Clinical trial NCT00900770: Implications of Amyloid Pathology
Official title: Implications of Amyloid Deposition in Clinically Normal Older Individuals
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Alzheimer's Disease
Keywords: dementia
mild cognitive impairment
beta amyloid
Lead sponsor: National Institute on Aging (NIA)
Sponsor class: NIH
First posted: 2009-05-13
Enrollment: 100
Sex: ALL
Minimum age (years): 60
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Longitudinal cohort of the Massachusetts Alzheimer's Disease Research Center and community volunteers

Brief summary: The purpose of this study is to determine whether asymptomatic older individuals with high amyloid burden will subsequently manifest cognitive impairment and eventually progress to clinical Alzheimer's Disease (AD).

Detailed description: There is compelling evidence supporting amyloid as one of the key pathologic agents in AD. Autopsy studies suggest the amount and location of fibrillar amyloid deposition does not relate strongly to the degree and type of clinical impairment, compared to tau pathology and neuronal loss. A substantial percentage of individuals known to be cognitively intact prior to death demonstrate significant amyloid pathology at autopsy. PIB-PET studies of older normal individuals have also demonstrated significant amyloid deposition in substantial percentages.

This study will test the hypothesis that amyloid is associated with synaptic dysfunction and neuronal damage. While some individuals are able to compensate for amyloid-related toxicity for an extended time period, sensitive imaging and neuropsychological markers will reveal that normal subjects with evidence of high amyloid burden do demonstrate evidence of abnormality consistent with prodromal AD.

The study will use a combination of functional, structural, and cognitive measures to detect early effects of amyloid deposition, and will utilize PIB retention in order to characterize the relationship of amyloid to neuropsychological and imaging markers of prodromal AD. The relationship of PIB retention to genetic, plasma and cerebrospinal fluid (CSF) biomarkers will be explored. These preliminary data will be used to determine whether asymptomatic older individuals with high amyloid burden will subsequently manifest cognitive impairment and eventually progress to clinical AD. When completed, this project will either provide evidence that the presence of amyloid deposition is a useful biomarker for incipient AD or raise the possibility that amyloid deposition examined in isolation is insufficient to predict early symptoms and progression of AD.

Eligibility criteria: Inclusion Criteria:

* Age range from 60 to 90 years
* Clinical Dementia Rating (CDR) Score of 0
* Mini Mental State Exam of 27-30
* A study partner who can answer questions pertaining to daily functioning
* Perform within 1.5 standard deviation of age and education matched norms on screening tests of attention and executive function, language, visuospatial perception and episodic memory
* Stable medications for at least 30 days
* Fluent in English
* Modified Hachinski Score of \<4
* Geriatric Depression Scale Score \<10

Exclusion Criteria:

* Diagnosis of MCI or dementia
* Individuals with contraindications to MRI (i.e., implanted metal including pacemakers, cerebral spinal fluid shunts, aneurysm clips, artificial heart valves, ear implants or metal/foreign objects in the eyes and those with a history of claustrophobia)
* Unstable medications or on medications with CNS effects including cholinesterase inhibitors, memantine, and antidepressants
* Major psychiatric disorders such as schizophrenia, schizoaffective disorder, major affective disorder, or treatment with ECT (mild depression that is well treated with stable dose of SSRI antidepressants will be allowed)
* Multiple sclerosis or other autoimmune disorders
* Huntington's disease
* Head injury, post-traumatic dementia or seizures
* Metabolic encephalopathy, CNS infection, hydrocephalus
* Cardiovascular disease, stroke, congestive heart failure
* Substance abuse within the past 2 years
* Active cancer
* Active hematological, renal, pulmonary, endocrine or hepatic disorders

Primary outcomes:
measure: Pittsburgh Compound B (PiB) and F-18 fluorodeoxyglucose (FDG) PET Scan
timeFrame: at 1 month
Secondary outcomes:
measure: Cognitive and functional assessments
timeFrame: Baseline and annually for 5 years
measure: Lumbar Puncture (optional)
timeFrame: Baseline
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Director of Clinical Research, Memory Disorders Unit, Brigham and Women's Hospital
name: Reisa Sperling, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Dickerson BC, Bakkour A, Salat DH, Feczko E, Pacheco J, Greve DN, Grodstein F, Wright CI, Blacker D, Rosas HD, Sperling RA, Atri A, Growdon JH, Hyman BT, Morris JC, Fischl B, Buckner RL. The cortical signature of Alzheimer's disease: regionally specific cortical thinning relates to symptom severity in very mild to mild AD dementia and is detectable in asymptomatic amyloid-positive individuals. Cereb Cortex. 2009 Mar;19(3):497-510. doi: 10.1093/cercor/bhn113. Epub 2008 Jul 16.
citation: Aizenstein HJ, Nebes RD, Saxton JA, Price JC, Mathis CA, Tsopelas ND, Ziolko SK, James JA, Snitz BE, Houck PR, Bi W, Cohen AD, Lopresti BJ, DeKosky ST, Halligan EM, Klunk WE. Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch Neurol. 2008 Nov;65(11):1509-17. doi: 10.1001/archneur.65.11.1509.
citation: Jack CR Jr, Lowe VJ, Senjem ML, Weigand SD, Kemp BJ, Shiung MM, Knopman DS, Boeve BF, Klunk WE, Mathis CA, Petersen RC. 11C PiB and structural MRI provide complementary information in imaging of Alzheimer's disease and amnestic mild cognitive impairment. Brain. 2008 Mar;131(Pt 3):665-80. doi: 10.1093/brain/awm336. Epub 2008 Feb 7.
citation: Mintun MA, Larossa GN, Sheline YI, Dence CS, Lee SY, Mach RH, Klunk WE, Mathis CA, DeKosky ST, Morris JC. [11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease. Neurology. 2006 Aug 8;67(3):446-52. doi: 10.1212/01.wnl.0000228230.26044.a4.