How can we improve clinical trials in amyotrophic lateral sclerosis?

Since the approval of riluzole for the treatment of amyotrophic lateral sclerosis (ALS) 17 years ago, more than 30 large clinical trials have been conducted, but none has proved successful. The failure to translate positive preclinical results into the clinical setting raises questions about the validity of the rodent model that is used to study ALS, and about the quality of both preclinical and clinical studies. However, the greatest challenge is the disease itself as, with rare exceptions, the causes are unknown. In this Perspectives article, we highlight key issues related to the pathophysiology, preclinical studies and clinical trials that should be addressed in the future. These areas include the relationships between different disease mechanisms, the challenges presented by the heterogeneity of the disease, and the need for early intervention, optimal dose selection and effective biomarkers.     

Are we close to using Alzheimer blood biomarkers in clinical practice?

<正>Alzheimer’s disease(AD) is a progressive neurodegenerative disease histologically characterized by the presence of extraneuronal plaques,mainly formed by the 42-aminoacid isoform of amyloid-(Aβ_1-42),and by intraneuronal neurofibrillary to ngles,mainly formed by the tau protein and its hyperphosphorylated isoforms(p-tau).AD is the most common cause of dementia,with an estimated lifetime risk of about 1 in 10 for men and 1 in 5 for women.As     

Worsening of depressive symptoms prior to randomization in clinical trials: a possible screen for placebo responders?

A common practice in depression trials is to exclude patients whose depressive symptoms improve between Screen and Baseline evaluations under the assumption that they are more likely to respond to placebo. The present study investigated this contention by examining the relationship between pre-randomization changes in Hamilton depression rating scale (HAMD) scores to post-randomization placebo response and drug-placebo separation. Four randomized, double-blind, placebo-controlled trials (active medication=fluoxetine or paroxetine) were conducted in outpatients with Major Depressive Disorder using a novel design in which a depressive severity inclusion criterion (HAMD >/= 22) was utilized only at Screen. Patients with no change or minimal (1 point) improvement on the HAMD between Screen and Baseline had the lowest placebo response and the best drug-placebo separation. Patients with pre-randomization improvement of 2 points or greater had moderately higher placebo response and poorer drug-placebo separation. Patients who worsened between Screen and Baseline showed the highest placebo response and the poorest drug-placebo separation. There were no obvious differences in demographic variables between the groups which could account for the findings. In our original analyses 3/4 studies failed to show significant drug-placebo separation. When only patients with no change or pre-randomization improvement of 1 point were used in the analyses, 3/4 studies showed significant drug-placebo separation while the other study approached significance, p < 0.07. These results suggest that pre-randomization changes in HAMD scores may predict post-randomization placebo response and drug-placebo separation. Further, pre-randomization increases in HAMD scores (i.e., worsening) may be the best predictor of heightened placebo responding and poor drug placebo separation.     

Should we be anxious when assessing anxiety using the Beck Anxiety Inventory in clinical insomnia patients?

Assessing for clinical levels of anxiety is crucial, as comorbid insomnias far outnumber primary insomnias (PI). Such assessment is complex since those with Anxiety Disorders (AD) and those with PI have overlapping symptoms. Because of this overlap, we need studies that examine the assessment of anxiety in clinical insomnia groups. Participants (N = 207) were classified as having insomnia: 1) without an anxiety disorder (I-ND), or 2) with an anxiety disorder (I-AD). Mean Beck Anxiety Inventory (BAI) item responses were compared using multivariate analysis of variance (MANOVA) and follow-up ANOVAs. As a validity check, a receiver operating characteristic (ROC) curve analysis was conducted to determine if the BAI suggested clinical cutoff was valid for identifying clinical levels of anxiety in this comorbid patient group. The I-ND had lower mean BAI scores than I-AD. There were significant group differences on 12 BAI items. The ROC curve analysis revealed the suggested BAI cutoff (≥16) had 55% sensitivity and 78% specificity. Although anxiety scores were highest in those with insomnia and an anxiety disorder, those with insomnia only had scores in the mild range for anxiety. Nine items did not distinguish between those insomnia sufferers with and without an anxiety disorder. Additionally, published cutoffs for the BAI were not optimal for identifying anxiety disorders in those with insomnia. Such limitations must be considered before using this measure in insomnia patient groups. In addition, the poor specificity and high number of overlapping symptoms between insomnia and anxiety highlight the diagnostic challenges facing clinicians.     

Manual and quantitative muscle testing in neuromuscular disorders. How to assess the consistency of strength measurements in clinical trials?

Evaluation of functional capacities of patients suffering of neuromuscular disorders, particularly muscle strength, is a critical issue for their diagnosis and follow-up. Within the framework of the natural history of any given disease, such an evaluation may improve the clinician's knowledge of the pathophysiological processes involved, and may help to anticipate and sometimes prevent deleterious consequences as the disease progresses. It is also helpful for identifying correlation between the severity of organic damage and the functional impact of the disease. The measurement of functional capacities must be done with accuracy, sensitivity and reliability, essentially when used as an outcome measure for therapeutic trials. Several evaluation tools for measuring muscle strength are available. They are usually classified into two groups: manual muscle testing (MMT) methods and quantified muscle testing (QMT) methods. In this article, we present the principles of strength measurements, and the different tools and materials that are commonly used in clinical settings. Their limitations and drawbacks are illustrated through several examples. Although QMT is theoretically and potentially more consistent than MMT to precisely follow the muscle capacities of the patients, precise and robust procedures must be elaborated and validated for each tested muscle function. Strength measurements must be performed by trained and experimented clinical evaluators. This issue is critical in the follow up of multicentric therapeutic trials. Inter-rater reliability must be assessed to guarantee the statistical power of the trial.     

Epigenetic regulation of neurodevelopmental genes in response to in utero exposure to phthalate plastic chemicals: How can we delineate causal effects?

Accumulating evidence, from animal models and human observational studies, implicates the in utero (and early postnatal) environment in the ‘programming’ of risk for a variety of adverse outcomes and health trajectories. The modern environment is replete with man-made compounds such as plastic product chemicals (PPC), including phenols and phthalates. Evidence from several human cohorts implicates exposure to these chemicals in adverse offspring neurodevelopment, though a direct causal relationship has not been firmly established. In this review we consider a potential causal pathway that encompasses epigenetic human variation, and how we might test this mechanistic hypothesis in human studies. In the first part of this report we outline how PPCs induce epigenetic change, focusing on the brain derived neurotrophic factor (BDNF) gene, a key regulator of neurodevelopment. Further, we discuss the role of the epigenetics of BDNF and other genes in neurodevelopment and the emerging human evidence of an association between phthalate exposure and adverse offspring neurodevelopment. We discuss aspects of epidemiological and molecular study design and analysis that could be employed to strengthen the level of human evidence to infer causality. We undertake this using an exemplar recent research example: maternal prenatal smoking, linked to methylation change at the aryl hydrocarbon receptor repressor (AHRR) gene at birth, now shown to mediate some of the effects of maternal smoking on birth weight. Characterizing the relationship between the modern environment and the human molecular pathways underpinning its impact on early development is paramount to understanding the public health significance of modern day chemical exposures.     

Do we need to flick the switch? The need for a broader conceptualization of iatrogenic course aggravation in clinical trials of bipolar disorder

The term ‘switching’ is often used in bipolar disorder when describing polarity changes in bipolar disorder, but this term is ambiguous and imprecise, and is sometimes used interchangeably with the term ‘cycling’. Furthermore, polarity changes in bipolar disorder can be understood in different ways, because their clinical manifestations range from the emergence of subthreshold symptoms to a full episode of the opposite pole. Besides the need to tighten the meaning of the term ‘switching’, this paper also argues that switching does not adequately describe the complex phenomena that occur with course aggravation of bipolar disorder, such as alteration in episode frequency or amplitude. A more‐fine grained approach to course aggravation in bipolar disorder is proposed, which incorporates trans‐polar switching, index polarity aggravation, as well as alterations in episodic amplitude, episodic duration, and inter‐episode length. This approach has the potential to capture a broader, more fine‐grained and clinically relevant picture of the process of aggravation of the bipolar cycle.