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    Genomic modifiers of neurological resilience in a Niemann‐Pick C family
    (Wiley, 2025-06-12)
    Macarena Las Heras
    ;
    Benjamín Szenfeld
    ;
    Valeria Olguín
    ;
    Juan Carlos Rubilar
    ;
    CALDERON GIADROSIC, JUAN FRANCISCO  
    Niemann-Pick type C (NPC) disease, caused by NPC1 or NPC2 variants, disrupts cholesterol and glycolipid trafficking, leading to diverse clinical manifestations. To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss-of-function variants in CCDC115, SLC4A5, DEPDC5, ETFDH, SNRNP200, and DOCK1 that co-segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC-like severity based on orthologous gene variants. RNA-seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the SLC4A5 ortholog, bor1, enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and SLC4A5 as a therapeutic target.
      6
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    Scopus© Citations 3  6
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    Scopus© Citations 2  3
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    NTS-Polyplex: a potential nanocarrier for neurotrophic therapy of Parkinson's disease
    (2012)
    Daniel Martinez-Fong
    ;
    Michael J. Bannon
    ;
    Louis-Eric Trudeau
    ;
    Juan A. Gonzalez-Barrios
    ;
    Martha L. Arango-Rodriguez
      3Scopus© Citations 56
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    Multivariate word properties in fluency tasks reveal markers of Alzheimer's dementia
    (2023)
    Franco J. Ferrante
    ;
    Joaquín Migeot
    ;
    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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    Chronic Voluntary Morphine Intake Is Associated with Changes in Brain Structures Involved in Drug Dependence in a Rat Model of Polydrug Use
    (2023)
    María Elena Quintanilla
    ;
    Paola Morales
    ;
    Daniela Santapau
    ;
    Alba Ávila
    ;
    Carolina Ponce
    <jats:p>Chronic opioid intake leads to several brain changes involved in the development of dependence, whereby an early hedonistic effect (liking) extends to the need to self-administer the drug (wanting), the latter being mostly a prefrontal–striatal function. The development of animal models for voluntary oral opioid intake represents an important tool for identifying the cellular and molecular alterations induced by chronic opioid use. Studies mainly in humans have shown that polydrug use and drug dependence are shared across various substances. We hypothesize that an animal bred for its alcohol preference would develop opioid dependence and further that this would be associated with the overt cortical abnormalities clinically described for opioid addicts. We show that Wistar-derived outbred UChB rats selected for their high alcohol preference additionally develop: (i) a preference for oral ingestion of morphine over water, resulting in morphine intake of 15 mg/kg/day; (ii) marked opioid dependence, as evidenced by the generation of strong withdrawal signs upon naloxone administration; (iii) prefrontal cortex alterations known to be associated with the loss of control over drug intake, namely, demyelination, axonal degeneration, and a reduction in glutamate transporter GLT-1 levels; and (iv) glial striatal neuroinflammation and brain oxidative stress, as previously reported for chronic alcohol and chronic nicotine use. These findings underline the relevance of polydrug animal models and their potential in the study of the wide spectrum of brain alterations induced by chronic morphine intake. This study should be valuable for future evaluations of therapeutic approaches for this devastating condition.</jats:p>
      7Scopus© Citations 9
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      1  1Scopus© Citations 103
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    Neuronal Rubicon Represses Extracellular APP/Amyloid β Deposition in Alzheimer’s Disease
    (2022)
    Sandra Espinoza
    ;
    Felipe Grunenwald
    ;
    Wileidy Gomez
    ;
    Felipe García
    ;
    Lorena Abarzúa-Catalan  
    <jats:p>Alzheimer’s disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon’s role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid β burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid β burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP/amyloid β secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP/amyloid β homeostasis, in which neuronal Rubicon is a repressor of APP/amyloid β secretion, defining a new way to target AD and other similar diseases therapeutically.</jats:p>
      5Scopus© Citations 4
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    Multi-feature computational framework for combined signatures of dementia in underrepresented settings
    (2022)
    Sebastian Moguilner
    ;
    Agustina Birba
    ;
    Sol Fittipaldi
    ;
    Cecilia Gonzalez-Campo
    ;
    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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    Multimodal neurocognitive markers of naturalistic discourse typify diverse neurodegenerative diseases
    (2021)
    Agustina Birba
    ;
    Sol Fittipaldi
    ;
    Judith C Cediel Escobar
    ;
    Cecilia Gonzalez Campo
    ;
    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