Pathologic and Cognitive Correlates of Plasma Biomarkers in Neurodegenerative Disease

Overview

Journal Alzheimers Dement

Specialties Neurology
Psychiatry

Date 2024 Apr 22

PMID 38644682

Authors

Katheryn A Q Cousins

Jeffrey S Phillips

Sandhitsu R Das

Kyra OBrien

Thomas F Tropea

Alice Chen-Plotkin

Leslie M Shaw

Ilya M Nasrallah

Dawn Mechanic-Hamilton

Corey T McMillan

David J Irwin

Edward B Lee

David A Wolk

Affiliations

Soon will be listed here.

Abstract

Introduction: We investigate pathological correlates of plasma phosphorylated tau 181 (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) across a clinically diverse spectrum of neurodegenerative disease, including normal cognition (NormCog) and impaired cognition (ImpCog).

Methods: Participants were NormCog (n = 132) and ImpCog (n = 461), with confirmed β-amyloid (Aβ+/-) status (cerebrospinal fluid, positron emission tomography, autopsy) and single molecule array plasma measurements. Logistic regression and receiver operating characteristic (ROC) area under the curve (AUC) tested how combining plasma analytes discriminated Aβ+ from Aβ-. Survival analyses tested time to clinical dementia rating (global CDR) progression.

Results: Multivariable models (p-tau+GFAP+NfL) had the best performance to detect Aβ+ in NormCog (ROCAUC = 0.87) and ImpCog (ROCAUC = 0.87). Survival analyses demonstrated that higher NfL best predicted faster CDR progression for both Aβ+ (hazard ratio [HR] = 2.94; p = 8.1e-06) and Aβ- individuals (HR = 3.11; p = 2.6e-09).

Discussion: Combining plasma biomarkers can optimize detection of Alzheimer's disease (AD) pathology across cognitively normal and clinically diverse neurodegenerative disease.

Highlights: Participants were clinically heterogeneous, with autopsy- or biomarker-confirmed Aβ. Combining plasma p-tau, GFAP, and NfL improved diagnostic accuracy for Aβ status. Diagnosis by plasma biomarkers is more accurate in amnestic AD than nonamnestic AD. Plasma analytes show independent associations with tau PET and post mortem Aβ/tau. Plasma NfL predicted longitudinal cognitive decline in both Aβ+ and Aβ- individuals.

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References

Cousins K, Shaw L, Chen-Plotkin A, Wolk D, Van Deerlin V, Lee E . Distinguishing Frontotemporal Lobar Degeneration Tau From TDP-43 Using Plasma Biomarkers. JAMA Neurol. 2022; 79(11):1155-1164. PMC: 9552044. DOI: 10.1001/jamaneurol.2022.3265. View

Shaw L, Vanderstichele H, Knapik-Czajka M, Figurski M, Coart E, Blennow K . Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol. 2011; 121(5):597-609. PMC: 3175107. DOI: 10.1007/s00401-011-0808-0. View

Chatterjee P, Pedrini S, Doecke J, Thota R, Villemagne V, Dore V . Plasma Aβ42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross-sectional and longitudinal study in the AIBL cohort. Alzheimers Dement. 2022; 19(4):1117-1134. DOI: 10.1002/alz.12724. View

Zhu N, Santos-Santos M, Illan-Gala I, Montal V, Estelles T, Barroeta I . Plasma glial fibrillary acidic protein and neurofilament light chain for the diagnostic and prognostic evaluation of frontotemporal dementia. Transl Neurodegener. 2021; 10(1):50. PMC: 8662866. DOI: 10.1186/s40035-021-00275-w. View

Thijssen E, Verberk I, Kindermans J, Abramian A, Vanbrabant J, Ball A . Differential diagnostic performance of a panel of plasma biomarkers for different types of dementia. Alzheimers Dement (Amst). 2022; 14(1):e12285. PMC: 9107685. DOI: 10.1002/dad2.12285. View

Xie S, Baek Y, Grossman M, Arnold S, Karlawish J, Siderowf A . Building an integrated neurodegenerative disease database at an academic health center. Alzheimers Dement. 2011; 7(4):e84-93. PMC: 3145967. DOI: 10.1016/j.jalz.2010.08.233. View

Xie L, Wisse L, Pluta J, de Flores R, Piskin V, Manjon J . Automated segmentation of medial temporal lobe subregions on in vivo T1-weighted MRI in early stages of Alzheimer's disease. Hum Brain Mapp. 2019; 40(12):3431-3451. PMC: 6697377. DOI: 10.1002/hbm.24607. View

Cullen N, Leuzy A, Palmqvist S, Janelidze S, Stomrud E, Pesini P . Individualized prognosis of cognitive decline and dementia in mild cognitive impairment based on plasma biomarker combinations. Nat Aging. 2023; 1(1):114-123. DOI: 10.1038/s43587-020-00003-5. View

Beyer L, Stocker H, Rujescu D, Holleczek B, Stockmann J, Nabers A . Amyloid-beta misfolding and GFAP predict risk of clinical Alzheimer's disease diagnosis within 17 years. Alzheimers Dement. 2022; 19(3):1020-1028. DOI: 10.1002/alz.12745. View

10.

Dickson D, Kouri N, Murray M, Josephs K . Neuropathology of frontotemporal lobar degeneration-tau (FTLD-tau). J Mol Neurosci. 2011; 45(3):384-9. PMC: 3208128. DOI: 10.1007/s12031-011-9589-0. View

11.

Lee E . Integrated neurodegenerative disease autopsy diagnosis. Acta Neuropathol. 2018; 135(4):643-646. PMC: 6186396. DOI: 10.1007/s00401-018-1827-x. View

12.

Forgrave L, Ma M, Best J, DeMarco M . The diagnostic performance of neurofilament light chain in CSF and blood for Alzheimer's disease, frontotemporal dementia, and amyotrophic lateral sclerosis: A systematic review and meta-analysis. Alzheimers Dement (Amst). 2020; 11:730-743. PMC: 6939029. DOI: 10.1016/j.dadm.2019.08.009. View

13.

Chatterjee P, Pedrini S, Ashton N, Tegg M, Goozee K, Singh A . Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer's disease. Alzheimers Dement. 2021; 18(6):1141-1154. DOI: 10.1002/alz.12447. View

14.

Folstein M, Folstein S, McHugh P . "Mini-mental state". A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975; 12(3):189-98. DOI: 10.1016/0022-3956(75)90026-6. View

15.

Cicognola C, Janelidze S, Hertze J, Zetterberg H, Blennow K, Mattsson-Carlgren N . Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment. Alzheimers Res Ther. 2021; 13(1):68. PMC: 8005231. DOI: 10.1186/s13195-021-00804-9. View

16.

Toledo J, Van Deerlin V, Lee E, Suh E, Baek Y, Robinson J . A platform for discovery: The University of Pennsylvania Integrated Neurodegenerative Disease Biobank. Alzheimers Dement. 2013; 10(4):477-484.e1. PMC: 3933464. DOI: 10.1016/j.jalz.2013.06.003. View

17.

Tropea T, Waligorska T, Xie S, Nasrallah I, Cousins K, Trojanowski J . Plasma phosphorylated tau181 predicts cognitive and functional decline. Ann Clin Transl Neurol. 2022; 10(1):18-31. PMC: 9852389. DOI: 10.1002/acn3.51695. View

18.

Baiardi S, Quadalti C, Mammana A, Dellavalle S, Zenesini C, Sambati L . Diagnostic value of plasma p-tau181, NfL, and GFAP in a clinical setting cohort of prevalent neurodegenerative dementias. Alzheimers Res Ther. 2022; 14(1):153. PMC: 9555092. DOI: 10.1186/s13195-022-01093-6. View

19.

De Bastiani M, Bellaver B, Brum W, Souza D, Ferreira P, Rocha A . Hippocampal GFAP-positive astrocyte responses to amyloid and tau pathologies. Brain Behav Immun. 2023; 110:175-184. DOI: 10.1016/j.bbi.2023.03.001. View

20.

Mielke M, Dage J, Frank R, Algeciras-Schimnich A, Knopman D, Lowe V . Performance of plasma phosphorylated tau 181 and 217 in the community. Nat Med. 2022; 28(7):1398-1405. PMC: 9329262. DOI: 10.1038/s41591-022-01822-2. View