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Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer's disease dementia in mild cognitive impairment.
Alzheimers Res Ther. 2018 03 20; 10(1):33.AR

Abstract

BACKGROUND

Cerebrospinal fluid (CSF) biomarkers have been used to increase the evidence of underlying Alzheimer's disease (AD) pathology in mild cognitive impairment (MCI). However, CSF biomarker-based classification often results in conflicting profiles with controversial prognostic value. Normalization of the CSF Aβ42 concentration to the level of total amyloid beta (Aβ), using the Aβ42/40 ratio, has been shown to improve the distinction between AD and non-AD dementia. Therefore, we evaluated whether the Aβ42/40 ratio would improve MCI categorization and more accurately predict progression to AD.

METHODS

Our baseline population consisted of 197 MCI patients, of which 144 had a follow-up ≥ 2 years, and comprised the longitudinal study group. To establish our own CSF Aβ42/40 ratio reference value, a group of 168 AD-dementia patients and 66 neurological controls was also included. CSF biomarker-based classification was operationalized according to the framework of the National Institute of Aging-Alzheimer Association criteria for MCI.

RESULTS

When using the core CSF biomarkers (Aβ42, total Tau and phosphorylated Tau), 30% of the patients fell into the high-AD-likelihood (HL) group (both amyloid and neurodegeneration markers positive), 30% into the low-AD-likelihood group (all biomarkers negative), 28% into the suspected non-Alzheimer pathophysiology (SNAP) group (only neurodegeneration markers positive) and 12% into the isolated amyloid pathology group (only amyloid-positive). Replacing Aβ42 by the Aβ42/40 ratio resulted in a significant increase in the percentage of patients with amyloidosis (42-59%) and in the proportion of interpretable biological profiles (61-75%), due to a reduction by half in the number of SNAP cases and an increase in the proportion of the HL subgroup. Survival analysis showed that risk of progression to AD was highest in the HL group, and increased when the Aβ42/40 ratio, instead of Aβ42, combined with total Tau and phosphorylated Tau was used for biomarker-based categorization.

CONCLUSIONS

Our results confirm the usefulness of the CSF Aβ42/40 ratio in the interpretation of CSF biomarker profiles in MCI patients, by increasing the proportion of conclusive profiles and enhancing their predictive value for underlying AD.

Authors+Show Affiliations

Laboratory of Neurochemistry, Neurology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal. ines.baldeiras@sapo.pt. Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal. ines.baldeiras@sapo.pt. Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal. ines.baldeiras@sapo.pt.Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal. Faculty of Medicine, University of Coimbra, 3000-548, Coimbra, Portugal. Dementia Clinic, Neurology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal.Laboratory of Neurochemistry, Neurology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal. Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.Dementia Clinic, Neurology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal.Laboratory of Neurochemistry, Neurology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal.Dementia Clinic, Neurology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal.Dementia Clinic, Neurology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal.Dementia Clinic, Neurology Department, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal.Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal.Center for Neuroscience and Cell Biology, University of Coimbra, 3004-504, Coimbra, Portugal. Research & Development Unit, Centro Hospitalar e Universitário de Coimbra, 3000-075, Coimbra, Portugal.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29558986

Citation

Baldeiras, Inês, et al. "Addition of the Aβ42/40 Ratio to the Cerebrospinal Fluid Biomarker Profile Increases the Predictive Value for Underlying Alzheimer's Disease Dementia in Mild Cognitive Impairment." Alzheimer's Research & Therapy, vol. 10, no. 1, 2018, p. 33.
Baldeiras I, Santana I, Leitão MJ, et al. Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer's disease dementia in mild cognitive impairment. Alzheimers Res Ther. 2018;10(1):33.
Baldeiras, I., Santana, I., Leitão, M. J., Gens, H., Pascoal, R., Tábuas-Pereira, M., Beato-Coelho, J., Duro, D., Almeida, M. R., & Oliveira, C. R. (2018). Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer's disease dementia in mild cognitive impairment. Alzheimer's Research & Therapy, 10(1), 33. https://doi.org/10.1186/s13195-018-0362-2
Baldeiras I, et al. Addition of the Aβ42/40 Ratio to the Cerebrospinal Fluid Biomarker Profile Increases the Predictive Value for Underlying Alzheimer's Disease Dementia in Mild Cognitive Impairment. Alzheimers Res Ther. 2018 03 20;10(1):33. PubMed PMID: 29558986.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Addition of the Aβ42/40 ratio to the cerebrospinal fluid biomarker profile increases the predictive value for underlying Alzheimer's disease dementia in mild cognitive impairment. AU - Baldeiras,Inês, AU - Santana,Isabel, AU - Leitão,Maria João, AU - Gens,Helena, AU - Pascoal,Rui, AU - Tábuas-Pereira,Miguel, AU - Beato-Coelho,José, AU - Duro,Diana, AU - Almeida,Maria Rosário, AU - Oliveira,Catarina Resende, Y1 - 2018/03/20/ PY - 2017/12/15/received PY - 2018/02/25/accepted PY - 2018/3/22/entrez PY - 2018/3/22/pubmed PY - 2019/8/28/medline KW - Alzheimer’s disease KW - Aβ42/40 ratio KW - CSF biomarkers KW - Mild cognitive impairment SP - 33 EP - 33 JF - Alzheimer's research & therapy JO - Alzheimers Res Ther VL - 10 IS - 1 N2 - BACKGROUND: Cerebrospinal fluid (CSF) biomarkers have been used to increase the evidence of underlying Alzheimer's disease (AD) pathology in mild cognitive impairment (MCI). However, CSF biomarker-based classification often results in conflicting profiles with controversial prognostic value. Normalization of the CSF Aβ42 concentration to the level of total amyloid beta (Aβ), using the Aβ42/40 ratio, has been shown to improve the distinction between AD and non-AD dementia. Therefore, we evaluated whether the Aβ42/40 ratio would improve MCI categorization and more accurately predict progression to AD. METHODS: Our baseline population consisted of 197 MCI patients, of which 144 had a follow-up ≥ 2 years, and comprised the longitudinal study group. To establish our own CSF Aβ42/40 ratio reference value, a group of 168 AD-dementia patients and 66 neurological controls was also included. CSF biomarker-based classification was operationalized according to the framework of the National Institute of Aging-Alzheimer Association criteria for MCI. RESULTS: When using the core CSF biomarkers (Aβ42, total Tau and phosphorylated Tau), 30% of the patients fell into the high-AD-likelihood (HL) group (both amyloid and neurodegeneration markers positive), 30% into the low-AD-likelihood group (all biomarkers negative), 28% into the suspected non-Alzheimer pathophysiology (SNAP) group (only neurodegeneration markers positive) and 12% into the isolated amyloid pathology group (only amyloid-positive). Replacing Aβ42 by the Aβ42/40 ratio resulted in a significant increase in the percentage of patients with amyloidosis (42-59%) and in the proportion of interpretable biological profiles (61-75%), due to a reduction by half in the number of SNAP cases and an increase in the proportion of the HL subgroup. Survival analysis showed that risk of progression to AD was highest in the HL group, and increased when the Aβ42/40 ratio, instead of Aβ42, combined with total Tau and phosphorylated Tau was used for biomarker-based categorization. CONCLUSIONS: Our results confirm the usefulness of the CSF Aβ42/40 ratio in the interpretation of CSF biomarker profiles in MCI patients, by increasing the proportion of conclusive profiles and enhancing their predictive value for underlying AD. SN - 1758-9193 UR - https://www.unboundmedicine.com/medline/citation/29558986/Addition_of_the_Aβ42/40_ratio_to_the_cerebrospinal_fluid_biomarker_profile_increases_the_predictive_value_for_underlying_Alzheimer's_disease_dementia_in_mild_cognitive_impairment_ L2 - https://alzres.biomedcentral.com/articles/10.1186/s13195-018-0362-2 DB - PRIME DP - Unbound Medicine ER -