Neuropathological correlates of amyloid PET imaging in Down syndrome

Abstract

Down syndrome (DS) results in an overproduction of amyloid-β (Aβ) peptide associated with early onset of Alzheimer's disease (AD). DS cases have Aβ deposits detectable histologically as young as 12-30 years of age, primarily in the form of diffuse plaques, the type of early amyloid pathology also seen at pre-clinical (i.e., pathological aging) and prodromal stages of sporadic late onset AD. In DS subjects aged >40 years, levels of cortical Aβ deposition are similar to those observed in late onset AD and in addition to diffuse plaques involve cored plaques associated with dystrophic neurites (neuritic plaques), which are of neuropathological diagnostic significance in AD. The purpose of this review is to summarize and discuss findings from amyloid PET imaging studies of DS in reference to postmortem amyloid-based neuropathology. PET neuroimaging applied to subjects with DS has the potential to (a) track the natural progression of brain pathology, including the earliest stages of amyloid accumulation, and (b) determine whether amyloid PET biomarkers predict the onset of dementia. In addition, the question that is still incompletely understood and relevant to both applications is the ability of amyloid PET to detect Aβ deposits in their earliest form.

Keywords: Alzheimer's disease; Down syndrome; amyloid; neuropathology; positron emission tomography; striatum.

Figure 1.

Heat map illustrating the regional progression of amyloid, tau, Lewy bodies, and TDP-43 pathology in subjects with DS aged 0–76 years. From Davidson et al., 2018.

Figure 2.

Pittsburgh compound B (PiB) standardized uptake value ratio (SUVR) images of subjects with DS showing different levels of ligand retention (the axial images are shown at the top and the sagittal images at the bottom). Left: Amyloid-negative 34 year-old DS subject showing only nonspecific PiB retention in white matter; Middle: Moderately amyloid-positive 38 year-old DS subject showing early striatal PiB retention; and Right: Heavily amyloid-positive 44 year-old DS subject which is very similar to those seen in late-onset AD, but with a predominant striatal signal. Adapted from Handen et al., 2012.

Figure 3.

Biochemical analyses of [H-3]PiB binding and concentration of formic acid-extracted (insoluble) 42 amino acid-long amyloid-β peptide (Aβ1–42) in the frontal cortex (BA10) from subjects with normal cognition (NC, age range 78–92 years) and Alzheimer’s disease (AD, age range 76–101 years) from the Rush Religious Order Study brain bank compared to adults with Down syndrome and AD (DS+AD, range 43–63 years) from the University of California Irvine brain bank. (A) [H-3]PiB binding differed between groups (F (2, 41) = 35.76, P < 0.0001; Tukey multiple comparisons, NC < AD, DS; AD < DS). (B) Concentration of insoluble Aβ1–42 differed between groups (F (2, 43) = 34.5, P < 0.0001; Tukey multiple comparisons, NCI < mild AD, mod/sev AD, DS; mild AD, mod/sev AD < DS). (C) Insoluble Aβ1–42 and [H-3]PiB binding correlated across groups by linear regression analysis (Y = 0.09746*X + 7.256, R square = 0.59, P < 0.0001). **0.01 < P<0.05; ***0.0001 < P< 0.001; ****P < 0.0001.

Figure 4.

Representative images of CN-PiB fluorescence in diffuse plaques in the striatum (A) and both diffuse and cored plaques as well as cerebral amyloid angiopathy in the frontal cortex of a 57-year old female with DS and confirmed AD pathology (B) from the University of California Irvine brain bank. Scale bar = 200 μm.

Figure 5.

CN-PiB positive plaque load (expressed as percent area coverage) analyzed separately for diffuse (A) and cored (B) plaques in the frontal cortex from cases with normal cognition (NC, age range 74–93 years) and Alzheimer’s disease (AD, age range 76–100 years) from the Rush Religious Order Study brain bank compared to adults with Down syndrome and AD (DS+AD, range 43–63 years) from the University of California Irvine brain bank. CN-PiB-labeled diffuse plaque load differed between groups (F (2, 39) = 17.36, P < 0.0001; Tukey multiple comparisons, AD > NC, DS+AD). CN-PiB-labeled load of cored plaques differed between groups (F (2, 39) = 26.54, P < 0.0001; Tukey multiple comparisons, NCI < AD, DS+AD; AD < DS+AD. *P < 0.05; ***0.0001 < P < 0.001; ****P < 0.0001.