Hierarchical Organization of Tau and Amyloid Deposits in the Cerebral Cortex

Abstract

Importance  Abnormal accumulation of tau and amyloid-β (Aβ) proteins in the human brain are 2 pathologic hallmarks of Alzheimer disease (AD). Because pathologic processes begin decades before the onset of the clinical manifestations, the study of the cortical distribution of early-stage pathologic alterations is critical in understanding the underpinnings of the disease.

Objectives  To identify the in vivo brain spatial distributions of tau and Aβ deposits in a sample of cognitively normal participants in the Harvard Aging Brain Study, determine spatial patterns of pathologic alterations, and provide means for improved individual in vivo staging.

Design, Setting, and Participants  Eighty-eight individuals from the general community 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. Using cerebellar gray reference, ¹⁸F-T807 data were expressed as standardized uptake value ratio, and ¹¹C-PiB were given as distribution volume ratio.

Main Outcomes and Measures  Main in vivo and hierarchically organized tau and Aβ deposits in the elderly brain.

Results  Of the 88 study participants, 39 (44%) were men, with a mean (SD) age of 76.2 (6.2) years. The tau and Aβ maps both displayed optimal cortical partitions at 4 clusters. The tau deposits were grouped in the temporal lobe, 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. Moreover, tau deposits in the temporal lobe and distributed heteromodal areas were tightly nested.

Conclusions and Relevance  Tau and Aβ deposits in the elderly brain generally display well-defined hierarchical cortical relationships as well as overlaps between the principal clusters of both pathologic alterations in the heteromodal association regions. These findings represent systematic, large-scale mechanisms of early AD pathology.

JAMA Neurology 2017