Clinical trial NCT01231971: Alzheimer's Disease Neuroimaging Initiative 2
Official title: Alzheimer's Disease Neuroimaging Initiative 2
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Mild Cognitive Impairment (MCI)
Alzheimer's Disease (AD)
Significant Memory Concern (SMC)
Early Mild Cognitive Impairment (EMCI)
Late Mild Cognitive Impairment (LMCI)
Keywords: amyloid
plaques
neuroimaging
biomarkers
cognition disorder
early detection
Amnestic MCI
pre-dementia
dementia
Alzheimer's disease
tau
Lead sponsor: University of Southern California
Sponsor class: OTHER
Collaborators: name: Northern California Institute of Research and Education
name: National Institute on Aging (NIA)
name: Alzheimer's Therapeutic Research Institute
First posted: 2010-11-01
Enrollment: 1182
Sex: ALL
Minimum age (years): 55
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
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) 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Rate of volume change of whole brain, hippocampus and other structural MRI measures
timeFrame: 5 Years
Secondary outcomes:
measure: Rate of Decline as measured by: Cognitive Tests, Activities of Daily Living, and CDR Sum of Boxes
timeFrame: 5 Years
measure: Rate of conversion will be evaluated among all five groups
timeFrame: 5 Years
measure: Rates of change on each specified biochemical biomarker
timeFrame: 5 Years
measure: Rates of change of glucose metabolism (FDG-PET)
timeFrame: 5 Years
measure: Extent of amyloid deposition as measured by Florbetapir F 18
timeFrame: 4 Years
measure: Group differences for each imaging and biomarker measurement
timeFrame: 5 Years
measure: Correlations among biomarkers and biomarker change
timeFrame: 4 Years
measure: APOE genotype, low CSF Aβ42, positive amyloid imaging with florbetapir F 18 (AV-45)
timeFrame: 5 Years
measure: Rate of change of tau and extent of tau deposition as measured by flortaucipir (18F-AV-1451)
timeFrame: 1 Year
measure: Rate of cognitive decline using computer based testing as measured by Cogstate Brief Battery (CBB)
timeFrame: 1 year
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama, 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: La Jolla
country: United States
facility: University of California, San Diego
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: Orange
country: United States
facility: University of California, Irvine (Brain Imaging Center)
state: California
city: Palo Alto
country: United States
facility: Stanford University / PAIRE
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 for Clinical Research
state: Florida
city: Tampa
country: United States
facility: USF Health Byrd Alzheimer's Institute
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: Iowa City
country: United States
facility: University of Iowa
state: Iowa
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
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan, Ann Arbor
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
state: Nevada
city: Lebanon
country: United States
facility: Dartmouth Medical Center
state: New Hampshire
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Amherst
country: United States
facility: Dent Neurologic Institute
state: New York
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Orangeburg
country: United States
facility: Nathan S. Kline Institute for Psychiatric Research
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 Health Sciences
state: North Carolina
city: Beachwood
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 and Aging Program
state: Rhode Island
city: North Charleston
country: United States
facility: Roper St. Francis Healthcare
state: South Carolina
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
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, Clinic for Alzheimer's Disease and Related Disorders Program
state: British Columbia
city: London
country: Canada
facility: Parkwood Institute
state: Ontario
city: London
country: Canada
facility: St. Joseph's Health Center - Cognitive Neurology
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Montreal
country: Canada
facility: McGill University / Jewish General Hospital Memory Clinic
state: Quebec
Study officials:
affiliation: Mayo Clinic
name: Ronald Petersen, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Michael W. Weiner, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Southern California
name: Paul S. Aisen, MD
role: PRINCIPAL_INVESTIGATOR
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.
citation: Rauchmann BS, Schneider-Axmann T, Perneczky R; Alzheimer's Disease Neuroimaging Initiative (ADNI). Associations of longitudinal plasma p-tau181 and NfL with tau-PET, Abeta-PET and cognition. J Neurol Neurosurg Psychiatry. 2021 Dec;92(12):1289-1295. doi: 10.1136/jnnp-2020-325537. Epub 2021 Jun 29.