Biology subjects

Pagonabarraga, J.

Publications and source records attributed to Pagonabarraga, J..

6 recordsLinked to original sources

bioRxiv2026

Plasmatic immune extracellular vesicle profiles identify prodromal and early stages of Parkinson's disease

Extracellular vesicles (EVs) hold promise as minimally invasive biomarkers for neurodegenerative proteinopathies, but disease- and stage-specific profiles remain unclear. For this study, we enrolled 378 participants across five centers and the MJFF-BioFIND cohort: 100 healthy controls [HC], 64 isolated REM sleep behavior disorder [iRBD], 41 DeNovo Parkinsons Disease [PD], 89 Late PD, 32 other Synucleinopathies, and 52 Tauopathies. All participants underwent clinical evaluation and blood collection. The 77 subjects from the BioFIND cohort also provided CSF samples. EV concentration and size were assessed by nanoparticle tracking analysis; flow cytometry quantified tetraspanins (CD9/CD63/CD81) and 37 surface markers. Multivariable logistic regression, receiver operating characteristic analyses (ROC), and repeated random forest (rRF) classifiers evaluated diagnostic utility. Late PD showed the highest EV concentrations compared to HC and other disease groups. Participants exhibited distinct EV surface immunophenotypes, with the iRBD group displaying the most extensive immune activation signature vs HC, followed by PD patients. Multivariate logistic regression analysis identified diagnostic marker panels: CD3/CD9/CD25/CD56 for iRBD, SSEA4 for Late PD, CD146/CD209 for Synucleinopathies, and CD8/CD45/CD62P for Tauopathies. ROC confirmed good discriminatory performance, with CD56 emerging as the strongest single predictor for iRBD vs HC, SSEA4 showing high sensitivity for Late PD, and marker combinations providing optimal balance for Synucleinopathy/Tauopathy classification vs HC. In the CSF BioFIND subset, Late PD EVs exhibited increased myeloid (CD1c), adhesion (CD29), activation (CD69), and epithelial (CD326) markers compared to HC. Among these, CD326 was independently associated with Late PD diagnosis. Machine learning classifiers using all 37 surface antigens achieved excellent training performance (91.7-94.3% accuracy for iRBD/Synucleinopathies vs HC) and maintained robust validation accuracy, particularly for iRBD (77.8%) and DeNovo PD (76.6%) vs HC. EV immuno-phenotyping reveals distinct signatures across the neurodegenerative proteinopathies spectrum, with the highest diagnostic utility for prodromal iRBD detection. Longitudinal validation and cell-of-origin refinement represent key next steps toward clinical translation.

neuroscience↗

bioRxiv2025

Connectome-based brain fingerprints predict early cognitive decline in Parkinson's patients with minor hallucinations

Individual variability in connectome organization offers a unique framework for capturing patient-specific alterations and advancing personalized models in medicine. Minor hallucinations (MH) affect up to 40% of Parkinsons disease (PD) patients and are early indicators of cognitive decline and dementia, hence crucial for early intervention. While previous studies focused on group-level differences, connectome-based brain fingerprinting enables deeper, individualized analysis of neural change. Applying this approach to PD patients with and without MH using resting-state fMRI, we show that each patient exhibited unique brain fingerprint, revealing rich quantifiable personalized features with medical relevance. MH-patients showed a loss of subject-specific features in brain networks linked to cognitive health, while somatosensory regions - typically less distinctive - became more prominent, emphasizing their role in MH pathogenesis. These differences enabled to identify - in an entirely data driven manner - patient-specific networks linked to early subclinical cognitive alterations, as well differential spatial fingerprinting organization linked to cortical densities of neurotransmitters. These findings reveal a distinct, patient-specific connectomic signature that differentiates PD patients with MH, uncovering early neural markers for precision medicine in PD.

neuroscience↗

bioRxiv2022

Theta oscillations and minor hallucinations in Parkinson's disease reveal decrease in frontal lobe functions and later cognitive decline

Cognitive decline and hallucinations are common and debilitating non-motor symptoms, occurring during later phases of Parkinsons disease (PD). Minor hallucinations (MH), appear at early phases and have been suggested to predict cognitive impairment in PD, however, this has not been well-established by clinical research. Here, we investigated whether non-demented PD patients with MH show altered brain oscillations and whether such MH-related electrophysiological changes are associated with cognitive impairments that increase over time. Combining model-driven EEG analysis with neuropsychiatric and neuropsychological examinations in 75 PD patients, we reveal enhanced frontal theta oscillations in PD patients suffering from MH and link these oscillatory changes with lower cognitive frontal-subcortical functions. Neuropsychological follow-up examinations five years later confirmed MH-specific theta oscillations and revealed a stronger decline in frontal-subcortical functions in MH-patients with stronger frontal theta alterations, defining an MH and theta oscillation-based early marker of a cognitive decline in PD.

neuroscience↗

bioRxiv2020

Neural signatures of predictive language processing in Parkinson's disease with and without mild cognitive impairment

Cognitive deficits are common in Parkinsons disease (PD), with some PD patients meeting criteria for mild cognitive impairment (MCI). An unaddressed question is whether linguistic prediction is preserved in PD. This ability is nowadays deemed crucial in achieving fast and efficient comprehension, and it may be negatively impacted by cognitive deterioration. To fill this gap of knowledge, we used event-related potentials (ERPs) to evaluate mechanisms of linguistic prediction in a sample of PD patients (on dopamine compensation) with and without MCI. To this end, participants read sentence contexts that were predictive or not about a sentence-final word. The final word appeared after 1 second, matching or mismatching the prediction. The introduction of the interval allowed to capture neural responses both before and after sentence-final words, reflecting semantic anticipation and processing. PD patients with normal cognition (N = 58) showed ERP responses comparable to those of matched controls. Specifically, in predictive contexts, a slow negative potential developed prior to sentence-final words, reflecting semantic anticipation. Later, expected words elicited reduced N400 responses (compared to unexpected words), indicating facilitated semantic processing. Besides, PD patients with MCI (N = 20) showed a prolongation of the N400 congruency effect (compared to matched PD patients without MCI), indicating that further cognitive decline impacts semantic processing. Finally, lower verbal fluency scores correlated with prolonged N400 congruency effects and with reduced pre-word differences in all PD patients (N = 78). This relevantly points to a role of deficits in temporal-dependent mechanisms in PD, besides prototypical frontal dysfunction, in altered semantic anticipation and semantic processing during sentence comprehension.

neuroscience↗

bioRxiv2020

Sensorimotor hallucinationsin Parkinson's disease

Hallucinations in Parkinsons disease (PD) are one of the most disturbing non-motor symptoms, affect half of the patients, and constitute a major risk factor for adverse clinical outcomes such as psychosis and dementia. Here we report a robotics-based approach, enabling the induction of a specific clinically-relevant hallucination (presence hallucination, PH) under controlled experimental conditions and the characterization of a PD subgroup with enhanced sensorimotor sensitivity for such robot-induced PH. Using MR-compatible robotics in healthy participants and lesion network mapping analysis in neurological non-PD patients, we identify a fronto-temporal network that was associated with PH. This common PH-network was selectively disrupted in a new and independent sample of PD patients and predicted the presence of symptomatic PH. These robotics-neuroimaging findings determine the behavioral and neural mechanisms of PH and reveal pathological cortical sensorimotor processes of PH in PD, identifying a more severe form of PD associated with psychosis and cognitive decline.

neuroscience↗

bioRxiv2019

The genetic architecture of Parkinson disease in Spain: characterizing population-specific risk, differential haplotype structures, and providing etiologic insight

BackgroundThe Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases.\n\nObjectivesTo perform the largest Parkinson disease (PD) genome-wide association study (GWAS) restricted to a single country.\n\nMethodsWe performed a GWAS for both risk of PD and age-at-onset (AAO) in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations and burden analyses.\n\nResultsWe identified a novel population-specific GWAS signal at PARK2 associated with AAO. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence via two-sample Mendelian randomization in expression and methylation datasets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls.\n\nConclusionsOur data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain.

neuroscience↗