@article {aCumplido-Mayoral, title = {The mediating role of neuroimaging-derived biological brain age between risk factors for dementia and cognitive decline in middle/late-aged asymptomatic individuals: a cohort study}, journal = {The Lancet Healthy Longevity}, year = {Submitted}, author = {Irene Cumplido-Mayoral and Anna Brugulat-Serra and Gonzalo S{\'a}nchez-Benavides and Jose Luis Molinuevo and Marc Suarez-Calvet and Ver{\'o}nica Vilaplana and Juan Domingo Gispert} } @article {aCumplido-Mayoral22, title = {Biological Brain Age Prediction Using Machine Learning on Structural Neuroimaging Data: Multi-Cohort Validation Against Biomarkers of Alzheimer{\textquoteright}s Disease and Neurodegeneration stratified by sex}, journal = {eLife}, volume = {12}, year = {2023}, month = {04/2023}, abstract = {

Brain-age can be inferred from structural neuroimaging and compared to chronological age (brain-age delta) as a marker of biological brain aging. Accelerated aging has been found in neurodegenerative disorders like Alzheimer9s disease (AD), but its validation against markers of neurodegeneration and AD is lacking. Here, imaging-derived measures from the UK Biobank dataset (N=22,661) were used to predict brain-age in 2,314 cognitively unimpaired (CU) individuals at higher risk of AD and mild cognitive impaired (MCI) patients from four independent cohorts with available biomarker data: ALFA+, ADNI, EPAD and OASIS. Brain-age delta was associated with abnormal amyloid-β, more advanced stages (AT) of AD pathology and APOE-ε4 status. Brain-age delta was positively associated with plasma neurofilament light, a marker of neurodegeneration, and sex differences in the brain effects of this marker were found. These results validate brain-age delta as a non-invasive marker of biological brain aging related to markers of AD and neurodegeneration.

}, issn = {2050-084X}, doi = {https://doi.org/10.7554/eLife.81067}, author = {Irene Cumplido-Mayoral and Marina Garc{\'\i}a-Prat and Gregory Operto and Carles Falcon and Mahnaz Shekari and Raffaele Cacciaglia and Marta Mila-Aloma and Luigi Lorenzini and Carolina Minguillon and Jose Luis Molinuevo and Marc Suarez-Calvet and Ver{\'o}nica Vilaplana and Juan Domingo Gispert} } @conference {cCumplido-Mayoral23, title = {Brain-age prediction and its associations with glial and synaptic CSF markers}, booktitle = {Alzheimer{\textquoteright}s Association International Conference}, year = {2023}, month = {07/2023}, address = {Amsterdam, Netherlands}, author = {Irene Cumplido-Mayoral and Marta Mila-Aloma and Carles Falcon and Raffaele Cacciaglia and Carolina Minguillon and Karine Fauria and Jose Luis Molinuevo and Ver{\'o}nica Vilaplana and Juan D. Gispert} } @conference {cMayoral21a, title = {Brain structural alterations in cognitively unimpaired individuals with discordant amyloid-β PET and CSF Aβ42 status: findings using Machine Learning}, booktitle = {Alzheimer{\textquoteright}s Association International Conference}, year = {2021}, month = {07/2021}, author = {Irene Cumplido-Mayoral and Mahnaz Shekari and Gemma Salvad{\'o} and Greg Operto and Raffaele Cacciaglia and Carles Falcon and Aida Ni{\~n}erola Baiz{\'a}n and Andr{\'e}s Perissinotti and Carolina Minguillon and Karine Fauria and Ivonne Suridjan and Gwendlyn Kollmorgen and Jose Luis Molinuevo and Henrik Zetterberg and Kaj Blennow and Marc Suarez Calvet and Ver{\'o}nica Vilaplana and Juan D. Gispert} } @conference {cMayoral21, title = {Machine learning on combined neuroimaging and plasma biomarkers for triaging participants of secondary prevention trials in Alzheimer{\textquoteright}s Disease}, booktitle = {Alzheimer{\textquoteright}s Association International Conference}, year = {2021}, month = {07/2021}, author = {Irene Cumplido-Mayoral and Gemma Salvad{\'o} and Mahnaz Shekari and Carles Falcon and Marta Mil{\`a} Alom{\`a} and Aida Ni{\~n}erola Baiz{\'a}n and Jose Luis Molinuevo and Henrik Zetterberg and Kaj Blennow and Marc Suarez Calvet and Ver{\'o}nica Vilaplana and Juan D. Gispert} } @conference {cMayoral21b, title = {Prediction of amyloid pathology in cognitively unimpaired individuals using structural MRI}, booktitle = {Alzheimer{\textquoteright}s Association International Conference}, year = {2021}, month = {07/2021}, author = {Irene Cumplido-Mayoral and Silvia Ingala and Luigi Lorenzini and Alle Meije Wink and Sven Haller and Jose Luis Molinuevo and Robin Wolz and Alessandro Palombit and Adam J Schwarz and Ga{\"e}l Chetelat and Pierre Payoux and Pablo Martinez-Lage and Giovanni Frisoni and Nick C Fox and Craig W Ritchie and Joanna M Wardlaw and Adam Waldman and Frederik Barkhof and Ver{\'o}nica Vilaplana and Juan D. Gispert} } @article {aCasamitjanac, title = {Projection to Latent Spaces disentangles pathological effects on brain morphology in the asymptomatic phase of Alzheimer{\textquoteright}s disease}, journal = {Frontiers in Neurology, section Applied Neuroimaging}, volume = {11}, year = {2020}, month = {07/2020}, chapter = {648}, abstract = {

Alzheimer{\textquoteright}s disease (AD) continuum is defined as a cascade of several neuropathological processes that can be measured using biomarkers such as cerebrospinal fluid (CSF) levels of Aβ, p-tau and t-tau. In parallel, brain anatomy can be characterized through imaging techniques such as magnetic resonance imaging (MRI). In this work, we relate both sets of measurements seeking associations between biomarkers and brain structure that can be indicative of AD progression. The goal is to uncover underlying multivariate effects of AD pathology on regional brain morphological information. For this purpose, we use the projection to latent structures (PLS)\ method. Using PLS, we find a low dimensional latent space that best describes the covariance between both sets of measurements on the same subjects. Possible confounder effects (age and sex) on brain morphology are included in the model and regressed out using an orthogonal PLS model. We look for statistically significant correlations between brain morphology and CSF biomarkers that explain part of the volumetric variance at each region-of-interest (ROI). Furthermore, we use a clustering technique to discover a small set of CSF-related patterns describing the AD continuum. We apply this technique to the study of subjects in the whole AD continuum from the preclinical asymptomatic stages all through to the symptomatic groups. Subsequent analyses involve splitting the course of the disease into diagnostic categories: cognitively unimpaired subjects (CU), mild cognitive impaired subjects (MCI) and dementia subjects (AD-dementia) where all symptoms are due to AD.

}, keywords = {Alzheimer{\textquoteright}s disease, brain morphology, CSF biomarkers, Latent model, PLS, preclinical AD}, author = {Adri{\`a} Casamitjana and Paula Petrone and Jose Luis Molinuevo and Juan D. Gispert and Ver{\'o}nica Vilaplana} } @article {aPetrone, title = {Prediction of amyloid pathology in cognitively unimpaired individuals using voxelwise analysis of longitudinal structural brain MRI}, journal = {Alzheimer{\textquoteright}s Research \& Therapy}, volume = {11}, year = {2019}, month = {12/2019}, abstract = {

Background: Magnetic resonance imaging (MRI) has unveiled specific alterations at different stages of Alzheimer{\textquoteright}s disease (AD) pathophysiologic continuum constituting what has been established as {\textquoteleft}AD signature{\textquoteright}. To what extent MRI can detect amyloid-related cerebral changes from structural MRI in cognitively unimpaired individuals is still an area open for exploration.

Method: Longitudinal 3D-T1 MRI scans were acquired from a subset of the ADNI cohort comprising 403 subjects: 79 controls (Ctrls), 50 preclinical AD (PreAD), 274 MCI and dementia due to AD (MCI/AD). Amyloid CSF was used as gold-standard measure with established cut-offs (\<192pg/mL) to establish diagnostic categories. Cognitively unimpaired individuals were defined as Ctrls if were amyloid negative and PreAD otherwise. The MCI/AD group was amyloid positive. Only subjects with the same diagnostic category at baseline and follow-up visits were considered for the study. Longitudinal morphometric analysis was performed using SPM12 to calculate Jacobian determinant maps. Statistical analysis was carried out on these jacobian maps to identify structural changes that were significantly different between diagnostic categories. A machine learning classifier was applied on Jacobian determinant maps to predict the presence of abnormal amyloid levels in cognitively unimpaired individuals. The performance of this classifier was evaluated using receiver operating characteristic curve analysis and as a function of the follow-up time between MRI scans. We applied a cost function to assess the benefit of using this classifier in the triaging of individuals in a clinical trial-recruitment setting.

Results: The optimal follow-up time for classification of Ctrls vs PreAD was Δt\>2.5 years and hence, only subjects within this temporal span are used for evaluation (15 Ctrls, 10 PreAD). The longitudinal voxel-based classifier achieved an AUC=0.87 (95\%CI:0.72-0.97). The brain regions that showed the highest discriminative power to detect amyloid abnormalities were the medial, inferior and lateral temporal lobes, precuneus, caudate heads, basal forebrain and lateral ventricles.

Conclusions: Our work supports that machine learning applied to longitudinal brain volumetric changes can be used to predict, with high precision, presence of amyloid abnormalities in cognitively unimpaired subjects. Used as a triaging method to identify a fixed number of amyloid positive individuals, this longitudinal voxelwise classifier is expected to avoid 55\% of unnecessary CSF and/or PET scans and reduce economic cost by 40\%.

}, doi = {https://doi.org/10.1186/s13195-019-0526-8}, url = {https://link.springer.com/article/10.1186/s13195-019-0526-8}, author = {Paula Petrone and Adri{\`a} Casamitjana and Carles Falcon and Miguel Artigues C{\`a}naves and G. Operto and R. Cacciaglia and Jose Luis Molinuevo and Ver{\'o}nica Vilaplana and Juan D. Gispert} } @article {aCasamitjana, title = {MRI-Based Screening of Preclinical Alzheimer{\textquoteright}s Disease for Prevention Clinical Trials}, journal = {Journal of Alzheimer{\textquoteright}s Disease}, volume = {64}, year = {2018}, month = {07/2018}, chapter = {1099}, abstract = {

The identification of healthy individuals harboring amyloid pathology constitutes one important challenge for secondary prevention clinical trials in Alzheimer{\textquoteright}s disease (AD). Consequently, noninvasive and cost-efficient techniques to detect preclinical AD constitute an unmet need of critical importance. In this manuscript, we apply machine learning to structural MRI (T1 and DTI) of 96 cognitively normal subjects to identify amyloid-positive ones. Models were trained on public ADNI data and validated on an independent local cohort. Used for subject classification in a simulated clinical trial setting, the proposed method is able to save 60\% unnecessary CSF/PET tests and to reduce 47\% of the cost of recruitment when used in a simulated clinical trial setting. This recruitment strategy capitalizes on already acquired MRIs to reduce the overall amount of invasive PET/CSF tests in prevention trials, demonstrating a potential value as a tool for AD screening. This protocol could foster the development of secondary prevention strategies for AD.

}, author = {Adri{\`a} Casamitjana and Paula Petrone and Alan Tucholka and Carles Falcon and Stavros Skouras and Jose Luis Molinuevo and Ver{\'o}nica Vilaplana and Juan D. Gispert} } @conference {cCasamitjanac, title = {Shared latent structures between imaging features and biomarkers in early stages of Alzheimer{\textquoteright}s disease}, booktitle = {Workshop on Predictive Intelligence in Medicine (PRIME), MICCAI}, year = {2018}, month = {2018}, address = {Granada, Spain}, abstract = {

In this work, we identify meaningful latent patterns in MR images for patients across the Alzheimer{\textquoteright}s disease (AD) continuum. For this purpose, we apply Projection to Latent Structures (PLS) method using cerebrospinal fluid (CSF) biomarkers (t-tau, p-tau, amyloid-beta) and age as response variables and imaging features as explanatory variables. Freesurfer pipeline is used to compute MRI surface and volumetric features\  \ resulting in 68 cortical ROIs and 84 cortical and subcortical ROIs, respectively. The main assumption of this work is that there are two main underlying processes governing brain morphology along the AD continuum: brain aging and dementia. We use two different and orthogonal PLS models to describe each process: PLS-aging and PLS-dementia. To define PLS-aging model we use normal aging subjects and age as predictor and response variables, respectively, while for PLS-dementia we only use demented subjects and biomarkers as response variables.\ 

}, author = {Adri{\`a} Casamitjana and Ver{\'o}nica Vilaplana and Paula Petrone and Jose Luis Molinuevo and Juan D. Gispert} } @inbook {bCasamitjana18a, title = {Shared Latent Structures Between Imaging Features and Biomarkers in Early Stages of Alzheimer{\textquoteright}s Disease}, booktitle = {PRedictive Intelligence in MEdicine}, volume = {11121}, year = {2018}, pages = {60-67}, publisher = {Springer International Publishing}, organization = {Springer International Publishing}, abstract = {

In this work, we identify meaningful latent patterns in MR images for patients across the Alzheimer{\textquoteright}s disease (AD) continuum. For this purpose, we apply Projection to Latent Structures (PLS) method using cerebrospinal fluid (CSF) biomarkers (t-tau, p-tau, amyloid-beta) and age as response variables and imaging features as explanatory variables. Freesurfer pipeline is used to compute MRI surface and volumetric features resulting in 68 cortical ROIs and 84 cortical and subcortical ROIs, respectively. The main assumption of this work is that there are two main underlying processes governing brain morphology along the AD continuum: brain aging and dementia. We use two different and orthogonal PLS models to describe each process: PLS-aging and PLS-dementia. To define PLS-aging model we use normal aging subjects and age as predictor and response variables, respectively, while for PLS-dementia we only use demented subjects and biomarkers as response variables.

}, issn = {978-3-030-00320-3}, doi = {10.1007/978-3-030-00320-3}, author = {Adri{\`a} Casamitjana and Ver{\'o}nica Vilaplana and Paula Petrone and Jose Luis Molinuevo and Juan D. Gispert} }