World Brain Day 2023 - Brain Health and Disability: "Leave no one behind".

Worldwide, the number of persons with disability is assumed to be around 1.3 billion. Although several definitions exist, such as the medical and social models, the social model has more holistic approaches and engulfs more aspects. Historically, many considerations were based on eugenics until the middle of the 20th century when a change of paradigm occurred, and disability has since been subject to many developments in the past decades. Previously dependent on mercy and good will, disability has now become a human right, and the implementation of this change is still ongoing. Neurological diseases contribute worldwide to a large proportion of disability and can be classified as reversible or permanent, by their time course, and by disease specific elements. Addtionally, neurological diseases are often accepted and managed differently across cultures and are exposed to variable degrees of stigma. The World Federation of Neurology (WFN) has initiated and continues to promote the concept of brain health, which has a wide range of inclusion and is best summarized in the World Health Organization paper (World Health Organization, 2022a). This concept is embedded in the Intersectoral Global Action Plan (IGAP) (World Health Organization, 2022b), which created a global tool to promote neurology, and the WFN is using this tool for the 2023 World Brain Day to promote and introduce the concept of disability.

Interictal dysphoric disorder in people with and without epilepsy.

OBJECTIVE: Interictal dysphoric disorder (IDD) has been regarded as an affective disorder occurring only in people with epilepsy (PWE). Data showing similar characteristics and similar prevalence of IDD in patients with migraine and with psychogenic nonepileptic seizures question the epilepsy-specific nature of IDD. The aim of the study was to investigate the nature of IDD in people with prevalent epilepsy with mood disorders and people with mood disorders who are free of neurological disease. METHODS: This is a case-control study, with 142 patients with a confirmed diagnosis of epilepsy and major depressive disorder (MDD; cases) and 222 patients with MDD only (controls). MDD diagnosis was confirmed by a structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, 4th edition (SCID-I-RV). We used the Beck Depression Inventory and the Beck Anxiety Inventory to estimate anxiety and depression levels and the Interictal Dysphoric Disorder Inventory (IDDI) to confirm the presence of IDD. Mann-Whitney U test, Pearson chi-squared, Spearman correlation, and logistic regression were used. RESULTS: No differences were found in the prevalence of IDD between PWE with MDD and people with MDD alone (88.73% vs. 85.13%, χ2 = .96, p = .32). There were no differences between the groups overall or for any IDDI subscales (all p > .05). In both groups, IDD symptoms were grouped with the same incidence and had the same duration and periodicity. IDD was not associated with epilepsy (odds ratio = .84, 95% confidence interval = .40-1.98, p = .72). No significant correlation was found between epilepsy, demographic characteristics, and all IDDI subscales (all p > .05). Notably, patients with IDD suffered from affective disorders longer (6.68 ± 6.82 years vs. 3.7 ± 3.97 years, p = .001) and also received higher scores on all psychometric scales (all p < .05). SIGNIFICANCE: This study does not confirm the specificity of IDD for epilepsy. The presence of IDD symptoms may be associated with a more severe course of MDD and significant anxiety distress.

Acute stress response to a cognitive task in patients with major depressive disorder: potential metabolic and proinflammatory biomarkers.

Responses of the hypothalamic-pituitary-adrenal axis (HPAA), immune system and metabolic pathways are involved in adaptation to stress, while alterations in these responses have been implicated in the development of major depressive disorder (MDD). Multiple laboratory indices are known to react in response to the acute stress, however, no valid biomarkers have been reported, which can differentiate stress response in depressed individuals. The aim of this study was to assess changes in a set of laboratory parameters in patients with MDD in response to a moderate mental stress and to find potential markers of altered stress reactivity associated with depression. A group of 33 MDD patients and 43 control subjects underwent clinical evaluation to assess depression and anxiety symptoms, as well as heart rate variability (HRV) analysis. Participants were asked to perform a time constrained cognitive task, and selected hormones (cortisol, ACTH), cytokines (IL-6, IL-1ß, TNF-α), neurotrophic factors (BDNF, CNTF) and metabolic parameters (glucose, cholesterol, triglycerides) were measured before and 60 min after the task performance. HRV analysis showed increased sympathetic input in MDD patients. The MDD group manifested an elevated HPAA activity as well as IL-6 and CNTF levels at baseline. A specific stress-induced increase in glucose and TNF-α was revealed in the MDD group, which was absent in control subjects. The data confirm the impairments of stress response in MDD and suggest that the reaction of simple metabolic and pro-inflammatory indices to a mild stressogenic challenge may be indicative of a depressive state.

Hair cortisol as a marker of hypothalamic-pituitary-adrenal Axis activity in female patients with major depressive disorder.

Hair cortisol is regarded as a promising marker of hypothalamic-pituitary-adrenal axis (HPAA) activity alterations due to stress, somatic and mental health conditions. Hair cortisol was previously reported to be elevated in patients with depression, however the data related to remission and recurrent depressive episodes are different. In this study, levels of hair cortisol were assessed in female patients with major depressive disorder (MDD) and the validity of hair cortisol as a marker of HPAA activity in this condition was evaluated. Hair cortisol was measured in 1 cm hair segments of 21 female patients with MDD and 22 female age-matched controls using enzyme-immunoassay analysis. Concurrently, serum cortisol was assessed and psychological status was evaluated using 17-item Hamilton Depression Rating Scale (HAMD-17), Beck Depression Inventory (BDI) and the Spielberger state trait anxiety inventory (STAI). The levels of hair cortisol were significantly lower in the MDD group, while serum cortisol levels were significantly higher in patients, as compared with controls. A significant negative correlation was found between HAMD-17 scores and hair cortisol. Decreased hair cortisol found in female patients with MDD as compared to controls suggests downregulation of HPAA activity during the preceding month. Further studies are needed to investigate the profiles of hair cortisol at different stages of depressive disorder to establish this parameter as a handy clinical tool.

Defining survival as an outcome measure in amyotrophic lateral sclerosis.

OBJECTIVES: To examine how respiratory interventions affect survival as an outcome measure and to define survival rate for trials in amyotrophic lateral sclerosis. DESIGN AND SETTING: We reviewed the data of 3 phase 3 clinical trials and examined differences in times to death, tracheostomy, and permanent assisted ventilation. We assessed the outcomes with chi(2) and Fisher exact tests for categorical variables and unpaired, 2-tailed t tests for continuous variables. We used Kaplan-Meier methods to estimate the differences in survival times between interventions. A power analysis generated sample size estimates for different end points. PATIENTS: In all, 2077 patients in 2 phase 3 trials of xaliproden and 400 patients in a phase 3 trial of pentoxifylline. MAIN OUTCOME MEASURES: Death or combined death, tracheostomy, or permanent assisted ventilation. RESULTS: Of 745 deaths, 611 (82.0%) were owing to respiratory failure and 134 (18.0%) to other causes. The use of respiratory interventions across centers ranged from 0% to 6.6% (P = .001) of patients for tracheostomy and 11.1% to 23.1% (P = .05) of patients for noninvasive ventilation. Twelve of 55 patients (21.8%) undergoing tracheostomy had a vital capacity of 50% or more. Mean (SD) survival time was 457.9 (3.1) days using a combined end point and 467.2 (2.9) days with death alone as the outcome (P = .02). An estimated sample size to detect a 10% difference at 18 months between groups was 490 patients per arm for the combined end point and 410 patients for death alone. CONCLUSIONS: Tracheostomy and permanent assisted ventilation are not equivalent to death in amyotrophic lateral sclerosis. The use of respiratory interventions differs between centers, leading to variability in combined outcome assessments. The time to the end point can differ significantly depending on its definition, and combining outcomes does not reduce the estimated sample size of a trial. The death rate alone is the least variable and most easily identifiable measure of survival rate in amyotrophic lateral sclerosis.

TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.

Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.