Differential effects of Down's syndrome and Alzheimer's neuropathology on default mode connectivity

Abstract

Down's syndrome is a chromosomal disorder that invariably results in both intellectual disability and Alzheimer's disease neuropathology. However, only a limited number of studies to date have investigated intrinsic brain network organisation in people with Down's syndrome, none of which addressed the links between functional connectivity and Alzheimer's disease. In this cross-sectional study, we employed ¹¹ C-Pittsburgh Compound-B (PiB) positron emission tomography in order to group participants with Down's syndrome based on the presence of fibrillar beta-amyloid neuropathology. We also acquired resting state functional magnetic resonance imaging data to interrogate the connectivity of the default mode network; a large-scale system with demonstrated links to Alzheimer's disease. The results revealed widespread positive connectivity of the default mode network in people with Down's syndrome (n = 34, ages 30-55, median age = 43.5) and a stark lack of anti-correlation. However, in contrast to typically developing controls (n = 20, ages 30-55, median age = 43.5), the Down's syndrome group also showed significantly weaker connections in localised frontal and posterior brain regions. Notably, while a comparison of the PiB-negative Down's syndrome group (n = 19, ages 30-48, median age = 41.0) to controls suggested that alterations in default mode connectivity to frontal brain regions are related to atypical development, a comparison of the PiB-positive (n = 15, ages 39-55, median age = 48.0) and PiB-negative Down's syndrome groups indicated that aberrant connectivity in posterior cortices is associated with the presence of Alzheimer's disease neuropathology. Such distinct profiles of altered connectivity not only further our understanding of the brain physiology that underlies these two inherently linked conditions but may also potentially provide a biomarker for future studies of neurodegeneration in people with Down's syndrome.

Keywords: Alzheimer's disease; Down's syndrome; anti-correlation; default mode network; functional connectivity; memory.

Figure 1

Within group default mode network connectivity in (a) typically developing age‐matched controls and (b) all participants with Down's syndrome. The statistical maps (T‐scores) represent positive correlation (red) and anti‐correlation (blue) of the medial prefrontal cortex (mPFC) seed region (connectivity with subcortical structures and cerebellum is not shown) [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 2

Differences in default mode network connectivity (mPFC seed) between the typically developing control and Down's syndrome groups, showing (a) controls > Down's syndrome (all), and (b) Down's syndrome (all) > typically developing controls. Where prefixed to the abbreviation of a brain region, L and R indicate the left and right hemisphere, respectively. ACG, anterior cingulate gyrus; CAL, calcarine cortex; CER9, region 9 of the cerebellum; CER7b, region 7 of the cerebellum; IFG, inferior frontal gyrus; IOG, inferior occipital gyrus; ITG, inferior temporal gyrus; MFG, inferior/middle frontal gyrus; MTG, middle temporal gyrus; PAL, pallidum; PCG, posterior cingulate gyrus; PCUN, precuneus; PreCG, precentral gyrus; SFGmed, medial superior frontal gyrus; SMA, supplementary motor area; SMG, supramarginal gyrus; SPG, superior parietal gyrus [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 3

Differences in default mode network connectivity between typically developing controls and PiB‐negative participants with Down's syndrome, showing (a) controls > PiB −ve Down's syndrome, and (b) PiB −ve Down's syndrome > controls. PiB −ve, PiB‐negative; where prefixed to the abbreviation of a brain region, L and R indicate the left and right hemisphere, respectively. Furthermore, a suffix of 1 or 2 to an abbreviation serves to differentiate different significant clusters located within a single brain region. ACG, anterior cingulate gyrus; CERcr2, cerebellum crus 2; CER7b, region 7b of the cerebellum; ITG, inferior temporal gyrus; MFG, middle frontal gyrus; MTG, middle temporal gyrus; ORBmid, middle orbitofrontal gyrus; PHG, parahippocampal gyrus; SPG, superior parietal gyrus; SFGmed, medial superior frontal gyrus [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 4

Differences in default mode network connectivity between the PiB‐negative and PiB‐positive Down's syndrome groups (PiB‐negative > PiB‐positive). The reverse contrast is not shown. PiB –ve, PiB‐negative; PiB +ve, PiB‐positive; RMTG, right middle temporal gyrus; RPCUN, right precuneus [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 5

Default mode network connectivity in the PiB‐positive Down's syndrome group compared to the typically developing control group, showing (a) controls > PiB‐positive Down's syndrome, and (b) PiB‐negative Down's syndrome > controls. PiB +ve, PiB‐positive; prefixed to the abbreviation of a brain region, L and R indicate the left and right hemisphere, respectively. Furthermore, a suffix of 1 or 2 to an abbreviation serves to differentiate different significant clusters located within a single brain region. ACG, anterior cingulate gyrus; CER9, region 9 of the cerebellum; IFGtriang, inferior frontal gyrus pars triangularis; IOG, inferior occipital gyrus; IPL, inferior parietal lobule; ITG, inferior temporal gyrus; MTG, middle temporal gyrus; PCUN, precuneus; SFGmed, medial superior frontal gyrus; SMA, supplementary motor area; SPG, superior parietal gyrus [Color figure can be viewed at http://wileyonlinelibrary.com]

Figure 6

Correlations between IQ, memory and language and default mode network (DMN) connectivity in the Down's syndrome (all) group. MFG, middle frontal gyrus; PPC, posterior cingulate cortex