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Advanced Neurology Limbic-predominant TDP-43 encephalopathy

inclusions (NCIs) and fewer ropy dystrophic neurons in Therefore, concomitant abnormal deposits of TDP-43
the middle frontal gyrus and anterior cingulate cortex. 30 appear to have an active pathological effect.
The simplified and widely utilized staging system for 4.4.1. Coexistence of LATE-NC and AD
LATE-NC comprises three distinct stages: (i) Stage 1: TDP-
43 immunoreactivity for NCIs is confined to the amygdala; The coexistence of LATE-NC and AD is prevalent, with
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(ii) Stage 2: NCIs are present in both the amygdala and up to 54.5% of AD cases meeting LATE-NC criteria.
hippocampus; and (iii) Stage 3: NCIs are additionally It is well known that the coexistence of LATE with AD
detected in the middle frontal gyrus (Figure 1). 8,27,28 leads to worse cognitive performance in logical memory,
However, an extended staging system was proposed, semantic memory, processing speed, and executive
including three substages for stage 1: (i.a) NCIs located function. 8,37,38 Similarly, neuropsychiatric symptoms,
in the amygdala region, absent in the hippocampus; (i.b) including hallucinations and delusional ideation, are more
NCIs found in the hippocampal region, but not in the common when LATE-NC and AD coexist compared to
amygdala; and (i.c.) TDP-43 immunoreactivity observed in either condition in isolation. 39-41 These effects become
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the medial temporal lobe, without NCIs involvement. This more pronounced as LATE-NC progresses. Furthermore,
extended system accounts for TDP-43 deposits outside the if LATE-NC coexists with AD at the same time of symptom
cell body. 21,27 However, the presence of deposits outside the evolution and there is equality in other demographic
cell body without NCIs should still be classified as stage variables, AD tends to be in more severe CERAD and
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1 of LATE-NC. In addition, it should be considered that Braak stages. This suggests that the presence of TDP-43
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it is unlikely for LATE-NC to be the cause of amnestic NCIs lowers the threshold at which senile plaques and
cognitive decline in stage 1. The involvement of the neurofibrillary tangles can cause damage and trigger the
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hippocampus-entorhinal cortex is considered essential to symptomatic onset of AD. In addition, it could be related
justify its contribution to the symptoms. 12 to the resilience and resistance to developing AD when
amyloid and tau hallmarks are already present. Notably,
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4.4. Comorbidities of LATE-NC there is a higher density of TDP-43 immunoreactive
The coexistence of LATE-NC with other proteinopathies NCIs in the CA1 region of the hippocampus compared
commonly associated with neurodegenerative diseases is to other regions and a correlation between the number of
common, such as AD due to amyloid and tau deposits, 13,31 neurofibrillary tangles and TDP-43 immunoreactive NCIs
LBD due to alpha-synuclein deposits, and even with HS, in the medial temporal lobe. 7,8,42
which is not necessarily of neurodegenerative origin. 21,27,32 In 4.4.2. Coexistence of LATE-NC and LBD
cases of copathology with LATE-NC and AD or LATE-NC
and LBD, it has been demonstrated that LATE-NC has The coexistence of LBD and LATE-NC is very common,
a negative effect at both clinical (faster progression of with some studies suggesting that up to 30% of LBD cases
17
cognitive and functional decline) and biological levels exhibit LATE-NC pathology. There is evidence indicating
(greater progression of neurodegeneration, such as that the risk of coexisting with both pathologies may be
17
more severe hippocampal atrophy). 5,29,33 Furthermore, slightly higher in females. The copathology of LBD and
copathology of HS, present in up to 10% of individuals LATE-NC leads to worse cognitive performance (in all
over 80 years old, with LATE-NC is quite common. analyzed domains, but especially in episodic and semantic
This dual pathology seems to worsen amnestic cognitive memory) compared to pure LBD or even LBD associated
performance more than either condition alone. 34,35 with frequent copathology of cerebral vascular disease. 43,44

Figure 1. Limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes staging. Image created using Biorender.com

Volume 3 Issue 2 (2024) 4 doi: 10.36922/an.2603