<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03039647</url>
  </required_header>
  <id_info>
    <org_study_id>38733</org_study_id>
    <nct_id>NCT03039647</nct_id>
  </id_info>
  <brief_title>Insulin Resistance and Accelerated Cognitive Aging</brief_title>
  <official_title>Insulin Resistance and Accelerated Cognitive Aging</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Premature and accelerated brain aging trajectories have been observed among people with&#xD;
      metabolic dysfunction, but mechanisms of these altered trajectories are not understood.&#xD;
      Insulin resistance (IR) is known to change with age and affect cognition in older and elderly&#xD;
      adults as well as in patients with mood disorders. The main purpose of the study is to&#xD;
      describe the developmental trajectory of cognitive and neural biomarkers across the spectrum&#xD;
      of metabolic dysfunction in overweight/obese adults younger than 50 years of age. The&#xD;
      innovative study design will allow the investigators to examine cognitive outcome development&#xD;
      over a 25-year span without an investment into the longitudinal observation of changes in&#xD;
      cognition and neural function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Premature and accelerated brain aging trajectories started to be recognized in cognitive and&#xD;
      neural responses, but specific mechanisms for the course of cognitive aging remain to be&#xD;
      elucidated. Insulin resistance (IR) is known to change with age, affect cognition in older&#xD;
      and elderly adults as well as in patients with affective disorders. It is unknown whether IR&#xD;
      can predict cognitive decline in individuals younger than age 50 without overt mental&#xD;
      illness. Studies in younger adults afford a unique opportunity to assess whether IR mediates&#xD;
      cognitive and correlating neural processes decades before the manifestation of cognitive&#xD;
      decline. The investigators propose to use an innovative accelerated longitudinal design (ALD)&#xD;
      to characterize trajectories of cognitive and neural biomarkers and to: 1) describe baseline&#xD;
      cognitive and neural biomarkers of brain function across the spectrum of IR in persons ages&#xD;
      25-50; 2) assess how the baseline IR and change in IR at a younger age affects the pattern of&#xD;
      decline in cognitive and neural biomarkers and 3) explore the effects of baseline IR on&#xD;
      changes in cognitive and neural variables of interest as moderated by non-modifiable risk&#xD;
      factors for cognitive decline (gender, and APOE4/family history of AD). The current proposal&#xD;
      aims to describe the developmental trajectory of cognitive and neural biomarkers across the&#xD;
      spectrum of metabolic dysfunction in overweight/obese adults younger than 50 years of age.&#xD;
      Utilizing an accelerated longitudinal design (ALD) we will recruit overweight/obese&#xD;
      individuals (total N=160) aged 25-50. Based on semi-longitudinal data, this design will allow&#xD;
      us to examine outcome development over 25 years between ages 25-50 after 3-year follow-up.&#xD;
      All subjects will undergo baseline qualitative measure of IR, cognitive assessments and&#xD;
      multimodal magnetic resonance imaging (MMRI). Neuropsychological evaluation will focus on&#xD;
      cognitive flexibility/set shifting tests reflecting hippocampal connectivity to the medial&#xD;
      prefrontal region. MMRI will include memory-related hippocampal function and connectivity&#xD;
      (measured with task- and resting-state fMRI) and hippocampal volumes. The ALD design will&#xD;
      allow investigation of the relation between cognitive performance and a corresponding neural&#xD;
      response across the IR spectrum over a long period of time and the predictive value of IR of&#xD;
      long-term trajectories of change in cognitive and neural biomarkers over span of 25 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2017</start_date>
  <completion_date type="Actual">May 1, 2022</completion_date>
  <primary_completion_date type="Actual">May 1, 2022</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change in hippocampal connectivity</measure>
    <time_frame>Change in hippocampal connectivity from entry point to exit point three years later</time_frame>
    <description>This will be assessed by MRI and cognitive assessments.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in hippocampal volume</measure>
    <time_frame>Change in hippocampal volume from entry point to exit point three years later</time_frame>
    <description>This will be determined by MRI analysis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in memory-related functional activation</measure>
    <time_frame>Change in memory-related functional activation from entry point to exit point three years later</time_frame>
    <description>This will be determined by MRI analysis.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">126</enrollment>
  <condition>Insulin Resistance</condition>
  <arm_group>
    <arm_group_label>Entry Point IR (SSPG, HOMA-IR)</arm_group_label>
    <description>All subjects will undergo baseline indirect (HOMA-IR) and direct (SSPG) measures of IR. The investigators hypothesize that a higher entry point IR will predict steeper decline in memory and executive function performance and hippocampal connectivity.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Change in IR (HOMA-IR)</arm_group_label>
    <description>The investigators predict that change in IR (as measured by HOMA-IR) will predict the pattern of decline in memory and executive function performance and hippocampal connectivity.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        The investigators will consent and enroll 160 medically stable men and women in and around&#xD;
        Stanford. Stanford will be the only study site. Subjects will be 25-50 years old, with a&#xD;
        body mass index (BMI) of 25 to 35kg/m2, and will have at least 12 years of education.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Between 25 and 50 years of age&#xD;
&#xD;
          -  BMI of 25 to 33 kg/m^2&#xD;
&#xD;
          -  At least 12 years of education&#xD;
&#xD;
          -  All subjects will be medically stable (i.e. no uncontrolled or poorly controlled&#xD;
             medical illnesses), cognitively intact as defined by Mini Mental Status Exam (MMSE)&#xD;
             score of &gt; 27, and will have adequate visual and auditory acuity to allow for&#xD;
             cognitive testing. Glycemic history will be collected together with other pertinent&#xD;
             medical information from primary care providers.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diagnosis of possible or probably dementia, MCI, or any other dementia&#xD;
&#xD;
          -  Evidence of cognitive decline by MMSE &lt; 27 or self-reported significant decline in&#xD;
             memory within the past year (per the Memory Function Questionnaire)&#xD;
&#xD;
          -  History of Type 1 or Type 2 Diabetes&#xD;
&#xD;
          -  Fasting plasma glucose &gt; 126 mg/dL&#xD;
&#xD;
          -  History of significant cardiovascular disease or myocardial infarction,&#xD;
             cerebrovascular/pulmonary disease, cancer, untreated hypothyroidism, unstable or&#xD;
             untreated hypertension, history of head trauma, MRI-contraindications (i.e. metal in&#xD;
             body, claustrophobia), premature birth (which may affect MRI findings), history of&#xD;
             neurological disorder (ischemic attacks, carotid bruits, or lacunes upon MRI scan), or&#xD;
             evidence of neurological or other physical illness that could produce cognitive&#xD;
             deterioration&#xD;
&#xD;
          -  Use of any drug that may significantly affect the SSPG or cognitive testing results&#xD;
             (specifically: centrally active beta-blockers, narcotics, clonidine, antipsychotics,&#xD;
             benzodiazepines, systemic corticosteroids, medications with significant cholinergic or&#xD;
             anticholinergic effects, anti-convulsants, anti-diabetics, or anti-cholesterol&#xD;
             medications)&#xD;
&#xD;
          -  Drug or alcohol abuse or dependence within the past 6 months, or positive urine&#xD;
             toxicology screen for illicit substances at eligibility screening&#xD;
&#xD;
          -  History of mental illness, with the exception of past mood disorder, or evidence of&#xD;
             acute depression as determined by a 17-item Hamilton Depression Rating Scale (HDRS-17)&#xD;
             score of 8 or more&#xD;
&#xD;
          -  Participants with history of mood disorder must be in remission for at least 6 months&#xD;
             prior to study entry&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>25 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Natalie Rasgon, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Stanford Psychiatry Building</name>
      <address>
        <city>Stanford</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>January 26, 2017</study_first_submitted>
  <study_first_submitted_qc>January 30, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 1, 2017</study_first_posted>
  <last_update_submitted>May 6, 2022</last_update_submitted>
  <last_update_submitted_qc>May 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 9, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Natalie Rasgon</investigator_full_name>
    <investigator_title>Professor of Psychiatry and Behavioral Sciences</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Insulin Resistance</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03039647
org study id: 38733
nct id: NCT03039647
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Premature and accelerated brain aging trajectories have been observed among people with
      metabolic dysfunction, but mechanisms of these altered trajectories are not understood.
      Insulin resistance (IR) is known to change with age and affect cognition in older and elderly
      adults as well as in patients with mood disorders. The main purpose of the study is to
      describe the developmental trajectory of cognitive and neural biomarkers across the spectrum
      of metabolic dysfunction in overweight/obese adults younger than 50 years of age. The
      innovative study design will allow the investigators to examine cognitive outcome development
      over a 25-year span without an investment into the longitudinal observation of changes in
      cognition and neural function.
Premature and accelerated brain aging trajectories started to be recognized in cognitive and
      neural responses, but specific mechanisms for the course of cognitive aging remain to be
      elucidated. Insulin resistance (IR) is known to change with age, affect cognition in older
      and elderly adults as well as in patients with affective disorders. It is unknown whether IR
      can predict cognitive decline in individuals younger than age 50 without overt mental
      illness. Studies in younger adults afford a unique opportunity to assess whether IR mediates
      cognitive and correlating neural processes decades before the manifestation of cognitive
      decline. The investigators propose to use an innovative accelerated longitudinal design (ALD)
      to characterize trajectories of cognitive and neural biomarkers and to: 1) describe baseline
      cognitive and neural biomarkers of brain function across the spectrum of IR in persons ages
      25-50; 2) assess how the baseline IR and change in IR at a younger age affects the pattern of
      decline in cognitive and neural biomarkers and 3) explore the effects of baseline IR on
      changes in cognitive and neural variables of interest as moderated by non-modifiable risk
      factors for cognitive decline (gender, and APOE4/family history of AD). The current proposal
      aims to describe the developmental trajectory of cognitive and neural biomarkers across the
      spectrum of metabolic dysfunction in overweight/obese adults younger than 50 years of age.
      Utilizing an accelerated longitudinal design (ALD) we will recruit overweight/obese
      individuals (total N=160) aged 25-50. Based on semi-longitudinal data, this design will allow
      us to examine outcome development over 25 years between ages 25-50 after 3-year follow-up.
      All subjects will undergo baseline qualitative measure of IR, cognitive assessments and
      multimodal magnetic resonance imaging (MMRI). Neuropsychological evaluation will focus on
      cognitive flexibility/set shifting tests reflecting hippocampal connectivity to the medial
      prefrontal region. MMRI will include memory-related hippocampal function and connectivity
      (measured with task- and resting-state fMRI) and hippocampal volumes. The ALD design will
      allow investigation of the relation between cognitive performance and a corresponding neural
      response across the IR spectrum over a long period of time and the predictive value of IR of
      long-term trajectories of change in cognitive and neural biomarkers over span of 25 years.
observational model: Cohort
time perspective: Prospective
measure: Change in hippocampal connectivity
time frame: Change in hippocampal connectivity from entry point to exit point three years later
description: This will be assessed by MRI and cognitive assessments.
measure: Change in hippocampal volume
time frame: Change in hippocampal volume from entry point to exit point three years later
description: This will be determined by MRI analysis.
measure: Change in memory-related functional activation
time frame: Change in memory-related functional activation from entry point to exit point three years later
description: This will be determined by MRI analysis.
arm group label: Entry Point IR (SSPG, HOMA-IR)
description: All subjects will undergo baseline indirect (HOMA-IR) and direct (SSPG) measures of IR. The investigators hypothesize that a higher entry point IR will predict steeper decline in memory and executive function performance and hippocampal connectivity.
arm group label: Change in IR (HOMA-IR)
description: The investigators predict that change in IR (as measured by HOMA-IR) will predict the pattern of decline in memory and executive function performance and hippocampal connectivity.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 25 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Natalie Rasgon, M.D., Ph.D.
role: Principal Investigator
affiliation: Stanford University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Stanford University
investigator full name: Natalie Rasgon
investigator title: Professor of Psychiatry and Behavioral Sciences
mesh term: Insulin Resistance
sharing ipd: No