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The vestibular ganglion contains primary sensory neurons that are postsynaptic to the transducing hair cells (HC) and project to the central nervous system. Understanding the response of these neurons to HC stress or loss is of great interest as their survival and functional competence will determine the functional outcome of any intervention aiming at repair or regeneration of the HCs. We have shown that subchronic exposure to the ototoxicant 3,3'-iminodipropionitrile (IDPN) in rats and mice causes a reversible detachment and synaptic uncoupling between the HCs and the ganglion neurons. Here, we used this paradigm to study the global changes in gene expression in vestibular ganglia using RNA-seq. Comparative gene ontology and pathway analyses of the data from both model species indicated a robust downregulation of terms related to synapses, including presynaptic and postsynaptic functions. Manual analyses of the most significantly downregulated transcripts identified genes with expressions related to neuronal activity, modulators of neuronal excitability, and transcription factors and receptors that promote neurite growth and differentiation. For choice selected genes, the mRNA expression results were replicated by qRT-PCR, validated spatially by RNA-scope, or were demonstrated to be associated with decreased expression of the corresponding protein. We conjectured that decreased synaptic input or trophic support on the ganglion neurons from the HC was triggering these expression changes. To support this hypothesis, we demonstrated decreased expression of BDNF mRNA in the vestibular epithelium after subchronic ototoxicity and also downregulated expression of similarly identified genes (e.g Etv5, Camk1g, Slc17a6, Nptx2, Spp1) after HC ablation with another ototoxic compound, allylnitrile. We conclude that vestibular ganglion neurons respond to decreased input from HCs by decreasing the strength of all their synaptic contacts, both as postsynaptic and presynaptic players. This work was supported by Ministerio de Ciencia e Innovación, Agencia Estatal de Investigación, MCIU/AEI, 10.13039/501100011033, and European Regional Development Fund, FEDER [grant numbers RTI2018-096452-B-I00 and PID2021-124678OB-100], the MCIU/AEI, 10.13039/501100011033, NextGenerationEU/PRTR, ERANET NEURON Program VELOSO [grant number PCI2020-120681-2] and Agència de Gestió d'Ajuts Universitaris i de Recerca, AGAUR, Generalitat de Catalunya [grant number 2017SGR621]. A.E.C. is funded by ISCIII /MINECO and co-funded by FEDER [grant number PT17/0009/0019]. A.B.G is a Serra-Húnter fellow (Generalitat de Catalunya). E.A.G. and M.B. were supported by the Formación del Profesorado Universitario (FPU) program (Ministerio de Universidades).

Background and purpose Oxaliplatin-induced neuropathy (OIN) implies axonal damage of both small and large sensory nerve fibers. We aimed at comparing the neurophysiological changes occurred after treatment and the capability to recovery based on histological marker of re-innervation GAP-43. Methods 48 patients with cancer were assessed before and after chemotherapy (at 3 months and 12 months if available). We recorded ulnar and sural sensory nerve action potentials (SNAP), determined quantitative sensory thresholds for warm and cold (WDT, CDT), pain thresholds and collected a distal biopsy of skin to assess the intra-epidermal nerve fiber density (IENFD) with PGP9.5 and GAP-43 markers (in a subgroup of 19 patients). Results Increased WDT and CDT as well as diminished IENFD at distal leg were already found in 30% of oncologic patients before treatment. After oxaliplatin, there was a significant increase in thermal thresholds in 52% of patients, and a decrease of SNAP amplitude in the sural nerve in 67% patients. IENFD was reduced in 47% and remained unchanged in 37% after oxiplatin. The density of GAP-43 + fibers and GAP-43/PGP 9.5 ratio was similar before and after treatment showing that cutaneous re-innervation is preserved despite no clinical recovery was observed after one year. Conclusion Non-selective axonal loss affects sensory fibers in OIN. However, the presence of intra-epidermal regenerative sprouts detected by GAP-43 may reduce the impact of neurotoxicity in the small fibers with long-term sequelae mostly on myelinated nerve endings. Pre-oxaliplatin GAP-43 failed to identify patients with higher risk of damage or worse recovery after treatment.

The implementation and access to combined antiretroviral treatment (cART) have dramatically improved the quality of life of people living with HIV (PLWH). However, some comorbidities, such as neurological disorders associated with HIV infection still represent a serious clinical challenge. Soluble factors in plasma that are associated with control of HIV replication and neurological dysfunction could serve as early biomarkers and as new therapeutic targets for this comorbidity. We used a customized antibody array for determination of blood plasma factors in 40 untreated PLWH with different levels of viremia and found sirtuin-2 (SIRT2), an NAD-dependent deacetylase, to be strongly associated with elevated viral loads and HIV provirus levels, as well as with markers of neurological damage (a-synuclein [SNCA], brain-derived neurotrophic factor [BDNF], microtubule-associated protein tau [MAPT], and neurofilament light protein [NFL]). Also, longitudinal analysis in HIV-infected individuals with immediate (n = 9) or delayed initiation (n = 10) of cART revealed that after 1 year on cART, SIRT2 plasma levels differed between both groups and correlated inversely with brain orbitofrontal cortex involution. Furthermore, targeting SIRT2 with specific small-molecule inhibitors in in vitro systems using J-LAT A2 and primary glial cells led to diminished HIV replication and virus reactivation from latency. Our data thus identify SIRT2 as a novel biomarker of uncontrolled HIV infection, with potential impact on neurological dysfunction and offers a new therapeutic target for HIV treatment and cure. IMPORTANCE Neurocognitive disorders are frequently reported in people living with HIV (PLWH) even with the introduction of combined antiretroviral treatment (cART). To identify biomarkers and potential therapeutic tools to target HIV infection in peripheral blood and in the central nervous system (CNS), plasma proteomics were applied in untreated chronic HIV-infected individuals with different levels of virus control. High plasma levels of sirtuin-2 (SIRT2), an NAD+ deacetylase, were detected in uncontrolled HIV infection and were strongly associated with plasma viral load and proviral levels. In parallel, SIRT2 levels in the peripheral blood and CNS were associated with markers of neurological damage and brain involution and were more pronounced in individuals who initiated cART later in infection. In vitro infection experiments using specific SIRT2 inhibitors suggest that specific targeting of SIRT2 could offer new therapeutic treatment options for HIV infections and their associated neurological dysfunction. This work was supported by grants from the Ministerio de Ciencia e Innovación (SAF2012-32078 and PID2020-119710RB-I00), the European Union’s Horizon 2020 research and innovation program under grant agreement 681137-EAVI2020, European Commission (EPIVINF-GA6932308), NIH grant P01-AI131568, JR13/00024, the Institució Catalana de Recerca i Estudis Avançats; ICREA, Swedish State Support for Clinical Research (ALFGBG-717531) and a research agreement with Aelix Therapeutics and Grifols.

The clinical spectrum of GRIN-related neurodevelopmental disorders (GRD) results from gene- and variant-dependent primary alterations of the NMDA receptor, disturbing glutamatergic neurotransmission. Despite GRIN gene variants’ functional annotations being dually critical for stratification and precision medicine design, genetically diagnosed pathogenic GRIN variants currently outnumber their relative functional annotations. Based on high-resolution crystal 3D models and topological domains conservation between GluN1, GluN2A, and GluN2B subunits of the NMDAR, we have generated GluN1-GluN2A-GluN2B subunits structural superimposition model to find equivalent positions between GluN subunits. We have developed a GRIN structural algorithm that predicts functional changes in the equivalent structural positions in other GluN subunits. GRIN structural algorithm was computationally evaluated to the full GRIN missense variants repertoire, consisting of 4,525 variants. The analysis of this structure-based model revealed an absolute predictive power for GluN1, GluN2A, and GluN2B subunits, both in terms of pathogenicity-association (benign vs. pathogenic variants) and functional impact (loss-of-function, benign, gain-of-function). Further, we validated this computational algorithm experimentally, using an in silico library of GluN2B-equivalent GluN2A artificial variants, designed from pathogenic GluN2B variants. Thus, the implementation of the GRIN structural algorithm allows to computationally predict the pathogenicity and functional annotations of GRIN variants, resulting in the duplication of pathogenic GRIN variants assignment, reduction by 30% of GRIN variants with uncertain significance, and increase by 70% of functionally annotated GRIN variants. Finally, GRIN structural algorithm has been implemented into GRIN variants Database (http://lmc.uab.es/grindb), providing a computational tool that accelerates GRIN missense variants stratification, contributing to clinical therapeutic decisions for this neurodevelopmental disorder.

Background: Ulnar nerve entrapment is one of the most common entrapment neuropathies, usually occurring in the cubital tunnel of the elbow and in Guyon’s canal of the wrist. However, it can also occur at other anatomical locations. Purpose: Our aim was to review other possible locations of ulnar nerve entrapment in an ultrasound and anatomical study. Material and Methods: Eleven upper limbs from eight adult corpses were ultrasonographically examined and subsequently dissected in a dissection laboratory. Four specific anatomical points were analysed, and any anatomical variations were documented. Moreover, six samples of the nerve were taken for histological analysis. Results: Distinct anatomical relationships were observed during ultrasound and dissection between the ulnar nerve and the medial intermuscular septum, the triceps aponeurosis, Osborne’s fascia at the elbow, the arcuate ligament of Osborne and the intermuscular aponeurosis between the flexor carpi ulnaris and the flexor digitorum superficialis muscles. A statistical study showed that these locations are potential areas for ulnar nerve compression. In addition, a fourth head of the triceps brachii muscle was found in some specimens. Conclusion: Results demonstrate that ultrasound is a good tool to investigate ulnar nerve entrapment neuropathy and to identify other anatomical points where the nerve can remain compressed.

Objectives: To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients.Methods: We performed a retrospective longitudinal study of prospectively collected data for all domino liver transplant recipients with acquired amyloid neuropathy who received diflunisal at our hospital. Neurological deterioration was defined as an score increase of >= 2 points from baseline on the Neurological Impairment Scale/Neurological Impairment Scale-Lower Limbs.Results: Twelve patients who had received compassionate use treatment with diflunisal were identified, of whom seven had follow-up data for >= 12 months. Five patients (71.4%) presented with neurological deterioration on the Neurological Impairment Scale after 12 months (p = 0.0382). The main adverse effects were cardiovascular and renal, leading to diflunisal being stopped in five patients and the dose being reduced in two patients.Conclusion: Our study suggests that most domino liver transplant recipients with acquired amyloid neuropathy will develop neurological deterioration by 12 months of treatment with diflunisal. This therapy was also associated with a high incidence of adverse effects and low treatment retention. The low efficacy and low tolerability of diflunisal treatment encourage the search for new therapeutic options.

Huntington’s disease (HD) is a hereditary neurodegenerative disorder caused by the expression of mutant huntingtin (mHtt). One of the main features of HD is the degeneration of the striatum that leads to motor discoordination. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that acts through three receptors named PAC1R, VPAC1R, and VPAC2R. In the present study, we first investigated the effect of PACAP on STHdhQ7/Q7 and STHdhQ111/Q111 cells that express wild-type Htt with 7 and mHtt with 111 glutamines, respectively. Then we explored the capacity of PACAP to rescue motor symptoms in the R6/1, a murine model of HD. We found that PACAP treatment (10–7 M) for 24 h protects STHdhQ111/Q111 cells from mHtt-induced apoptosis. This effect is associated with an increase in PAC1R transcription, phosphorylation of ERK and Akt, and an increase of intracellular c-fos, egr1, CBP, and BDNF protein content. Moreover, the use of pharmacological inhibitors revealed that activation of ERK and Akt mediates these antiapoptotic and neurotrophic effects of PACAP. To find out PAC1R implication, we treated STHdh cells with vasoactive intestinal peptide (VIP), which exhibits equal affinity for VPAC1R and VPAC2R, but lower affinity for PAC1R, in contrast to PACAP which has same affinity for the three receptors. VIP reduced cleaved caspase-3 protein level, without promoting the expression of c-fos, egr1, CBP, and the neurotrophin BDNF. We next measured the protein level of PACAP receptors in the striatum and cortex of R6/1 mice. We observed a specific reduction of PAC1R at the onset of motor symptoms. Importantly, the intranasal administration of PACAP to R6/1 animals restored the motor function and increased the striatal levels of PAC1R, CBP, and BDNF. In conclusion, PACAP exerts antiapoptotic and neurotrophic effects in striatal neurons mainly through PAC1R. This effect in HD striatum allows the recovery of motor function and point out PAC1R as a therapeutic target for treatment of HD.

Many patients experiencing a rare disease remain undiagnosed even after genomic testing. Reanalysis of existing genomic data has shown to increase diagnostic yield, although there are few systematic and comprehensive reanalysis efforts that enable collaborative interpretation and future reinterpretation. The Undiagnosed Rare Disease Program of Catalonia project collated previously inconclusive good quality genomic data (panels, exomes, and genomes) and standardized phenotypic profiles from 323 families (543 individuals) with a neurologic rare disease. The data were reanalyzed systematically to identify relatedness, runs of homozygosity, consanguinity, single-nucleotide variants, insertions and deletions, and copy number variants. Data were shared and collaboratively interpreted within the consortium through a customized Genome-Phenome Analysis Platform, which also enables future data reinterpretation. Reanalysis of existing genomic data provided a diagnosis for 20.7% of the patients, including 1.8% diagnosed after the generation of additional genomic data to identify a second pathogenic heterozygous variant. Diagnostic rate was significantly higher for family-based exome/genome reanalysis compared with singleton panels. Most new diagnoses were attributable to recent gene-disease associations (50.8%), additional or improved bioinformatic analysis (19.7%), and standardized phenotyping data integrated within the Undiagnosed Rare Disease Program of Catalonia Genome-Phenome Analysis Platform functionalities (18%). Supported by Generalitat de Catalunya through Departament de Salut (SLT002/16/00174 to URD-Cat consortium) and Departament d’Empresa i Coneixement and the CERCA Program; FP7 and H2020 EU projects RD-Connect, Solve-RD, and EJP-RD grants FP7 305444, H2020 779257, and H2020 825575 for CNAG-CRG; Spanish Ministry of Science and Innovation to the EMBL partnership and through the Instituto de Salud Carlos III grants PT13/0001/0044 and PT17/0009/0019 for CNAG-CRG and grants PI16/01048, PI19/01310, PI18/00451, PI18/00498, and PI21/00935 for IDIBAPS (Instituto Nacional de Bioinformática); ELIXIR Implementation Studies (CNAG-CRG); Centro de Investigaciones Biomédicas en Red de Enfermedades Raras; Centro de Excelencia Severo Ochoa grant SEV-2016-0571 (CNAG-CRG) and grant CEX 2018-000806-S (ISGLOBAL); and cofinancing with funds from the European Regional Development Fund by the Spanish Ministry of Science and Innovation corresponding to the Programa Operativo FEDER Plurirregional de España (POPE) 2014 to 2020 and by the Secretaria d’Universitats i Recerca, Departament d’Empresa i Coneixement of the Generalitat de Catalunya corresponding to the Programa Operatiu FEDER de Catalunya 2014 to 2020.

Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A.

Background Guillain–Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain–Barré syndrome. Methods Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. Results None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. Conclusion Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.

[eng] BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a neuronal antibody-mediated disease that associates with prominent neuropsychiatric symptoms and predominantly affects women of childbearing age. Animal models of this disease have enabled the demonstration that patients’ antibodies are pathogenic as they bind to NMDARs and cause their internalization, resulting in a decrease of synaptic levels of these receptors, impairment of synaptic plasticity, memory deficits, and depressive-like and psychotic-like behaviors. These antibodies are class G immunoglobulins (IgG); thus, they can be transferred across the placenta in pregnant patients with anti-NMDAR encephalitis and potentially be detrimental for the fetus/newborn. On the other hand, novel therapeutic strategies to accelerate patients’ recovery are of interest. OBJECTIVES: 1) Report the effects of anti-NMDAR encephalitis in pregnant patients and their babies, 2) develop an animal model of placental transfer of IgG antibodies from patients with anti-NMDAR encephalitis to determine their potential pathogenic effects in the fetus and offspring, 3) investigate whether treatment with a neonatal Fc receptor (FcRn) inhibitor prevents the placental transfer of patients’ IgG and abrogates the antibody-mediated alterations in the previously developed mouse model, and 4) study the potential therapeutic use of a positive allosteric modulator (PAM) of NMDAR (i.e., SGE-301) in a reported mouse model of cerebroventricular infusion of patients’ cerebrospinal fluid (CSF) antibodies. CONCLUSIONS: My studies have contributed to gain insight into the outcome of babies from pregnant patients with anti-NMDAR encephalitis and to unravel the antibody-mediated synaptic alterations underlying the transient developmental and behavioral impairment using a mouse model of placental transfer of patients’ IgG. Overall, these findings have provided potential therapeutic strategies in antibody-mediated diseases of the CNS during pregnancy (i.e., FcRn inhibitor) or in an adult mouse model of anti-NMDAR encephalitis (SGE-301).

Human adipose-derived mesenchymal stem cells (hASCs) may be used in some nervous system pathologies, although obtaining an adequate degree of neuronal differentiation is an important barrier to their applicability. This requires a deep understanding of the expression and epigenetic changes of the most important genes involved in their differentiation. We used hASCs from human lipoaspirates to induce neuronal-like cells through three protocols (Neu1, 2, and 3), determined the degree of neuronal differentiation using specific biomarkers in culture cells and neurospheres, and analyzed epigenetic changes of genes involved in this differentiation. Furthermore, we selected the Hoxa-5 gene to determine its potential to improve neuronal differentiation. Our results showed that an excellent hASC neuronal differentiation process using Neu1 which efficiently modulated NES, CHAT, SNAP25, or SCN9A neuronal marker expression. In addition, epigenetic studies showed relevant changes in Hoxa-5, GRM4, FGFR1, RTEL1, METRN, and PAX9 genes. Functional studies of the Hoxa-5 gene using CRISPR/dCas9 and lentiviral systems showed that its overexpression induced hASCs neuronal differentiation that was accelerated with the exposure to Neu1. These results suggest that Hoxa-5 is an essential gene in hASCs neuronal differentiation and therefore, a potential candidate for the development of cell therapy strategies in neurological disorders., Fundació La Marató TV3 (111430/31), CTS-107 Group from Junta de Andalucía

BackgroundAlexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in GFAP. Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist.MethodsA family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by whole exome sequencing (WES). A candidate variant was functionally tested in an astrocytoma cell line.ResultsThe novel variant in GFAP (Glial Fibrillary Acidic Protein) N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterised so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models.ConclusionWe suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander disease type II, probably associated with alternative pathogenic mechanisms, that is, astrocyte enlargement. GFAP analysis should be considered in adult-onset neurological presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases.

[spa] La neuroinflamación sostenida es un factor de riesgo de enfermedades relacionadas con la edad, incluidas las lesiones cerebrovasculares y la enfermedad de Alzheimer (EA). De hecho, los procesos inflamatorios se consideran cada vez más los culpables de la fragilidad y la enfermedad de la población envejecida. Como resultado, se ha intensificado la búsqueda de biomarcadores inflamatorios fiables y objetivos de intervención para combatir la demencia y otras enfermedades discapacitantes. Cada año se registran cerca de 8 millones de nuevos casos de demencia, y se estima que, para el 2050, la demencia afecte a 150 millones de personas. La enfermedad de Alzheimer (EA) es la más prevalente de las demencias, suponiendo entre un 60 y un 70% de todos los casos de demencia. Esta enfermedad se caracteriza por la pérdida cognitiva y de memoria, junto a la presentación de síntomas conductuales y psicológicos asociados a la demencia (BPSD) que disminuyen de manera drástica la calidad de vida del paciente y sus cuidadores. La neuropatología de la EA se caracteriza por el depósito proteico del péptido amiloide y tau hiperfosforilada que, eventualmente, desembocan en la agregación de placas seniles y ovillos neurofibrilares. Esta patología además, suele ir acompañada de neuroinflamación, aumento del estrés oxidativo y disfunción mitocondrial, alteración neurovascular, pérdida sináptica y neurodegeneración. Actualmente no existe cura para el Alzheimer, por ello, nuevas terapias que aborden su prevención o presenten nuevas vías de investigación son imprescindibles. En esta tesis se ha pretendido evaluar la contribución de la proteína monomérica C-reactiva al desarrollo de demencia de tipo EA. La proteína C-Reactiva (CRP) es una pentraxina, secretada por el hígado en respuesta a la inflamación y ampliamente conocida por ser un marcador de procesos inflamatorios. Así cuando el pentámero que es la CRP se une a las membranas de los tejidos dañados, esta se disocia dando lugar a sus subunidades monoméricas, altamente pro-inflamatorias y poco solubles, que quedan depositadas de manera crónica en la matriz extracelular del tejido afectado. La proteína monomérica C-reactiva es, por lo tanto, una de las subunidades monoméricas de la CRP. Así, la mCRP depositada en la matriz extracelular del tejido dañado favorece un ambiente proinflamatorio crónico que, sumado a su alta capacidad angiogénica favorece el agravamiento de la enfermedad. Estudios recientes han confirmado la presencia de mCRP en el tejido cerebral de enfermos de EA, así como la capacidad de las placas amiloides para disociar CRP generando mCRP. Asimismo, se ha demostrado cómo mCRP favorece la fosforilización de tau in vitro y cómo la tau fosforilada colocaliza a nivel intraneuronal con mCRP en cerebros de pacientes de EA. Por otra parte, estudios previos de nuestro grupo de investigación demostraron que la mCRP inyectada en el hipocampo de ratones inducía pérdida de memoria después de 4 semanas, así como otros rasgos de la EA, como patología amiloide y de tau en neuronas del hipocampo y áreas corticales. Estos estudios también han confirmado a mCRP como un posible vínculo entre el ictus y el posterior desarrollo de demencia que aparece en un tercio de los casos de accidente cerebrovascular. Así, la hipótesis en que se basa esta tesis es que la mCRP, la forma activada de la CRP, contribuye al desarrollo y progresión de la enfermedad de EA. Con el fin de probar esta hipótesis, desarrollamos un modelo de ratón de demencia inducido mediante la infusión bilateral de mCRP en el hipocampo de los ratones. Los animales fueron evaluados tras 1, 3 y 6 meses de tratamiento con mCRP con el fin de caracterizar la pérdida cognitiva y de BPSD de este modelo, así como la neuropatología adyacente.

Pharmacological treatment is not very effective for neuropathic pain (NP). A progressive decrease in the estimated effect of NP drugs has been reported, giving rise to an increase in the use of the multimodal analgesic approach. We performed a new, independent review to assess whether more evidence and of better-quality has become available since the last systematic review. We evaluated the efficacy, tolerability, and safety of double-blinded, randomized, controlled trials involving only adult participants and comparing combination therapy (CT: ≥ 2 drugs) to a placebo and/or at least one other comparator with an NP indication. The primary outcome assessed was the proportion of participants reporting ≥50% pain reductions from baseline. The secondary outcome assessed was the proportion of drop-outs due to treatment-emergent adverse events. After removing duplicates, 2323 citations were screened, with 164 articles assessed for eligibility, from which 16 were included for qualitative analysis. From the latter, only five lasted for at least 12 weeks and only six complied with the required data for complete analysis. CT has been adopted for years without robust evidence. Efforts have been made to achieve better-quality evidence, but the quality has not improved over the years. In this regard, guidelines for NP should attempt to make recommendations about CT research, prioritizing which combinations to analyze.

GPR37 is an orphan G protein-coupled receptor (GPCR) implicated in several neurological diseases and important physiological pathways in the brain. We previously reported that its long N-terminal ectodomain undergoes constitutive metalloprotease-mediated cleavage and shedding, which have been rarely described for class A GPCRs. Here, we demonstrate that the protease that cleaves GPR37 at Glu167↓Gln168 is a disintegrin and metalloprotease 10 (ADAM10). This was achieved by employing selective inhibition, RNAi-mediated downregulation, and genetic depletion of ADAM10 in cultured cells as well as in vitro cleavage of the purified receptor with recombinant ADAM10. In addition, the cleavage was restored in ADAM10 knockout cells by overexpression of the wild type but not the inactive mutant ADAM10. Finally, postnatal conditional depletion of ADAM10 in mouse neuronal cells was found to reduce cleavage of the endogenous receptor in the brain cortex and hippocampus, confirming the physiological relevance of ADAM10 as a GPR37 sheddase. Additionally, we discovered that the receptor is subject to another cleavage step in cultured cells. Using site-directed mutagenesis, the site (Arg54↓Asp55) was localized to a highly conserved region at the distal end of the ectodomain that contains a recognition site for the proprotein convertase furin. The cleavage by furin was confirmed by using furin-deficient human colon carcinoma LoVo cells and proprotein convertase inhibitors. GPR37 is thus the first multispanning membrane protein that has been validated as an ADAM10 substrate and the first GPCR that is processed by both furin and ADAM10. The unconventional N-terminal processing may represent an important regulatory element for GPR37.

BACKGROUND Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare disorder that usually involves long-term impairment. Despite the chronic health-care needs that are often associated, research evaluating the economic burden of this disorder is still scarce. This study aimed to assess the characteristics of patients admitted with CIDP in Spanish hospitals and to determine the associated medical costs. METHODS A retrospective multicenter study was designed analyzing records of hospital and ambulatory visits of patients with CIDP in Spanish hospitals between 2004 and 2018. Medical costs registered in hospital facilities were evaluated. RESULTS Admission files corresponding to 2805 patients diagnosed with CIDP were extracted from the database: 64.7% of patients were males, and median age was 60 years. Patients presented comorbidities that included essential hypertension, hypercholesterolemia, and diabetes mellitus. The raw number of admissions for CIDP increased significantly over the study period, similarly to mean admission costs for all age groups. Consequently, total hospital medical costs associated with CIDP increased over the study period. The mean medical cost per admission was €3953. CONCLUSIONS The increasing number of hospital cases of CIDP is associated with rising medical costs. Further research will be required to fully evaluate the medical and societal burdens of this disorder.

The CACNA1A gene encodes the pore-forming α1A subunit of the voltage-gated CaV2.1 Ca2+ channel, essential in neurotransmission, especially in Purkinje cells. Mutations in CACNA1A result in great clinical heterogeneity with progressive symptoms, paroxysmal events or both. During infancy, clinical and neuroimaging findings may be unspecific, and no dysmorphic features have been reported. We present the clinical, radiological and evolutionary features of three patients with congenital ataxia, one of them carrying a new variant. We report the structural localization of variants and their expected functional consequences. There was an improvement in cerebellar syndrome over time despite a cerebellar atrophy progression, inconsistent response to acetazolamide and positive response to methylphenidate. The patients shared distinctive facial gestalt: oval face, prominent forehead, hypertelorism, downslanting palpebral fissures and narrow nasal bridge. The two α1A affected residues are fully conserved throughout evolution and among the whole human CaV channel family. They contribute to the channel pore and the voltage sensor segment. According to structural data analysis and available functional characterization, they are expected to exert gain- (F1394L) and loss-of-function (R1664Q/R1669Q) effect, respectively. Among the CACNA1A-related phenotypes, our results suggest that non-progressive congenital ataxia is associated with developmental delay and dysmorphic features, constituting a recognizable syndromic neurodevelopmental disorder. This work was funded by the Spanish Ministry of Health, Consumer Affairs and Social Welfare, the Spanish Ministry of Science and Innovation, the State Research Agency (AEI, Agencia Estatal de Investigación), and FEDER Funds (Fondo Europeo de Desarrollo Regional): Grants RTI2018-094809-B-I00 to J.M.F.F. and CEX2018-000792-M through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”. M.S. is supported by the Generalitat de Catalunya (PERIS SLT008/18/00194) and National Grant PI17/00101 from the National R&D&I Plan, cofinanced by the Instituto de Salud Carlos III (Subdirectorate-General for Evaluation and Promotion of Health Research) and FEDER (European Regional Development Fund).

[spa] El término de Patología Dual (PD) hace referencia a la coexistencia o concurrencia de, al menos, un Trastorno por Uso de Sustancias (TUS) y un Trastorno Mental (TM) en una misma persona. Si bien existe una amplia variedad de combinaciones posibles dada la naturaleza heterogénea de esta condición, en este trabajo se ha considerado la comorbilidad de los TM severos esquizofrenia, trastorno bipolar y depresión mayor. La relevancia de la PD se relaciona con su etiología y expresión fenotípica compleja en la que intervienen múltiples factores de riesgo y de protección junto a su elevada prevalencia, gravedad clínica y psicosocial, difícil manejo terapéutico y peor pronóstico funcional. La evidencia científica y la práctica clínica demuestran que en pacientes duales existen variaciones neurocognitivas y de ritmicidad circadiana asociadas al tipo de TM comórbido que derivan en implicaciones clínicas y funcionales de diferente impacto. El objetivo de la presente tesis doctoral consistió en explorar tales diferencias y la interrelación con otras variables sociodemográficas y clínicas atendiendo al tipo de diagnóstico psiquiátrico comórbido. Con ello se pretende contribuir al conocimiento de un perfil cognitivo y circadiano diferencial en pacientes duales que pueda trasladarse al desarrollo de posibles intervenciones preventivas y de estrategias terapéuticas más dirigidas a sus necesidades individuales y recuperación. La investigación abarcó tres áreas de estudio. En la primera se analizaron las variables sociodemográficas y clínicas de los tres grupos de pacientes duales en tratamiento, permitiendo definir y precisar características asociadas al diagnóstico psiquiátrico y su riesgo o influencia en el inicio y desarrollo del trastorno comórbido. La segunda consistió en la evaluación del rendimiento neurocognitivo, el análisis del efecto que la inteligencia premórbida tiene en el mismo y la interrelación de ambos con variables clínicas. Las alteraciones cognitivas se consideran endofenotipos de algunos TM y, en los últimos años, diferencias individuales en la actividad cerebral y un buen funcionamiento premórbido se han relacionado con el mejor rendimiento cognitivo y funcional. Por último, se exploraron las diferencias en la expresión rítmica circadiana ─temperatura corporal periférica (TCP), horarios de sueño-vigilia y tipología circadiana─ incluyendo la comparación con un grupo de controles sanos (CS) y la influencia del tipo de tratamiento ambulatorio o residencial (mayoritariamente en comunidad terapéutica). Se ha señalado que las alteraciones rítmicas circadianas, tanto en pacientes TUS como en algunos TM, podrían ser una característica clínica significativa que afecta la aparición y el curso del trastorno comórbido. Los datos en pacientes duales, aunque muy escasos, apuntan la existencia de recuperación rítmica asociada al tiempo de abstinencia y al tipo de tratamiento. Se evaluó un total de 114 participantes varones de edades comprendidas entre 20 y 50 años. Todos ellos con diagnóstico de PD en tratamiento ambulatorio o residencial (mayoritariamente en comunidad terapéutica). Los participantes fueron divididos en tres grupos atendiendo al diagnóstico psiquiátrico comórbido de esquizofrenia (SZ+=38), bipolar (BP+=37) o depresión mayor (DM+=39). Fueron criterios de inclusión al estudio la vinculación regular al tratamiento y estabilidad clínica, remisión inicial del TUS (no inducido) y abstinencia mínima de tres meses y hasta un año. Los resultados indicaron que los pacientes con SZ+ presentaron indicadores de mayor riesgo para el inicio y mantenimiento del trastorno comórbido así como de mayor gravedad social y clínica, como inactividad laboral por discapacidad/incapacidad, nivel más bajo de estudios, una edad de inicio tanto del TM como del TUS más temprana, más antecedentes familiares de consumo, uso simultáneo de más sustancias y más consumo de nicotina. A diferencia de éstos, los pacientes con DM+ mostraron una edad media superior, mayor probabilidad de estar separado/divorciado y de tener hijos, desempleo por paro o baja laboral, edad de inicio del TM más tardía, pauta más reducida de fármacos y menor consumo de nicotina. Además, la mitad de ellos se encontraba realizando tratamiento intensivo en comunidad terapéutica. Los BP+ se situaron en una posición intermedia en la mayoría de variables, si bien presentaron más años de estudios y menor dependencia de la adicción. Respecto al rendimiento cognitivo, el funcionamiento premórbido estuvo conservado en los tres grupos, así como las habilidades visuoconstructivas y espaciales, y el span atencional. El aprendizaje y memoria verbal estuvieron afectados en SZ+ y relativamente conservados en DM+ y BP+, exceptuando la evocación inmediata. Destacó un buen procesamiento de la información en DM+, con algunas dificultades en SZ+ y BP+. El funcionamiento ejecutivo de los tres grupos fue adecuado excepto en la tarea TMT, donde SZ+ y BP+ mostraron déficits en la inhibición cognitiva de secuencias automáticas y flexibilidad mental. La inteligencia premórbida influyó en casi todos los dominios cognitivos evaluados y, en menor medida, también la edad de los pacientes, la duración de la abstinencia, la estabilidad clínica y la edad de inicio tanto del TUS como del TM. En cuanto a la expresión rítmica circadiana, los pacientes SZ+, seguidos de BP+, mostraron una acrofase más tardía y un mínimo y mesor más elevados que DM+ y CS. Los pacientes DM+ presentaron mayor amplitud y estabilidad del ritmo respecto a los otros grupos de pacientes y a CS. Además, DM+ fueron predominantemente matutinos, dormían menos horas al día y se levantaban más temprano. Todos los grupos diagnóstico aportaron una menor fragmentación del ritmo comparados con CS. El índice de circadianidad fue menor en SZ+ y DM+ que el observado en CS y según el rango normativo. Por otra parte, respecto a los pacientes residenciales, aquellos ambulatorios presentaron un valor mínimo, mesor y L10 más elevado, una acrofase más tardía y un retraso de la hora central del periodo de vigilia. También refirieron mayor duración de sueño diario, horas más tardías de levantarse y acostarse así como una tipología intermedia. Junto al tipo de tratamiento las variables de edad, abstinencia y consumo de nicotina fueron factores indicativos de afectación o recuperación rítmica. Tales hallazgos apuntan la importancia de la preservación o recuperación cognitiva y circadiana en la funcionalidad de los pacientes duales, siendo indicadores la inteligencia premórbida y el tratamiento residencial respectivamente. Entre las implicaciones preventivas y clínicas que se derivan destaca el incluir en primeros episodios y a edades más avanzadas evaluaciones neuropsicológicas y del CI premórbido e incorporar intervenciones para enriquecer la reserva cognitiva en caso necesario. Así mismo, evaluar el estado rítmico circadiano antes y a lo largo del tratamiento, incorporando estrategias cronoterapéuticas en los pacientes ambulatorios. En conclusión, la consideración de las alteraciones neurocognitivas y circadianas y el impacto en ellas del TM comórbido contribuirá a la detección de posibles marcadores de vulnerabilidad y pueden ser predictores de pronóstico y adherencia al tratamiento junto al establecimiento de objetivos y estrategias de tratamiento más precisas orientadas a la prevención o rehabilitación así como a mantener cambios de comportamiento y hábitos saludables a medio y largo plazo para la evitación de recaídas., [eng] The term Dual Pathology (DP) refers to the coexistence or concurrence of at least one Substance Use Disorder (SUD) and a Mental Disorder (MD) in the same person. Although there is a wide variety of possible combinations given the heterogeneous nature of this condition, this work has considered the comorbidity of three very prevalent severe MDs in DP (schizophrenia, bipolar disorder and major depression). The relevance of DP seems to be related to its etiology and complex phenotypic expression in which multiple risk and protection factors are involved. Added to this is the high prevalence, clinical and psychosocial severity, difficult therapeutic management and worse overall functional prognosis. Today, the correct detection, diagnosis and therapeutic intervention in DP is a difficult task and a pending challenge among professionals and researchers in the fields of mental health and addictions. Scientific evidence and clinical practice show that in dual patients there are cognitive and circadian rhythmic variations associated with the type of comorbid MD, which may result in clinical and functional implications of different impact. Therefore, the objective of the present doctoral thesis was to explore such differences and the interrelation with other sociodemographic and clinical variables based on the type of comorbid psychiatric diagnosis. Our purpose is to try to contribute to the knowledge of a differential profile in dual patients according to the comorbid pathology that could be transferred to the development of possible preventive interventions and therapeutic strategies especially directed to their individual needs. This research covered three areas of study. First, the sociodemographic and clinical variables of the three groups of dual patients under treatment were analyzed, allowing to define and specify characteristics associated with the psychiatric diagnosis and their risk or influence on the onset and development of the comorbid disorder. Secondly, was the evaluation of neurocognitive performance, the analysis of the effect that premorbid intelligence has on it and the interrelation of both with clinical variables. Cognitive alterations are considered as endophenotypes of some MD and, in recent years, individual differences in brain activity and good premorbid functioning have been linked to a better cognitive and functional performance. Finally, differences in circadian rhythmic expression - peripheral body temperature (PBT), sleep-wake time and circadian typology- were explored, including a comparison with a group of healthy controls (HC) and the influence of the type of outpatient treatment or residential (mostly in therapeutic community). The evidence indicates the existence of circadian rhythmic alterations in both SUD and in some MD, suggesting that these alterations could be a significant clinical feature that affects the onset and course of comorbid disorder. Data in dual patients, although scarce, suggest the existence of rhythmic recovery associated with withdrawal time and the type of treatment. A total of 114 male participants aged 20 to 50 years were evaluated, all of them with diagnosis of DP in outpatient or residential treatment (most in the therapeutic community). The participants were divided into three groups based on the comorbid psychiatric diagnosis of schizophrenia (SZ+=38), bipolar disorder (BP+=37) or major depression (MD+=39). Inclusion criteria to the study were regular treatment adherence and clinical stability, initial remission of SUD (not induced), and minimum abstinence period of three months and up to one year. The results indicated that patients with SZ+ presented indicators of a greater risk for the onset and maintenance of the comorbid disorder as well as greater social and clinical severity, such as inactivity due to disability, lower level of studies, and an earlier age of onset for both MD and SUD, more family history of substance use, simultaneous use of more substances, and more nicotine consumption. In contrast to these, patients with MD+ exhibited an older average age, greater probability of being separated/divorced and having children, unemployment due to work stoppage or work leave, age of onset of the latest MD, reduced pattern of drugs, and lower consumption of nicotine. In addition, half of them were undergoing an intensive treatment in a therapeutic community. The BP+ patients were placed in an intermediate position in the majority of the variables, although the group highlighted a higher level of education and a lower severity of addiction. Regarding the cognitive performance, premorbid functioning was conserved in the three groups, as well as visoconstructive and spatial skills, and attention span. Learning and verbal memory were affected in SZ+ and relatively conserved in MD+ and BP+, except for immediate memory. Thus, we observed a good processing of information for MD+, and some difficulties for SZ+ and BP+. The executive functioning of the three groups was adequate except in the TMT task, in which SZ+ and BP+ showed deficits in the cognitive inhibition of automatic sequences and mental flexibility. Moreover, premorbid intelligence influenced almost all cognitive domains evaluated and, to a lesser extent also the age of the patients, the abstinence period, clinical stability, and the age of onset for both SUD and MD+. Regarding the circadian rhythmic expression, the SZ+ patients, followed by BP+, showed a late acrophase and a higher mesor than MD+ and HC. The MD+ patients presented greater amplitude and stability of the rhythm compared with the other groups of patients and HC. In addition, patients MD+ were predominantly within a morning typology, slept less hours a day and got up earlier. All the diagnostics groups exhibited less fragmentation of the rhythm compared to HC. The circadianity index was lower in SZ+ and MD+ than that observed for HC, and according to the normative range. On the other hand, regarding residential patients, those outpatients had a higher minimum, mesor and L10 value, a late acrophase and a delay in the central time of the waking period. They also reported a longer duration of daily sleep, later hours of getting up and going to bed, as well as an intermediate typology. Together with the type of treatment, age, abstinence period and nicotine consumption were indicative factors of rhythmic involvement or recovery. Our findings point out the importance of the cognitive preservation and circadian recovery in the functionality of dual patients; being indicators of these aspects the premorbid intelligence and the residential treatment, respectively. Among the preventive and clinical implications that arise from such findings, it is worth mentioning the inclusion of neuropsychological and premorbid IC assessment in early episodes and at older ages, also incorporating interventions to enrich the cognitive reserve if necessary. Likewise, other clinical implications from our observations are to evaluate the circadian rhythmic state before and throughout the SUD treatment, incorporating chronotherapeutic strategies for outpatients. In conclusion, the consideration of neurocognitive and circadian alterations and the posible impact on them of comorbid MD will contribute to the detection of possible markers of vulnerability and can be predictors of prognosis and adherence to treatment together with the establishment of more precise goals and strategies; oriented to prevention or rehabilitation as well as to maintaining changes in behavior and healthy habits in the medium and long term to avoid relapses.

Background: BSCL2 heterozygote mutations are a common cause of distal hereditary motor neuropathies (dHMN). We present a series of BSCL2 patients and correlate clinical, neurophysiological and muscle-MRI findings. Methods: 26 patients from 5 families carrying the p.N88S mutation were ascertained. Age of onset, clinical phenotype (dHMN, Charcot-Marie-Tooth/CMT, spastic paraplegia), physical examination, disability measured as modified Rankin score (mRS) and neurophysiological findings were collected. A whole body muscle-MRI had been performed in 18 patients. We analyzed the pattern of muscle involvement on T1-weighted and STIR sequences. Hierarchical analysis using heatmaps and a MRI Composite Score (MRI CS) were generated. Statistical analysis was carried out with STATA SE v.15. Results Mean age was 51.54+/-19.94 years and 14 patients were males. dHMN was the most common phenotype (50%) and 5 patients (19.23%) showed no findings on examination. Disease onset was commonly in childhood and disability was low (mRS=1.34+/-1.13) although median time since onset of disease was 32 years (range=10-47). CMT-like patients were more disabled and disability correlated with age. On muscle-MRI, thenar eminence, soleus and tibialis anterior were most frequently involved, irrespective of clinical phenotype. MRI CS was strongly correlated with disability. Conclusion: Patients with the p.N88S BSCL2 gene mutation are phenotypically variable, although dHMN is most frequent and generally slowly progressive. Muscle-MRI pattern is consistent regardless of phenotype and correlates with disease severity, probably serving as a reliable outcome measure for future clinical trials.

Sanfilippo syndrome type C (mucopolysaccharidosis IIIC) is an early-onset neurodegenerative lysosomal storage disorder, which is currently untreatable. The vast majority of studies focusing on disease mechanisms of Sanfilippo syndrome were performed on non-neural cells or mouse models, which present obvious limitations. Induced pluripotent stem cells (iPSCs) are an efficient way to model human diseases in vitro. Recently developed transcription factor-based differentiation protocols allow fast and efficient conversion of iPSCs into the cell type of interest. By applying these protocols, we have generated new neuronal and astrocytic models of Sanfilippo syndrome using our previously established disease iPSC lines. Moreover, our neuronal model exhibits disease-specific molecular phenotypes, such as increase in lysosomes and heparan sulfate. Lastly, we tested an experimental, siRNA-based treatment previously shown to be successful in patients’ fibroblasts and demonstrated its lack of efficacy in neurons. Our findings highlight the need to use relevant human cellular models to test therapeutic interventions and shows the applicability of our neuronal and astrocytic models of Sanfilippo syndrome for future studies on disease mechanisms and drug development.

Campylobacter jejuni causes campylobacteriosis, a bacterial gastroenteritis with high incidence worldwide. Moreover, C. jejuni infection can trigger the polyneuropathic disorder denominated Guillain-Barr&eacute, syndrome (GBS). The C. jejuni strains that can elicit GBS carry either wlaN or cgtB, coding both genes for a &beta, 1,3-galactosyltransferase enzyme that is required for the production of sialylated lipooligosaccharide (LOSSIAL). We described a differential prevalence of the genes wlaN and cgtB in C. jejuni isolates from three different ecological niches: humans, broiler chickens, and wild birds. The distribution of both genes, which is similar between broiler chicken and human isolates and distinct when compared to the wild bird isolates, suggests a host-dependent distribution. Moreover, the prevalence of the wlaN and cgtB genes seems to be restricted to some clonal complexes. Gene sequencing identified the presence of new variants of the G- homopolymeric tract within the wlaN gene. Furthermore, we detected two variants of a G rich region within the cgtB gene, suggesting that, similarly to wlaN, the G-tract in the cgtB gene mediates the phase variation control of cgtB expression. Caco-2 cell invasion assays indicate that there is no evident correlation between the production of LOSSIAL and the ability to invade eukaryotic cells.

The severe acute respiratory syndrome coronavirus 2 disease (SARS-CoV-2) is the most severe manifestation of the coronavirus disease 2019 (COVID-19) pandemic. Accruing evidence indicates that the COVID-19 pandemic may have profound deleterious neurological, psychiatric, and psychological outcomes. The number of systematic reviews (SRs) and meta-analyses (MAs) on this topic has grown exponentially. This protocol aims to synthesize all evidence from SRs and MAs on the associations between the COVID-19 pandemic and neuropsychiatric outcomes. The following electronic databases will be systematically searched from inception up to 15 January 2022: PubMed, Embase, APA PsycINFO, and Cochrane Reviews. An umbrella review (UR) of SRs and MAs of observational studies will be conducted. SRs and/or MAs of observational studies examining any direct or indirect association of COVID-19 with the neuropsychiatric outcomes will be deemed eligible for potential inclusion in this UR. The direct associations include the impact on the (1) prognosis of COVID-19 and (2) neuropsychiatric sequelae after COVID-19 infection. The indirect associations include the influence of the COVID-19 pandemic on the (1) treatments and (2) outcomes of neurological and psychiatric conditions associated with the COVID-19 pandemic.

Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function.

[eng] Progressive ototoxicity of the inner ear is prevalent in patients administered aminoglycoside antibiotics with little understanding of how this damage occurs and to what extent it can be recovered. Numerous in vitro and in vivo studies using acute methods have been completed to demonstrate various types of damage in vestibular and auditory tissue, including hair cell damage that results in apoptosis or necrosis, excitotoxic damage, and/or degeneration of their afferents. However, progressive damage has only just recently been studied utilizing a sub-chronic exposure rat model; this model takes into account the progressive exposure mirrored in aminoglycoside administration that is not implied in acute experimentation. With this in mind, the sub-chronic exposure model was adapted for a new mouse model to characterize the progressive damage taking place in vestibular sensory epithelia and ganglia, along with a preliminary characterization in cochlear sensory epithelia. Mice were exposed to 30 mM IDPN (3,3’- iminodipropionitrile) in regular drinking water for 8 weeks, and monitored for vestibular deficits using an established test battery; auditory deficits were recorded using auditory brainstem response (ABR) measurements. Various techniques for identifying functional, histological (scanning/transmission electron microscopy; immunoconfocal), and molecular (mRNA; protein) data were utilized to study alterations in the vestibular and auditory tissues after sub-chronic intoxication. In the vestibular tissue, SEM/TEM imaging demonstrated progressive damage with the loss of calyceal junctions between type I hair cells and their calyx afferents, the fragmentation and retraction of the afferents, stereociliary bundle coalescence, and the unique mechanism of hair cell extrusion, where the cell is ejected from the epithelia into the endolymphatic cavity. Immunoconfocal and qRT-PCR data demonstrated a loss of caspr1 and tenascin-c in the calyceal junctions of type I hair cells and their afferents. A loss of active synapses between hair cells and their afferents was also noted, where active synapses were defined by the pre-synaptic ribeye of the hair cells and the post-synaptic GluA2 receptor of the afferents. Synaptic scaffolding protein expression was upregulated (PSD95, Homer1), which translated into an increase in the protein level (PSD95), likely for hair cell-afferent synapse stabilization and compensation. Progressive damage was noted to be at least partially or completely recoverable up until stereocilia coalescence of the hair cells. Finally, the expression of numerous scaffolding and signaling proteins were shown to be downregulated (qRT-PCR; RNAseq) during the exposure in the vestibular epithelium and ganglion, leading to the hypothesis of a depression in cell-cell adhesion between hair cells and their afferents and a depression in afferent signaling, resulting in an overall depressed system. In the cochlea, profound hearing loss was observed in a tonotopic pattern during the exposure; higher frequencies were affected first with longer exposure times affecting lower frequencies. Outer hair cells were lost tonotopically due to prolonged exposure, followed by active synapse loss of the inner hair cells. Those intoxicated for the first two weeks demonstrated a capacity for recovery before any outer hair cell or active synapse losses were seen. A sub-chronic ototoxic IDPN model demonstrates the progressive damage of the inner ear, allowing for the study of this damage and its potential for recoverability, gaining a clearer understanding of the mechanisms affecting the tissues., [spa] La ototoxicidad progresiva del oído interno prevalece en los pacientes a los que se les administraron antibióticos aminoglucósidos con poca comprensión de cómo se produce este daño y hasta qué punto se puede recuperar. Se han completado numerosos estudios in vitro e in vivo para demostrar diversos tipos de daño en el tejido vestibular y auditivo; recientemente, se ha estudiado el daño progresivo utilizando un modelo de intoxicación subcrónica en rata. Este modelo tiene en cuenta la exposición progresiva reflejada en la administración de aminoglucósidos que no está implícita en los experimentos agudos. El modelo de intoxicación subcrónica se adaptó a un nuevo modelo de ratón para describir como se caracteriza el daño progresivo que se produce en los epitelios sensoriales vestibulares y los ganglios, junto con una caracterización preliminar en los epitelios sensoriales cocleares. Los ratones se expusieron a IDPN 30 mM (3,3'-iminodipropionitrilo) en agua potable normal durante 8 semanas y se observaron los déficits vestibulares utilizando una batería de pruebas establecida; los déficits auditivos se registraron utilizando medidas de respuesta auditiva del tronco cerebral. Se utilizaron diversas técnicas para estudiar las alteraciones en los tejidos vestibular y auditivo después de una intoxicación subcrónica. En el tejido vestibular, demostró un daño progresivo con la pérdida de las uniones calíceas entre las células ciliadas tipo I y sus aferentes del cáliz, la fragmentación y retracción de los aferentes, la coalescencia estereociliar y el mecanismo único de extrusión de células ciliadas. También se observó una pérdida de sinapsis activas y se demostró que la expresión de numerosas proteínas de andamiaje y señalización estaba regulada a la baja durante la intoxicación. En la cóclea, se observó una pérdida auditiva profunda en un patrón tonotópico durante la exposición y las células ciliadas externas se perdieron tonotópicamente debido a la exposición prolongada, seguida de la pérdida activa de sinapsis de las células ciliadas internas. Un modelo de IDPN ototóxico subcrónico demuestra el daño progresivo del oído interno, lo que permite el estudio de este daño y su potencial de recuperación, obteniendo una comprensión más clara de los mecanismos que afectan a los tejidos.

[spa] Los gabapentinoides son una familia de fármacos que se unen con gran afinidad a la subunidad α2δ-1 de los canales de calcio voltaje-dependientes (VGCCs). Fármacos de esta familia como la pregabalina o la gabapentina se utilizan como tratamientos de primera línea para aliviar el dolor neuropático en enfermedades como la fibromialgia, la neuropatía diabética o la neuralgia del trigémino. Sin embargo, su uso extensivo contrasta con el limitado conocimiento sobre las implicaciones funcionales que produce la interacción de los gabapentinoides con la subunidad α2δ-1 y cuáles son sus efectos sobre la neurotransmisión. Los resultados generados a lo largo de esta tesis ayudan a obtener una imagen más nítida sobre la capacidad de la pregabalina para modificar la neurotransmisión de forma aguda. Estudiando la población homogénea de sinapsis presentes en los cultivos autápticos de neuronas colinérgicas del ganglio cervical superior de rata (SCMs), demostramos que la interacción de la pregabalina y del ectodominio de la neurexina-1α con la subunidad α2δ-1 inhibe la liberación sincrónica de vesículas sinápticas controlada por los canales de calcio dependientes de voltaje de tipo N, de forma aguda. Visualizando de manera simultánea la entrada de calcio presináptico mientras registramos las respuestas postsinápticas, comprobamos que el efecto de la pregabalina no está relacionado con una reducción significativa en la entrada de calcio presináptico. Por el contrario, el efecto reside en una alteración de la organización física establecida entre los canales de calcio y las vesículas sinápticas de la zona activa, reduciéndose de manera notable el tamaño efectivo del depósito de vesículas de liberación rápida. Asimismo, comprobamos que la sobreexpresión de la subunidad α2δ-1 potencia los efectos observados con la pregabalina y la neurexina-1α en la neurotransmisión; efectos que son mutuamente excluyentes. En esta tesis desvelamos la implicación de la región extracelular de la neurexina-1α en la regulación de la liberación de neurotransmisores. Debido a su privilegiada localización extracelular en las zonas activas, las subunidades α2δ sinápticas emergen como una diana sináptica común desde donde fármacos como los gabapentinoides o moléculas endógenas como el ectodominio de la neurexina-1 pueden controlar de forma aguda el acoplamiento entre los canales de calcio voltaje-dependientes con la liberación de las vesículas sinápticas del RRP. La variabilidad en la composición molecular de las sinapsis, como por ejemplo los niveles de α2δ presentes en los pacientes que padecen dolor neuropático, así como un posible incremento de los niveles de la región extracelular de la neurexina-1α durante las condiciones inflamatorias relacionadas con el dolor neuropático, podrían ser factores claves para explicar la efectividad del tratamiento con los gabapentinoides., [eng] Gabapentinoids are drugs that bind with high affinity voltage-gated calcium channel alpha2delta subunits. For example, α2δ-1 binds with high-affinity gabapentinoid drugs such as gabapentin (2-(1-(aminomethyl)-cyclohexyl) acetic acid) or pregabalin (3-(aminomethyl)-5-methyl-hexanoic acid), which are widely used for treating neuropathic pain. The present study sheds new light on how the interaction of gabapentinoids with alpha2delta subunits affects neurotransmission. Here we show that α2δ-1 operates as a molecular platform binding exogenous and endogenous ligands to acutely regulate the size of the readily releasable pool (RRP). The RRP of synaptic vesicles is a key determinant of phasic neurotransmission. Although the size of the RRP is tightly regulated by intracellular factors, there is little evidence for its modification by extracellular signals. By studying the homogeneous population of synapses present in autaptic microcultures, we show that pregabalin decreases the effective RRP size. Simultaneous imaging of presynaptic calcium influx and recording of postsynaptic responses shows that the effect is not related to a reduction of calcium entry. The main cause is the impairment of the functional coupling among N-type calcium channels and the RRP, resembling an increase of intracellular mobile calcium buffers such as BAPTA and/or EGTA. The ectodomain of neurexin-1α shows a similar action to pregabalin, acting as an endogenous ligand of α2δ-1 that reduces the RRP size without affecting presynaptic calcium influx. The regulatory actions described for pregabalin and the ectodomain of neurexin-1α are mutually exclusive. The overexpression of α2δ-1 enhances the effect of pregabalin and the ectodomain of neurexin-1α on neurotransmission by decreasing their effective concentration. In contrast, knockdown of α2δ-1 causes a profound inhibition of synaptic transmission. These observations prompt to consider α2δ-1 as an outside-in signaling platform that binds exogenous and endogenous cues for regulating the coupling of voltage-gated calcium channels to synaptic vesicles.

[eng] Huntington’s disease (HD) is a rare genetic disorder caused by an aberrant expansion of a CAG trinucleotide in the huntingtin gene (Htt). The neuropathology of the disease is characterized by progressive neuronal dysfunction and degeneration in specific regions within the central nervous system, which causes a triad of symptoms including motor, cognitive and psychiatric features. Current treatments only alleviate some of these symptoms without preventing the inevitable neuropathological progression and, therefore, there is great need for finding new therapies that act at the root of the illness. Transcriptional dysregulation, somatic CAG repeat instability and neurotrophic signaling alterations appear early in HD and have been considered important underlying pathogenic mechanisms. Additionally, it has been recently suggested that HDAC3 and p75NTR could participate in some of these processes. Accordingly, the main aim of this thesis was to evaluate the potential therapeutic benefits of the pharmacological inhibition of HDAC3 and the genetic reduction of p75NTR in a knock-in mouse model of HD, termed HdhQ7/Q111. Our results have demonstrated that the selective inhibition of HDAC3 ameliorates cognitive deficits (motor learning and long-term memory alterations) in HdhQ7/Q111 mice by restoring the neuronal activity- dependent transcription of important memory-related genes, such as Arc and Nr4a2. This effect could be due to an increase in histone acetylation, leading to a relaxed DNA configuration, as well as an increase in CBP acetylation, potentially promoting its transcriptional activity. Besides, we have observed that chronic HDAC3 inhibition suppresses somatic CAG repeat expansions in Htt gene. Results of this thesis have shown that HDAC3 inhibition increases Msh2 acetylation at lysine 73, probably altering its DNA repair activity, which has been involved in promoting somatic CAG repeat length increases. Finally, our results have shown that p75NTR levels are increased in HdhQ7/Q111 mice from symptomatic stages. Interestingly, p75NTR normalization delays the onset of motor coordination alterations, several neuropathological HD hallmarks and the overall neurotrophic signaling imbalance in HdhQ7/Q111 mice, which comprise a reduction of the neurotrophin BDNF, a reduction and disrupted activation of its specific receptor, TrkB, and an overactivation of the p75NTR-dependent JNK signaling pathway. However, normalization of p75NTR levels at late disease stages is not able to prevent the loss of striatal integrity and motor coordination in KI mice. This might be the result of the unstoppable advance of other pathological mechanisms that do not depend on p75NTR expression. Therefore, a pharmacological strategy aimed to reduce the expression or activity of p75NTR in HD could provide some benefits at early stages of the disease but, as the pathogenic process progresses, the benefits would be limited. Collectively, our results have provided further insight into the contribution of transcriptional dysregulation, somatic CAG instability and neurotrophin signaling disturbances to HD neuropathological progression and highlight HDAC3 and p75NTR as promising therapeutic targets to correct these pathogenic mechanisms and ameliorate cognitive and motor behavioral impairments in HD., [cat] La malaltia de Huntington (MH) és un trastorn neurodegeneratiu i hereditari que es caracteritza per la presència d’alteracions motrius, cognitives i psiquiàtriques. Actualment no existeix cap tractament que aconsegueixi frenar la progressió d’aquesta patologia, de manera que l’avaluació de dianes terapèutiques esdevé de vital importància. La desregulació transcripcional, l’expansió somàtica del triplet CAG i l’alteració de la senyalització neurotròfica s’han descrit com importants mecanismes subjacents i s’ha determinat que les proteïnes HDAC3 i p75NTR podrien promoure alguns d’aquests processos. Per això, en aquesta tesi hem avaluat els possibles beneficis resultants de la inhibició farmacològica de la HDAC3 o de la reducció genètica del receptor p75NTR en un model de ratolí de la MH, anomenat HdhQ7/Q111. Els nostres resultats han demostrat que la inhibició de la HDAC3 en ratolins HdhQ7/Q111 aporta millores cognitives degut a la prevenció de les alteracions transcripcionals. Aquest efecte podria ser conseqüència d’un increment de l’acetilació d’histones, promovent una conformació més relaxada de l’ADN, i d’un increment de l’acetilació de la proteïna CBP, estimulant la seva activitat transcripcional. A més, hem demostrat que la inhibició de la HDAC3 suprimeix l’expansió somàtica del triplet CAG en el gen mutat de la proteïna huntingtina, possiblement degut a que s’incrementen els nivells d’acetilació de la proteïna Msh2 en un residu que podria alterar la seva activitat, la qual s’ha vist recentment implicada en l’allargament del tram CAG. Per últim, els nostres resultats han determinat que la normalització del receptor p75NTR en els ratolins HdhQ7/Q111 endarrereix l’aparició de les alteracions en coordinació motora, coincidint amb una millora de diferents característiques neuropatològiques de la MH i amb una recuperació de l’alterada senyalització neurotròfica. No obstant, en etapes avançades de la malaltia, l’efecte d’altres mecanismes patogènics que ocorren de forma progressiva en la MH acaben anul·lant els efectes positius de la reducció en els nivells de p75NTR. Les evidències experimentals recopilades permeten concloure que les proteïnes HDAC3 i p75NTR participen en l’aparició de mecanismes patològics clau per a la correcta funció neuronal en diferents regions cerebrals i, per tant, representen prometedores dianes terapèutiques per tractar la simptomatologia motora i cognitiva de la MH.

[spa] La enfermedad de Alzheimer (EA) es el tipo de demencia progresiva más común. En base al incremento de la prevalencia esperada, es considera la epidemia del siglo XXI. En consecuencia, surge una gran necesidad de encontrar un tratamiento eficaz contra esta patología. Diversos estudios han relacionado la diabetes mellitus del tipo 2 (DMT2) con esta enfermedad neurodegenerativa. De hecho, estudios epidemiológicos han confirmado que las personas con DMT2 presentan mayor prevalencia de desarrollar la EA y viceversa. Uno de los principales problemas es que no existen marcadores precoces para poder detectar la enfermedad y tratarla en estadios previos a la muerte neuronal por lo que el primer estudio de esta tesis doctoral se ha centrado en la detección molecular de estos marcadores en el modelo de ratón APPswe/PS1dE9, modelo experimental de la EA familiar alimentados con dieta en rica en grasa a 3 meses de edad. Los resultados obtenidos demostraron la disminución de los niveles proteicos de IDE, ADAM10 Y PGC1alfa, además de pNMDAR2B, lo cual favorece el incremento de beta1-40 y beta1-42 insoluble y beta1- 40 soluble, favoreciendo la temprana neuropatología de la EA. Diversos estudios epidemiológicos han demuestrado que el tratamiento crónico con antiinflamatorios previene el desarrollo de la EA o al menos retrasa su progresión. Uno de los principales problemas del uso crónico de estos fármacos es la toxicidad gástrica que provocan, por lo que este trabajo se ha centrado en el estudio del tratamiento con dexibuprofeno (DXI), enantiomero activo del ibuprofeno, durante 3 meses en ratones APPswe/PS1dE9 hembras de 6 meses de edad. Los resultados obtenidos han demostrado que el tratamiento crónico del DXI disminuye la activación glial y, por consiguiente, la liberación de citocinas proinflamatorias. Esta situación resulta en una reducción de la fosforilación de TAU a través de vía de señalización de c-ABL/CABLES/pCDK5 y de la insulina. Además, los ratones tratados mostraron niveles proteicos más bajos de BACE1 lo que conduce al incremento de p-CREB y disminución de la beta1- 42 soluble e insoluble, lo cual conduce la disminución de placas beta amiloide. Acorde con esto, IDE también mostró un incremento en los animales tratados, datos que concuerdan con la mejora cognitiva observada. Por todo ello, el tratamiento crónico con DXI podría constituir un fármaco potencial para la EA. Como se ha comentado previamente, se ha descrito que existe una relación directa entre la DMT2 asociada a la ingesta de la dieta rica en grasa y la EA. Sin embargo, el mecanismo que les relaciona mantiene sin esclarecerse. La memantina (MEM) es un antagonista del receptor de NMDA que actualmente se utiliza para la EA. El objetivo de este estudio es esclarecer los efectos de este fármaco, administrado durante 2 meses, en ratones APP/PS1 de 6 meses de edad exacerbados con la ingesta de dieta rica en grasa, además de intentar determinar los posibles mecanismos moleculares que conectan la EA y DMT2. Los resultados obtenidos mostraron la mejora significativa de los parámetros periféricos en los animales tratados con MEM y alimentados con dieta rica en grasa. Además, se demostró una disminución de la neuroinflamación, pérdida cognitiva, deposición de placas beta amiloide y resistencia a la insulina en el hipocampo. A su vez, los animales tratados presentaron la activación de moléculas involucradas en la vía de la insulina en el hígado, sin embargo, curiosamente, no se detectaron niveles proteicos ni expresión del receptor de NMDA en el tejido hepático. Por consiguiente, además de demostrar el papel fundamental del beta amiloide en los desórdenes metabólicos, este estudio sugiere la posible aplicación de la MEM en los desórdenes metabólicos como es el caso de la DMT2., [eng] Alzheimer´s disease (AD) is most common form of dementia which is considered as the epidemic of XXI century. Several studies have demonstrated the link between AD and type 2 diabetes mellitus (T2DM), in fact, epidemiological studies have suggested that people suffering from AD have more prevalence to develop T2DM and vice versa. The lack of early biomarkers for the diagnosis of this neurogenerative disease makes its prevention and treatment less effective. Therefore, the aim of this first study has been to detect early changes in a presymptomatic APPswe/PS1dE9 familial AD mouse model at 3 months of age fed with high fat diet (HFD). Our results demonstrated the IDE, ADAM10 and PGC1alpha together with NMDA2B receptor are involved in the increase of insoluble beta1-40 and beta1-42 and soluble beta1-40, favoring the early neuropathology of AD. In addition, it has been published that antiinflamatory chronic treatments prevent the development of AD, however, the main adverse effect is its gastric toxicity. Our study has focused on the effect of dexibuprofen, the active enantiomer or ibuprofen, in APPswe/PS1dE9 mice at 6 months old after a chronic treatment. The observed results showed that the reduction of glial activation caused by dexibuprofen intake, decrease the TAU phosphorylation through c-ABL/CABLES/pCDK5 and insulin pathway. Moreover, BACE1 protein level was decreased in treated animals dealing to reduction of beta amyloid deposits and, therefore, improvement of cognitive decline. Finally, the link between T2DM and AD has been widely described, however, the mechanism which connect both pathologies remains unclear. Memantine is an antagonist of NMDA receptor used nowadays as treatment for AD. The objective of this last study has been to clarify the effects of MEM in a mixed, T2DM and AD, mice model in APPswe/PS1dE9 fed with high fat diet at 6 months old. Our results demonstrated that MEM improves the peripheral parameters, likewise the neuroinflammation, Beta amyloid plaque deposition, memory decline and insulin resistance in the hippocampus. In addition, MEM activated insulin pathway in the liver. Therefore, the use of this drug could be a possible therapeutic strategy for metabolic disorders such as T2DM

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the major dose-limiting adverse events of widely used drugs in both the oncologic and hematologic setting (1). Among its cardinal symptoms, neuropathic pain is frequently present (2). In particular, the incidence of bortezomib-induced peripheral neurotoxicity (BIPN) and neuropathic pain ranges from 14–45% and 5–39%, respectively, in myeloma multiple patients. BIPN is more frequently developed in pretreated patients, compared to those being chemotherapy-naïve (3,4), and this difference mostly accounts for the wide variability in the observed incidence rates. Bortezomib is the first proteasome inhibitor introduced in clinical practice. The mechanisms underlying the pathogenesis of peripheral neurotoxicity in bortezomib- treated patients are, yet, not fully elucidated (3,4).

Chemotherapy-induced peripheral neuropathy is a very frequent neurological complication in cancer. Oxaliplatin (OXA) is a platinum analogue used as a first-line agent in the treatment of colorectal cancer. OXA induced peripheral neuropathy (OIN) is the main toxicity both during and after the completion of chemotherapy that presents as two distinct syndromes: acute and chronic neuropathy. None of the neuroprotective agents previously tested had prevented or limited the acute and/or chronic OIN. MR309 (previously developed as E-52862) is a novel selective sigma-1 receptor (S1R) antagonist with preclinical analgesic activity in OXA-induced neuropathic pain in animal models. This review analyzes the results of the recently published phase II, randomized, double-blind, placebo-controlled clinical trial including 124 patients with colorectal cancer (CRC) treated with MR309. This study shows encouraging findings in the setting of neuroprotection against OIN with an acceptable safety profile. The study demonstrated MR309 usefulness in decreasing acute OIN, by reducing cold hypersensitivity experienced by patients, and pointed to the amelioration of chronic OIN by lowering the proportion of patients who developed severe chronic OIN. In addition, we provide a summary and discussion on the pathways that can be modulated by the S1R to explain the observed clinical benefits in the OIN.

[spa]Las enfermedades del sistema nervioso central (SNC) engloban a un conjunto de patologías de elevada gravedad debido a la importancia de este sistema para el organismo. La Epilepsia del Lóbulo Temporal (TLE) y la Enfermedad de Alzheimer (EA) son unas de las enfermedades de este grupo con mayor prevalencia, las cuales afectan actualmente a unos 50 millones de personas en todo el mundo. Debido a la falta de tratamientos eficaces para ambas patologías, surge la necesidad de buscar nuevas moléculas para su tratamiento. Uno de los compuestos que mayor interés ha suscitado en la última década por sus numerosas propiedades es la Epigalocatequina-3-galato (EGCG), pero sus problemas de estabilidad y biodisponibilidad comprometen su éxito terapéutico. La encapsulación de este tipo de moléculas en sistemas de liberación controlada de fármacos, como las nanopartículas poliméricas (NPs), es una de las alternativas farmacológicas más utilizadas para solventar estos problemas y aumentar con ello su efectividad terapéutica. En este contexto, en la presente tesis doctoral se desarrollaron dos nanovehículos de EGCG asociado a una matriz polimérica de PLGA-PEG para su evaluación en dos modelos preclínicos de ratón de la TLE y la EA. Los resultados obtenidos evidenciaron que ambos sistemas nanoestructurados mostraban características fisicoquímicas óptimas que aumentaban la estabilidad del EGCG y garantizaban una liberación sostenida del fármaco para su administración in vivo. Ambos sistemas no mostraron signos de citotoxicidad en diferentes líneas celulares y evidenciaron una protección de la integridad de la barrera hematoencefálica (BHE) respecto a los efectos perjudiciales del fármaco libre. Los ensayos de paso de barrera evidenciaron una penetración de la BHE por parte de estos sistemas tanto en un modelo in vitro como in vivo. Del mismo modo, los resultados de farmacocinética y biodistribución mostraron un aumento de la permanencia en el organismo respecto al fármaco libre y el alcance de las zonas cerebrales más profundas por parte del nanovehículo. Finalmente, en los ensayos de eficacia, ambos sistemas nanoestructurados demostraron ser más efectivos que el fármaco libre. En el estudio de la TLE, el fármaco mostró poseer una actividad anticonvulsiva evidente, reduciendo en mayor medida los procesos de neuroinflamación y muerte neuronal cuando se administró encapsulado en las NPs. En el estudio de la EA, los resultados obtenidos pusieron de relieve una mejora estadísticamente significativa de los procesos cognitivos y de memoria en los ratones transgénicos APP/PS1 (modelo de la EA) tratados con NPs de EGCG respecto a aquellos que recibieron el fármaco libre. Así mismo, estos ratones mostraron una disminución de la neuroinflamación en diferentes áreas cerebrales, disminución de los depósitos de placas β- amiloide (βA), disminución de los niveles del péptido βA42 (tanto soluble como insoluble) y un aumento de las sinapsis, muy superiores en todos ellos a los encontrados en los ratones tratados con fármaco libre. En definitiva, los resultados obtenidos en esta tesis doctoral sugieren que la administración de nanopartículas poliméricas de EGCG podría constituir una nueva alternativa terapéutica, segura y eficaz para el tratamiento de la TLE, la EA y otras enfermedades del SNC., [eng] Central nervous system (CNS) diseases include a group of pathologies of high severity due to the importance of this system for the body. Temporal Lobe Epilepsy (TLE) and Alzheimer's disease (AD) are some of these neurological diseases which currently affect around 50 million people worldwide. Due to the lack of effective treatments for both pathologies, there is a need to find new molecules for their treatment. Epigallocatechin-3-gallate (EGCG) is one of the compounds most studied nowadays due to its multiple properties, but its stability and bioavailability problems compromise its therapeutic success. The encapsulation of this type of molecules in controlled drug delivery systems, as polymeric nanoparticles, is one of the most used pharmacological alternatives to solve these obstacles and thus improve their therapeutic effectiveness. In this context, in the present doctoral thesis, two EGCG PLGA-PEG nanovehicles were developed for their evaluation in two mouse models of TLE and AD. The results obtained showed that both nanosystems exhibited optimal physicochemical characteristics that increased the stability of the EGCG, guaranteed a sustained release of the drug, did not show cytotoxic effect and protected blood-brain barrier (BBB) integrity. Likewise, the BBB permeation assays evidenced a concentration dependent penetration by these systems, and pharmacokinetics/biodistribution results showed an increase of the bloodstream permanence with respect to the free drug reaching the deepest cerebral regions. Finally, in the in vivo evaluation of their effectiveness, both nanostructured systems proved to be more effective than the free drug. In the study of TLE, the drug exhibited anticonvulsant activity, reducing to a greater extent the processes of neuroinflammation and neuronal death when it was administered encapsulated in the NPs. In the study of AD, the obtained results showed a statistically significant improvement of the cognitive and memory processes in the APP/PS1 transgenic mice (EA model) treated with the drug encapsulated nanosystem with respect to those that received the free drug. Likewise, those mice showed a decrease in neuroinflammation in different brain areas, a decrease of β-amyloid (Aβ) plaques, a decrease of soluble and insoluble Aβ42 peptide levels and an increase in synapsis expression, higher than those mice treated with free drug. In conclusion, the results obtained in this doctoral thesis suggest that the administration of polymeric nanoparticles of EGCG could be a new, safe and effective therapeutic alternative for the treatment of TLE, AD and other CNS diseases.

The study of life and living organisms and the way in which these interact and organize to form social communities 7 have been central to my career. I have been fascinated by biology, neurology, and neuropathology, but also by history, 8 sociology, and art. Certain current historical, political, and social events, some occurring proximally but others affecting 9 people in apparently distant places, have had an impact on me. Epicurus, Seneca, and Camus shared their philosophical 10 positions which I learned from. Many scientists from various disciplines have been exciting sources of knowledge as well. 11 I have created a world of hypothesis and experiments but I have also got carried away by serendipity following unexpected 12 observations. It has not been an easy path; errors and wanderings are not uncommon, and opponents close to home much 13 more abundant than one might imagine. Ambition, imagination, resilience, and endurance have been useful in moving ahead 14 in response to setbacks. In the end, I have enjoyed my dedication to science and I am grateful to have glimpsed beauty in it. These are brief memories of a Spanish neuropathologist born and raised in Barcelona, EU.

BACKGROUND: Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin ( TTR) that induce transthyretin misfolding and systemic deposition of amyloid. Progressive amyloid accumulation leads to multiorgan dysfunction and death. Inotersen, a 2'- O-methoxyethyl-modified antisense oligonucleotide, inhibits hepatic production of transthyretin. METHODS: We conducted an international, randomized, double-blind, placebo-controlled, 15-month, phase 3 trial of inotersen in adults with stage 1 (patient is ambulatory) or stage 2 (patient is ambulatory with assistance) hereditary transthyretin amyloidosis with polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 (mNIS+7; range, -22.3 to 346.3, with higher scores indicating poorer function; minimal clinically meaningful change, 2 points) and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating poorer quality of life). A decrease in scores indicated improvement. RESULTS: A total of 172 patients (112 in the inotersen group and 60 in the placebo group) received at least one dose of a trial regimen, and 139 (81%) completed the intervention period. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (95% confidence interval [CI], -26.4 to -13.0; P

Treball Final de Grau de Podologia, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, curs: 2017-2018, Tutor: Rosa M. Vila Espinalt, El neuroma de Morton és una causa comuna de neuropatia intermetatarsal, que provoca la inflamació dels nervis interdigitals, la seva localització més freqüent és en el tercer espai intermetatarsal. Aquesta patologia ofereix diversitat de tractaments, entre els que destaquen el tractament conservador recomanat com a primera línia d’actuació, i es basa en l’ús d’un calçat adequat, suports plantars personalitzats i infiltracions. No obstant, quan aquests no funcionen s’aconsella la cirurgia. Els objectius d’aquest treball són determinar l’efectivitat que tenen les infiltracions com a tractament, així com identificar-ne els agents més emprats en l’actualitat. Aquest estudi, es tracta d’una revisió bibliogràfica sobre el tractament d’infiltracions en el neuroma de Morton, i s’ha realitzat mitjançant la recerca d’articles en les bases de dades electròniques Medline i Science Direct. Els autors recomanen les infiltracions amb corticoides i alcohol, ja que son les que resulten més efectives a curt-mitjà termini per pal·liar la simptomatologia produïda pel neuroma en la majoria de pacients. En referència a les substàncies innovadores es necessiten més estudis per poder concloure la seva efectivitat i seguretat.

y. Immunochemical detection of G-proteincoupled receptors (GPCRs) in cells and tissues was a technical challenge for years. After the discovery of formation of GPCR dimers/trimers/tetramers in transfected cells, a most recent challenge has been to confirm receptor-receptor interactions in natural sources. The occurrence of dimers or higher order oligomers is important from a therapeutic point of view, mainly because their physiology/pharmacology is different from those of individual receptors. On the one hand, pathophysiological factors need to count more on GPCR dimers than on individual receptors. On the other hand, the expression of dimers, trimers, etc. may change in pathological conditions and/or along the course of a disease. This review will focus on G-protein-coupled receptor dimers, on how to detect them by novel histological techniques and on how the detection may be used in diagnosis and therapy of ailments of the central nervous system, for instance in neurodegenerative diseases and gliomas.

[eng] Nowadays, it is estimated that about 450 million people suffer from a mental or behavioural disorder in the world. According to World health organization (WHO), 33% of the years lived with disability (YLD) are due to psychiatric disorders. In this regard, psychotic disorders including schizophrenia (SZ), remain one of the most mysterious and costliest mental disorders in terms of human suffering and social expenditure. In recent years, the field of molecular genetics has been uncovering evidence of the complex polygenetic architecture of SZ and related disorders. In addition, GWAS studies have identified several genes associated with SZ, which have been shown to converge in complex and identifiable molecular pathways related to synaptic plasticity, neurotransmission and connectivity processes. Also, these studies have reported an important genetic overlap across several psychiatric disorders such as Schizophrenia (SZ), Bipolar disorder (BPD), Major Depressive Disorder (MDD) or Autism Spectrum Disorders (ASD), which adds to the consideration of common pathophysiological mechanisms among these disorders. In this sense, a growing body of evidence has established that connectivity and synaptic plasticity, modulated by neuronal activity, is an inherent feature of brain function during both development and adulthood. The present dissertation hypothesizes that genetic variability of genes involved in either synaptic plasticity (NRN1, BDNF and DTNBP1) and/or white matter related pathways (and their interactions) will be associated with SSD. In addition, due to the clinical, cognitive, neuroimaging and genetic overlap observed across different psychiatric disorders, we also hypothesize that the studied genetic variability will be also associated with other neurodevelopmental psychiatric disorders, such as ASD and BPD. In this sense, four studies have been carried out. The first three studies, analyse genetic variability at Neuritin-1 gene (NRN1) and its relationship with the risk for developing SSD and BPD, and also with some clinical and cognitive phenotypes both in patients and in healthy subjects from the general population. Moreover, in these studies we also analyzed whether NRN1 action is modulated by other genes such as BDNF and DTNBP1. The fourth study analyses the integrative effects of a set of white matter related genes (Oligodendrocyte/myelination related genes - OMR) and its contribution to both SSD and ASD. Our results focused on the genetic variability at NRN1 gene, suggest that genetic variability of NRN1 gene has an impact on the risk for developing SSD/BPD and also on the presence of depressive symptoms in the general population. Its pleiotropic effect is also evidenced by its effect on different phenotypes: such as cognitive performance and age at onset. Moreover, our genexgene interaction results suggest that NRN1 action is modulated by the BDNF and DTNBP1 genes. On the other hand, the results of the fourth study suggest that some of the OMR genetic risk variants seem to be shared across SZ-ASD continuum. The fact that some OMR genes are marginally associated with both disorders and also, due to their involvement in the detected epistatic effects, seem to support the notion that dysregulation in myelination processes may underlie susceptibility to develop ASD or SSD. To conclude, further genetic studies are needed to elucidate the biological background underlying mental disorders, which can ultimately lead to better treatment in order to improve the quality life of the patients., [spa] Actualmente, se estima que alrededor de 450 millones de personas en el mundo sufren de un trastorno mental o de la conducta. Según la Organización Mundial de la Salud (OMS), el 33% de los años vividos con discapacidad (YLD) se asocian a trastornos psiquiátricos. En este sentido, los trastornos psicóticos, incluyendo la esquizofrenia (EQ), siguen siendo uno de los trastornos mentales más desconocidos y costosos en términos de sufrimiento humano y gasto social. En los últimos años, el campo de la genética molecular ha estado descubriendo evidencias acerca de la compleja arquitectura poligénica de la EQ y de otros trastornos relacionados. Además, los estudios GWAS han identificado varios genes asociados con EQ, los cuales se ha demostrado que convergen en vías moleculares complejas e identificables relacionados con la plasticidad sináptica, la neurotransmisión y los procesos de conectividad. Además, estos estudios han informado de un importante solapamiento genético a través de varios trastornos psiquiátricos como la esquizofrenia (EQ), el trastorno bipolar (TB), el trastorno depresivo mayor (TDM) o los trastornos del espectro autista (TEA), lo que se suma a la consideración de mecanismos fisiopatológicos comunes en estos trastornos. En este sentido, el creciente cuerpo de evidencias ha establecido que la conectividad y la plasticidad sináptica modulada por la actividad neuronal, es una característica inherente de la función cerebral durante el desarrollo y la edad adulta. La presente tesis plantea la hipótesis de que la variabilidad genética en genes implicados en la plasticidad sináptica (NRN1, BDNF y DTNBP1) y/o en las vías relacionadas con la materia blanca (y sus interacciones) se asociarán con Trastornos del Espectro de la Esquizofrenia (TEE). Además, debido al solapamiento clínico, cognitivo, de neuroimagen y genético observado a través de los diferentes trastornos psiquiátricos, también hipotetizamos que la variabilidad genética estudiada se asocia con otros trastornos psiquiátricos del neurodesarrollo, como el TEE y TEA. En este sentido, se han llevado a cabo cuatro estudios. Los tres primeros estudios analizan la variabilidad genética del gen Neuritin-1 (NRN1) y su relación con el riesgo de desarrollar TEE y TB, así como algunos fenotipos clínicos y cognitivos tanto en pacientes como en sujetos sanos de la población general. Además, en estos estudios también analizamos si la acción de NRN1 es modulada por otros genes como BDNF y DTNBP1. El cuarto estudio analiza los efectos integradores de un conjunto de genes relacionados con la materia blanca (genes relacionados con Oligodendrocitos/mielinización - OMR) y su contribución a TEE y TEA. Nuestros resultados centrados en la variabilidad genética del gen NRN1, sugieren que su variabilidad genética tendría un impacto en el riesgo de desarrollar TEE / TB y también en la presencia de síntomas depresivos en la población general. Este efecto pleiotrópico también se ve respaldado por sus efectos sobre otros fenotipos: como el rendimiento cognitivo y la edad de inicio. Además, nuestros resultados de interacción genéticas (gxg) sugieren que la acción de NRN1 es modulada por los genes BDNF y DTNBP1. Por otro lado, los resultados del cuarto estudio sugieren que algunas de las variantes de riesgo genético de los genes OMR parecen ser compartidas a través de del continuum TEE-TEA. El hecho de que algunos genes OMR estén ligeramente asociados con ambos trastornos, así como también, debido a su participación en los efectos epistáticos detectados, parece apoyar la noción de que la desregulación en los procesos de mielinización podría ser subyacente a la susceptibilidad para desarrollar TEE o TEA. Para concluir, se necesitan más estudios genéticos que ayuden a descifrar el trasfondo biológico subyacente a los trastornos mentales, lo que en última instancia puede conducir a un mejor tratamiento con el fin de mejorar la calidad de vida de los pacientes.

Treball Final de Grau de Podologia, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, curs: 2016-2017, Tutor: Montse Marugán de los Bueis, La neuropatía de Baxter es una patología de origen neural que ocasiona dolor en el talón, representa un 15-20% de las talalgias y está considerada como la principal causa de dolor crónico en el talón. Los objetivos de este trabajo son establecer el diagnóstico diferencial de dicha enfermedad con otras patologías propias del talón a más de analizar las diferentes opciones terapéuticas más actuales y relacionar la neuropatía con diferentes alteraciones morfogénicas del pie. Se realizó una búsqueda bibliográfica de artículos publicados en la base de datos biomédica Pubmed y en distintas revistas científicas como la Revista Española de Podología, entre otras, hasta marzo de 2017. Las talalgias engloban un gran número de patologías donde es preciso establecer el diagnóstico diferencial debido a las múltiples causas que originan el dolor por lo que una anamnesis detallada y una exploración exhaustiva son esenciales para diferenciar la neuropatía de Baxter de otras patologías que repercutan en el talón y, si es necesario, ayudarse de pruebas complementarias con el fin de escoger el tratamiento más adecuado.

[eng] X-linked adrenoleukodystrophy (X-ALD) is a rare neurometabolic disease characterized by the loss of function of the peroxisomal transporter ABCD1, which leads to an accumulation of very long-chain fatty acids, inducing mitochondrial reactive oxygen species. Clinical phenotypes in humans range from adrenal insufficiency to fatal inflammatory cerebral demyelination. Abcd1-null mice (Abcd1- mice) develop late onset axonal degeneration in the spinal cord and locomotor disability resembling the most common phenotype in humans, adrenomyeloneuropathy (AMN). Oxidative stress and mitochondrial dysfunction are key common features in X-ALD patients as well as in Abcd1- mouse. In this thesis, we sought to explore novel therapeutic targets that would contribute to better understand the pathophysiology of the disease, based on the existing knowledge on these hallmarks of X-ALD. First, we studied the nuclear factor erythroid-derived 2, like 2 (NFE2L2, also known as NRF2), in X-ALD mouse models (Abcd1- and Abcd1-/Abcd2-/- mice) and in fibroblasts derived from healthy subjects and X-ALD patients. Here, we identify that NRF2, the master regulator of endogenous antioxidant response, and its target genes are impaired in X-ALD due to an aberrant activity of the AKT/GSK-3β axis. Moreover, GSK-3β inhibitors reactivated the blunted NRF2-dependent response upon oxidative stress in X-ALD fibroblasts (Chapter I). In a second study, we sought to determine the role of RIP140 (receptor interacting protein 140), a transcriptional coregulator essential for metabolic homeostasis and inflammatory response, in X-ALD pathophysiology. To address this objective we studied RIP140 in Abcd1- mouse, organotypic spinal cord slice cultures (OSCSC) from mice and normal appearing white matter (NAWM) from healthy subjects and cerebral X-ALD patients. We found out a redox-dependent increase of RIP140 in the spinal cord and OSCSC from Abcd1- mice, as well as an induction of RIP140 in the NAWM of childhood cerebral ALD (ccALD) patients (Chapter II). Finally, we explored the therapeutic potential of targeting NRF2 and RIP140, independently, in X-ALD mice (Abcd1- and Abcd1-/Abcd2-/- mice). Regarding NRF2, we followed a pharmacologic approach, by treating Abcd1- and Abcd1-/Abcd2-/- mice with dimethyl fumarate, an FDA-approved NRF2 activator (Chapter I). In the case of RIP140, we followed a genetic approach, by crossing RIP140-deficient mice with X-ALD mouse models (Chapter II). In both cases, the therapeutic intervention led to an amelioration of i) mitochondrial dysfunction, ii) bioenergetic failure, iii) oxidative damage and iv) dysregulated inflammatory profile, and most importantly, halted axonal degeneration and behavioural abnormalities in X-ALD mice (Chapters I and II). Collectively, these findings reveal an impairment of the AKT/GSK-3β/NRF2 axis that controls endogenous response against oxidative stress, as well as point to RIP140 as a candidate for the impaired mitochondrial biogenesis and induction of proinflammatory response in X-ALD. Finally, the results of this doctoral thesis indicate that therapies based on NRF2 activation and RIP140 inhibition may be valuable strategies to treat X-ALD and other neurodegenerative disorders which share impaired redox homeostasis, mitochondrial dysfunction and neuroinflammation among their hallmarks., [spa] La adrenoleuocodistrofia ligada al cromosoma X (X-ALD) es una enfermedad neurometabólica rara, que se caracteriza por la pérdida de función del transportador peroxisomal ABCD1. Como consecuencia se acumulan ácidos grasos de cadena muy larga, que inducen la producción de especies reactivas de oxígeno en la mitocondria. El cuadro clínico de X-ALD en humanos es variable, desde la insuficiencia adrenal hasta una desmielinización inflamatoria cerebral que suele ser fatal. Los ratones nulos para el gen Abcd1 (ratones Abcd1-) desarrollan una degeneración axonal de aparición tardía en la médula espinal, además de presentar incapacidad locomotora, un fenotipo similar al más común en humanos, la adrenomieloneuropatía (AMN). El estrés oxidativo y la disfunción mitocondrial son unas características claves de X-ALD, tanto en el modelo de ratón como en humanos. En esta tesis, hemos decidido explorar nuevas dianas terapéuticas que contribuyan a una mejor comprensión de la fisiopatología de esta enfermedad, basándonos en el conocimiento existente sobre estas alteraciones en X-ALD. En primer lugar, estudiamos el factor nuclear NRF2 (nuclear factor, erythroid-derived 2, like 2; también NFE2L2) en los modelos animales de X-ALD (ratones Abcd1- y Abcd1-/Abcd2-/-) y en fibroblastos de pacientes con X-ALD y sujetos sanos. Así, identificamos que NRF2, el regulador maestro de la respuesta antioxidante endógena, así como sus genes diana, están inhibidos en X-ALD, debido a una actividad aberrante del eje AKT/GSK-3β. Además, inhibidores de GSK-3β reactivaron la respuesta frente al estrés oxidativo dependiente de NRF2, que estaba bloqueada en los fibroblastos de pacientes con X-ALD (Capítulo I). En el segundo estudio, pretendemos determinar el papel de RIP140 (receptor interacting protein 140) en la fisiopatología de X-ALD. RIP140 es un coregulador transcripcional esencial para la homeostasis metabólica y la respuesta inflamatoria. Para lograr este objetivo, primero estudiamos RIP140 en los ratones Abcd1-, en cultivos organotípicos de láminas de médula espinal (OSCSC) de ratón, y en sustancia blanca cerebral de apariencia normal (NAWM) de pacientes X-ALD. De este modo, encontramos una inducción mediada por estrés oxidativo de RIP140 en la médula espinal y en OSCSC de los ratones Abcd1-, además de una activación de RIP140 en NAWM de pacientes con ALD cerebral infantil (ccALD) (Capítulo II). Por último, investigamos el potencial terapéutico de estas vías para tratar X-ALD, mediante la administración en la dieta de dimetil fumarato, un activador de NRF2 aprobado por la FDA, a los ratones X-ALD (Capítulo I); y a través de la deleción del gen Rip140 en los ratones X-ALD (Capítulo II). En ambos casos, la intervención terapéutica conllevó una mejora de i) la disfunción mitocondrial, ii) el fallo bioenergético, iii) el daño oxidativo, iv) la alteración del perfil inflamatorio, y sobre todo, detuvo la degeneración axonal y previno las alteraciones en el comportamiento en los ratones X-ALD (Capítulos I y II). En conjunto, estos resultados muestran una disfunción del eje AKT/GSK-3β/NRF2, que controla la respuesta antioxidante endógena, así como apuntan a RIP140 como responsable de la disminuida biogenesis mitocondrial y la inducción de la respuesta pro-inflamatoria que observamos en X-ALD. Finalmente, los resultados derivados de esta tesis doctoral indican que terapias basadas en la activación de NRF2 o la inhibición de RIP140 tienen un valor potencial como estrategias terapéuticas para tratar pacientes con X-ALD u otras enfermedades neurodegenerativas, que compartan como sello distintivo, un fallo en la homeostasis redox, disfunción mitocondrial y neuroinflamación., [cat] L’adrenoleuocodistròfia lligada al cromosoma X (X-ALD) és una malaltia neurometabòlica rara, que es caracteritza per la pèrdua de funció del transportador peroxisomal ABCD1. Com a conseqüència s'acumulen àcids grassos de cadena molt llarga, que indueixen la producció d'espècies reactives d'oxigen en el mitocondri. El quadre clínic de X-ALD en humans és variable, des de la insuficiència adrenal fins a una desmielinització inflamatòria cerebral que sol ser fatal. Els ratolins nuls per al gen Abcd1 (ratolins Abcd1-) desenvolupen una degeneració axonal d'aparició tardana en la medul·la espinal, a més de presentar incapacitat locomotora, un fenotip similar al més comú en humans, l’adrenomieloneuropatia (AMN). L'estrès oxidatiu i la disfunció mitocondrial són unes característiques claus de X-ALD, tant en el model de ratolí com en humans. En aquesta tesi, hem decidit explorar noves dianes terapèutiques que contribueixin a una millor comprensió de la fisiopatologia d'aquesta malaltia, basant-nos en el coneixement existent sobre aquestes alteracions en X-ALD. En primer lloc, hem estudiat el factor nuclear NRF2 (nuclear factor, erythroid-derived 2, like 2; també NFE2L2) en els models animals de X-ALD (ratolins Abcd1- i Abcd1-/ Abcd2-/-) i en fibroblasts de pacients amb X-ALD i subjectes sans. Així, hem identificat que NRF2, el regulador mestre de la resposta antioxidant endògena, així com els seus gens diana, estan inhibits en X-ALD, a causa d'una activitat aberrant de l'eix AKT/GSK-3β. A més, inhibidors de GSK-3β van reactivar la resposta enfront de l'estrès oxidatiu dependent de NRF2, que estava bloquejada en els fibroblasts de pacients amb X-ALD (Capítol I). En el segon estudi, pretenem determinar el paper de RIP140 (receptor interacting protein 140) en la fisiopatologia de X-ALD. RIP140 és un coregulador transcripcional essencial per a l'homeòstasi metabòlica i la resposta inflamatòria. Per aconseguir aquest objectiu, primer hem estudiat RIP140 en els ratolins Abcd1-, en cultius organotípics de làmines de medul·la espinal (OSCSC) de ratolí, i en substància blanca cerebral d'aparença normal (NAWM) de pacients X-ALD. D'aquesta manera, hem trobat una inducció de RIP140 intervinguda per estrès oxidatiu en la medul·la espinal i en OSCSC dels ratolins Abcd1-, a més d'una activació de RIP140 en NAWM de pacients amb ALD cerebral infantil (ccALD) (Capítol II). Finalment, hem investigat el potencial terapèutic d'aquestes vies per tractar X-ALD, mitjançant l'administració en la dieta de dimetil fumarat, un activador de NRF2 aprovat per la FDA, als ratolins X-ALD (Capítol I); i a través de la deleció del gen Rip140 en els ratolins X-ALD (Capítol II). En tots dos casos, la intervenció terapèutica va comportar una millora de i) la disfunció mitocondrial, ii) la fallada bioenergètica, iii) el dany oxidatiu, iv) l'alteració del perfil inflamatori i, sobretot, va aturar la degeneració axonal i va prevenir les alteracions en el comportament en els ratolins X-ALD (Capítols I i II). En conjunt, aquests resultats mostren una disfunció de l'eix AKT/GSK-3β/NRF2, que controla la resposta antioxidant endògena, així com senyalen a RIP140 com a responsable de la disminuïda biogènesis mitocondrial i la inducció de la resposta pro- inflamatòria que observem en X-ALD. Finalment, els resultats derivats d'aquesta tesi doctoral indiquen que teràpies basades en l'activació de NRF2 o la inhibició de RIP140 tenen un valor potencial com a estratègies terapèutiques per tractar pacients amb X-ALD o altres malalties neurodegeneratives, que comparteixin com a segell distintiu, una fallada en l'homeòstasi redox, disfunció mitocondrial i neuroinflamació.

Introduction Subjective cognitive decline (SCD) has been proposed as a potential preclinical stage of Alzheimer's disease (AD). Nevertheless, the genetic and biomarker profiles of SCD individuals remain mostly unexplored. Methods We evaluated apolipoprotein E ( APOE ) e4's effect in the risk of presenting SCD, using the Fundacio ACE Healthy Brain Initiative (FACEHBI) SCD cohort and Spanish controls, and performed a meta-analysis addressing the same question. We assessed the relationship between APOE dosage and brain amyloid burden in the FACEHBI SCD and Alzheimer's Disease Neuroimaging Initiative cohorts. Results Analysis of the FACEHBI cohort and the meta-analysis demonstrated SCD individuals presented higher allelic frequencies of APOE e4 with respect to controls. APOE dosage explained 9% (FACEHBI cohort) and 11% (FACEHBI and Alzheimer's Disease Neuroimaging Initiative cohorts) of the variance of cerebral amyloid levels. Discussion The FACEHBI sample presents APOE e4 enrichment, suggesting that a pool of AD patients is nested in our sample. Cerebral amyloid levels are partially explained by the APOE allele dosage, suggesting that other genetic or epigenetic factors are involved in this AD endophenotype.

[spa] Existe una correlación positiva entre el incremento de la esperanza de vida y el aumento de las enfermedades crónicas. Se ha establecido que el envejecimiento es el principal factor de riesgo en la aparición de trastornos neuropsiquiátricos, deterioro cognitivo, y las demencias, concretamente en la enfermedad de Alzheimer (EA). La epigenética ha demostrado jugar un papel importante en la función cognitiva. Por tanto, estudiar los mecanismos epigenéticos que subyacen en los efectos deletéreos del envejecimiento y el deterioro asociado a la EA, así como los factores que pueden modificarlos son de vital importancia para establecer nuevas estrategias ya sean farmacológicas o no, para prevenirlos o tratarlos. En este contexto, la primera parte de esta tesis se ha centrado en estudiar la participación de los mecanismos epigenéticos que intervienen en el envejecimiento, específicamente en el deterioro cognitivo en modelos animales de envejecimiento y de la EA. Para ello, hemos utilizado dos modelos de ratón de la EA que presentan alteraciones cognitivas y rasgos neuropatológicos de la enfermedad pero con factores causales iniciales diferentes, dichos modelos murinos son la cepa transgénica, 5xFAD y la cepa con senescencia acelerada, SAMP8. Nuestros resultados sugieren que existe una correlación entre los trastornos conductuales, la acumulación de la proteína ß- amiloide y las alteraciones epigenéticas en la metilación global (5-mC) del ADN y de expresión de ciertas enzimas epigenéticas, en el caso del modelo murino 5xFAD y una correlación entre el estrés oxidativo, la inflamación, los trastornos conductuales, el deterioro cognitivo y las alteraciones epigenéticas incluyendo la metilación (5-mC) e hidroximetilación (5-hmC) global del ADN, la acetilación de histonas H3 y H4 y cambios en la expresión de las enzimas epigenéticas que regulan dichas marcas en el modelo murino SAMP8. Además, se han establecido los procesos de estrés oxidativo y neuroinflamación como indicadores del estado microambiental de la célula sobre los cuales la epigenética se altera y modula de manera aberrante la expresión génica en los animales SAMP8 en referencia a los SAMR1 y con la edad. Por otra parte, hoy en día no existe ningún tratamiento eficaz para la EA. Esta falta de terapias junto con el cambio de paradigma que ha provocado la epigenética ha suscitado especial interés en la influencia del entorno, las experiencias y los hábitos de vida sobre la regulación de la expresión génica, tanto por su potencial regulador como terapéutico. Por lo que se ha descrito que la estimulación cognitiva mediante intervenciones de enriquecimiento ambiental (EE) produce cambios beneficiosos a nivel cerebral. Pocos, son los estudios de EE en ratones no transgénicos de EA y aún menos los relacionados con los mecanismos epigenéticos. Así, la segunda parte de esta tesis se ha centrado en demostrar, el efecto neuroprotector del EE y la participación de la modulación epigenética en dicho proceso. En este sentido, nuestros resultados confirman la modificación conductual, la reducción del deterioro cognitivo y de la neurodegeneración, como consecuencia de un incremento en la neurogénesis y plasticidad neuronal en el hipocampo de los ratones SAMP8. Dichos cambios correlacionan con la modificación de las marcas epigenéticas incluyendo la 5- mC e 5-hmC global del ADN y la acetilación global de las histonas H3 y H4, junto con alteraciones en la expresión génica de diversas enzimas epigenéticas que se traducen en una acción antioxidante, inducción de genes por el factor de transcripción NRF2 y antiinflamatoria reducción de la inducción de citoquinas proinflamatorias por el factor de transcripción NF-kß. De esta forma, los resultados presentados confirmar el papel clave de los mecanismos epigenéticos como factor principal en el proceso de envejecimiento, y la EA, así como el uso de las intervenciones con EE para determinar las modificaciones epigenéticas que pueden ayudar a entender los procesos que subyacen a la patología y descubrir nuevas dianas terapéuticas., [eng] There is a positive correlation between the increase in life expectancy and the increase in chronic diseases. It has been established that aging is the main risk factor in the onset of neuropsychiatric disorders, cognitive impairment, and dementias, specifically in Alzheimer's disease (AD). Epigenetics has been shown to play an important role in cognitive function. Therefore, to study the epigenetic mechanisms that underlie the deleterious effects of aging and the deterioration associated with AD, as well as the factors that can modify them are of vital importance to establish new strategies, whether pharmacological or not, to prevent or treat them. In this context, the first part of this thesis has focused on studying the involvement of epigenetic mechanisms involved in aging, specifically cognitive impairment in animal models of aging and AD. To do this, we used two mouse models of EA that present cognitive alterations and neuropathological features of the disease but with different initial causal factors, such murine models are the transgenic strain, 5xFAD and the strain with accelerated senescence, SAMP8. Our results suggest that there is a correlation between behavioural disorders, ß-amyloid protein accumulation and epigenetic alterations in the global methylation (5-mC) of DNA and expression of certain epigenetic enzymes, in the case of the murine model 5xFAD And a correlation between oxidative stress, inflammation, behavioral disorders, cognitive impairment and epigenetic alterations including methylation (5-mC) and global hydroxymethylation (5-hmC) of DNA, acetylation of histones H3 and H4 and changes In the expression of the epigenetic enzymes that regulate these marks in the SAMP8 murine model. In addition, the processes of oxidative stress and neuroinflammation have been established as indicators of the microenvironmental state of the cell over which epigenetics aberrantly alters and modulates gene expression in SAMP8 animals in reference to SAMR1 and with age. On the other hand, there is no effective treatment for AD today. This lack of therapies coupled with the paradigm shift that has provoked epigenetics has aroused special interest in the influence of the environment, experiences and life habits on the regulation of gene expression, both for its regulatory and therapeutic potential. Thus, it has been described that cognitive stimulation through environmental enrichment (EE) interventions produces beneficial changes at the brain level. Few, are EE studies in non-transgenic EA mice and even less those related to epigenetic mechanisms. Thus, the second part of this thesis has focused on demonstrating the neuroprotective effect of EE and the participation of epigenetic modulation in this process. In this sense, our results confirm the behavioural modification, reduction of cognitive deterioration and neurodegeneration, as a result of an increase in neurogenesis and neuronal plasticity in the hippocampus of SAMP8 mice. These changes correlate with the modification of epigenetic marks including 5-mC and 5-hmC global DNA and the global acetylation of histones H3 and H4, together with alterations in the gene expression of various epigenetic enzymes that result in an action Antioxidant, induction of genes by transcription factor NRF2 and anti-inflammatory reduction of induction of proinflammatory cytokines by the transcription factor NF-kß. Thus, the results presented confirm the key role of epigenetic mechanisms as a major factor in the aging process, and AD, as well as the use of EE interventions to determine epigenetic modifications that may help to understand the processes that Underlie the pathology and discover new therapeutic targets.

The cellular and molecular bases of neurological diseases have been studied for decades; however, the underlying mechanisms are not yet fully elucidated. Compared with other disorders, diseases of the nervous system have been very difficult to study mainly due to the inaccessibility of the human brain and live neurons in vivo or in vitro and difficulties in examination of human postmortem brain tissue. Despite the availability of various genetically engineered animal models, these systems are still not adequate enough due to species variation and differences in genetic background. Human induced pluripotent stem cells (hiPSCs) reprogrammed from patient somatic cells possess the potential to differentiate into any cell type, including neural progenitor cells and postmitotic neurons; thus, they open a new area to in vitro modeling of neurological diseases and their potential treatment. Currently, many protocols for generation of various neuronal subtypes are being developed; however, most of them still require further optimization. Here, we highlight accomplishments made in the generation of dopaminergic and cholinergic neurons, the two subtypes most affected in Alzheimer’s and Parkinson’s diseases and indirectly affected in Huntington’s disease. Furthermore, we discuss the potential role of hiPSC-derived neurons in the modeling and treatment of neurological diseases related to dopaminergic and cholinergic system dysfunction.

Background: Frontostriatal and frontoamygdalar connectivity alterations in patients with obsessive–compulsive disorder (OCD) have been typically described in functional neuroimaging studies. However, structural covariance, or volumetric correlations across distant brain regions, also provides network-level information. Altered structural covariance has been described in patients with different psychiatric disorders, including OCD, but to our knowledge, alterations within frontostriatal and frontoamygdalar circuits have not been explored.Methods: We performed a mega-analysis pooling structural MRI scans from the Obsessive–compulsive Brain Imaging Consortium and assessed whole-brain voxel-wise structural covariance of 4 striatal regions (dorsal and ventral caudate nucleus, and dorsal-caudal and ventral-rostral putamen) and 2 amygdalar nuclei (basolateral and centromedial-superficial). Images were preprocessed with the standard pipeline of voxel-based morphometry studies using Statistical Parametric Mapping software.Results: Our analyses involved 329 patients with OCD and 316 healthy controls. Patients showed increased structural covariance between the left ventral-rostral putamen and the left inferior frontal gyrus/frontal operculum region. This finding had a significant interaction with age; the association held only in the subgroup of older participants. Patients with OCD also showed increased structural covariance between the right centromedial-superficial amygdala and the ventromedial prefrontal cortex.Limitations: This was a cross-sectional study. Because this is a multisite data set analysis, participant recruitment and image acquisition were performed in different centres. Most patients were taking medication, and treatment protocols differed across centres.Conclusion: Our results provide evidence for structural network–level alterations in patients with OCD involving 2 frontosubcortical circuits of relevance for the disorder and indicate that structural covariance contributes to fully characterizing brain alterations in patients with psychiatric disorders.

Frataxin (FXN) deficiency causes Friedreich's ataxia (FRDA), a multisystem disorder with neurological and non-neurological symptoms. FRDA pathophysiology combines developmental and degenerative processes of dorsal root ganglia (DRG), sensory nerves, dorsal columns and other central nervous structures. A dying-back mechanism has been proposed to explain the peripheral neuropathy and neuropathology. In addition, affected individuals have non-neuronal symptoms such as diabetes mellitus or glucose intolerance. To go further in the understanding of the pathogenic mechanisms of neuropathy and diabetes associated with the disease, we have investigated the humanized mouse YG8R model of FRDA. By biochemical and histopathological studies, we observed abnormal changes involving muscle spindles, dorsal root axons and DRG neurons, but normal findings in the posterior columns and brain, which agree with the existence of a dying-back process similar to that described in individuals with FRDA. In YG8R mice, we observed a large number of degenerated axons surrounded by a sheath exhibiting enlarged adaxonal compartments or by a thin disrupted myelin sheath. Thus, both axonal damage and defects in Schwann cells might underlie the nerve pathology. In the pancreas, we found a high proportion of senescent islets of Langerhans in YG8R mice, which decreases the β-cell number and islet mass to pathological levels, being unable to maintain normoglycemia. As a whole, these results confirm that the lack of FXN induces different pathogenic mechanisms in the nervous system and pancreas in the mouse model of FRDA: dying back of the sensory nerves, and pancreatic senescence., This work was supported by grants from Ministerio de Economía y Competitividad (Spanish Ministry of Economy and Competitiveness) [grant no. PI11/00678] within the framework of the National R+D+I Plan and co-funded by the Instituto de Salud Carlos III (ISCIII)-Subdirección General de Evaluación y Fomento de la Investigación and FEDER funds; the European Community's Seventh Framework Programme FP7/2007-2013 [grant agreement no. 242193 EFACTS]; the Generalitat Valenciana (Prometeo programme); the Fundació la Marató de TV3; the Fundación Alicia Koplowitz. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER) is an initiative developed by the Instituto de Salud Carlos III in cooperative and translational research on rare diseases.

[spa] El dolor es una experiencia sensorial y emocional desagradable. Es un mecanismo muy complejo determinado por dos componentes: el componente sensorial discriminativo, que corresponde a los mecanismos neurofisiológicos de la nocicepción y que informa de las características del dolor (naturaleza, duración, intensidad,…) y el componente afectivo-motivacional, que expresa la connotación desagradable relacionada con la percepción del dolor y que conlleva consecuencias emocionales que afectan al estado de ánimo y al bienestar del individuo. En la presente Tesis Doctoral se estudian estos dos componentes que conforman el dolor, evaluando respuestas de comportamiento en dos modelos animales de dolor, un modelo de dolor agudo visceral y un modelo de dolor crónico de origen neuropático. Además, se estudia el papel del receptor sigma-1 (σ1R) en cada modelo animal de dolor, evaluando su posible implicación tanto en el componente sensorial como en el afectivo. Para ello, se pusieron en práctica dos estrategias experimentales. Por un lado, se utilizaron ratones modificados genéticamente a los que se les ha eliminado el gen del receptor del sigma-1 (ratones knock-out σ1R) y por otro lado, se realizó un tratamiento farmacológico sistémico en ratones salvajes (wild-type) con el E-52862 (S1RA), un antagonista del receptor sigma-1 altamente selectivo. El E-52862 es un compuesto que ha sido desarrollado por ESTEVE y que tras su primera evaluación en seres humanos ha demostrado un buen perfil de seguridad y tolerabilidad (estudios clínicos de Fase I). Actualmente continúa siendo evaluado en subsecuentes estudios clínicos como indicación para el dolor neuropático de diferentes etiologías (estudios de Fase II). Los resultados de esta Tesis Doctoral proporcionan nuevos conocimientos sobre el receptor sigma-1 que apoyan el desarrollo clínico del antagonista selectivo para este receptor, el E-52862, como una opción terapéutica adecuada para el tratamiento del dolor neuropático y las comorbilidades afectivas asociadas a esta patología., [eng] The present Doctoral Thesis focuses on the study of the sigma-1 receptor (σ1R) in the field of pain. This research has been a part of the preclinical σ1R project focusing on drug discovery of σ1R ligands for the treatment of pain at the pharmaceutical company ESTEVE. The overall purpose of this Doctoral Thesis was to explore the role of σ1R in the sensory-discriminative and affective-motivational components of pain. To this end, acetic acid-induced visceral pain and partial sciatic nerve ligation in mice were used to model an acute and chronic pain state, respectively. The sensory discriminative and affective-motivational components of pain in these models were infered by changes in reflexive and non-reflexive behavioural outcomes, respectively. Abdominal contractions (writhing) and paw behavioural hypersensitivity to mechanical and thermal stimuli were analysed as reflexive outcomes. On the other hand, pain-related changes of sweet preference, locomotor activity and reward-seeking behaviour were analysed as non reflexive outcomes. These models and behavioural outcomes were used to evaluate the effect of pharmacological and genetic blockade of σ1R and also the effects of some reference compounds. Furthermore, electrophysiological and molecular studies in knock-out (σ1R /-) mice were used to understand the role of σ1R in the sensory discriminative component of chronic pain. Taken together, the results of this Doctoral Thesis provide new knowledge about σ1R and support the clinical development of selective σ1R antagonists as a suitable therapeutic intervention to treat neuropathic pain and its mood-related comorbidities.

[eng] BACKGROUND: Acute transverse myelitis (ATM) may be the prelude of a wide range of diseases such as Multiple Sclerosis (MS), autoimmune, infectious, post-vacunal, post-radiotherapy and tumor related disorders. Nonetheless, the underlying etiology remains elusive in up to 16% of ATM patients. In 2002, the Transverse Myelitis Consortium Working Group (TMCWG) proposed some criteria in order to unify the concept of idiopathic ATM (IATM). ATM may present as a longitudinal extensive transverse myelitis (LETM) on the spinal Magnetic Resonance Imaging. LETM is a cardinal symptom of Neuromyelitis optica (NMO), an autoimmune chronic disease characterized by recurrent optic neuritis (ON) or LETM. In 2004, a pathogenic antibody, known as aquaporin-4 antibody (AQP4–ab) was directly related to NMO or limited forms of the disease such as LETM. Nonetheless, up to 50% of LETM patients are AQP4-ab seronegative. Recently, antibodies against the myelin- oligodendrocyte glycoprotein (MOG-ab) have been described in AQP4-ab seronegative NMO patients or limited forms of the disease. AIMS: The current work is divided in three studies. In the first study, we aimed to describe the MS conversion ratio and to identify baseline factors related to MS conversion, as well as to analyze baseline prognostic factors of disability in IATM patients fulfilling the 2002 TMCWG. In the second study, we sought to describe the etiological LETM spectrum and to analyze baseline prognostic factors related to outcome in this subgroup of patients. Finally, in the third study, we set out to describe the frequency of MOG-ab in AQP4-ab seronegative LETM and searched for differences between MOG-ab positive and negative AQP4-ab seronegative LETM patients. METHODOLOGY: The first and second studies were performed in a single center and we reviewed the epidemiological, clinical, laboratory and radiological data of 85 IATM patients fulfilling the TMCWG and 72 LETM patients. The third study is a multicenter European study with data collected in a prospective manner. AQP4-ab or MOG- ab were detected by immunohistochemistry in the two first studies and by cell based assays in the third study. All data were retrospectively analyzed. RESULTS: At the end of the first study, 13% of IATM converted to MS and an early onset of symptoms was related to MS conversion. However, laboratory findings such a negative result in the combination of oligoclonal bands (OCB) and IgG index in the cerebrospinal fluid (CSF) ruled out MS conversion. We observed that LETM and urinary sphincter dysfunction were independent baseline prognostic factors related to disability and that up to 37% of IATM patients had a final modified Rankin Score more (mRS) ≥ 2. In LETM patients, the idiopathic group and MS were the most frequent disorders involved (30.5% and 25%, respectively). NMO or limited forms were observed in less than 5%. The mRS was ≥2 at the end of follow-up in 72.2%. The presence of higher disability at onset of symptoms and elderly were independent baseline prognostic factors of disability. Up to 23% of patients presenting with AQP4-ab seronegative LETM tested positive for MOG-ab in serum. MOG-ab positive patients were younger, had CSF pleocytosis more frequently and had better outcome. Moreover, MOG-ab positive patients also showed an increase risk of ON relapse and NMO conversion. CONCLUSIONS: We identified that a subgroup of IATM patients may convert to MS, even when fulfilling the 2002 TMCWG criteria. Functional recovery in IATM is poorer in patients with urinary sphincter dysfunction at admission or LETM on MRI. We established the LETM etiological spectrum. In this subgroup of patients, while idiopathic and MS group were the most frequently involved, others such as NMO were marginally observed. Older age and clinically severe disease at onset were independent prognostic factors of poorer functional recovery in LETM patients. Finally we found that MOG-ab are present in a proportion of AQP4-ab seronegative LETM patients defining a subgroup of patients with clinical distinctive features, higher risk of ON relapses, and better outcome., [spa] Las mielitis transversas agudas (MTA) pueden ser el comienzo de una amplia diversidad de enfermedades, siendo la más frecuente la Esclerosis Múltiple (EM). Hasta en el 16% de los pacientes que presentan una MTA, la etiología será desconocida. Un consorcio internacional (TMCWG) propuso en el año 2002 unos criterios con el fin de unificar el concepto de MTA idiopática (MTAI). Las MTA pueden presentarse como una afectación extensa de la médula espinal (LETM), siendo ésta una característica de la Neuromielitis óptica (NMO). Los anticuerpos aquaporina 4 (AQP4-ac) se objetivan en la mayoría de estos pacientes y formas limitadas de esta enfermedad, como la LETM. Sin embargo, una proporción de estos pacientes no presentan AQP4-ac y otros anticuerpos como los anticuerpos contra myelin oligodendrocyte glycoprotein (MOG-ac) han sido recientemente asociados. El presente trabajo se divide en tres estudios (dos unicéntricos y un tercero multicéntrico europeo) que tienen como objetivo describir las características de los pacientes con una MTAI, pacientes con LETM así como identificar las características de aquellos pacientes con una LETM que presenten MOG-ac. Se identificó un subgrupo no despreciable de pacientes que convertirán a EM aunque cumplan los criterios de la TMCGW para MTAI. Además se objetivó que el pronóstico es peor en pacientes con una MTAI que presentan disfunción urinaria y LETM al comienzo de los síntomas. Por otra parte, describimos el espectro etiológico de pacientes con LETM, objetivando que en la mayor parte de ellos, la causa es idiopática. Los pacientes con una LETM tendrán peor pronóstico a más edad y a mayor discapacidad al inicio de los síntomas. Finalmente, encontramos que hasta un 23% de los pacientes que presentan LETM y son seronegativos para AQP4-ac, tienen MOG-ac en el suero. Estos pacientes presentan características clínicas distintivas, mayor riesgo de neuritis óptica, de recidivas y mejor pronóstico que los pacientes sin el anticuerpo.

Treball Final de Grau de Podología, Escola Universitaria d'Infermeria, Universitat de Barcelona, curs: 2014-2015, Tutor: Antonio Zalacain, La Resonancia Magnética es una prueba de diagnóstico por imagen que se basa en el procesamiento de ondas de radio que pasan por el paciente, el cual es sometido a un potente campo magnético. Esta técnica no utiliza radiaciones ionizantes como es el caso de la tomografía axial computarizada o las radiografías simples. Nos presenta imágenes muy detalladas en cualquier perspectiva y con diferentes secuencias. Las imágenes obtenidas con la RM permiten evaluar de una forma muy precisa el sistema nervioso central y determinar la presencia de ciertas patologías que pueden afectar a la marcha humana. A pesar de que la RM no es una exploración que soliciten habitualmente los podólogos, ante una exploración podológica en que nos aparezcan signos de neuropatía traducidos en una alteración de la marcha, se debe valorar con la anamnesis (puede aportar una RM) si bien son secuelas de alguna patología del sistema nervioso ya conocida o bien son signos de una posible patología reciente, por lo que entonces el podólogo debe realizar un informe con los hallazgos de la exploración, para que su médico le solicite una RM si lo considera necesario. Una vez este paciente ya está diagnosticado y nos vuelve a la consulta para realizarle el tratamiento podológico oportuno, hemos de saber interpretar mínimamente las imágenes de dicha patología neurológica. Este trabajo nos proporciona las bases para interpretar imágenes de RM de neuropatías más habituales del sistema nervioso que nos suelen dar alteraciones de la marcha. Estas patologías neurológicas son la meningitis, la encefalitis, la mielitis, la esclerosis múltiple, degeneraciones discales, los gliomas, los meningiomas, las metástasis, la espina bífida, el ictus y el aneurisma cerebral.

Cocoa consumption began in America and in the mid sixteenth Century it quickly spread to Europe. Beyond being considered a pleasant habit due to its rich sweet lingering taste, chocolate was considered a good nutrient and even a medicine. Traditionally, health benefits of cocoa have been related with the high content of antioxidants of Theobroma cocoa beans. However, the direct psychoactive effect due to methylxanthines in cocoa is notable. Theobromine and caffeine, in the proportions found in cocoa, are responsible for the liking of the food/beverage. These compounds influence in a positive way our moods and our state of alertness. Theobromine, which is found in higher amounts than caffeine, seems to be behind several effects attributed to cocoa intake. The main mechanisms of action are inhibition of phosphodiesterases and blockade of adenosine receptors. Further mechanisms are being explored to better understand the health benefits associated to theobromine consumption. Unlike what happens in other mammals -pets- included, theobromine is safe for humans and has fewer unwanted effects than caffeine. Therefore, theobromine deserves attention as one of the most attractive molecules in cocoa.

The present Doctoral Thesis focuses on the study of the sigma-1 receptor (σ1R) in the field of pain. This research has been a part of the preclinical σ1R project focusing on drug discovery of σ1R ligands for the treatment of pain at the pharmaceutical company ESTEVE. The overall purpose of this Doctoral Thesis was to explore the role of σ1R in the sensory-discriminative and affective-motivational components of pain. To this end, acetic acid-induced visceral pain and partial sciatic nerve ligation in mice were used to model an acute and chronic pain state, respectively. The sensory discriminative and affective-motivational components of pain in these models were infered by changes in reflexive and non-reflexive behavioural outcomes, respectively. Abdominal contractions (writhing) and paw behavioural hypersensitivity to mechanical and thermal stimuli were analysed as reflexive outcomes. On the other hand, pain-related changes of sweet preference, locomotor activity and reward-seeking behaviour were analysed as non reflexive outcomes. These models and behavioural outcomes were used to evaluate the effect of pharmacological and genetic blockade of σ1R and also the effects of some reference compounds. Furthermore, electrophysiological and molecular studies in knock-out (σ1R /-) mice were used to understand the role of σ1R in the sensory discriminative component of chronic pain. Taken together, the results of this Doctoral Thesis provide new knowledge about σ1R and support the clinical development of selective σ1R antagonists as a suitable therapeutic intervention to treat neuropathic pain and its mood-related comorbidities., El dolor es una experiencia sensorial y emocional desagradable. Es un mecanismo muy complejo determinado por dos componentes: el componente sensorial discriminativo, que corresponde a los mecanismos neurofisiológicos de la nocicepción y que informa de las características del dolor (naturaleza, duración, intensidad,…) y el componente afectivo-motivacional, que expresa la connotación desagradable relacionada con la percepción del dolor y que conlleva consecuencias emocionales que afectan al estado de ánimo y al bienestar del individuo. En la presente Tesis Doctoral se estudian estos dos componentes que conforman el dolor, evaluando respuestas de comportamiento en dos modelos animales de dolor, un modelo de dolor agudo visceral y un modelo de dolor crónico de origen neuropático. Además, se estudia el papel del receptor sigma-1 (σ1R) en cada modelo animal de dolor, evaluando su posible implicación tanto en el componente sensorial como en el afectivo. Para ello, se pusieron en práctica dos estrategias experimentales. Por un lado, se utilizaron ratones modificados genéticamente a los que se les ha eliminado el gen del receptor del sigma-1 (ratones knock-out σ1R) y por otro lado, se realizó un tratamiento farmacológico sistémico en ratones salvajes (wild-type) con el E-52862 (S1RA), un antagonista del receptor sigma-1 altamente selectivo. El E-52862 es un compuesto que ha sido desarrollado por ESTEVE y que tras su primera evaluación en seres humanos ha demostrado un buen perfil de seguridad y tolerabilidad (estudios clínicos de Fase I). Actualmente continúa siendo evaluado en subsecuentes estudios clínicos como indicación para el dolor neuropático de diferentes etiologías (estudios de Fase II). Los resultados de esta Tesis Doctoral proporcionan nuevos conocimientos sobre el receptor sigma-1 que apoyan el desarrollo clínico del antagonista selectivo para este receptor, el E-52862, como una opción terapéutica adecuada para el tratamiento del dolor neuropático y las comorbilidades afectivas asociadas a esta patología.

Antagonistic and reciprocal interactions are known to exist between adenosine and dopamine receptors in the striatum. In the present study, double immunofluorescence experiments with confocal laser microscopy showed a high degree of colocalization of adenosine A(2A) receptors (A(2A)R) and dopamine D(2) receptors (D(2)R) in cell membranes of SH-SY5Y human neuroblastoma cells stably transfected with human D(2)R and in cultured striatal cells. A(2A)R/D(2)R heteromeric complexes were demonstrated in coimmunoprecipitation experiments in membrane preparations from D(2)R-transfected SH-SY5Y cells and from mouse fibroblast Ltk(-) cells stably transfected with human D(2)R (long form) and transiently cotransfected with the A(2A)R double-tagged with hemagglutinin. Long term exposure to A(2A)R and D(2)R agonists in D(2)R-cotransfected SH-SY5Y cells resulted in coaggregation, cointernalization and codesensitization of A(2A)R and D(2)R. These results give a molecular basis for adenosine-dopamine antagonism at the membrane level and have implications for treatment of Parkinson's disease and schizophrenia, in which D(2)R are involved.

El síndrome de Ross es una rara entidad de disfunción degenerativa del sistema nervioso autónomo, que se caracteriza por la tríada de pupila tónica de Adie, arreflexia osteotendinosa y hipohidrosis/anhidrosis segmentaria. Se asocia a este cuadro clínico una hiperhidrosis contralateral secundaria probablemente a un mecanismo de compensación de las glándulas sudoríparas indemnes, siendo éste el principal motivo de consulta médica. De etiología desconocida, fue descrito por primera vez el año 1958 por Ross, y desde entonces se encuentran alrededor de unos 40 casos descritos en la bibliografía [1]. A continuación se presenta el caso de una paciente diagnosticada de síndrome de Ross.