Do Frontoparietal Regions Shrink First in Preclinical Alzheimer’s?

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.

Comments

  1. This study is an excellent example of the importance of longitudinal biomarker studies in different stages of AD, from the preclinical to the dementia stage.

    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. The basis for this knowledge will expand from end-stage neuropathology in cross-sectional clinical studies to longitudinal biomarker studies, including those in the preclinical stage of the disease. Indeed, the authors conclude that the results from this study will modify previous models of the relationship between Aβ and regional atrophy during the development of AD.

    View all comments by Kaj Blennow

  2. In this article, Mattson et al. examine gray-matter atrophy in clinically normal (CN) participants with 1) high and stable levels of CSF Aβ (s-Aβneg), 2) high and declining levels of CSF Aβ, and 3) low levels of CSF Aβ (ABpos). Although gray-matter differences between groups were not observed at baseline, d-Aβneg CNs showed greater frontoparietal atrophy over time, whereas a more diffuse pattern of atrophy was observed in Aβpos normal controls. Interestingly, these gray-matter changes were not accompanied by changes in CSF tau measures, suggesting this pattern of atrophy may occur independently of tangle formation during the early stages of Aβ accumulation.

    Although limited by a small sample size, these results suggest that initial changes in the trajectory towards Alzheimer’s disease may occur in neocortical areas known to show early Aβ deposition.  The spatial pattern of Aβ deposition during the earliest stages of accumulation within CNs remains unknown, and it would be interesting to use amyloid imaging to examine whether frontoparietal regions are among the first regions to show it.  A major remaining question is why does frontoparietal atrophy slow down over time?  It is possible that this early effect in frontoparietal regions is purely related to Aβ, given that these regions typically do not show tangle pathology until late in the disease.  Thus, more drastic effects may eventually occur in regions displaying con-current amyloid and tangle pathologies, such as in temporal cortex. To understand these distinct patterns of regional vulnerabilities, it will be critical to investigate longer follow ups of CNs undergoing the earliest signs of Aβ accumulation. 

    View all comments by Elizabeth Mormino

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References

News Citations

  1. Cortical Changes Precede Hippocampal in ApoE Carriers
  2. Do Earliest Cognitive Deficits in Alzheimer's Appear in the Entorhinal Cortex?

Paper Citations

  1. Chételat G, Villemagne VL, Bourgeat P, Pike KE, Jones G, Ames D, Ellis KA, Szoeke C, Martins RN, O'Keefe GJ, Salvado O, Masters CL, Rowe CC, . Relationship between atrophy and beta-amyloid deposition in Alzheimer disease. Ann Neurol. 2010 Mar;67(3):317-24. PubMed.
  2. Becker JA, Hedden T, Carmasin J, Maye J, Rentz DM, Putcha D, Fischl B, Greve DN, Marshall GA, Salloway S, Marks D, Buckner RL, Sperling RA, Johnson KA. Amyloid-β associated cortical thinning in clinically normal elderly. Ann Neurol. 2011 Jun;69(6):1032-42. PubMed.
  3. Oh H, Habeck C, Madison C, Jagust W. Covarying alterations in Aβ deposition, glucose metabolism, and gray matter volume in cognitively normal elderly. Hum Brain Mapp. 2012 Sep 11; PubMed.

External Citations

  1. Alzheimer’s Disease Neuroimaging Initiative

Further Reading

Primary Papers

  1. Mattsson N, Insel PS, Nosheny R, Tosun D, Trojanowski JQ, Shaw LM, Jack CR Jr, Donohue MC, Weiner MW, Alzheimer’s Disease Neuroimaging Initiative. Emerging β-amyloid pathology and accelerated cortical atrophy. JAMA Neurol. 2014 Jun;71(6):725-34. PubMed.

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