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Advanced Neurology Limbic-predominant TDP-43 encephalopathy

of TDP-43 deposition is essential. Furthermore, the Conflict of interest
requirement for Alzheimer’s pathology confirmation
(biological confirmation) for the administration of anti- The author declares that she has no competing interests.
amyloid therapies will prevent the erroneous administration Author contributions
of such treatments in patients with possible pure LATE.
This is a single-authored article.
At present, there are no modifiers of TDP-43
phosphorylation or other mechanisms involved in the Ethics approval and consent to participate
formation of pathological NCIs in LATE-NC. Similarly,
there are no medications that allow intervention in the Not applicable.
TDP-43 co-pathology associated with AD or LBD, serving Consent for publication
as another potential therapeutic target. It is hypothesized
that reducing TDP-43 NCIs in cases of AD and LATE-NC Not applicable.
copathology could benefit by decreasing abnormal
deposition of both beta-amyloid and phosphorylated tau Availability of data
aggregates, as it has been postulated that there is a synergistic Not applicable.
effect of their propagation and neurotoxicity among all of
them. There is only one study in animal models supporting References
that oral administration of hydroxocobalamin could 1. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer
reduce oxidative stress and mitochondrial dysfunction disease in the United States (2010-2050) estimated using the
resulting from TDP-43 NCIs, although it would not lead 2010 census. Neurology. 2013;80(19):1778-1783.
to a reduction in abnormal aggregates of TDP-43. These
results have not been confirmed in humans to date. 47 doi: 10.1212/WNL.0b013e31828726f5
It is evident that due to the high prevalence of 2. Garre-Olmo J. Epidemiology of Alzheimer’s disease and
copathologies among different proteinopathies other dementias. Rev Neurol. 2018;66(11):377-386.
contributing to cognitive decline, it is essential to modify doi: 10.33588/rn.6611.2017519
58
the approach to identifying new treatments. This involves 3. Nelson PT, Dickson DW, Trojanowski JQ, et al. Limbic-
focusing on multiple therapeutic targets simultaneously, predominant age-related TDP-43 encephalopathy (LATE):
with phosphorylated TDP-43 being a potential target not Consensus working group report. Brain. 2019;142(6):1503-1527.
only for LATE-NC but also for AD and LBD. 48 doi: 10.1093/brain/awz099
9. Conclusion 4. Harrison WT, Lusk JB, Liu B, et al. Limbic-predominant age-
related TDP-43 encephalopathy neuropathological change
At present, LATE is often underdiagnosed due to the lack (LATE-NC) is independently associated with dementia and
of universally applicable diagnostic criteria and reliable strongly associated with arteriolosclerosis in the oldest-old.
biomarkers. It is essential, whenever feasible, to conduct Acta Neuropathol. 2021;142(5):917-919.
a complete etiological diagnosis of amnestic-predominant doi: 10.1007/s00401-021-02360-w
cognitive decline to confirm/dismiss AD through core
AT(N) biomarkers in CSF or PET, especially in the elderly. 5. Butler Pagnotti RM, Pudumjee SB, Cross CL, Miller JB.
The absence of AD biomarkers, along with a typical clinical Cognitive and clinical characteristics of patients with
syndrome and characteristic neuroimaging findings such limbic-predominant age-related TDP-43 encephalopathy.
as disproportionate hippocampal atrophy, should raise Neurology. 2023;100(19):e2027-e2035.
suspicion of possible LATE. This is significant not only doi: 10.1212/WNL.0000000000207159
because potentially modifying treatments for AD are 6. Nelson PT, Brayne C, Flanagan ME, et al. Frequency of
becoming available but also because pure LATE may have LATE neuropathologic change across the spectrum of
a presumably more benign clinical-biological course, Alzheimer’s disease neuropathology: Combined data from
carrying both therapeutic and prognostic implications. 13 community-based or population-based autopsy cohorts.
Acta Neuropathol. 2022;144(1):27-44.
Acknowledgments
doi: 10.1007/s00401-022-02444-1
None.
7. Nichols E, Merrick R, Hay SI, et al. The prevalence,
Funding correlation, and co-occurrence of neuropathology in old
age: Harmonisation of 12 measures across six community-
None. based autopsy studies of dementia. Lancet Healthy Longev.

Volume 3 Issue 2 (2024) 8 doi: 10.36922/an.2603