Medicine:Limbic-predominant age-related TDP-43 encephalopathy

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Short description: (LATE) -- a form of dementia

File:LATE fig.tif LATE is a term that describes a prevalent condition with impaired memory and thinking in advanced age, often culminating in the dementia clinical syndrome.[1] In other words, the symptoms of LATE are similar to those of Alzheimer's disease.  

The acronym LATE stands for Limbic-predominant Age-related TDP-43 Encephalopathy: “limbic” is related to the brain areas first involved, “age-related” and the name “LATE” itself refer to the onset of disease usually in persons aged 80 or older,  “TDP-43” indicates the aberrant mis-folded protein (or proteinopathy) deposits in the brain that characterize LATE, and “encephalopathy” means illness of brain.

At present LATE can only be diagnosed with certainty at autopsy. The terminology used to refer to the brain changes identified in autopsy-confirmed LATE is: LATE neuropathologic change (LATE-NC). The diagnosis of LATE-NC at autopsy requires detection of pathologic TDP-43 protein deposits in the brain, especially in the amygdala and hippocampus.

LATE is a very common condition: autopsy studies around the world indicate that LATE is present in the brains of about one-third of people over 85.[1][2] LATE typically affects persons older than 75 years of age (with some exceptions; please see below) and becomes increasingly prevalent every year in advanced old age.[1] This is in contrast to Alzheimer's disease pathology, which tends to level off and perhaps decrease in prevalence among persons beyond age 85 years.[1] LATE is often comorbid with (i.e., occurs in the same brain as) other pathologic changes that are associated with dementia, such as Alzheimer's disease and cerebrovascular disease(s).[3][4]

LATE has a large impact on public health. Clinical-pathologic correlation studies have established that the presence of LATE-NC is associated with impairments in memory and thinking.[1] In older persons whose brains lack Alzheimer's disease-type amyloid plaques and neurofibrillary tangles, the presence of LATE-NC at autopsy is associated with a relatively slow cognitive decline (in comparison with Alzheimer's disease), mostly affecting the memory domain.[5] However, most people (~75%) beyond age 85 have some Alzheimer's disease-type pathology and in this common scenario the impact of LATE-NC is very important.[6] Approximately one-half of persons with Alzheimer's disease pathology also have LATE-NC.[7][8][9] In these persons, the presence of LATE-NC is associated with a swifter disease course and with more severe clinical (memory and thinking) impairment than when only Alzheimer's disease pathology is present.[10][11][12][5] A common combination of brain pathologies—with Alzheimer's disease pathology, Lewy body pathology, and LATE-NC in the same brain—tends to affect younger individuals (often <75 yrs of age) and, on average, is associated with more aggressive (faster) cognitive deterioration.[4][13][10] With or without co-existing Alzheimer's disease pathology or other brain changes, persons with LATE-NC generally lack the clinical features of frontotemporal dementia (FTD).[14][15]

For reasons that are presently unknown, the disease process of LATE-NC preferentially affects medial temporal lobe structures of the brain, particularly the amygdala and hippocampus.[16] In a significant proportion of persons with LATE-NC, there is atrophy, cell loss and astrogliosis in the hippocampus, diagnosable at autopsy (and somewhat less specifically via MRI during life) as hippocampal sclerosis.[17] Brains with LATE-NC and hippocampal sclerosis are relatively more affected clinically than those with LATE-NC alone.[18] The phenomenon of hippocampal sclerosis-linked dementia, as well as the link to TDP-43, were first described by Dr. Dennis Dickson and colleagues,[19][17] and this clinical-pathologic entity was subsequently confirmed by many others.[20][21][22][23][24] However, brain changes diagnosable as "hippocampal sclerosis" is/are also seen in other diseases (such as epilepsy), and many LATE-NC brains lack full-blown hippocampal sclerosis, so, hippocampal sclerosis is neither a sensitive nor specific feature of LATE-NC.[1]

The major known risk factors for LATE-NC are genetic: variations in the TMEM106B, GRN, APOE, ABCC9, KCNMB2, and WWOX genes have been linked to altered risk for LATE-NC (and/or hippocampal sclerosis dementia).[1][25][26][27][28][29][30][31]

There currently is no known cure or preventative strategy for LATE-NC.

The deleterious impact(s) of TDP-43 proteinopathy may influence the brain via a number of different mechanisms. In normal brains and other tissues, the TDP-43 protein helps to ensure proper functioning of genes in the cell; the misfolded TDP-43 may thus impair normal gene expression regulation (so in LATE-NC, there is a loss-of-normal-function), and, the aberrant TDP-43 protein in LATE-NC may induce toxic gains of function also.[32][33]

TDP-43 proteinopathy (a disease-associated phenomenon discovered by Dr. Manuela Neumann and colleagues at UPENN in the Drs John Trojanowski/Virginia Lee CNDR Lab[34]) is also implicated in frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and other diseases.[35][36][34]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Nelson, Peter T; Dickson, Dennis W; Trojanowski, John T; Boyle, Patricia A; Arfanakis, Konstantinos; Rademakers, Rosa; Alafuzoff, Irina; Attems, Johannes et al. (30 April 2019). "Limbic-predominant age-related TDP-43 encephalopathy (LATE): consensus working group report". Brain Online first (6): 1503–1527. doi:10.1093/brain/awz099. PMID 31039256. 
  2. ↑ Nelson, Peter T.; Brayne, Carol; Flanagan, Margaret E.; Abner, Erin L.; Agrawal, Sonal; Attems, Johannes; Castellani, Rudolph J.; Corrada, Maria M. et al. (July 2022). "Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts". Acta Neuropathologica 144 (1): 27–44. doi:10.1007/s00401-022-02444-1. ISSN 1432-0533. PMID 35697880. 
  3. ↑ Harrison, William T.; Lusk, Jay B.; Liu, Beiyu; Ervin, John F.; Johnson, Kim G.; Green, Cynthia L.; Wang, Shih-Hsiu J. (November 2021). "Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is independently associated with dementia and strongly associated with arteriolosclerosis in the oldest-old". Acta Neuropathologica 142 (5): 917–919. doi:10.1007/s00401-021-02360-w. ISSN 1432-0533. PMID 34415381. 
  4. ↑ 4.0 4.1 Wang, Shih-Hsiu J.; Guo, Yuanyuan; Ervin, John F.; Lusk, Jay B.; Luo, Sheng (2022-05-12). "Neuropathological associations of limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) differ between the oldest-old and younger-old". Acta Neuropathologica 144 (1): 45–57. doi:10.1007/s00401-022-02432-5. ISSN 1432-0533. PMID 35551470. 
  5. ↑ 5.0 5.1 Nag, Sukriti; Yu, Lei; Wilson, Robert S.; Chen, Er-Yun; Bennett, David A.; Schneider, Julie A. (2017-02-14). "TDP-43 pathology and memory impairment in elders without pathologic diagnoses of AD or FTLD". Neurology 88 (7): 653–660. doi:10.1212/WNL.0000000000003610. ISSN 1526-632X. PMID 28087828. 
  6. ↑ Braak, Heiko; Thal, Dietmar R.; Ghebremedhin, Estifanos; Del Tredici, Kelly (November 2011). "Stages of the pathologic process in Alzheimer disease: age categories from 1 to 100 years". Journal of Neuropathology and Experimental Neurology 70 (11): 960–969. doi:10.1097/NEN.0b013e318232a379. ISSN 1554-6578. PMID 22002422. 
  7. ↑ Buciuc, Marina; Wennberg, Alexandra M.; Weigand, Stephen D.; Murray, Melissa E.; Senjem, Matthew L.; Spychalla, Anthony J.; Boeve, Bradley F.; Knopman, David S. et al. (2020). "Effect Modifiers of TDP-43-Associated Hippocampal Atrophy Rates in Patients with Alzheimer's Disease Neuropathological Changes". Journal of Alzheimer's Disease 73 (4): 1511–1523. doi:10.3233/JAD-191040. ISSN 1875-8908. PMID 31929165. 
  8. ↑ Nag, Sukriti; Barnes, Lisa L.; Yu, Lei; Wilson, Robert S.; Bennett, David A.; Schneider, Julie A. (2020-10-13). "Limbic-predominant age-related TDP-43 encephalopathy in Black and White decedents". Neurology 95 (15): e2056–e2064. doi:10.1212/WNL.0000000000010602. ISSN 1526-632X. PMID 32759188. 
  9. ↑ Hunter, Sally; Hokkanen, Suvi R. K.; Keage, Hannah A. D.; Fleming, Jane; Minett, Thais; Polvikoski, Tuomo; Allinson, Kieren; Brayne, Carol et al. (2020). "TDP-43 Related Neuropathologies and Phosphorylation State: Associations with Age and Clinical Dementia in the Cambridge City over-75s Cohort". Journal of Alzheimer's Disease 75 (1): 337–350. doi:10.3233/JAD-191093. ISSN 1875-8908. PMID 32280087. https://pubmed.ncbi.nlm.nih.gov/32280087. 
  10. ↑ 10.0 10.1 Karanth, Shama; Nelson, Peter T.; Katsumata, Yuriko; Kryscio, Richard J.; Schmitt, Frederick A.; Fardo, David W.; Cykowski, Matthew D.; Jicha, Gregory A. et al. (2020-10-01). "Prevalence and Clinical Phenotype of Quadruple Misfolded Proteins in Older Adults". JAMA Neurology 77 (10): 1299–1307. doi:10.1001/jamaneurol.2020.1741. ISSN 2168-6157. PMID 32568358. 
  11. ↑ Josephs, Keith A.; Whitwell, Jennifer L.; Tosakulwong, Nirubol; Weigand, Stephen D.; Murray, Melissa E.; Liesinger, Amanda M.; Petrucelli, Leonard; Senjem, Matthew L. et al. (November 2015). "TAR DNA-binding protein 43 and pathological subtype of Alzheimer's disease impact clinical features". Annals of Neurology 78 (5): 697–709. doi:10.1002/ana.24493. ISSN 1531-8249. PMID 26224156. 
  12. ↑ Josephs, Keith A.; Dickson, Dennis W.; Tosakulwong, Nirubol; Weigand, Stephen D.; Murray, Melissa E.; Petrucelli, Leonard; Liesinger, Amanda M.; Senjem, Matthew L. et al. (November 2017). "Rates of hippocampal atrophy and presence of post-mortem TDP-43 in patients with Alzheimer's disease: a longitudinal retrospective study". The Lancet. Neurology 16 (11): 917–924. doi:10.1016/S1474-4422(17)30284-3. ISSN 1474-4465. PMID 28919059. 
  13. ↑ Katsumata, Yuriko; Abner, Erin L.; Karanth, Shama; Teylan, Merilee A.; Mock, Charles N.; Cykowski, Matthew D.; Lee, Edward B.; Boehme, Kevin L. et al. (November 2020). "Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy". Acta Neuropathologica 140 (5): 659–674. doi:10.1007/s00401-020-02211-0. ISSN 1432-0533. PMID 32797255. 
  14. ↑ Nelson, Peter T. (2021-08-11). "LATE Neuropathologic Changes with Little or No Alzheimer Disease is Common and is Associated with Cognitive Impairment but Not Frontotemporal Dementia". Journal of Neuropathology and Experimental Neurology 80 (7): 649–651. doi:10.1093/jnen/nlab050. ISSN 1554-6578. PMID 34270750. 
  15. ↑ Amador-Ortiz, Catalina; Ahmed, Zeshan; Zehr, Cynthia; Dickson, Dennis W. (March 2007). "Hippocampal sclerosis dementia differs from hippocampal sclerosis in frontal lobe degeneration". Acta Neuropathologica 113 (3): 245–252. doi:10.1007/s00401-006-0183-4. ISSN 0001-6322. PMID 17195931. 
  16. ↑ Josephs, Keith A.; Murray, Melissa E.; Whitwell, Jennifer L.; Tosakulwong, Nirubol; Weigand, Stephen D.; Petrucelli, Leonard; Liesinger, Amanda M.; Petersen, Ronald C. et al. (April 2016). "Updated TDP-43 in Alzheimer's disease staging scheme". Acta Neuropathologica 131 (4): 571–585. doi:10.1007/s00401-016-1537-1. ISSN 1432-0533. PMID 26810071. 
  17. ↑ 17.0 17.1 Amador-Ortiz, Catalina; Lin, Wen-Lang; Ahmed, Zeshan; Personett, David; Davies, Peter; Duara, Ranjan; Graff-Radford, Neill R.; Hutton, Michael L. et al. (May 2007). "TDP-43 immunoreactivity in hippocampal sclerosis and Alzheimer's disease". Annals of Neurology 61 (5): 435–445. doi:10.1002/ana.21154. ISSN 0364-5134. PMID 17469117. 
  18. ↑ Nelson, Peter T.; Abner, Erin L.; Schmitt, Frederick A.; Kryscio, Richard J.; Jicha, Gregory A.; Smith, Charles D.; Davis, Daron G.; Poduska, John W. et al. (January 2010). "Modeling the association between 43 different clinical and pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons". Brain Pathology (Zurich, Switzerland) 20 (1): 66–79. doi:10.1111/j.1750-3639.2008.00244.x. ISSN 1750-3639. PMID 19021630. 
  19. ↑ Dickson, D. W.; Davies, P.; Bevona, C.; Van Hoeven, K. H.; Factor, S. M.; Grober, E.; Aronson, M. K.; Crystal, H. A. (1994). "Hippocampal sclerosis: a common pathological feature of dementia in very old (> or = 80 years of age) humans". Acta Neuropathologica 88 (3): 212–221. doi:10.1007/BF00293396. ISSN 0001-6322. PMID 7810292. https://pubmed.ncbi.nlm.nih.gov/7810292. 
  20. ↑ Hokkanen, Suvi R. K.; Hunter, Sally; Polvikoski, Tuomo M.; Keage, Hannah A. D.; Minett, Thais; Matthews, Fiona E.; Brayne, Carol; MRC CFAS and CC75C Study Group (July 2018). "Hippocampal sclerosis, hippocampal neuron loss patterns and TDP-43 in the aged population". Brain Pathology (Zurich, Switzerland) 28 (4): 548–559. doi:10.1111/bpa.12556. ISSN 1750-3639. PMID 28833898. 
  21. ↑ Spina, Salvatore; La Joie, Renaud; Petersen, Cathrine; Nolan, Amber L.; Cuevas, Deion; Cosme, Celica; Hepker, Mackenzie; Hwang, Ji-Hye et al. (2021-08-17). "Comorbid neuropathological diagnoses in early versus late-onset Alzheimer's disease". Brain: A Journal of Neurology 144 (7): 2186–2198. doi:10.1093/brain/awab099. ISSN 1460-2156. PMID 33693619. 
  22. ↑ Zarow, Chris; Weiner, Michael W.; Ellis, William G.; Chui, Helena Chang (July 2012). "Prevalence, laterality, and comorbidity of hippocampal sclerosis in an autopsy sample". Brain and Behavior 2 (4): 435–442. doi:10.1002/brb3.66. ISSN 2162-3279. PMID 22950047. 
  23. ↑ Makkinejad, Nazanin; Schneider, Julie A.; Yu, Junxiao; Leurgans, Sue E.; Kotrotsou, Aikaterini; Evia, Arnold M.; Bennett, David A.; Arfanakis, Konstantinos (May 2019). "Associations of amygdala volume and shape with transactive response DNA-binding protein 43 (TDP-43) pathology in a community cohort of older adults". Neurobiology of Aging 77: 104–111. doi:10.1016/j.neurobiolaging.2019.01.022. ISSN 1558-1497. PMID 30784812. 
  24. ↑ Nelson, Peter T.; Schmitt, Frederick A.; Lin, Yushun; Abner, Erin L.; Jicha, Gregory A.; Patel, Ela; Thomason, Paula C.; Neltner, Janna H. et al. (May 2011). "Hippocampal sclerosis in advanced age: clinical and pathological features". Brain: A Journal of Neurology 134 (Pt 5): 1506–1518. doi:10.1093/brain/awr053. ISSN 1460-2156. PMID 21596774. 
  25. ↑ Dickson, Dennis W.; Baker, Matthew; Rademakers, Rosa (2010). "Common variant in GRN is a genetic risk factor for hippocampal sclerosis in the elderly". Neuro-Degenerative Diseases 7 (1–3): 170–174. doi:10.1159/000289231. ISSN 1660-2862. PMID 20197700. 
  26. ↑ Murray, Melissa E.; Cannon, Ashley; Graff-Radford, Neill R.; Liesinger, Amanda M.; Rutherford, Nicola J.; Ross, Owen A.; Duara, Ranjan; Carrasquillo, Minerva M. et al. (September 2014). "Differential clinicopathologic and genetic features of late-onset amnestic dementias". Acta Neuropathologica 128 (3): 411–421. doi:10.1007/s00401-014-1302-2. ISSN 1432-0533. PMID 24899141. 
  27. ↑ Nelson, Peter T.; Estus, Steven; Abner, Erin L.; Parikh, Ishita; Malik, Manasi; Neltner, Janna H.; Ighodaro, Eseosa; Wang, Wang-Xia et al. (2014). "ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology". Acta Neuropathologica 127 (6): 825–843. doi:10.1007/s00401-014-1282-2. ISSN 1432-0533. PMID 24770881. 
  28. ↑ Dugan, Adam J.; Nelson, Peter T.; Katsumata, Yuriko; Shade, Lincoln M. P.; Boehme, Kevin L.; Teylan, Merilee A.; Cykowski, Matthew D.; Mukherjee, Shubhabrata et al. (2021-09-15). "Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study". Acta Neuropathologica Communications 9 (1): 152. doi:10.1186/s40478-021-01250-2. ISSN 2051-5960. PMID 34526147. 
  29. ↑ Yang, Hyun-Sik; Yu, Lei; White, Charles C.; Chibnik, Lori B.; Chhatwal, Jasmeer P.; Sperling, Reisa A.; Bennett, David A.; Schneider, Julie A. et al. (September 2018). "Evaluation of TDP-43 proteinopathy and hippocampal sclerosis in relation to APOE ε4 haplotype status: a community-based cohort study". The Lancet. Neurology 17 (9): 773–781. doi:10.1016/S1474-4422(18)30251-5. ISSN 1474-4465. PMID 30093249. 
  30. ↑ Beecham, Gary W.; Hamilton, Kara; Naj, Adam C.; Martin, Eden R.; Huentelman, Matt; Myers, Amanda J.; Corneveaux, Jason J.; Hardy, John et al. (September 2014). "Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias". PLOS Genetics 10 (9): e1004606. doi:10.1371/journal.pgen.1004606. ISSN 1553-7404. PMID 25188341. 
  31. ↑ Dugan, Adam J.; Nelson, Peter T.; Katsumata, Yuriko; Shade, Lincoln M. P.; Teylan, Merilee A.; Boehme, Kevin L.; Mukherjee, Shubhabrata; Kauwe, John S. K. et al. (2021-10-29). "Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes" (in en). Neurobiology of Aging 111: 95–106. doi:10.1016/j.neurobiolaging.2021.10.011. ISSN 0197-4580. PMID 34852950. 
  32. ↑ Chen, Han-Jou; Mitchell, Jacqueline C. (2021-06-02). "Mechanisms of TDP-43 Proteinopathy Onset and Propagation". International Journal of Molecular Sciences 22 (11): 6004. doi:10.3390/ijms22116004. ISSN 1422-0067. PMID 34199367. 
  33. ↑ Gendron, Tania F.; Rademakers, Rosa; Petrucelli, Leonard (2013). "TARDBP mutation analysis in TDP-43 proteinopathies and deciphering the toxicity of mutant TDP-43". Journal of Alzheimer's Disease 33 (Suppl 1): S35–45. doi:10.3233/JAD-2012-129036. ISSN 1875-8908. PMID 22751173. 
  34. ↑ 34.0 34.1 Neumann, Manuela; Sampathu, Deepak M.; Kwong, Linda K.; Truax, Adam C.; Micsenyi, Matthew C.; Chou, Thomas T.; Bruce, Jennifer; Schuck, Theresa et al. (2006-10-06). "Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis". Science 314 (5796): 130–133. doi:10.1126/science.1134108. ISSN 1095-9203. PMID 17023659. Bibcode: 2006Sci...314..130N. https://pubmed.ncbi.nlm.nih.gov/17023659. 
  35. ↑ "Newly recognized form of dementia could now be easier to diagnose". New Scientist. 30 April 2019. https://www.newscientist.com/article/2201236-newly-recognised-form-of-dementia-could-now-be-easier-to-diagnose. 
  36. ↑ Chornenkyy, Yevgen; Fardo, David W.; Nelson, Peter T. (July 2019). "Tau and TDP-43 proteinopathies: kindred pathologic cascades and genetic pleiotropy". Laboratory Investigation 99 (7): 993–1007. doi:10.1038/s41374-019-0196-y. ISSN 1530-0307. PMID 30742063. 

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