High resolution structural and functional MRI of the hippocampus in young adults with Down syndrome

Abstract

Down syndrome is the phenotypic consequence of trisomy 21, with clinical presentation including both neurodevelopmental and neurodegenerative components. Although the intellectual disability typically displayed by individuals with Down syndrome is generally global, it also involves disproportionate deficits in hippocampally-mediated cognitive processes. Hippocampal dysfunction may also relate to Alzheimer’s disease-type pathology, which can appear in as early as the first decade of life and becomes universal by age 40. Using 7-tesla MRI of the brain, we present an assessment of the structure and function of the hippocampus in 34 individuals with Down syndrome (mean age 24.5 years ± 6.5) and 27 age- and sex-matched typically developing healthy controls. In addition to increased whole-brain mean cortical thickness and lateral ventricle volumes (p < 1.0 × 10−4), individuals with Down syndrome showed selective volume reductions in bilateral hippocampal subfields CA1, dentate gyrus, and tail (p < 0.005). In the group with Down syndrome, bilateral hippocampi showed widespread reductions in the strength of functional connectivity, predominately to frontal regions (p < 0.02). Age was not related to hippocampal volumes or functional connectivity measures in either group, but both groups showed similar relationships of age to whole-brain volume measures (p < 0.05). Finally, we performed an exploratory analysis of a subgroup of individuals with Down syndrome with both imaging and neuropsychological assessments. This analysis indicated that measures of spatial memory were related to mean cortical thickness, total gray matter volume, and right hemisphere hippocampal subfield volumes (p < 0.02). This work provides a first demonstration of the usefulness of high-field MRI to detect subtle differences in structure and function of the hippocampus in individuals with Down syndrome, and suggests the potential for development of MRI-derived measures as surrogate markers of drug efficacy in pharmacological studies designed to investigate enhancement of cognitive function.

Youth with Down syndrome display widespread increased functional connectivity during rest

“…In addition to these neocortical abnormalities, reduced regional brain volume of the hippocampus (e.g. 14 , 17 ) has been found using high-resolution imaging. Similarly, volumetric and diffusion tensor imaging (DTI) investigations have documented reductions in the volume of the cerebellum in individuals with DS (e.g.…”

“…In contrast, 68% of DMN connections to the posterior cingulate and 26% of DMN connections to the anterior cingulate revealed reduced connectivity in the DS group relative to the control group. Lastly, Koenig 17 conducted a resting-state (eyes closed) functional connectivity study of the hippocampus and DMN in 22 teenagers and adults with DS ( M age = 24.5 years, range 15–35 years) relative to neurotypical age-matched controls which revealed largely reduced hippocampi-DMN connectivity in the DS group.…”

“…The studies by Anderson 28 , Pujol 27 , Figueroa-Jimenez 34 , and Koenig 17 , 35 provide an important foundation for understanding network connectivity in the developing brain in individuals with DS. However, they are characterized by the following limitations: (a) the use of a quasi-resting-state design 28 ; (b) a focus on predefined networks rather than the whole brain 17 , 28 , 34 , 35 ; and (c) the use of global signal regression or a similar normalization step 17 , 27 , 35 , which has been shown to alter group differences both quantitatively and qualitatively in prior research (see 36 – 42 for discussion). In addition, these studies did not address two important, open questions in the field: (a) are differences in connectivity in DS network specific or diffuse, and (b) how does the degree of connectivity observed in DS relate to the network selectivity?…”

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

“…Regarding structural MRI, brain abnormalities have been demonstrated in the DS population. Koenig et al 7 demonstrated differences in the hippocampus in the DS group compared with the non-DS group. Similarly, Beacher et al 8 demonstrated that the frontal, temporal, and parietal lobes show more significant age-related reduction in DS than in the general population.…”

“…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 .…”