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 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.

Using fMRI to Assess Brain Activity in People With Down Syndrome: A Systematic Review

“…The works of Jacola et al (2011Jacola et al ( , 2014 were especially consistent since they only found statistically significant effects in the Control > DS comparisons in all the areas studied. Inconsistent and irregular activation patterns, as we mentioned, can be seen in the remaining works (Vega et al, 2015;Wan et al, 2017;Wilson et al, 2019). The two works carried out with a resting-state approach (Anderson et al, 2015) showed less activation in the functional connectivity networks presented in the DS samples.…”

“…It is a source of noise to consider in this type of work. Except for the work of Wilson et al (2019), this issue is not mentioned in the rest of the works. In this regard, the proposals of Ciric et al (2017) should be taken into account in all fMRI studies and with more intensity in high-movement populations such as persons with DS.…”

“…Even if their suggestions do not provide specific corrections for DS samples, they have been shown to be effective in reducing the perverse effects of excess movement. The work of Wilson et al (2019) may be a reference for the appropriate application of these corrections.…”

Multi-Modal Imaging in Down's Syndrome: Maximizing Utility Through Innovative Neuroimaging Approaches

“…Neuroimaging contributes to these rising developments by providing biomarkers that could improve comorbid AD diagnosis, inform prognosis, aid in deep phenotyping, allow for risk stratification, and track therapeutic efficacy in future clinical trials for people with DS. Models of AD pathophysiology propose a sequential progression of brain changes that are reflected by neuroimaging abnormalities, beginning with an early increase in Aβ PET tracer binding, followed by a gradual progression of neurofibrillary tau tangles, deficits in cerebral glucose metabolism (i.e., [ 18 F]-fluorodeoxyglucose-PET (FDG-PET) and gray matter atrophy and white matter dysfunction as seen with structural T 1 -weighted MRI, resting-state connectivity differences ( 5 ) and diffusion imaging ( 6 ). Indeed, as we will summarize in the next section, these stereotypical AD biomarker changes have often been recapitulated in the small but growing number of neuroimaging studies in DS.…”

Relationship between Quality of Life and the Complexity of Default Mode Network in Resting State Functional Magnetic Resonance Image in Down Syndrome

“…Based on previous works focused on DS, the connectivity of the DMN to other brain regions shows different profiles in contrast to healthy control groups. The main characteristics of the connectivity in DS are the increased positive networks identified (i.e., hyper-connectivity), even in regions that, in control groups, are negative, and the decreasing of anti-correlation [ 19 , 20 , 21 ]. These data can explain the altered brain functioning of DS, due to the fact that anti-correlation is necessary to organize and segregate networks in the healthy brain [ 22 ].…”