Down’s syndrome has close links to Alzheimer’s disease: People with Down’s carry an extra copy of the β amyloid precursor gene APP, have a heightened risk of AD, and typically show AD pathology at autopsy. In this month’s Archives of Neurology, researchers led by Gary Small at the University of California, Los Angeles, report the results of one of the first studies to look for AD pathology in living DS brains with positron emission tomography (PET). Small and colleagues report that middle-aged people with Down’s syndrome have amyloid and tau deposits comparable to those in the brains of elderly people with AD, and that these deposits correlate with behavioral changes that may indicate dementia. The results add to the evidence for Alzheimer’s-like pathology in DS, and imply that some future AD treatments might also help people with DS.

“I think it is a significant milestone to have this type of functional imaging available in Down’s syndrome,” said Ira Lott at the University of California, Irvine. He was not involved in the study. “I suspect we are going to see a lot more work in this area.”

First author Linda Nelson compared PET scans from 19 people with DS, whose average age was about 37, to scans from 10 middle-aged controls and 10 elderly people with AD. The authors used the ligand [18F]FDDNP, which binds to both β amyloid and tau deposits (described in ARF related news story and ARF news story). They found that middle-aged DS brains had comparable deposits to AD brains in most regions, as shown by FDDNP binding levels, and heavier deposits in the parietal and frontal areas. The number of deposits correlated with participants’ age. The data match findings from previous neuropathological studies of DS brains.

They also agree with a study published in March that used PET with Pittsburgh Compound B (PIB) to scan nine people with DS (see Landt et al., 2011). In people with Down’s who were over 45 years old, but not in younger people with DS, PIB lit up brain regions that are associated with amyloid pathology in AD patients. PIB is specific for amyloid deposits, and has been shown to have higher specificity and sensitivity for AD than does FDDNP (see Tolboom et al., 2010).

In ongoing work, Small said he is using both PIB and FDDNP to scan larger groups of people with DS. He also plans to follow participants over time to try to understand how the brain ages in Down’s syndrome, and what factors predict cognitive decline.

The Down’s syndrome patients scanned by Small and colleagues were not demented, according to the Dementia Questionnaire for Mentally Retarded Persons, a standardized test for people with the condition. However, Small notes, “It is a challenge to diagnose dementia in these patients, because cognitive deficits are already present. What clinicians and investigators tend to see are behavioral changes.” Pragnosia, or loss of socially appropriate communication, may be one of the earliest signs of dementia that people with DS manifest, Lott noted (see Nelson et al., 2001). Small and colleagues found that levels of pragnosia, indifference, and inappropriate behavior in the participants with DS correlated with their level of FDDNP binding. William Mobley, who leads the Down Syndrome Center for Research and Treatment at the University of California, San Diego, said that better cognitive tests for DS have recently been developed by Len Nadel and colleagues at the University of Arizona (see Edgin et al., 2010). In future studies, it would be valuable to combine these newer cognitive measures with brain scans, Mobley suggested.

This study “draws a very nice parallel between the pathology of DS and the pathology of AD,” Mobley told ARF (see also ARF Webinar). Mobley suggested that people with DS might be excellent candidates for trials of anti-amyloid therapies, and that brain scans will be a useful tool for monitoring the effects of therapy. Intriguingly, reducing soluble Aβ in young DS model mice improves their cognitive abilities (see ARF related news story on Netzer et al., 2010). William Netzer at The Rockefeller University, New York City, noted “There is a theoretical possibility that Aβ accumulation could contribute to mental retardation in early DS.” All researchers contacted for this article hailed the increasing focus on treating the cognitive issues of DS. “I think people with DS have been relatively underserved when it comes to these types of investigations,” Lott said.—Madolyn Bowman Rogers.

Reference:
Nelson LD, Siddarth P, Kepe V, Scheibel KE, Huang SC, Barrio JR, Small GW. Positron emission tomography of brain {beta}-amyloid and tau levels in adults with down syndrome. Arch Neurol. 2011 Jun;68(6):768-74. Abstract

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References

News Citations

  1. New PET Probe to Aid Diagnosis and Monitoring of Alzheimer's Disease
  2. PET Probe Lights Up MCI, AD
  3. New Findings Offer Hope for Down Syndrome

Webinar Citations

  1. Volunteers Help Scientists Explore Down’s, Alzheimer’s Nexus

Paper Citations

  1. . Using positron emission tomography and Carbon 11-labeled Pittsburgh Compound B to image Brain Fibrillar β-amyloid in adults with down syndrome: safety, acceptability, and feasibility. Arch Neurol. 2011 Jul;68(7):890-6. PubMed.
  2. . Molecular imaging in the diagnosis of Alzheimer's disease: visual assessment of [11C]PIB and [18F]FDDNP PET images. J Neurol Neurosurg Psychiatry. 2010 Aug;81(8):882-4. PubMed.
  3. . Neurological changes and emotional functioning in adults with Down Syndrome. J Intellect Disabil Res. 2001 Oct;45(Pt 5):450-6. PubMed.
  4. . Development and validation of the Arizona Cognitive Test Battery for Down syndrome. J Neurodev Disord. 2010 Sep 1;2(3):149-164. PubMed.
  5. . Lowering beta-amyloid levels rescues learning and memory in a Down syndrome mouse model. PLoS One. 2010;5(6):e10943. PubMed.
  6. . Positron emission tomography of brain β-amyloid and τ levels in adults with Down syndrome. Arch Neurol. 2011 Jun;68(6):768-74. PubMed.

External Citations

  1. Down Syndrome Center for Research and Treatment

Further Reading

Papers

  1. . Positron emission tomography of brain β-amyloid and τ levels in adults with Down syndrome. Arch Neurol. 2011 Jun;68(6):768-74. PubMed.

Primary Papers

  1. . Positron emission tomography of brain β-amyloid and τ levels in adults with Down syndrome. Arch Neurol. 2011 Jun;68(6):768-74. PubMed.