23 March 2007. Researchers have published the first postmortem confirmation of amyloid pathology corresponding to a positive PET scan using the amyloid tracer Pittsburg Compound B (PIB). In the March issue of Archives of Neurology, Brian Bacskai and colleagues from the Massachusetts General Hospital in Charlestown report on the autopsy of a 76-year-old man who died 3 months after PET-PIB imaging. Regional PIB binding detected in living tissue correlated with biochemical measures of Aβ after death. Interestingly, the patient, whose clinical diagnosis of dementia with Lewy bodies was confirmed by the exam, had only moderate levels of amyloid plaques, but severe cerebral amyloid angiopathy (CAA). The results suggest that in vivo PIB binding accurately reports the presence of amyloid, but may not differentiate between deposits in blood vessels or in brain parenchyma.
PET scanning with the amyloid binding dye PIB shows great promise as a biomarker to both diagnose AD and to monitor the effects of Aβ-reducing therapies (see ARF related news story). Despite extensive indirect experimental evidence, the tracer had never been directly proven to label amyloid-β in living brain. The new results provide an important confirmation of the presence of Aβ in this patient, but highlight the potential for error if positive PIB signals are presumed to indicate either current or impending AD. Despite a high level of PIB binding, the autopsy findings only support a classification of possible AD, by the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) criteria.
“Our report substantiates the view that PiB uptake is a sensitive method to detect Aβ in the brain, but points out the fact that clinical conditions other than probable or definite AD may harbor PiB-detectable amyloid deposits—thus broadening the range of clinically defined syndromes in which a PiB scan may be positive,” the authors write. It may be best, they say, “not to equate amyloid deposition to clinical diagnosis from the outset but to think of PiB retention more fundamentally as a method to detect and quantify brain β-amyloidosis.” In this regard, the technique will serve as a diagnostic aid, but will be of “great value” in evaluating therapies aimed at reducing Aβ, they conclude.
Because a large proportion of the PIB signal in this patient appears to originate from CAA, it will be important to study additional patients to determine if this is a common result, or an unusual state.
“This article provides strong validation that PiB retention is very likely reflective of Aβ that is deposited as amyloid,” writes David Holtzman of Washington University in St. Louis, Missouri, in an accompanying commentary.
However, Holtzman writes, “Because the pattern of cortical PiB retention in this individual was very similar to that described in other cases of AD, these findings suggest that PiB imaging with current PET scanning technology cannot definitively distinguish whether amyloid deposition is present in blood vessels (as CAA), brain parenchyma (as amyloid plaques) or both.” Further studies will be necessary to determine the predictive power of PIB binding, both in PIB-positive bona fide AD patients and in PIB-negative controls.—Pat McCaffrey.
Bacskai BJ, Frosch MP, Freeman SH, Raymond SB, Augustinack JC, Johnson KA, Irizarry MC, Klunk WE, Mathis CA, Dekosky ST, Greenberg SM, Hyman BT, Growdon JH. Molecular imaging with Pittsburgh compound B confirmed at autopsy: a case report. Arch Neurol. 2007 Mar;64(3):431-4. Abstract
Holtzman DM. Pittsburgh compound B retention and verification of amyloid deposition.
Arch Neurol. 2007 Mar;64(3):315-6. Abstract