This month’s Archives of Neurology provides a gold mine of studies on the neuropathological correlates of mild cognitive impairment, and the predictive value of this syndrome as a precursor of Alzheimer disease. One paper from Ron Petersen, Gregory Jicha, and colleagues at the Mayo Clinic in Rochester, Minnesota, describes an autopsy study of amnestic MCI (aMCI) patients who died while still in this stage of limited cognitive impairment. The results confirm that aMCI lies at a midway point between normal aging and AD as judged by the extent and localization of plaque and tangle pathology. But is aMCI truly an AD prodrome? That question was addressed by a second study from the same group, which examined subjects who progressed from aMCI to dementia before their death. Those results showed that while most (70 percent) of the elderly with amnestic MCI developed Alzheimer disease, the rest developed dementia from other causes.
These studies should reassure researchers that they are on the right track in their pursuit of MCI, and particularly aMCI as a clinical predictor and early intervention point for AD. However, the results also point out an important problem with this approach, which is that in the general population, many people with MCI do not go on to develop AD, or even dementia. Trying to find better predictors of progression is the topic of a third report, where investigators Liana Apostolova, Paul Thompson, and their colleagues at the University of California, Los Angeles, used imaging to measure hippocampal size and shape in aMCI patients, and then followed the cohort over 3 years. They found that a smaller hippocampus with evidence of atrophy was associated with progression from MCI to dementia.
The Mayo studies are part of the clinic’s decades-long longitudinal community-based study of aging and dementia, which pairs years of clinical follow-up of subjects with postmortem pathological studies. Petersen and Jicha worked with Joseph Parisi and colleagues in Minnesota, plus Dennis Dickson at the Mayo Clinic in Jacksonville, Florida, and Heiko Braak at the J. W. Goethe University, Frankfurt, Germany, on an extensive neuropathological workup, including ,quantification of plaques, tangles and other disease markers throughout the brain.
In the first paper, lead author Petersen and colleagues describe the neuropathology of 15 elderly subjects who died between 1986 and 2004, while they were classified with MCI of the amnestic type (aMCI). Compared to age-matched healthy controls and people with AD, the aMCI group generally fell right in the middle—their brains were not normal, but the pathology did not rise to the level of AD. The quantity and distribution of tau-containing neurofibrillary tangles (rated by Braak score) were higher in the aMCI group than in normal aging, but not as high as in AD. Consistent with previous studies, amyloid plaque scores were very similar to normal aged brains, and much lower than in AD brains. Other abnormalities were commonly seen in a subset of the cases, including argyrophilic grain disease, hippocampal sclerosis, and vascular lesions.
Despite significant heterogeneity in the amount and type of pathology, all 15 subjects showed some involvement in the medial temporal lobe, which was consistent with their diagnosis of memory loss. In particular, the researchers observed NFTs in the entorhinal cortex and hippocampus, and diffuse amyloid in the neocortex—all previously reported signs of prodromal AD. From these results, the authors conclude that, “The regional involvement by NFTs correlated best with the degree of clinical impairment across the spectrum of healthy to aMCI to AD. In contrast, the amyloid plaque burden was less discriminating.” This observation fits with previous studies (see ARF related news story).
The companion study takes a further step down the road to dementia by asking about the neuropathology of patients with MCI who progress to dementia. First author Jicha describes the characterization of a group of 34 subjects who died after progression from aMCI to dementia. Most (71 percent) fit the pathological criteria for AD. But the remaining 29 percent showed non-AD primary pathologies including vascular disease, argyrophilic disease, and Lewy body disease.
No matter what the pathology, though, all had involvement of the medial temporal lobe sufficient to cause memory loss. In most cases, the problem was NFT degeneration, but in some instances the researchers observed hippocampal sclerosis, leading them to write that the “anatomy of neurodegeneration is more predictive of the clinical syndrome than the specific pathologic process. That which unites these various processes is their predilection for the medial temporal lobe.”
In this group, neither demographic nor diagnostic variables predicted which patients would develop AD, and which would develop dementia from other causes. Complicating the picture, most showed two or more pathological processes that might contribute to dementia.
Two editorials, one accompanying each paper, stress the importance of these kinds of painstaking, long-term human studies to understanding the pathogenesis and potential for treating AD. In one, Harry Vinters of the University of California, Los Angeles, raises the question of whether the early “Alzheimerization” of brains seen in MCI means that irreversible cellular and molecular events have already been set in motion, a question that only pharmacological intervention will answer.
Commenting on the progression study, Lawrence Hansen of the University of California, San Diego, calls the results “a sobering reminder that even with a thoroughly documented clinical course progression from MCI to dementia, a final clinical diagnosis of AD may be wrong in a significant minority of patients. As the authors note, these data raise concern about potential pathologic heterogeneity in subjects recruited for therapeutic trials in MCI.”
The heterogeneity issue has dogged the testing of early treatments for AD. While a diagnosis of MCI raises the risk of conversion to dementia, the majority of people with MCI either remain stable or improve when followed for 1 or 2 years. In prospective studies in a general population, conversion rates run 15 percent per year (and, as Jicha and colleagues have now shown, not all of these will have bona fide AD).
This is where the third paper fits in. To try to separate out the progressors from non-progressors, Apostolova, Thompson, and colleagues are investigating the use of magnetic resonance imaging to measure hippocampal morphology as a predictor of who will progress from MCI to dementia. They applied their technique for comparing hippocampal volume and shape (Thompson et al., 2004) to a cohort of 20 amnestic MCI patients, who were then followed up for 3 years.
During the study, six subjects developed clinical AD, seven remained cognitively stable, and seven improved. The group that progressed started with 9 and 13 percent lower hippocampal volume on the left and right side, respectively, relative to the stable group, and 24 and 27 percent lower volume compared to the improved group. The changes were statistically significant except for the right side changes between the progressors and the non-progressors. Regional analysis showed atrophy in the CA1 and subicular regions, with significant increases in patients that progressed to AD compared to the group that improved. The results agree with work done using similar techniques by John Csernansky and colleagues, who detected hippocampal shape changes in the CA1 region that predicted onset of dementia in elderly subjects (see Csernansky et al., 2005).—Pat McCaffrey