Mechanisms of Insulin Facilitation of Memory

The study described in the present application will test the hypothesis that insulin mediated facilitation of memory in Alzheimer's disease (AD) is achieved through enhanced glutamatergic neurotransmission due to improvements in cerebral glucose metabolism. The effect of a single dose of intranasal insulin on memory and cerebral glutamate concentrations in adults with mild AD or amnestic mild cognitive impairment (aMCI), the presumed prodromal phase of AD will be studied. Successful completion of this study may set the stage for a larger-scale treatment trial of intranasal insulin for adults with memory disorders. However, the use of insulin in this manner at this point in time is purely experimental.

The specific aims of this project will be accomplished through a cross sectional repeated measures design in which 15 participants with mild AD or amnestic MCI will undergo assessments of brain structure and function 15 minutes after a single dose of insulin (20 IU) or placebo. Insulin and placebo conditions will be counterbalanced across participants. Intranasal insulin or placebo administration: Saline and insulin (NovoLog) will be ordered though the UT Student Health Services Pharmacy (Sharon Roberson, Chief Pharmacist) and stored at 4°C, according to standard pharmacy protocols. Three ml doses of saline or insulin will be packaged in nasal spray bottles (e.g., Spectrum Pharmacy Products bottles 969-17404P and actuators 551-24362P) designed to deliver 100μL dose with each spray. A total volume of 200μL will be delivered during each administration (one 100μL dose in each nostril).

20 IU of insulin was administered once daily on two occasions in either the first intervention period or second intervention period using a nasal spray bottle

200 micro liters of saline was administered once daily on two separate occasions in either the first intervention period or second intervention period using a nasal spray bottle

20 IU of insulin was administered once daily on two occasions in either the first intervention period or second intervention period using a nasal spray bottle

200 micro liters of saline was administered once daily on two separate occasions in either the first intervention period or second intervention period using a nasal spray bottle

Glutamate concentration was expressed as the ratio of glutamate to creatine. This was determined using magnetic resonance spectroscopy (MRS), a magnetic resonance technique that uses the same equipment as magnetic resonance imaging (MRI), but allows researchers to extract information about the concentrations of various neurochemicals of neurobiological significance.

Memory performance was assessed using delayed recall (number of units recalled) on the Wechsler Memory Scale (WMS-IV) logical memory (story recall) test. Scores represent a sum of recalled units of two different stories after a 30 minute delay. Total scores range from 0 to 50 (0-25 for each story) with higher scores reflecting better memory performance

Inclusion Criteria: Clinical diagnosis of probable AD Age over 21 Clinical Dementia Rating of 0.5 or 1.0 Mini Mental State Exam Score>15 Exclusion Criteria: preexisting diabetes significant neurological disease that might affect cognition, other than AD, including stroke, Parkinson's disease, multiple sclerosis severe head injury with loss of consciousness > 30 minutes or with permanent neurological sequelae significant medical illness or organ failure, such as uncontrolled hypertension or cardiovascular disease, chronic obstructive pulmonary disease, liver disease, or kidney disease current use of anti-psychotic or anti-convulsant medications current or previous use of hypoglycemic agents or insulin MRI contraindications claustrophobia pregnancy