Early brain changes observed in children with Alzheimer mutation

By Will Boggs MD

NEW YORK (Reuters Health) - Children who carry presenilin 1 (PSEN1) E280A mutations associated with autosomal dominant Alzheimer disease (ADAD) show functional and structural brain changes and abnormal levels of plasma Abeta1-42, according to results from a Colombian kindred with ADAD.

Nearly 100% of PSEN1 E280A carriers develop early-onset AD in adulthood, with mild cognitive impairment coming at a median age of 44 years and dementia beginning at a median age of 49 years.

Dr. Yakeel T. Quiroz, from Massachusetts General Hospital, Boston, and colleagues investigated brain and biomarker changes in 18 children (age 9 to 17 years) with PSEN1 mutation E280A, compared with 19 noncarriers matched by age, sex, and education, all from the Colombian Alzheimer Prevention Initiative registry.

Carriers of the PSEN1 mutation E280A had significantly higher plasma Abeta1-42 levels (mean, 18.8 pg/mL) than did noncarriers (mean, 13.1 pg/mL; p<0.001), according to the June 29 JAMA Neurology online report.

Mutation carriers showed reduced posterior parietal deactivation during a memory encoding task, but this difference lost significance after correction for multiple regional comparisons.

Unlike previous reports of changes in later preclinical and clinical stages of AD, mutation carriers did not show reduced functional connectivity of brain networks. Instead, they had paradoxically greater functional connectivity between the posterior cingulate cortex and bilateral medial temporal lobes. This latter difference also lost significance after correction for multiple regional comparisons.

Mutation carriers had greater gray matter volumes in the parahippocampal gyrus and temporal pole, whereas they showed no gray matter volume reductions in brain regions when compared with noncarriers.

"Further research is needed to determine the meaning and relevance of these changes for early detection of the disease and to evaluate them as reliable preclinical markers of AD," the researchers conclude. "Further research is also needed to define how the presenilin variants might modify brain development and how these neurodevelopmental changes may or may not be related to present or future pathophysiological changes associated with the predisposition to AD."

Dr. Peter St. George-Hyslop, from Cambridge Institute for Medical Research, Cambridge, UK, told Reuters Health by email, "If these findings can be confirmed in carriers of other PSEN1 mutations (i.e., if it can be shown to be something other than an idiosyncrasy of this large family) it would confirm the previous work that there is a long preclinical window. The practical implication is obviously that this represents a time during which treatments, once they become available, can be applied to prevent/delay the onset of neurodegeneration."

"Whether there is a lifelong developmental difference remains to be seen," he said, "but the vast majority of PSEN1 mutation carriers function normally until they are in their 40s. So the practical message is simply, once treatments become available they should be instituted as early as possible. However, the precise timing of when such preventative treatment begins will need to be worked out based on safety profiles of those potentially long-term therapies."

"Right now there are no proven and approved treatments, of course," Dr. St. George-Hyslop said.

This lack of effective treatments leads genetic counselor Jill S. Goldman, from Columbia University Medical Center's Taub Institute, New York, to address possible ethical issues concerning the rights of children. She told Reuters Health by email, "At present, guidelines for genetic testing of children recommend that unless some effective intervention exists, no genetic testing should be performed until they reach the age of majority and can make their own decision about learning their own genetic status. The use of biomarkers can similarly identify genetic status and thus should follow the guidelines. These guidelines will change when effective intervention exists that would warrant genetic testing of children or biomarker testing for children so that treatment could be initiated."

"The great majority of individuals who are at 50% risk for diseases like autosomal dominant AD and Huntington disease, for which no treatment exists, do not opt for genetic testing," Goldman said. "When they do wish to proceed, testing is done following extensive genetic counseling, as well as psychological and neurological evaluation. In this way, the at-risk individual is prepared for learning their status."

She concluded, "I would hope that the medical community is as careful with their use of biomarkers. Ethics committees will have to establish guidelines on the use of biomarkers in children."

Dr. Quiroz did not respond to a request for comments.

Supporters of this study included the Banner Alzheimer's Foundation, the Nomis Foundation, the National Institutes of Health, and an anonymous foundation. Ten coauthors reported relationships with pharmaceutical companies.

SOURCE: http://bit.ly/1emwFej

JAMA Neurol 2015.

(c) Copyright Thomson Reuters 2015. Click For Restrictions - http://about.reuters.com/fulllegal.asp