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Frontotemporal lobar degeneration
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<h2 id="classification">Classification</h2> <p>There are 3 main histological subtypes found at post-mortem: </p> <ul><li>FTLD-tau is characterised by <a href="/facts/Tau_protein/RpU7pquD">tau</a> positive <a href="/facts/Inclusion_bodies/TJnRUnT0">inclusion bodies</a> often referred to as Pick-bodies.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> Examples of FTLD-tau include; <a href="/facts/Pick%2527s_disease/Xxso4JA5">Pick's disease</a>, <a href="/facts/Corticobasal_degeneration/W1H3eagt">corticobasal degeneration</a>, <a href="/facts/Progressive_supranuclear_palsy/xWn8Mowl">progressive supranuclear palsy</a>.</li> <li>FTLD-TDP (or FTLD-U ) is characterised by <a href="/facts/Ubiquitin/hpulmU3m">ubiquitin</a> and TDP-43 positive, tau negative, <a href="/facts/FUS_(gene)/guvWctqt">FUS</a> negative inclusion bodies. The pathological histology of this subtype is so diverse it is subdivided into four subtypes based on the detailed histological findings:</li></ul> <ul><li>Type A presents with many small neurites and neuronal cytoplasmic inclusion bodies in the upper (superficial) cortical layers. Bar-like neuronal intranuclear inclusions can also be seen they are fewer in number.</li> <li>Type B presents with many neuronal and <a href="/facts/Glia_cells/F8BhPmaA">glial</a> cytoplasmic inclusions in both the upper (superficial) and lower (deep) cortical layers, and lower motor neurons. However neuronal intranuclear inclusions are rare or absent. This is often associated with <a href="/facts/ALS/9fIXnNL4">ALS</a> and <a href="/facts/C9orf72/NCPSERyC">C9ORF72</a> mutations (see next section).</li> <li>Type C presents many long neuritic profiles found in the superficial cortical laminae, very few or no neuronal cytoplasmic inclusions, neuronal intranuclear inclusions or glial cytoplasmic inclusions. This is often associated with <a href="/facts/Semantic_dementia/AQV0XBDW">semantic dementia</a>.</li> <li>Type D presents with many neuronal intranuclear inclusions and dystrophic neurites, and an unusual absence of inclusions in the <a href="/facts/Hippocampal_formation/WR8eRp58">granule cell layer of the hippocampus</a>. Type D is associated with VCP mutations.</li> <li>Type E presents with neuronal granulofilamentous inclusions and abundant fine grains involving upper (superficial) and lower (deep) cortical layers. This has been associated with behavioral variant of frontotemporal dementia with a rapid clinical course.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a></li></ul> <p>Two groups independently categorized the various forms of TDP-43 associated disorders. Both classifications were considered equally valid by the medical community, but the physicians and researchers in question have jointly proposed a compromise classification to avoid confusion.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> </p> <ul><li>FTLD-FUS; which is characterised by <a href="/facts/FUS_(gene)/guvWctqt">FUS</a> positive cytoplasmic inclusions, intra nuclear inclusions, and neuritic threads. All of which are present in the cortex, <a href="/facts/Medulla_oblongata/KdSbCCkB">medulla</a>, <a href="/facts/Hippocampal_formation/WR8eRp58">hippocampus</a>, and motor cells of the spinal cord and XIIth <a href="/facts/Cranial_nerve/8zAVI3Ua">cranial nerve</a>.</li></ul> <p>In December 2021 the structure of TDP-43 was resolved with <a href="/facts/Cryogenic_electron_microscopy/Hjbcf4Ec">cryo-EM</a><a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a><a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> but shortly after it was argued that in the context of FTLD-TDP the protein involved could be <a href="/facts/TMEM106B/Glj7NhM8">TMEM106B</a> (which has been also resolved with cryo-EM), rather than of TDP-43.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a><a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h2 id="genetics">Genetics</h2> <p>There have been numerous advances in descriptions of genetic causes of FTLD, and the related disease <a href="/facts/Amyotrophic_lateral_sclerosis/9fIXnNL4">amyotrophic lateral sclerosis</a>. </p> <ul><li>Mutations in the <a href="/facts/Tau_protein/RpU7pquD">Tau</a> gene (known as <a href="/facts/MAPT/RpU7pquD">MAPT</a> or Microtubule Associated Protein Tau) can cause a FTLD presenting with tau pathology (FTLD-tau).<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> There are over 40 known mutations at present.</li> <li>Mutations in the <a href="/facts/Progranulin/JL5ko9yu">progranulin</a> gene (PGRN) can cause a FTLD presenting with TDP-43 pathology (FTLD-TDP43). Patients with progranulin mutations have type 3 ubiquitin-positive, TDP-43 positive, tau-negative pathology at post-mortem. Progranulin is associated with tumorgenesis when overproduced, however the mutations seen in FTLD-TDP43 produce a haploinsufficiency, meaning that because one of the two <a href="/facts/Alleles/8FxCS9KA">alleles</a> is damaged, only half as much progranulin is produced.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a></li> <li>Mutations in the <a href="/facts/CHMP2B/pUoYyAk8">CHMP2B</a> gene are associated with a rare behavioural syndrome akin to bvFTLD (mainly in a large Jutland cohort), presenting with a <a href="/facts/Tau_protein/RpU7pquD">tau</a> negative, <a href="/facts/TDP-43/6yWs5erA">TDP-43</a> negative, <a href="/facts/FUS_(gene)/guvWctqt">FUS</a> negative, <a href="/facts/Ubiquitin/hpulmU3m">Ubiquitin</a> positive pathology.</li> <li>Hypermorphic mutations in the <a href="/facts/Valosin-containing_protein/5X6EA7So">VCP</a> gene cause a TDP-43-positive FTLD which is associated with <a href="/facts/Multisystem_proteinopathy/wEeQkHAW">multisystem proteinopathy</a> (MSP), also known as IBMPFD (inclusion body myopathy, Paget's disease and frontotemporal dementia)<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a></li> <li>A hypomorphic mutation in the <a href="/facts/Valosin-containing_protein/5X6EA7So">VCP</a> gene cause a unique type of FTLD-tau called vacuolar tauopathy with neurofibrillary tangles and neuronal vacuoles <a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a></li> <li>Mutations in the TDP-43 gene (known as TARBP or TAR DNA-binding protein) are an exceptionally rare cause of FTLD, despite this protein being present in the pathological inclusions of many cases (FTLD-TDP43).<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> However, mutations in TARBP are a more common cause of <a href="/facts/Amyotrophic_lateral_sclerosis/9fIXnNL4">ALS</a>, which can present with frontotemporal dementia. Since these instances are not considered a pure FTLD they are not included here.</li></ul> <p>Mutations in all of the above genes cause a very small fraction of the FTLD spectrum. Most of the cases are sporadic (no known genetic cause). </p> <ul><li>A proportion of FTLD-TDP43 [with <a href="/facts/Amyotrophic_lateral_sclerosis/9fIXnNL4">ALS</a>] cases had shown genetic <a href="/facts/Linkage_disequilibrium/k84N6kIA">linkage</a> to a region on <a href="/facts/Chromosome_9/8NB7HQad">chromosome 9</a> (FTLD-TDP43/Ch9). This linkage has recently been pinned down to the <a href="/facts/C9orf72/NCPSERyC">C9ORF72</a> gene. Two groups published identical findings back-to-back in the journal Neuron in mid-2011, showing that a hexanucleotide repeat expansion of the GGGGCC genetic sequence within an <a href="/facts/Intron/LS6YdBEK">intron</a> of this gene was responsible. This expansion was found to be present in a large proportion of familial and sporadic cases, particularly in the Finnish population<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a></li></ul> <h2 id="diagnosis">Diagnosis</h2> <p>For diagnostic purposes, magnetic resonance imaging (MRI) and ([18F]fluorodeoxyglucose) positron emission tomography (FDG-PET) are applied. They measure either atrophy or reductions in glucose utilization. </p><p>The three clinical subtypes of frontotemporal lobar degeneration, frontotemporal dementia, <a href="/facts/Semantic_dementia/AQV0XBDW">semantic dementia</a> and <a href="/facts/Progressive_nonfluent_aphasia/uRhe8vdl">progressive nonfluent aphasia</a>, are characterized by impairments in specific neural networks.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> The first subtype, frontotemporal dementia, mainly affects a frontomedian network and impairs <a href="/facts/Social_cognition/Vhd8AdyG">social cognition</a>. Semantic dementia is mainly related to the inferior temporal poles and <a href="/facts/Amygdala/AAy2mHb5">amygdalae</a>; brain regions enabling conceptual knowledge, semantic information processing, and <a href="/facts/Social_cognition/Vhd8AdyG">social cognition</a>, whereas progressive nonfluent aphasia affects the entire left frontotemporal network for phonological and syntactical processing. </p> <h2 id="treatment">Treatment</h2> <p>There is no known treatment. </p> <h2 id="society">Society</h2> <p><a href="/facts/United_States/P0sCdLe5">United States</a> Senator <a href="/facts/Pete_Domenici/RwjfsrSm">Pete Domenici</a> (<a href="/facts/Republican_Party_(United_States)/XXM1EVPr">R</a>-<a href="/facts/New_Mexico/wosJCGaW">NM</a>) suffered from FTLD, and the illness was the main reason for his October 4, 2007 announcement of retirement at the end of his term in office.<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a> American film director, producer, and screenwriter <a href="/facts/Curtis_Hanson/PtPw9ylr">Curtis Hanson</a> died as a result of FTLD on September 20, 2016.<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> British journalist <a href="/facts/Ian_Black_(journalist)/qaIT5sNX">Ian Black</a> died from the disease on January 22, 2023.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> </p> <h2 id="see-also">See also</h2> <ul><li><a href="/facts/Frontotemporal_dementia_and_parkinsonism_linked_to_chromosome_17/YX8VaHC3">Frontotemporal dementia and parkinsonism linked to chromosome 17</a></li></ul> <h2 id="bibliography">Bibliography</h2> <ul><li>Cairns, Nigel J.; Bigio, Eileen H.; MacKenzie, Ian R. A.; Neumann, Manuela; Lee, Virginia M.-Y.; Hatanpaa, Kimmo J.; White, Charles L.; Schneider, Julie A.; Grinberg, Lea Tenenholz; Halliday, Glenda; Duyckaerts, Charles; Lowe, James S.; Holm, Ida E.; Tolnay, Markus; Okamoto, Koichi; Yokoo, Hideaki; Murayama, Shigeo; Woulfe, John; Munoz, David G.; Dickson, Dennis W.; Ince, Paul G.; Trojanowski, John Q.; Mann, David M. A.; Consortium for Frontotemporal Lobar Degeneration (2007). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827877">"Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: Consensus of the Consortium for Frontotemporal Lobar Degeneration"</a>. <i>Acta Neuropathologica</i>. 114 (1): 5–22. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2Fs00401-007-0237-2">10.1007/s00401-007-0237-2</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827877">2827877</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17579875">17579875</a>.</li> <li>Cairns, N. J.; Grossman, M.; Arnold, S. E.; Burn, D. J.; Jaros, E.; Perry, R. H.; Duyckaerts, C.; Stankoff, B.; Pillon, B.; Skullerud, K.; Cruz-Sanchez, F. F.; Bigio, E. H.; MacKenzie, I. R.A.; Gearing, M.; Juncos, J. L.; Glass, J. D.; Yokoo, H.; Nakazato, Y.; Mosaheb, S.; Thorpe, J. R.; Uryu, K.; Lee, V. M.-Y.; Trojanowski, JQ. (2004). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516854">"Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease"</a>. <i>Neurology</i>. 63 (8): 1376–1384. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1212%2F01.wnl.0000139809.16817.dd">10.1212/01.wnl.0000139809.16817.dd</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3516854">3516854</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/15505152">15505152</a>.</li> <li>Mackenzie IR, Baborie A, Pickering-Brown S, et al. (November 2006). <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668618">"Heterogeneity of ubiquitin pathology in frontotemporal lobar degeneration: classification and relation to clinical phenotype"</a>. <i>Acta Neuropathologica</i>. 112 (5): 539–49. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2Fs00401-006-0138-9">10.1007/s00401-006-0138-9</a>. <a href="/facts/PMC_(identifier)/dX1zMt71">PMC</a> <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2668618">2668618</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17021754">17021754</a>.</li> <li>MacKenzie, Ian R. A.; Munoz, David G.; Kusaka, Hirofumi; Yokota, Osamu; Ishihara, Kenji; Roeber, Sigrun; Kretzschmar, Hans A.; Cairns, Nigel J.; Neumann, Manuela (2011). "Distinct pathological subtypes of FTLD-FUS". <i>Acta Neuropathologica</i>. 121 (2): 207–218. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2Fs00401-010-0764-0">10.1007/s00401-010-0764-0</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/21052700">21052700</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:21435429">21435429</a>.</li> <li>Davidson Y, Kelley T, Mackenzie IR, et al. (May 2007). "Ubiquitinated pathological lesions in frontotemporal lobar degeneration contain the TAR DNA-binding protein, TDP-43". <i>Acta Neuropathologica</i>. 113 (5): 521–33. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1007%2Fs00401-006-0189-y">10.1007/s00401-006-0189-y</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17219193">17219193</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:22524747">22524747</a>.</li> <li>Neary D, Snowden JS, Gustafson L, et al. (December 1, 1998). <a href="http://www.neurology.org/cgi/content/abstract/51/6/1546">"Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria"</a>. <i>Neurology</i>. 51 (6): 1546–54. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1212%2Fwnl.51.6.1546">10.1212/wnl.51.6.1546</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/9855500">9855500</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:37238391">37238391</a>. Retrieved 2009-06-20.</li> <li>Pickering-Brown SM (July 2007). "The complex aetiology of frontotemporal lobar degeneration". <i>Experimental Neurology</i>. 206 (1): 1–10. <a href="/facts/Doi_(identifier)/muM9Etpq">doi</a>:<a href="https://doi.org/10.1016%2Fj.expneurol.2007.03.017">10.1016/j.expneurol.2007.03.017</a>. <a href="/facts/PMID_(identifier)/JlHAvMHt">PMID</a> <a href="https://pubmed.ncbi.nlm.nih.gov/17509568">17509568</a>. <a href="/facts/S2CID_(identifier)/ldJsHa2Y">S2CID</a> <a href="https://api.semanticscholar.org/CorpusID:1280814">1280814</a>.</li></ul> <h2 id="further-reading">Further reading</h2> <ul><li>Hodges, John R. The Frontotemporal Dementia Syndromes. Cambridge University Press. 2007 <a href="/facts/ISBN_(identifier)/15AdSPa9">ISBN</a> 978-0-521-85477-1</li> <li><a href="http://www.omim.org/search?index=entry&start=1&limit=10&sort=score+desc&search=number:(105550+OR+614260)">OMIM entries on FRONTOTEMPORAL DEMENTIA AND/OR AMYOTROPHIC LATERAL SCLEROSIS as well as C9ORF72</a></li> <li><a href="https://www.ncbi.nlm.nih.gov/books/NBK1450/">GeneReviews/NCBI/NIH/UW entry on Amyotrophic Lateral Sclerosis Overview</a></li></ul> <h2 id="external-links">External links</h2> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Whitwell, Jennifer L.; Anderson, Valerie M.; Scahill, Rachael I.; Rossor, Martin N.; Fox, Nick C. (2004). "Longitudinal Patterns of Regional Change on Volumetric MRI in Frontotemporal Lobar Degeneration". Dementia and Geriatric Cognitive Disorders. 17 (4): 307–310. doi:10.1159/000077160. ISSN 1420-8008. PMID 15178942. <a href="https://www.karger.com/Article/FullText/77160" target="_blank">https://www.karger.com/Article/FullText/77160</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Lu, Po H.; Mendez, Mario F.; Lee, Grace J.; Leow, Alex D.; Lee, Hyun-Woo; Shapira, Jill; Jimenez, Elvira; Boeve, Bradley B.; Caselli, Richard J.; Graff-Radford, Neill R.; Jack, Clifford R.; Kramer, Joel H.; Miller, Bruce L.; Bartzokis, George; Thompson, Paul M. (2013-01-09). "Patterns of Brain Atrophy in Clinical Variants of Frontotemporal Lobar Degeneration". Dementia and Geriatric Cognitive Disorders. 35 (1–2): 34–50. doi:10.1159/000345523. ISSN 1420-8008. PMC 3609420. PMID 23306166. <a href="https://doi.org/10.1159/000345523" target="_blank">https://doi.org/10.1159/000345523</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>van der Zee, Julie; Van Broeckhoven, Christine (7 January 2014). "Dementia in 2013: Frontotemporal lobar degeneration—building on breakthroughs". Nature Reviews Neurology. 10 (2): 70–72. doi:10.1038/nrneurol.2013.270. PMID 24394289. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Kumar, Vinay; Abbas, Abul K.; Aster, Jon C. (2018). Robbins basic pathology (Tenth ed.). Philadelphia, Pennsylvania. p. 877. ISBN 9780323353175.{{cite book}}: CS1 maint: location missing publisher (link) <a href="9780323353175" target="_blank">9780323353175</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Lee, Edward B.; et al. (Jan 2017). "Expansion of the classification of FTLD-TDP: distinct pathology associated with rapidly progressive frontotemporal degeneration". Acta Neuropathol. 134 (1): 65–78. doi:10.1007/s00401-017-1679-9. PMC 5521959. PMID 28130640. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521959" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521959</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Ian R. A. Mackenzie; Manuela Neumann; Atik Baborie; Deepak M. Sampathu; Daniel Du Plessis; Evelyn Jaros; Robert H. Perry; John Q. Trojanowski; David M. A. Mann & Virginia M. Y. Lee (July 2011). "A harmonized classification system for FTLD-TDP pathology". Acta Neuropathol. 122 (1): 111–113. doi:10.1007/s00401-011-0845-8. PMC 3285143. PMID 21644037. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285143" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285143</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Arseni, Diana; Hasegawa, Masato; Murzin, Alexey G.; Kametani, Fuyuki; Arai, Makoto; Yoshida, Mari; Ryskeldi-Falcon, Benjamin (2022-01-06). "Structure of pathological TDP-43 filaments from ALS with FTLD". Nature. 601 (7891): 139–143. Bibcode:2022Natur.601..139A. doi:10.1038/s41586-021-04199-3. ISSN 0028-0836. PMC 7612255. PMID 34880495. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612255" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612255</a> <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>"An ALS Protein, Revealed". www.science.org. Retrieved 2022-04-04. <a href="https://www.science.org/content/blog-post/als-protein-revealed" target="_blank">https://www.science.org/content/blog-post/als-protein-revealed</a> <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Jiang, Yi Xiao; Cao, Qin; Sawaya, Michael R.; Abskharon, Romany; Ge, Peng; DeTure, Michael; Dickson, Dennis W.; Fu, Janine Y.; Ogorzalek Loo, Rachel R.; Loo, Joseph A.; Eisenberg, David S. (2022-03-28). "Amyloid fibrils in disease FTLD-TDP are composed of TMEM106B not TDP-43". Nature. 605 (7909): 304–309. doi:10.1038/s41586-022-04670-9. 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