Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline

Abstract

Objective: The aim of this article was to evaluate in normal older adults and preclinical Alzheimer's disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline.

Methods: We acquired positron emission tomography using F18 flortaucipir (tau), C11 Pittsburgh compound B (amyloid), and F18 fluorodeoxyglucose (FDG) in 90 clinically normal elderly of the Harvard Aging Brain Study.

Results: Posterior cingulate metabolism decreased when both amyloid and neocortical tau were high and predicted subsequent memory decline in a larger sample of normal elderly. In contrast, frontal hypometabolism related to the common age-related entorhinal tauopathy, but this dysfunction was independent of amyloid, and did not predict significant memory decline. Neocortical tauopathy was positively associated with metabolism in individuals with subthreshold amyloid, suggesting that glucose metabolism increases before decreasing in the course of preclinical AD.

Interpretation: Our study identified a synergistic effect of amyloid and tau deposits and demonstrated, for the first time, in normal elderly its link to AD-like hypometabolism and to AD-like memory decline. The amyloid effect was observed with tau in neocortex, but not with tau in entorhinal cortex, which is the common site of age-related tauopathy. Entorhinal tau was associated with frontal hypometabolism, but this dysfunction was not associated with memory loss. Ann Neurol 2017;81:583-596.

Conflict of interest statement

POTENTIAL CONFLICT OF INTEREST DR, RS, and KJ have been consultants for Eli Lilly/Avid, which owns FTP, the tau tracer used in this study.

© 2017 American Neurological Association.

Figures

Figure 1. Tau deposition locally associated with hypometabolism in the temporal lobe

A. Mean SUVR maps for Flortaucipir (FTP) and Fluorodeoxyglucose (FDG) across the 90 study participants. B. Left: Local correlation map between FTP and FDG, adjusting for age. Temporal tau deposition is locally associated with FDG hypometabolism. Right: Interaction effect of global continuous PiB on the local FTP-FDG association, adjusting for age. FTP-associated temporal hypometabolism is dependent on PiB levels. C. Local FTP-associated hypometabolism is only observed in the high-PiB participants. Scale: cold colors represent hypometabolism. Threshold: T<−2·65, p<0·010. Arrows indicate peak statistics.

Figure 2. Tau deposition in the inferior temporal neocortex associated with amyloid-dependent hypometabolism

Age-adjusted FDG maps showing the association between the FDG PET signal in each vertex and FTP (tau-PET) signal in two regions of interest (ROI): entorhinal versus inferior temporal. A. Left: Entorhinal FTP-associated FDG hypometabolism includes inferior frontal, insular, and cingulate gyri. Right: Inferior temporal FTP-associated FDG hypometabolism is restricted to the temporal lobe. B. Interaction effect of global continuous PiB and FTP ROIs on FDG, adjusting for main effects and age. Entorhinal FTP-associated hypometabolism is not PiB-dependent (left) while inferior temporal FTP is associated with PiB-dependent temporo-parietal FDG hypometabolism (right). C. Inferior Temporal FTP is associated with FDG hypermetabolism in the subset of low-PiB individuals (left) but FDG hypometabolism in the subset of high-PiB individuals (right). See Figure Sup1 for entorhinal FTP. Scale: cold colors represent hypometabolism. Threshold: T>±2·65, p<0·010. Arrows indicate peak statistics.

Figure 3. Tau deposition in the entorhinal cortex associated with amyloid-independent inferior frontal and insular hypometabolism

Age-adjusted FDG maps in the subsets of low- and high-PiB individuals showing the association between the FDG PET signal in each vertex and entorhinal FTP (tau-PET) signal. Left: In the low-PiB individuals, entorhinal FTP is associated with inferior frontal and insular hypometabolism (arrow indicates peak p-value = 3*e-4, minimal t=−3·9). Right: In the high-PiB individuals, entorhinal FTP is associated with widespread temporo-parietal hypometabolism, including locally in the entorhinal cortex (arrow indicates peak p-value = 4*e-6, minimal t=−5·6). Scale: cold colors represent hypometabolism. Threshold: T>±2·65, p<0·010. Arrows indicate peak statistics.

Figure 4. PiB status only has an effect on hypometabolism associated with inferior temporal tau, not with entorhinal tau

Scatterplots of FTP (tau-PET) against FDG SUVR signals in selected ROIs. P-values in the right-upper corners indicate the significance of the interaction effect between FTP and PiB status on FDG (see Table 2 box 3.A). Dots are categorized by PiB status (blue: low-PiB (n=57), red: high-PiB (n=33)). Entorhinal and inferior temporal FTP have different impact on posterior cingulate FDG in low-PiB, but similar in high-PiB participants.

Figure 5. FDG hypometabolism predicts subsequent memory decline in high-PiB participants only

Scatterplots showing annual change in memory scores against FDG metabolism (SUVR) in selected ROIs. Memory and FDG data were residualized for age, sex, and education. P-values indicate the significance of the interaction effect between FDG and PiB status on memory changes (see Table 3). Dots are categorized by PiB status (blue: low-PiB (n=198), red: high-PiB (n=79)).