Alzheimer-Like Pattern of Hypometabolism Emerges with Elevated Amyloid-β Burden in Down Syndrome

Abstract

Background The Down syndrome (DS) population is genetically predisposed to amyloid-β protein precursor overproduction and Alzheimer’s disease (AD). Objective The temporal ordering and spatial association between amyloid-β, glucose metabolism, and gray matter (GM) volume in the DS population can provide insight into those associations in the more common sporadic AD. Methods Twenty-four adults (13 male, 11 female; 39 ± 7 years) with DS underwent [11C]PiB, [18F]FDG, and volumetric MRI scans. Voxel-wise associations between PiB SUVR, FDG SUVR, and GM volume were investigated, with and without individual adjustments for variables of interest. Results Positive associations of PiB and age were widespread throughout the neocortex and striatum. Negative associations of FDG and age (frontal, parietal, and temporal cortex) and of GM volume and age (frontal and insular cortex) were observed. PiB and FDG were negatively associated in parietal cortex, after adjustment for GM volume. Conclusions In adults with DS, early amyloid-β accumulation in the striatum is divergent from sporadic AD; however, despite the early striatal amyloid-β, glucose hypometabolism was confined to the typical AD-associated regions, which occurs similarly in autosomal dominant AD. Importantly, the glucose hypometabolism was not explained solely by increased partial volume effect due to GM volume reductions.

Neuropathological correlates of amyloid PET imaging in Down syndrome

“…Interestingly, the DS/no dementia/PiB positive group had [C‐11]PiB retention levels exceeding threshold cutoffs in anterior cingulate, frontal cortex, and striatum, and levels at threshold cutoffs in the precuneus cortex, lateral parietal cortex, and temporal cortex. In contrast, the DS/dementia/PiB positive group had [C‐11]PiB PET levels higher than cutoff values in all regions examined despite similar mean age when compared to the DS/no dementia/PiB positive group (Lao et al, ). Another [C‐11]PiB PET study of DS/no dementia/PiB negative ( n = 41, mean age 35 years) and DS/no dementia/PiB positive ( n = 22, mean age 44 years) found that PET amyloid status did not influence between‐person differences in cognition independent of age (Hartley et al, ).…”

“…However, as discussed earlier, patterns of amyloid PET ligand retention likely do not fully recapitulate patterns described in neuropathology studies at least at initial stages of amyloid deposition in DS. In a smaller study including DS/no dementia/PiB negative ( n = 16, mean age 35 years), DS/no dementia/PiB positive ( n = 5, mean age 47 years), and DS/dementia/PiB positive subjects ( n = 3, mean age 49 years) the same group reported correlations of SUVR with age (all participants combined) in multiple neocortical areas and striatum (Lao et al, ). Correlations between [18‐F]Florbetapir PET amyloid and age were reported in a small study including DS/no dementia ( n = 10, mean age 36 years) and DS/dementia ( n = 5, mean age 50 years) subjects (Sabbagh et al, ).…”

“…A non‐linear correlation of [C‐11]PiB binding potential and age was also seen in a study of DS/PiB positive ( n = 20, mean age 50 years) and DS/PiB negative subjects (29, mean age 36 years), with a sharp increase in binding potential observed at approximately 45–50 years of age (Annus et al, ). Though beyond the scope of the current review, several DS studies report correlations of age with brain volume reductions (neurodegeneration), fluorodeoxyglucose PET (metabolism), and a PET ligand for neurofibrillary tangles (Annus et al, ; Lao et al, ; Matthews et al, ; Rafii et al, ; Sabbagh et al, ). The correlation between amyloid accumulation and age in DS underscores the need to control for chronological age in studies attempting to discriminate amyloid patterns in DS/dementia from DS/no dementia, addressed in the following section.…”

“…Sabbagh and colleagues reported greater mean cortical and striatal [F‐18]Florbetapir retention in DS/dementia ( n = 5, mean age 50 years) compared to DS/no dementia subjects ( n = 10, mean age 36 years) after adjusting for age, with both groups having higher retention values than controls (Sabbagh et al, ). Lao et al () reported [C‐11]PiB values above threshold levels in both DS/dementia ( n = 3, mean age 49 years, all PiB positive) and DS/no dementia subjects (16 PiB negative, mean age 35 years; 5 PiB+, mean age 47 years). Interestingly, the DS/no dementia/PiB positive group had [C‐11]PiB retention levels exceeding threshold cutoffs in anterior cingulate, frontal cortex, and striatum, and levels at threshold cutoffs in the precuneus cortex, lateral parietal cortex, and temporal cortex.…”

“…Understanding structural properties, biochemical constituents, and evolution of morphologically diverse Aβ plaques and other AD‐related pathology within and between brain regions in relation to age and development of dementia is needed to guide interpretation of amyloid PET imaging of subjects with DS (Head, Helman, Powell, & Schmitt, ; Neale, Padilla, Fonseca, Holland, & Zaman, ). Compared to the extensive number of amyloid PET studies performed in AD (Cohen et al, ), there are relatively few amyloid PET studies of DS (Annus et al, , ; Cohen et al, ; Cole et al, ; Handen et al, ; Hartley et al, ; Jennings et al, ; Landt et al, ; Lao et al, , ; Mak et al, ; Matthews et al, ; Rafii et al, ; Sabbagh et al, ), even fewer longitudinal studies (Hartley et al, ; Lao et al, ; Tudorascu et al, ), and only one imaging‐to‐autopsy analysis (Sabbagh et al, ). Building upon the understanding that AD and DS brains/pathology are not the same, the purpose of this article is to summarize amyloid PET imaging studies of people with DS in the context of neuropathology defined at autopsy, to guide interpretation of future investigations in larger numbers of subjects with DS over longer periods of time.…”