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Comprehensive Analysis of Genetic Contributions to Alzheimer’s Disease and Frontotemporal Dementia in Admixed Latin American Populations
(Wiley, 2024-12)
Juliana Acosta‐Uribe
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Stefanie Danielle Pina Escudero
;
J. Nicholas Cochran
;
Jared W Taylor
;
Caroline Warly Solsberg
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Most research initiatives have emerged from high‐income countries (HIC), leaving a gap in understanding the disease’s genetic basis in diverse populations like those in Latin American countries (LAC). ReDLat tackles this gap, focusing on LAC’s unique genetics and socioeconomic factors to identify specific Alzheimer’s Disease (AD) and Frontotemporal Dementia (FTD) risk factors in Mexico, Colombia, Peru, Chile, Argentina, and Brazil.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>We employed a comprehensive genetic analysis approach, integrating Whole Genome Sequencing (WGS), Exome Sequencing, and SNP arrays to understand the cohort’s unique genetic architecture. We conducted ancestry analysis and searched for disease‐causing variants with mendelian inheritance, genome‐wide association studies (GWAS), rare variant enrichment, and evaluation of Polygenic Risk Scores (PRS).</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>We recruited and genotyped an initial cohort of 1046 participants with AD, 423 with FTD, and 855 healthy controls (HC) between 2020 and 2023. Analysis is ongoing, and we expect to sequence ∼600 additional samples in the coming months. Ancestry analysis revealed tri‐continental admixture, except for Brazil, which showed an additional Asian component (Figure 1). Top candidate gene rare variant enrichment associations (SKAT p < 0.05) were <jats:italic>TREM2</jats:italic> for FTD and <jats:italic>ABCA7</jats:italic> and <jats:italic>ABCA1</jats:italic> for AD. GWAS identified a robust association with the <jats:italic>APOE</jats:italic> locus on chromosome 19 in AD vs. HC.. We tested an AD PRS developed in European populations by Bellenguez et al (2020). on our cohort using 83 single‐nucleotide polymorphisms.. The PRS modestly distinguishes between all patients and HC (p = 2.4 × 10^‐12), AD vs. HC (p = 2.2 × 10^‐12), and even FTD vs. HC (p = 4.3 × 10^‐5), albeit with modest separation between groups, as expected for its application in a genetically admixed population.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Our findings represent a pivotal step in understanding the genetic landscape of AD and FTD in admixed populations. They underscore the importance of including diverse populations in genetic research, paving the way for future studies. These findings have the potential to inform more personalized approaches to the diagnosis and treatment of neurodegenerative diseases in diverse global populations, as well as identify novel targets for therapeutic development.</jats:p></jats:sec>
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Multivariate word properties in fluency tasks reveal markers of Alzheimer's dementia
(2023)
Franco J. Ferrante
;
Joaquín Migeot
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Agustina Birba
;
Lucía Amoruso
;
Gonzalo Pérez
<jats:title>Abstract</jats:title><jats:sec><jats:title>INTRODUCTION</jats:title><jats:p>Verbal fluency tasks are common in Alzheimer's disease (AD) assessments. Yet, standard valid response counts fail to reveal disease‐specific semantic memory patterns. Here, we leveraged automated word‐property analysis to capture neurocognitive markers of AD vis‐à‐vis behavioral variant frontotemporal dementia (bvFTD).</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>Patients and healthy controls completed two fluency tasks. We counted valid responses and computed each word's frequency, granularity, neighborhood, length, familiarity, and imageability. These features were used for group‐level discrimination, patient‐level identification, and correlations with executive and neural (magnetic resonanance imaging [MRI], functional MRI [fMRI], electroencephalography [EEG]) patterns.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Valid responses revealed deficits in both disorders. Conversely, frequency, granularity, and neighborhood yielded robust group‐ and subject‐level discrimination only in AD, also predicting executive outcomes. Disease‐specific cortical thickness patterns were predicted by frequency in both disorders. Default‐mode and salience network hypoconnectivity, and EEG beta hypoconnectivity, were predicted by frequency and granularity only in AD.</jats:p></jats:sec><jats:sec><jats:title>DISCUSSION</jats:title><jats:p>Word‐property analysis of fluency can boost AD characterization and diagnosis.</jats:p></jats:sec><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="bullet"> <jats:list-item><jats:p>We report novel word‐property analyses of verbal fluency in AD and bvFTD.</jats:p></jats:list-item> <jats:list-item><jats:p>Standard valid response counts captured deficits and brain patterns in both groups.</jats:p></jats:list-item> <jats:list-item><jats:p>Specific word properties (e.g., frequency, granularity) were altered only in AD.</jats:p></jats:list-item> <jats:list-item><jats:p>Such properties predicted cognitive and neural (MRI, fMRI, EEG) patterns in AD.</jats:p></jats:list-item> <jats:list-item><jats:p>Word‐property analysis of fluency can boost AD characterization and diagnosis.</jats:p></jats:list-item> </jats:list></jats:p></jats:sec>
3Scopus© Citations 10
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Moral Emotions and Their Brain Structural Correlates Across Neurodegenerative Disorders
(2023)
Sandra Baez
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Catalina Trujillo-Llano
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Leonardo Cruz de Souza
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Patricia Lillo
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Gonzalo Forno
<jats:p>Background: Although social cognition is compromised in patients with neurodegenerative disorders such as behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD), research on moral emotions and their neural correlates in these populations is scarce. No previous study has explored the utility of moral emotions, compared to and in combination with classical general cognitive state tools, to discriminate bvFTD from AD patients. Objective: To examine self-conscious (guilt and embarrassment) and other-oriented (pity and indignation) moral emotions, their subjective experience, and their structural brain underpinnings in bvFTD (n = 31) and AD (n = 30) patients, compared to healthy controls (n = 37). We also explored the potential utility of moral emotions measures to discriminate bvFTD from AD. Methods: We used a modified version of the Moral Sentiment Task measuring the participants’ accuracy scores and their emotional subjective experiences. Results: bvFTD patients exhibited greater impairments in self-conscious and other-oriented moral emotions as compared with AD patients and healthy controls. Moral emotions combined with general cognitive state tools emerged as useful measures to discriminate bvFTD from AD patients. In bvFTD patients, lower moral emotions scores were associated with lower gray matter volumes in caudate nucleus and inferior and middle temporal gyri. In AD, these scores were associated with lower gray matter volumes in superior and middle frontal gyri, middle temporal gyrus, inferior parietal lobule and supramarginal gyrus. Conclusion: These findings contribute to a better understanding of moral emotion deficits across neurodegenerative disorders, highlighting the potential benefits of integrating this domain into the clinical assessment.</jats:p>
24Scopus© Citations 3
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Multidimensional inhibitory signatures of sentential negation in behavioral variant frontotemporal dementia
(2022)
Mariano N Díaz-Rivera
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Agustina Birba
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Sol Fittipaldi
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Débora Mola
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Yurena Morera
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p>Processing of linguistic negation has been associated to inhibitory brain mechanisms. However, no study has tapped this link via multimodal measures in patients with core inhibitory alterations, a critical approach to reveal direct neural correlates and potential disease markers.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>Here we examined oscillatory, neuroanatomical, and functional connectivity signatures of a recently reported Go/No-go negation task in healthy controls and behavioral variant frontotemporal dementia (bvFTD) patients, typified by primary and generalized inhibitory disruptions. To test for specificity, we also recruited persons with Alzheimer's disease (AD), a disease involving frequent but nonprimary inhibitory deficits.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>In controls, negative sentences in the No-go condition distinctly involved frontocentral delta (2–3 Hz) suppression, a canonical inhibitory marker. In bvFTD patients, this modulation was selectively abolished and significantly correlated with the volume and functional connectivity of regions supporting inhibition (e.g. precentral gyrus, caudate nucleus, and cerebellum). Such canonical delta suppression was preserved in the AD group and associated with widespread anatomo-functional patterns across non-inhibitory regions.</jats:p> </jats:sec> <jats:sec> <jats:title>Discussion</jats:title> <jats:p>These findings suggest that negation hinges on the integrity and interaction of spatiotemporal inhibitory mechanisms. Moreover, our results reveal potential neurocognitive markers of bvFTD, opening a new agenda at the crossing of cognitive neuroscience and behavioral neurology.</jats:p> </jats:sec>
Scopus© Citations 18 4
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Multi-feature computational framework for combined signatures of dementia in underrepresented settings
(2022)
Sebastian Moguilner
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Agustina Birba
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Sol Fittipaldi
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Cecilia Gonzalez-Campo
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Enzo Tagliazucchi
<jats:title>Abstract</jats:title> <jats:p> <jats:italic>Objective.</jats:italic> The differential diagnosis of behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD) remains challenging in underrepresented, underdiagnosed groups, including Latinos, as advanced biomarkers are rarely available. Recent guidelines for the study of dementia highlight the critical role of biomarkers. Thus, novel cost-effective complementary approaches are required in clinical settings. <jats:italic>Approach</jats:italic>. We developed a novel framework based on a gradient boosting machine learning classifier, tuned by Bayesian optimization, on a multi-feature multimodal approach (combining demographic, neuropsychological, magnetic resonance imaging (MRI), and electroencephalography/functional MRI connectivity data) to characterize neurodegeneration using site harmonization and sequential feature selection. We assessed 54 bvFTD and 76 AD patients and 152 healthy controls (HCs) from a Latin American consortium (ReDLat). <jats:italic>Main results</jats:italic>. The multimodal model yielded high area under the curve classification values (bvFTD patients vs HCs: 0.93 (±0.01); AD patients vs HCs: 0.95 (±0.01); bvFTD vs AD patients: 0.92 (±0.01)). The feature selection approach successfully filtered non-informative multimodal markers (from thousands to dozens). <jats:italic>Results</jats:italic>. Proved robust against multimodal heterogeneity, sociodemographic variability, and missing data. <jats:italic>Significance</jats:italic>. The model accurately identified dementia subtypes using measures readily available in underrepresented settings, with a similar performance than advanced biomarkers. This approach, if confirmed and replicated, may potentially complement clinical assessments in developing countries.</jats:p>
Scopus© Citations 19 1 3
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Automated text‐level semantic markers of Alzheimer's disease
(2022)
Camila Sanz
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Facundo Carrillo
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Andrea Slachevsky
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Gonzalo Forno
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Maria Luisa Gorno Tempini
Scopus© Citations 30 1
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Multimodal neurocognitive markers of naturalistic discourse typify diverse neurodegenerative diseases
(2021)
Agustina Birba
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Sol Fittipaldi
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Judith C Cediel Escobar
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Cecilia Gonzalez Campo
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Agustina Legaz
<jats:title>Abstract</jats:title> <jats:p>Neurodegeneration has multiscalar impacts, including behavioral, neuroanatomical, and neurofunctional disruptions. Can disease-differential alterations be captured across such dimensions using naturalistic stimuli? To address this question, we assessed comprehension of four naturalistic stories, highlighting action, nonaction, social, and nonsocial events, in Parkinson’s disease (PD) and behavioral variant frontotemporal dementia (bvFTD) relative to Alzheimer’s disease patients and healthy controls. Text-specific correlates were evaluated via voxel-based morphometry, spatial (fMRI), and temporal (hd-EEG) functional connectivity. PD patients presented action–text deficits related to the volume of action–observation regions, connectivity across motor-related and multimodal-semantic hubs, and frontal hd-EEG hypoconnectivity. BvFTD patients exhibited social–text deficits, associated with atrophy and spatial connectivity patterns along social-network hubs, alongside right frontotemporal hd-EEG hypoconnectivity. Alzheimer’s disease patients showed impairments in all stories, widespread atrophy and spatial connectivity patterns, and heightened occipitotemporal hd-EEG connectivity. Our framework revealed disease-specific signatures across behavioral, neuroanatomical, and neurofunctional dimensions, highlighting the sensitivity and specificity of a single naturalistic task. This investigation opens a translational agenda combining ecological approaches and multimodal cognitive neuroscience for the study of neurodegeneration.</jats:p>
2Scopus© Citations 39
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Allostatic-Interoceptive Overload in Frontotemporal Dementia
(2022)
Agustina Birba
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Hernando Santamaría-García
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Pavel Prado
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Josefina Cruzat
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Agustín Sainz Ballesteros
Scopus© Citations 54 1
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Alzheimer’s Disease or Behavioral Variant Frontotemporal Dementia? Review of Key Points Toward an Accurate Clinical and Neuropsychological Diagnosis
(2020)
Gada Musa
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Andrea Slachevsky
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Carlos Muñoz-Neira
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Carolina Méndez-Orellana
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Roque Villagra
29Scopus© Citations 73
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Evaluating the reliability of neurocognitive biomarkers of neurodegenerative diseases across countries: A machine learning approach
(2020)
M. Belen Bachli
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Lucas Sedeño
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Jeremi K. Ochab
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Olivier Piguet
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Fiona Kumfor
16 1Scopus© Citations 56

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