Limbic-predominant age-related TDP-43 encephalopathy
Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a common neurodegenerative disorder of elderly adults (usually >80 years old). It manifests clinically as amnestic dementia and pathologically as TDP-43 proteinopathy in limbic system structures such as the hippocampus.
Limbic-predominant age-related TDP-43 encephalopathy (LATE) is the preferred term (and convenient initialism) according to a 2019 consensus working group report 1. The term encompasses several previously used terms for TDP-43-related cognitive impairment, including hippocampal sclerosis 2 (not to be confused with mesial temporal lobe epilepsy with hippocampal sclerosis), hippocampal sclerosis dementia 3, hippocampal sclerosis of aging 4, and cerebral age-related TDP-43 with sclerosis (CARTS) 5.
While LATE represents the clinical disorder, the term limbic-predominant age-related TDP-43 encephalopathy-neuropathological changes (LATE-NC) refers to the pathologic findings regardless of the clinical manifestations.
The prevalence increases with age, dramatically so after age 80-85 years. Based on population autopsy studies, LATE neuropathologic change is present in 20-50% of individuals older than 80 years 1.
Patients have cognitive impairment, usually an amnestic dementia similar to that of, and often comorbid with, Alzheimer disease. The rate of cognitive decline is usually slower than that in Alzheimer disease 13.
LATE neuropathological change is characterized by proteinopathy of TDP-43 (transactive response DNA-binding protein 43), which is also implicated in amyotrophic lateral sclerosis and most cases of frontotemporal lobar degeneration 1. TDP-43 is a multifunctional protein that regulates gene transcription and translation. When the protein is hyperphosphorylated in disease states, TDP-43 mislocalizes to the cytoplasm rather than the nucleus and forms inclusion bodies. Abnormal TDP-43 accumulates in not only neurons but also oligodendrocytes and astrocytes.
The medial temporal lobe is predominantly affected. An autopsy staging system is proposed for describing the anatomic distribution of TDP-43 proteinopathy 1:
Other areas specifically affected include the inferior frontal, anterior temporal, and insular cortices.
The affected areas are unilateral in up to half of cases 1.
Immunohistochemistry using antibodies against phosphorylated TDP-43 demonstrate inclusion bodies in the nucleus and cytoplasm of affected cells 1.
The typical finding in severe cases is hippocampal sclerosis, seen as atrophy and T2 prolongation in the hippocampus and temporal lobe white matter 1,6-12.
Hippocampal atrophy and medial temporal lobe hypometabolism is also seen in Alzheimer disease, which LATE can mimic clinically or be comorbid with. However, LATE can be suggested if amyloid and/or tau PET biomarkers are negative 1. Moreover, the rate of hippocampal atrophy is more rapid in LATE 11.
- 1. Nelson PT, Dickson DW, Trojanowski JQ, Jack CR, Boyle PA, Arfanakis K, Rademakers R, Alafuzoff I, Attems J, Brayne C, Coyle-Gilchrist ITS, Chui HC, Fardo DW, Flanagan ME, Halliday G, Hokkanen SRK, Hunter S, Jicha GA, Katsumata Y, Kawas CH, Keene CD, Kovacs GG, Kukull WA, Levey AI, Makkinejad N, Montine TJ, Murayama S, Murray ME, Nag S, Rissman RA, Seeley WW, Sperling RA, White Iii CL, Yu L, Schneider JA. Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report. (2019) Brain : a journal of neurology. 142 (6): 1503-1527. doi:10.1093/brain/awz099 - Pubmed
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- 4. Nelson PT, Smith CD, Abner EL, Wilfred BJ, Wang WX, Neltner JH, Baker M, Fardo DW, Kryscio RJ, Scheff SW, Jicha GA, Jellinger KA, Van Eldik LJ, Schmitt FA. Hippocampal sclerosis of aging, a prevalent and high-morbidity brain disease. (2013) Acta neuropathologica. 126 (2): 161-77. doi:10.1007/s00401-013-1154-1 - Pubmed
- 5. Nelson PT, Trojanowski JQ, Abner EL, Al-Janabi OM, Jicha GA, Schmitt FA, Smith CD, Fardo DW, Wang WX, Kryscio RJ, Neltner JH, Kukull WA, Cykowski MD, Van Eldik LJ, Ighodaro ET. "New Old Pathologies": AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS). (2016) Journal of neuropathology and experimental neurology. 75 (6): 482-98. doi:10.1093/jnen/nlw033 - Pubmed
- 6. Dawe RJ, Bennett DA, Schneider JA, Leurgans SE, Kotrotsou A, Boyle PA, Arfanakis K. Ex vivo T2 relaxation: associations with age-related neuropathology and cognition. (2014) Neurobiology of aging. 35 (7): 1549-61. doi:10.1016/j.neurobiolaging.2014.01.144 - Pubmed
- 7. Jagust WJ, Zheng L, Harvey DJ, Mack WJ, Vinters HV, Weiner MW, Ellis WG, Zarow C, Mungas D, Reed BR, Kramer JH, Schuff N, DeCarli C, Chui HC. Neuropathological basis of magnetic resonance images in aging and dementia. (2008) Annals of neurology. 63 (1): 72-80. doi:10.1002/ana.21296 - Pubmed
- 8. Josephs KA, Whitwell JL, Knopman DS, Hu WT, Stroh DA, Baker M, Rademakers R, Boeve BF, Parisi JE, Smith GE, Ivnik RJ, Petersen RC, Jack CR, Dickson DW. Abnormal TDP-43 immunoreactivity in AD modifies clinicopathologic and radiologic phenotype. (2008) Neurology. 70 (19 Pt 2): 1850-7. doi:10.1212/01.wnl.0000304041.09418.b1 - Pubmed
- 9. Zarow C, Wang L, Chui HC, Weiner MW, Csernansky JG. MRI shows more severe hippocampal atrophy and shape deformation in hippocampal sclerosis than in Alzheimer's disease. (2011) International journal of Alzheimer's disease. 2011: 483972. doi:10.4061/2011/483972 - Pubmed
- 10. Dallaire-Théroux C, Callahan BL, Potvin O, Saikali S, Duchesne S. Radiological-Pathological Correlation in Alzheimer's Disease: Systematic Review of Antemortem Magnetic Resonance Imaging Findings. (2017) Journal of Alzheimer's disease : JAD. 57 (2): 575-601. doi:10.3233/JAD-161028 - Pubmed
- 11. Josephs KA, Dickson DW, Tosakulwong N, Weigand SD, Murray ME, Petrucelli L, Liesinger AM, Senjem ML, Spychalla AJ, Knopman DS, Parisi JE, Petersen RC, Jack CR, Whitwell JL. Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer's disease: a longitudinal retrospective study. (2017) The Lancet. Neurology. 16 (11): 917-924. doi:10.1016/S1474-4422(17)30284-3 - Pubmed
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