Effects of Liraglutide on Hippocampal Structure and Function in Aging Adults With Prediabetes
Condition: Insulin Resistance; Dementia
MeSH terms: Dementia; Insulin Resistance; Prediabetic State
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to evaluate the effects of liraglutide on the memory and
      attention of people with insulin resistance. Liraglutide is a medication that makes the body
      more sensitive to insulin, and therefore may allow it to manage sugar more effectively.

      The investigators are looking specifically at a region of the brain that is associated with
      memory and attention, called the hippocampus, in order to see whether treatment this
      treatment will change performance on memory and attention tasks. The investigators are also
      taking an MRI of the brain to see whether there are changes to the size and shape of the
      hippocampus after treatment.

      All subjects in this study will be 50-70 years old and have pre- diabetes. Half of all
      subjects will have a family history of dementia, while the other half will not.
    

Detailed description: 
      Data from this study will be used to measure changes in hippocampal morphology, functional
      alterations in the hippocampus during a paired associative memory task, functional
      connectivity during rest, and neuropsychological performance on hippocampally-mediated
      cognitive tasks, following double-blind treatment with liraglutide and placebo.

      Primary Hypothesis: Subjects receive liraglutide will show significant differences in
      hippocampal morphology, functional activation and connectivity, and neuropsychological
      performance, compared to subjects receiving placebo.

      Exploratory Aim: To test for potential interactions between modifiable (IR/prediabetes) and
      non-modifiable (FamHxAD, APOE 4) risk factors with respect to morphological, functional, and
      neuropshchological changes during double-blind liraglutide treatment.

      Study Procedures

      The study will be explained to the participant and informed consent obtained. Participant
      will also be asked whether or not they consent to being videotaped during the study, and if
      they do, parts of their study participation may be videotaped for staff training purposes.
      Participants will continue any current psychiatric medication(s) or psychotherapy during the
      duration of the study (eg. no changes will be made to currently received treatments).
      Psychiatric Assessment - This will consist of the Mini International Neuropsychiatric
      Interview(MINI), the 17-item Hamilton Depression Rating Scale (HDRS-17), and the Mini Mental
      Status Examination (MMSE). The MINI interview takes approximately 20-30 minutes depending on
      the individual presentation and has screening and skip-out questions that allow for rapid
      assessment of psychiatric history, current or in remission, to ensure screen-out for
      psychiatric exclusions.

      The HDRS-17 will be used to screen out current depression, as characterized by a score of >
      8. Administration of the HDRS will be repeated during and at the end of double-blind
      treatment. The MMSE, a brief measure of cognitive functioning that assesses arithmetic,
      memory and orientation, will screen out current cognitive impairment.

      Physical Examination and Monitoring:

      A general physical examination will be conducted at baseline and at the end of treatment.
      Vital signs (e.g. blood pressure, pulse, temperature, body weight) will be assessed at each
      in-person study visit. Individual energy (in kilocalories) expenditure per day will be
      assessed using self-report questionnaires (Stanford 7-Day Physical Activity Recall Scale and
      the Food Frequency Questionnaire).

      In addition, subjects will complete the Pittsburgh Sleep Quality Index, the Memory Function
      Questionnaire (to assess subjective cognitive complaints) baseline and final visit, as well
      as report on the frequency of any alcohol or nicotine use.

      All of this information will be used to adjust for differences in the experimental variables
      between the two experimental groups both at baseline and over the course of double-blind
      treatment.

      Oral Glucose Tolerance Test (OGTT): After an overnight fast, subjects will be given a oral
      glucose challenge, wherein plasma glucose concentrations will be measured at baseline,
      T30min, T60min, T90min, and T120min after 75gm oral glucose load. Individuals with fasting
      glucose of 100-125 mg/dl and/or a 2-hour glucose of 140-199 mg/dL and less than 200 mg/dL
      will be eligible for study enrollment. OGTT will be repeated at the end of the study.

      Oral Cortisol Swabs: The participants will be asked to take oral cortisol measures for 3 days
      at waking, 30 minutes after waking and at 9pm. These measures will be taken at baseline and
      final follow up.

      Genotyping for APOE:

      If the subject consents to the collection of a buffy coat sample, this will be done during
      the collection of blood for the blood screening tests. The amount of blood required for the
      buffy coat sample is approximately 2-3 teaspoons. The subject will have the right to withdraw
      consent for this test now or at any time and this will not affect his or her ability to
      participate in the research study. The sample will be stored in a minus 80 freezer for as
      long as, but not limited to 5 years. We will not use this sample for any other purpose
      without the subject's specific permission.

      Genetic analysis will be conducted by experienced laboratory technicians under the
      supervision of Dr. Joachim Hallmayer. Blood for genotyping (approximately 6ccs) will be drawn
      at the time of eligibility screening, after informed consent. Genotype results will not be
      released to participants. Blood samples will be labeled with a unique subject identifier
      known only to the PI's research staff. Genotyping for APOE will be the primary genetic
      analysis and will be performed according to the restriction isotyping protocol of Hixson and
      Vernier. Two observers blind to clinical status of the individuals will carry out assignment
      of genotypes.

      Structural and Functional MRI: Scans will be acquired on a 3.0T GE magnet at baseline and
      upon 12-week follow-up at the Stanford Center for Cognitive and Neurobiological Imaging
      (CNI). Both structural and functional brain imaging will be conducted, and total scan time
      will be 1 hour. All scans will be examined by a neuroradiologist to detect the presence of
      unanticipated structural lesions, including tumors, infarcts, and other abnormalities or
      signs of vascular injury. Data from subjects with abnormalities will be excluded from further
      analysis and they will be contacted and referred for a clinical scan. We expect less than 10%
      of scans to be excluded on this basis.

      Cognitive Testing: Cognitive testing will be conducted on all subjects at baseline and at
      12-week follow-up. The battery includes measures that we expect to be sensitive to subtle
      changes in cognitive function, as well as instruments that appear to have value in
      prospectively identifying individuals at risk for cognitive decline and/or dementia.
      Specifically, measures of working memory, memory recall, verbal fluency, executive function,
      and motor function will be used to detect early functional cognitive changes commonly seen in
      MCI.

      The following battery of tests will take approximately 90 minutes (at both baseline and
      12-week follow-up) to complete and will be administered during the afternoon to avoid diurnal
      effects: Auditory Consonant Trigrams; Benton Visual Retention Test 5th Edition, Boston Naming
      Test, Buschke-Fuld Selective Reminding Test, Delis Kaplan Executive Function System (DKEFS),
      Color-Word subtest, DKEFS Tower Test, DKEFS Trail Making Test, DKEFS Verbal Fluency subtest,
      Purdue Pegboard, Rey-Osterrieth Complex Figure Test, Taylor Complex Figure Task, Wechsler
      Abbreviated Scale of Intelligence, and the Wechsler Adult Intelligence Scale-3rd Edition.

      Double-Blind Intervention: Following completion of the baseline assessments, volunteers will
      be randomly assigned to one of two 12- week interventions; double-blind placebo injection or
      liraglutide for 12 weeks. Subjects will be started on a subcutaneous morning dose of 0.6 mg,
      and this will be titrated to 1.2 mg after one week, and then titrated to 1.8 mg after one
      week and they will remain on this dose for the duration of the study (see Table 1). Subjects
      will be thoroughly instructed on how to self-administer the subcutaneous injection.

      Any subject who cannot tolerate the highest dose, 1.8 mg due to side effects will be allowed
      to return to the 1.2 mg for the duration of the study. This dosing schedule is based on
      evidence that even the lowest dose has been shown to improve glycemic control in patients
      with type 2 diabetes, whereas the higher amounts have been used in studies in which estimates
      have been made of both insulin secretion and insulin sensitivity.

      Subjects will have weekly phone visits with the clinical research coordinator during the
      first month, and then every two weeks for the remainder of the intervention. These calls will
      include an adverse events assessment. This assessment will be provided to the study's
      investigator and endocrinologist, Dr. Sun Kim, in order to determine patient dose. We will
      follow up on dose changes with patients within 48 hours to discuss these changes with them.
      Dr. Kim will meet with the patient if additional follow up on dosing is required.

      After 12 weeks of treatment, all baseline evaluations will be repeated.

      Anyone dropped from the study will not be replaced. All subjects will be unblinded upon
      completion of treatment or drop-out from the study. Open label treatment will not be offered.
    

Intervention name(s): Liraglutide; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 90 days of liraglutide up to 1.8mg/day.; Placebo medication
Other intervention name(s): Victoza
Intervention MeSH terms: Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Other
Keywords: Insulin Resistance; Family History of Dementia; Cognition