Molecular Imaging in Alzheimer’s Disease 11C-PIB.16,17
These results demonstrate the robustness and clinical applicability of the method. The cerebellar cortex, which may exhibit diffuse but not fibrillary amyloid in AD, is generally used as a reference region without specific PIB binding.
Most normal control subjects exhibit very low cortical binding of PIB, with less than 1.5-fold PIB uptake relative to the cerebellar cortex. In addition, unspecific binding is observed mainly in white matter. A proportion of normal elderly controls show higher cortical PIB binding, typically resulting in a bimodal distribution of PIB uptake in samples of control subjects. Current studies indicate that the frequency of increased cortical PIB binding in controls increases rapidly from 10% or less below 70 years of age to 30–40% at 80 years of age, largely reflecting similar findings in previous autopsy studies.18
The clinical
implications of Aβ deposition in elderly controls are not yet clear. Some elderly controls have indicators of the start of neurodegeneration19,20 will develop cognitive deficits,21
or but cerebral function in others may be
resistant to Aβ deposition. Long-term follow-up studies are currently under way to clarify this issue.
Findings in patients with mild cognitive impairment (MCI) are heterogeneous. In most studies approximately two-thirds of patients showed increased binding, such as AD patients, while the rest were within normal limits. Published results from follow-up studies indicate that patients with increased binding are at high risk for progressing to AD with manifest dementia,22,23
scans very rarely develop dementia.24 more PIB binding than non-amnestic MCI.25
Figure 1: Amyloid PET and MRI Brain Scans of Normal, Dementia, and Alzheimer’s Disease Patients
Normal control
Fronto-temporal dementia
Alzheimer’s disease
while MCI patients with negative PIB Patients with amnestic MCI show Aβ deposition is high in
posterior association areas, where it correlates with a decline in glucose metabolism. However, it is also high in the frontal association cortex where that correlation is absent.26
The amount of Aβ deposition and PIB binding is highly variable in AD. Despite this, PIB imaging is very sensitive for detection of AD. It is likely that a significant proportion of the PIB-negative AD patients in clinical series (up to 10%) will be due to clinical misdiagnoses. Only under exceptional circumstances has PIB-negativity been confirmed in AD.27
Besides APOE e4, additional genetic factors that have not yet been identified appear to play a role.28
in AD have indicated that there is little further increase in tracer uptake during progression of the disease.29
Initital follow-up studies with 11C-PIB Howerver, recent preliminary
results from large multicenter studies (ADNI and AIBL) do indicate further increase. A decrease in PIB binding has been observed in patients undergoing clinical trials of drugs that remove Aβ from the brain,30
but it has not yet been demonstrated that this would be associated with clinical benefit.
Differential Diagnosis using Amyloid Imaging Amyloid imaging is expected to provide excellent differentiation of AD from frontotemporal dementia, which is not associated with Aβ deposition and increased 11C-PIB binding (see Figure 1).31
Dementia with
Lewy bodies (DLB) often also shows fibrillary Aβ deposition in pathological studies and correspondingly positive PIB scans are reported in most patients.32,33
US NEUROLOGY Moderately increased PIB binding, predominantly in
Amyloid positron emission tomography scans using florbetapir (with coregistered magnetic resonance imaging scans), demonstrating low normal cortical uptake in an aged normal control and a patient with fronto-temporal dementia in contrast to high cortical uptake in Alzheimer’s disease.
occipital regions and on average less than in AD, has also been observed in non-demented patients with cerebral Aβ angiopathy.34
Tracers in Clinical Trials
There are currently three 18F-labeled tracers being studied in clinical trials that have been developed as proprietary tracers for commercial distribution. These are flutemetamol (GE-067, 3’-fluoro-PIB), florbetaben (BAY-94-9172, AV-1), and florbetapir (AV-45). They show high-affinity binding for fibrillary Aβ with Ki <10nM, similar to 11C-PIB, while non-specific binding in white matter is higher than with 11C-PIB. Ongoing research is aiming to develop tracers that show a lower level of non-specific binding.35,36
Flutemetamol, florbetaben, and florbetapir appear to have largely similar imaging properties, although the optimum scanning time after intravenous injection varies. Results from clinical trials indicate that they will likely provide high diagnostic power for discrimination between AD patients and controls.37,38
They also demonstrate a close correlation
between the cortical binding of 11C-PIB and 18F-fluoro-PIB in cortical regions.39
Preliminary results demonstrate a close correspondence of 29
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