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Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets

Alzheimer's disease (AD) is characterized by an accumulation of β-amyloid (Aβ(42)) accompanied by brain atrophy and cognitive decline. Several recent studies have shown that Aβ(42) accumulation is associated with gray matter (GM) changes prior to the development of cognitive impairment, in the...

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Autores principales: Falcon, Carles, Tucholka, Alan, Monté-Rubio, Gemma C., Cacciaglia, Raffaele, Operto, Grégory, Rami, Lorena, Gispert, Juan Domingo, Molinuevo, José Luis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050455/
https://www.ncbi.nlm.nih.gov/pubmed/30023169
http://dx.doi.org/10.1016/j.nicl.2018.04.016
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author Falcon, Carles
Tucholka, Alan
Monté-Rubio, Gemma C.
Cacciaglia, Raffaele
Operto, Grégory
Rami, Lorena
Gispert, Juan Domingo
Molinuevo, José Luis
author_facet Falcon, Carles
Tucholka, Alan
Monté-Rubio, Gemma C.
Cacciaglia, Raffaele
Operto, Grégory
Rami, Lorena
Gispert, Juan Domingo
Molinuevo, José Luis
author_sort Falcon, Carles
collection PubMed
description Alzheimer's disease (AD) is characterized by an accumulation of β-amyloid (Aβ(42)) accompanied by brain atrophy and cognitive decline. Several recent studies have shown that Aβ(42) accumulation is associated with gray matter (GM) changes prior to the development of cognitive impairment, in the so-called preclinical stage of the AD (pre-AD). It also has been proved that the GM atrophy profile is not linear, both in normal ageing but, especially, on AD. However, several other factors may influence this association and may have an impact on the generalization of results from different samples. In this work, we estimate differences in rates of GM volume change in cognitively healthy elders in association with baseline core cerebrospinal fluid (CSF) AD biomarkers, and assess to what these differences are sample dependent. We report the dependence of atrophy rates, measured in a two-year interval, on Aβ(42), computed both over continuous and categorical values of Aβ(42), at voxel-level (p < 0.001; k < 100) and corrected for sex, age and education. Analyses were performed jointly and separately, on two samples. The first sample was formed of 31 individuals (22 Ctrl and 9 pre-AD), aged 60–80 and recruited at the Hospital Clinic of Barcelona. The second sample was a replica of the first one with subjects selected from the ADNI dataset. We also investigated the dependence of the GM atrophy rate on the basal levels of continuous p-tau and on the p-tau/Aβ(42) ratio. Correlation analyses on the whole sample showed a dependence of GM atrophy rates on Aβ(42) in medial and orbital frontal, precuneus, cingulate, medial temporal regions and cerebellum. Correlations with p-tau were located in the left hippocampus, parahippocampus and striatal nuclei whereas correlation with p-tau/Aβ(42) was mainly found in ventral and medial temporal areas. Regarding analyses performed separately, we found a substantial discrepancy of results between samples, illustrating the complexities of comparing two independent datasets even when using the same inclusion criteria. Such discrepancies may lead to significant differences in the sample size needed to detect a particular reduction on cerebral atrophy rates in prevention trials. Higher cognitive reserve and more advanced pathological progression in the ADNI sample could partially account for the observed discrepancies. Taken together, our findings in these two samples highlight the importance of comparing and merging independent datasets to draw more robust and generalizable conclusions on the structural changes in the preclinical stages of AD.
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spelling pubmed-60504552018-07-18 Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets Falcon, Carles Tucholka, Alan Monté-Rubio, Gemma C. Cacciaglia, Raffaele Operto, Grégory Rami, Lorena Gispert, Juan Domingo Molinuevo, José Luis Neuroimage Clin Regular Article Alzheimer's disease (AD) is characterized by an accumulation of β-amyloid (Aβ(42)) accompanied by brain atrophy and cognitive decline. Several recent studies have shown that Aβ(42) accumulation is associated with gray matter (GM) changes prior to the development of cognitive impairment, in the so-called preclinical stage of the AD (pre-AD). It also has been proved that the GM atrophy profile is not linear, both in normal ageing but, especially, on AD. However, several other factors may influence this association and may have an impact on the generalization of results from different samples. In this work, we estimate differences in rates of GM volume change in cognitively healthy elders in association with baseline core cerebrospinal fluid (CSF) AD biomarkers, and assess to what these differences are sample dependent. We report the dependence of atrophy rates, measured in a two-year interval, on Aβ(42), computed both over continuous and categorical values of Aβ(42), at voxel-level (p < 0.001; k < 100) and corrected for sex, age and education. Analyses were performed jointly and separately, on two samples. The first sample was formed of 31 individuals (22 Ctrl and 9 pre-AD), aged 60–80 and recruited at the Hospital Clinic of Barcelona. The second sample was a replica of the first one with subjects selected from the ADNI dataset. We also investigated the dependence of the GM atrophy rate on the basal levels of continuous p-tau and on the p-tau/Aβ(42) ratio. Correlation analyses on the whole sample showed a dependence of GM atrophy rates on Aβ(42) in medial and orbital frontal, precuneus, cingulate, medial temporal regions and cerebellum. Correlations with p-tau were located in the left hippocampus, parahippocampus and striatal nuclei whereas correlation with p-tau/Aβ(42) was mainly found in ventral and medial temporal areas. Regarding analyses performed separately, we found a substantial discrepancy of results between samples, illustrating the complexities of comparing two independent datasets even when using the same inclusion criteria. Such discrepancies may lead to significant differences in the sample size needed to detect a particular reduction on cerebral atrophy rates in prevention trials. Higher cognitive reserve and more advanced pathological progression in the ADNI sample could partially account for the observed discrepancies. Taken together, our findings in these two samples highlight the importance of comparing and merging independent datasets to draw more robust and generalizable conclusions on the structural changes in the preclinical stages of AD. Elsevier 2018-04-16 /pmc/articles/PMC6050455/ /pubmed/30023169 http://dx.doi.org/10.1016/j.nicl.2018.04.016 Text en © 2018 Published by Elsevier Inc. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Regular Article
Falcon, Carles
Tucholka, Alan
Monté-Rubio, Gemma C.
Cacciaglia, Raffaele
Operto, Grégory
Rami, Lorena
Gispert, Juan Domingo
Molinuevo, José Luis
Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets
title Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets
title_full Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets
title_fullStr Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets
title_full_unstemmed Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets
title_short Longitudinal structural cerebral changes related to core CSF biomarkers in preclinical Alzheimer's disease: A study of two independent datasets
title_sort longitudinal structural cerebral changes related to core csf biomarkers in preclinical alzheimer's disease: a study of two independent datasets
topic Regular Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050455/
https://www.ncbi.nlm.nih.gov/pubmed/30023169
http://dx.doi.org/10.1016/j.nicl.2018.04.016
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