Imaging brain amyloid in Alzheimer’s disease with Pittsburgh Compound-B
Klunk WE, Engler H, Nordberg A, Wang Y, Blomqvist G, Holt DP, Bergström M, et al.;
Commented by , 24 Mar 2004
Aim of the study
Proof-of-concept study to test the validity of Pittsburgh Compound-B (PIB) as an amyloid-imaging positron emission tomography (PET) tracer in patients with mild Alzheimer’s disease (AD) compared to controls.
Methods
Sixteen patients with mild AD, age ranging from 51 to 81 and Mini Mental State Examination scores ranging from 18 to 29, were compared to nine controls, three young and six older volunteers age 21 and 59 to 77 respectively.
In vitro studies had shown that PIB binds to aggregated fibrillar Abeta deposits, and preclinical studies in mice have shown that this compound enters the brain rapidly after intravenous injection and is cleared rapidly. PIB was given intravenously and PET scanning was performed over one hour.
In addition regional glucose metabolic rate was measured using conventional 18F-fluorodeoxyglucose PET scanning 120 minutes after the injection of PIB. Statistical comparisons utilized a two-sample, unequal variance, two-tailed Student’s t test.
A Bonferonni correction was applied because of multiple comparisons in eight brain areas. Linear regression analyses were conducted to yield the Pearson product moment correlation coefficient, r.
Results
Compared to controls, patients with mild AD showed marked retention of PIB in areas of association cortex known to contain large amounts of amyloid deposits in AD. PIB retention was most prominent in frontal cortex (1.94 fold; p=0.0001), then parietal cortex (1.71 fold; p=0.0002), temporal (1.52 fold; p=0.002) and occipital (1.54 fold; p=0.002).
The striatum also showed retention (1.76 fold; p=0.0001) in AD patients. The PIB retention correlated inversely with cerebral glucose metabolism, particularly in the parietal cortex (r = -0.72; p=0.0001).
There was no correlation between PIB retention and duration of illness, gender, treatment with a cholinesterase inhibitor, or ApoE genotype.
Discussion
This study opens the possibility of in vivo imaging of amyloid in patients with AD which could be used for early and possibly preclinical diagnosis. Furthermore it offers the possibility of a surrogate outcome in randomized clinical trials with disease-modification drugs that act though modification of amyloid metabolism.
Despite the small number of controls and patients in this study, a number of interesting observations were made and need to be followed up by larger validation studies: the oldest control showed PIB retention similar to AD patients, suggesting an asymptomatic amyloid-positive case, whereas three patients with mild AD had cortical PIB retention and regional glucose metabolism similar to controls, raising doubt about the clinical diagnosis of probable AD.
The specificity of these observations will need to be assessed in non-AD dementias, where amyloid deposition is not a prominent pathological feature.
This important breakthrough in the imaging of brain beta-amyloidosis will be further described and compared to other imaging modalities during the 9th International Research Conference on Alzheimer’s Disease and Related Disorders, July 18th-22nd, Philadelphia, PA, USA.