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The last decade has witnessed substantial progress in understanding the pathogenesis of many categories of neurological disorders. This reflects several circumstances including advances in neurobiology and human neurogenetics, which have led to a diversity of cellular and animal models of the major neurological diseases. To a remarkable degree, animal models predicated on genetic defects in human neurological diseases often reproduce the phenotypes of the corresponding human disorders. Such cellular and animal models have facilitated dissection of molecular pathways underlying selected neurological disorders. In some instances these insights have lead to effective therapies. Successful rational therapies have included l-dopa in Parkinson's disease, mexilitine for myotonia in hyperkalemic paralysis, the monoclonal antibody natalizumab to modulate immunoreactivity in multiple sclerosis, serine in hereditary sensory neuropathy and trials of exon-skipping in Duchenne dystrophy. These examples notwithstanding, we still lack robust preclinical models for many common, genetically complex, neurological disorders, and this may be part of the reason why exciting advances in neurological sciences have not been fully exploited for therapy development. The cost of developing new neurological drugs is immense and the process is lengthy. For these and other reasons, including expensive failed trials (e.g. latrepirdine/Dimebon and bapineuzumab in Alzheimer's disease) some of the larger pharmaceutical companies have reduced research in the CNS sector. This is particularly problematic given the enormous clinical and financial burden of neurological and psychiatric illness. The prevalence parameters are staggering: traumatic brain injury 0.1%, epilepsy 1%, migraine 10%, Parkinson's disease 1%, Alzheimer's disease > 10% (after 80 years of age) with an aggregate cost of more than $2 trillion. It is heartening that the federal government has grasped the significance of these figures and also the huge opportunities inherent in accelerated CNS research. Islands of success, for example drugs for multiple sclerosis that now approach $20 billion in annual revenues, highlight the enormous economic potential in the neurologic sector. In April, the Obama administration announced a new BRAIN initiative (Brain Research through Advancing Innovative Neurotechnologies), which hopes to allocate $3 billion ($300 million per year for decade) to map the location, connectivity and activity of every neuron in the human brain.

At its annual meeting in October, 2012, the American Neurological Association sponsored a workshop to discuss the challenges of accelerating translational research in neurology. This meeting, co-sponsored by the American Society for Experimental Neurotherapeutics, assembled colleagues from academic neurology, funding agencies including the NINDS, and the pharmaceutical industry. Many aspects of these issues were considered in a constructive, day-long discussion. It was suggested that it would be useful to compile a series of white papers describing concisely the present understanding of the biology of several major neurological disorders, along with outlines of potential routes forward in therapy discovery. The present, special issue of the Annals of Neurology is the set of these reviews. While a single issue cannot possibly cover all disciplines within neurology, this nonetheless spans a broad reach of neurological disorders: metabolism and genetics of peripheral neuropathy, critical aspect of infections of the nervous system, salient focal points in the treatment of stroke, developmetal pathology of the CNS, neurodegeneration (ALS, Parkinson disease, Alzheimer disease), multiple sclerosis, sleep and neurorehabilitation. Authors were requested not to provide comprehensive summaries of clinical features of the sort encountered in textbooks, but rather to attend to present therapies and pipelines, recent critical discoveries and the potential for new therapy development. They were also encouraged to embrace viewpoints that reflected their own longstanding expertises in these topics. As we now assemble these papers we believe that they have indeed achieved the desired focus. We are hopeful that these essays will provide clarity and direction in the roadmap for new treatments in these neurological disorders.

  • Robert H. Brown Jr, DPhil, MD and Stephen L. Hauser, MD