One-year regional brain volume changes as potential predictors of cognitive function in multiple sclerosis: a pilot study

BackgroundThe most reliable magnetic resonance imaging (MRI) marker of cognitive dysfunction in multiple sclerosis (MS) is brain atrophy. However, 1-year volumetric changes prior to cognitive assessment were never studied as potential predictors of cognition, which we aim to assess with this pilot work.MethodsTwenty-two MS patients were submitted to a baseline measure of 83 regional brain volumes with MRI and re-evaluated 1 year later; they were also tested with the Brief International Cognitive Assessment for MS (BICAMS): sustained attention and processing speed were examined with the Symbol Digit Modalities Test (SDMT), verbal and visuo-spatial learning and memory with the learning trials from the California Verbal Learning Test-II (CVLT) and the Brief Visuo-spatial Memory Test-revised (BVMT), respectively. Controlling for age, sex, and years of education, a multivariate linear regression model was created for each cognitive score at 1-year follow-up in a backward elimination manner, considering cross-sectional regional volumes and 1-year volume changes as potential predictors.ResultsDecreases in the volumes of the left amygdala and the right lateral orbitofrontal cortex in the year prior to assessment were identified as possible predictors of worse performance in verbal memory (P = 0.009) and visuo-spatial memory (P = 0.001), respectively, independently of cross-sectional brain regional volumes at time of testing.ConclusionOur work reveals novel 1-year regional brain volume changes as potential predictors of cognitive deficits in MS. This suggests a possible role of these regions in such deficits and might contribute to uncover cognitively deteriorating patients, whose detection is still unsatisfying in clinical practice.Open access funding provided by FCT|FCCN (b-on). Biogen, Fundacao para a Ciencia e Tecnologia, UIDB/50026/2020, Fundacao para a ciencia e tecnologia, UIDP/50026/2020, Fundacao para a Ciencia e a Tecnologia, EXPL/MEC-NEU/0888/2021, Torcato Meira

MS Prevalence and Patients' Characteristics in the District of Braga, Portugal

Multiple Sclerosis (MS) is a chronic autoimmune disease of the Central Nervous System causing inflammation and neurodegeneration. There are only 3 epidemiological studies in Portugal, 2 in the Centre and 1 in the North, and there is the need to further study MS epidemiology in this country. The objective of this work is to contribute to the MS epidemiological knowledge in Portugal, describing the patients' epidemiological, demographic, and clinical characteristics in the Braga district of Portugal. This is a cross-sectional study of 345 patients followed in two hospitals of Braga district. These hospitals cover a resident population of 866,012 inhabitants. The data was collected from the clinical records, and 31/12/2009 was established as the prevalence day. For all MS patients, demographic characteristics and clinical outcomes are reported. We have found an incidence of 2.74/100,000 and a prevalence of 39.82/100,000 inhabitants. Most patients have an EDSS of 3 or lower and a mean age of 42 years. The diagnosis was done at mean age of 35, with RRMS being the disease type in more than 80% of patients. In this cohort, we found a female : male ratio of 1.79. More than 50% of patients are treated with Interferon β-1b IM or IFNβ-1a SC 22 μg

Cost-effectiveness Analysis of Ocrelizumab for the Treatment of Relapsing and Primary Progressive Multiple Sclerosis in Portugal

Objectives: Ocrelizumab demonstrated significant clinical benefit for the treatment of relapsing (RMS) and primary progressive (PPMS) multiple sclerosis (MS), an incurable disease characterized by disability progression. This study evaluated the clinical and economic impact of ocrelizumab relative to current clinical practice, including other disease-modifying therapies (DMT), available in Portugal. Methods: Markov models for MS were adapted to estimate the impact of ocrelizumab across three patient populations: treatment-naïve RMS, previously treated RMS, and PPMS. Health states were defined according to the Expanded Disability Status Scale. For RMS, the model further captured the occurrence of relapses and progression to secondary progressive multiple sclerosis (SPMS). A lifetime time-horizon and Portuguese societal perspective were adopted. Results: For RMS patients, ocrelizumab was estimated to maximize the expected time (years) without progression to SPMS (10.50) relative to natalizumab (10.10), dimethyl fumarate (8.64), teriflunomide (8.39), fingolimod (8.38), interferon β-1a (8.33) and glatiramer acetate (8.18). As the most effective option, with quality-adjusted life year (QALY) gains between 0.3 and 1.2, ocrelizumab was found to be cost-saving relative to natalizumab and fingolimod, and presented incremental cost-effectiveness ratios (ICER) below €16,720/QALY relative to the remaining DMT. For PPMS patients, the ICER of ocrelizumab versus best supportive care was estimated at €78,858/QALY. Conclusions: Ocrelizumab provides important health benefits for RMS and PPMS patients, comparing favourably with other widely used therapies. In RMS, ocrelizumab was revealed to be either cost-saving or have costs-per-QALY likely below commonly accepted cost-effectiveness thresholds. In PPMS, ocrelizumab fills a clear clinical gap in the current clinical practice. Overall, ocrelizumab is expected to provide good value for money in addressing the need of MS patients.info:eu-repo/semantics/publishedVersio

Consenso Português para a Identificação Precoce de Esclerose Múltipla Secundária Progressiva: Painel Delphi

Introduction: Multiple sclerosis is a disease with a heterogeneous evolution. The early identification of secondary progressive multiple sclerosis is a clinical challenge, which would benefit from the definition of biomarkers and diagnostic tools applicable in the transition phase from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis. We aimed to reach a Portuguese national consensus on the monitoring of patients with multiple sclerosis and on the more relevant clinical variables for the early identification of its progression. Material and methods: A Delphi panel which included eleven Portuguese Neurologists participated in two rounds of questions between July and August of 2021. In the first round, 39 questions which belonged to the functional, cognitive, imaging, biomarkers and additional evaluations were included. Questions for which no consensus was obtained in the first round (less than 80% of agreement), were appraised by the panel during the second round. Results: The response rate was 100% in both rounds and consensus was reached for a total of 33 questions (84.6%). Consensus was reached for monitoring time, evaluation scales and clinical variables such as the degree of brain atrophy and mobility reduction, changes suggestive of secondary progressive multiple sclerosis. Additionally, digital devices were considered tools with potential to identify disease progression. Most questions for which no consensus was obtained referred to the cognitive assessment and the remaining referred to both functional and imaging domains. Conclusion: Consensus was obtained for the determination of the monitorization interval and for most of the clinical variables. Most questions that did not reach consensus were related with the confirmation of progression taking into account only one test/domain, reinforcing the multifactorial nature of multiple sclerosis.Introdução: A esclerose múltipla é uma doença de evolução heterogénea. A identificação precoce da forma secundária progressiva é um desafio clínico, carecendo da definição de biomarcadores e ferramentas de diagnóstico aplicáveis na fase de transição da forma surto-remissão para a forma secundária progressiva. Este trabalho teve como objetivo estabelecer um consenso nacional português sobre a monitorização dos doentes e das variáveis clínicas mais relevantes para a identificação precoce da progressão da esclerose múltipla. Material e Métodos: Um painel Delphi constituído por 11 neurologistas portugueses respondeu a duas rondas de perguntas entre julho e agosto de 2021. Na primeira ronda foram incluídas 39 questões relacionadas com a avaliação funcional, cognitiva, imagiológica, de biomarcadores e outras, e na segunda, as questões para as quais não foi atingido consenso (menos de 80% de concordância) na primeira ronda voltaram a ser submetidas a avaliação pelo painel. Resultados: A taxa de resposta foi de 100% em ambas as rondas e 33 das 39 questões (84,6%) atingiram concordância. Foi atingido consenso relativamente ao tempo de monitorização dos doentes, às escalas de avaliação a empregar e a variáveis clínicas tais como o grau de atrofia cerebral ou redução da mobilidade, cuja alteração é sugestiva de esclerose múltipla secundária progressiva. Adicionalmente, os dispositivos digitais foram considerados ferramentas com potencial para identificar a progressão da doença. A maioria das questões para as quais não foi obtido consenso dizem respeito à avaliação cognitiva, estando as restantes inseridas nos domínios funcional e imagiológico. Conclusão: Foi obtido consenso para a determinação do intervalo de monitorização e para a maioria das variáveis clínicas. A maioria das questões sem consenso estavam relacionadas com a confirmação do diagnóstico de progressão tendo em conta apenas um teste/domínio, realçando a natureza multifatorial da esclerose múltipla.info:eu-repo/semantics/publishedVersio

REALMS Study: Real-World Effectiveness and Safety of Fingolimod in Patients with Relapsing-Remitting Multiple Sclerosis in Portugal

Background: Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is approved by EMA for relapsing-remitting multiple sclerosis (RRMS). Objectives: To assess the effectiveness and safety of fingolimod in patients with RRMS in real-world clinical practice in Portugal. Methods: Retrospective, multicentre, non-interventional study, reporting 3 years follow-up of data collected from October 2015 to July 2016. Sociodemographic data and previous treatments at baseline and data regarding disease evolution, including number of relapses, annualised relapse rates (ARR) and Expanded Disability Status Scale (EDSS), were collected. Results: Two-hundred and seventy-five participants were enrolled in the REALMS study. Results showed that the main reason to switch to fingolimod was failure of previous treatment (56.7%) and only 3.6% were naïve patients. In the total population, there was a significant decrease in ARR of 64.6% in the first year of treatment, 79.7% in the second year and 82.3% in the third year, compared with baseline. More than 67.0% of patients had no relapses during the 3 years after switching to fingolimod. EDSS remained stable throughout the study. Conclusions: Therapy with fingolimod showed a sustained effectiveness and safety over the 3 years, particularly on patients switched from first-line drugs (BRACE). No new safety issues were reported.info:eu-repo/semantics/publishedVersio

Tau mislocation in glucocorticoid-triggered hippocampal pathology

The exposure to high glucocorticoids (GC) triggers neuronal atrophy and cognitive deficits, but the exact cellular mechanisms underlying the GC-associated dendritic remodeling and spine loss are still poorly understood. Previous studies have implicated sustained GC elevations in neurodegenerative mechanisms through GC-evoked hyperphosphorylation of the cytoskeletal protein Tau while Tau mislocation has recently been proposed as relevant in Alzheimer's disease (AD) pathology. In light of the dual cytoplasmic and synaptic role of Tau, this study monitored the impact of prolonged GC treatment on Tau intracellular localization and its phosphorylation status in different cellular compartments. We demonstrate, both by biochemical and ultrastructural analysis, that GC administration led to cytosolic and dendritic Tau accumulation in rat hippocampus, and triggered Tau hyperphosphorylation in epitopes related to its malfunction (Ser396/404) and cytoskeletal pathology (e.g., Thr231 and Ser262). In addition, we show, for the first time, that chronic GC administration also increased Tau levels in synaptic compartment; however, at the synapse, there was an increase in phosphorylation of Ser396/404, but a decrease of Thr231. These GC-triggered Tau changes were paralleled by reduced levels of synaptic scaffolding proteins such as PSD-95 and Shank proteins as well as reduced dendritic branching and spine loss. These in vivo findings add to our limited knowledge about the underlying mechanisms of GC-evoked synaptic atrophy and neuronal disconnection implicating Tau missorting in mechanism(s) of synaptic damage, beyond AD pathology.We would like to thank Rui Fernandes for TEM technical support. IS was supported by the Portuguese Foundation for Science and Technology (FCT).This work was funded by the Portuguese Foundation for Science and Technology (FCT) (grant NMC-113934 to IS and grant SFRH/BPD/80118/2011 to JC), Canon Foundation and project DoIT - Desenvolvimento e Operacionalização da Investigação de Translação (N° do projeto 13853), funded by Fundo Europeu de Desenvolvimento Regional (FEDER) through the Programa Operacional Fatores de Competitividade (POFC).info:eu-repo/semantics/publishedVersio

Early Adverse Events, HPA Activity and Rostral Anterior Cingulate Volume in MDD

Prior studies have independently reported associations between major depressive disorder (MDD), elevated cortisol concentrations, early adverse events and region-specific decreases in grey matter volume, but the relationships among these variables are unclear. In the present study, we sought to evaluate the relationships between grey matter volume, early adverse events and cortisol levels in MDD.Grey matter volume was compared between 19 controls and 19 individuals with MDD using voxel-based morphometry. A history of early adverse events was assessed using the Childhood Trauma Questionnaire. Subjects also provided salivary cortisol samples. Depressed patients showed decreased grey matter volume in the rostral ACC as compared to controls. Rostral ACC volume was inversely correlated with both cortisol and early adverse events.These findings suggest a key relationship between ACC morphology, a history of early adverse events and circulating cortisol in the pathophysiology of MDD

Mindfulness-based interventions for young offenders: a scoping review

Youth offending is a problem worldwide. Young people in the criminal justice system have frequently experienced adverse childhood circumstances, mental health problems, difficulties regulating emotions and poor quality of life. Mindfulness-based interventions can help people manage problems resulting from these experiences, but their usefulness for youth offending populations is not clear. This review evaluated existing evidence for mindfulness-based interventions among such populations. To be included, each study used an intervention with at least one of the three core components of mindfulness-based stress reduction (breath awareness, body awareness, mindful movement) that was delivered to young people in prison or community rehabilitation programs. No restrictions were placed on methods used. Thirteen studies were included: three randomized controlled trials, one controlled trial, three pre-post study designs, three mixed-methods approaches and three qualitative studies. Pooled numbers (n = 842) comprised 99% males aged between 14 and 23. Interventions varied so it was not possible to identify an optimal approach in terms of content, dose or intensity. Studies found some improvement in various measures of mental health, self-regulation, problematic behaviour, substance use, quality of life and criminal propensity. In those studies measuring mindfulness, changes did not reach statistical significance. Qualitative studies reported participants feeling less stressed, better able to concentrate, manage emotions and behaviour, improved social skills and that the interventions were acceptable. Generally low study quality limits the generalizability of these findings. Greater clarity on intervention components and robust mixed-methods evaluation would improve clarity of reporting and better guide future youth offending prevention programs

Astrocyte pathology in the prefrontal cortex impairs the cognitive function of rats

Interest in astroglial cells is rising due to recent findings supporting dynamic neuron-astrocyte interactions. There is increasing evidence of astrocytic dysfunction in several brain disorders such as depression, schizophrenia or bipolar disorder; importantly these pathologies are characterized by the involvement of the prefrontal cortex and by significant cognitive impairments. Here, to model astrocyte pathology, we injected animals with the astrocyte specific toxin L-a-aminoadipate (L-AA) in the medial prefrontal cortex (mPFC); a behavioral and structural characterization two and six days after the injection was performed. Behavioral data shows that the astrocyte pathology in the mPFC affects the attentional set-shifting, the working memory and the reversal learning functions. Histological analysis of brain sections of the L-AA-injected animals revealed a pronounced loss of astrocytes in the targeted region. Interestingly, analysis of neurons in the lesion sites showed a progressive neuronal loss that was accompanied with dendritic atrophy in the surviving neurons. These results suggest that the L-AA-induced astrocytic loss in the mPFC triggers subsequent neuronal damage leading to cognitive impairment in tasks depending on the integrity of this brain region. These findings are of relevance to better understand the pathophysiological mechanisms underlying disorders that involve astrocytic loss/dysfunction in the PFC.This work was supported by the Marie Curie Fellowship FP7-PEOPLE-2010-IEF 273936, BIAL Foundation Grants 138/2008 and 61/2010, FEDER funds through Operational program for competitiveness factors-COMPETE -, ON2 Programa Operacional Regional do Norte (ON.2-O Novo Norte), QREN/FEDER, and by national funds through FCT-Foundation for Science and Technology-project (PTDC/SAU-NSC/118194/2010) and fellowships (SFRH/BPD/66151/2009 and SFRH/BD/89714/2012)

Structural and molecular correlates of cognitive aging in the rat

Aging is associated with cognitive decline. Herein, we studied a large cohort of old age and young adult male rats and confirmed that, as a group, old  rats display poorer spatial learning and behavioral flexibility than younger adults. Surprisingly, when animals were clustered as good and bad performers, our data revealed that while in younger animals better cognitive performance was associated with longer dendritic trees and increased levels of synaptic markers in the hippocampus and prefrontal cortex, the opposite was found in the older group, in which better performance was associated with shorter dendrites and lower levels of synaptic markers. Additionally, in old, but not young individuals, worse performance correlated with increased levels of BDNF and the autophagy substrate p62, but decreased levels of the autophagy complex protein LC3. In summary, while for younger individuals "bigger is better", "smaller is better" is a more appropriate aphorism for older subjects.Portuguese Foundation for Science and Technology (FCT) with fellowships granted to: Cristina Mota (SFRH/BD/81881/2011), Susana Monteiro (SFRH/BD/69311/2010), Sofia Pereira das Neves and Sara Monteiro-Martins (PIC/IC/83213/2007); and by the European Commission within the 7th framework program, under the grant agreement: Health-F2-2010-259772 (Switchbox). In addition, this work was co-funded by the Northern Portugal Regional Operational Programme (ON.2 SR&TD Integrated Program – NORTE-07-0124-FEDER-000021), through the European Regional Development Fund (FEDER) and by national funds granted by FCT (PEst-C/SAU/LA0026/2013), and FEDER through the COMPETE (FCOMP-01-0124-FEDER-037298)