Association between lower body temperature and increased tau pathology in cognitively normal older adults

Esther M Blessing, Ankit Parekh, Rebecca A Betensky, James Babb, Natalie Saba, Ludovic Debure, Andrew W Varga, Indu Ayappa, David M Rapoport, Tracy A Butler, Mony J de Leon, Thomas Wisniewski, Brian J Lopresti, Ricardo S Osorio, Esther M Blessing, Ankit Parekh, Rebecca A Betensky, James Babb, Natalie Saba, Ludovic Debure, Andrew W Varga, Indu Ayappa, David M Rapoport, Tracy A Butler, Mony J de Leon, Thomas Wisniewski, Brian J Lopresti, Ricardo S Osorio

Abstract

Background: Preclinical studies suggest body temperature (Tb) and consequently brain temperature has the potential to bidirectionally interact with tau pathology in Alzheimer's Disease (AD). Tau phosphorylation is substantially increased by a small (<1 °C) decrease in temperature within the human physiological range, and thermoregulatory nuclei are affected by tau pathology early in the AD continuum. In this study we evaluated whether Tb (as a proxy for brain temperature) is cross-sectionally associated with clinically utilized markers of tau pathology in cognitively normal older adults.

Methods: Tb was continuously measured with ingestible telemetry sensors for 48 h. This period included two nights of nocturnal polysomnography to delineate whether Tb during waking vs sleep is differentially associated with tau pathology. Tau phosphorylation was assessed with plasma and cerebrospinal fluid (CSF) tau phosphorylated at threonine 181 (P-tau), sampled the day following Tb measurement. In addition, neurofibrillary tangle (NFT) burden in early Braak stage regions was imaged with PET-MR using the [18F]MK-6240 radiotracer on average one month later.

Results: Lower Tb was associated with increased NFT burden, as well as increased plasma and CSF P-tau levels (p < 0.05). NFT burden was associated with lower Tb during waking (p < 0.05) but not during sleep intervals. Plasma and CSF P-tau levels were highly correlated with each other (p < 0.05), and both variables were correlated with tau tangle radiotracer uptake (p < 0.05).

Conclusions: These results, the first available for human, suggest that lower Tb in older adults may be associated with increased tau pathology. Our findings add to the substantial preclinical literature associating lower body and brain temperature with tau hyperphosphorylation.

Clinical trial number: NCT03053908.

Keywords: Aging; Alzheimer's disease; Body temperature; Neurofibrillary tangle; Phosphorylation; Tau; [(18)F]MK-6240.

Conflict of interest statement

Declaration of Competing Interest

The authors declare that they have no competing interests.

Copyright © 2022. Published by Elsevier Inc.

Figures

Fig. 1. |
Fig. 1. |
Protocol for integrated measurement of body temperature and sleep. Time of body temperature sensor (pill) ingestion and recording indicated by line continuing from pill. Nocturnal polysomnography (NPSG) on Nights 1 and 2. Sleep interval (grey) included time between lights off (L. Off) and lights on (L. On), occurring in the sleep lab during NPSG. The Waking interval (white) included time on Days 1 and 2 between lights On and lights Off. During this time, subjects were free to return home and behave according to their normal schedule, indicated by activities bracketed under ‘?’.
Fig. 2.
Fig. 2.
Relationships between aggregated and soluble markers of tau pathology. A, Coronal [18F] MK-6240 tau tangle MR-PET images from two subjects: upper, T-negative 65 yo male, lower, T+ positive 63 yo female. B-D, associations between plasma P-tau, CSF P-tau and MK6240 SUVR uptake. Solid lines show linear regression, dashed lines show mean confidence intervals. Spearman’s rank correlation results at lower right of each plot.
Fig. 3. |
Fig. 3. |
Raw and DRAGO processed body temperature data for one participant. Upper panel, raw body temperature (Tb) data, yellow shading indicates data outlier, blue shading indicates data gap. Lower panel, DRAGO processed Tb data divided into Sleep (nights 1 and 2) and Waking (days 1 and 2) intervals. Shaded areas show Tb values under indicated threshold (37 °C). Waking interval Tb metrics were Mean Tb, 37.15 °C, and time Tb under threshold (TimeSubThr), 21.44%.
Fig. 4. |
Fig. 4. |
Correlation matrix of associations between body temperature, MK-6240 SUVR uptake in Braak I-III regions, CSF P-tau and plasma P-tau. Significant correlations are color coded by magnitude according to the indicated scale. Abbreviations: Tb, body temperature; SUVR, standardized uptake value ratio, TimeSubThr, body temperature under threshold.
Fig. 5. |
Fig. 5. |
Associations between Waking Tb and MK-6240 SUVR uptake. A, C associations for mean Tb and MK6240 SUVR uptake in Braak I and parahippocampal gyrus regions, respectively. B, D, equivalent associations for the proportion of time Tb was under threshold during Waking intervals. Results of Spearman’s rank correlations are shown, dashed lines show mean confidence intervals. Abbreviations, PHG, parahippocampal gyrus, Tb, body temperature, TimeSubThr, time Tb was under threshold, MK6240, [18F]MK-6240 tau tangle tracer, SUVR, standardized uptake value ratio.
Fig. 6. |
Fig. 6. |
Bidirectional relationship between body and brain temperature dysregulation and tau pathology. Arm 1 (black arrow) represents a direct effect of body and brain temperature upon tau phosphorylation and other molecular targets affecting tau pathology. Arm 2 (grey arrows) represents a multifactorial pathway by which tau pathology impacts body and brain temperature. Dashed line indicates minimal data available. Abbreviations, TR, thermoregulatory, S/WP, sleep- or wake promoting (neuron), CR, circadian rhythm.

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