Recent developments in dystonia.

PURPOSE OF REVIEW: The dystonias are a family of related disorders with many different clinical manifestations and causes. This review summarizes recent developments regarding these disorders, focusing mainly on advances with direct clinical relevance from the past 2 years. RECENT FINDINGS: The dystonias are generally defined by their clinical characteristics, rather than by their underlying genetic or neuropathological defects. The many varied clinical manifestations and causes contribute to the fact that they are one of the most poorly recognized of all movement disorders. A series of recent publications has addressed these issues, offering a revised definition and more logical means for classifying the many subtypes. Our understanding of the genetic and neurobiological mechanisms responsible for different types of dystonias also has grown rapidly, creating new opportunities and challenges for diagnosis, and identifying increasing numbers of rare subtypes for which specific treatments are available. SUMMARY: Recent advances in describing the clinical phenotypes and determining associated causes have pointed to the need for new strategies for diagnosis, classification, and treatment of the dystonias.

Designing clinical trials for dystonia.

With advances in the understanding of the pathophysiology of dystonia, novel therapeutics are being developed. Such therapies will require clinical investigation ranging from exploratory studies to examine safety, tolerability, dosage selection, and preliminary efficacy to confirmatory studies to evaluate efficacy definitively. As dystonia is a rare and complex disorder with clinical and etiological heterogeneity, clinical trials will require careful consideration of the trial design, including enrollment criteria, concomitant medication use, and outcome measures. Given the complexities of designing and implementing efficient clinical trials, it is important for clinicians and statisticians to collaborate closely throughout the clinical development process and that each has a basic understanding of both the clinical and statistical issues that must be addressed. To facilitate designing appropriate clinical trials in this field, we review important general clinical trial and regulatory principles, and discuss the critical components of trials with an emphasis on considerations specific to dystonia. Additionally, we discuss designs used in early exploratory, late exploratory, and confirmatory phases, including adaptive designs.

Phenomenology and classification of dystonia: a consensus update.

This report describes the consensus outcome of an international panel consisting of investigators with years of experience in this field that reviewed the definition and classification of dystonia. Agreement was obtained based on a consensus development methodology during 3 in-person meetings and manuscript review by mail. Dystonia is defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements, postures, or both. Dystonic movements are typically patterned and twisting, and may be tremulous. Dystonia is often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia is classified along 2 axes: clinical characteristics, including age at onset, body distribution, temporal pattern and associated features (additional movement disorders or neurological features); and etiology, which includes nervous system pathology and inheritance. The clinical characteristics fall into several specific dystonia syndromes that help to guide diagnosis and treatment. We provide here a new general definition of dystonia and propose a new classification. We encourage clinicians and researchers to use these innovative definition and classification and test them in the clinical setting on a variety of patients with dystonia. © 2013 Movement Disorder Society.

Amyloid-beta peptide Abetap3-42 affects early aggregation of full-length Abeta1-42.

The major amyloid-beta (Abeta) peptides found in the brain of familial and late onset Alzheimer's disease include the full-length Abeta1-42 and N-terminally truncated, pyroglutamylated peptides Abetap3-42 and Abetap11-42. The biophysical properties of Abeta1-42 have been extensively studied, yet little is known about the other modified peptides. We investigated the aggregation kinetics of brain-specific Abeta peptides to better understand their potential roles in plaque formation. Synthetic peptides were analyzed individually and in mixtures representing various ratios found in the brain. Spectrofluorometric analyses using Thioflavin-T showed that the aggregation of Abeta1-42 was faster compared to Abetap3-42; however, Abetap11-42 displayed similar kinetics. Surprisingly, mixtures of full-length Abeta1-42 and Abetap3-42 showed an initial delay in beta-sheet formation from both equimolar and non-equimolar samples. Electron microscopy of peptides individually and in mixtures further supported fluorescence data. These results indicate that Abeta-Abeta peptide interactions involving different forms may play a critical role in senile plaque formation and maintenance of the soluble Abeta pool in the brain.

Diethylamine extraction of proteins and peptides isolated with a mono-phasic solution of phenol and guanidine isothiocyanate.

Representative extraction of both RNA and protein from a single biological sample is required for reliable assessment of coordinated changes in gene and protein expression. Such a simultaneous extraction can be performed by using Trizol Reagent. Here, we demonstrate that, as an alternative to SDS, 2% diethylamine is an effective solvent, which can be conveniently used in extraction of Trizol-isolated proteins from various tissues. Diethylamine provides efficient extraction of proteins and compatibility with a variety of common downstream analytical applications.