Altered connectivity of the default mode network in cognitively stable adults with Down syndrome: “Accelerated aging” or a prelude to Alzheimer's disease?

Abstract

Introduction: Most individuals with Down syndrome (DS) have the neuropathological changes of Alzheimer's disease (AD) by age 40 and will have developed dementia by age 60. Alterations of the intrinsic connectivity of the default mode network (DMN) are associated with AD in the neurotypical population. In this study, we sought to determine whether, and how, connectivity between the hubs of the DMN were altered in cognitively stable adults with DS who did not have evidence of either mild cognitive impairment or AD. Methods: Resting state functional MRI scans were collected from 26 healthy adults with DS and 26 healthy age-matched non-DS controls. Nodes comprising the DMN were generated as ROI's (regions of interest) and inter-nodal correlations estimated. Results: Analysis of intra-network connectivity of the DMN revealed anteriorposterior DMN dissociation and hyper-and hypo-connectivity, suggesting "accelerated aging" in DS. Discussion: Disruption of the DMN may serve as a prelude for AD in DS.

Youth with Down syndrome display widespread increased functional connectivity during rest

“…Regarding the DMN, researchers have found a mix of increased and decreased connectivity in adults with DS relative to controls. Whereas Wilson 30 found generally widespread increased connectivity (apart from a few localized regions of decrease), Rosas 31 found a mix of increased connectivity (e.g., in frontal DMN regions) and decreased connectivity in other components of the DMN. Beyond the DMN, one study of 10 individuals with DS conducted by Vega 29 investigated 21 pairs of predefined networks and revealed increased connectivity across six of the 21 network pairs examined relative to healthy adults.…”

“…Resting-state studies that have included middle-aged adults with DS have tended to focus on the default mode network (DMN) 30 , 31 or select, predefined networks 29 . Regarding the DMN, researchers have found a mix of increased and decreased connectivity in adults with DS relative to controls.…”

“…However, the age of the participants studied and the heightened risk for early neuropathological signs of dementia in DS make it difficult to ascertain which findings relate to atypical neurodevelopment and which relate to age-related neurodegeneration. More specifically, as these studies included middle-aged and older individuals with DS (Wilson 30 : Age range 29–49 years; Rosas 31 : 40 years and above; Vega 29 : 30–55 years) and virtually all individuals with DS will present with the neurofibrillary plaques and tangles characteristic of dementia by 40 years of age 32 , these studies are limited in their ability to describe the neurodevelopmental phenotype in DS.…”

Altered spontaneous brain activity in Down syndrome and its relation with cognitive outcome

“…This paradigm has been suggested as a suitable biomarker for abnormal brain function and predicting later adverse neurodevelopment in DS 16 . The majority of studies using rs- f MRI in this population have focused on specific areas or predetermined networks, such as the default mode network 17 – 19 (DMN) or the hippocampus 7 . However, few studies have focused on the whole brain 20 .…”

“…The DMN is related to high structural and FC while a person is at rest and has been demonstrated to be disrupted in several diseases 32 , such as DS. Results indicating abnormalities in DS through the DMN were found 17 – 19 : first, a disrupted connectivity between posterior brain regions, and second, hyperconnectivity and hypoconnectivity, including different subregions of the DMN. Finally, they found weaker strength in frontal regions, consistent with other studies 29 .…”