OBJECTIVE: The objective of this study was to identify predictors in common between different clinical and magnetic resonance imaging (MRI) outcomes in multiple sclerosis (MS) by comparing predictive models.
METHODS: We analyzed 704 patients from our center seen at MS onset, measuring 37 baseline demographic, clinical, treatment, and MRI predictors, and 10-year outcomes. Our primary aim was identifying predictors in common among clinical outcomes: aggressive MS, benign MS, and secondary-progressive (SP)MS. We also investigated MRI outcomes: T2 lesion volume (T2LV) and brain parenchymal fraction (BPF). The performance of the full 37-predictor model was compared with a least absolute shrinkage and selection operator (LASSO)-selected model of predictors in common between each outcome by the area under the receiver operating characteristic curves (AUCs).
RESULTS: The full 37-predictor model was highly predictive of clinical outcomes: in-sample AUC was 0.91 for aggressive MS, 0.81 for benign MS, and 0.81 for SPMS. After variable selection, 10 LASSO-selected predictors were in common between each clinical outcome: age, Expanded Disability Status Scale, pyramidal, cerebellar, sensory and bowel/bladder signs, timed 25-foot walk ≥6 seconds, poor attack recovery, no sensory attacks, and time-to-treatment. This reduced model had comparable cross-validation AUC as the full 37-predictor model: 0.84 versus 0.81 for aggressive MS, 0.75 versus 0.73 for benign MS, and 0.76 versus 0.75 for SPMS, respectively. In contrast, 10-year MRI outcomes were more strongly influenced by initial T2LV and BPF than clinical outcomes.
INTERPRETATION: Early prognostication of MS is possible using LASSO modeling to identify a limited set of accessible clinical features. These predictive models can be clinically usable in treatment decision making once implemented into web-based calculators. ANN NEUROL 2022;92:87-96.
BACKGROUND: Obesity is linked to increased risk of multiple sclerosis (MS) and worsening disease severity. Recent experimental and clinical data indicates that adipokines are involved in regulating immune response and serve as cross talk between immune and neural system. Dimethyl fumarate (DMF) is an oral MS medication with unknown mechanism of action. It upregulates the nuclear factor E2-related factor 2 (Nrf2) pathway, a pathway for adipocyte differentiation. To determine a possible relationship between treatment with dimethyl fumarate, serum adipokine profiles and treatment response in patients with MS, we conducted an observational cohort study and measured serum adipokine and Vitamin D levels before and after treatment with DMF and examined their association with treatment response.
METHODS: We identified patients enrolled in the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) study who were treated with dimethyl fumarate and had available serum samples. Longitudinal pre-treatment and on-treatment samples were available in 23 patients. Cross-sectional on-treatment samples were available in 91 patients, who were classified into DMF responders and non-responders based on radiologic and clinical relapse activity or disability progression. We measured serum leptin, adiponectin, resistin, ghrelin, fatty acid binding protein-4 (FABP-4) and-5 (FABP-5), vitamins D2 and D3. Statistical analysis was performed with paired t-tests, Wilcoxon signed-rank and Mann-Whitney U tests.
RESULTS: After treatment with DMF, serum adiponectin levels significantly increased, whereas FABP-4 levels significantly decreased compared to baseline levels, without a statistically significant change in the patients' BMI. Ghrelin levels were insignificantly lower post-treatment. FABP-4 levels were significantly higher in DMF responders compared to non-responders. This effect was sex-specific, with higher FABP4 levels associated with treatment response in males, but not females.
CONCLUSION: DMF treatment is associated with significant changes in serum adipokine levels, primarily adiponectin and FABP-4. Sex may affect the association between FABP-4 and treatment response.
Creativity, art and artistic creation in music, dance and visual arts are brain activities specific to humans. Their genetic background remained unexplored for years, but many recent studies have uncovered significant associations with cognition-related genes and loci. These studies are summarized in the present article. Creativity is a trait with heavy genetic influences, which are also associated with mental disorders and altruism. Associated genes include dopaminergic, serotoninergic and other genes (a1-antitrypsin, neuregulin, Brain-derived neurotrophic factor). Music is another complex phenotype with important genetic background. Studies in musicians and their families have highlighted the contribution of loci (e.g., 4q22) and specific genes (vasopressin receptor 1α and serotonin transporter). The latter two are also associated with dancing. Although few studies have investigated visual arts, they appear to be influenced by genetic differences, which could explain the increased prevalence of synesthesia in artists and individuals with autism. Lastly, although genes play an important role in creativity and art, epigenetics and the environment should not be overlooked. The genetic exploration of artistic creativity may provide useful knowledge on cognition, behavior and brain function. It may also enable targeted and personalized art therapy in health and disease.
Introduction: Schizophrenia is a severe psychiatric disorder affecting millions worldwide. However, available treatment options do not fully address the disease. Whereas current antipsychotics may control psychotic symptoms, they seem notoriously ineffective in improving negative and cognitive symptoms or in preventing functional decline. As the etiology of schizophrenia eludes us, the development of valid animal models for screening new drug targets appears to be a strenuous task.Areas covered: In this review, the authors present the key concepts that validate animal models of schizophrenia, as well as the different screening approaches for novel schizophrenia treatments. The models covered are either based on major neurotransmitter systems or neurodevelopmental, immune, and genetic approaches.Expert opinion: Sadly, due to inertia, research focuses on developing 'anti-psychotics', instead of 'anti-schizophrenia' drugs that would tackle the entire syndrome of schizophrenia. Whereas no perfect model may ever exist, combining different experimental designs may enhance validity, as the over-reliance on a single model is inappropriate. Multi-model approaches incorporating vulnerability, the 'two-hit' hypothesis, and endophenotypes offer a promise for developing new strategies for schizophrenia treatment. Forward and reverse translation between preclinical and clinical research will increase the probability of success and limit failures in drug development.
BACKGROUND: Although recovery from relapses in MS appears to contribute to disability, it has largely been ignored as a treatment endpoint and disability predictor.
OBJECTIVE: To identify demographic and clinical predictors of relapse recovery in the first 3 years and examine its contribution to 10-year disability and MRI outcomes.
METHODS: Relapse recovery was retrospectively assessed in 360 patients with MS using the return of the Expanded Disability Status Scale (EDSS), Functional System Scale and neurologic signs to baseline at least 6 months after onset. Univariate and multivariable models were used to associate recovery with demographic and clinical factors and predict 10-year outcomes.
RESULTS: Recovery from relapses in the first 3 years was better in patients who were younger, on disease-modifying treatment, with a longer disease duration and without bowel or bladder symptoms. For every incomplete recovery, 10-year EDSS increased by 0.6 and 10-year timed 25-foot walk increased by 0.5 s. These outcomes were also higher with older age and higher baseline BMI. Ten-year MRI brain atrophy was associated only with older age, and MRI lesion volume was only associated with smoking.
CONCLUSIONS: Early initiation of disease-modifying treatment in MS was associated with improved relapse recovery, which in turn prevented long-term disability.
The aim of this study was to determine the cognitive and behavioral effects of extra virgin olive oil total phenolic content (TPC) and Sideritis (SID) extracts in female mice, and identify the associated neurochemical changes in the hippocampus and the prefrontal cortex. All animals received intraperitoneal low or high doses of TPC, SID or vehicle treatment for 7 days and were subjected to the Open Field (OF), Novel Object Recognition (NOR) and Tail Suspension Test (TST). The prefrontal cortex and hippocampus were dissected for analysis of neurotransmitters and aminoacids with high performance liquid chromatography with electrochemical detection (HPLC-ED). Both TPC doses enhanced vertical activity and center entries in the OF, which could indicate an anxiolytic-like effect. In addition, TPC enhanced non-spatial working memory and, in high doses, exerted antidepressant effects. On the other hand, high SID doses remarkably decreased the animals' overall activity. Locomotor and exploratory activities were closely associated with cortical increases in serotonin turnover induced by both treatments. Cognitive performance was linked to glutamate level changes. Furthermore, TPC reduced cortical taurine levels, while SID reduced cortical aspartate levels. TPC seems to have promising cognitive, anxiolytic and antidepressant effects, whereas SID has sedative effects in high doses. Both extracts act in the brain, but their specific actions and properties merit further exploration.
In light of the current shifts in medical education from traditional lectures to more active teaching modalities, a peer-teaching program was introduced to a compulsory, second-year neuroanatomy course. A cross-sectional survey of 527 medical students in the six-year medical program of the National and Kapodistrian University of Athens was administered. The primary aim of the survey, which was distributed to second- through sixth-year medical students, who had completed the neuroanatomy course, was to assess student perception of peer teachers (PTs). Across the five years assessed, students increasingly acknowledged the contribution of PTs to their learning (P < 0.001). Attributes of PTs (e.g., contribution to learning, motivation, effective usage of material, and team environment) were significantly related to the student's opinion of the importance of laboratory activities (P < 0.001). Students who received "average" final grades scored the importance of laboratory exercises, and by inference PTs, significantly lower than students who received "excellent" final grades (P < 0.05). The amount of training that PTs had received was also significantly related to student perceptions of a PT's contribution. Better trained PTs were associated with significantly higher scores regarding learning, motivation, and positive environment compared to less trained PTs (P < 0.05). The results of the present study show that peer-teaching was well received by students attending the neuroanatomy course. While the results express the evolution of the program across the years, the findings also show that learners believed that PTs and the laboratory program contributed significantly to their understanding of neuroanatomy.
The aim of this systematic review was to identify the challenges imposed on medical and surgical education by the COVID-19 pandemic, and the proposed innovations enabling the continuation of medical student and resident training. A systematic review on the MEDLINE and EMBASE databases was performed on April 18th, 2020, and yielded 1288 articles. Sixty-one of the included manuscripts were synthesized in a qualitative description focused on two major axes, "challenges" and "innovative solutions", and two minor axes, "mental health" and "medical students in the frontlines". Shortage of personal protective equipment, suspension of clinical clerkships and observerships and reduction in elective surgical cases unavoidably affect medical and surgical education. Interesting solutions involving the use of virtual learning, videoconferencing, social media and telemedicine could effectively tackle the sudden cease in medical education. Furthermore, trainee's mental health should be safeguarded, and medical students can be involved in the COVID-19 clinical treatment if needed.
Bone Morphogenetic Proteins (BMP) and Transforming Growth Factor-beta (TGF-β) are cytokines with similar receptors and messengers. They are important for immune cell function, with BMPs exerting mainly proinflammatory but also anti-inflammatory effects, and TGF-β suppressing inflammation. Patients with Multiple Sclerosis exhibit BMP overactivity and suppressed TGF-β signaling. This dysregulated signaling participates in the crosstalk between infiltrating immune cells and glia, where BMP inhibits remyelination. Reciprocal antagonism between the two pathways takes place via a variety of mechanisms. Although this antagonism has not been studied in the setting of Multiple Sclerosis, it could inform further research and treatment discovery.
RATIONALE: Νeurosteroids, like dehydroepiandrosterone (DHEA), play an important role in neurodegeneration and neural protection, but they are metabolized in androgens, estrogens, or other active metabolites. A newly developed synthetic DHEA analog, BNN27 ((20R)-3β,21-dihydroxy-17R,20-epoxy-5-pregnene), exerts neurotrophic and neuroprotective actions without estrogenic or androgenic effects.
OBJECTIVES: This study aimed to investigate potential anxiolytic or antidepressant properties of BNN27.
METHODS: Male and female adult Wistar rats were treated with BNN27 (10, 30, or 90 mg/kg, i.p.) and subjected to behavioral tests measuring locomotion, exploration, and "depressive-like" behavior (open field, light/dark box, hole-board, and forced swim tests). The hippocampus and prefrontal cortex were collected for glutamate and GABA measurements, and trunk blood was collected for gonadal hormone analysis.
RESULTS: Acute high-dose BNN27 reduced locomotion and exploratory behavior in both sexes. Intermediate acute doses (30 mg/kg) of BNN27 reduced exploration and testosterone levels only in males, and enhanced progesterone levels in both sexes. Notably, with the present design, BNN27 had neither anxiolytic nor antidepressant effects and did not affect estrogen levels. Interestingly, acute administration of a low BNN27 dose (10 mg/kg) increased glutamate turnover, GABA, and glutamine levels in the hippocampus. The same dose also enhanced glutamate levels in the prefrontal cortex of males only. Sex differences were apparent in the basal levels of behavioral, hormonal, and neurochemical parameters, as expected.
CONCLUSIONS: BNN27 affects locomotion, progesterone, and testosterone levels, as well as the glutamatergic and GABAergic systems of the hippocampus and prefrontal cortex in a sex-dependent way.