Measuring amyloid-beta (Abeta) protein levels in cerebrospinal fluid (CSF) and using positron emission tomography (PET) to image amyloid in the brain might become the best diagnostic test for presymptomatic Alzheimer disease (AD), according to a study published online in December 2005 and appearing in the March issue of Annals of Neurology.Colleagues from the Washington University School of Medicine (WUSM) and the University of Pittsburgh recruited 24 patients from the Alzheimer Disease Research Center at WUSM. Eighteen patients were diagnosed as cognitively normal, 3 as very mildly demented, 2 as mildly demented, and 1 as moderately demented. Participants underwent PET using the radiotracer Pittsburgh compound B (PIB), which binds to brain amyloid plaques. Patients also underwent lumbar puncture for samples of CSF.Patients fell into 2 nonoverlapping groups. Seven study participants with positive PIB binding (ie, high levels of amyloid plaque) had the lowest levels of CSF Abeta42, and 17 subjects with negative PIB binding had the highest levels of CSF Abeta42. Interestingly, the diagnosis of cognitively normal was made for 3 of the 7 positive PIB scans. It was hypothesized that the respective patients had preclinical AD, said lead author Anne M. Fagan, PhD, research associate professor of neurology at WUSM. These patients will be observed over time to see whether dementia develops."If they do develop AD, it would mean that we have a way to screen individuals for the presence of AD pathology before the appearance of clinical symptoms," said Fagan.Already, PIB-PET results have determined that 1 patient whose impairment had been associated with AD had frontotemporal dementia instead. Another patient's impairment was traced to possible abuse of sleeping pills.In patient workups, clinicians increasingly have to decide whether memory impairment is caused by normal aging or dementia, and whether dementia is AD. This study demonstrates a sequential process to make these determinations, said William E. Klunk, MD, PhD, associate professor of psychiatry at the University of Pittsburgh and the codeveloper of PIB. A suspicious clinical evaluation would lead to a spinal tap.Low CSF Abeta42 levels would lead to a PIB-PET scan for confirmation of AD. Performing the tap in the middle of the process could increase the yield and justify the use of amyloid imaging, when it's available, for routine clinical use or even for identifying a homogeneous research population, Klunk said."What we're shooting for in Alzheimer's disease isn't a better way of diagnosing a moderately demented AD patient. We can do that just fine," he said. "But waiting till patients are moderately demented hampers our efforts to develop new therapies. We need to be running trials in people who are diagnosed at the very first sniff of the disease."The current citation for the study is Fagan AM, Mintun MA, Mach RH, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta(42) in humans. Ann Neurol. 2006;59:512-519.A version of this article appeared in the March 2006 issue of Diagnostic Imaging. It has been revised for Applied Neurology.C. P. KAISER is a news editor for the journal Diagnostic Imaging. He is based in Philadelphia.