One of the big surprises at this year’s Human Amyloid Imaging meeting, held 11 April 2008 in Chicago, was the finding that a significant proportion of healthy controls are PIB-positive. In a study that directly addresses the frequency of amyloid positivity among normal seniors, Mark Mintun and colleagues at Washington University, St. Louis, Missouri, are using PIB-PET imaging to look for high PIB retention in normal elderly and determine whether any pattern predicts dementia down the road. Here is what they have learned thus far. Of the 203 non-demented subjects who have submitted to PIB-PET scanning as part of this longitudinal study, 7.3 percent of people in their fifties had elevated PIB retention, followed by 14.9 percent of sixty-somethings and 30 percent of those in their seventies. Between ages 50 and 80, PIB uptake basically doubled each decade. Curiously, only 28 percent of subjects in the 80- to 90-year-old group had high PIB uptake, but it was suggested during the Q&A that this could reflect a survivor effect among those in the study who have reached their eighties without yet succumbing to dementia. Mintun noted that all subjects have agreed to return for further evaluation, which should help determine PIB’s ability to forecast conversions to dementia. The data thus far, which show particularly high PIB uptake in the precuneus and pregenual anterior cingulate, support the notion that amyloid gums up the brain well before cognitive deficits appear.
In Chicago, Mintun also reported results of a newer study, led by Washington University colleague Alison Goate, which addressed whether amyloid patterns revealed by PIB-PET imaging are a heritable phenotype. In this study of healthy volunteers from more than 25 local “sibships” consisting of 70- to 75-year-olds with at least one other sibling within five years of age, the answer seems to be yes. Nearly a third of the participants had elevated PIB retention, and the heritability estimate was calculated to be 0.72 (heritability of 1 indicates perfect genetic linkage).
Questions about a possible relationship between amyloid buildup and genetic predisposition to AD were at the root of new work presented by Eric Reiman, executive director of the Banner Alzheimer's Institute in Phoenix, Arizona. As apolipoprotein E4 (ApoE4) is a well-known risk factor for AD, this study involved eight cognitively normal ApoE4 homozygotes and six ApoE4 non-carriers in their fifties and sixties who were already enrolled in an ongoing longitudinal study and had agreed to add PIB-PET to their battery of procedures. Fibrillar amyloid burden, as assessed by PIB retention, was found to be higher in the ApoE4 homozygote group as compared with non-carriers in all brain areas tested. The anterior cingulate, temporal cortex, and hippocampus showed the most significant differences. These preliminary findings suggest a means for subject enrichment or stratification in primary prevention trials, and support PIB’s use as a readout in human trials of amyloid-reducing agents, Reiman said.
PIB also showed promise as a predictor of cognitive decline in work presented by Victor Villemagne of the Department of Nuclear Medicine at Austin Hospital, Melbourne, Australia. In an ongoing longitudinal study of 51 subjects, three of eight PIB-positive controls and all four PIB-positive MCI subjects showed cognitive decline (to MCI or AD, respectively) in neuropsychological reassessments done almost two years after the initial PIB-PET scan. Among non-demented study participants, the researchers found a strong correlation between episodic memory and Aβ burden.
At the Turku PET Center in Finland, one of very few countries allowing human brain biopsies, work presented in Chicago by Juha Rinne suggests that PIB-PET data correlates well with Aβ deposits seen in cortical brain biopsy. For this study, researchers looked at 10 patients undergoing intraventricular pressure monitoring with a frontal cortical biopsy for suspected normal pressure hydrocephalus (NPH). NPH is a brain condition, the treatment of which involves surgical placement of a shunt to drain excess CSF from the brain into the abdomen. Some NPH patients have concomitant AD pathology, which has been shown to predict a poor response to shunting. In six patients with Aβ deposits in the frontal cortical biopsy, post-surgery PET scans showed higher PIB uptake in the frontal, parietal, and lateral temporal cortices and in the striatum compared with the four patients without frontal Aβ deposits. Follow-up evaluation is needed to determine whether a higher PIB level is correlated with progressive cognitive decline. In the Q&A, Rinne noted that of the eight NPH patients who were shunted, the only one who didn’t improve was the one who had AD pathology, as well.—Esther Landhuis.
See also Part 1 of this story.