Cognition and Central Nervous System Disorders

The inability to recognize a loved one, the loss of independence, and reduced intellectual function can have a devastating impact on an individual's life. Two groups within SRI are addressing these issues:

Neuroscience Program

Researchers in the Center for Health Sciences' Neuroscience Program study and develop treatments for cognitive impairments. Research focuses on neurological and psychiatric conditions, such as Alzheimer's and Parkinson's diseases, depression, and schizophrenia.

Translational Neuroscience Research Laboratory

An important approach to reducing attrition rates in the clinical development of treatments for central nervous system (CNS) disorders such as Alzheimer’s disease and schizophrenia is to improve the validity of preclinical models used to advance drug candidates. Measuring CNS function (e.g., learning and memory, mood) is inherently complicated in a preclinical setting. However, choosing appropriate systems that model the targeted disease state or that represent more accurately the cognitive and mental capabilities of humans (e.g., higher order species) may help.

SRI's Translational Neuroscience Research Laboratory employs non-human primates (NHPs) operantly trained on basic lever pressing machinery and/or on the Cambridge Neuropsychological Automated Test Battery (CANTAB™). The laboratory facilitates early clinical development by designing preclinical studies that will directly translate into a human population. Pharmacokinetic-pharmacodynamic relationships can be established in the behaving NHPs that allow for better efficacy and safety estimates that have been used to inform clinical study design.

The laboratory's key features include:

• Forward and backward translation

• Unique positioning at the interface between drug discovery and early clinical development

• Profiling of novel drug candidates to inform clinical study design

• Pharmacologically validated and sensitive assays that can assess both improvements and impairments in behavioral function

• Extensive pharmacological model validation

• NHP behavior that is individually titrated based on performance criteria to optimize model sensitivity

• Test assessments currently include, but are not limited to

  • Working memory (delayed match-to-sample; paired associates learning)

  • Attention (object retrieval)

  • Impulsivity (differential reinforcement of low-rate behavior)

  • Antidepressant efficacy (differential reinforcement of low-rate behavior)

  • Side effects (catalepsy, locomotion, sedation, extrapyramidal symptoms)

  • Pharmacokinetic (plasma, serum, cerebrospinal fluid)

  • Biochemical (e.g., Prolactin)

Employing NHPs as an intermediate step between rodent and human efficacy determinations provides a unique opportunity to improve drug discovery efforts, reduce costs, and enhance our fundamental understanding of learning and memory in NHP and human brain function.