Reduced CSF p-Tau 181 to Tau ratio is a biomarker for FTLD-TDP
Open accessAbstract
OBJECTIVES: To validate the ability of candidate CSF biomarkers to distinguish between the 2 main forms of frontotemporal lobar degeneration (FTLD), FTLD with TAR DNA-binding protein 43 (TDP-43) inclusions (FTLD-TDP) and FTLD with Tau inclusions (FTLD-Tau). METHODS: Antemortem CSF samples were collected from 30 patients with FTLD in a single-center validation cohort, and CSF levels of 5 putative FTLD-TDP biomarkers as well as levels of total Tau (t-Tau) and Tau phosphorylated at threonine 181 (p-Tau181) were measured using independent assays. Biomarkers most associated with FTLD-TDP were then tested in a separate 2-center validation cohort composed of subjects with FTLD-TDP, FTLD-Tau, Alzheimer disease (AD), and cognitively normal subjects. The sensitivity and specificity of FTLD-TDP biomarkers were determined. RESULTS: In the first validation cohort, FTLD-TDP cases had decreased levels of p-Tau181 and interleukin-23, and increased Fas. Reduced ratio of p-Tau181 to t-Tau (p/t-Tau) was the strongest predictor of FTLD-TDP pathology. Analysis in the second validation cohort showed CSF p/t-Tau ratio <0.37 to distinguish FTLD-TDP from FTLD-Tau, AD, and healthy seniors with 82% sensitivity and 82% specificity. CONCLUSION: A reduced CSF p/t-Tau ratio represents a reproducible, validated biomarker for FTLD-TDP with performance approaching well-established CSF AD biomarkers. Introducing this biomarker into research and the clinical arena can significantly increase the power of clinical trials targeting abnormal accumulations of TDP-43 or Tau, and select the appropriate patients for target-specific therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the CSF p/t-Tau ratio distinguishes FTLD-TDP from FTLD-Tau.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
CSF p-tau/t-tau ratio demarcates FTD-TDP patients from FTD-tau cases with sensitivity and specificity values around 82% and 62%, respectively.
“Several independent studies have shown that CSF p‐tau/t‐tau ratio demarcate FTD‐TDP patients from FTD‐tau cases with sensitivity and specificity values around 82% and 62%, respectively.”
From New developments of biofluid‐based biomarkers for routine diagnosis and disease trajectories in frontotemporal dementia (2022) · cites this paper as [93]
The results connect Aβ pathology to a distinct change in soluble tau levels and phosphorylation patterns, explaining why p-tau is significantly elevated in AD but not in other neurodegenerative tauopathies.
“Our results link Aβ pathology to a distinct change in soluble tau levels and phosphorylation patterns, shedding light on the phenomenon in which significant elevation of p-tau occurs in AD but not in other neurodegenerative tauopathies17,18.”
From A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer’s disease (2020) · cites this paper as [17]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., & Stadlan, E. M. (1984) · Neurology · doi:10.1212/wnl.34.7.939 · Cited by 27,915 · see citing works
Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Neumann, M., Sampathu, D. M., Kwong, L. K., Truax, A. C., Micsenyi, M. C., Chou, T. T., Bruce, J., Schuck, T., Grossman, M., Clark, C. M., et al. (2006) · Science · doi:10.1126/science.1134108 · Cited by 6,576 · see citing works
Self-citationSensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia
Rascovsky, K., Hodges, J. R., Knopman, D., Mendez, M. F., Kramer, J. H., Neuhaus, J., van Swieten, J. C., Seelaar, H., Dopper, E. G. P., Onyike, C. U., et al. (2011) · Brain · doi:10.1093/brain/awr179 · Cited by 5,221 · see citing works
Self-citationFrontotemporal lobar degeneration: A consensus on clinical diagnostic criteria
Neary, D., Snowden, J. S., Gustafson, L., Passant, U., Stuss, D., Black, S., Freedman, M., Kertesz, A., Robert, P. H., Albert, M., et al. (1998) · Neurology · doi:10.1212/wnl.51.6.1546 · Cited by 5,047 · see citing works
A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD
Renton, A. E., Majounie, E., Waite, A., Simón-Sánchez, J., Rollinson, S., Gibbs, J. R., Schymick, J. C., Laaksovirta, H., van Swieten, J. C., Myllykangas, L., et al. (2011) · Neuron · doi:10.1016/j.neuron.2011.09.010 · Cited by 4,409 · see citing works
Clinical and biomarker changes in dominantly inherited Alzheimer's disease
Bateman, R. J., Xiong, C., Benzinger, T. L. S., Fagan, A. M., Goate, A., Fox, N. C., Marcus, D. S., Cairns, N. J., Xie, X., Blazey, T. M., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1202753 · Cited by 3,814 · see citing works
Weıntraub, S. (1990) · Archives of Neurology · doi:10.1001/archneur.1990.00530120075013 · Cited by 3,012 · see citing works
Appelhof, B., Bakker, C., den IJssel, J. C. L. V. D., Zwijsen, S. A., Smalbrugge, M., Verhey, F. R. J., de Vugt, M. E., Zuidema, S. U., & Koopmans, R. T. C. M. (2017) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000477087 · Cited by 2,773 · see citing works
Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects
Shaw, L. M., Vanderstichele, H., Knapik‐Czajka, M., Clark, C. M., Aisen, P. S., Petersen, R. C., Blennow, K., Soares, H., Simon, A., Lewczuk, P., et al. (2009) · Annals of Neurology · doi:10.1002/ana.21610 · Cited by 2,065 · see citing works
Self-citationMutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
Baker, M., Mackenzie, I. R., Pickering-Brown, S. M., Gass, J., Rademakers, R., Lindholm, C., Snowden, J., Adamson, J., Sadovnick, A. D., Rollinson, S., et al. (2006) · Nature · doi:10.1038/nature05016 · Cited by 2,058 · see citing works
DJ-1 and α-synuclein in human cerebrospinal fluid as biomarkers of Parkinson’s disease
Hong, Z., Shi, M., Chung, K. A., Quinn, J. F., Peskind, E. R., Galasko, D., Jankovic, J., Zabetian, C. P., Leverenz, J. B., Baird, G., et al. (2010) · Brain · doi:10.1093/brain/awq008 · Cited by 615 · see citing works
Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration
Gass, J. M., Cannon, A. D., Mackenzie, I. R., Boeve, B. F., Baker, M. C., Adamson, J. L., Crook, R., Melquist, S., Kuntz, K., Petersen, R. C., et al. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl241 · Cited by 574 · see citing works
Frontotemporal dementia: Clinicopathological correlations
Forman, M. S., Farmer, J., Johnson, J. K., Clark, C. M., Arnold, S. E., Coslett, H. B., Chatterjee, A., Hurtig, H. I., Karlawish, J. H., Rosen, H. J., et al. (2006) · Annals of Neurology · doi:10.1002/ana.20873 · Cited by 478 · see citing works
Self-citationClinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP
Josephs, K. A., Petersen, R. C., Knopman, D. S., Boeve, B. F., Whitwell, J. L., Duffy, J. R., Parisi, J. E., & Dickson, D. W. (2006) · Neurology · doi:10.1212/01.wnl.0000191307.69661.c3 · Cited by 455 · see citing works
Cerebrospinal fluid biomarkers for Parkinson disease diagnosis and progression
Shi, M. Y., Bradner, J. M., Hancock, A. M., Chung, K. A., Quinn, J. F., Peskind, E. R., Galasko, D., Jankovic, J. J., Zabetian, C. P., Kim, H. M., et al. (2010) · Annals of Neurology · doi:10.1002/ana.22311 · Cited by 418 · see citing works
Primary progressive aphasia: clinicopathological correlations
Grossman, M. (2010) · Nature Reviews Neurology · doi:10.1038/nrneurol.2009.216 · Cited by 414 · see citing works
Self-citationCSF biomarker variability in the Alzheimer's Association quality control program
Mattsson, N., Andréasson, U., Persson, S., Carrillo, M. C., Collins, S. J., Chalbot, S., Cutler, N. E., Dufour‐Rainfray, D., Fagan, A. M., Heegaard, N. H. H., et al. (2013) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2013.01.010 · Cited by 383 · see citing works
Self-citationClinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease
(2012) · New England Journal of Medicine · doi:10.1056/nejmx120056 · Cited by 382 · see citing works
Alzheimer's Prevention Initiative: A Plan to Accelerate the Evaluation of Presymptomatic Treatments
Reiman, E. M., Langbaum, J. B. S., Fleisher, A., Caselli, R. J., Chen, K., Ayutyanont, N., Quiroz, Y. T., Kosik, K. S., Lopera, F. J., & Tariot, P. N. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-0059 · Cited by 340 · see citing works
Kos, K., Harte, A. L., da Silva, N. F., Tonchev, A. B., Chaldakov, G., James, S. G., Snead, D. R. J., Hoggart, B., O’Hare, J. P., McTernan, P. G., et al. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2006-1841 · Cited by 234 · see citing works
Plasma multianalyte profiling in mild cognitive impairment and Alzheimer disease
Hu, W. T., Holtzman, D. M., Fagan, A. M., Shaw, L. M. J., Perrin, R. J., Arnold, S. E., Grossman, M., Xiong, C., Craig‐Schapiro, R., Clark, C. M., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e318266fa70 · Cited by 234 · see citing works
Self-citationPlasma Biomarkers Associated With the Apolipoprotein E Genotype and Alzheimer Disease
Soares, H. D. (2012) · Archives of Neurology · doi:10.1001/archneurol.2012.1070 · Cited by 218 · see citing works
CSF biomarkers in frontotemporal lobar degeneration with known pathology
Bian, H., Van Swieten, J. C., Leight, S., Massimo, L., Wood, E., Forman, M., Moore, P., de Koning, I., Clark, C. M., Rosso, S., et al. (2008) · Neurology · doi:10.1212/01.wnl.0000311445.21321.fc · Cited by 216 · see citing works
Self-citationMorris, J. C., Aisen, P. S. S., Bateman, R. J., Benzinger, T. L. S., Cairns, N. J., Fagan, A. M., Ghetti, B. F., Goate, A., Holtzman, D. M., Klunk, W. E., et al. (2012) · Clinical Investigation · doi:10.4155/cli.12.93 · Cited by 205 · see citing works
Novel CSF biomarkers for Alzheimer’s disease and mild cognitive impairment
Hu, W. T., Chen‐Plotkin, A. S., Arnold, S. E., Grossman, M., Clark, C. M., Shaw, L. M. J., Pickering, E. H., Kühn, M., Chen, Y., McCluskey, L. F., et al. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0667-0 · Cited by 196 · see citing works
Self-citationPeskind, E. R., Li, G., Shofer, J., Quinn, J. F., Kaye, J. A., Clark, C. M., Farlow, M. R., DeCarli, C., Raskind, M. A., Schellenberg, G. D., et al. (2006) · Archives of Neurology · doi:10.1001/archneur.63.7.936 · Cited by 131 · see citing works
Novel CSF biomarkers for frontotemporal lobar degenerations
Hu, W. T., Chen‐Plotkin, A. S., Grossman, M., Arnold, S. E., Clark, C. M., Shaw, L. M. J., McCluskey, L. F., Elman, L., Hurtig, H. I., Siderowf, A. D., et al. (2010) · Neurology · doi:10.1212/wnl.0b013e318200d78d · Cited by 101 · see citing works
Self-citationBaker, M., Kwok, J. B. J., Kucera, S., Crook, R., Farrer, M., Houlden, H., Isaacs, A., Lincoln, S., Onstead, L., Hardy, J., et al. (1997) · Annals of Neurology · doi:10.1002/ana.410420516 · Cited by 83 · see citing works
Acevedo, A., Krueger, K. R., Navarro, E., Ortiz, F., Manly, J. J., Padilla-Vélez, M. M., Weıntraub, S., López, O. L., & Mungas, D. (2009) · Alzheimer Disease & Associated Disorders · doi:10.1097/wad.0b013e318193e376 · Cited by 68 · see citing works
Protein instability following transport or storage on dry ice
Murphy, B. M., Swarts, S., Mueller, B. M., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2409 · Cited by 58 · see citing works
Boxer, A. L., Gold, M., Huey, E. D., Hu, W. T., Rosen, H. J., Kramer, J. H., Gao, F., Burton, E. A., Chow, T. W., Kao, A. W., et al. (2012) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2012.03.003 · Cited by 54 · see citing works
Self-citationIngelsson, M., Ramasamy, K., Russ, C., Freeman, S. H., Orne, J. D., Raju, S., Matsui, T., Growdon, J. H., Frosch, M. P., Ghetti, B. F., et al. (2007) · Acta Neuropathologica · doi:10.1007/s00401-007-0280-z · Cited by 47 · see citing works
Critical appraisal of the role of davunetide in the treatment of progressive supranuclear palsy
Gozes, I., Gold, Lorenzl, Stewart, A. J., Morimoto, B. H., & Williams (2012) · Neuropsychiatric Disease and Treatment · doi:10.2147/ndt.s12518 · Cited by 39 · see citing works
Delaisi, B., & Gérardin, M. (2003) · PubMed · Cited by 18 · see citing works
Using blood markers for Alzheimer disease in clinical practice?
O’Bryant, S. E. (2012) · Neurology · doi:10.1212/wnl.0b013e318266fd21 · Cited by 7 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
the Dominantly Inherited Alzheimer Network, Barthélemy, N. R., Li, Y., Joseph-Mathurin, N., Gordon, B. A., Hassenstab, J., Benzinger, T. L. S., Buckles, V., Fagan, A. M., Perrin, R. J., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-0781-z · Cited by 651 · see citing works
Imaging and fluid biomarkers in frontotemporal dementia
Meeter, L. H., Kaat, L. D., Rohrer, J. D., & van Swieten, J. C. (2017) · Nature Reviews Neurology · doi:10.1038/nrneurol.2017.75 · Cited by 210 · see citing works
Clinical value of neurofilament and phospho-tau/tau ratio in the frontotemporal dementia spectrum
Meeter, L. H. H., Vijverberg, E. G., Del Campo, M., Rozemuller, A. J. M., Donker Kaat, L., de Jong, F. J., van der Flier, W. M., Teunissen, C. E., van Swieten, J. C., & Pijnenburg, Y. A. L. (2018) · Neurology · doi:10.1212/wnl.0000000000005261 · Cited by 122 · see citing works
Teunissen, C. E., Elias, N., Koel‐Simmelink, M. J. A., Durieux‐Lu, S., Malekzadeh, A., Pham, T. V., Piersma, S. R., Beccari, T., Meeter, L. H. H., Dopper, E. G. P., et al. (2016) · Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring · doi:10.1016/j.dadm.2015.12.004 · Cited by 103 · see citing works
Phosphorylated Tau as a Candidate Biomarker for Amyotrophic Lateral Sclerosis
Grossman, M., Elman, L., McCluskey, L., McMillan, C. T., Boller, A., Powers, J., Rascovsky, K., Hu, W., Shaw, L., Irwin, D. J., et al. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2013.6064 · Cited by 94 · see citing works
Self-citationPijnenburg, Y. A. L., Verwey, N. A., van der Flier, W. M., Scheltens, P., & Teunissen, C. E. (2015) · Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring · doi:10.1016/j.dadm.2015.11.001 · Cited by 91 · see citing works
Csf p-tau<sub>181</sub>/tau ratio as biomarker for TDP pathology in frontotemporal dementia
Borroni, B., Benussi, A., Archetti, S., Galimberti, D., Parnetti, L., Nacmias, B., Sorbi, S., Scarpini, E., & Padovani, A. (2015) · Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration · doi:10.3109/21678421.2014.971812 · Cited by 77 · see citing works
Irwin, D. J., Lleó, A., Xie, S. X., McMillan, C. T., Wolk, D. A., Lee, E. B., Van Deerlin, V. M., Shaw, L. M., Trojanowski, J. Q., & Grossman, M. (2017) · Annals of Neurology · doi:10.1002/ana.24996 · Cited by 67 · see citing works
Self-citationA 2-Step Cerebrospinal Algorithm for the Selection of Frontotemporal Lobar Degeneration Subtypes
Lleó, A., Irwin, D. J., Illán-Gala, I., McMillan, C. T., Wolk, D. A., Lee, E. B., Van Deerlin, V. M., Shaw, L. M., Trojanowski, J. Q., & Grossman, M. (2018) · JAMA Neurology · doi:10.1001/jamaneurol.2018.0118 · Cited by 71 · see citing works
Self-citationBiomarkers for diseases with TDP-43 pathology
Steinacker, P., Barschke, P., & Otto, M. (2019) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2018.10.003 · Cited by 57 · see citing works
del Campo, M., Zetterberg, H., Gandy, S., Onyike, C. U., Oliveira, F., Udeh‐Momoh, C., Lleó, A., Teunissen, C. E., & Pijnenburg, Y. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12643 · Cited by 52 · see citing works
Cerebrospinal fluid biomarkers predict frontotemporal dementia trajectory
Ljubenkov, P. A., Staffaroni, A. M., Rojas, J. C., Allen, I. E., Wang, P., Heuer, H., Karydas, A., Kornak, J., Cobigo, Y., Seeley, W. W., et al. (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.643 · Cited by 49 · see citing works
Vijverberg, E. G. B., Dols, A., Krudop, W. A., Del Campo Milan, M., Kerssens, C. J., Gossink, F., Prins, N. D., Stek, M. L., Scheltens, P., Teunissen, C. E., et al. (2017) · Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring · doi:10.1016/j.dadm.2017.01.009 · Cited by 46 · see citing works
Novel <scp>CSF</scp> biomarkers to discriminate <scp>FTLD</scp> and its pathological subtypes
del Campo, M., Galimberti, D., Elias, N., Boonkamp, L., Pijnenburg, Y. A., van Swieten, J. C., Watts, K., Paciotti, S., Beccari, T., Hu, W., et al. (2018) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.629 · Cited by 30 · see citing works
Self-citationLower CSF amyloid-beta1–42 predicts a higher mortality rate in frontotemporal dementia
Vieira, D., Durães, J., Baldeiras, I., Santiago, B., Duro, D., Lima, M., Leitão, M. J., Tábuas-Pereira, M., & Santana, I. (2019) · Diagnostics · doi:10.3390/diagnostics9040162 · Cited by 6 · see citing works
- Authors
- Hu, W. T., Watts, K., Grossman, M., Glass, J., Lah, J. J., Hales, C., Shelnutt, M., Van Deerlin, V., Trojanowski, J. Q., & Levey, A. I.
- Affiliations
- Emory University (US)
- From the Department of Neurology (W.T.H., K.W., J.G., J.J.L., C.H., M.S., A.I.L.), Center for Neurodegenerative Diseases Research (W.T.H., K.W., J.G., J.J.L., C.H., A.I.L.), Alzheimer's Disease Research Center (W.T.H., J.G., J.J.L., C.H., A.I.L.), Emory University School of Medicine, Atlanta, GA; and Departments of Neurology (M.G.) and Laboratory Medicine and Pathology (V.V.D., J.Q.T.), University of Pennsylvania, Philadelphia.
- ORCID
- Venue
- Neurology
- Published
- 2013-11-26
- Volume
- 81
- Issue
- 22
- Pages
- 1945-1952
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC3843382
- OpenAlex
- W2155980849
- Cited by
- 113
- References
- 35
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 7 · 2023: 6 · 2022: 10 · 2021: 9 · 2020: 7 · 2019: 13 · 2018: 16 · 2017: 9 · 2016: 8 · 2015: 12 · 2014: 9
- FWCI
- 6.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (P30AG010124, P01AG017586, AG17586, AG-10124, K23AG042856, AG-25688, P50AG025688)
- National Institute of Neurological Disorders and Stroke (NS-44266, R01NS044266)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- FTLD-TDP, frontotemporal lobar degeneration, TDP-43, cerebrospinal fluid biomarkers, FTLD-tau, Alzheimer's disease, IL-23, Fas, differential diagnosis, sensitivity and specificity
- MeSH terms
- C9orf72 Protein, Progranulins, DNA-Binding Proteins, Female, Humans, Male, Peptide Fragments, Phosphorylation, Proteins, Sensitivity and Specificity, Threonine, Cohort Studies, Biomarkers, Chi-Square Distribution, Amyloid beta-Peptides, tau Proteins, Intercellular Signaling Peptides and Proteins, Interleukin-23, Frontotemporal Lobar Degeneration
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
