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 d...

Distinct clinical and metabolic deficits in PCA and AD are not related to amyloid distribution

“…25 Given the differential atrophy patterns seen in AD and PCA, 26 we corrected PET data for atrophy by applying a 2-compartmental partial volume correction 27 to all subjects with an MRI (10/12 PCA, 12/14 AD, and all NC) (see appendix e-1). 15,27 Since the benefit of partial volume correction for PiB data are controversial, all primary analyses were performed using uncorrected PET data, while confirmatory analyses were conducted with atrophy-corrected data in the subset of patients with an MRI.…”

“…Based on the preponderance of postmortem data and previously demonstrated dissociations between PiB binding and clinical features of AD, 14,15 we hypothesized that patients with PCA would show diffuse cortical PiB binding in a pattern indistinguishable from clinically "typical" AD, but greater glucose hypometabolism than patients with AD in occipital cortex, correlating with their selective impairment in visual processing.…”

Early-onset and late-onset Alzheimer's disease are associated with distinct patterns of memory impairment

“…The subgroups of AD patients were classified based on a determined cut-off of 65 years of age at onset, based on previous studies comparing features of EOAD and LOAD patients (Kemp et al, 2003;Kim et al, 2005;Shiino et al, 2006;Frisoni et al, 2007;Rabinovici et al, 2010;Canu et al, 2012;Sa et al, 2012;Smits et al, 2012;Cho et al, 2013), as well as on clinical grounds (Amaducci et al, 1986). This cut-off is also used in the DSM-IV TR nomenclature to specify subtypes (American Psychiatric Association, 2000).…”

Imaging Approaches for Dementia

“…26 Brain areas showing increased PIB uptake do not completely overlap typical sites of neurodegeneration; PIB binding does not increase with time 27 ; not all patients with positive PIB PET develop AD; and the mechanism by which ␤ amyloid leads to neurofibrillary tangle formation, synaptic loss, and cell death, characteristic of pathology is still not clear. 28 In addition, in a comparison of early-onset (younger than 65 years) and late-onset (older than 65 years) AD, there was no difference in the extent or severity of PIB uptake, but metabolic defects on FDG-PET were, as expected, greater in the early-onset group.…”

“…28 In addition, in a comparison of early-onset (younger than 65 years) and late-onset (older than 65 years) AD, there was no difference in the extent or severity of PIB uptake, but metabolic defects on FDG-PET were, as expected, greater in the early-onset group. 26 Positive PIB PET correlates with CSF amyloid ␤ 42 , but there is poor correlation of PIB PET with hippocampal volume. 29 While both (neurofibrillary tangles) and amyloid (plaques) have been regarded as hallmarks of AD, it is evident that these act on the brain, and, therefore, influence brain imaging at REVIEW ARTICLE different phases of disease evolution.…”