Clinical trial NCT01078636: Alzheimer's Disease Neuroimaging Initiative Grand Opportunity
Official title: Alzheimer's Disease Neuroimaging Initiative Grand Opportunity
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Mild Cognitive Impairment
Alzheimer's Disease
Keywords: amyloid
plaques
imaging
early detection
Amnestic MCI
pre-dementia
Lead sponsor: Alzheimer's Disease Cooperative Study (ADCS)
Sponsor class: OTHER
Collaborators: name: Northern California Institute of Research and Education
name: National Institute on Aging (NIA)
First posted: 2010-03-02
Enrollment: 342
Sex: ALL
Minimum age (years): 55
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: community sample

Brief summary: The purpose of this study is to build upon the information obtained in the original Alzheimer's Disease Neuroimaging Initiative (ADNI1), 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). ADNI-GO seeks to define and characterize the mildest symptomatic phase of AD, referred to in this study as early amnestic MCI (EMCI). This information will aid in the early detection of AD, and in measuring the effectiveness of treatments in future clinical trials.

Detailed description: This project continues the work from ADNI1, the goal of which is to test whether serial magnetic resonance imaging (MRI), positron emission tomography (PET), other biological markers, and clinical and neuropsychological assessments can be combined to measure the progression of mild cognitive impairment (MCI) and early Alzheimer's disease (AD). The goal of the study is to determine relationships among the clinical, cognitive, imaging, genetic, and biochemical biomarker characteristics of the stage of the AD spectrum that precedes MCI, the mildest symptomatic phase of AD, referred to here as EMCI. The ADNI-GO model posits that AD begins with amyloid β (Aβ) deposition in the cortex, which leads to synaptic dysfunction, neurodegeneration, and cognitive/ functional decline.

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 (F-AV-45) 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.)

All participants from ADNI1 who are in the normal and MCI stages will continue to be followed in ADNI-GO. The next step is to scan and analyze the brains of people with EMCI; 200 EMCI participants will be enrolled to narrow the gap between cognitively normal (CN) and "late MCI (LMCI)" participants currently enrolled in ADNI.

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 of treatments to slow disease progression, ultimately contributing to the prevention of AD.

Eligibility criteria: EMCI Inclusion Criteria:

* Between 55 and 90 years of age
* Study partner to accompany patient to all clinic visits for the duration of the protocol
* Memory complaint by patient and/or study partner
* Abnormal memory function score on Wechsler Memory Scale (adjusted for education)
* Mini-Mental State Exam score between 24 and 30 (inclusive)
* Clinical Dementia Rating = 0.5; Memory Box score at least 0.5
* General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by the site physician at the time of the screening visit
* Stability of the following permitted medications for 4 weeks (unless stated otherwise):

  * 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 if stable for 12 weeks prior to screening
* Geriatric Depression Scale less than 6
* Visual and auditory acuity adequate for neuropsychological testing
* Good general health with no diseases expected to interfere with the study
* Not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile)
* Hachinski less than or equal to 4
* Six grade education or has a good work history (sufficient to exclude mental retardation)
* Fluent in English or Spanish
* Agrees to at least one lumbar puncture for the collection of CSF
* Willing and able to complete all baseline assessments
* Willing to undergo repeated MRIs and at least two PET scans and willing to provide DNA and plasma samples as specified
* Willing and able to participate in a longitudinal imaging study

Specific Inclusion Criteria for follow-up participants from ADNI1:

* Must have been enrolled and followed in ADNI for at least one year diagnosed as either Mild Cognitive Impairment (MCI) or Cognitively Normal (CN) regardless of whether a diagnostic conversion has occurred since enrolling in ADNI
* Willing and able to continue to participate in an ongoing longitudinal study; a reduced battery of tests can be requested from the project directors if the participant is not able/willing to complete the full battery
* Study partner who has frequent contact with participant and can accompany participant to all clinic visits for the duration of the protocol

Exclusion Criteria:

* 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
* Screening/baseline MRI scans with evidence of infection, infarction, or other focal lesions; multiple lacunes or lacunes in a critical memory structure
* 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 DSM-IV within the past 1 year
* Psychotic features, agitation or behavioral problems within the last 3 months which could lead to difficulty complying with the protocol
* 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 (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 amyloid imaging with 18F -AV-45: 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

Primary outcomes:
measure: Rate of Decline as measured by: Cognitive tests, Activities of Daily Living, and CDR Sum of Boxes
timeFrame: at screening, baseline, 6 (EMCI only) and 12 months
Secondary outcomes:
measure: Rate of conversion will be evaluated among all four groups
timeFrame: at screening , baseline, 6 (EMCI only) and 12 months
measure: Rate of volume change of whole brain, hippocampus, and other structural MRI measures
timeFrame: at screening and 3, 6, and 12 months (EMCI); at baseline and 12 months (follow-up patients)
measure: Rates of change on each specified biochemical biomarker
timeFrame: at baseline, 6 (EMCI only) and 12 months
measure: Rates of change of glucose metabolism (FDG-PET)
timeFrame: at baseline
measure: Extent of amyloid deposition as measured by 18F-AV-45
timeFrame: at baseline
measure: Group differences for each imaging and biomarker measurement
timeFrame: at screening, baseline, 6 (EMCI only) and 12 months
measure: Correlations among biomarkers and biomarker change
timeFrame: at screening, baseline, 6 (EMCI only) and 12 months
measure: Subgroups analyses: APOE genotype, low CSF Aβ42, positive amyloid imaging with 18F-AV-45
timeFrame: at baseline
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Banner Alzheimer's Institute
state: Arizona
city: Sun City
country: United States
facility: Banner Sun Health Research Institute
state: Arizona
city: Irvine
country: United States
facility: University of California, Irvine
state: California
city: Irvine
country: United States
facility: University of California, Irvine - BIC
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Martinez
country: United States
facility: University of California, Davis
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Washington
country: United States
facility: Georgetown University
state: District of Columbia
city: Washington
country: United States
facility: Howard University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic, Jacksonville
state: Florida
city: Miami Beach
country: United States
facility: Wien Center
state: Florida
city: West Palm Beach
country: United States
facility: Premiere Research Institute
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic, Rochester
state: Minnesota
city: St. Louis
country: United States
facility: Washington University, St. Louis
state: Missouri
city: Las Vegas
country: United States
facility: Cleveland Clinic Lou Ruvo Center for Brain Health (CCLRBC)
state: Nevada
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Amherst
country: United States
facility: Dent Neurological Group
state: New York
city: New York
country: United States
facility: New York University
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Providence
country: United States
facility: Butler Hospital Memory & Aging Program
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas SWMC
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Hamilton
country: Canada
facility: Saint Joseph's Hospital
state: Ontario
city: London
country: Canada
facility: Parkwood Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital / McGill University
state: Quebec
Study officials:
affiliation: Mayo Clinic - Rochester, Minnesota
name: Ronald Petersen, MD, PhD
role: STUDY_CHAIR
affiliation: University of California, San Francisco
name: Michael W Weiner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Diego
name: Paul Aisen, MD
role: STUDY_CHAIR
References:
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.
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. doi: 10.2174/156720509788929273.
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.
citation: 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.