Increased metabolic vulnerability in early-onset Alzheimer's disease is not related to amyloid burden

Abstract

Patients with early age-of-onset Alzheimer's disease show more rapid progression, more generalized cognitive deficits and greater cortical atrophy and hypometabolism compared to late-onset patients at a similar disease stage. The biological mechanisms that underlie these differences are not well understood. The purpose of this study was to examine in vivo whether metabolic differences between early-onset and late-onset Alzheimer's disease are associated with differences in the distribution and burden of fibrillar amyloid-beta. Patients meeting criteria for probable Alzheimer's disease (National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's; Disease and Related Disorders Association criteria) were divided based on estimated age at first symptom (less than or greater than 65 years) into early-onset (n = 21, mean age-at-onset 55.2 +/- 5.9 years) and late-onset (n = 18, 72.0 +/- 4.7 years) groups matched for disease duration and severity. Patients underwent positron emission tomography with the amyloid-beta-ligand [(11)C]-labelled Pittsburgh compound-B and the glucose analogue [(18)F]-labelled fluorodeoxyglucose. A group of cognitively normal controls (n = 30, mean age 73.7 +/- 6.4) was studied for comparison. [(11)C]-labelled Pittsburgh compound-B images were analysed using Logan graphical analysis (cerebellar reference) and [(18)F]-labelled fluorodeoxyglucose images were normalized to mean activity in the pons. Group differences in tracer uptake were assessed on a voxel-wise basis using statistical parametric mapping, and by comparing mean values in regions of interest. To account for brain atrophy, analyses were repeated after applying partial volume correction to positron emission tomography data. Compared to normal controls, both early-onset and late-onset Alzheimer's disease patient groups showed increased [(11)C]-labelled Pittsburgh compound-B uptake throughout frontal, parietal and lateral temporal cortices and striatum on voxel-wise and region of interest comparisons (P < 0.05). However, there were no significant differences in regional or global [(11)C]-labelled Pittsburgh compound-B binding between early-onset and late-onset patients. In contrast, early-onset patients showed significantly lower glucose metabolism than late-onset patients in precuneus/posterior cingulate, lateral temporo-parietal and occipital corticies (voxel-wise and region of interest comparisons, P < 0.05). Similar results were found for [(11)C]-labelled Pittsburgh compound-B and [(18)F]-labelled fluorodeoxyglucose using atrophy-corrected data. Age-at-onset correlated positively with glucose metabolism in precuneus, lateral parietal and occipital regions of interest (controlling for age, education and Mini Mental State Exam, P < 0.05), while no correlations were found between age-at-onset and [(11)C]-labelled Pittsburgh compound-B binding. In summary, a comparable burden of fibrillar amyloid-beta was associated with greater posterior cortical hypometabolism in early-onset Alzheimer's disease. Our data are consistent with a model in which both early amyloid-beta accumulation and increased vulnerability to amyloid-beta pathology play critical roles in the pathogenesis of Alzheimer's disease in young patients.

Figure 1

Patterns of PIB binding in early-onset (EO) and late-onset (LO) Alzheimer’s disease (AD) compared to normal controls (NC) and to each other. Voxel-wise comparisons included sex, education and MMSE as nuisance variables. T-score maps prior to atrophy correction are rendered on the ch2 template brain (left), while T-score maps following atrophy correction are rendered on the minimal deformation template 2 template (right). All results are presented at a threshold of P < 0.001, uncorrected for multiple comparisons.

Figure 2

Scatter-plots of PIB index (A) and normalized FDG uptake in precuneus (B) by diagnosis, pre- (left) and post-atrophy correction (right). Hatched bars represent mean values for each diagnostic group. DVR = distribution volume ratio. CONT = controls; EO = early-onset; LO = late-onset; AD = Alzheimer's disease.

Figure 3

Patterns of glucose hypometabolism in early-onset (EO) and late-onset (LO) Alzheimer’s disease (AD) compared to normal controls (NC) and to each other. Voxel-wise comparisons included sex, education and MMSE as nuisance variables. T-score maps prior to atrophy correction are rendered on the ch2 template brain (left), while T-score maps following atrophy correction are rendered on the minimal deformation template 2 template (right). All results are presented at a threshold of P < 0.001, uncorrected for multiple comparisons.

Figure 4

Relationships between age-at-onset, PIB and FDG. (A) and (B) demonstrate the unadjusted relationships between age-at-onset (as a continuous variable) and (A) PIB or (B) FDG. Regression lines have been added to best fit the data. (C) Plots PIB (x axis) versus FDG (y axis) in precuneus. Reference lines denoting one standard deviation above normal controls mean for PIB (vertical line), and one standard deviation below the normal controls mean for FDG (horizontal line) have been added to divide the data into quadrants. See text for discussion. DVR = distribution volume ratio; EO = early-onset; LO = late-onset; AD = Alzheimer’s disease; CONT = controls.