David Borsook

Chapter 8.1:Imaging as a CNS Biomarker

The discovery of novel safe and effective medicines for the treatment of many CNS disorders remains uniquely challenging due to their slowly progressive yet ill-defined pathophysiology, the subjective nature of the clinical assessment of signs and symptoms of disease and the relative inaccessibility of the brain to biological investigation. Clinical trials consequently require the study of large numbers of subjects, but still fail frequently because of the lack of objective markers for drug target engagement and functional pharmacodynamics that can be used to guide clinical dose and patient selection, to increase the likelihood of detecting robust efficacy signals. Recent advances in brain imaging provide opportunities to develop biomarkers for diseases of the central nervous system (CNS) that provide objective evaluations of disease state and drug effects. This review provides an overview of the potential for neuroimaging to provide readouts of brain function, structure and chemistry that could be used as biomarkers to facilitate decision making during the development of therapies for CNS disease, or that can be used clinically to guide diagnosis and treatment. The scientific validation, clinical qualification and regulatory acceptance of imaging biomarkers for CNS disease will help speed up the identification, development and registration of new therapeutics targeted to patients most likely to benefit from them.

Functional Magnetic Resonance Imaging in Drug Development

The field of drug development and discovery encounters a number of challenges in identifying effective therapeutics to treat central nervous system (CNS) diseases. Experimental methods such as pharmacokinetic/pharmacodynamic (PK/PD) modeling and behavioral testing have been the conventional means to assess drug efficacy. Here we introduce functional Magnetic Resonance Imaging (fMRI) as a complimentary technique that can be implemented to assess the effectiveness of a therapeutic in CNS disease. FMRI has the unique ability to characterize the de novo drug effect on specific CNS targets, as is done in Positron Emission Tomography, as well as determine how neuronal substrates or networks are influenced by the therapeutic of interest during sensory stimulation or cognitive and motor tasks. Furthermore, fMRI measures can easily be related to the results obtained from conventional standards, such as PK/PD modeling. FMRI is believed to be a promising experimental method that can assist in defining drug effect in early stages of drug development and discovery; and thus, improve the go-no-go decision-making process of newly identified drugs to treat CNS disease.