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Advanced Neurology Limbic-predominant TDP-43 encephalopathy

ABCC9 (rs1914361 and rs701478), KCNMB2, and and the absence of reliable and accessible biomarkers.
APOE genes were found to be associated with the risk of However, it is essential to consider LATE as a potential
developing LATE-NC. 8,21,22 Some of these genes are related diagnosis in patients with predominantly amnestic MCI,
to HS or AD and exhibit similar associations between white where core AT(N) biomarkers are not consistent with
23
and black Afro-American populations. Among them, the pathophysiological process of AD, especially in older
the one most widely associated with an increased risk of individuals showing cognitive decline that follows a
LATE-NC is TMEM106B, located on chromosome 7p21. slightly slower, more benign clinical course than typically
24
The TMEM106B gene is expressed highest in neurons associated with AD. Despite these challenges, a definitive
and oligodendrocytes, with subcellular localization in late diagnosis of LATE still relies on post-mortem, with
endosome/lysosome areas. 24 findings consistent with LATE-NC.

4. Anatomopathological examination It is now highly recommended to determine TDP-
43 immunoreactivity in the brains of all individuals with
4.1. Transactive response DNA binding protein of a history of cognitive decline, particularly among the
43 kDa (TDP‐43) elderly. This assessment should cover at least three brain
8
LATE neuropathologic changes are a proteinopathy regions: (i) The amygdala and surrounding structures
characterized by abnormal deposition of TDP-43. In at the level of the uncus, including adjacent entorhinal,
1996, TDP-43 was first described as having functions transentorhinal (BA35), anterior temporal (BA36)
related to gene expression regulation. However, it was cortices, and anterior parts of the hippocampus and the
not until 2006 that the connection between TDP-43 subiculum/presubiculum, sub-pial, subependymal regions,
and neurodegenerative diseases was demonstrated. and white matter; (ii) the hippocampus and associated
25
Specifically, the relationship between intranuclear medial temporal cortical structures at the level of the
and cytoplasmic phosphorylated TDP-43 aggregation lateral geniculate nucleus; and (iii) the middle frontal
3,27,28
(both in neurons and glia) was described in relation to gyrus (corresponding to BA46). The antibodies used
amyotrophic lateral sclerosis (ALS) and frontotemporal in the immunoreactivity study for the detection of TDP-
lobar degeneration. LATE is the newest TDP-43-related 43 must be capable of: (i) detecting abnormal cytoplasmic
21
neurodegenerative disease described in 2019. 8,26 aggregates/inclusions of phosphorylated TDP-43 (the
most widely used being pS409/410) and (ii) determining
Encoded by the TARDP gene, TDP-43 is located in the levels of non-phosphorylated intranuclear TDP-43.
27
majority of tissues and cell types. Under physiological Positivity for TDP-43 can be established at the level of
8
conditions, it primarily resides intranuclearly, with only 5 intracytoplasmic inclusions or in cellular components
21
– 10% found in the cytoplasm, present in both neurons outside of neuronal bodies (around corpora amylacea or
and glia, where it regulates RNA processing (binding and aging-related astroglipathy pathology). 27
splicing functions). However, in physiological states, there
is also active transport between the nucleus and cytoplasm. 4.3. Criteria of LATE-NC
In the cytoplasm, TDP-43 is involved in mediating The characteristics of LATE-NC include: (i) massive
mRNA stability, RNA transport, and the formation of neuronal loss and astrogliosis in limbic structures;
ribonucleoprotein complexes within stress granules. 8,13,25 (ii) abnormal deposition of TDP-43, including loss of
However, under pathological conditions, TDP-43 is nuclear immunoreactivity, presence of cytoplasmic
abnormally phosphorylated and ubiquitinated, leading to TDP-43 inclusion bodies, intranuclear deposition of
its misfolding and aberrant aggregation in the cytoplasm. phosphorylated TDP-43, and involvement of neurites,
8
The aberrant cytoplasmic aggregation of TDP-43 is oligodendroglia, and astrocytes; and (iii) HS (severe loss
associated with LATE-NC. It is believed that this abnormal of pyramidal neurons and gliosis in CA1 areas of the
aggregation exerts a neurotoxic effect, promoting both hippocampus and subiculum, disproportionate to the
direct dysfunction of neurons (organelle dysfunction, damage induced by protein deposition) in up to 40% of the
including mitochondrial dysfunction and loss of dendritic cases (frequently asymmetrical). HS, which could be of
3
integrity) as well as indirect dysfunction by activating multifactorial origin (not necessarily neurodegenerative) in
3,13
neuroinflammatory microglia. 25 relation to conditions such as epilepsy or hypoglycemia, is
not a required diagnostic criterion for LATE-NC. In turn,
29
4.2. Recommendations for assessment of possible there are not only topographical but also morphological
LATE-NC
differences that help diagnose LATE-NC vs. DLFT with
The clinical diagnosis of LATE at present is complex greater certainty. In the case of LATE-NC, there is a lower
due to the lack of applicable criteria in clinical practice density of TDP-43 immunoreactive neuritic cytoplasmic

Volume 3 Issue 2 (2024) 3 doi: 10.36922/an.2603