Amnestic mild cognitive impairment is neuropathologically the same entity as early Alzheimer's disease and represents a transition from the normal aging brain to the profound pathology of Alzheimer's, according to Dr. William Markesberry and colleagues.
The transition appears to be marked more by an increase in neurofibrillatory tangles than in dendritic or neuritic plaques, wrote Dr. Markesberry of the University of Kentucky, Lexington, and his associates.
The researchers followed 43 elderly subjects who were cognitively normal at baseline, until their deaths: 23 of them remained cognitively normal, 10 developed amnestic MCI, and 10 developed early Alzheimer's disease (EAD).
All of the brains were available for autopsy via prior arrangement with the subjects (Arch. Neurol. 2006;63:38–46).
Comparison of the brains from patients with EAD to normal brains found significant increases in all the pathologic hallmarks of the disease (dendritic plaques, neuritic plaques, and neurofibrillatory tangles) in all of the neocortical and ventromedial regions.
There were no significant differences in the number of dendritic plaques between the controls and those with MCI, nor between the MCI brains and the EAD brains. “Because dendritic plaques were so common in normal control subjects, our data suggest that they are not critical neuropathologic determinants of the transition from normal to MCI, or MCI to EAD,” the investigators wrote.
Neuritic plaques were significantly more common in the MCI brains than in the control brains. But when the MCI brains were compared with EAD brains, the plaques only increased significantly in the amygdala and subiculum.
“This indicates that the pathologic deposition of insoluble β-amyloid peptide and formation of neurites in the cerebral cortex progress from normal to MCI, but in contrast, they do not distinguish MCI from EAD.”
The most striking difference between the brains was the amount of neurofibrillatory tangling. Compared with normal brains, the MCI brains showed significantly more tangles in the inferior parietal lobule, amygdala, entorhinal cortex, and subiculum. When compared with MCI brains, EAD brains showed an expansion of the tangles, with significantly more in the middle temporal gyrus, middle temporal gyrus, amygdala, and subiculum.
These changes imply neuropathologic progression, the researchers wrote. “The increase in [tangles] in all of the neocortical and ventromedial lobe structures in EAD, compared with controls, further supports a gradual increase in [tangle] formation from normal aging to having MCI to having EAD.”
The conclusions argue for a change in the diagnostic criteria of early Alzheimer's and MCI, Dr. John Morris wrote in an accompanying editorial.
The standard criteria, which were developed years ago, can't distinguish between the mild stages of Alzheimer's and MCI that are now identifiable, wrote Dr. Morris of Washington University, St. Louis (Arch. Neurol. 2006;63:15–6).
“Revised criteria should permit the diagnosis of AD at these early stages, because … AD pathology is already established. Moreover, the earliest stages of AD may be the optimal time for interventions with drugs now in development that have the potential to retard or even arrest the AD process.”