The Down syndrome brain in the presence and absence of fibrillar β-amyloidosis

Annus, Tiina; Wilson, Liam R.; Acosta‐Cabronero, Julio; Cárdenas-Blanco, Arturo; Hong, Young T.; Fryer, Tim D.; Coles, Jonathan P.; Menon, David; Zaman, Shahid; Holland, Anthony; Nestor, Peter J.

doi:10.1016/j.neurobiolaging.2017.01.009

Cited by 51 publications

(61 citation statements)

References 61 publications

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“…Similar regions underwent changes in PiB SUVR, FDG SUVR, and GM volume as reported in Sabbagh et al [32] and those changes are driven by older, PiB(+) or demented participants. A number of other studies have investigated these three biomarkers in the DS population to varying extents [26, 31, 49, 59–63]. As an extension of the current literature, we incorporated information from all three biomarkers into a single multi-modal voxel-wise model, and verified the regional specificity of AD-related neurodegeneration in DS.…”

Section: Discussionmentioning

confidence: 90%

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

Lao

Handen

Betthauser

et al. 2017

JAD

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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.

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Section: Discussionmentioning

confidence: 90%

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

Lao

Handen

Betthauser

et al. 2017

JAD

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“…A number of volumetric MRI studies primarily employing ROI‐based approaches (please see Annus et al, for a summary) have identified reduced overall grey matter volumes in people with Down's syndrome relative to controls (Beacher et al, ; Pearlson et al, ; White, Alkire, & Haier, ), while specific reductions in volume have also been reported in the frontal lobes, the hippocampus and the cerebellum (Aylward et al, ; Beacher et al, ; Koran et al, ; Pearlson et al, ; White et al, ). Meanwhile, increases in grey matter volume have been noted in the parahippocampal gyrus and in the parietal and occipital cortices (Beacher et al, ; White et al, ).…”

Section: Discussionmentioning

confidence: 99%

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

Wilson

Vatansever

Annus

et al. 2019

Human Brain Mapping

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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 11C‐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.

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“…Brain atrophy in DS is likely to be gradual and cumulative, caused by factors such as increased amyloid deposition or secondary effects of exposure to abnormal neurodevelopment, rather than resulting from a one-off insult. While DS brains have been shown to be abnormal in size and morphology (Annus et al., 2017, Wang, 1996), brain-PAD scores did not correlate with ICV, nor does ICV correlate with brain-PAD in healthy individuals, so global size differences do not appear to be driving the results. Distinctive brain morphology in DS also did not seem to influence our findings as we observed no differences in the MAE of age prediction in the DS and control groups; age prediction accuracy was not hindered by any morphologic features of DS.…”

Section: Discussionmentioning

confidence: 99%

Brain-predicted age in Down syndrome is associated with beta amyloid deposition and cognitive decline

Cole

Annus

Wilson

et al. 2017

Neurobiology of Aging

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Individuals with Down syndrome (DS) are more likely to experience earlier onset of multiple facets of physiological aging. This includes brain atrophy, beta amyloid deposition, cognitive decline, and Alzheimer's disease—factors indicative of brain aging. Here, we employed a machine learning approach, using structural neuroimaging data to predict age (i.e., brain-predicted age) in people with DS (N = 46) and typically developing controls (N = 30). Chronological age was then subtracted from brain-predicted age to generate a brain-predicted age difference (brain-PAD) score. DS participants also underwent [11C]-PiB positron emission tomography (PET) scans to index the levels of cerebral beta amyloid deposition, and cognitive assessment. Mean brain-PAD in DS participants' was +2.49 years, significantly greater than controls (p < 0.001). The variability in brain-PAD was associated with the presence and the magnitude of PiB-binding and levels of cognitive performance. Our study indicates that DS is associated with premature structural brain aging, and that age-related alterations in brain structure are associated with individual differences in the rate of beta amyloid deposition and cognitive impairment.

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The Down syndrome brain in the presence and absence of fibrillar β-amyloidosis

Cited by 51 publications

References 61 publications

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

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

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

Brain-predicted age in Down syndrome is associated with beta amyloid deposition and cognitive decline

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