardless of the clinical manifestations.

Epidemiology

The prevalence increases with age, dramatically so after age 80-85 years. Based on population autopsy studies, LATE neuropathologic change is present in 20-50% of individuals older than 80 years ¹.

Clinical presentation 

Patients have cognitive impairment, usually an amnestic dementia similar to that of, and often comorbid with, Alzheimer disease. The rate of cognitive decline is usually slower than that in Alzheimer disease¹³.

Pathology 

Etiology 

LATE neuropathological change is characterized by proteinopathy of TDP-43 (transactive response DNA-binding protein 43), which is also implicated in amyotrophic lateral sclerosis and most cases of frontotemporal lobar degeneration ¹. TDP-43 is a multifunctional protein that regulates gene transcription and translation. When the protein is hyperphosphorylated in disease states, TDP-43 mislocalizes to the cytoplasm rather than the nucleus and forms inclusion bodies. Abnormal TDP-43 accumulates in not only neurons but also oligodendrocytes and astrocytes. 

Location 

The medial temporal lobe is predominantly affected. An autopsy staging system is proposed for describing the anatomic distribution of TDP-43 proteinopathy ¹: 

• Stage 1: amygdala only  
• Stage 2: + hippocampus
• Stage 3: + middle frontal gyrus

Other areas specifically affected include the inferior frontal, anterior temporal, and insular cortices.

The affected area isareas are unilateral in up to half of cases¹.

Immunophenotype

Immunohistochemistry using antibodies against phosphorylated TDP-43 demonstrate inclusion bodies in the nucleus and cytoplasm of affected cells ¹.

Radiographic features 

MRI

The typical finding in severe cases is hippocampal sclerosis, seen as atrophy and T2 prolongation in the hippocampus and temporal lobe white matter ^1,6-12.

Differential diagnosis

The diagnosis is established on autopsy. Hippocampal sclerosis can also be seen with hypoxia or with epilepsy, but these can be distinguished clinically.

Hippocampal atrophy and medial temporal lobe hypometabolism is also seen in Alzheimer disease, which LATE can mimic clinically or be comorbid with. However, LATE can be suggested if amyloid and/or tau PET biomarkers are negative ¹. Moreover, the rate of hippocampal atrophy is more rapid in LATE ¹¹.