Clinical trial NCT02854033: Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3)
Official title: Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Mild Cognitive Impairment (MCI)
Alzheimer's Disease (AD)
Keywords: amyloid
plaques
neuroimaging
biomarkers
cognition disorder
early detection
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: 2016-08-03
Enrollment: 2000
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: Cognitively normal (CN), mild cognitive impairment (MCI), and mild AD dementia participants.

Brief summary: Since its launch in 2004, the overarching aim of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has been realized in informing the design of therapeutic trials in AD. ADNI3 continues the previously funded ADNI-1, ADNI-GO, and ADNI-2 studies that have been combined public/private collaborations between academia and industry to determine the relationships between the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of Alzheimer's disease (AD). The overall goal of the study is to continue to discover, optimize, standardize, and validate clinical trial measures and biomarkers used in AD research.

Detailed description: The overall goal of ADNI3 is to determine the relationships among the clinical, cognitive, imaging, genetic and biochemical biomarker characteristics of the entire spectrum of Alzheimer's disease (AD), as the pathology evolves from normal aging through very mild symptoms, to mild cognitive impairment (MCI), to dementia. ADNI3 continues the previously funded AD Neuroimaging Initiative (ADNI1, ADNI-GO, and ADNI-2), and remains a public/private collaboration between academia and industry to study biomarkers of AD. ADNI will continue to inform the neuroscience of AD, identify diagnostic and prognostic markers, identify outcome measures that can be used in clinical trials, and help develop the most effective clinical trial scenarios.

This is multi-center, a non-randomized, natural history, non-treatment study. 1,070-2,000 total participants will be enrolled across three cohorts: cognitively normal\* (CN), mild cognitive impairment (MCI) and mild Alzheimer's Disease (AD) dementia. Participants between the ages of 55-90 (inclusive) will be enrolled at 59 sites in the United States and Canada. Approximately, 700 - 800 will be rollover participants from previous ADNI studies, and 370 - 1200 will be newly enrolled. Clinical/cognitive, imaging, biomarker, and genetic characteristics will be assessed across the three cohorts.

Participants will undergo longitudinal clinical and cognitive assessments, computerized cognitive batteries, biomarker and genetic tests, PET (FDG, amyloid and tau) and MRI scans and cerebral spinal fluid (CSF) collection for up to 5 years.

\*currently recruiting non-Caucasian participants only for the cognitively normal cohort.

Eligibility criteria: Inclusion Criteria (all CN participants):

1. Participant with or without subjective memory complaints, verified by a study partner, beyond what one would expect for age
2. Normal memory function documented by scoring above education adjusted cutoffs on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale -Revised (the maximum score is 25):

   1. 9 for 16 or more years of education
   2. 5 for 8-15 years of education
   3. 3 for 0-7 years of education
3. Mini-Mental State Exam score between 24 and 30 inclusive (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director)
4. Clinical Dementia Rating = 0. Memory Box score must be 0
5. Cognitively normal, based on an absence of significant impairment in cognitive functions or activities of daily living
6. Stability of Permitted Medications for at least 4 weeks:

   1. Stable doses of antidepressants lacking significant anticholinergic side effects (if they are currently adequately treated for depressive symptoms and do not have a history of major depression within the past 1 years)
   2. Estrogen replacement therapy is permissible
   3. Gingko biloba is permissible, but discouraged
   4. Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening.

Inclusion Criteria (all MCI participants):

1. Participant must express a subjective memory concern as reported by participant, or recalled by study partner or clinician.
2. Abnormal memory function documented by scoring below education adjusted cutoffs on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale -Revised (the maximum score is 25):

   a. \< 11 for 16 or more years of education b. ≤ 9 for 8-15 years of education c. ≤ 6 for 0-7 years of education
3. Mini-Mental State Exam score between 24 and 30 inclusive (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director)
4. Clinical Dementia Rating = 0.5. Memory Box score must be at least 0.5
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
6. Stability of Permitted Medications for at least 4 weeks:

   1. Stable doses of antidepressants lacking significant anticholinergic side effects (if they are currently adequately treated for depressive symptoms and do not have a history of major depression within the past 1 years)
   2. Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to Screening Visit
   3. Estrogen replacement therapy is permissible
   4. Gingko biloba is permissible, but discouraged
   5. Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening.

Inclusion Criteria (all AD participants):

1. Participant must express a subjective memory concern as reported by participant, or recalled by study partner or clinician.n.
2. Abnormal memory function documented by scoring below education adjusted cutoffs on the Logical Memory II subscale (Delayed Paragraph Recall, Paragraph A only) from the Wechsler Memory Scale -Revised (the maximum score is 25):

   1. ≤ 8 for 16 or more years of education
   2. ≤ 4 for 8-15 years of education
   3. ≤ 2 for 0-7 years of education
3. Mini-Mental State Exam score between 20 and 26 inclusive (Exceptions may be made for participants with less than 8 years of education at the discretion of the Project Director)
4. Clinical Dementia Rating = 0.5 or 1.0
5. NINCDS (National Institute of Neurological and Communicative Disorders and Stroke) -ADRDA (Alzheimer's Disease and Related Disorders Association) criteria for probable AD
6. Stability of Permitted Medications for at least 4 weeks:

   1. Stable doses of antidepressants lacking significant anticholinergic side effects (if they are currently adequately treated for depressive symptoms and do not have a history of major depression within the past 1 years)
   2. Cholinesterase inhibitors and memantine are allowable if stable for 12 weeks prior to Screening Visit
   3. Estrogen replacement therapy is permissible
   4. Gingko biloba is permissible, but discouraged
   5. Washout from psychoactive medication (e.g., excluded antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics, etc.) for at least 4 weeks prior to screening.

Inclusion Criteria Specific to Newly Enrolled Participants

1. Geriatric Depression Scale score less than 6.
2. Age between 55-90 years (inclusive).
3. Study partner who has frequent contact with the participant (i.e., minimum average of 10 hours per week) and is available to accompany the participant to all clinic visits for the duration of the protocol.
4. Visual and auditory acuity adequate for neuropsychological testing.
5. Good general health with no diseases expected to interfere with the study.
6. Participant is not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile).
7. Willing and able to participate in a longitudinal imaging study.
8. Modified Hachinski Ischemic Score less than or equal to 4.
9. Completed six grades of education or has a good work history (sufficient to exclude mental retardation).
10. Must speak English or Spanish fluently.
11. Willing to undergo repeated MRIs (3Tesla) and at least two PET scans
12. Agrees to collection of blood for genomic analysis (including GWAS (genome-wide association study) sequencing and other analysis), APOE (Apolipoprotein E) testing and biospecimen banking.
13. Agrees to collection of blood for biomarker testing.
14. Agrees to at least one lumbar puncture for the collection of CSF.
15. Agrees to share genomic data and biomarker samples. Inclusion Criteria Specific to Rollover Participants"

The following additional inclusion criteria apply to all diagnostic categories for rollover participants only:

1. Must have been enrolled and followed in ADNI-1, ADNI-GO, or ADNI-2 for at least one year.
2. 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.

Exclusion Criteria (all CN participants):

1. 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 deficits or known structural brain abnormalities

Exclusion Criteria (all MCI participants):

1. 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 deficits or known structural brain abnormalities.

Exclusion Criteria (all AD participants):

1. 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 deficits or known structural brain abnormalities.

Exclusion Criteria (all participants):

The following additional exclusion criteria apply to all diagnostic categories:

1. Screening/Baseline MRI brain scan with evidence of infection, infarction, or other focal lesions or multiple lacunes or lacunes in a critical memory structure
2. Subjects that have any contraindications for MRI studies, including the presence of cardiac pacemakers, or metal fragments or foreign objects in the eyes, skin or body.
3. 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 that could lead to difficulty complying with the protocol.
4. Currently treated with medication for obsessive-compulsive disorder or attention deficit disorder.
5. History of schizophrenia (DSM IV criteria).
6. History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).
7. Any significant systemic illness or unstable medical condition, which could lead to difficulty complying with the protocol.
8. Clinically significant abnormalities in B12 or thyroid function tests (TFTs) that might interfere with the study. A low B12 is exclusionary, unless follow-up labs (homocysteine (HC) and methylmalonic acid (MMA)) indicate that it is not physiologically significant.
9. Residence in a skilled nursing facility.
10. Current use of specific psychoactive medications (e.g., certain antidepressants, neuroleptics, chronic anxiolytics or sedative hypnotics). Current use of warfarin or other anticoagulants such as dabigatran, rivaroxaban and apixaban (exclusionary for lumbar puncture).
11. Current use of any other exclusionary medications
12. Investigational agents are prohibited one month prior to entry and for the duration of the trial.
13. Participation in clinical studies involving neuropsychological measures being collected more than one time per year.

Exclusion Criteria Specific to AV-1451 PET:

The following criteria are exclusionary only for the AV-1451 scanning portion of the study:

1. History of risk factors for torsades de pointes (a cardiac dysrhythmia associated with sudden death) or taking medications known to prolong the QT interval. A list of restricted medications will be provided.
2. Have an ECG obtained prior to the AV-1451 PET scan that in the opinion of the investigator is clinically significant with regard to the subject's participation in the study. Bazett's corrected QT (QTcB) interval must be evaluated and must not exceed 458 msec in males, or 474 msec in females.

Primary outcomes:
measure: Rate of change in cognition as measured by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog13)
timeFrame: 5 years
measure: Rate of change in cognition as measured by the Logical Memory Test I and II
timeFrame: 5 years
measure: Rate of change in cognition as measured by the Mini-Mental State Examinations (MMSE)
timeFrame: 5 years
Secondary outcomes:
measure: Rate of change in cognition as measured by the Cogstate Brief Battery (CBB)
timeFrame: 5 years
measure: Rate of change in cognition as measured by the American National Adult Reading Test (ANART)
timeFrame: 5 years
measure: Rate of change in cognition as measured by the Montreal Cognitive Assessment (MoCA)
timeFrame: 5 years
measure: Rate of change in cognition as measured by the Rey Auditory Verbal Learning Test
timeFrame: 5 years
measure: Rate of change in cognition as measured by the Trail Making Test: A and B
timeFrame: 5 years
measure: Change in tau deposition as measured by 18F-AV-1451
timeFrame: 5 years
measure: Change in amyloid deposition as measured by Florbetapir
timeFrame: 5 years
measure: Change in amyloid deposition as measured by Florbetaben
timeFrame: 5 years
measure: Rate of conversion to MCI or dementia due to AD
timeFrame: 5 years
measure: Rates of change of glucose metabolism (FDG-PET)
timeFrame: 5 years
measure: Change in Cerebral Spinal Fluid (CSF) Tau Biomarkers
timeFrame: 5 years
measure: Change in brain structure using magnetic resonance imaging (MRI)
timeFrame: 5 years
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: Phoenix
country: United States
facility: Barrow Neurological 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: Long Beach
country: United States
facility: Long Beach VA Neuropsychiatric Research Program
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: Palo Alto
country: United States
facility: VA Palo Alto HSC / Stanford School of Medicine
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Walnut Creek
country: United States
facility: University of California, Davis
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: University of South Florida - Health Byrd Alzheimer 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: Fairway
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, Ann Arbor
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic, Rochester
state: Minnesota
city: Saint 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: Albany
country: United States
facility: Albany Medical College
state: New York
city: Buffalo
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: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Orangeburg
country: United States
facility: Nathan Kline Institute for Psychiatric Research
state: New York
city: Rochester
country: United States
facility: University of Rochester
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 & 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: Charleston
country: United States
facility: Ralph H. Johnson VA Health Care System
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas, Southwestern MC at Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Houston Methodist
state: Texas
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Vancouver
country: Canada
facility: University of British Columbia, Clinic for AD & Related
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: Jewish General Hospital Memory Clinic
state: Quebec
Study officials:
affiliation: University of California, San Francisco
name: Michael W. Weiner, MD
role: STUDY_DIRECTOR
affiliation: USC Alzheimer's Therapeutic Research Institute (ATRI)
name: Paul Aisen, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mayo Clinic
name: Ronald Peterson, MD, PHD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: Bullich S, Roe-Vellve N, Marquie M, Landau SM, Barthel H, Villemagne VL, Sanabria A, Tartari JP, Sotolongo-Grau O, Dore V, Koglin N, Muller A, Perrotin A, Jovalekic A, De Santi S, Tarraga L, Stephens AW, Rowe CC, Sabri O, Seibyl JP, Boada M. Early detection of amyloid load using 18F-florbetaben PET. Alzheimers Res Ther. 2021 Mar 27;13(1):67. doi: 10.1186/s13195-021-00807-6.