Lumipulse-Measured Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer Disease
Michelle Safransky1, Jenna R Groh1, Kaj Blennow1
1From the Boston University Alzheimer's Disease Research Center (M.S., J.R.G., J.W., W.W.Q.Q., A.C.M., T.D.S., J.M., M.L.A.), Boston University CTE Center, Department of Neurology, Boston University Chobanian & Avedisian School of Medicine, MA; Clinical Neurochemistry Laboratory (K.B., H.Z.), Sahlgrenska University Hospital; Department of Psychiatry and Neurochemistry (K.B., H.Z.), Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; Institut du Cerveau et de la Moelle épinière (ICM) (K.B.), Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France; University of Science and Technology of China and First Affiliated Hospital of USTC (K.B.), Hefei, Anhui, P.R. China; Department of Neurodegenerative Disease (H.Z.), UCL Institute of Neurology; UK Dementia Research Institute at UCL (H.Z.), UCL Institute of Neurology, University College London, United Kingdom; Department of Biostatistics (Y.T.); Biostatistics and Epidemiology Data Analytics Center (BEDAC) (B.M.), Boston University School of Public Health, MA; University of Florida (B.M.A.), Gainesville, FL; Memory & Aging Center (G.D.R.), Department of Neurology, Weill Institute for Neurosciences; Department of Radiology and Biomedical Imaging (G.D.R.), University of California, San Francisco; Department of Psychiatry (W.W.Q.Q.); Department of Pharmacology and Experimental Therapeutics (W.W.Q.Q.), Boston University Chobanian & Avedisian School of Medicine, MA; VA Boston Healthcare System (A.C.M., T.D.S.), US Department of Veteran Affairs, Jamaica Plain, MA; Department of Pathology and Laboratory Medicine (A.C.M., T.D.S.), Boston University Chobanian & Avedisian School of Medicine; VA Bedford Healthcare System (A.C.M., T.D.S.), US Department of Veteran Affairs, Bedford; Framingham Heart Study (J.M.), Framingham, MA; Department of Neurology (R.L.H., J.L., J.C.M., R.J.P., S.E.S.), Knight Alzheimer's Disease Research Center, Washington University School of Medicine; Department of Neurology (M.L.A.), Boston Medical Center; and Department of Anatomy & Neurobiology (M.L.A.), Boston University Chobanian & Avedisian School of Medicine, MA.
Background And Objectives:
CSF biomarkers of Aβ42 and phosphorylated tau (p-tau181) are used clinically for the detection of Alzheimer disease (AD) pathology during life. CSF biomarker validation studies have largely used clinical diagnoses and/or amyloid PET imaging as the reference standard. The few existing CSF-to-autopsy studies have been restricted to late-stage AD. This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathologic changes among brain donors who had normal cognition at the time of lumbar puncture (LP).
Methods:
This was a retrospective study of brain donors from the National Alzheimer's Coordinating Center who had normal cognition at the time of LP and who had measurements of CSF Aβ42 and p-tau181 performed with Lumipulse assays. All brain donors were from Washington University Knight ADRC. Staging of AD neuropathologic change (ADNC) was made based on National Institute on Aging-Alzheimer's Association criteria. For this study, participants were divided into 2 categories: "AD-" (no AD/low ADNC) and "AD+" (intermediate/high ADNC). Accuracy of each biomarker for discriminating AD status was evaluated using area under the curve (AUC) statistics generated using predicted probabilities from binary logistic regressions that controlled for age, sex, APOE ε4, and interval between LP and death.
Results:
The average age at LP was 79.3 years (SD = 5.6), and the average age at death was 87.1 years (SD = 6.5). Of the 49 brain donors, 24 (49%) were male and 47 (95.9%) were White. 20 (40.8%) had autopsy-confirmed AD. The average interval from LP until death was 7.76 years (SD = 4.31). CSF p-tau181/Aβ42 was the optimal predictor of AD, having excellent discrimination accuracy (AUC = 0.97, 95% CI 0.94-1.00, p = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, p = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, p = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, p = 0.005). Effects remained after controlling for prevalent comorbid neuropathologies. CSF p-tau181/Aβ42 was strongly associated with CERAD ratings of neuritic amyloid plaque scores and Braak staging of NFTs.
Discussion:
This study supports Lumipulse-measured CSF Aβ42 and p-tau181 and, particularly, the ratio of p-tau181 to Aβ42, for the early detection of AD pathophysiologic processes.
Classification Of Evidence:
This study provides Class II evidence that Lumipulse measures of p-tau181/Aβ42 in the CSF accurately discriminated cognitively normal participants with and without Alzheimer disease neuropathologic change.
