David J Irwin1, Sharon X Xie2, David Coughlin2, Naomi Nevler2, Rizwan S Akhtar2, Corey T McMillan2, Edward B Lee2, David A Wolk2, Daniel Weintraub2, Alice Chen-Plotkin2, John E Duda2, Meredith Spindler2, Andrew Siderowf2, Howard I Hurtig2, Leslie M Shaw2, Murray Grossman2, John Q Trojanowski2. 1. From Penn Frontotemporal Degeneration Center (D.J.I., N.N., C.T.M., M.G.), Alzheimer's Disease Core Center (D.A.W., J.Q.T.), Department of Neurology (D.J.I., D.C., R.S.A., C.T.M., D.A.W., D.W., A.C.-P., M.S., A.S., H.I.H., M.G.), Penn Morris K. Udall Parkinson's Disease Research Center of Excellence (D.J.I., R.S.A., C.T.M., D.W., A.C.-P., J.E.D., M.G., J.Q.T.), Center for Neurodegenerative Disease Research (L.M.S., J.Q.T.), Translational Neuropathology Research Laboratory (E.B.L.), Department of Pathology and Laboratory Medicine (E.B.L., L.M.S., J.Q.T.), and Department of Biostatistics and Epidemiology Perelman School of Medicine (S.X.X.), University of Pennsylvania; and Parkinson's Disease Research, Education and Clinical Center (D.W., J.E.D.), Michael J. Crescenz VA Medical Center, Philadelphia, PA. dirwin@pennmedicine.upenn.edu. 2. From Penn Frontotemporal Degeneration Center (D.J.I., N.N., C.T.M., M.G.), Alzheimer's Disease Core Center (D.A.W., J.Q.T.), Department of Neurology (D.J.I., D.C., R.S.A., C.T.M., D.A.W., D.W., A.C.-P., M.S., A.S., H.I.H., M.G.), Penn Morris K. Udall Parkinson's Disease Research Center of Excellence (D.J.I., R.S.A., C.T.M., D.W., A.C.-P., J.E.D., M.G., J.Q.T.), Center for Neurodegenerative Disease Research (L.M.S., J.Q.T.), Translational Neuropathology Research Laboratory (E.B.L.), Department of Pathology and Laboratory Medicine (E.B.L., L.M.S., J.Q.T.), and Department of Biostatistics and Epidemiology Perelman School of Medicine (S.X.X.), University of Pennsylvania; and Parkinson's Disease Research, Education and Clinical Center (D.W., J.E.D.), Michael J. Crescenz VA Medical Center, Philadelphia, PA.
Abstract
OBJECTIVE: To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD). METHODS: Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine181, and Aβ1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN - AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves. RESULTS: SYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ1-42 (mean difference -84.0 ± 22.9 g/mL) compared to SYN - AD (p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau (R2 = 0.15-0.16, p < 0.05, both) and lower Aβ1-42 (R2 = 0.43-0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aβ1-42 (R2 = 0.31, p < 0.001) and higher CSF t-tau/Aβ1-42 ratio (R2 = 0.27, p = 0.01). CSF t-tau/Aβ1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage. CONCLUSIONS: Higher antemortem CSF t-tau/Aβ1-42 and lower Aβ1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.
OBJECTIVE: To test the association of antemortem CSF biomarkers with postmortem pathology in Lewy body disorders (LBD). METHODS: Patients with autopsy-confirmed LBD (n = 24) and autopsy-confirmed Alzheimer disease (AD) (n = 23) and cognitively normal (n = 36) controls were studied. In LBD, neuropathologic criteria defined Lewy body α-synuclein (SYN) stages with medium/high AD copathology (SYN + AD = 10) and low/no AD copathology (SYN - AD = 14). Ordinal pathology scores for tau, β-amyloid (Aβ), and SYN pathology were averaged across 7 cortical regions to obtain a global cerebral score for each pathology. CSF total tau (t-tau), phosphorylated tau at threonine181, and Aβ1-42 levels were compared between LBD and control groups and correlated with global cerebral pathology scores in LBD with linear regression. Diagnostic accuracy for postmortem categorization of LBD into SYN + AD vs SYN - AD or neocortical vs brainstem/limbic SYN stage was tested with receiver operating curves. RESULTS: SYN + AD had higher CSF t-tau (mean difference 27.0 ± 8.6 pg/mL) and lower Aβ1-42 (mean difference -84.0 ± 22.9 g/mL) compared to SYN - AD (p < 0.01, both). Increasing global cerebral tau and plaque scores were associated with higher CSF t-tau (R2 = 0.15-0.16, p < 0.05, both) and lower Aβ1-42 (R2 = 0.43-0.49, p < 0.001, both), while increasing cerebral SYN scores were associated with lower CSF Aβ1-42 (R2 = 0.31, p < 0.001) and higher CSF t-tau/Aβ1-42 ratio (R2 = 0.27, p = 0.01). CSF t-tau/Aβ1-42 ratio had 100% specificity and 90% sensitivity for SYN + AD, and CSF Aβ1-42 had 77% specificity and 82% sensitivity for neocortical SYN stage. CONCLUSIONS: Higher antemortem CSF t-tau/Aβ1-42 and lower Aβ1-42 levels are predictive of increasing cerebral AD and SYN pathology. These biomarkers may identify patients with LBD vulnerable to cortical SYN pathology who may benefit from both SYN and AD-targeted disease-modifying therapies.
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