Working...
ClinicalTrials.gov
ClinicalTrials.gov Menu

Examining Neuroinflammation in AlzHeimer's (ENHANCE)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03548883
Recruitment Status : Enrolling by invitation
First Posted : June 7, 2018
Last Update Posted : June 21, 2018
Sponsor:
Information provided by (Responsible Party):
Florida Hospital

Brief Summary:

Alzheimer disease (AD) is a neurodegenerative disorder with a poorly understood pathology. It is an irreversible progressive brain disease that slowly deteriorates memory, thinking and behavior. It affects the elderly population and is also hereditary. The incidence doubles with every decade after sixty with no signs of leveling off. More than 35 million people Worldwide, including 5.5 million living in the United States, suffer from AD. As the United States population ages, it is expected that the number of people with AD will increase, reaching 13.2 to 16.0 million by the year 2050. The cost of care for patients with AD in the United States is expected to rise as well, from $172 billion a year in 2010 to a trillion dollars a year by 2050.

Although the exact etiopathology is not known there are several lines of evidence that suggest that metabolic and inflammatory features are important. It also has been known for many years that the Blood Brain Barrier (BBB) of Alzheimer's patients allow more harmful particles to cross into the brain than the BBBs of those without the disease do. It's known that this barrier, which is regulating transfer of molecules between the brain and blood, and vice versa blood and brain, can become leaky and dysfunctional (in particular capillaries dysfunction) and lead to subsequent problems likely contributing to onset and progression of dementia. This protocol will explore several of the most promising putative factors that cause AD.


Condition or disease
Alzheimer Disease, Early-Onset

Layout table for study information
Study Type : Observational
Estimated Enrollment : 18 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Examining Neuroinflammation in AlzHeimer's Disease Via TrAnscriptomic ProfiliNg and MiCroglia ModEling Using Human Peripheral Blood Mononuclear Cells (ENHANCE)
Study Start Date : June 2016
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine


Group/Cohort
Alzheimer subject Group
In phase I, up 50 AD patients will be recruited and screened until we obtain 6 AD subjects. All potential subjects recruit will be pre-screened for initial inclusion/exclusion criteria via examination of standard of care (SOC) medical history, labs, imaging, and cognitive assessment. Recruited subjects will be scheduled for Study Visit #1 (@TRI) and will be further screened with protocol cognitive assessments, depression screening, assessment of daily activities, and labs. During Study Visit #2, these subjects will undergo structural imaging with high resolution magnetic resonance imaging (@ TRI) without contrast (MRI), to rule out other causes of cognitive decline.
Control Group
In phase II, up to 50 age, sex, race ethnicity, group matched healthy controls will be recruited and screened until we have 6 healthy control subjects. All potential subjects recruit will be pre-screened for initial inclusion/exclusion criteria via examination of medical history (including a review of past images, current medication and labs if available). Recruited subjects will be scheduled for Study Visit #1 and will be further screened with protocol cognitive assessments, depression screening, assessment of daily activities, and labs. During Study Visit #2, these subjects will undergo structural imaging with high resolution magnetic resonance imaging (@ TRI) without contrast (MRI), to confirm that there are no undiagnosed conditions.
Type 2 diabetes group
In phase III, up to 50 age, sex, race ethnicity, group matched T2D patients will be recruited and screened until we have 6 T2D subjects. All potential subjects recruit will be pre-screened for initial inclusion/exclusion criteria via examination of medical history (including a review of past images, current medication and labs if available). Recruited subjects will be scheduled for Study Visit #1 and will be further screened with protocol cognitive assessments, depression screening, assessment of daily activities, and labs. During Study Visit #2, these subjects will undergo structural imaging with high resolution magnetic resonance imaging (@ TRI) without contrast (MRI), to confirm that there are no undiagnosed conditions.



Primary Outcome Measures :
  1. Compare the Blood Brain Barrier leaking between AD, T2D and healthy control subjects. [ Time Frame: Two years ]
    A MRI of the brain with contrast will be used to assess the permeability of the Blood Brain Barrier.

  2. Age [ Time Frame: Two years ]
    Measured in years

  3. Gender [ Time Frame: Two years ]
    (Male or Female)

  4. Body composition [ Time Frame: Two years ]
    Measured by Dexascan

  5. Weight [ Time Frame: Two years ]
    Measured in kilograms

  6. Height [ Time Frame: Two years ]
    Measured in meters

  7. BMI [ Time Frame: Two years ]
    will be determined by dividing weight by height (square)

  8. Race [ Time Frame: Two years ]
    White/Black or African American/Asian/Other/Unknown or not reported

  9. Cognitive data [ Time Frame: Two years ]

    Evaluated by ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) questionnaire. Total scoring range of 0 - 70.

    The ADAS score is based on the number of errors made in each item. A score of 70 represents the most severe impairment and 0 represents the least impairment.


  10. Lipid profile [ Time Frame: Two years ]
    Measured of the HDL, LDL and VLDL content in the blood (measured in mg/dL)

  11. Insulin [ Time Frame: Two years ]
    Measured of insulin level in the blood

  12. Adiponectin [ Time Frame: Two years ]
    Measured of adiponectin level in the blood

  13. Free Fatty Acid [ Time Frame: Two years ]
    Measured of free fatty acid level in the blood

  14. Transcriptomic profiles of the cells isolated from the blood [ Time Frame: Two years ]
    after isolation of the peripheral blood mononuclear cell (PBMC) from the blood, measure of gene expression by RT-qPCR (real time quantitative polymerase chain reaction)

  15. Activity monitoring - energy cost of free-living activity [ Time Frame: Two years ]
    measured by wearing an arm band - measured in minutes

  16. Epigenetic [ Time Frame: Two years ]
    after isolation of the PBMC from the blood measure of DNA methylation

  17. Metabolic of the cells isolated from the blood [ Time Frame: Two years ]
    after isolation of the PBMC from the blood measure of metabolites by MS

  18. Proteomic of the cells isolated from the blood [ Time Frame: Two years ]
    after isolation of the PBMC from the blood, measure of proteins by western blot

  19. Activity monitoring - lying down time [ Time Frame: Two years ]
    measured by wearing an arm band - measured in minutes

  20. Activity monitoring - sleeping time [ Time Frame: Two years ]
    measured by wearing an arm band - measured in minutes

  21. Cognitive data [ Time Frame: Two years ]
    Evaluated by Clinical Dementia Rating (CDR) questionnaire

  22. Cognitive data [ Time Frame: Two years ]
    Evaluated by the Mini Mental Status Exam (MMSE)

  23. Cognitive data [ Time Frame: Two years ]
    Evaluated by the Blessed Dementia Scale (BDS) questionnaire

  24. Cognitive data [ Time Frame: Two years ]
    Evaluated by the Confusion Assessment Method (CAM)

  25. Cognitive data [ Time Frame: Two years ]
    Evaluated by the Geriatric Depression Scale (GDS)


Biospecimen Retention:   Samples With DNA

Serum

Materials of human origin will be collected in the manner described in the specific study visits. Testing that is not conducted at FH will be conducted at SBP, University of Miami or other collaborating laboratories. A Material Transfer Agreement will be obtained, which will govern the transfer of tissue and the chain of custody of the tissue outside of FH for this endpoint testing. If any requests are received from an outside entity for archived tissue, a Material Transfer Agreement will be obtained, which will govern the transfer of tissue and the use of the tissue outside of FH.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   60 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

The team will have 12 AD patients for phase III. The team will have 12 healthy age and sex match controls for phase III.

Due to the target study population, patients with AD, it is expected that the subjects will have cognitive impairments. The objectives of this study cannot be met with research only involving subjects who can personally give consent. Patients with AD who have cognitive impairments would have to be included in this study in order for us to accurately study the disease. For this study, a score of 24 or below on the Mini Mental Status Examination (MMSE), will indicate cognitive impairment. In these cases, we will get written consent from the legally authorized representative (LAR).

Criteria

INCLUSION criteria AD Subject Group:

  • Age ≥ 60
  • Subject must have a diagnosis of AD by a licensed neurologist, psychiatrist, or geriatrician
  • Subject must have mild to moderate AD as determined by cognitive or behavioral symptoms that interfere with functioning in usual daily activities found in the medical history and/or demonstrated by the following assessments results:
  • Mini Mental Status Examination (MMSE) score of 12≤x≤24
  • Alzheimer's Disease Assessment Scale ADAS-cog score of 18≤x≤37
  • Clinical Dementia Rating (CDR) Score of 1 or 2
  • Blessed Dementia Scale (Activities of Daily Living) Score of 1≤x≤11
  • Under Changes in Performance of Everyday Activity
  • Subject/LAR cannot report severe loss (score of 1) in the following categories because it indicates severe dementia:

Inability to find way about indoors (home or familiar location) Inability to interpret surroundings, for example, to recognize whether in hospital or home, etc.

Under Changes in Habit

  • Subject/LAR cannot report severe loss (score of 3) in any of the following categories because it indicates severe dementia Eating Dressing Sphincter control No history of neurological or non-neurological conditions that cause cognitive impairments found in physician notes and/or CT or MRI results (from medical history or protocol MRI)such as Dementia with Lewy bodies Frontotemporal dementia History of strokes in which the patient did not return to previous level of activity and cognition Seizure History in which the patient had residual cognitive deficits Presence of multiple or extensive infarcts or severe white matter hyper-intensity burden Subjects with history of head trauma will be reviewed by PI and Sub-Is and will be included or not at the their discretion.
  • No history psychiatric diagnosis that predates AD diagnosis by 3 years or more
  • No active delirium Assessed by the Confusion Assessment Method (CAM). Subject will be considered positive for delirium if patient has presence of features 1 and 2 and either 3 or 4
  • Individuals willing and able to sign the informed consent either by themselves or with the assistance of an interpreter or legally authorized representative
  • Individuals capable of having an MRI with contrast
  • A score in the normal or mild depression range (0 to 19 on the Geriatric Depression Scale

INCLUSION criteria Healthy Control and Type 2 Diabetes (T2D) Subject Groups:

  • Volunteers who are ≥ 60 and age (±5years), sex, race, and ethnicity matched to participating AD subjects
  • No self-reported or document medical history of current or prior psychiatric, neurological, or non-neurological conditions that cause cognitive impairments, such as Lewy bodies, or other conditions the PI thinks would impact the study results, found in physician notes CT or MRI results (from medical history or protocol MRI)
  • Subjects with history of head trauma will be reviewed by PI and Sub-Is and will be included or not at the their discretion. Subjects with history of strokes in which the patient did not return to previous level of activity and cognition will be excluded. If a subject with a previous stroke returned to the baseline, the subject can be included in the study.
  • History of seizure in which the patient had residual cognitive deficits. If subject seizure history did not result in cognitive impairments the subject can be included
  • Mini Mental Status Examination (MMSE) score of x≥25
  • Alzheimer's Disease Assessment Scale- Cognitive Subscale (ADAS-Cog) score of 18≥x
  • Blessed Dementia Scale (Activities of Daily Living) Score of 0
  • Clinical Dementia Rating (CDR) Score of 0
  • No history of psychiatric diagnosis
  • No active delirium
  • Subjects will be considered positive for delirium if patient has presence of features 1 and 2 and either 3 or 4
  • A score in the normal range (0 to 9) on the Geriatric Depression Scale Individuals willing and able to sign the informed consent by themselves Individuals capable of having an MRI with contrast

INCLUSION criteria T2D Subject Group:

  • Glycosylated hemoglobin (Hba1c) ≥ 7.5%
  • For subjects who are treated with glucose lowering medications, should be controlled (defined as HbA1c ≤ 9.5%) on a stable dose of medications for at least 3 months prior to screening.

EXCLUSION criteria for AD Subject , Healthy Control Subject and T2D Subject Groups:

  • Age ≤ 60
  • Unable/Does not wish to provide blood sample
  • Unable to have MRI with and without contrast to exclude other diagnoses
  • Patient who is allergic
  • Patient who requires sedation for any reason/unable to tolerate MRI imaging ( ex.(ex. claustrophobia, or anxiety)
  • Past or current medical history of psychiatric or neurological conditions that cause cognitive impairments, such as Lewy bodies, stroke, seizure, any other medications PI thinks would impact the study results.
  • Subjects with history of head trauma will be reviewed by PI and Sub-Is and will be included or not at the their discretion.
  • Subjects with history of strokes in which the patient did not return to previous level of activity and cognition will be excluded. If a subject with a previous stroke returned to their baseline the subject can be included in the study.
  • History of seizure in which the patient had residual cognitive deficits. If subject seizure history did not result in cognitive impairments, the subject can be included
  • Research team has the right to exclude any subjects based on any findings that might impact the subjects ability to participate in the study
  • Active delirium (Subjects will be considered positive for delirium if patient has presence of features 1 and 2 and either 3 or 4)
  • Abnormal results indicated the possibility of secondary cause of dementia such as Vitamin B12 deficiency, hypothyroidism, hypoparathyroidism, anemia, hypoxia, or hypercapnia, hepatic and renal encephalopathies, and dehydration would make the subject a screen failure. Specifically:
  • Liver disease (AST or ALT >2.5 times the upper limit of normal)
  • Anemia (hemoglobin <12 g/dl in men, <11 g/dl in women)
  • Thyroid dysfunction (TSH below the lower limit of normal; TSH above the upper limit of normal if symptomatic; TSH >10 mIU/L if symptomatic or asymptomatic); if TSH above the upper the limit of normal and ≤10 mIU/L, subject will be informed about the finding to make a decision on whether or not to participate in the study, which will be recorded in the subject's medical record.
  • History of diabetes type I
  • History of diabetes type II with HbA1c >7.5%
  • Erectile dysfunction drugs (If subject can stop taking erectile dysfunction drug for 2 weeks prior to study participation and remain off the drug through Study Visit #2 participation, the subject can be enrolled)
  • Acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73m2); or renal dysfunction due to the hepato-renal syndrome or in the perioperative liver transplantation period. In the hepato-renal syndrome or in the perioperative liver transplantation period, the risk applies to any severity of renal dysfunction.
  • Uncontrolled hypertension (BP > 140 systolic or 90 diastolic). Will rescreen if controlled and patients can return for a second screening be reviewed by PI/Sub-I (assessing incidences of White Coat Syndrome). Inclusion in the study will be at the discretion of the PI.
  • Patients taking anti-hypertensive medications will be excluded if the eGFR is <40ml min/1.73 m2 [28]. (eGFR will be calculated as per MDRD equation: eGFR (mL / min/1.73 m2) = 175 × (serum creatinine in mg/dl)-1.154 × (age in years)-0.203 ×(0.742 if female) × (1.212 if African American) or Updated Schwartz equation: eGFR (mL / min/1.73 m2) = (0.413 × height in cm)/serum creatinine in mg/dl. Patients with eGFR of > 40ml min/1.73 m2 will be included in the study. For GFR < 60 and >40 oral hydration is recommended, to consist of at least 500 ml (i.e. 2 cups) before contrast administration. We will follow the recommendation.
  • Use of oral contraceptives or hormone replacement therapy.
  • History of drug or alcohol abuse (> 3 drinks per day) in the last 5 years, or psychiatric disease prohibiting adherence to study protocol.
  • History of cancer that is still ongoing. If cancer has been resolved, patient can be enrolled
  • History of organ transplant.
  • History of HIV, active Hepatitis B or C, or Tuberculosis.
  • History of myocardial infarction within the past 6 months.
  • Presence of clinically significant abnormalities on EKG.
  • Current smokers (smoking within the past 3 months)
  • Medication history will be taken and medications included or not at the PI's discretion.

EXCLUSION criteria only for AD Subject Group:

- If in the medical history, the subject's geriatrician, psychiatrist, or neurologist indicates that the subject has severe or advanced AD (not mild or moderate AD) and/or if the subject scores the following on Visit #1 assessments: Subject scores x≤18 and x≥37on the ADAS-cog Subject scores x≤12 and x≥24 and on the MMSE Subject scores 0 or x≥11 and on the Blessed Dementia Scale Subject scores x=0,0.5,or 3 and on the Clinical Dementia Scale

  • Subject's MRI indicates any comorbid neurological or non-neurological conditions that could have a substantial effect on cognition. In the event that AD subject MRI indicates any comorbid neurological or non-neurological conditions, the subject will be considered a screen failure
  • Use of narcotic medication that could have substantial effect on cognition
  • History of psychiatric diagnosis that predates AD diagnosis by 3 years or more
  • Subject scores above mild depression x > 19 on the GDS scale

EXCLUSION criteria only for control Subject and T2D Subject Groups:

  • Subject scores ≥18 on ADAS-Cog (cognitive assessment).
  • Subject's MRI indicates neurological or non-neurological conditions that could have a substantial effect on cognition. In the event that AD subject MRI indicates any neurological or non-neurological conditions that could have a substantial effect on cognition, the subject will be considered a screen failure and referred for medical evaluation.
  • Subjects unable to sign consent themselves
  • History of psychiatric diagnosis
  • Use of medication that could have substantial effect on cognition: Psychoactive, Narcotic, Long-acting benzodiazepines, Anticonvulsants, Histamine H2 Receptor antagonist (Ex. Stimulants, Depressants, , Hallucinogens, Cannabis, Xanax, CodeinCodeine, Zyrtec, Zantac, Pepcid, Neurontin, Depakote, Depakene any other medications PI thinks would impact the study results)
  • Subject scores above normal x > 9 on the GDS scale

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03548883


Sponsors and Collaborators
Florida Hospital
Investigators
Layout table for investigator information
Principal Investigator: Steve Smith, MD Florida Hospital Translation Research Institute

Publications of Results:
Layout table for additonal information
Responsible Party: Florida Hospital
ClinicalTrials.gov Identifier: NCT03548883     History of Changes
Other Study ID Numbers: 864676
First Posted: June 7, 2018    Key Record Dates
Last Update Posted: June 21, 2018
Last Verified: June 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

Additional relevant MeSH terms:
Layout table for MeSH terms
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders