Frontal white matter integrity in adults with Down syndrome with and without dementia.

Neurobiol Aging. 2014 Jul;35(7):1562-9. doi: 10.1016/j.neurobiolaging.2014.01.137.

Powell D1, Caban-Holt A2, Jicha G3, Robertson W4, Davis R2, Gold BT5, Schmitt FA3, Head E6.
  • 1Magnetic Resonance Imaging and Spectroscopy Center, University of Kentucky, Lexington, KY, USA.
  • 2Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
  • 3Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Neurology, University of Kentucky, Lexington, KY, USA.
  • 4Department of Neurology, University of Kentucky, Lexington, KY, USA.
  • 5Magnetic Resonance Imaging and Spectroscopy Center, University of Kentucky, Lexington, KY, USA; Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY, USA.
  • 6Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA; Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY, USA. Electronic address:


Adults with Down syndrome (DS) are at high risk for developing Alzheimer’s disease (AD) after 40 years of age. To detect white matter (WM) changes in the brain linked to dementia, fractional anisotropy (FA) from diffusion tensor imaging (DTI) was used.  We hypothesized that adults with DS without dementia (DS n=10), DS with dementia (DSAD n=10) and age matched non-DS subjects (CTL n=10) would show differential levels of FA and an association with scores from the Brief Praxis Test (BPT) and the Severe Impairment Battery (SIB). WM integrity differences in DS compared to CTL were found predominantly in the frontal lobes. Across all DS adults, poorer BPT performance correlated with reduced FA in the corpus callosum as well as several association tracts, primarily within frontoparietal regions. Our results demonstrate significantly lower WM integrity in DS compared to controls, particularly in frontal tracts. DS-related WM integrity reductions in a number of tracts were associated with poorer cognition.  These preliminary results suggest that late myelinating frontal pathways may be vulnerable to aging in DS. Copyright © 2014 Elsevier Inc.

PMID: 24582640



The most common cause of Down syndrome (DS) is triplication of chromosome 21, resulting in differences in brain development and other neurologic features.  However, a key challenge for people with DS as they age is the increasing risk for developing Alzheimer’s disease (AD).  AD neuropathology appears in almost all adults with trisomy 21 after 40 years of age (see Figure 1), which includes beta-amyloid plaques and neurofibrillary tangles. Our study has been characterizing brain changes in people with DS as they age and one of the questions we have is: Do the connections in the brain weaken as people age and develop AD in DS and does this predict changes in learning and memory?

Figure 1.  Alzheimer’s disease neuropathology the frontal cortex in a person with Down syndrome who is 61 years old.  Brown staining shows beta-amyloid plaques and blue shows neurofibrillary tangles.


We used magnetic resonance imaging to compare the health of the brain’s white matter and how strongly it connects different parts of the brain.  Specifically, we used an MRI method called, diffusion tensor imaging (DTI) that represents a non-invasive method for characterizing the microstructural properties of white matter (WM).  Using this method we can measure the rate and direction of diffusion of water molecules in neural tissue.  Diffusion occurs preferentially along healthy and robust WM tracts. As WM integrity is compromised, water diffusion becomes equal in all directions, called isotropic..

The goal of the study was to specifically test the hypothesis that frontal dysfunction (measured by white matter integrity) would distinguish DS from non-DS and DS without dementia from those with dementia.

To test this hypothesis, we enrolled participants with DS that were over 35 years of age, with some of these people having dementia, as well as people without DS that were of a similar age. People with Down syndrome show differences in the structure of their brains when compared to people without Down syndrome (Figure 2).

Figure 2. Structural MR images taken as a sagittal slice. The right image is a Down syndrome volunteer. The left image is an age matched control without Down syndrome. Note the differences in the shape of the cerebellum and in the frontal cortex.

We first tested this hypothesis by comparing people with DS to those without DS of a similar age. Using MRI technologies, brain scans of participants with Down syndrome showed some compromise in the white matter of the frontal lobe compared to those from the control group (Figure 2). This could be due to developmental differences as we see structural differences in the brains of people with DS (Figure 3).  It could also be that people with DS over the age of 35 years already have some changes in their white matter.

When people with Down syndrome and dementia were compared to people with Down syndrome without dementia, those same white matter connections were even less healthy (see Figure 3).  These results suggest that white matter integrity may be compromised as dementia develops or possibly leads to cognitive changes.

We next looked at the correlation between white matter integrity and scores on a test called the Brief Praxis Test.  This test measures simple movements and movement planning.  This led to one of the more intriguing aspects of the study– those who had higher motor skill coordination and better learning and memory ability (based on the SIB test that measures memory, language, eye-hand coordination, and orientation) had healthier frontal white matter connections.

The results indicate a compelling progression of changes in the integrity of white matter in the brains of our study participants that parallels changes in their cognitive health.

Figure 3.  A 3D transparent view of the brain showing regions where white matter structural integrity is associated with Down syndrome, dementia and Brief Praxis Test scores.  Blue shows areas that had reduced white matter integrity when comparing nondemented adults with Down syndrome to non-Down syndrome controls.  Green shows areas where demented adults with Down syndrome have lower white matter integrity than nondemented adults with Down syndrome.  Red shows areas where lower white matter integrity is associated with lower brief praxis test scores in Down syndrome adults.


If we are able to identify people who, based on biomarkers such as brain imaging, have a higher risk of developing Alzheimer’s disease, we might be able to intervene at an earlier point to slow or possibly prevent the progression of this disease in Down syndrome.  Such findings could also possibly be useful in determining treatments for sporadic AD. Further work that relates the timing of reduced WM integrity, cortical atrophy (shrinkage), and the development of dementia in adult DS is needed.  Such research may provide insights that would be useful for the development of biomarkers not only for the development of DSAD, but for the global health threat of AD in the general population as well.