Artículos de revista (CUN)
Permanent URI for this collectionhttps://hdl.handle.net/10171/70263
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136 results
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- Structural neuroimaging changes associated with subjective cognitive decline from a clinical sample(Elsevier, 2024) Dominguez, P. (Pablo); Solis-Barquero, S.M. (Sergio M.); Arrondo, C. (Carlota); Montoya-Murillo, G. (Genoveva); Garcia-Eulate, R. (Reyes); Fernández-Seara, M.A. (María A.); Ríos-Rivera, M.M. (Mirla); Riverol, M. (Mario); Villino, R. (Rafael); Imaz-Aguayo, L. (Laura)Background: Alzheimer's disease (AD) is characterized by progressive deterioration of cognitive functions. Some individuals with subjective cognitive decline (SCD) are in the early phase of the disease and subsequently progress through the AD continuum. Although neuroimaging biomarkers could be used for the accurate and early diagnosis of preclinical AD, the findings in SCD samples have been heterogeneous. This study established the morphological differences in brain magnetic resonance imaging (MRI) findings between individuals with SCD and those without cognitive impairment based on a clinical sample of patients defined according to SCD-Initiative recommendations. Moreover, we investigated baseline structural changes in the brains of participants who remained stable or progressed to mild cognitive impairment or dementia. Methods: This study included 309 participants with SCD and 43 healthy controls (HCs) with high-quality brain MRI at baseline. Among the 99 subjects in the SCD group who were followed clinically, 32 progressed (SCDp) and 67 remained stable (SCDnp). A voxel-wise statistical comparison of gray and white matter (WM) volume was performed between the HC and SCD groups and between the HC, SCDp, and SCDnp groups. XTRACT ATLAS was used to define the anatomical location of WM tract damage. Region-of-interest (ROI) analyses were performed to determine brain volumetric differences. White matter lesion (WML) burden was established in each group. Results: Voxel-based morphometry (VBM) analysis revealed that the SCD group exhibited gray matter atrophy in the middle frontal gyri, superior orbital gyri, superior frontal gyri, right rectal gyrus, whole occipital lobule, and both thalami and precunei. Meanwhile, ROI analysis revealed decreased volume in the left rectal gyrus, bilateral medial orbital gyri, middle frontal gyri, superior frontal gyri, calcarine fissure, and left thalamus. The SCDp group exhibited greater hippocampal atrophy (p < 0.001) than the SCDnp and HC groups on ROI analyses. On VBM analysis, however, the SCDp group exhibited increased hippocampal atrophy only when compared to the SCDnp group (p < 0.001). The SCD group demonstrated lower WM volume in the uncinate fasciculus, cingulum, inferior fronto-occipital fasciculus, anterior thalamic radiation, and callosum forceps than the HC group. However, no significant differences in WML number (p = 0.345) or volume (p = 0.156) were observed between the SCD and HC groups. Conclusions: The SCD group showed brain atrophy mainly in the frontal and occipital lobes. However, only the SCDp group demonstrated atrophy in the medial temporal lobe at baseline. Structural damage in the brain regions was anatomically connected, which may contribute to early memory decline.
- Magnetic resonance-guided focused ultrasound (MRgFUS)-Thalamotomy for essential tremor: lesion location and clinical outcomes(Wiley, 2024) Arcadi, A. (Alana); Gorospe, A. (Arantza); Jiménez-Huete, A. (Adolfo); González-Quarante, L.H. (Lain Hermes); Martín-Bastida, A. (Antonio); Aviles-Olmos, I. (Iciar); Guridi, J. (Jorge); Macías-de-la-Corte, M. (Marta); Rodriguez-Oroz, M.C. (María Cruz); Riverol, M. (Mario); Villino, R. (Rafael); Parras, O. (Olga)Background: Factors predicting clinical outcomes after MR-guided focused ultrasound (MRgFUS)-thalamotomy in patients with essential tremor (ET) are not well known. Objective: To examine the clinical outcomes and their relationship with patients’ baseline demographic and clinical features and lesion characteristics at 6-month follow-up in ET patients. Methods: A total of 127 patients were prospectively evaluated at 1 (n = 122), 3 (n = 102), and 6 months (n = 78) after MRgFUS-thalamotomy. Magnetic resonance imaging (MRI) was obtained at 6 months (n = 60). Primary outcomes included: (1) change in the Clinical Rating Scale of Tremor (CRST)-A+B score in the treated hand and (2) frequency and severity of adverse events (AEs) at 6 months. Secondary outcomes included changes in all subitems of the CRST scale in the treated hand, CRST-C, axial tremor (face, head, voice, tongue), AEs, and correlation of primary outcomes at 6 months with lesion characteristics. Statistical analysis included linear mixed, standard, and logistic regression models. Results: Scores for CRST-A+B, CRST-A, CRST-B in the treated hand, CRST-C, and axial tremor were improved at each evaluation (P < 0.001). Five patients had severe AEs at 1 month that became mild throughout the follow-up. Mild AEs occurred in 71%, 45%, and 34% of patients at 1, 3, and 6 months, respectively. Lesion volume was associated with the reduction in the CRST-A (P = 0.003) and its overlapping with the ventralis intermedius nucleus (Vim) nucleus with the reduction in CRST-A+B (P = 0.02) and CRST-B (P = 0.008) at 6 months. Conclusions: MRgFUS-thalamotomy improves hand and axial tremor in ET patients. Transient and mild AEs are frequent. Lesion volume and location are associated with tremor reduction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- Automatic segmentation and quantification of Nigrosome-1 Neuromelanin and Iron in MRI: a candidate biomarker for Parkinson’s disease(Wiley Periodicals LLC, 2023) Martinez, M. (Martín); Castellanos, G. (Gabriel); Ortiz-de-Solorzano, C. (Carlos); Pastor, P. (Pau); Fernández-Seara, M.A. (María A.); Pastor, M.A. (María A.); Álvarez, I. (Ignacio); Ariz, M. (Mikel)Parkinson’s disease (PD) is caused by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). The incidence of PD increases with age and is one of the major causes of disability. PD early diagnosis is still a challenge as it is based on the clinical assessment of the subject discarding other potential causes of parkinsonism, and the patient’s positive response to Levodopa therapy, leading to a misdiagnosis rate of approximately 16%. The substantia nigra (SN), located in the ventral tegmentum of the midbrain, is divided into two main regions: the iron-rich ventral SN pars reticulata (SNr), and the dorsal SNc, where the neuromelanin-containing dopaminergic neurons (NM) are located. NM is believed to have a neuroprotective function against the toxicity of iron-mediated oxidative processes. Specifically, the death of dopaminergic neurons of the SNc causes NM depigmentation, followed by an increase of iron load. Indeed, it has been reported that a relative decrease of SNc NM leads to a relative increase of SNc iron in PD patients, when compared with age-matched healthy controls (HCs).
- Agrypnia Excitata and Supranuclear Vertical Gaze Palsy Linked to Anti-Ma Encephalitis(Wiley Periodicals LLC, 2024) Arbizu, J. (Javier); Espinoza-Vinces, C. (Christian); Horrillo-Maysonnial, A. (Alejandro); Aviles-Olmos, I. (Iciar); Calvo-Imirizaldu, M. (Marta); Pérez-Álvarez, A.I (Ángel Ignacio); Urrestarazu, E. (Elena); Gallego-Perez-Larraya, J. (Jaime)Paraneoplastic neurological syndromes result from cancer’s immune impact on the nervous system.1 Anti-Ma-associated encephalitis causes diencephalic, brainstem, and limbic symptoms such as memory loss, narcolepsy and rapid eye movement (REM) behavior disorder (RBD), eye movement abnormalities, and parkinsonism. It can precede cancer diagnosis, often linked to testicular tumors. Agrypnia excitata (AE) is a unique electroclinical syndrome that can disrupt sleep structure with changes in physiological cyclic organization, autonomic overactivity, and oneiric stupor episodes. We report on a patient with anti-Ma encephalitis who exhibits a diencephalic syndrome and AE, not previously reported to our knowledge.
- Hippocampal synaptic failure is an early event in experimental parkinsonism with subtle cognitive deficit(Oxford University Press, 2023) Cotman, C.W. (Carl W.); Quiroga-Varela, A. (Ana); Belloso-Iguerategui, A. (Arantzazu); Prieto, C.A. (C. Aleph); Zamarbide-González, M. (Marta); Fernandez-Irigoyen, J. (Joaquín); Gago, B. (Belén); Rodríguez-Chinchilla, T. (Tatiana); Rodriguez-Oroz, M.C. (María Cruz); Merino-Galán, L. (Leire); Santamaria, E. (Enrique)Learning and memory mainly rely on correct synaptic function in the hippocampus and other brain regions. In Parkinson's disease, subtle cognitive deficits may even precede motor signs early in the disease. Hence, we set out to unravel the earliest hippocampal synaptic alterations associated with human α-synuclein overexpression prior to and soon after the appearance of cognitive deficits in a parkinsonism model. We bilaterally injected adeno-associated viral vectors encoding A53T-mutated human α-synuclein into the substantia nigra of rats, and evaluated them 1, 2, 4 and 16 weeks post-inoculation by immunohistochemistry and immunofluorescence to study degeneration and distribution of α-synuclein in the midbrain and hippocampus. The object location test was used to evaluate hippocampal-dependent memory. Sequential window acquisition of all theoretical mass spectrometry-based proteomics and fluorescence analysis of single-synapse long-term potentiation were used to study alterations to protein composition and plasticity in isolated hippocampal synapses. The effect of L-DOPA and pramipexole on long-term potentiation was also tested. Human α-synuclein was found within dopaminergic and glutamatergic neurons of the ventral tegmental area, and in dopaminergic, glutamatergic and GABAergic axon terminals in the hippocampus from 1 week post-inoculation, concomitant with mild dopaminergic degeneration in the ventral tegmental area. In the hippocampus, differential expression of proteins involved in synaptic vesicle cycling, neurotransmitter release and receptor trafficking, together with impaired long-term potentiation were the first events observed (1 week post-inoculation), preceding cognitive deficits (4 weeks post-inoculation). Later on, at 16 weeks post-inoculation, there was a deregulation of proteins involved in synaptic function, particularly those involved in the regulation of membrane potential, ion balance and receptor signalling. Hippocampal long-term potentiation was impaired before and soon after the onset of cognitive deficits, at 1 and 4 weeks post-inoculation, respectively. L-DOPA recovered hippocampal long-term potentiation more efficiently at 4 weeks post-inoculation than pramipexole, which partially rescued it at both time points. Overall, we found impaired synaptic plasticity and proteome dysregulation at hippocampal terminals to be the first events that contribute to the development of cognitive deficits in experimental parkinsonism. Our results not only point to dopaminergic but also to glutamatergic and GABAergic dysfunction, highlighting the relevance of the three neurotransmitter systems in the ventral tegmental area-hippocampus interaction from the earliest stages of parkinsonism. The proteins identified in the current work may constitute potential biomarkers of early synaptic damage in the hippocampus and hence, therapies targeting these could potentially restore early synaptic malfunction and consequently, cognitive deficits in Parkinson's disease.
- Oncolytic virotherapy for the treatment of pediatric brainstem gliomas(Elsevier, 2023) Alonso, M.M. (Marta M.); Garcia-Moure, M. (Marc); Gallego-Perez-Larraya, J. (Jaime)Diffuse intrinsic pontine glioma (DIPG) is the most frequent brainstem glioma and the most lethal brain tumor in childhood. Despite transient benefit with radiotherapy, the prognosis of children with this disease remains dismal with severe neurological morbidity and median survival less than 12 months. Oncolytic immunovirotherapy is emerging as a potential therapeutic approach in neuro-oncology. The oncolytic adenovirus Delta-24-RGD has shown efficacy in adult patients with recurrent GBM. Our group has demonstrated that Delta-24-RGD has oncolytic activity and triggers immune response in preclinical models of DIPG, and has a synergistic effect with radiotherapy in animal models of this disease. In this scenario, we conducted a first-in-human phase 1 clinical trial to evaluate the safety and efficacy of intratumoral injection of Delta-24-RGD in pediatric patients with newly diagnosed DIPG prior to standard radiotherapy. The study confirmed the feasibility of this treatment with an acceptable safety profile and encouraging efficacy results. Correlative analyses showed a biological activity from Delta-24-RGD in DIPG. Further advanced trials are needed to validate these results. Meanwhile, plenty of opportunities to increase the potential contribution of oncolytic viruses in the management of devastating tumors with no current effective treatment such as DIPG need to be explored and exploited.
- Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model(Wiley, 2023) Ferrero, R. (Roberto); Artieda, J. (Julio); Nicolas, M.J. (María Jesús); Pineda-Lucena, A. (Antonio); Valencia, M. (Miguel); Peregrín, N. (Nuria); Aragón, T. (Tomás); Marlin, E. (Elías); Arrasate, M. (Montserrat); Vinueza-Gavilanes, R. (Rodrigo)Background and purpose: The integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, which mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (Integrated Stress Response InhiBitor, an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB-like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1G93A mice. Experimental approach: After biochemical characterization in primary neurons, SOD1G93A mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with the hanging wire motor test. Motor neuronal survival was assessed by immunohistochemistry. Key results: In primary neurons, 2BAct and PRXS571 relieve the ISR-imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1G93A mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time. Conclusion and implications: 2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1G93A mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients.
- Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma(Nature Publishing Group, 2019) Berraondo, P. (Pedro); Perez-Gracia, J.L. (Jose Luis); Rodriguez-Ruiz, M.E. (María Esperanza); Lopez-Diaz-de-Cerio, A. (Ascensión); Tejada-Solis, S. (Sonia); Diez-Valle, R. (Ricardo); Goicoechea, I. (Iosune); Inoges, S. (Susana); Gurpide, A. (Alfonso); Melero, I. (Ignacio); Choi, J. (Jungmin); Porciuncula, A. (Angelo); Idoate, M.A. (Miguel Ángel); Andrea, C.E. (Carlos Eduardo) de; López-Janeiro, Á. (Álvaro); Gallego-Perez-Larraya, J. (Jaime); Villarroel-Espindola, F. (Franz); Schalper, K.A. (Kurt A.); Giraldez, M. (Miriam); Fernandez-Sanmamed, M. (Miguel)Glioblastoma is the most common primary central nervous system malignancy and has a poor prognosis. Standard first-line treatment, which includes surgery followed by adjuvant radio-chemotherapy, produces only modest benefits to survival1,2. Here, to explore the feasibility, safety and immunobiological effects of PD-1 blockade in patients undergoing surgery for glioblastoma, we conducted a single-arm phase II clinical trial (NCT02550249) in which we tested a presurgical dose of nivolumab followed by postsurgical nivolumab until disease progression or unacceptable toxicity in 30 patients (27 salvage surgeries for recurrent cases and 3 cases of primary surgery for newly diagnosed patients). Availability of tumor tissue pre- and post-nivolumab dosing and from additional patients who did not receive nivolumab allowed the evaluation of changes in the tumor immune microenvironment using multiple molecular and cellular analyses. Neoadjuvant nivolumab resulted in enhanced expression of chemokine transcripts, higher immune cell infiltration and augmented TCR clonal diversity among tumor-infiltrating T lymphocytes, supporting a local immunomodulatory effect of treatment. Although no obvious clinical benefit was substantiated following salvage surgery, two of the three patients treated with nivolumab before and after primary surgery remain alive 33 and 28 months later.
- Theta-phase closed-loop stimulation induces motor paradoxical responses in the rat model of Parkinson disease(Elsevier, 2018) Artieda, J. (Julio); Nicolas, M.J. (María Jesús); Valencia, M. (Miguel); Arrieta, S. (Sandra); Alegre-Esteban, M. (Manuel); Cordon, I. (Ivan)Background: High-frequency deep brain stimulation (DBS) has become a widespread therapy used in the treatment of Parkinson's Disease (PD) and other diseases. Although it has proved beneficial, much recent attention has been centered around the potential of new closed-loop DBS implementations. Objective: Here we present a new closed-loop DBS scheme based on the phase of the theta activity recorded from the motor cortex. By testing the implementation on freely moving 6-OHDA lesioned and control rats, we assessed the behavioral and neurophysiologic effects of this implementation and compared it against the classical high-frequency DBS. Results: Results show that both stimulation modalities produce significant and opposite changes on the movement and neurophysiological activity. Close-loop stimulation, far from improving the animals' behavior, exert contrary effects to those of high-frequency DBS which reverts the parkinsonian symptoms. Motor improvement during open-loop, high-frequency DBS was accompanied by a reduction in the amount of cortical beta oscillations while akinetic and disturbed behavior during close-loop stimulation coincided with an increase in the amplitude of beta activity. Conclusion: Cortical-phase-dependent close-loop stimulation of the STN exerts significant behavioral and oscillatory changes in the rat model of PD. Open-loop and close-loop stimulation outcomes differed dramatically, thus suggesting that the scheme of stimulation determines the output of the modulation even if the target structure is maintained. The current framework could be extended in future studies to identify the correct parameters that would provide a suitable control signal to the system. It may well be that with other stimulation parameters, this sort of DBS could be beneficial.
- Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma(Massachusetts Medical Society, 2022) Tavira, B. (Beatriz); Patiño-García, A. (Ana); Stunnenberg, H. (Henk); Alonso-Roldán, M.M. (Marta María); Gomez-Manzano, C. (Candelaria); Zalacain, M. (Marta); Martinez-Velez, N. (Naiara); Robbins, J. (Joan); Lang, F.F. (Frederick F.); Ewald, B. (Brett); Gonzalez-Huarriz, M. (Marisol); Tejada-Solis, S. (Sonia); Cruz, O. (Ofelia); Esparragosa-Vázquez, I. (I.); Astigarraga, I. (Itziar); Marrodán, L. (Lucía); Villalba, M. (María); Alkorta-Aranburu, G. (Gorka); Oscoz-Lizarbe, M. (Miren); Diez-Valle, R. (Ricardo); Garcia-Moure, M. (Marc); Hervas-Stubbs, S. (Sandra); Dobbs, J. (Jessica); Lugt, J. (Jasper) van der; Puigdelloses-Vallcorba, M. (Montserrat); Idoate, M.A. (Miguel Ángel); Dharmadhikari, G. (Gitanjali); Lopez-Ibor, B. (Blanca); Andrea, C.E. (Carlos Eduardo) de; Labiano, S. (Sara); Hulleman, E. (Esther); Tamayo, I. (Ibon); Laspidea, V. (Virginia); Hernandez-Alcoceba, R. (Rubén); Fueyo, J. (Juan); Gallego-Perez-Larraya, J. (Jaime); Ruiz-Moreno, C. (Cristian); Nuñez-Cordoba, J.M. (Jorge M.); Jones, C. (Chris)Background: Pediatric patients with diffuse intrinsic pontine glioma (DIPG) have a poor prognosis, with a median survival of less than 1 year. Oncolytic viral therapy has been evaluated in patients with pediatric gliomas elsewhere in the brain, but data regarding oncolytic viral therapy in patients with DIPG are lacking. Methods: We conducted a single-center, dose-escalation study of DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells, in patients with newly diagnosed DIPG. The patients received a single virus infusion through a catheter placed in the cerebellar peduncle, followed by radiotherapy. The primary objective was to assess the safety and adverse-event profile of DNX-2401. The secondary objectives were to evaluate the effect of DNX-2401 on overall survival and quality of life, to determine the percentage of patients who have an objective response, and to collect tumor-biopsy and peripheral-blood samples for correlative studies of the molecular features of DIPG and antitumor immune responses. Results: A total of 12 patients, 3 to 18 years of age, with newly diagnosed DIPG received 1×1010 (the first 4 patients) or 5×1010 (the subsequent 8 patients) viral particles of DNX-2401, and 11 received subsequent radiotherapy. Adverse events among the patients included headache, nausea, vomiting, and fatigue. Hemiparesis and tetraparesis developed in 1 patient each. Over a median follow-up of 17.8 months (range, 5.9 to 33.5), a reduction in tumor size, as assessed on magnetic resonance imaging, was reported in 9 patients, a partial response in 3 patients, and stable disease in 8 patients. The median survival was 17.8 months. Two patients were alive at the time of preparation of the current report, 1 of whom was free of tumor progression at 38 months. Examination of a tumor sample obtained during autopsy from 1 patient and peripheral-blood studies revealed alteration of the tumor microenvironment and T-cell repertoire. Conclusions: Intratumoral infusion of oncolytic virus DNX-2401 followed by radiotherapy in pediatric patients with DIPG resulted in changes in T-cell activity and a reduction in or stabilization of tumor size in some patients but was associated with adverse events. (Funded by the European Research Council under the European Union's Horizon 2020 Research and Innovation Program and others; EudraCT number, 2016-001577-33; ClinicalTrials.gov number, NCT03178032.).