The bivariate distribution of amyloid-β and tau: relationship with established neurocognitive clinical syndromes

Clifford R Jack, Heather J Wiste, Hugo Botha, Stephen D Weigand, Terry M Therneau, David S Knopman, Jonathan Graff-Radford, David T Jones, Tanis J Ferman, Bradley F Boeve, Kejal Kantarci, Val J Lowe, Prashanthi Vemuri, Michelle M Mielke, Julie A Fields, Mary M Machulda, Christopher G Schwarz, Matthew L Senjem, Jeffrey L Gunter, Ronald C Petersen, Clifford R Jack, Heather J Wiste, Hugo Botha, Stephen D Weigand, Terry M Therneau, David S Knopman, Jonathan Graff-Radford, David T Jones, Tanis J Ferman, Bradley F Boeve, Kejal Kantarci, Val J Lowe, Prashanthi Vemuri, Michelle M Mielke, Julie A Fields, Mary M Machulda, Christopher G Schwarz, Matthew L Senjem, Jeffrey L Gunter, Ronald C Petersen

Abstract

Large phenotypically diverse research cohorts with both amyloid and tau PET have only recently come into existence. Our objective was to determine relationships between the bivariate distribution of amyloid-β and tau on PET and established clinical syndromes that are relevant to cognitive ageing and dementia. All individuals in this study were enrolled in the Mayo Clinic Study of Aging, a longitudinal population-based study of cognitive ageing, or the Mayo Alzheimer Disease Research Center, a longitudinal study of individuals recruited from clinical practice. We studied 1343 participants who had amyloid PET and tau PET from 2 April 2015 to 3 May 2019, and met criteria for membership in one of five clinical diagnostic groups: cognitively unimpaired, mild cognitive impairment, frontotemporal dementia, probable dementia with Lewy bodies, and Alzheimer clinical syndrome. We examined these clinical groups in relation to the bivariate distribution of amyloid and tau PET values. Individuals were grouped into amyloid (A)/tau (T) quadrants based on previously established abnormality cut points of standardized uptake value ratio 1.48 (A) and 1.33 (T). Individual participants largely fell into one of three amyloid/tau quadrants: low amyloid and low tau (A-T-), high amyloid and low tau (A+T-), or high amyloid and high tau (A+T+). Seventy per cent of cognitively unimpaired and 74% of FTD participants fell into the A-T- quadrant. Participants with mild cognitive impairment spanned the A-T- (42%), A+T- (28%), and A+T+ (27%) quadrants. Probable dementia with Lewy body participants spanned the A-T- (38%) and A+T- (44%) quadrants. Most (89%) participants with Alzheimer clinical syndrome fell into the A+T+ quadrant. These data support several conclusions. First, among 1343 participants, abnormal tau PET rarely occurred in the absence of abnormal amyloid PET, but the reverse was common. Thus, with rare exceptions, amyloidosis appears to be required for high levels of 3R/4R tau deposition. Second, abnormal amyloid PET is compatible with normal cognition but highly abnormal tau PET is not. These two conclusions support a dynamic biomarker model in which Alzheimer's disease is characterized first by the appearance of amyloidosis and later by tauopathy, with tauopathy being the proteinopathy associated with clinical symptoms. Third, bivariate amyloid and tau PET relationships differed across clinical groups and thus have a role for clarifying the aetiologies underlying neurocognitive clinical syndromes.

Keywords: Alzheimer’s disease; amyloid PET; dementia with Lewy bodies; frontotemporal dementia; tau PET.

© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.

Figures

Figure 1
Figure 1
Amyloid and tau PET distributions by clinical group overall and within study. Scatter plots of tau PET SUVR versus amyloid PET SUVR among all individuals combined (A) and separately among individuals in the MCSA (B) and ADRC (C). Tau PET and amyloid PET values are in SUVR units but the data is plotted on log scale, which accounts for the uneven spacing. Points are coloured by clinical diagnosis. Histograms in the margins show the distributions of tau PET SUVR (right) and amyloid PET SUVR (top). Axis labels on the top represent amyloid PET values on a centiloid scale.
Figure 2
Figure 2
Amyloid and tau PET clusters. Scatterplot of tau PET SUVR versus amyloid PET SUVR with points coloured according to the three-cluster classification from a bivariate mixture model (A). Points shown in black represent individuals who were inconsistent with one of the three clusters. The vertical and horizontal lines represent the cut points of 1.48 SUVR for amyloid PET and 1.33 SUVR for tau PET. The ellipses show the centre 50% of the data for the three cluster distributions with a black star indicating the bivariate mean from the clustering. In B, these ellipses are shown along with a square for each clinical diagnosis group representing the bivariate median (centroid) of the tau and amyloid distributions. Tau PET and amyloid PET values are in SUVR units but the data is plotted on log scale, which accounts for the uneven spacing. Axis labels on the top represent amyloid PET values on a centiloid scale.
Figure 3
Figure 3
Amyloid and tau PET groups within clinical diagnosis. Per cent of individuals in each quadrant (A) or cluster (B) within each clinical diagnostic group. (A) Percentages according to amyloid and tau PET groupings based on the established cut points of 1.48 SUVR for amyloid PET and 1.33 SUVR for tau PET. (B) Percentages according to the bivariate mixture model clusters. These are labelled according to amyloid (low or high) and tau (low or high). Those individuals whose values were inconsistent with one of the three clusters were labelled as other.
Figure 4
Figure 4
Scatter plots of tau PET SUVR versus amyloid PET SUVR by age groups among cognitively unimpaired (CU), MCI, and AlzCS individuals. MCSA individuals are shown in the left column and ADRC individuals in the right column. The vertical and horizontal lines represent the cut points of 1.48 SUVR for amyloid PET and 1.33 SUVR for tau PET. Points are coloured by clinical diagnosis. Tau PET and amyloid PET values are in SUVR units but the data is plotted on a log scale, which accounts for the uneven spacing. Axis labels on the top of the columns represent amyloid PET values on a centiloid scale.
Figure 5
Figure 5
Scatter plots of tau PET SUVR versus amyloid PET SUVR among all individuals combined and separately among individuals in the MCSA and ADRC for three alternative tau PET regions of interest. Points are coloured by clinical diagnosis. Histograms in the margins show the distributions of tau PET SUVR (right) and amyloid PET SUVR (top). Axis labels on the top of each plot represent amyloid PET values on a centiloid scale. Tau PET and amyloid PET values are in SUVR units but the data is plotted on a log scale, which accounts for the uneven spacing.

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