Looking for an early sign of LATE

Limbic predominate age-related TDP-43 encephalopathy or LATE is a recently recognized form of dementia that affects memory, thinking and social skills. It mimics Alzheimer’s disease or AD (and sometimes co-exists with it), but LATE is a different condition, with its own risks and causes.

In a new study, published December 15, 2022 in the journal Alzheimer’s & Dementia, researchers at University of California San Diego School of Medicine, with colleagues elsewhere, provide new insights into the pathology of LATE, which could help lead to development of diagnostics for a disease that is currently poorly understood and very difficult to identify in living patients.

Specifically, the researchers, led by senior study author Robert Rissman, PhD, professor of neurosciences at UC San Diego School of Medicine, reported significantly elevated plasma levels of TDP-43, a DNA-binding protein that has previously been associated with other neurodegenerative diseases, such as frontotemporal lobar degeneration, amyotrophic lateral sclerosis and AD, though the last condition is much more commonly characterized by accumulation of two other proteins: amyloid-beta and tau.

The study analyzed levels of TDP-43 extracted from the exosomes secreted into the blood stream by various cell types, including neurons and glial cells. Exosomes are extracellular vesicles or sacs that transport DNA, RNA and proteins inside the cell until their release. Researchers analyzed the brains of 64 patients post-mortem, 22 with autopsy-confirmed LATE and 42 patients who died without an indication of LATE.

The effect was detected only in astrocyte-derived exosomes, not neuronal or microglial. Astrocytes are a sub-type of glial cell that perform many essential functions in the central nervous system, from regulating blood flow to providing the building blocks of neurotransmitters. They outnumber neurons more than fivefold.

Effective treatment of all neurological diseases depends greatly upon early diagnosis. At the moment, however, LATE can only be diagnosed after death, and it is often confounded by the fact that living patients may have both LATE and AD. The findings that increased plasma concentrations of TDP-43 could be a tell-tale indicator of LATE are encouraging, said Rissman.

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