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- Utility of cortical inhibitory and facilitatory neuronal circuits in amyotrophic lateral sclerosis diagnosisPublication . Santos Silva, Cláudia; Pavey, Nathan; Calma, Aicee Dawn; Kiernan, Matthew C.; Menon, Parvathi; van den Bos, Mehdi; Vucic, SteveBackground: Cortical hyperexcitability is an early feature of amyotrophic lateral sclerosis (ALS), linked to dysfunction in inhibitory and facilitatory cortical circuits, measurable using paired-pulse transcranial magnetic stimulation (TMS). Short-interval intracortical inhibition (SICI) is a robust biomarker of inhibitory function and an ALS diagnostic marker. Short interval intracortical facilitation (SICF) serves as a biomarker of facilitatory function, while the index of excitation assesses the contribution of these circuits to hyperexcitability. This study aimed to evaluate the diagnostic effectiveness of SICF and the index of excitation in distinguishing ALS from non-ALS mimic disorders. Methods: This cross-sectional study assessed cortical excitability in participants with suspected ALS from two Sydney centres, classified using the Gold Coast criteria. Threshold tracking TMS measured SICI, SICF, and the index of excitation. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis, with sensitivity, specificity, and optimal cut-off values determined. Results: Of 154 participants, 95 were diagnosed with ALS and 48 with non-ALS mimics. SICI demonstrated a marginally higher diagnostic accuracy (AUC 0.84, 95% CI:0.77-0.89) compared to SICF (AUC 0.77, 95% CI:0.68-0.84, p = 0.028). The index of excitation showed comparable accuracy to SICI (AUC 0.82, 95% CI: 0.75-0.88, p = 0.328). The optimal SICF cut-off (≤ -13.6%) provided 70.5% sensitivity and 70.8% specificity, while the index of excitation cut-off (≥ 64.5%) yielded 71.6% sensitivity and 70.8% specificity. Conclusions: The present study established modest diagnostic potential of increased SICF and index of excitation in differential ALS from mimic disorders, thereby enhancing understanding of the role of inhibitory and facilitatory cortical circuits in ALS diagnosis.
- Cognitive comorbidities of experimental absence seizures are independent of anxietyPublication . Neuparth-Sottomayor, Mariana; Pina, Carolina; Morais, Tatiana P.; Farinha Ferreira, Jorge Miguel; Abreu, Daniela Sofia; Solano, Filipa; Mouro, Francisco; Good, Mark; Sebastião, Ana M; Di Giovanni, Giuseppe; Crunelli, Vincenzo; Vaz, Sandra H.Typical absence seizures (ASs) are brief periods of lack of consciousness, associated with 2.5-4 Hz spike-wave discharges (SWDs) in the EEG, which are highly prevalent in children and teenagers. The majority of probands in these young epileptic cohorts show neuropsychological comorbidities, including cognitive, memory and mood impairments, even after the seizures are pharmacologically controlled. Similar cognition and memory deficits have been reported in different, but not all, genetic animal models of ASs. However, since these impairments are subtle and highly task-specific their presence may be confounded by an anxiety-like phenotype and no study has tested anxiety and memory in the same animals. Moreover, the majority of studies used non-epileptic inbred animals as the only control strain and this may have contributed to a misinterpretation of these behavioural results. To overcome these issues, here we used a battery of behavioural tests to compare anxiety and memory in the same animals from the well-established inbred model of Genetic Absence Epilepsy Rats from Strasbourg (GAERS), their inbred strain of Non-Epileptic Control (NEC) strain (that lack ASs) and normal outbred Wistar rats. We found that GAERS do not exhibit increased anxiety-like behavior and neophobia compared to both NEC and Wistar rats. In contrast, GAERS show decreased spontaneous alternation, spatial working memory and cross-modal object recognition compared to both NEC and Wistar rats. Furthermore, GAERS preferentially used egocentric strategies to perform spatial memory tasks. In summary, these results provide solid evidence of memory deficits in GAERS rats that do not depend on an anxiety or neophobic phenotype. Moreover, the presence of differences between NEC and Wistar rats stresses the need of using both outbred and inbred control rats in behavioural studies involving genetic models of ASs.
- Adenosinergic system and BDNF signaling changes as a cross-sectional feature of RTT: characterization of Mecp2 heterozygous mouse femalesPublication . Miranda-Lourenço, Catarina; Rosa, Jéssica; Rei, Nádia; Belo, Rita F.; Lopes, Ana Luísa; Silva, Diogo; Vieira, Cátia; Magalhães-Cardoso, Teresa; Viais, Ricardo; Correia-de-Sá, Paulo; Sebastião, Ana M; Diógenes, Maria JoséRett Syndrome is an X-linked neurodevelopmental disorder (RTT; OMIM#312750) associated to MECP2 mutations. MeCP2 dysfunction is seen as one cause for the deficiencies found in brain-derived neurotrophic factor (BDNF) signaling, since BDNF is one of the genes under MeCP2 jurisdiction. BDNF signaling is also dependent on the proper function of the adenosinergic system. Indeed, both BDNF signaling and the adenosinergic system are altered in Mecp2-null mice (Mecp2-/y), a representative model of severe manifestation of RTT. Considering that symptoms severity largely differs among RTT patients, we set out to investigate the BDNF and ADO signaling modifications in Mecp2 heterozygous female mice (Mecp2+/-) presenting a less severe phenotype. Symptomatic Mecp2+/- mice have lower BDNF levels in the cortex and hippocampus. This is accompanied by a loss of BDNF-induced facilitation of hippocampal long-term potentiation (LTP), which could be restored upon selective activation of adenosine A2A receptors (A2AR). While no differences were observed in the amount of adenosine in the cortex and hippocampus of Mecp2+/- mice compared with healthy littermates, the density of the A1R and A2AR subtype receptors was, respectively, upregulated and downregulated in the hippocampus. Data suggest that significant changes in BDNF and adenosine signaling pathways are present in an RTT model with a milder disease phenotype: Mecp2+/- female animals. These features strengthen the theory that boosting adenosinergic activity may be a valid therapeutic strategy for RTT patients, regardless of their genetic penetrance.
- Astrocytes control hippocampal synaptic plasticity through the vesicular-dependent release of D-serinePublication . Abreu, Daniela Sofia; Gomes, Joana I.; Ribeiro, Filipa; Diógenes, Maria José; Sebastião, Ana M; Vaz, Sandra H.Astrocytes, the most abundant glial cells in the central nervous system (CNS), sense synaptic activity and respond through the release of gliotransmitters, a process mediated by intracellular Ca2+ level changes and SNARE-dependent mechanisms. Ionotropic N-methyl-D-aspartate (NMDA) receptors, which are activated by glutamate along with D-serine or glycine, play a crucial role in learning, memory, and synaptic plasticity. However, the precise impact of astrocyte-released D-serine on neuronal modulation remains insufficiently characterized. To address this, we have used the dominant negative SNARE (dnSNARE) mouse model, which selectively inhibits SNARE-dependent exocytosis from astrocytes. We recorded field excitatory postsynaptic potentials (fEPSPs) in CA3-CA1 synapses within hippocampal slices obtained from dnSNARE mice and wild-type (Wt) littermates. Our results demonstrate that hippocampal θ-burst long-term potentiation (LTP), a critical form of synaptic plasticity, is impaired in hippocampal slices from dnSNARE mice. Notably, this LTP impairment was rescued upon incubation with D-serine. To further investigate the involvement of astrocytes in D-serine-mediated mechanisms of LTP maintenance, we perfused hippocampal slices with L-serine - a substrate used by both neurons and astrocytes for D-serine production. The enhancement in LTP observed in dnSNARE mice was exclusively associated with D-serine presence, with no effects evident in the presence of L-serine. Additionally, both D- and L-serine reduced basal synaptic strength in the hippocampal slices of both Wt and dnSNARE mice. These results provide compelling evidence that distinct processes underlie the modulation of basal synaptic transmission and LTP through D-serine. Our findings underscore the pivotal contribution of astrocytes in D-serine-mediated processes that govern LTP establishment and basal transmission. This study not only provides essential insights into the intricate interplay between neurons and astrocytes but also emphasizes their collective role in shaping hippocampal synaptic function.
- Age-related impact of social isolation in mice: young vs middle-agedPublication . Magalhães, Daniela M; Mampay, Myrthe; Sebastião, Ana M; Sheridan, Graham K.; Valente, Cláudia A.Social isolation is a chronic mild stressor and a significant risk factor for mental health disorders. Herein we explored the impact of social isolation on depression- and anxiety-like behaviours, as well as spatial memory impairments, in middle-aged male mice compared to post-weaning mice. We aimed to quantify and correlate social isolation-induced behaviour discrepancies with changes in hippocampal glial cell reactivity and pro-inflammatory cytokine levels. Post-weaning and middle-aged C57BL7/J6 male mice were socially isolated for a 3-week period and behavioural tests were performed on the last five days of isolation. We found that 3 weeks of social isolation led to depressive-like behaviour in the forced swim test, anxiety-like behaviour in the open field test, and spatial memory impairment in the Morris water maze paradigm in middle-aged male mice. These behavioural alterations were not observed in male mice after post-weaning social isolation, indicating resilience to isolation-mediated stress. Increased Iba-1 expression and NLRP3 priming were both observed in the hippocampus of socially isolated middle-aged mice, suggesting a role for microglia and NLRP3 pathway in the detrimental effects of social isolation on cognition and behaviour. Young socially isolated mice also demonstrated elevated NLRP3 priming compared to controls, but no differences in Iba-1 levels and no significant changes in behaviour. Ageing-induced microglia activation and enhancement of IL-1β, TNF-α and IL-6 proinflammatory cytokines, known signs of a chronic low-grade inflammatory state, were also detected. Altogether, data suggest that social isolation, in addition to inflammaging, contributes to stress-related cognitive impairment in middle-aged mice.
- Spatiotemporal dysregulation of neuron-glia related genes and pro-/anti-inflammatory mirnas in the 5xFAD mouse model of Alzheimer’s diseaseouse model of Alzheimer’s diseasePublication . Ianni, Marta; Corraliza-Gomez, Miriam; Costa-Coelho, Tiago; Ferreira-Manso, Mafalda; Inteiro-Oliveira, Sara; Alemãn-Serrano, Nuno; Sebastião, Ana M; Garcia, Gonçalo; Diógenes, Maria José; Brites, DoraAlzheimer's disease (AD), the leading cause of dementia, is a multifactorial disease influenced by aging, genetics, and environmental factors. miRNAs are crucial regulators of gene expression and play significant roles in AD onset and progression. This exploratory study analyzed the expression levels of 28 genes and 5 miRNAs (miR-124-3p, miR-125b-5p, miR-21-5p, miR-146a-5p, and miR-155-5p) related to AD pathology and neuroimmune responses using RT-qPCR. Analyses were conducted in the prefrontal cortex (PFC) and the hippocampus (HPC) of the 5xFAD mouse AD model at 6 and 9 months old. Data highlighted upregulated genes encoding for glial fibrillary acidic protein (Gfap), triggering receptor expressed on myeloid cells (Trem2) and cystatin F (Cst7), in the 5xFAD mice at both regions and ages highlighting their roles as critical disease players and potential biomarkers. Overexpression of genes encoding for CCAAT enhancer-binding protein alpha (Cebpa) and myelin proteolipid protein (Plp) in the PFC, as well as for BCL2 apoptosis regulator (Bcl2) and purinergic receptor P2Y12 (P2yr12) in the HPC, together with upregulated microRNA(miR)-146a-5p in the PFC, prevailed in 9-month-old animals. miR-155 positively correlated with miR-146a and miR-21 in the PFC, and miR-125b positively correlated with miR-155, miR-21, while miR-146a in the HPC. Correlations between genes and miRNAs were dynamic, varying by genotype, region, and age, suggesting an intricate, disease-modulated interaction between miRNAs and target pathways. These findings contribute to our understanding of miRNAs as therapeutic targets for AD, given their multifaceted effects on neurons and glial cells.
- Brain-derived neurotrophic factor modulation in response to oxidative stress and corticosterone: role of scopolamine and mirtazapinePublication . Correia, Ana Salomé; Torrado, Marília; Costa-Coelho, Tiago; Carvalho, Eva Daniela; Inteiro-Oliveira, Sara; Diógenes, Maria José; Pêgo, Ana Paula; Santos, Sofia Duque; Sebastião, Ana M; Vale, NunoMajor Depressive Disorder (MDD) is a very complex disease, challenging to study and manage. The complexities of MDD require extensive research of its mechanisms to develop more effective therapeutic approaches. Crucial in the context of this disease is the role of brain-derived neurotrophic factor (BDNF) signaling pathway. Aim: This manuscript aims to explore the complex relationship between MDD and BDNF signaling pathway, focusing on how BDNF is modulated in response to oxidative stress and corticosterone, known to be altered in MDD and contributing to the pathology of the disorder, when treated with scopolamine and mirtazapine. Methods: To assess BDNF levels after the different treatment conditions, rat hippocampal slices and mice primary hippocampus and cortical cell culture were analyzed by immunofluorescence and Western blot. Key findings: Both mirtazapine and scopolamine under stress conditions induced by hydrogen peroxide (H2O2) and corticosterone, had a significant impact on BDNF levels, and this was distinct in different neuronal models. Mirtazapine, especially when combined with H2O2, altered BDNF expression. Scopolamine when combined with both stressors also altered BDNF levels. However, its effects varied depending on the specific neuronal model and stress condition. In accordance with BDNF results, phosphorylated tropomyosin receptor kinase B (pTrkB) presented increased activation when neuronal cells subjected to stress were treated with mirtazapine or scopolamine. Significance: Collectively, this study highlights the complex connection between these compounds, stress conditions, and BDNF/TrkB modulation, supporting the potential therapeutic effects of scopolamine and mirtazapine in modulating BDNF levels, even in stressful conditions.
- PepH3-modified nanocarriers for delivery of therapeutics across the blood-brain barrierPublication . Szecskó, Anikó; Mészáros, Mária; Simões, Beatriz T.; Cavaco, Marco; Chaparro, Catarina; Porkoláb, Gergő; Castanho, Miguel A. R. B.; Deli, Mária A.; Neves, Vera; Veszelka, SzilviaBackground: Nanocarriers targeting the blood-brain barrier (BBB) are promising drug delivery systems to enhance the penetration of therapeutic molecules into the brain. Immunotherapy, particularly monoclonal antibodies designed to bind amyloid-beta peptides have become a promising strategy for Alzheimer's disease, but ensuring efficacy and safety is challenging and crucial for these therapies. Our aim was to develop an innovative nanocarriers conjugated with PepH3, a cationic peptide derived from Dengue virus type-2 capsid protein that crosses the BBB and acts as a shuttle peptide for the encapsulated single domain antibody (sdAb) recognizing Aβ oligomers. Results: PepH3 peptide enhanced the uptake of the nanoparticles (NPs) into brain endothelial cells, and transcytosis of sdAb, as a potential therapeutic molecule, across both rat and human BBB culture models. The cargo uptake was a temperature dependent active process that was reduced by metabolic and endocytosis inhibitors. The cellular uptake of the cationic PepH3-tagged NPs decreased when the negative surface charge of brain endothelial cells became more positive after treatments with a cationic lipid or with neuraminidase by digesting the glycocalyx. The NPs colocalized mostly with endoplasmic reticulum and Golgi apparatus and not with lysosomes, indicating the cargo may avoid cellular degradation. Conclusions: Our results support that combination of NPs with a potential brain shuttle peptide such as PepH3 peptide can improve the delivery of antibody fragments across the BBB.
- Disparities in the organisation of national healthcare systems for treatment of patients with psoriatic arthritis and axial spondyloarthritis across EuropePublication . Michelsen, Brigitte; Østergaard, Mikkel; Nissen, Michael John; Ciurea, Adrian; Möller, Burkhard; Midtbøll Ørnbjerg, Lykke; Horák, Pavel; Glintborg, Bente; MacDonald, Alan; Laas, Karin; Sokka-Isler, Tuulikki; Gudbjornsson, Bjorn; Iannone, Florenzo; Hellamand, Pasoon; Kvien, Tore Kristian; Rodrigues, Ana Maria; Codreanu, Catalin; Rotar, Ziga; Castrejón, Isabel; Wallman, Johan Karlsson; Pavelka, Karel; Loft, Anne Gitte; Heddle, Maureen; Vorobjov, Sigrid; Relas, Heikki; Gröndal, Gerdur; Gremese, Elisa; van der Horst-Bruinsma, Irene; Kristianslund, Eirik Klami; Santos, Maria; Mogosan, Corina; Tomsic, Matija; Diaz-Gonzalez, Federico; Giuseppe, Daniela Di; Nielsen, Stig Winther; Hetland, Merete LundBackground: Studies on national policies for biologics are warranted. Objectives: To map and compare national healthcare set-ups for prescription, start, switch, tapering, and discontinuation of biologic/targeted synthetic disease-modifying antirheumatic drugs (DMARDs) in patients with psoriatic arthritis and axial spondyloarthritis across Europe, and assess the healthcare set-ups in relation to countries' socio-economic status. Methods: An electronic survey was developed to collect and compare information on national healthcare systems. The relationship between the cumulative score of biologic/targeted synthetic DMARD regulations, socioeconomic indices, and biologic originator costs were assessed by linear regression. Results: National healthcare set-ups differed considerably across the 15 countries, with significantly fewer regulations with increasing socioeconomic status measured by GDP/current health expenditure/human development index, and with increasing biologic originator costs. In most countries, the biologic/targeted synthetic DMARD prescribing doctor was required to adhere to country and/or hospital recommendations, and about a third of countries had a national/regional tender process. Prescription regulations for biologic/targeted synthetic DMARDs, including pre-treatment and disease activity requirements, varied substantially. Approximately a third of countries had criteria for discontinuation and tapering, whereas only few had for switching. Notably, two countries disallowed biologic/targeted synthetic DMARD retrials, and one imposed limit on the maximum number of biologic/targeted synthetic DMARDs permitted. Conclusion: The findings highlight substantial variability in healthcare set-ups for biologic/targeted synthetic DMARD use in psoriatic arthritis and axial spondyloarthritis across Europe and their association with socioeconomic status and drug costs. These insights provide a basis for rheumatology societies, policymakers, and stakeholders to evaluate and potentially optimize healthcare policies.
- Diagnostic utility of threshold tracking TMS paradigms in early amyotrophic lateral sclerosisPublication . Calma, Aicee Dawn; Pavey, Nathan; Santos Silva, Cláudia; van den Bos, Mehdi A.J.; Yiannikas, Con; Farrar, Michelle A.; Kiernan, Matthew C; Menon, Parvathi; Vucic, SteveObjective: Threshold tracking transcranial magnetic stimulation (TMS) has exhibited utility as a diagnostic technique in Amyotrophic Lateral Sclerosis (ALS). Different threshold tracking paradigms have recently been proposed. The present study assessed the diagnostic utility of serial ascending and parallel threshold tracking TMS in ALS. Methods: Threshold tracking TMS was undertaken on 90 prospectively recruited participants suspected of ALS. Short interval intracortical inhibition (SICI) was recorded with serial ascending and parallel threshold tracking paradigms between Interstimulus Interval (ISI) 1-to-7 ms. The primary outcome measure was differences in diagnostic utility of the paradigms in differentiating ALS from ALS mimicking disorders using receiver operating characteristic (ROC) analysis (DeLong statistical method). Results: Reduction in SICI reliably differentiated ALS from mimic disorders, irrespective of the threshold tracking paradigm. Comparison of area under the curve (AUC) established a significantly higher value for mean SICI (1-7 ms) with the serial ascending SICI paradigm (0.81, 95 % confidence interval 0.72-0.91) compared to the parallel paradigm (SICI 0.72, 95 % confidence interval 0.61-0.83, p = 0.0065). The better diagnostic utility of serial ascending paradigm was evident for SICI recorded between 1-to-5 ms, and was maintained irrespective of disease onset site, degree of functional impairment, and the degree of lower motor neuron dysfunction. A comparable diagnostic utility across threshold tracking paradigms was evident in ALS participants who presented with a relative paucity of upper motor neuron signs. Conclusion: While threshold tracking TMS reliably differentiated ALS from mimic disorders, the present study established better diagnostic utility with the serial ascending threshold tracking TMS paradigm. Significance: The serial ascending threshold tracking TMS should be used in a clinical setting as a diagnostic tool for ALS.