Biodistribution of 11C-PIB PET in Alzheimer's Disease, Frontotemporal Dementia, and Cognitively Normal Elderly

Biomarkers of Alzheimer's disease (AD) have recently become extremely important for a number
of reasons: to improve diagnosis, to measure severity of disease, to measure progression of
disease, to measure effects of novel disease-modifying drugs and to speed development of
these novel experimental drugs by reducing time needed to follow patients, number of
patients to be followed per study, and cost of research. (Thal, 2006, Nichols, 2006)

The neuropathology of AD is characterized by neuritic plaques, neurofibrillary tangles, and
neuronal cell loss. (Braak and Braak 1997) Amyloid plaques are believed to play an integral
role in AD. (Selkoe, 1993) Plaques are neurotoxic. (Yankner, 1989) Elevated levels of Aβ in
the brain are correlated with cognitive decline. (Naslund, 2000) Removal of plaques in
animal models of AD results in behavioral improvements. (Arendash, 2001)

There are no approved in vivo markers of amyloid load in humans. Several compounds with
affinity for binding amyloid in vivo are under investigation. All of these compounds use
radioactive chemical tags for PET imaging. Attempts at finding non-radioactive amyloid
tracers are underway, but still poorly developed. The most promising compound is 11C-PIB.
Pittsburgh Compound-B has statistically significant increased retention in AD cortical
areas, relative to controls (P<0.05). (Price, 2005) To our knowledge, 11C-PIB imaging has
not been compared against FTD controls.

We will recruit (from our clinic population), a total of 30 subjects, 10 from each of the
following 3 diagnostic categories: frontal temporal dementia, Alzheimer's disease, normal
volunteers. All subjects will be given an FDG-PET scan (if they haven't had one in the
past) and a PIB-PET scan.

Objective and Hypothesis:

The overall objective of this project is to study the biodistribution of 11C-PIB using PET
imaging in normal elderly volunteers and relevant patient groups. Comparison with FDG-PET
is essential to confirm group membership and for anatomic co-registration of 11C-PIB images.

Specific Aim 1: Determine the biodistribution of 11C-PIB in AD, FTD, and cognitively normal
elderly individuals and determine whether it reflects the distribution of amyloid plaques in
the brain expected from postmortem studies.

Hypothesis 1: The agent 11C-PIB has similar biodistribution outside the brain in AD, FTD,
and cognitively normal elderly individuals.

Hypothesis 2: Patients with AD scanned with 11C-PIB will have higher standardized uptake
values (SUVs) than cognitively normal elderly in brain regions where beta amyloid are
expected to be over-expressed.

Hypothesis 3: Patients with FTD scanned with 11C-PIB will have similar standardized uptake
values (SUVs) as cognitively normal elderly subjects and lower values than in AD subjects in
brain regions where beta amyloid are expected in AD to be overexpressed.

Specific Aim 2: Correlate glucose metabolism with 11C-PIB PET results.

Hypothesis 4: Patients with a pattern of glucose hypometabolism suggestive of FTD with
FDG-PET have 11C-PIB uptake and brain biodistribution similar to cognitively normal elderly,
while those with a pattern of glucose hypometabolism suggestive of AD have abnormal PIB
uptake and brain biodistribution of 11C-PIB