Preclinical and Clinical Understanding Major Gaps in Our Understanding and Capabilities

Age-associated diseases are an inevitable, costly, and burdensome outcome to societies as life expectancy increases. All countries face this growing problem even as there are notable successes in treating some of these diseases. For example, effective control of hypertension has been accompanied by a noteworthy reduction in the incidence of cerebrovascular disease. Unfortunately, the same cannot be said for neurodegenerative diseases, such as Alzheimer, Parkinson, motor neuron, and Huntington diseases, despite the tremendous recent progress that has been made in understanding the molecular pathogenesis of this group of brain disorders. Currently there is no effective treatment that delays the onset or slows the natural progression of these diseases. Even the very effective pharmacologic and surgical therapies for Parkinson disease are directed solely at motor symptoms; neither the nonmotor symptoms nor the gradual deterioration can be effectively treated or prevented. This chapter discusses some of the difficulties faced in discovering and developing effective treatments for these diseases, from both the preclinical and clinical perspectives. Some of the gaps in our knowledge and critical questions that must be addressed in the near future are described, with an emphasis on Alzheimer disease. The challenges are many and include incomplete understanding of disease pathophysiology, deficiencies in animal models, and inefficiencies in translating new genetic, molecular, cellular, and neurobiological insights into the clinical arena. There is increasing consensus that treatments which target the potential disease triggers will likely be more effective when given before the onset of clinical symptoms. This,however, brings additional challenges-from the need for new biomarkers to improvements in the design and execution of clinical trials-which the research community must quickly address.