Changes in Brain Structure Evident Before Cognitive Symptoms Develop in Alzheimer’s Disease

The observable symptoms of Alzheimer’s disease (AD), which include memory loss and cognitive decline, may be what most people associate with the devastating disease. Research has shown, however, that many changes are taking place inside the brain prior to cognitive impairment, in an asymptomatic phase of AD. Pathological changes in the brain, neurofibrillary tangles and amyloid plaques, are suspected of playing a role in the death of neurons in AD. These plaques and tangles are present before the cognitive symptoms of AD are apparent.

Changes that may occur in the brain structure prior to the onset of cognitive impairment are not as well understood. Previous studies suggested that structural changes occurring in the brain correspond with cognitive symptoms in AD. A recent study reported in the Neurobiology of Aging investigated whether structural brain changes could be detected by structural magnetic resonance imaging (MRI) in the asymptomatic phase of AD. Volunteer subjects underwent a screening and MRI scan at the start of the study to confirm they were all healthy and cognitively normal. Subjects were followed for a period of ten years, and assessed throughout the study to determine if changes had taken place in their cognitive health. At completion of the ten year follow-up period the subjects were grouped based on their cognitive health. Those who developed amnestic Mild Cognitive Impairment (MCI) – memory impairments beyond that of normal aging, that do not meet diagnosis criteria for AD – were included in the preclinical MCI group. Those who developed AD were included in the preclinical AD group. Lastly, those who did not show any change in cognitive health were included in the healthy control group.

Using the baseline MRIs, a voxel-based morphometry analysis and shape analysis allowed the researchers to compare the brain volumes between the groups of subjects. A decrease in gray matter volume was seen in the preclinical MCI and preclinical AD groups when compared to the healthy controls. Specifically, atrophy of the bilateral medial and lateral temporal lobes, fronto-orbital cortex, posterior cingulate, and precuneus was present in the preclinical AD group. These are the same areas of atrophy that are present in clinically diagnosed AD. In other words, before the onset of cognitive impairment, the group destined to develop AD showed the same areas of atrophy seen in clinically diagnosed AD.

The hippocampus is known to play a role in MCI and AD progression. In this study the right hippocampus showed greater and earlier atrophy than the left in the preclinical AD group. The authors of this study suggest that the atrophy seen in the right hippocampus may be an early feature in the disease process, when considered with an earlier study that showed hippocampal asymmetry decreasing as AD progressed.

The small sample size and the high education level of subjects in the preclinical AD group must be considered when interpreting the study results. Those with a higher education may continue to perform well on cognitive tasks and not receive the diagnosis of AD, relative to the structural brain changes already taking place. While there is still much to learn, this study contributes to the growing body of information that illustrates the many changes taking place inside the brain before symptoms of AD are present.


Manuela Tondelli, Gordon K. Wilcock, Paolo Nichelli, Celeste A. De Jager, Mark Jenkinson, Giovanna Zamboni, Structural MRI changes detectable up to ten years before clinical Alzheimer’s disease, Neurobiology of Aging, In Press, Corrected Proof, Available online 22 July 2011, ISSN 0197-4580, DOI: 10.1016/j.neurobiolaging.2011.05.018.


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