Limbic-predominant age-related TDP-43 encephalopathy

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

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.

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.

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 disease 13.

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

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

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

The affected areas are unilateral in up to half of cases 1.

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

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.

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.

Neurodegenerative diseases

Neurodegenerative diseases are legion and their classification just as protean. A useful approach is to divide them according to underlying pathological process, although even using this schema, there is much overlap and thus resulting confusion.

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Article information

rID: 70377
Tag: cases
Synonyms or Alternate Spellings:
  • Limbic-predominant age-related TDP-43 encephalopathy-neuropathological changes
  • Cerebral age-related TDP-43 with sclerosis
  • Cerebral age-related TDP-43 with sclerosis (CARTS)
  • Hippocampal sclerosis of aging
  • LATE
  • Hippocampal sclerosis dementia

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