Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease

Jorge J. Llibre-Guerra, Yan Li, Suzanne E. Schindler, Brian A. Gordon, Anne M. Fagan, John C. Morris, Tammie L.S. Benzinger, Jason Hassenstab, Guoqiao Wang, Ricardo Allegri, Sarah B. Berman, Jasmeer Chhatwal, Martin R. Farlow, David M. Holtzman, Mathias Jucker, Johannes Levin, James M. Noble, Stephen Salloway, Peter Schofield, Celeste KarchNick C. Fox, Chengjie Xiong, Randall J. Bateman, Eric McDade

Research output: Contribution to journalArticle

Abstract

Importance: The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease. Objectives: To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging. Design, Setting, and Participants: This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019. Main Outcomes and Measures: Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume. Results: Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], -0.3 [0.4]) and 10 years (mean [SE], -0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181. Conclusions and Relevance: These findings suggest that CSF tTau and pTau181 may have different associations with brain atrophy across the disease time course. These results have implications for understanding the dynamics of disease pathobiology and interpreting neuronal injury biomarker concentrations in response to Alzheimer disease progression and disease-modifying therapies.

Original languageEnglish (US)
Pages (from-to)e1917126
JournalJAMA Network Open
Volume2
Issue number12
DOIs
StatePublished - Dec 2 2019

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Atrophy
Cerebrospinal Fluid
Disease Progression
Alzheimer Disease
Brain
Dementia
Mutation
Magnetic Resonance Imaging
Pedigree
Amyloid
Cohort Studies
Biomarkers
Outcome Assessment (Health Care)
Wounds and Injuries

ASJC Scopus subject areas

  • Medicine(all)

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Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease. / Llibre-Guerra, Jorge J.; Li, Yan; Schindler, Suzanne E.; Gordon, Brian A.; Fagan, Anne M.; Morris, John C.; Benzinger, Tammie L.S.; Hassenstab, Jason; Wang, Guoqiao; Allegri, Ricardo; Berman, Sarah B.; Chhatwal, Jasmeer; Farlow, Martin R.; Holtzman, David M.; Jucker, Mathias; Levin, Johannes; Noble, James M.; Salloway, Stephen; Schofield, Peter; Karch, Celeste; Fox, Nick C.; Xiong, Chengjie; Bateman, Randall J.; McDade, Eric.

In: JAMA Network Open, Vol. 2, No. 12, 02.12.2019, p. e1917126.

Research output: Contribution to journalArticle

Llibre-Guerra, JJ, Li, Y, Schindler, SE, Gordon, BA, Fagan, AM, Morris, JC, Benzinger, TLS, Hassenstab, J, Wang, G, Allegri, R, Berman, SB, Chhatwal, J, Farlow, MR, Holtzman, DM, Jucker, M, Levin, J, Noble, JM, Salloway, S, Schofield, P, Karch, C, Fox, NC, Xiong, C, Bateman, RJ & McDade, E 2019, 'Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease', JAMA Network Open, vol. 2, no. 12, pp. e1917126. https://doi.org/10.1001/jamanetworkopen.2019.17126
Llibre-Guerra, Jorge J. ; Li, Yan ; Schindler, Suzanne E. ; Gordon, Brian A. ; Fagan, Anne M. ; Morris, John C. ; Benzinger, Tammie L.S. ; Hassenstab, Jason ; Wang, Guoqiao ; Allegri, Ricardo ; Berman, Sarah B. ; Chhatwal, Jasmeer ; Farlow, Martin R. ; Holtzman, David M. ; Jucker, Mathias ; Levin, Johannes ; Noble, James M. ; Salloway, Stephen ; Schofield, Peter ; Karch, Celeste ; Fox, Nick C. ; Xiong, Chengjie ; Bateman, Randall J. ; McDade, Eric. / Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease. In: JAMA Network Open. 2019 ; Vol. 2, No. 12. pp. e1917126.
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title = "Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease",
abstract = "Importance: The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease. Objectives: To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging. Design, Setting, and Participants: This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019. Main Outcomes and Measures: Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume. Results: Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3{\%}) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], -0.3 [0.4]) and 10 years (mean [SE], -0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181. Conclusions and Relevance: These findings suggest that CSF tTau and pTau181 may have different associations with brain atrophy across the disease time course. These results have implications for understanding the dynamics of disease pathobiology and interpreting neuronal injury biomarker concentrations in response to Alzheimer disease progression and disease-modifying therapies.",
author = "Llibre-Guerra, {Jorge J.} and Yan Li and Schindler, {Suzanne E.} and Gordon, {Brian A.} and Fagan, {Anne M.} and Morris, {John C.} and Benzinger, {Tammie L.S.} and Jason Hassenstab and Guoqiao Wang and Ricardo Allegri and Berman, {Sarah B.} and Jasmeer Chhatwal and Farlow, {Martin R.} and Holtzman, {David M.} and Mathias Jucker and Johannes Levin and Noble, {James M.} and Stephen Salloway and Peter Schofield and Celeste Karch and Fox, {Nick C.} and Chengjie Xiong and Bateman, {Randall J.} and Eric McDade",
year = "2019",
month = "12",
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doi = "10.1001/jamanetworkopen.2019.17126",
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pages = "e1917126",
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TY - JOUR

T1 - Association of Longitudinal Changes in Cerebrospinal Fluid Total Tau and Phosphorylated Tau 181 and Brain Atrophy With Disease Progression in Patients With Alzheimer Disease

AU - Llibre-Guerra, Jorge J.

AU - Li, Yan

AU - Schindler, Suzanne E.

AU - Gordon, Brian A.

AU - Fagan, Anne M.

AU - Morris, John C.

AU - Benzinger, Tammie L.S.

AU - Hassenstab, Jason

AU - Wang, Guoqiao

AU - Allegri, Ricardo

AU - Berman, Sarah B.

AU - Chhatwal, Jasmeer

AU - Farlow, Martin R.

AU - Holtzman, David M.

AU - Jucker, Mathias

AU - Levin, Johannes

AU - Noble, James M.

AU - Salloway, Stephen

AU - Schofield, Peter

AU - Karch, Celeste

AU - Fox, Nick C.

AU - Xiong, Chengjie

AU - Bateman, Randall J.

AU - McDade, Eric

PY - 2019/12/2

Y1 - 2019/12/2

N2 - Importance: The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease. Objectives: To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging. Design, Setting, and Participants: This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019. Main Outcomes and Measures: Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume. Results: Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], -0.3 [0.4]) and 10 years (mean [SE], -0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181. Conclusions and Relevance: These findings suggest that CSF tTau and pTau181 may have different associations with brain atrophy across the disease time course. These results have implications for understanding the dynamics of disease pathobiology and interpreting neuronal injury biomarker concentrations in response to Alzheimer disease progression and disease-modifying therapies.

AB - Importance: The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease. Objectives: To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging. Design, Setting, and Participants: This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019. Main Outcomes and Measures: Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume. Results: Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], -0.3 [0.4]) and 10 years (mean [SE], -0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181. Conclusions and Relevance: These findings suggest that CSF tTau and pTau181 may have different associations with brain atrophy across the disease time course. These results have implications for understanding the dynamics of disease pathobiology and interpreting neuronal injury biomarker concentrations in response to Alzheimer disease progression and disease-modifying therapies.

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