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Advanced Neurology Limbic-predominant TDP-43 encephalopathy

Furthermore, in cases of LBD and LATE-NC comorbidity, However, it is known that phosphorylated TDP-43 is
higher immunoreactivity of NCIs of TDP-43 is observed exocytosed through vesicles (exosomes), suggesting a
in the CA3 regions of the hippocampus, where deposits prion-like spread of TDP-43, similar to the proposed
of alpha-synuclein are particularly abundant. Moreover, mechanisms of other proteinopathies associated with
the likelihood of progression for both proteinopathies, degenerative cognitive impairment. 49
including progression to the brainstem, is accelerated There is a direct relationship between genetic risk
7,17
in the presence of pathologies. The harmful effect factors, specifically variants of GRN and TMEM106B,
on cognition, behavior, functionality, and biological shared between HS and LATE-NC, and a higher risk of
aspects (on neurodegeneration) worsens when LBD and damage induced by TDP-43 NCIs in CA1 neurons of the
LATE-NC coexist with the definitive anatomopathological hippocampus. Specifically, both GRN and TMEM106B
hallmarks of AD. It has been postulated that the harmful variants lead to a reduction in progranulin levels,
effects of different proteinopathies have a synergistic effect, promoting a proinflammatory response and associating
increasing the risk of developing dementia. 17
greater susceptibility of neurons to oxidative stress.
21
4.4.3. Coexistence of LATE-NC and HS In addition to the proinflammatory effect mediated by
reduced progranulin levels, it has been postulated that NCI
The risk of both HS and LATE-NC increases exponentially deposits have a direct proinflammatory effect by increasing
with age. The likelihood of presenting HS in the context of levels of IL-6, TNF-alpha, and GFAP. 13
LATE-NC increases up to 20% as one progresses through
the anatomopathological stages of LATE-NC, 20,45,46 with a Moreover, it has been suggested that phosphorylated
higher prevalence observed in Stages 2 and 3 compared TDP-43 has a direct impact on the pathophysiology of AD,
to Stage 1. The risk of developing HS in the context influencing both Aβ42 levels (amyloid cascade) and p-tau.
33
of LATE-NC also increases with the presence of other Specifically, in animal models, phosphorylated TDP-43
associated comorbidities, such as AD and, to a lesser may influence the expression and activity of BACE1, with
extent, LBD, argyrophilic grain disease, or even chronic higher levels of phosphorylated TDP-43 associated with
50
traumatic encephalopathy. In turn, the presence of increased levels of soluble Aβ42 oligomers. Furthermore,
12
LATE-NC copathology with HS significantly worsens phosphorylated TDP-43 NCIs, as well as Aβ42 deposition,
performance in both episodic and semantic memory, promote a pro-inflammatory response with a synergistic
affecting individuals with pure LATE-NC and pure HS. effect, demonstrating a greater increase in IL-6 and GFAP.
12
From a pathophysiological standpoint, the coexistence This pro-inflammatory response, in turn, reduces solubility
of LATE-NC, HS, and AD increases the likelihood of and enhances the abnormal aggregation and distribution of
significant astrogliosis in the hippocampus. 45 TDP-43 and Aβ42, closing the loop between TDP-43, the
amyloid cascade, and neuroinflammation. 13,50 However, it
5. Pathophysiology is important to note that the relationship between TDP-43
The abnormal intracytoplasmic aggregates of TDP-43 and the anatomopathological hallmarks of AD goes beyond
have a potential neurotoxic effect, mediated by various the direct association with Aβ42. 38,51 It has been noted that
mechanisms: (i) promoting mitochondrial dysfunction higher levels of TDP-43 promote (i) the instability of tau
(due to modifications of mitochondrial morphology, mRNA and suppression of its physiological expression;
disturbance of oxidative respiratory chain complex I and IV (ii) the aggregation of phosphorylated tau (p-tau); and
37
activity, dissipation of the mitochondrial transmembrane (iii) its spread; and are associated with higher absolute
potential, and reduced mitochondrial ATP synthesis and levels of p-tau, with its corresponding neurotoxic effect
3,13
localization) and reactive oxidative species production, and neuronal death. 13,37 Furthermore, in vitro studies
47
and (ii) exacerbating the proinflammatory response in the suggest that tau oligomers promote the accumulation
38
central nervous system (CNS). If these NCIs affect upper of cytoplasmic phosphorylated TDP-43. In addition,
and lower motor neurons, they can contribute to ALS. On in animal models of DLFT, tau-tubulin kinases (TTBK1
the other hand, if they predominantly affect frontotemporal and TTBK2) that phosphorylate tau in AD can also
regions, they are associated with frontotemporal phosphorylate TDP-43. 37,51
dementia (DLFT), and if they predominantly affect the 6. Clinical phenotype
limbic system, they are associated with LATE, with or
13
without AD co-pathology. While it is believed that The characteristic clinical syndrome of LATE is a
phosphorylated TDP-43 NCIs may also exist in astrocytes, progressive cognitive decline, with predominant and
oligodendrocytes, and microglia, the direct toxic effect initial involvement of episodic memory showing a clear
of this effect has not been conclusively demonstrated. 25,48 temporal gradient (greater impairment of recent memory

Volume 3 Issue 2 (2024) 5 doi: 10.36922/an.2603