PREFERENTIAL ANTERIOR INSULA INVOLVEMENT BY TDP-43 PATHOLOGY IN LATE-NC AND ALS: A NEUROPATHOLOGICAL STUDY
Main Article Content
Keywords
Agranular insula, Amygdala, Amyotrophic lateral sclerosis (ALS), lower motor neuron, Anterior insula, Limbic-predominant age-related TDP-43 encephalopathy (LATE), Posterior insula, TAR DNA-binding protein 43 kDa (TDP-43)
Abstract
We investigated whether the anterior insula stands as a primary spot for TDP-43 pathology progression in LATE-NC by taking into account its relation to the amygdala via anatomical position and functional and neural connections. An analysis of phospho-TDP (pTDP) aggregate pathology based on matched anterior and posterior insula tissue from 105 autopsied patients with Alzheimer’s disease, Lewy body disease, hippocampal sclerosis among LATE-NC patients, amyotrophic lateral sclerosis (ALS) and additional conditions took place without considering clinical or neuropathologic information. Among all subjects, pTDP pathology existed in 34.3% of cases and researchers discovered this pathology as cluster formations inside lamina II neurons as well as short neuritic structures inside lamina II and subpial formations resembling amygdala pTDP pathology. Among cases with positive pTDP pathology the protein distribution extended to the anterior insula in 41.7% of cases but was also found in both anterior and posterior insula in 58.3% of cases; anterior insula showed higher pTDP pathology burden in all diagnostic conditions (p < .001). pTDP pathology occurred in 46.7% of ALS cases although protein pathology was generally minimal. The presence of pTDP-43 appeared in 30.4% of LATE-NC patients (mainly stage 2 and 3) when it appeared alongside basal forebrain disease and HS thus suggesting this phase marks the key stage when pathology spreads away from temporal brain regions.
References
2. Josephs KA, Murray ME, Whitwell JL, et al. Staging TDP-43 pathology in Alzheimer’s disease. Acta Neuropathol 2014;127:441–50
3. Josephs KA, Whitwell JL, Weigand SD, et al. TDP-43 is a key player in the clinical features associated with Alzheimer’s disease. Acta Neuropathol 2014;127:811–24
4. Cykowski MD, Powell SZ, Schulz PE, et al. Hippocampal sclerosis in older patients: Practical examples and guidance with a focus on cerebral age-related TDP-43 with sclerosis. Arch Pathol Lab Med 2017;141:1113–26
5. Amador-Ortiz C, Lin WL, Ahmed Z, et al. TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer’s disease. Ann Neurol 2007;61:435–45
6. Nelson PT, Smith CD, Abner EL, et al. Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease. Acta Neuropathol 2013;126:161–77
7. Dickson DW, Davies P, Bevona C, et al. Hippocampal sclerosis: A common pathological feature of dementia in very old (> or = 80 years of age) humans. Acta Neuropathol 1994;88:212–21
8. Cykowski MD, Takei H, Van Eldik LJ, et al. Hippocampal sclerosis but not normal aging or Alzheimer disease is associated with TDP-43 pathology in the basal forebrain of aged persons. J Neuropathol Exp Neurol 2016;75:397–407
9. Nelson PT, Lee EB, Cykowski MD, et al. LATE-NC staging in routine neuropathologic diagnosis: An update. Acta Neuropathol 2023;145:159–73
10. Josephs KA, Murray ME, Whitwell JL, et al. Updated TDP-43 in Alzheimer’s disease staging scheme. Acta Neuropathol 2016;131:571–85
11. Butler Pagnotti RM, Pudumjee SB, Cross CL, et al. Cognitive and clinical characteristics of patients with limbic-predominant age-related TDP-43 encephalopathy. Neurology 2023;100:e2027–35
12. Gauthreaux K, Mock C, Teylan MA, et al. Symptomatic profile and cognitive performance in autopsy-confirmed limbic-predominant age-related TDP-43 encephalopathy with comorbid Alzheimer disease. J Neuropathol Exp Neurol 2022;81:975–87
13. Ringholz GM, Appel SH, Bradshaw M, et al. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 2005;65:586–90
14. Cykowski MD, Arumanayagam AS, Powell SZ, et al. Patterns of amygdala region pathology in LATE-NC: Subtypes that differ with regard to TDP-43 histopathology, genetic risk factors, and comorbid pathologies. Acta Neuropathol 2022;143:531–45
15. Price JL. Comparative aspects of amygdala connectivity. Ann N Y Acad Sci 2003;985:50–8
16. Kurth F, Zilles K, Fox PT, et al. A link between the systems: Functional differentiation and integration within the human insula revealed by meta-analysis. Brain Struct Funct 2010;214:519–34
17. Seeley WW. Anterior insula degeneration in frontotemporal dementia. Brain Struct Funct 2010;214:465–75
18. Mesulam MM, Mufson EJ.. Insula of the old world monkey. I. Architectonics in the insulo-orbito-temporal component of the paralimbic brain. J Comp Neurol 1982;212:1–22
19. Nieuwenhuys R. The insular cortex: A review. Prog Brain Res 2012;195:123–63
20. Hyman BT, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer’s Association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimers Dement 2012;8:1–13
21. Kovacs GG, Ferrer I, Grinberg LT, et al. Aging-related tau astrogliopathy (ARTAG): Harmonized evaluation strategy. Acta Neuropathol 2016;131:87–102
22. Jicha GA, Petersen RC, Knopman DS, et al. Argyrophilic grain disease in demented subjects presenting initially with amnestic mild cognitive impairment. J Neuropathol Exp Neurol 2006;65:602–9
23. Cathcart SJ, Appel SH, Peterson LE, et al. Fast progression in amyotrophic lateral sclerosis is associated with greater TDP-43 burden in spinal cord. J Neuropathol Exp Neurol 2021;80:754–63
24. R: A Language and Environment for Statistical Computing. Vienna: R Foundation for Statistical Computing; 2021
25. Cykowski MD, Powell SZ, Peterson LE, et al. Clinical significance of TDP-43 neuropathology in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 2017;76:402–13
26. Braak H. Architectonics of the Human Telencephalic Cortex. Berlin; NY: Springer-Verlag; 1980
27. Nag S, Yu L, Boyle PA, et al. TDP-43 pathology in anterior temporal pole cortex in aging and Alzheimer’s disease. Acta Neuropathol Commun 2018;6:33. [DOI] [PMC free article] [PubMed] [Google Scholar
28. Crary JF, Trojanowski JQ, Schneider JA, et al. Primary age-related tauopathy (PART): A common pathology associated with human aging. Acta Neuropathol 2014;128:755–66 [DOI]
29. Braak H, Alafuzoff I, Arzberger T, et al. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 2006;112:389–404
30. Salameh JS, Brown RH Jr, Berry JD.. Amyotrophic lateral sclerosis: Review. Semin Neurol 2015;35:469–76
Article Sidebar
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
Dr. Hemalatha Surupanga
Assistant Professor, Department of Pathology, Sri Lakshmi Narayana Institute of Medical Sciences & Hospital, Osudu, Puducherry - 605502