The CSF p-tau181/Aβ42 Ratio Offers a Good Accuracy “In Vivo” in the Differential Diagnosis of Alzheimer’s Dementia

Author(s): Roberto Santangelo*, Alessandro Dell'Edera, Arianna Sala, Giordano Cecchetti, Federico Masserini, Francesca Caso, Patrizia Pinto, Letizia Leocani, Monica Falautano, Gabriella Passerini, Vittorio Martinelli, Giancarlo Comi, Daniela Perani, Giuseppe Magnani.

Journal Name: Current Alzheimer Research

Volume 16 , Issue 7 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer


Background: The incoming disease-modifying therapies against Alzheimer’s disease (AD) require reliable diagnostic markers to correctly enroll patients all over the world. CSF AD biomarkers, namely amyloid-β 42 (Aβ42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau181), showed good diagnostic accuracy in detecting AD pathology, but their real usefulness in daily clinical practice is still a matter of debate. Therefore, further validation in complex clinical settings, that is patients with different types of dementia, is needed to uphold their future worldwide adoption.

Methods: We measured CSF AD biomarkers’ concentrations in a sample of 526 patients with a clinical diagnosis of dementia (277 with AD and 249 with Other Type of Dementia, OTD). Brain FDG-PET was also considered in a subsample of 54 patients with a mismatch between the clinical diagnosis and the CSF findings.

Results: A p-tau181/Aβ42 ratio higher than 0.13 showed the best diagnostic performance in differentiating AD from OTD (86% accuracy index, 74% sensitivity, 81% specificity). In cases with a mismatch between clinical diagnosis and CSF findings, brain FDG-PET partially agreed with the p-tau181/Aβ42 ratio, thus determining an increase in CSF accuracy.

Conclusion: The p-tau181/Aβ42 ratio alone might reliably detect AD pathology in heterogeneous samples of patients suffering from different types of dementia. It might constitute a simple, cost-effective and reproducible in vivo proxy of AD suitable to be adopted worldwide not only in daily clinical practice but also in future experimental trials, to avoid the enrolment of misdiagnosed AD patients.

Keywords: Alzheimer's disease, amyloid beta 42, phosphorylated tau, cerebrospinal fluid biomarkers, diagnostic accuracy, dementia.

Karlawish J, Jack CR, Rocca WA, Snyder HM, Carrillo MC. Alzheimer’s disease: the next frontier-Special Report 2017. Alzheimers Dement J Alzheimers Assoc 13(4): 374-80. (2017)
Beach TG, Monsell SE, Phillips LE, Kukull W. Accuracy of the clinical diagnosis of Alzheimer disease at National Institute on Aging Alzheimer Disease Centers, 2005-2010. J Neuropathol Exp Neurol 71(4): 266-73. (2012)
[] [PMID: 22437338]
Harris JM, Thompson JC, Gall C, Richardson AMT, Neary D, du Plessis D, et al. Do NIA-AA criteria distinguish Alzheimer’s disease from frontotemporal dementia? Alzheimers Dement 11(2): 207-15. (2015)
[] [PMID: 25022535]
Fiandaca MS, Mapstone ME, Cheema AK, Federoff HJ. The critical need for defining preclinical biomarkers in Alzheimer’s disease. Alzheimers Dement 10(3): S196-212. (2014)
[] [PMID: 24924671]
Aisen PS, Cummings J, Jack CR Jr, Morris JC, Sperling R, Frölich L, et al. On the path to 2025: understanding the Alzheimer’s disease continuum. Alzheimers Res Ther 9(1): 60. (2017)
[] [PMID: 28793924]
Ahmed RM, Paterson RW, Warren JD, Zetterberg H, O’Brien JT, Fox NC, et al. Biomarkers in dementia: clinical utility and new directions. J Neurol Neurosurg Psychiatry 85(12): 1426-34. (2014)
[] [PMID: 25261571]
Olsson B, Lautner R, Andreasson U, Öhrfelt A, Portelius E, Bjerke M, et al. CSF and blood biomarkers for the diagnosis of Alzheimer’s disease: a systematic review and meta-analysis. Lancet Neurol 15(7): 673-84. (2016)
[] [PMID: 27068280]
Tapiola T, Alafuzoff I, Herukka S-K, Parkkinen L, Hartikainen P, Soininen H, et al. Cerebrospinal fluid beta-amyloid 42 and tau proteins as biomarkers of Alzheimer-type pathologic changes in the brain. Arch Neurol 66(3): 382-9. (2009)
[] [PMID: 19273758]
Mulder C, Verwey NA, van der Flier WM, Bouwman FH, Kok A, van Elk EJ, et al. Amyloid-beta(1-42), total tau, and phosphorylated tau as cerebrospinal fluid biomarkers for the diagnosis of Alzheimer disease. Clin Chem 56(2): 248-53. (2010)
[] [PMID: 19833838]
Rivero-Santana A, Ferreira D, Perestelo-Pérez L, Westman E, Wahlund LO, Sarría A, et al. Cerebrospinal fluid biomarkers for the differential diagnosis between Alzheimer’s disease and frontotemporal lobar degeneration: systematic review, HSROC analysis, and confounding factors. J Alzheimers Dis 55(2): 625-44. (2017)
[] [PMID: 27716663]
Irwin DJ, Trojanowski JQ, Grossman M. Cerebrospinal fluid biomarkers for differentiation of frontotemporal lobar degeneration from Alzheimer’s disease. Front Aging Neurosci 5: 6. (2013)
[] [PMID: 23440936]
Mollenhauer B, Cepek L, Bibl M, Wiltfang J, Schulz-Schaeffer WJ, Ciesielczyk B, et al. Tau protein, Abeta42 and S-100B protein in cerebrospinal fluid of patients with dementia with Lewy bodies. Dement Geriatr Cogn Disord 19(2-3): 164-70. (2005)
[] [PMID: 15637452]
Ewers M, Mattsson N, Minthon L, Molinuevo JL, Antonell A, Popp J, et al. CSF biomarkers for the differential diagnosis of Alzheimer’s disease: a large-scale international multicenter study. Alzheimers Dement 11(11): 1306-15. (2015)
[] [PMID: 25804998]
Ritchie C, Smailagic N, Noel-Storr AH, Ukoumunne O, Ladds EC, Martin S. CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev 3CD010803 (2017)
[] [PMID: 28328043]
Cummings J. Alzheimer’s disease diagnostic criteria: practical applications. Alzheimers Res Ther 4(5): 35. (2012)
[] [PMID: 22947665]
Josephs KA, Petersen RC, Knopman DS, Boeve BF, Whitwell JL, Duffy JR, et al. Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66(1): 41-8. (2006)
[] [PMID: 16401843]
Lippa CF, Smith TW, Swearer JM. Alzheimer’s disease and Lewy body disease: a comparative clinicopathological study. Ann Neurol 35(1): 81-8. (1994)
[] [PMID: 8285597]
Graff-Radford NR. Alzheimer CSF biomarkers may be misleading in normal-pressure hydrocephalus. Neurology 83(17): 1573-5. (2014)
[] [PMID: 25332445]
Levy Nogueira M, Epelbaum S, Steyaert J-M, Dubois B, Schwartz L. Mechanical stress models of Alzheimer’s disease pathology. Alzheimers Dement 12(3): 324-33. (2016)
[] [PMID: 26718585]
Santangelo R, Cecchetti G, Bernasconi MP, Cardamone R, Barbieri A, Pinto P, et al. Cerebrospinal fluid amyloid-β 42, total tau and phosphorylated tau are low in patients with normal pressure hydrocephalus: analogies and differences with Alzheimer’s disease. J Alzheimers Dis 60(1): 183-200. (2017)
[] [PMID: 28826180]
Nägga K, Gottfries J, Blennow K, Marcusson J. Cerebrospinal fluid phospho-tau, total tau and beta-amyloid(1-42) in the differentiation between Alzheimer’s disease and vascular dementia. Dement Geriatr Cogn Disord 14(4): 183-90. (2002)
[] [PMID: 12411760]
Niemantsverdriet E, Feyen BFE, Le Bastard N, Martin JJ, Goeman J, De Deyn PP, et al. Added diagnostic value of cerebrospinal fluid biomarkers for differential dementia diagnosis in an autopsy-confirmed cohort. J Alzheimers Dis 63(1): 373-81. (2018)
[] [PMID: 29614653]
Seeburger JL, Holder DJ, Combrinck M, Joachim C, Laterza O, Tanen M, et al. Cerebrospinal fluid biomarkers distinguish postmortem-confirmed Alzheimer’s disease from other dementias and healthy controls in the OPTIMA cohort. J Alzheimers Dis 44(2): 525-39. (2015)
[] [PMID: 25391385]
Skillbäck T, Farahmand BY, Rosén C, Mattsson N, Nägga K, Kilander L, et al. Cerebrospinal fluid tau and amyloid-β1-42 in patients with dementia. Brain 138(Pt 9): 2716-31. (2015)
[] [PMID: 26133663]
Bombois S, Duhamel A, Salleron J, Deramecourt V, Mackowiak MA, Deken V, et al. A new decision tree combining Abeta 1-42 and p-Tau levels in Alzheimer’s diagnosis. Curr Alzheimer Res 10(4): 357-64. (2013)
[] [PMID: 23061918]
Fourier A, Portelius E, Zetterberg H, Blennow K, Quadrio I, Perret-Liaudet A. Pre-analytical and analytical factors influencing Alzheimer’s disease cerebrospinal fluid biomarker variability. Clin Chim Acta 449: 9-15. (2015)
[] [PMID: 26141614]
Hort J, Bartos A, Pirttilä T, Scheltens P. Use of cerebrospinal fluid biomarkers in diagnosis of dementia across Europe. Eur J Neurol 17(1): 90-6. (2010)
[] [PMID: 19659752]
Verwey NA, van der Flier WM, Blennow K, Clark C, Sokolow S, De Deyn PP, et al. A worldwide multicentre comparison of assays for cerebrospinal fluid biomarkers in Alzheimer’s disease. Ann Clin Biochem 46(Pt 3): 235-40. (2009)
[] [PMID: 19342441]
Ferreira D, Perestelo-Pérez L, Westman E, Wahlund L-O, Sarría A, Serrano-Aguilar P. Meta-review of CSF core biomarkers in alzheimer’s disease: the state-of-the-art after the new revised diagnostic criteria. Front Aging Neurosci 6: 47. (2014)
[] [PMID: 24715863]
Palmqvist S, Hertze J, Minthon L, Wattmo C, Zetterberg H. Blennow Ket al. Comparison of brief cognitive tests and CSF biomarkers in predicting Alzheimer’s disease in mild cognitive impairment: six-year follow-up study. PLoS One 7(6)e38639 (2012)
[] [PMID: 22761691]
Perani D, Cerami C, Caminiti SP, Santangelo R, Coppi E, Ferrari L, et al. Cross-validation of biomarkers for the early differential diagnosis and prognosis of dementia in a clinical setting. Eur J Nucl Med Mol Imaging 43(3): 499-508. (2016)
[] [PMID: 26341365]
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3): 263-9. (2011)
[] [PMID: 21514250]
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 134(Pt 9): 2456-77. (2011)
[] [PMID: 21810890]
Gorno-Tempini ML, Hillis AE, Weintraub S, Mendez MF, Kramer JH, Neuhaus J, et al. Classification of primary progressive aphasia and its variants. Neurology 76(11): 1006-14. (2011)
[] [PMID: 21325651]
Litvan I, Agid Y, Calne D, Campbell G, Dubois B, Duvoisin RC, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP international workshop. Neurology 47(1): 1-9. (1996)
[] [PMID: 8710059]
Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia KP, Borroni B, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology 80(5): 496-503. (2013)
[] [PMID: 23359374]
McKeith IG, Boeve BF, Dickson DW, Halliday G, Taylor JP, Weintraub D, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89(1): 88-100. (2017)
[] [PMID: 28592453]
Erkinjuntti T. Clinical criteria for vascular dementia: the NINDS-AIREN criteria. Dementia 5(3-4): 189-92. (1994)
[PMID: 8087178]
Marmarou A, Bergsneider M, Relkin N, Klinge P, Black PM. Development of guidelines for idiopathic normal-pressure hydrocephalus: introduction. Neurosurgery 57(3): S1-3. (2005)
[] [PMID: 16160424]
Magni E, Binetti G, Bianchetti A, Rozzini R, Trabucchi M. Mini-Mental State Examination: a normative study in Italian elderly population. Eur J Neurol 3(3): 198-202. (1996)
[] [PMID: 21284770]
Morris JC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr 9(1): 173-6. (1997)
[] [PMID: 9447441]
Katz S. Assessing self-maintenance: activities of daily living, mobility, and instrumental activities of daily living. J Am Geriatr Soc 31(12): 721-7. (1983)
[] [PMID: 6418786]
Varrone A, Asenbaum S, Borght TV, Booij J, Nobili F, Någren K, et al. EANM procedure guidelines for PET brain imaging using [<Superscript>18</Superscript>F]FDG, version 2. Eur J Nucl Med Mol Imaging 36(12): 2103. (2009)
[] [PMID: 19838705]
Perani D, Della Rosa PA, Cerami C, Gallivanone F, Fallanca F, Vanoli EG, et al. Validation of an optimized SPM procedure for FDG-PET in dementia diagnosis in a clinical setting. Neuroimage Clin 6: 445-54. (2014)
[] [PMID: 25389519]
Cerami C, Dodich A, Lettieri G, Iannaccone S, Magnani G, Marcone A, et al. Different FDG-PET metabolic patterns at single-subject level in the behavioral variant of fronto-temporal dementia. Cortex 83: 101-12. (2016)
[] [PMID: 27498041]
Kalpouzos G, Eustache F, de la Sayette V, Viader F, Chételat G, Desgranges B. Working memory and FDG-PET dissociate early and late onset Alzheimer disease patients. J Neurol 252(5): 548-58. (2005)
[] [PMID: 15726251]
Drzezga A, Grimmer T, Henriksen G, Stangier I, Perneczky R, Diehl-Schmid J, et al. Imaging of amyloid plaques and cerebral glucose metabolism in semantic dementia and Alzheimer’s disease. Neuroimage 39(2): 619-33. (2008)
[] [PMID: 17962045]
Bousiges O, Cretin B, Lavaux T, Philippi N, Jung B, Hezard S, et al. Diagnostic value of cerebrospinal fluid biomarkers (phospho-Tau181, total-Tau, Aβ42, and Aβ40) in prodromal stage of alzheimer’s disease and dementia with lewy bodies. J Alzheimers Dis 51(4): 1069-83. (2016)
[] [PMID: 26923009]
Parnetti L, Chiasserini D, Eusebi P, Giannandrea D, Bellomo G, De Carlo C, et al. Performance of aβ1-40, aβ1-42, total tau, and phosphorylated tau as predictors of dementia in a cohort of patients with mild cognitive impairment. J Alzheimers Dis 29(1): 229-38. (2012)
[] [PMID: 22232006]
Schoonenboom NSM, Reesink FE, Verwey NA, Kester MI, Teunissen CE, van de Ven PM, et al. Cerebrospinal fluid markers for differential dementia diagnosis in a large memory clinic cohort. Neurology 78(1): 47-54. (2012)
[] [PMID: 22170879]
Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 14(4): 535-62. (2018)
[] [PMID: 29653606]
Abu-Rumeileh S, Giannini G, Polischi B, Albini-Riccioli L, Milletti D, Oppi F, et al. Revisiting the cerebrospinal fluid biomarker profile in idiopathic normal pressure hydrocephalus: the bologna pro-hydro study. J Alzheimers Dis 68(2): 723-33. (2019)
[] [PMID: 30883350]
Consensus report of the Working Group on: “Molecular and Biochemical Markers of Alzheimer’s Disease. Neurobiol Aging 19(2): 109-16. (1998)
[PMID: 9558143]
Silverman DH, Small GW, Chang CY, Lu CS, Kung De Aburto MA, Chen W, et al. Positron emission tomography in evaluation of dementia: Regional brain metabolism and long-term outcome. JAMA 286(17): 2120-7. (2001)
[] [PMID: 11694153]
Elias A, Woodward M, Rowe CC. Management impact of FDG-PET in dementia: results from a tertiary center memory clinic. J Alzheimers Dis 42(3): 885-92. (2014)
[] [PMID: 24961944]
Sarikaya I, Sarikaya A, Elgazzar AH. Current status of 18F-FDG PET brain imaging in patients with dementia. J Nucl Med Technol 46(4): 362-7. (2018)
[] [PMID: 30076253]
Rahimi J, Kovacs GG. Prevalence of mixed pathologies in the aging brain. Alzheimers Res Ther 6(9): 82. (2014)
[] [PMID: 25419243]
Savva GM, Wharton SB, Ince PG, Forster G, Matthews FE, Brayne C. Age, neuropathology, and dementia. N Engl J Med 360(22): 2302-9. (2009)
[] [PMID: 19474427]
Ossenkoppele R, Jansen WJ, Rabinovici GD, Knol DL, van der Flier WM, van Berckel BN, et al. Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA 313(19): 1939-49. (2015)
[] [PMID: 25988463]
Ballard C, Ziabreva I, Perry R, et al. Differences in neuropathologic characteristics across the Lewy body dementia spectrum. Neurology 67(11): 1931-4. (2006)
[] [PMID: 17159096]
Howlett DR, Whitfield D, Johnson M, Attems J, O’Brien JT, Aarsland D, et al. Regional multiple pathology scores are associated with cognitive decline in lewy body dementias. Brain Pathol 25(4): 401-8. (2015)
[] [PMID: 25103200]
Kraybill ML, Larson EB, Tsuang DW, Teri L, McCormick WC, Bowen JD, et al. Cognitive differences in dementia patients with autopsy-verified AD, Lewy body pathology, or both. Neurology 64(12): 2069-73. (2005)
[] [PMID: 15985574]
Kapaki E, Paraskevas GP, Papageorgiou SG, Bonakis A, Kalfakis N, Zalonis I, et al. Diagnostic value of CSF biomarker profile in frontotemporal lobar degeneration. Alzheimer Dis Assoc Disord 22(1): 47-53. (2008)
[] [PMID: 18317246]
Schoonenboom NSM, Pijnenburg YA, Mulder C, Rosso SM, Van Elk EJ, Van Kamp GJ, et al. Amyloid beta(1-42) and phosphorylated tau in CSF as markers for early-onset Alzheimer disease. Neurology 62(9): 1580-4. (2004)
[] [PMID: 15136685]

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [587 - 595]
Pages: 9
DOI: 10.2174/1567205016666190725150836
Price: $58

Article Metrics

PDF: 34