Alzheimer's Disease Neuroimaging Initiative 2

Mild Cognitive Impairment (MCI) Clinical Trial

— ADNI2  

Official title:

Alzheimer's Disease Neuroimaging Initiative 2

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01231971
• Other study ID #: ADC-039-ADNI2
• Secondary ID: U01AG024904
• Status: Completed
• Start date: February 14, 2011
• Est. completion date: November 29, 2017

Study information

• Verified date: February 2022
• Source: University of Southern California
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The purpose of this study is to build upon the information obtained in the original Alzheimer's Disease Neuroimaging Initiative (ADNI1) and ADNI-GO (Grand Opportunity; a study funded through an NIH grant under the American Recovery and Reinvestment Act), to examine how brain imaging technology can be used with other tests to measure the progression of mild cognitive impairment (MCI) and early Alzheimer's disease (AD). ADNI2 seeks to inform the neuroscience of AD. This information will aid in the early detection of AD, and in measuring the effectiveness of treatments in future clinical trials.

Description:

The Alzheimer's Disease Neuroimaging Initiative (ADNI) began in October 2004 as a landmark study with a public-private partnership that gathered and analyzed thousands of brain scans, genetic profiles and biomarkers in blood and cerebrospinal fluid (CSF). Although the original goal was to define biomarkers for use in clinical trials to determine the best way to measure treatment effects of Alzheimer's disease (AD), the goal has been expanded to using biomarkers to identify AD at a pre-dementia stage. ADNI1 involves scientists at 59 research centers, 54 in the U.S. and five in Canada. Originally 800 participants were enrolled. This group was comprised of 200 participants with AD, 400 with mild cognitive impairment (MCI) and 200 with normal cognition. In ADNI-GO, an estimated 200 participants with early amnestic MCI (EMCI) were enrolled to understand and characterize the mildest symptomatic phase of AD. An additional 650 participants will be enrolled under ADNI2.

Some of the leading-edge technologies under study are brain-imaging techniques, such as positron emission tomography (PET), including FDG-PET (which measures glucose metabolism in the brain); PET using a radioactive compound (Florbetapir F 18) that measures brain beta-amyloid; and structural MRI. Brain scans are showing scientists how the brain's structure and function change as AD starts and progresses. Biomarkers in cerebrospinal fluid are revealing other changes that could identify which patients with MCI will develop Alzheimer's. Scientists are looking at levels of beta-amyloid and tau in cerebrospinal fluid. (Abnormal amounts of the amyloid and tau proteins in the brain are hallmarks of Alzheimer's disease.)

ADNI2 extends the work of ADNI1 and ADNI GO to understand the progression of AD. The overall goal is to determine the relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of AD, as the pathology evolves from normal aging through very mild symptoms, to MCI, to dementia.

The overall impact of this study will be increased knowledge concerning the sequence and timing of events leading to MCI and AD, development of better clinical and imaging/fluid biomarker methods for early detection and for monitoring the progression of these conditions, and facilitation of clinical trials to slow disease progression, ultimately contributing to the prevention of AD.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1182
• Est. completion date: November 29, 2017
• Est. primary completion date: November 29, 2017
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 55 Years to 90 Years

Eligibility

Inclusion Criteria:

Participants will be classified as either normal controls, SMC, EMCI, LMCI or AD participants. General Inclusion Criteria will apply to all groups, with specific criteria for each group as described below:

General (applies to each category):

• Geriatric Depression Scale less than 6.

• Age between *55-90 (inclusive). *For normal controls and SMC participants, age must be between 65-90.

• Study partner is available who has frequent contact with the participant (e.g. an average of 10 hours per week or more), and can accompany the participant to all clinic visits for the duration of the protocol.

• Visual and auditory acuity adequate for neuropsychological testing.

• Good general health with no diseases expected to interfere with the study.

• Participant is not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile).

• Willing and able to participate in a longitudinal imaging study.

• Hachinski less than or equal to 4.

• Completed six grades of education or has a good work history (sufficient to exclude mental retardation).

• Must speak English or Spanish fluently.

• Willing to undergo repeated MRIs (3Tesla) and at least two PET scans (one FDG and one Amyloid imaging) and no medical contraindications to MRI.

• Agrees to collection of blood for Genome Wide Association Studies (GWAS), APOE testing and DNA and RNA banking.

• Agrees to collection of blood for biomarker testing.

• Agrees to at least one lumbar puncture for the collection of CSF.

Specific Inclusion Criteria for normal controls:

• Participant must be free of memory complaints, verified by a study partner.

• Normal memory function score on Wechsler Memory Scale (adjusted for education)

• Mini-Mental State Exam (MMSE) score between 24 and 30 (inclusive)

• Clinical Dementia Rating (CDR) = 0; Memory Box score must be 0

• Cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living

• Stability of Permitted Medications for 4 weeks. In particular, participants may take:

• Antidepressants lacking significant anticholinergic side effects

• Estrogen replacement therapy is permissible

• Gingko biloba is permissible, but discouraged

• Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening

Specific Inclusion Criteria for SMC participants:

• Subjects that are "self-referrals" that have a significant subjective memory concern

• Significant memory concern confirmed by a Cognitive Change Index score of more than or equal to 16

• Normal memory function score on Wechsler Memory Scale (adjusted for education)

• Mini-Mental State Exam (MMSE) score between 24 and 30 (inclusive)

• Clinical Dementia Rating (CDR) = 0; Memory Box score must be 0

• Cognitively normal, based on the absence of significant memory impairment in cognitive function or activities of daily living

• Stability of Permitted Medications for 4 weeks. In particular, subjects may take:

• Antidepressants lacking significant anticholinergic side effects

• Estrogen replacement therapy is permissible

• Gingko biloba is permissible, but discouraged

• Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening

Specific Inclusion Criteria for EMCI and LMCI participants:

• Participant must have a subjective memory concern as reported by participant, study partner, or clinician

• Abnormal memory function score on Wechsler Memory Scale (adjusted for education)

• Mini-Mental State Exam (MMSE) score between 24 and 30 (inclusive)

• Clinical Dementia Rating (CDR) = 0.5; Memory Box score must be at least 0.5

• General cognition and functional performance sufficiently preserved such that a diagnosis of AD cannot be made by the site physician at the time of the screening visit

• Stability of Permitted Medications for 4 weeks. In particular, participants may take:

• Antidepressants lacking significant anticholinergic side effects

• Estrogen replacement therapy

• Gingko biloba is permissible, but discouraged

• Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening

• Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to screening

Specific Inclusion Criteria for AD participants:

• Participant must have a subjective memory concern as reported by participant, study partner, or clinician

• Abnormal memory function score on Wechsler Memory Scale (adjusted for education)

• Mini-Mental State Exam (MMSE) score between 20 and 26 (inclusive)

• Clinical Dementia Rating (CDR) = 0.5 or 1.0

• National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for probable AD

• Stability of Permitted Medications for 4 weeks. In particular, participants may take:

• Antidepressants lacking significant anticholinergic side effects

• Estrogen replacement therapy

• Gingko biloba is permissible, but discouraged

• Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening

• Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to screening

Specific Inclusion Criteria for follow-up participants from ADNI1 and ADNI GO:

• Must have been enrolled and followed in ADNI1 for at least one year or enrolled in ADNI-GO with original diagnosis of Cognitively Normal (CN), Mild Cognitive Impairment (MCI), or Early Mild Cognitive Impairment (EMCI) regardless of whether a diagnostic conversion has occurred since initial enrollment in ADNI.

• Willing and able to continue to participate in an ongoing longitudinal study. A reduced battery of tests is allowable if the participant is not able/willing to complete the full battery.

• Study partner is available who has frequent contact with the participant (e.g. an average of 10 hours per week or more), and can accompany the participant to all clinic visits for the duration of the protocol.

Exclusion Criteria:

General (applies to each category):

• Screening/baseline MRI scan with evidence of infection, infarction, or other focal lesions; Participants with multiple lacunes or lacunes in a critical memory structure are excluded

• Presence of pacemakers, aneurysm clips, artificial heart valves, ear implants, metal fragments or foreign objects in the eyes, skin or body

• Major depression, bipolar disorder as described in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) within the past 1 year

• Currently treated with medication for obsessive-compulsive disorder or attention deficit disorder

• History of schizophrenia

• History of alcohol or substance abuse or dependence within the past 2 years

• Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol

• Clinically significant abnormalities in B12, or TFTs that might interfere with the study

• Residence in skilled nursing facility

• Current use of specific psychoactive medications (e.g.,certain antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.); Current use of warfarin or dabigatran (exclusionary for lumbar puncture).

• Use of investigational agents one month prior to entry and for the duration of the trial

• Participation in clinical studies involving neuropsychological measures being collected more than one time per year

• Exclusion for FDG PET scan and amyloid imaging with Florbetapir F 18: Current or recent participation in any procedures involving radioactive agents such that the total radiation dose exposure to the participant in any given year would exceed the limits of annual and total dose commitment set forth in the US Code of Federal Regulations (CFR) Title 21 Section 361.1.

• Exceptions to these guidelines may be considered on a case-by-case basis at the discretion of the protocol director

Specific Exclusion Criteria for normal controls and SMC participants:

• Any significant neurologic disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities

Specific Exclusion Criteria for EMCI and LMCI participants:

• Any significant neurologic disease other than suspected incipient Alzheimer's disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.

Specific Exclusion Criteria for AD participants:

• Any significant neurologic disease other than Alzheimer's disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.

Specific Exclusion Criteria for follow-up participants from ADNI1 and ADNI GO:

• Participants will not be able to participate in FDG PET scan and amyloid imaging with Florbetapir F 18 if the following is true: Current or recent participation in any procedures involving radioactive agents such that the total radiation dose exposure to the participant in any given year would exceed the limits of annual and total dose commitment set forth in the US Code of Federal Regulations (CFR) Title 21 Section 361.1.

Related Conditions & MeSH terms

• Alzheimer Disease
• Alzheimer's Disease (AD)
• Cognitive Dysfunction
• Early Mild Cognitive Impairment (EMCI)
• Late Mild Cognitive Impairment (LMCI)
• Mild Cognitive Impairment (MCI)
• Significant Memory Concern (SMC)

Intervention

Drug:
• Florbetapir
Participants will receive a single bolus intravenous injection of 10 mCi (370 MBq) (+/- 10%) florbetapir F18. At approximately 50-minutes post dose, scanning will begin. An approximately 20-minute image acquisition scan will be performed.
• Flortaucipir
Participants will receive a single bolus intravenous injection of 10 mCi (370 MBq) flortaucipir injection followed by a saline flush. At approximately 75-minutes post dose, scanning will begin. An approximately 30-minute image acquisition scan will be performed.

Locations

Country	Name	City	State
Canada	Parkwood Institute	London	Ontario
Canada	St. Joseph's Health Center - Cognitive Neurology	London	Ontario
Canada	McGill University / Jewish General Hospital Memory Clinic	Montreal	Quebec
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University of British Columbia, Clinic for Alzheimer's Disease and Related Disorders Program	Vancouver	British Columbia
United States	Albany Medical College	Albany	New York
United States	Dent Neurologic Institute	Amherst	New York
United States	University of Michigan, Ann Arbor	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Case Western Reserve University	Beachwood	Ohio
United States	University of Alabama, Birmingham	Birmingham	Alabama
United States	Boston University	Boston	Massachusetts
United States	Brigham and Women's Hospital	Boston	Massachusetts
United States	Northwestern University	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	Ohio State University	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Duke University Medical Center	Durham	North Carolina
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	University of California, Irvine	Irvine	California
United States	Mayo Clinic, Jacksonville	Jacksonville	Florida
United States	University of Kansas	Kansas City	Kansas
United States	University of California, San Diego	La Jolla	California
United States	Cleveland Clinic Lou Ruvo Center for Brain Health	Las Vegas	Nevada
United States	Dartmouth Medical Center	Lebanon	New Hampshire
United States	University of Kentucky	Lexington	Kentucky
United States	University of California, Los Angeles	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	University of Wisconsin	Madison	Wisconsin
United States	University of California, Davis	Martinez	California
United States	Wien Center for Clinical Research	Miami Beach	Florida
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Columbia University	New York	New York
United States	Mount Sinai School of Medicine	New York	New York
United States	New York University Medical Center	New York	New York
United States	Roper St. Francis Healthcare	North Charleston	South Carolina
United States	University of California, Irvine (Brain Imaging Center)	Orange	California
United States	Nathan S. Kline Institute for Psychiatric Research	Orangeburg	New York
United States	Stanford University / PAIRE	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Banner Alzheimer's Institute	Phoenix	Arizona
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Butler Hospital Memory and Aging Program	Providence	Rhode Island
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Mayo Clinic, Rochester	Rochester	Minnesota
United States	University of Rochester Medical Center	Rochester	New York
United States	Washington University, St. Louis	Saint Louis	Missouri
United States	University of California, San Francisco	San Francisco	California
United States	Banner Sun Health Research Institute	Sun City	Arizona
United States	USF Health Byrd Alzheimer's Institute	Tampa	Florida
United States	Georgetown University	Washington	District of Columbia
United States	Howard University	Washington	District of Columbia
United States	Premiere Research Institute	West Palm Beach	Florida
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
University of Southern California	Alzheimer's Therapeutic Research Institute, National Institute on Aging (NIA), Northern California Institute of Research and Education

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (4)

Misra C, Fan Y, Davatzikos C. Baseline and longitudinal patterns of brain atrophy in MCI patients, and their use in prediction of short-term conversion to AD: results from ADNI. Neuroimage. 2009 Feb 15;44(4):1415-22. doi: 10.1016/j.neuroimage.2008.10.031. Epub 2008 Nov 5. — View Citation

Petersen RC, Aisen PS, Beckett LA, Donohue MC, Gamst AC, Harvey DJ, Jack CR Jr, Jagust WJ, Shaw LM, Toga AW, Trojanowski JQ, Weiner MW. Alzheimer's Disease Neuroimaging Initiative (ADNI): clinical characterization. Neurology. 2010 Jan 19;74(3):201-9. doi: 10.1212/WNL.0b013e3181cb3e25. Epub 2009 Dec 30. — View Citation

Risacher SL, Saykin AJ, West JD, Shen L, Firpi HA, McDonald BC; Alzheimer's Disease Neuroimaging Initiative (ADNI). Baseline MRI predictors of conversion from MCI to probable AD in the ADNI cohort. Curr Alzheimer Res. 2009 Aug;6(4):347-61. — View Citation

Shen L, Kim S, Risacher SL, Nho K, Swaminathan S, West JD, Foroud T, Pankratz N, Moore JH, Sloan CD, Huentelman MJ, Craig DW, Dechairo BM, Potkin SG, Jack CR Jr, Weiner MW, Saykin AJ; Alzheimer's Disease Neuroimaging Initiative. Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort. Neuroimage. 2010 Nov 15;53(3):1051-63. doi: 10.1016/j.neuroimage.2010.01.042. Epub 2010 Jan 25. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Rate of volume change of whole brain, hippocampus and other structural MRI measures		5 Years
Secondary	Rate of Decline as measured by: Cognitive Tests, Activities of Daily Living, and CDR Sum of Boxes		5 Years
Secondary	Rate of conversion will be evaluated among all five groups		5 Years
Secondary	Rates of change on each specified biochemical biomarker		5 Years
Secondary	Rates of change of glucose metabolism (FDG-PET)		5 Years
Secondary	Extent of amyloid deposition as measured by Florbetapir F 18		4 Years
Secondary	Group differences for each imaging and biomarker measurement		5 Years
Secondary	Correlations among biomarkers and biomarker change		4 Years
Secondary	APOE genotype, low CSF Aß42, positive amyloid imaging with florbetapir F 18 (AV-45)		5 Years
Secondary	Rate of change of tau and extent of tau deposition as measured by flortaucipir (18F-AV-1451)		1 Year
Secondary	Rate of cognitive decline using computer based testing as measured by Cogstate Brief Battery (CBB)		1 year

External Links

•   Alzheimer's Disease Education and Referral Center
•   Alzheimer's Disease Neuroimaging Initiative
•   Alzheimer's Therapeutic Research Institute
•   Laboratory of Neuroimaging: Alzheimer's Disease Neuroimaging Initiative
•   List of Alzheimer's Disease Neuroimaging Initiative Publications