Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration

Elisabeth H Thijssen, Renaud La Joie, Amy Wolf, Amelia Strom, Ping Wang, Leonardo Iaccarino, Viktoriya Bourakova, Yann Cobigo, Hilary Heuer, Salvatore Spina, Lawren VandeVrede, Xiyun Chai, Nicholas K Proctor, David C Airey, Sergey Shcherbinin, Cynthia Duggan Evans, John R Sims, Henrik Zetterberg, Kaj Blennow, Anna M Karydas, Charlotte E Teunissen, Joel H Kramer, Lea T Grinberg, William W Seeley, Howie Rosen, Bradley F Boeve, Bruce L Miller, Gil D Rabinovici, Jeffrey L Dage, Julio C Rojas, Adam L Boxer, Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators, Leah Forsberg, David S Knopman, Neill Graff-Radford, Murray Grossman, Edward H Huey, Chiadi Onyike, Daniel Kaufer, Erik Roberson, Nupur Ghoshal, Sandra Weintraub, Brian Appleby, Irene Litvan, Diana Kerwin, Mario Mendez, Yvette Bordelon, Giovanni Coppola, Eliana Marisa Ramos, M Carmela Tartaglia, Ging-Yuek Hsiung, Ian MacKenzie, Kimiko Domoto-Reilly, Tatiana Foroud, Bradford C Dickerson, Elisabeth H Thijssen, Renaud La Joie, Amy Wolf, Amelia Strom, Ping Wang, Leonardo Iaccarino, Viktoriya Bourakova, Yann Cobigo, Hilary Heuer, Salvatore Spina, Lawren VandeVrede, Xiyun Chai, Nicholas K Proctor, David C Airey, Sergey Shcherbinin, Cynthia Duggan Evans, John R Sims, Henrik Zetterberg, Kaj Blennow, Anna M Karydas, Charlotte E Teunissen, Joel H Kramer, Lea T Grinberg, William W Seeley, Howie Rosen, Bradley F Boeve, Bruce L Miller, Gil D Rabinovici, Jeffrey L Dage, Julio C Rojas, Adam L Boxer, Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators, Leah Forsberg, David S Knopman, Neill Graff-Radford, Murray Grossman, Edward H Huey, Chiadi Onyike, Daniel Kaufer, Erik Roberson, Nupur Ghoshal, Sandra Weintraub, Brian Appleby, Irene Litvan, Diana Kerwin, Mario Mendez, Yvette Bordelon, Giovanni Coppola, Eliana Marisa Ramos, M Carmela Tartaglia, Ging-Yuek Hsiung, Ian MacKenzie, Kimiko Domoto-Reilly, Tatiana Foroud, Bradford C Dickerson

Abstract

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

Conflict of interest statement

Competing interest statement:

E.H.T, R.L.J., A.W., A.S., P.W., L.I., V.B., Y.C., H.H., S.S., A.M.K., C.E.T., J.H.K., W.W.S., H.R., B.F.B., and B.L.M. declare no conflict of interest. J.L.D., X.C., N.K.P., D.C.A., S.S., C.D.E., and J.R.S. are employees of Eli Lilly and Company. H.Z. has served at scientific advisory boards for Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. K.B. served as a consultant or at advisory boards for Alector, Biogen, CogRx, Lilly, MagQu, Novartis and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg, all unrelated to the work presented in this paper. L.T.G. receives research support from Avid Radiopharmaceuticals, Eli Lilly. She has received consulting fees from the Simon Foundation and Cura Sen, Inc. She serves as associate editor for Frontiers in Aging Neurosciences, Frontiers in Dementia and the Journal of Alzheimer Disease. G.D.R. receives research support from NIH, Alzheimer’s Association, American College of Radiology, Tau Research Consortium, Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, Life Molecular Imaging. He has served as a consultant for Eisai, Merck, Axon Neurosciences. He received speaking honoraria from GE Healthcare. He serves as Associate Editor for JAMA Neurology. J.C.R. is a site PI for clinical trials supported by Eli Lilly and receives support from NIH. A.L.B. receives research support from NIH, the Tau Research Consortium, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, Corticobasal Degeneration Solutions, the Alzheimer’s Drug Discovery Foundation and the Alzheimer's Association. He has served as a consultant for Aeton, Abbvie, Alector, AGTC, Amgen, Arkuda, Arvinas, Asceneuron, Ionis, Lundbeck, Novartis, Passage BIO, Sangamo, Samumed, Third Rock, Toyama and UCB, and received research support from Avid, Biogen, BMS, C2N, Cortice, Eli Lilly, Forum, Genentech, Janssen, Novartis, Pfizer, Roche and TauRx.

Figures

Extended Data Fig. 1. Plasma pTau/NfL ratio… — **Extended Data Fig. 1. Plasma pTau/NfL ratio per clinical diagnosis**
The ratio of pTau181/NfL was decreased in all FTLD diagnoses compared to controls, ADclin and MCI patients (n=212). **p<0.001 *p<0.05

Extended Data Fig. 2. Plasma Aβ 42/40… — **Extended Data Fig. 2. Plasma Aβ 42/40 ratio per clinical diagnosis and Amyloid PET and FTP-PET status**
A. There was no difference in plasma Aβ 42/40 ratio between the different phenotypes(n=178). B. The Aβ 42/40 ratio was decreased in Amyloid PET positive cases (n=135). C. The Aβ 42/40 ratio was decreased in FTP-PET positive cases (n=76)

Extended Data Fig. 3. Plasma NfL concentrations… — **Extended Data Fig. 3. Plasma NfL concentrations per autopsy determined Braak stage**
There was no difference in plasma NfL concentrations between the different Braak stages (n=69).

Extended Data Fig. 4. Plasma pTau181 and… — **Extended Data Fig. 4. Plasma pTau181 and plasma NfL concentrations in mutation carriers**
A. Plasma pTau181 concentrations did not differ between mutation carriers (n=120). B. Plasma NfL concentrations were elevated in *GRN* and *C9orf72* mutation carriers compared to the control group (p<0.0001) and MAPT mutation carriers (p<0.01) (n=59). **p<0.01

Extended Data Fig. 5. Association between plasma… — **Extended Data Fig. 5. Association between plasma pTau181 and CSF pTau181**
CSF pTau181 is associated with plasma pTau181 (β=0.51, p<0.0001; n=74), and is also associated within the AD/MCI (β=0.41, p=0.042; n=25), and the FTLD group (β=0.49, p<0.0001; n=29), but not in controls.

Extended Data Fig. 6. Receiver Operating Characteristic… — **Extended Data Fig. 6. Receiver Operating Characteristic analyses of plasma pTau181 for Aβ-PET status in MCI patients and in controls**
A. Plasma pTau181 concentrations are increased in Aβ-PET positive MCI cases. pTau181 could differentiate between Aβ-PET positive and negative cases (visual read). AUC=0.944 (95% CI: 0.873-1.000, p<0.0001, n= 18 Aβ-PET positive, 21 negative), with a cut-off of 8.4 pg/mL (0.944 sensitivity and 0.857 specificity). B. Plasma pTau181 concentrations are increased in Aβ-PET positive NC cases. pTau181 could differentiate between Aβ-PET positive and negative cases (visual read). AUC=0.859 (95% CI: 0.732-0.986, p=0.001, n=11 Aβ-PET positive, 29 negative), with a cut-off of 7.1 pg/mL (0.818 sensitivity and 0.828 specificity). Notch displays the confidence interval around the median. ***p<0.0001 **p<0.01

Extended Data Fig. 7. Plasma pTau181 and… — **Extended Data Fig. 7. Plasma pTau181 and plasma NfL concentrations per FTP-PET estimated Braak stage**
A. Plasma pTau181 was increased in Braak stage 5-6, and Braak stage 3-4 compared to Braak stage 0 (n=97). B. There was no difference in plasma NfL concentrations between the different Braak stages (n=61). ***p<0.0001

Figure 1.. Plasma pTau181 and plasma NfL… — **Figure 1.. Plasma pTau181 and plasma NfL per clinical diagnosis.**
A. pTau181 levels were elevated in ADclin compared to non-AD clinical diagnoses (n=362). B. Plasma NfL were lower in controls, MCI and AD patients compared to CBS, PSP, and bvFTD, and NfL levels in NC and MCI were lower than in nfvPPA and svPPA patients (n=213). C. Plasma pTau181 levels are elevated in lvPPA, which is typically caused by AD, as compared to nfvPPA and svPPA, that are typically caused by FTLD, and controls (n=136). D. Plasma pTau181 concentrations were increased in ADclin cases compared to FTLD clinical diagnoses and could differentiate between these groups (n=246). Notch displays the 95% confidence interval around the median. Shape reflects amyloid-PET status. ***p<0.0001, **p<0.01

Figure 2.. Plasma pTau181 in pathology-confirmed cases… — **Figure 2.. Plasma pTau181 in pathology-confirmed cases and *MAPT* mutation carriers**
A. pTau181 levels are elevated in ADpath (n=15, 7.5±8 pg/mL), compared to FTLD-tau (n=53, 3.4±3 pg/mL, p<0.0001), and FTLD-TDP (n=15, 2.1±2 pg/mL, p<0.0001). B. Plasma pTau181 levels differentiated between ADpath and pathology-confirmed FTLD (FTLD-Tau and FTLD-TDP combined). C. Plasma pTau181 was increased in Braak stage 5-6 compared to Braak stage 0, stage 1-2, and stage 3-4 D. pTau181 concentrations were increased in *MAPT* mutation carriers with mixed 3R/4R tau pathology (n=17, 4.4±4 pg/mL), compared to those with 4R pathology (n=44, 2.2±2, p=0.024), and controls (n=44, 2.0±2, p=0.011). Biomarker concentrations shown as median ± IQR, ***p<0.0001, *p<0.05

Figure 3.. Association of pTau181 and NfL,… — **Figure 3.. Association of pTau181 and NfL, PiB-PET SUVR, FTP-PET SUVR and Amyloid and FTP-PET status**
A. Plasma pTau181 and plasma NfL measures are not correlated. Plasma pTau181 is increased in amyloid positive cases, and plasma NfL in FTLD cases. The dashed lines represent the uncorrected cut-off value for amyloid positivity (3.6 pg/mL) and the median concentration NfL (27.2 pg/mL) (n=213). The color coding shows Aβ-PET status and the shape coding shows diagnostic group. B. The association between plasma pTau181 and PiB-PET standardized uptake values (SUVRs), β=0.75, p<0.0001. Color coding per Aβ-PET status by visual read, shape coding per clinical diagnosis (n=124) C. The association between plasma pTau181 and FTP-PET SUVRs, β=0.73, p<0.0001. Color coding per Aβ-PET status by visual read, shape coding per clinical diagnosis (n=97). D. Plasma pTau181 concentrations are increased in Aβ-PET positive cases and can differentiate between Aβ-PET positive and negative cases (n=185, Aβ status determined based on visual read). E. Plasma pTau181 concentrations are increased in FTP-PET positive cases and can differentiate between FTP-PET positive and negative cases (based on binarized cortical SUVR values using a 1.22 threshold; n=97). Notch displays the confidence interval around the median. ***p<0.0001

Figure 4.. Voxelwise correlations of plasma pTau181… — **Figure 4.. Voxelwise correlations of plasma pTau181 and plasma NfL with FTP-PET and grey matter atrophy**
A. Regions of correlation between plasma pTau181 concentration and FTP-PET uptake were strongest in AD-specific brain regions: frontal and temporoparietal cortex, posterior cingulate and precuneus regions (ρ~0.75). There was no correlation of FTP-PET with plasma NfL in the whole cohort. In the ADclin/MCI group correlations exist in the frontal and insular cortex (ρ~0.6). B. Negative correlations between plasma pTau181 and grey matter volume were highest in the bilateral temporal lobe and remained in the ADclin/MCI group, but no correlation was found in the FTLD group. The correlation between plasma NfL and grey matter volume was highest in the right putamen and insular region (ρ~−0.5). The association remained in the FTLD group but was not found in the ADclin/MCI group. All correlations were thresholded based on an uncorrected p<0.001 at the voxel level and family wise error-corrected p<0.05 at the cluster level.

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Source: PubMed

Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration

Abstract

Conflict of interest statement

Figures

References

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