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Nelson, P. T. et al. Reply: LATE to the PART-y. Brain 142, e48 \(2019\).\r:9\ 5)/F 4/H/N/Rect[347.977 646.52 350.585 636.34]/Subtype/Link/Type/Annot>> endobj 4 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:6. Nelson, P. T. et al. Limbic-predominant age-related TDP-43 encephalopathy \(LA\ TE\): consensus working group report. Brain 142, 1503 1527 \(2019\).\r:96)/F 4/H/N/Rect[421.032 614.27 423.946 604.09]/Subtype/Link/Type/Annot>> endobj 5 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:Box 1\rTDP43 localization in neurodegenerative diseases\rDiseases with primary TDP4\ 3 pathological change\rALS2,3,62\rGuam ALS208\rFTLD-TDP, types A E105,205,206\rLATE6\r\ Perry syndrome209,210\rDisease:97)/F 4/H/N/Rect[491.771 592.77 495.254 582.59]/Subtype/Link/Type/Annot>> endobj 6 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:10. Montine, T. J. et al. National Institute on Aging-Alzheimer s Association guid\ elines for the neuropathologic assessment of Alzheimer s disease: a practical approach. Acta Neuropathol. 123, 1 11 \(2012\).\ \r:98)/F 4/H/N/Rect[335.247 549.77 340.46 539.59]/Subtype/Link/Type/Annot>> endobj 7 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:11. McKee, A. C. et al. TDP-43 proteinopathy and motor neuron disease in chronic t\ raumatic encephalopathy. J. Neuropathol. Exp. Neurol. 69, 918 929 \(2010\).\r:99)/F 4/H/N/Rect[387.534 517.52 391.547 507.34]/Subtype/Link/Type/Annot>> endobj 8 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:12. Schwab, C., Arai, T., Hasegawa, M., Yu, S. & McGeer, P. L. Colocalization of t\ ransactivation-responsive DNA-binding protein 43 and huntingtin in inclusions of Huntington disease. J. Neuropathol. Exp. Neuro\ l. 67, 1159 1165 \(2008\).\r:100)/F 4/H/N/Rect[478.517 517.52 483.131 507.34]/Subtype/Link/Type/Annot>> endobj 9 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:Box 1\rTDP43 localization in neurodegenerative diseases\rDiseases with primary TDP\ 43 pathological change\rALS2,3,62\rGuam ALS208\rFTLD-TDP, types A E105,205,206\rLATE6\r\ Perry syndrome209,210\rDiseas:101)/F 4/H/N/Rect[373.855 485.27 377.23 475.09]/Subtype/Link/Type/Annot>> endobj 10 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:13. Sephton, C. F. et al. TDP-43 is a developmentally regulated protein essential \ for early embryonic development. J. Biol. Chem. 285, 6826 6834 \(2010\).\r:142)/F 4/H/N/Rect[460.658 259.52 465.361 249.34]/Subtype/Link/Type/Annot>> endobj 11 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:14. Buratti, E. & Baralle, F. E. Characterization and functional implications of t\ he RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9. J. Biol. Chem. 276, 36337 363\ 43 \(2001\).\r:143)/F 4/H/N/Rect[485.264 195.02 490.217 184.84]/Subtype/Link/Type/Annot>> endobj 12 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:15. Li, Y. R., King, O. D., Shorter, J. & Gitler, A. D. Stress granules as crucibl\ es of ALS pathogenesis. J. Cell Biol. 201, 361 372 \(2013\).\r:144)/F 4/H/N/Rect[429.425 173.52 433.906 163.34]/Subtype/Link/Type/Annot>> endobj 13 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:16. Mompean, M. et al. The TDP-43 N-terminal domain structure at high resolution. \ FEBS J. 283, 1242 1260 \(2016\).\r:145)/F 4/H/N/Rect[435.279 173.52 440.29 163.34]/Subtype/Link/Type/Annot>> endobj 14 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:Fig. 1 | TDP43 structure. a, Domain architecture of TAR DNA-binding protei\ n 43 \n\(TDP43\). Domain boundaries are numbered according to the full-length protein sequence19. b, Ribbon representation \ of the structure of the TDP43 RNA-recog:146)/F 4/H/N/Rect[460.29 173.52 463.682 163.34]/Subtype/Link/Type/Annot>> endobj 15 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:17. Harrison, A. F. & Shorter, J. RNA-binding proteins with prion-like domains in \ health and disease. Biochem. J. 474, 1417 1438 \(2017\).\r:147)/F 4/H/N/Rect[464.7 152.02 468.971 141.84]/Subtype/Link/Type/Annot>> endobj 16 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:18. de Boer, E. M. J. et al. TDP-43 proteinopathies: a new wave of neurodegenerati\ ve diseases. J. Neurol. Neurosurg. Psychiatry 92, 86 95 \(2020\).\r:148)/F 4/H/N/Rect[524.146 130.52 529.081 120.34]/Subtype/Link/Type/Annot>> endobj 17 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:18. de Boer, E. M. J. et al. TDP-43 proteinopathies: a new wave of neurodegenerat\ ive diseases. J. Neurol. Neurosurg. Psychiatry 92, 86 95 \(2020\).\r:152)/F 4/H/N/Rect[504.779 109.02 513.46 98.8399]/Subtype/Link/Type/Annot>> endobj 18 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:21. Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A. & Patel, B. K. Molecular\ mechanisms of TDP-43 misfolding and pathology in amyotrophic lateral sclerosis. Front. Mol. Neurosci. 12, 25 \(2019\).\r:15\ 3)/F 4/H/N/Rect[517.982 109.02 526.267 98.8399]/Subtype/Link/Type/Annot>> endobj 19 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:22. Lalmansingh, A. S., Urekar, C. J. & Reddi, P. P. TDP-43 is a transcriptional r\ epressor: the testis-specific mouse acrv1 gene is a TDP-43 target in vivo. J. Biol. Chem. 286, 10970 10982 \(2011\).\r:154)/F 4/H/N/Rect[553.374 87.5204 558.946 77.3399]/Subtype/Link/Type/Annot>> endobj 20 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:23. Freibaum, B. D., Chitta, R. K., High, A. A. & Taylor, J. P. Global analysis of\ TDP-43 interacting proteins reveals strong association with RNA splicing and translation machinery. J. Proteome Res. 9, 110\ 4 1120 \(2010\).\r:155)/F 4/H/N/Rect[348.028 66.0204 353.44 55.8399]/Subtype/Link/Type/Annot>> endobj 21 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:1. Ou, S. H., Wu, F., Harrich, D., Garcia-Martinez, L. F. & Gaynor, R. B. Cloning \ and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence mot\ ifs. J. 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Limbic-predominant age-related TDP-43 encephalopathy \(LATE\ \): consensus working group report. Brain 142, 1503 1527 \(2019\).\r:91)/F 4/H/N/Rect[77.8662 205.77 80.8255 195.59]/Subtype/Link/Type/Annot>> endobj 28 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:6. Nelson, P. T. et al. Limbic-predominant age-related TDP-43 encephalopathy \(LAT\ E\): consensus working group report. Brain 142, 1503 1527 \(2019\).\r:92)/F 4/H/N/Rect[194.784 141.27 197.592 131.09]/Subtype/Link/Type/Annot>> endobj 29 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:7. Josephs, K. A. et al. LATE to the PART-y. Brain 142, e47 \(2019\).\r:93)/F 4/H/N/Rect[202.496 66.0204 204.862 55.8399]/Subtype/Link/Type/Annot>> endobj 30 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:8. Abbasi, J. Debate sparks over LATE, a recently recognized dementia. J. Am. Med\ . 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Astrocytic TDP-43 pathology in Alexander disease. J. 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Commun. 6, 28 \(20\ 18\).\r:230)/F 4/H/N/Rect[281.991 603.52 287.755 593.34]/Subtype/Link/Type/Annot>> endobj 169 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:69. Mori, F. et al. Phosphorylated TDP-43 aggregates in skeletal and cardiac muscl\ e are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions. Acta Neuropathol. Commun. 7\ , 165 \(2019\).\r:231)/F 4/H/N/Rect[289.042 603.52 294.803 593.34]/Subtype/Link/Type/Annot>> endobj 170 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:69. Mori, F. et al. Phosphorylated TDP-43 aggregates in skeletal and cardiac musc\ le are a marker of myogenic degeneration in amyotrophic lateral sclerosis and various conditions. Acta Neuropathol. Commun. 7\ , 165 \(2019\).\r:232)/F 4/H/N/Rect[117.137 592.77 122.552 582.59]/Subtype/Link/Type/Annot>> endobj 171 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:70. Gasset-Rosa, F. et al. 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NVD%iq$,I^pDHݵ OOS9T M믩?>7qY*\s4# 4Fֹ(U7Y,bPŬ?RuOi]lZ|@ϱ2ak$vo%7[wi?Igꂱ{cw[O2%vW ?{Ũ+cʗ*1²,-wpZf MGxrWR(ÖPwKf];MBኋ$*_;ր $,͍eDxXo=W83E˿Hoeщ%5K p>Qo&$=-ݤIv &l./N~>r->7H'JUxf|dK@ Z;JY?ȥ#^aB @4l(#lW֓+"'w%m& ru^[pZpum9gX~`\ıžF2NObMw08L,?h&p|6k e=ѳQjrXPȱotZ"Q?qnI :@Cֶ.a:OIsa>$=5!tXh痐nw&)ۺ,)It7Џl @@T endstream endobj 228 0 obj <> endobj 229 0 obj [230 0 R 231 0 R 232 0 R 233 0 R 234 0 R 235 0 R 236 0 R 237 0 R 238 0 R 239 0 R 240 0 R 241 0 R 242 0 R 243 0 R 244 0 R 245 0 R 246 0 R 247 0 R 248 0 R 249 0 R 250 0 R 251 0 R 252 0 R 253 0 R 254 0 R 255 0 R 256 0 R 257 0 R 258 0 R 259 0 R 260 0 R 261 0 R 262 0 R 263 0 R 264 0 R 265 0 R 266 0 R 267 0 R 268 0 R 269 0 R 270 0 R 271 0 R 272 0 R 273 0 R 274 0 R] endobj 230 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:107. Neumann, M., Lee, E. B. & Mackenzie, I. R. Frontotemporal lobar degeneration \ TDP-43-immunoreactive pathological subtypes: clinical and mechanistic significance. Adv. Exp. Med. 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Commun. 6, 33 \(2018\).\r:198)/F 4/H/N/Rect[161.87 249.754 167.465 238.834]/Subtype/Link/Type/Annot>> endobj 272 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:149. Dawe, R. J., Bennett, D. A., Schneider, J. A. & Arfanakis, K. Neuropathologic\ correlates of hippocampal atrophy in the elderly: a clinical, pathologic, postmortem MRI study. PLoS One 6, e26286 \(2011\).\ \r:199)/F 4/H/N/Rect[127.735 185.254 134.798 174.334]/Subtype/Link/Type/Annot>> endobj 273 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:221. Fleischman, D. A. et al. Regional brain cortical thinning and systemic inflam\ mation in older persons without dementia. J. Am. Geriatr. Soc. 58, 1823 1825 \(2010\).\r:200)/F 4/H/N/Rect[136.067 185.254 142.886 174.334]/Subtype/Link/Type/Annot>> endobj 274 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:222. Nag, S. et al. Ex vivo MRI facilitates localization of cerebral microbleeds o\ f different \nages during neuropathology assessment. Free Neuropathol. 2, 2 35 \(2021\).\r:201)/F 4/H/N/Rect[144.155 185.254 151.83 174.334]/Subtype/Link/Type/Annot>> endobj 275 0 obj <>/ExtGState<>/Font<>/ProcSet[/PDF/Text]/XObject<>>> endobj 276 0 obj <>stream x]mqV0ءwG0wN']pg8;qѐs$UBV7=6sC/UOt-߿]w7l/ºս7_]Mw0nc\>;.~",ܰ82,7We/<:Y6^jj_7#$r/3C#ͅ"H=CxQ<"$H< 25 E Rݝ;{X)#?E'q<3Unrsα `y[8OGVmFZ.T8GD\+'xaLW;o|yWUeo_ \TEo݂Vfdl)_Y/ϲ|4[۪c}q4(:tؚa ݼJn[ ebUV !s~z}r k߯>jw_rEgb㭣İիfH=9߽AH&$?p{"Ō/O \E{l i%\~LxXypA*AwxT^D.dx_e B|.Q+K0yєZ>{q$%R)YYQw--Kԗ"+ ŽTxYdS/"[1tb8_ЁȌp\':n]լ0Ǘ3#'lhӨ {{/N3-+]m sKcZS =0lCߔS/~!ݫ9':aڲ' u'K 7_^~*H!;~Bn) `TñdWF(@}Yڢ=y!aKIAXphJb.p^M0:Au :Y{9z'DSJ \y)+o/@>p;. [gwj~[#՜W?J? ;Hm^f[)8[Fzs֘v[V}oQlƃD#,;<::ִλF rSW>?_C3_֟ty ugY*Ψ;yIW gIOiX gtJk#zn_+x1~D *"K^,18m @-͖IoqA( P:0Ih[!5C G6}P Y(j) kc:(h$)HO. 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Nag, S. et al. TDP-43 pathology and memory impairment in elders without p\ athologic diagnoses of AD or FTLD. Neurology 88, 653 660 \(2017\).\r:324)/F 4/H/N/Rect[277.002 678.77 282.241 668.59]/Subtype/Link/Type/Annot>> endobj 280 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:98. Rascovsky, K. et al. Sensitivity of revised diagnostic criteria for the behav\ ioural variant of frontotemporal dementia. Brain 134, 2456 2477 \(2011\).\r:325)/F 4/H/N/Rect[129.25 657.27 135.065 647.09]/Subtype/Link/Type/Annot>> endobj 281 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:99. Gorno-Tempini, M. L. et al. Classification of primary progressive aphasia and\ its variants. Neurology 76, 1006 1014 \(2011\).\r:326)/F 4/H/N/Rect[136.254 657.27 141.891 647.09]/Subtype/Link/Type/Annot>> endobj 282 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:101. Brettschneider, J. et al. Sequential distribution of pTDP-43 pathology in be\ havioral variant frontotemporal dementia \(bvFTD\). Acta Neuropathol. 127, 423 439 \(2014\).\r:327)/F 4/H/N/Rect[202.956 635.77 210.313 625.59]/Subtype/Link/Type/Annot>> endobj 283 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:34. Nag, S. et al. TDP-43 pathology in anterior temporal pole cortex in ag\ ing and Alzheimer s disease. Acta Neuropathol. Commun. 6, 33 \(2018\).\r:328)/F 4/H/N/Rect[161.091 625.02 166.631 614.84]/Subtype/Link/Type/Annot>> endobj 284 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:111. Robinson, J. L. et al. Limbic-predominant age-related TDP-43 encephalopathy \ differs from frontotemporal lobar degeneration. Brain 143, 2844 2857 \(2020\).\r:329)/F 4/H/N/Rect[286.206 592.77 292.54 582.59]/Subtype/Link/Type/Annot>> endobj 285 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:6. Nelson, P. T. et al. Limbic-predominant age-related TDP-43 encephalopath\ y \(LATE\): consensus working group report. Brain 142, 1503 1527 \(2019\).\r:330)/F 4/H/N/Rect[281 463.77 283.798 453.59]/Subtype/Link/Type/Annot>> endobj 286 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:124. Power, M. C. et al. Combined neuropathological pathways account for age-relat\ ed risk of dementia. Ann. Neurol. 84, 10 22 \(2018\).\r:331)/F 4/H/N/Rect[285.14 463.77 292.598 453.59]/Subtype/Link/Type/Annot>> endobj 287 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:6. Nelson, P. T. et al. Limbic-predominant age-related TDP-43 encephalopat\ hy \(LATE\): consensus working group report. Brain 142, 1503 1527 \(2019\).\r:332)/F 4/H/N/Rect[77.4369 442.303 80.2924 432.09]/Subtype/Link/Type/Annot>> endobj 288 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:6. Nelson, P. T. et al. 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Modeling the association between 43 different clinical a\ nd pathological variables and the severity of cognitive impairment in a large autopsy cohort of elderly persons. Brain Pathol.\ 20, 66 79 \(2010\).\r:336)/F 4/H/N/Rect[444.615 571.27 451.645 561.09]/Subtype/Link/Type/Annot>> endobj 292 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:47. Nag, S. et al. TDP-43 pathology and memory impairment in elders without\ pathologic diagnoses of AD or FTLD. Neurology 88, 653 660 \(2017\).\r:337)/F 4/H/N/Rect[535.738 571.27 540.626 561.09]/Subtype/Link/Type/Annot>> endobj 293 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:34. Nag, S. et al. TDP-43 pathology in anterior temporal pole cortex in a\ ging and Alzheimer s disease. Acta Neuropathol. Commun. 6, 33 \(2018\).\r:338)/F 4/H/N/Rect[323.482 496.02 332.947 485.84]/Subtype/Link/Type/Annot>> endobj 294 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:35. Wilson, R. S. et al. TDP-43 pathology, cognitive decline, and dementia in ol\ d age. JAMA Neurol. 70, 1418 1424 \(2013\).\r:339)/F 4/H/N/Rect[487.914 442.27 492.901 432.09]/Subtype/Link/Type/Annot>> endobj 295 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:49. Nag, S. et al. Hippocampal sclerosis and TDP-43 pathology in aging and Alzhe\ imer disease. Ann. Neurol. 77, 942 952 \(2015\).\r:340)/F 4/H/N/Rect[494.188 442.27 499.494 432.09]/Subtype/Link/Type/Annot>> endobj 296 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:Fig. 4 | The ROSMAP five-stage LATE-NC scheme. Coronal brain sections showin\ g the regional distribution of phosphorylated TAR DNA-binding \nprotein 43 \(TDP43\) cytoplasmic inclusions and the percentage of\ cases \nshowing inclusions at stages 1 :187)/F 4/H/N/Rect[191.112 94.1129 195.16 85.4748]/Subtype/Link/Type/Annot>> endobj 297 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:34. Nag, S. et al. TDP-43 pathology in anterior temporal pole cortex in aging a\ nd Alzheimer s disease. Acta Neuropathol. 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Diab\ etes and function in different cognitive systems in older individuals without dementia. Diabetes Care 29, 560 565 \(2006\).\r\ :362)/F 4/H/N/Rect[519.905 625.02 527.166 614.84]/Subtype/Link/Type/Annot>> endobj 355 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:138. Besser, L. M., Teylan, M. A. & Nelson, P. T. Limbic predominant age-related\ TDP-43 encephalopathy \(LATE\): clinical and neuropathological associations. J. Neuropathol. Exp. Neurol. 79, 305 313 \(2020\ \).\r:363)/F 4/H/N/Rect[491.728 603.52 499.12 593.34]/Subtype/Link/Type/Annot>> endobj 356 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:140. Kioumourtzoglou, M. A. et al. Diabetes mellitus, obesity, and diagnosis of am\ yotrophic lateral sclerosis: a population-based study. JAMA Neurol. 72, 905 911 \(2015\).\r:364)/F 4/H/N/Rect[536.736 571.27 544.927 561.09]/Subtype/Link/Type/Annot>> endobj 357 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:141. Mariosa, D., Kamel, F., Bellocco, R., Ye, W. & Fang, F. Association between d\ iabetes and amyotrophic lateral sclerosis in Sweden. Eur. J. Neurol. 22, 1436 1442 \(2015\).\r:365)/F 4/H/N/Rect[546.332 571.27 553.462 561.09]/Subtype/Link/Type/Annot>> endobj 358 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:142. Oveisgharan, S. et al. Association of hemoglobin A1C with TDP-43 pathology in\ community-based elders. Neurology 96, e2694 e2703 \(2021\).\r:366)/F 4/H/N/Rect[371.426 496.02 378.932 485.84]/Subtype/Link/Type/Annot>> endobj 359 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:39. Amador-Ortiz, C. et al. TDP-43 immunoreactivity in hippocampal sclerosis and\ Alzheimer s disease. Ann. Neurol. 61, 435 445 \(2007\).\r:367)/F 4/H/N/Rect[431.959 346.906 436.921 335.34]/Subtype/Link/Type/Annot>> endobj 360 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:116. Katsumata, Y., Fardo, D. W., Kukull, W. A. & Nelson, P. T. Dichotomous scori\ ng of TDP-43 proteinopathy from specific brain regions in 27 academic research centers: associations with Alzheimer s disease an\ d cerebrovascular disease pathologies:368)/F 4/H/N/Rect[438.282 346.906 445.202 335.34]/Subtype/Link/Type/Annot>> endobj 361 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:138. Besser, L. M., Teylan, M. A. & Nelson, P. T. Limbic predominant age-relate\ d TDP-43 encephalopathy \(LATE\): clinical and neuropathological associations. J. Neuropathol. Exp. Neurol. 79, 305 313 \(202\ 0\).\r:369)/F 4/H/N/Rect[446.563 346.906 454.173 335.34]/Subtype/Link/Type/Annot>> endobj 362 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:143. Arai, T. et al. Phosphorylated TDP-43 in Alzheimer s disease and dementia w\ ith Lewy bodies. 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Neurol. 79, 305 313 \(20\ 20\).\r:373)/F 4/H/N/Rect[363.736 259.52 371.379 249.34]/Subtype/Link/Type/Annot>> endobj 366 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:145. Josephs, K. A. et al. TAR DNA-binding protein 43 and pathological subtype of \ Alzheimer s disease impact clinical features. Ann. Neurol. 78, 697 709 \(2015\).\r:374)/F 4/H/N/Rect[499.617 227.27 506.844 217.09]/Subtype/Link/Type/Annot>> endobj 367 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:146. Josephs, K. A. et al. TDP-43 is a key player in the clinical features associa\ ted with Alzheimer s disease. Acta Neuropathol. 127, 811 824 \(2014\).\r:375)/F 4/H/N/Rect[531.833 173.52 539.709 163.34]/Subtype/Link/Type/Annot>> endobj 368 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:144. Josephs, K. A. et al. Abnormal TDP-43 immunoreactivity in AD modifies clini\ copathologic and radiologic phenotype. 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Josephs, K. A. et al. Pathological, imaging and genetic characteristics suppo\ rt the existence of distinct TDP-43 types in non-FTLD brains. Acta Neuropathol. 137, 227 238 \(2019\).\r:377)/F 4/H/N/Rect[129.022 625.02 136.078 614.84]/Subtype/Link/Type/Annot>> endobj 379 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:111. Robinson, J. L. et al. Limbic-predominant age-related TDP-43 encephalopathy\ differs from frontotemporal lobar degeneration. Brain 143, 2844 2857 \(2020\).\r:378)/F 4/H/N/Rect[286.368 410.02 292.576 399.84]/Subtype/Link/Type/Annot>> endobj 380 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:39. Amador-Ortiz, C. et al. TDP-43 immunoreactivity in hippocampal sclerosis an\ d Alzheimer s disease. Ann. Neurol. 61, 435 445 \(2007\).\r:379)/F 4/H/N/Rect[68.9102 334.77 73.9248 324.59]/Subtype/Link/Type/Annot>> endobj 381 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:49. Nag, S. et al. 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Contribution of TDP and hippocampal sclerosis to hippocampal vo\ lume loss in older-old persons. Neurology 94, e142 e152 \(2020\).\r:383)/F 4/H/N/Rect[195.466 324.02 203.067 313.84]/Subtype/Link/Type/Annot>> endobj 385 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:151. Zarow, C., Weiner, M. W., Ellis, W. G. & Chui, H. C. Prevalence, laterality, \ and comorbidity of hippocampal sclerosis in an autopsy sample. Brain Behav. 2, 435 442 \(2012\).\r:384)/F 4/H/N/Rect[233.171 302.52 239.942 292.34]/Subtype/Link/Type/Annot>> endobj 386 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:152. Josephs, K. A. & Dickson, D. W. Hippocampal sclerosis in tau-negative frontot\ emporal lobar degeneration. Neurobiol. Aging 28, 1718 1722 \(2007\).\r:385)/F 4/H/N/Rect[138.861 259.52 145.898 249.34]/Subtype/Link/Type/Annot>> endobj 387 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:155. Thom, M. et al. 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Nelson, P. T. et al. TDP-43 proteinopathy in aging: associations with risk-as\ sociated \ngene variants and with brain parenchymal thyroid hormone levels. Neurobiol. Dis. 125, 67 76 \(2019\).\r:422)/F 4/H/N/Rect[235.518 668.053 243.158 657.84]/Subtype/Link/Type/Annot>> endobj 428 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:165. Morte, B. & Bernal, J. Thyroid hormone action: astrocyte-neuron communication\ . Front. Endocrinol. 5, 82 \(2014\).\r:423)/F 4/H/N/Rect[268.302 614.27 275.564 604.09]/Subtype/Link/Type/Annot>> endobj 429 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:164. Nelson, P. T. et al. TDP-43 proteinopathy in aging: associations with risk-a\ ssociated \ngene variants and with brain parenchymal thyroid hormone levels. Neurobiol. Dis. 125, 67 76 \(2019\).\r:424)/F 4/H/N/Rect[258.766 592.77 266.562 582.59]/Subtype/Link/Type/Annot>> endobj 430 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:166. Nakashima-Yasuda, H. et al. Co-morbidity of TDP-43 proteinopathy in Lewy bod\ y related diseases. Acta Neuropathol. 114, 221 229 \(2007\).\r:425)/F 4/H/N/Rect[250.628 528.27 258.684 518.09]/Subtype/Link/Type/Annot>> endobj 431 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:113. McAleese, K. E. et al. TDP-43 pathology in Alzheimer s disease, dementia\ with Lewy bodies and ageing. Brain Pathol. 27, 472 479 \(2017\).\r:426)/F 4/H/N/Rect[123.654 506.77 130.553 496.59]/Subtype/Link/Type/Annot>> endobj 432 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:143. Arai, T. et al. Phosphorylated TDP-43 in Alzheimer s disease and dementia \ with Lewy bodies. Acta Neuropathol. 117, 125 136 \(2009\).\r:427)/F 4/H/N/Rect[207.265 496.02 214.899 485.84]/Subtype/Link/Type/Annot>> endobj 433 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:51. Uchino, A. et al. Incidence and extent of TDP-43 accumulation in aging huma\ n brain. 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Distinct characteristics of limbic-predominant age-relat\ ed TDP-43 encephalopathy in Lewy body disease. Acta Neuropathol. 143, 15 31 \(2022\).\r:431)/F 4/H/N/Rect[248.344 367.02 256.16 356.84]/Subtype/Link/Type/Annot>> endobj 437 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:169. Agrawal, S. et al. The association of Lewy bodies with limbic-predominant age\ -related TDP-43 encephalopathy neuropathologic changes and their role in cognition and Alzheimer s dementia in older persons. A\ cta Neuropathol. Commun. 9, 156 \(2:432)/F 4/H/N/Rect[90.1682 216.52 97.8288 206.34]/Subtype/Link/Type/Annot>> endobj 438 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:6. Nelson, P. T. et al. Limbic-predominant age-related TDP-43 encephal\ opathy \(LATE\): consensus working group report. 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Limbic-predominant age-related TDP-43 encephalopath\ y neuropathological change \(LATE-NC\) is independently associated with dementia and strongly associated with arteriolosclerosis \ in the oldest-old. Acta Neuropathol.:441)/F 4/H/N/Rect[429.425 367.02 436.374 356.84]/Subtype/Link/Type/Annot>> endobj 447 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:173. Agrawal, S. et al. Limbic-predominant age-related TDP-43 encephalopathy neuro\ pathologic change and microvascular pathologies in community-dwelling older persons. Brain Pathol. 31, e12939 \(2021\).\r:44\ 2)/F 4/H/N/Rect[494.225 302.52 501.472 292.34]/Subtype/Link/Type/Annot>> endobj 448 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:174. Crary, J. F. et al. Primary age-related tauopathy \(PART\): a common pathology\ associated with human aging. 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Phosphorylated TDP-43 staging of primary age-related tauopa\ thy. Neurosci. Bull. 35, 183 192 \(2019\).\r:445)/F 4/H/N/Rect[81.52 635.77 88.7667 625.59]/Subtype/Link/Type/Annot>> endobj 455 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:6. Nelson, P. T. et al. Limbic-predominant age-related TDP-43 encepha\ lopathy \(LATE\): consensus working group report. Brain 142, 1503 1527 \(2019\).\r:446)/F 4/H/N/Rect[68.3146 614.303 71.2265 604.09]/Subtype/Link/Type/Annot>> endobj 456 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:138. Besser, L. M., Teylan, M. A. & Nelson, P. T. Limbic predominant age-re\ lated TDP-43 encephalopathy \(LATE\): clinical and neuropathological associations. J. Neuropathol. Exp. Neurol. 79, 305 313 \(\ 2020\).\r:447)/F 4/H/N/Rect[280.4 506.77 288.043 496.59]/Subtype/Link/Type/Annot>> endobj 457 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:151. Zarow, C., Weiner, M. W., Ellis, W. G. & Chui, H. C. Prevalence, laterality,\ and comorbidity of hippocampal sclerosis in an autopsy sample. Brain Behav. 2, 435 442 \(2012\).\r:448)/F 4/H/N/Rect[71.0673 377.77 78.018 367.59]/Subtype/Link/Type/Annot>> endobj 458 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:151. Zarow, C., Weiner, M. W., Ellis, W. G. & Chui, H. C. Prevalence, laterality\ , and comorbidity of hippocampal sclerosis in an autopsy sample. Brain Behav. 2, 435 442 \(2012\).\r:449)/F 4/H/N/Rect[191.216 356.27 198.083 346.09]/Subtype/Link/Type/Annot>> endobj 459 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:177. Grothe, M. J. et al. Differential diagnosis of amnestic dementia patients bas\ ed on an FDG-PET signature of autopsy-confirmed LATE-NC. Alzheimers Dement. 19, 1234 1244 \(2023\).\r:450)/F 4/H/N/Rect[174.339 324.053 181.555 313.84]/Subtype/Link/Type/Annot>> endobj 460 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:178. Makkinejad, N. et al. Associations of amygdala volume and shape with transact\ ive response DNA-binding protein 43 \(TDP-43\) pathology in a community cohort of older adults. Neurobiol. Aging 77, 104 111 \ \(2019\).\r:451)/F 4/H/N/Rect[151.146 152.02 158.373 141.84]/Subtype/Link/Type/Annot>> endobj 461 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:179. Zhang, H. X., Tanji, K., Mori, F. & Wakabayashi, K. Epitope mapping of 2E2-D3\ , a monoclonal antibody directed against human TDP-43. Neurosci. Lett. 434, 170 174 \(2008\).\r:452)/F 4/H/N/Rect[137.939 98.2704 150.801 88.0899]/Subtype/Link/Type/Annot>> endobj 462 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:180. Feneberg, E., Gray, E., Ansorge, O., Talbot, K. & Turner, M. R. Towards a TDP\ -43-based biomarker for ALS and FTLD. Mol. Neurobiol. 55, 7789 7801 \(2018\).\r:453)/F 4/H/N/Rect[214.636 55.2704 222.836 45.0899]/Subtype/Link/Type/Annot>> endobj 463 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:112. Geser, F. et al. Pathological 43-kDa transactivation response DNA-binding \ protein in older adults with and without severe mental illness. Arch. Neurol. 67, 1238 1250 \(2010\).\r:454)/F 4/H/N/Rect[552.34 657.27 559.059 647.09]/Subtype/Link/Type/Annot>> endobj 464 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:181. Majumder, V., Gregory, J. M., Barria, M. A., Green, A. & Pal, S. TDP-43 as a \ potential biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis. \nBMC Neurol. 18, 90 \(2018\).\ \r:455)/F 4/H/N/Rect[365.194 625.02 372.429 614.84]/Subtype/Link/Type/Annot>> endobj 465 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:180. Feneberg, E., Gray, E., Ansorge, O., Talbot, K. & Turner, M. R. Towards a TD\ P-43-based biomarker for ALS and FTLD. Mol. Neurobiol. 55, 7789 7801 \(2018\).\r:456)/F 4/H/N/Rect[355.829 592.77 363.972 582.59]/Subtype/Link/Type/Annot>> endobj 466 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:182. Foulds, P. et al. TDP-43 protein in plasma may index TDP-43 brain pathology i\ n Alzheimer s disease and frontotemporal lobar degeneration. Acta Neuropathol. 116, 141 146 \(2008\).\r:457)/F 4/H/N/Rect[484.672 560.52 492.438 550.34]/Subtype/Link/Type/Annot>> endobj 467 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:183. Foulds, P. G. et al. Plasma phosphorylated-TDP-43 protein levels correlate wi\ th brain pathology in frontotemporal lobar degeneration. Acta Neuropathol. 118, 647 658 \n\(2009\).\r:458)/F 4/H/N/Rect[339.364 517.52 346.908 507.34]/Subtype/Link/Type/Annot>> endobj 468 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:15. Li, Y. R., King, O. D., Shorter, J. & Gitler, A. D. Stress granules as crucib\ les of ALS pathogenesis. J. Cell Biol. 201, 361 372 \(2013\).\r:459)/F 4/H/N/Rect[407.617 377.77 412.139 367.59]/Subtype/Link/Type/Annot>> endobj 469 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:184. Ramaswami, M., Taylor, J. P. & Parker, R. Altered ribostasis: RNA-protein gra\ nules in degenerative disorders. Cell 154, 727 736 \(2013\).\r:460)/F 4/H/N/Rect[413.531 377.77 421.509 367.59]/Subtype/Link/Type/Annot>> endobj 470 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:185. Prasad, A. et al. An acridine derivative, [4,5-bis{\(N-carboxy methyl imidazol\ ium\)methyl}acridine] dibromide, shows anti-TDP-43 aggregation effect in ALS disease models. \nSci. Rep. 6, 39490 \(2016\).\r\ :461)/F 4/H/N/Rect[524.08 367.02 531.593 356.84]/Subtype/Link/Type/Annot>> endobj 471 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:186. Parker, S. J. et al. 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J. & Taylor, J. P. Lost in transportation: nucleocytoplasmic transpor\ t defects in \nALS and other neurodegenerative diseases. Neuron 96, 285 297 \(2017\).\r:465)/F 4/H/N/Rect[531.471 238.02 539.728 227.84]/Subtype/Link/Type/Annot>> endobj 475 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:191. Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic tran\ sport. Nature 525, 56 61 \(2015\).\r:466)/F 4/H/N/Rect[472.075 173.553 479.562 163.34]/Subtype/Link/Type/Annot>> endobj 476 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:192. Chou, C. C. et al. TDP-43 pathology disrupts nuclear pore complexes and nucle\ ocytoplasmic transport in ALS/FTD. Nat. Neurosci. 21, 228 239 \(2018\).\r:467)/F 4/H/N/Rect[503.188 162.77 510.656 152.59]/Subtype/Link/Type/Annot>> endobj 477 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_NatRevNeuro_846.indd:193. Ederle, H. et al. Nuclear egress of TDP-43 and FUS occurs independently of Ex\ portin-1/CRM1. Sci. 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Acta Neuropathol. 126, 161 177 \(2013\).\r:121)[509 0 R/XYZ 305 65 null](SpringerNature_NatRevNeuro_846.indd:158. Neltner, J. H. et al. Arteriolosclerosis that affects multiple brain regions \ is linked to hippocampal sclerosis of ageing. Brain 137, 255 267 \(2014\).\r:389)[512 0 R/XYZ 39 681 null](SpringerNature_NatRevNeuro_846.indd:159. Gauthreaux, K. M. et al. Limbic-predominant age-related TDP-43 encephalopathy\ : medical and pathologic factors associated with comorbid hippocampal sclerosis. Neurology 98, e1422 e1433 \(2022\).\r:397)[512 0 R/XYZ 39 665 null](SpringerNature_NatRevNeuro_846.indd:16. Mompean, M. et al. The TDP-43 N-terminal domain structure at high resolution. \ FEBS J. 283, 1242 1260 \(2016\).\r:145)[480 0 R/XYZ 305 152 null](SpringerNature_NatRevNeuro_846.indd:160. Pao, W. C. et al. Hippocampal sclerosis in the elderly: genetic and pathologi\ c findings, some mimicking Alzheimer disease clinically. Alzheimer Dis. Assoc. Disord. 25, 364 368 \(2011\).\r:403)[512 0 R/XYZ 39 641 null](SpringerNature_NatRevNeuro_846.indd:161. Hokkanen, S. R. K. et al. Putative risk alleles for LATE-NC with hippocampal \ sclerosis in population-representative autopsy cohorts. Brain Pathol. 30, 364 372 \(2020\).\r:416)[512 0 R/XYZ 39 617 null](SpringerNature_NatRevNeuro_846.indd:162. Nelson, P. T. et al. ABCC9 gene polymorphism is associated with hippocampal s\ clerosis of aging pathology. Acta Neuropathol. 127, 825 843 \(2014\).\r:418)[512 0 R/XYZ 39 601 null](SpringerNature_NatRevNeuro_846.indd:163. Nelson, P. T. et al. ABCC9/SUR2 in the brain: implications for hippocampal sc\ lerosis of aging and a potential therapeutic target. Ageing Res. Rev. 24, 111 125 \(2015\).\r:419)[512 0 R/XYZ 39 585 null](SpringerNature_NatRevNeuro_846.indd:164. Nelson, P. T. et al. TDP-43 proteinopathy in aging: associations with risk-as\ sociated \ngene variants and with brain parenchymal thyroid hormone levels. Neurobiol. 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Agrawal, S. et al. The association of Lewy bodies with limbic-predominant age\ -related TDP-43 encephalopathy neuropathologic changes and their role in cognition and Alzheimer s dementia in older persons. A\ cta Neuropathol. Commun. 9, 156 \(2:432)[512 0 R/XYZ 39 473 null](SpringerNature_NatRevNeuro_846.indd:17. Harrison, A. F. & Shorter, J. RNA-binding proteins with prion-like domains in \ health and disease. Biochem. J. 474, 1417 1438 \(2017\).\r:147)[480 0 R/XYZ 305 136 null](SpringerNature_NatRevNeuro_846.indd:170. Blevins, B. L. et al. Brain arteriolosclerosis. Acta Neuropathol. 141, 1 \ 24 \(2021\).\r:436)[512 0 R/XYZ 39 449 null](SpringerNature_NatRevNeuro_846.indd:171. Ighodaro, E. T. et al. Risk factors and global cognitive status related to br\ ain arteriolosclerosis in elderly individuals. J. Cereb. Blood Flow. Metab. 37, 201 216 \n\(2017\).\r:437)[512 0 R/XYZ 39 441 null](SpringerNature_NatRevNeuro_846.indd:172. Bourassa, P., Tremblay, C., Schneider, J. A., Bennett, D. 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Acta Neuropathol. 124, 353 372 \(2012\).\r:281)[509 0 R/XYZ 39 681 null](SpringerNature_NatRevNeuro_846.indd:Box 1\rTDP43 localization in neurodegenerative diseases\rDiseases with primary TDP\ 43 pathological change\rALS2,3,62\rGuam ALS208\rFTLD-TDP, types A E105,205,206\rLATE6\r\ Perry syndrome209,210\rDiseas:101)[33 0 R/XYZ 311 673 null](SpringerNature_NatRevNeuro_846.indd:Fig. 1 | TDP43 structure. a, Domain architecture of TAR DNA-binding protei\ n 43 \n\(TDP43\). Domain boundaries are numbered according to the full-length protein sequence19. b, Ribbon representation \ of the structure of the TDP43 RNA-recog:146)[115 0 R/XYZ 39 364 null](SpringerNature_NatRevNeuro_846.indd:Fig. 2 | TDP43 pathology. Sparse \(part a\), moderate \(part b\) and frequ\ ent \(part c\) intracytoplasmic neuronal TAR DNA-binding protein 43 \(TDP43\) inclusions and neurite immunostaining in the anter\ ior temporal pole cortex. The areas depic:171)[164 0 R/XYZ 305 115 null](SpringerNature_NatRevNeuro_846.indd:Fig. 3 | Numbers of TDP43 inclusions by TDP43 stage. Box-and-whisker plots s\ how the total number of TAR DNA-binding protein 43 \(TDP43\) inclusions per 0.25 mm2 in eight brain regions \(as shown in Fig.\ 4\) by TDP43 stage in 1,160 individual:184)[277 0 R/XYZ 39 115 null](SpringerNature_NatRevNeuro_846.indd:Fig. 4 | The ROSMAP five-stage LATE-NC scheme. Coronal brain sections showin\ g the regional distribution of phosphorylated TAR DNA-binding \nprotein 43 \(TDP43\) cytoplasmic inclusions and the percentage of\ cases \nshowing inclusions at stages 1 :187)[311 0 R/XYZ 305 680 null](SpringerNature_NatRevNeuro_846.indd:Table 1 | Clinical, pathological and genetic features of the FTLD-TDP types\r\ :278)[344 0 R/XYZ 39 390 null](SpringerNature_NatRevNeuro_846.indd:112. Geser, F. et al. Pathological 43-kDa transactivation response DNA-binding \ protein in older adults with and without severe mental illness. Arch. Neurol. 67, 1238 1250 \(2010\).\r:454)[509 0 R/XYZ 39 313 null](SpringerNature_NatRevNeuro_846.indd:113. McAleese, K. E. et al. TDP-43 pathology in Alzheimer s disease, dementia w\ ith Lewy bodies and ageing. Brain Pathol. 27, 472 479 \(2017\).\r:302)[509 0 R/XYZ 39 297 null](SpringerNature_NatRevNeuro_846.indd:116. Katsumata, Y., Fardo, D. W., Kukull, W. A. & Nelson, P. T. Dichotomous sco\ ring of TDP-43 proteinopathy from specific brain regions in 27 academic research centers: associations with Alzheimer s disease \ and cerebrovascular disease pathologi:439)[509 0 R/XYZ 39 241 null](SpringerNature_NatRevNeuro_846.indd:118. Dugan, A. J. et al. Analysis of genes \(TMEM106B, GRN, ABCC9, KCNMB2, and A\ POE\) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic associati\ on study. Acta Neuropathol. Commun. :414)[509 0 R/XYZ 39 193 null](SpringerNature_NatRevNeuro_846.indd:127. Harrison, W. T. et al. Limbic-predominant age-related TDP-43 encephalopath\ y neuropathological change \(LATE-NC\) is independently associated with dementia and strongly associated with arteriolosclerosis \ in the oldest-old. Acta Neuropathol.:441)[509 0 R/XYZ 305 641 null](SpringerNature_NatRevNeuro_846.indd:138. Besser, L. M., Teylan, M. A. & Nelson, P. T. Limbic predominant age-relate\ d TDP-43 encephalopathy \(LATE\): clinical and neuropathological associations. J. Neuropathol. Exp. Neurol. 79, 305 313 \(202\ 0\).\r:369)[509 0 R/XYZ 305 409 null](SpringerNature_NatRevNeuro_846.indd:143. Arai, T. et al. Phosphorylated TDP-43 in Alzheimer s disease and dementia \ with Lewy bodies. Acta Neuropathol. 117, 125 136 \(2009\).\r:427)[509 0 R/XYZ 305 313 null](SpringerNature_NatRevNeuro_846.indd:148. Nelson, P. T. et al. Hippocampal sclerosis in advanced age: clinical and p\ athological features. Brain 134, 1506 1518 \(2011\).\r:402)[509 0 R/XYZ 305 225 null](SpringerNature_NatRevNeuro_846.indd:159. Gauthreaux, K. M. et al. Limbic-predominant age-related TDP-43 encephalopa\ thy: medical and pathologic factors associated with comorbid hippocampal sclerosis. Neurology 98, e1422 e1433 \(2022\).\r:40\ 7)[512 0 R/XYZ 39 665 null](SpringerNature_NatRevNeuro_846.indd:18. de Boer, E. M. J. et al. TDP-43 proteinopathies: a new wave of neurodegener\ ative diseases. J. Neurol. Neurosurg. Psychiatry 92, 86 95 \(2020\).\r:252)[480 0 R/XYZ 305 120 null](SpringerNature_NatRevNeuro_846.indd:2. Arai, T. et al. TDP-43 is a component of ubiquitin-positive tau-negative inc\ lusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem. Biophys. Res. Commun. 351, 602 611 \ \(2006\).\r:175)[480 0 R/XYZ 305 408 null](SpringerNature_NatRevNeuro_846.indd:3. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration\ and amyotrophic lateral sclerosis. Science 314, 130 133 \(2006\).\r:194)[480 0 R/XYZ 305 384 null](SpringerNature_NatRevNeuro_846.indd:34. Nag, S. et al. TDP-43 pathology in anterior temporal pole cortex in aging a\ nd Alzheimer s disease. Acta Neuropathol. Commun. 6, 33 \(2018\).\r:188)[506 0 R/XYZ 39 457 null](SpringerNature_NatRevNeuro_846.indd:35. Wilson, R. S. et al. TDP-43 pathology, cognitive decline, and dementia in o\ ld age. JAMA Neurol. 70, 1418 1424 \(2013\).\r:344)[506 0 R/XYZ 39 441 null]]>> endobj 1073 0 obj <> endobj 1074 0 obj <> endobj 1075 0 obj <> endobj 1076 0 obj <> endobj 1077 0 obj <> endobj 1078 0 obj <<>> endobj 1079 0 obj <>stream application/pdf doi:10.1038/s41582-023-00846-7 Springer US Nature Reviews Neurology, doi:10.1038/s41582-023-00846-7 Limbic-predominant age-related TDP43 encephalopathy (LATE) neuropathological change in neurodegenerative diseases Sukriti Nag Julie A. 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