Patterns of Brain Amyloid and Tau Deposition Seen on Imaging

Fran Lowry

June 14, 2017

Researchers have discovered in vivo patterns for tau and amyloid-β (Aβ) deposition across different systems in the human brain.

In a cross-sectional study that used advanced imaging techniques, tau and Aβ deposits in the brains of elderly, cognitively normal individuals displayed well-defined hierarchical cortical relationships.

Those deposits also displayed overlaps between the principal accumulations of both pathologic abnormalities in the heteromodal association regions, the researchers note.

Dr Jorge Sepulcre

These findings represent "systematic, large-scale mechanisms" of early pathologic changes of Alzheimer's disease in the elderly human brain, the authors, led by Jorge Sepulcre, MD, PhD, from Massachusetts General Hospital and Harvard Medical School, Boston, write.

Their report was published online May 30 in JAMA Neurology.

"We have been speculating about the progression patterns of Alzheimer's disease pathology in the human brain for decades, but most of the data that we have come from histology," Dr Sepulcre told Medscape Medical News.

"For years, people have been saying that it looks like the spatial distribution for amyloid and tau is following a hierarchical order, but that was an idea because we didn't have the methods, such as the tau PET for instance, to apply to the histological data to prove that. But in this study we were able to find these spatial dependencies and the relationships between the different parts of the brain," he said.

"Pathologic processes begin decades before the onset of the clinical manifestations of Alzheimer's disease, and therefore the study of the cortical distribution of early-stage pathologic alterations is critical in understanding the underpinnings of the disease," Dr Sepulcre said.

He and his team sought to discover the in vivo cortical distributions and the relationships between tau and Aβ  deposits in 88 elderly, cognitively normal participants in the Harvard Aging Brain Study.

The mean age of the participants was 76.2 years (standard deviation, 6.2 years); 39 participants (44%) were men, and all were living in the community.

The researchers hypothesized that Aβ and tau pathologic changes spread along interconnected systems beyond the constraints of spatial proximity.

The participants underwent flortaucipir 18 T807 (18F-T807) and carbon 11–labeled Pittsburgh compound B (11C-PiB) positron emission tomographic (PET) imaging.

A voxel-level hierarchical clustering approach was used to obtain the main clustering partitions corresponding to the cortical distribution maps of 18F-T807 and 11C-PiB.

Hierarchical relationships between areas of distinctive pathologic deposits were then studied. Through use of cerebellar gray reference, 18F-T807 data were expressed as standardized uptake value ratio, and 11C-PiB data were given as distribution volume ratio.

The scans showed that the tau and Aβ maps both displayed optimal cortical partitions at four clusters.

The tau deposits were grouped in the temporal lobe and distributed in heteromodal areas, medial and visual regions, and primary somatomotor cortex.

The Aβ deposits were clustered in the heteromodal areas and "rather patchy" in distributed regions involving the primary cortices, medial structures, and temporal areas, the authors write.

The scans also revealed that the tau deposits in the temporal lobe and distributed heteromodal areas were "tightly nested," they report.

"We were using a relatively new PET tracer for tau, and this allows us to look for interactions in vivo between amyloid and tau. The kind of nested patterns that we have seen gives us a lot of clues about the spatial distribution of the pathology and how it progresses," Dr Sepulcre said.

"Also, the other novelty is we are taking a whole brain approach looking for hierarchical structure, to see how tau and amyloid are organized in the neural systems. Now we can see the exact pattern," he said.

"One cluster for amyloid is important. It is the one that is distributed in the main cluster, the default mode network. From there, it looks as if it spreads to the neighboring areas. But tau jumps from the temporal lobe to distant areas in the association cortex," he said.

"Both pathologies are very distinct from each other, but they have specific areas that they target. What is new here is that we were able to find that tau is in fact spreading at the spatial domain, from the temporal to the association cortex. This is important with regard to Alzheimer's disease because we are targeting the very early stages of the pathology. If we are able to find the spreading pathways, then we are going to be able to find a specific target to try and stop the progression. That is the hope," Dr Sepulcre said.

In an accompanying editorial, Prashanthi Vemuri, PhD, from the Mayo Clinic, Rochester, Minnesota, and Michael Schöll, PhD, University of Gothenburg, Sweden, write that although these initial results are intriguing and may aid in individual staging of Alzheimer's disease abnormalities, further studies need to be undertaken to test "these novel findings that tau in the association cortex, and not the medial temporal lobe, is a significant factor in AD pathogenesis."

"The finding that tau shows up everywhere is important," Dr Vemuri told Medscape Medical News.

"This was not clearly known before. It is a unique finding, but it still needs to be investigated more. This is very preliminary work. Also, this was a cross-sectional study. People need to be followed longitudinally to see how tau changes," she said.

The Research was supported by the National Institutes of Health, Massachusetts Alzheimer's Disease Research Center, and Alzheimer's Association. Dr Sepulcre and Dr Vemuri have disclosed no relevant financial relationships.

JAMA Neurol.   Published online May 30, 2017. Abstract, Editorial

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