Hippocampal atrophy characterizes symptomatic Alzheimer’s disease, but a study in the April 28 JAMA Neurology makes the case that degeneration actually begins in the frontoparietal cortex. Researchers led by Niklas Mattsson at the University of California, San Francisco, found that these regions shrank in a small cohort of cognitively normal older adults who had normal but falling levels of Aβ42 in cerebrospinal fluid (CSF). By contrast, in participants who had CSF Aβ levels low enough to be considered preclinical AD, temporal regions atrophied as well. If the findings hold up in larger studies, they would point to the frontoparietal cortex as one of the first regions of the brain to be ravaged by AD.
Other researchers hailed the findings. “I think this is very exciting. We don’t have a lot of longitudinal data for preclinical sporadic AD,” said Tammie Benzinger at Washington University in St. Louis. Frontoparietal atrophy might help select participants for prevention trials, she suggested.
Atrophy heat map: Frontoparietal areas of the brain atrophy faster (red) in people with falling CSF Ab than in those with stable Aβ levels, while temporal regions deteriorate at about the same rate in both groups (green). [Image courtesy of Niklas Mattsson.]
Frontoparietal regions have been implicated in Alzheimer’s disease before. For example, in elderly people at genetic risk for AD, these areas exhibit poor glucose metabolism (see Dec 2012 news story). In other studies of cognitively healthy elderly, amyloid deposits and atrophy in these regions go hand in hand (see Chételat et al., 2010; Becker et al., 2011; Oh et al., 2014). However, previous research did not look at changes over time, and so could not place frontoparietal atrophy in context with the progression of known AD biomarkers.
To fill this gap, Mattsson and colleagues analyzed data from 62 participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were followed with CSF measures and structural MRI at yearly visits for up to four years. Fifteen of the volunteers had Alzheimer's, while the others were cognitively healthy. The researchers divided the healthy cohort into three groups based on their CSF Aβ. Thirteen had normal Aβ levels that stayed stable during the observation period; 13 had normal levels that fell steadily but remained above the cutoff for preclinical AD; and 21 had levels below the cutoff.
At baseline, the three cognitively healthy groups had similar brain volumes in all regions examined. Longitudinal data, however, revealed striking differences in atrophy rates. In people with declining Aβ, frontoparietal regions shrank more quickly than in the stable group. In the preclinical AD group, not only frontoparietal but also temporal and cingulate regions and the amygdala diminished in size. The mild atrophy in these groups contrasted with the symptomatic AD patients, where atrophy reached its peak. Shrinkage of temporal and cingulate regions greatly accelerated, and hippocampal atrophy appeared. As a result, AD patients also had smaller baseline brain volumes than the cognitively healthy groups did.
Why would atrophy begin in the neocortex? These regions are the first to accumulate amyloid, Mattsson noted. “One hypothesis is that atrophy results from local amyloid toxicity in frontal and parietal lobes, while the massive atrophy in the temporal lobes that we associate with AD may be more directly linked to the presence of tau pathology,” he told Alzforum. Intriguingly, the data may help to resolve a long-standing discrepancy in the amyloid hypothesis, namely that early amyloid deposits appear in the neocortex while most atrophy occurs in the temporal lobes. The new data hint that cortical amyloid does damage neurons, but tau might have a much greater effect, in keeping with the close correlation between tau tangles and cognitive decline, Mattsson said. In future studies, he plans to use amyloid and tau imaging in conjunction with structural MRI to tease out the regional effects of each type of pathology early in the disease. He will also try to replicate the findings in larger, independent cohorts.
The findings agree with other studies showing that neocortical amyloid accumulation precedes any hippocampal deficits in cognitively normal older adults (see Apr 2014 news story). It makes sense that hippocampal damage does not show up in preclinical groups, since memory problems only appear in symptomatic AD, Benzinger noted. It is not yet clear if the mild atrophy in other regions in preclinical patients has any functional effects.
Could frontoparietal atrophy serve as a biomarker? Mattsson cautioned that in his study, frontoparietal atrophy rates overlapped quite a bit between groups. “At this point, I don’t think this is useful as a biomarker in individual subjects. I see this more as a tool to understand disease mechanisms,” he said. However, Benzinger suggested that the idea deserves further investigation. In addition to being a potential selection marker for trials, frontoparietal atrophy might show promise as an outcome measure to reveal a drug effect, she speculated.
Other researchers suggested that the findings might help to refine models of AD progression. “Just as the map of the world was redrawn after the introduction of modern technology, knowledge about the evolution of AD pathology likely will have to be reconsidered based on this type of study,” Kaj Blennow at the University of Gothenburg, Sweden, wrote to Alzforum (see full comment below).—Madolyn Bowman Rogers.
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