Alzheimer's-Like Brain Alterations Seen in Cognitively Normal Elderly with Amyloid Plaques

Findings of this study may help identify individuals who could be candidates for therapies to prevent the development of dementia.

The study's findings have received early online publication in April 2011 in the journal Annals of Neurology. "Our findings support the theory that Alzheimer's disease begins many years before symptoms appear and that amyloid plaque is an early sign of this process,” said Keith Johnson, MD, Massachusetts General Hospital (MGH; Boston, MA, USA) Imaging, senior author of the study. "We see that when amyloid deposits are present, even in cognitively normal individuals, the degenerative changes of Alzheimer's are underway. Long-term studies to track these changes and observe how they evolve are ongoing.”

Definitive diagnosis of AD requires finding amyloid plaques and neurofibrillary tangles in the brain at autopsy. In recent years, it has been possible to detect amyloid in living brains by positron emission tomography (PET) scanning with an imaging agent known as Pittsburgh compound B (PiB). Plaques have been seen in the brains of seemingly healthy individuals, as well as those with dementia, but whether the presence of plaques indicates the early stages of AD is not yet known.

High-resolution magnetic resonance imaging (MRI) studies have identified characteristic alterations in brain structure--thinning of key cortical regions and reduced volume of structures such as the hippocampus--in individuals with mild cognitive impairment, in individuals known to carry gene mutations that directly cause AD, and in diagnosed Alzheimer's patients. A recent study reported similar brain changes in some cognitively normal elderly but did not differentiate those who had amyloid deposits from those who did not.

The current study involved 87 cognitively normal older individuals and 32 patients diagnosed with mild Alzheimer's--correlated for age, gender, and education--who had enrolled in the long-term Harvard Aging Brain Study. Participants underwent both high-resolution MR imaging of brain structure and PET scanning with PiB to detect amyloid plaques. The findings revealed that those cognitively normal individuals who had amyloid plaques also had structural alterations similar to but less evident than the neurodegenerative changes seen in the symptomatic patients. Structural changes were most pronounced in regions comprising what is called the default network, which is known to be affected early in the course of AD.

"If amyloidosis--deposits of amyloid plaques--in the brains of clinically normal people is associated with Alzheimer's-like neurodegeneration, then amyloidosis itself may signify ‘preclinical' AD,” said Dr. Johnson, an associate professor of radiology at Harvard Medical School (Boston, MA, USA). "We need to learn more about how long it takes a normal person with amyloid to develop AD, whether there are critical ‘second hit' factors that convert amyloidosis to Alzheimer's disease, and if there are measures that can halt the process of neurodegeneration.”

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