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Tuesday, September 08, 2015

Age Dependence of Beta Amyloid Deposition in Down Syndrome

Dear Readers,

As more and more clinical trials are focusing on enrolling persons with various genetic susceptibility genes that put them at risk for developing Alzheimer’s disease, clarifying the relationship between Down’s syndrome and Alzheimer’s disease has been a recurrent theme discussed in my community presentations. Not only do I typically discuss the role of amyloid precursor protein to the development of clinical symptoms similar to that of Alzheimer’s disease in patients with Down’s syndrome, I am increasingly asked to comment on the various neuroimaging changes noted in patients with Down’s syndrome. Are the changes similar to those seen in patients with Alzheimer’s disease or are they different?

A recent paper by Jennings et al, examined whether 18F florbetaben PET imaging – commonly used in research studies - in patients with cognitive changes and Alzheimer’s disease could reliably detect amyloid in relatively young patients with Down’s syndrome.

In this study, individuals with Down’s syndrome (DS) were recruited from two centers and were atleast 40 years of age. Genetic testing noted that all of the patients had a triplication of chromosome 21 with no evidence of partial trisomy. All participants underwent a screening visit, including a history and physical examination, clinical assessments, and cognitive screening. PET imaging was performed within 12 weeks of the screening visit. Cognitive status of individuals with DS was evaluated using the Dementia Screening Questionnaire for individuals with disabilities (DSQIID). The scale includes questions on baseline “best ability,” on behaviors and symptoms suggestive of dementia, and current level of function to that of baseline ability.

PET acquisition with 18 F florbetaben was performed, and uptake was calculated for seven specific pre-identified brain volumes of interest (VOIs): frontal cortex, lateral temporal cortex, anterior cingulate cortex, posterior cingulate cortex, parietal cortex, occipital cortex, and cerebellum. Three independent readers blind to the clinical data performed a visual assessment of the PET scans.

The current sample included 39 DS subjects with a mean age of 46.3 years +/- 4.7 years (54% males, 95 % Caucasian). 18 F florbetaben uptake increased with age for all VOIs and increased by 2.88 % for each year of age above 40 years. When stratifying the subjects with DS on five year age intervals, those in the 50 years and older groups showed an increase in mean composite SUVR compared with the two younger subgroups. Multiple readers blinded to each other’s radiological evaluations showed good inter-rater reliability assessing the scans and no safety concerns were noted for administration of the tracer.

Cognitive testing noted a mean score of 6.4 +/- 8.0 (range 0-41) on the DSQIID with only two of the 34 participants considered to have dementia based on a DSQIID score >20. Those with a score of .0, had a higher composite SUVR compared to those with a DSQIID of 0.

In patients with DS, an increase in beta amyloid as measured by 18 F florbetaben was present, and the increase in 18 F florbetaben correlated with increasing age. Other important findings from this examination noted that less than 50% of subjects with DS between 40 and 50 years and 90% of those DS patients older than 50 years had an 18F florbetaben binding in a range that corresponded to the typical range noted in cases of Alzheimer’s disease. Consistent with earlier neuropathological autopsy studies, amyloid plaques localized in this study by PET, appeared to be localized in the medial temporal lobes. Finally, amyloid deposits were present in DS patients before they demonstrated signs/ symptoms consistent with dementia based on the DSQIID evaluation.

These results demonstrate that PET imaging in populations to visualize amyloid deposition can be performed reliably in special populations with a genetic risk for developing AD. Further, early detection of beta amyloid deposition before cognitive impairment in patients with DS, offers an opportunity for researchers to characterize the natural history of beta amyloid deposition, and potentially can inform drug development in disease modifying therapies.

Want to read more? Here are 3 articles you can refer to, to learn about the relationship between Down’s Syndrome and Alzheimer’s Disease.

1. Jennings D, Seibyl J, Sabbagh M et al. Age dependence of brain beta amyloid deposition in Down Syndrome. An 18F florbetaben PET study. Neurology 2015 84: 500-507

2. Deb S, Hare M, Prior L, Bhaumik S. Dementia screening questionnaire for individuals with intellectual disabilities. Br J Psychiatry 2007; 190: 440-444

3. Mann DM. Alzheimer’s disease and Down’s syndrome. Histopathology 1988: 13; 125- 137.

Thanks for reading,

Neelum T. Aggarwal, MD
Steering Committee Member, ADCS
Rush Alzheimer’s Disease Center
Chicago, IL

Author: Neelum Aggarwal MD at 8:14 AM 0 Comments

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The Alzheimer's Disease Cooperative Study (ADCS) was formed in 1991 as a cooperative agreement between the National Institute on Aging (NIA) and the University of California, San Diego. The ADCS is a major initiative for Alzheimer's disease (AD) clinical studies in the Federal government, addressing treatments for both cognitive and behavioral symptoms. This is part of the NIA Division of Neuroscience's effort to facilitate the discovery, development and testing of new drugs for the treatment of AD and also is part of the Alzheimer's Disease Prevention Initiative.

The ADCS was developed in response to a perceived need to advance research in the development of drugs that might be useful for treating patients with Alzheimer's disease (AD), particularly drugs that might not be developed by industry.