Contribution of locus coeruleus activity patterns on TAU deposition in alzheimer's disease

Active Project Grant Awarded Last action

Award ID
R21AG081681
Recipient
Awarding agency
Obligated
$1,566,000

Award facts

Assistance listing
93.866 Aging Research
Completion date 88% complete
Originally
Place of performance
Boston, MA 02114, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Alzheimer's disease (ad)'s neuropathologic hallmarks are the accumulation of amyloid-beta (ASS) and TAU proteins. Thus far, therapeutic efforts have been mainly focused on ASS and showed limited success, underscoring the need for alternative approaches of intervention, particularly those that can target mechanisms related to the initial propagation of pathology. The locus coeruleus (LC) has been identified as one of the earliest regions affected by TAU: by the age of 40, 80% of individuals exhibit TAU aggregation in the LC, and by the age of 50, 50% of individuals exhibit TAU aggregation in the entorhinal cortex (EC), suggesting TAU progression from the LC to the medial temporal lobe (MTL). However, the mechanism of TAU propagation is yet unknown. Accumulated evidence from animal research suggests that pathologic TAU propagates via axons and cell-to-cell transmission and that synaptic and neuronal activity levels facilitate this process. Furthermore, a recent study using a RAT model of pretangle TAU in LC neurons and optogenetic stimulation suggested that novelty-like phasic LC activation protects against the deleterious changes linked to pretangle TAU. In contrast, stress-associated tonic LC activation worsens LC neuronal health and promotes depressive behaviors that have been associated with TAU accumulation in the EC. Our own preliminary data shows that lower novelty-related LC activation is related to higher TAU deposition in the EC and steeper memory decline in cognitively healthy older individuals. This evidence forms the scientific premise for the hypothesis that phasic versus tonic resting-state LC activity may be associated with mechanisms of TAU propagation and ultimately predict cognitive decline. The goal of this proposal is to examine the relationship between the balance between phasic versus tonic LC activity detected in resting- state fmri data and TAU deposition in the EC and the MTL across all stages of the ad continuum and cognitive decline. To achieve this, we will resolve two methodological barriers: (II) accounting for the hemodynamic blurring in resting-state fmri using deconvolution in terms of an optimally defined region- and subject-specific hemodynamic response function, and (II) using novel event-detection techniques for the detection of periods of phasic and tonic activity in the deconvoluted LC. Our methodology for quantifying the balance between phasic versus tonic LC activity will be fine-tuned and validated using simultaneous LC bold-fmri, fiber photometry calcium imaging, and pupil dilation data collected from awake rodents during resting-experimental conditions. Combining these state-of-the-art novel methods with TAU-, ASS-pet, and longitudinal cognitive data from the harvard aging brain study and the alzheimer disease neuroimaging initiative, will allow US to examine the following aims: aim 1) to investigate the associations between cross-sectional patterns of LC activity with age, SEX, TAU, and beta-amyloid pathology among individuals of varying biomarker levels, aim 2) to relate LC activation patterns to cognitive decline as a function of ad pathology. Together, these aims contribute to our understanding of the mechanistic underpinnings of initial TAU propagation and its relevance for cognition.

Transactions

Action Obligated Date
Amendment $0
Amendment $16,700
Amendment $150,300
Amendment $150,300
Amendment $0
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Amendment $249,550
Amendment $249,550
Amendment $249,550
Amendment $249,550
Original award $250,500
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Subawards

Subrecipient Amount Awarded
Universite De Geneve As part of this R21 grant (#R21AG081681) awarded to Dr. Prokopiou at MGH, Dr. Zerbi, the subcontract-PI, will collect simultaneous resting-state locus coeruleus… $32,400
Ecole Polytechnique Federale De Lausanne, Epfl Dr. Prokopiou at MGH, Dr. Zerbi, the subcontract-PI, will collect simultaneous resting-state locus coeruleus fMRI and fiber photometry data, as well as… $32,400

Quick answers

Who received award R21AG081681?

R21AG081681 was awarded to The General Hospital Corporation by National Institute on Aging (National Institutes of Health) on July 1, 2023.

How much is award R21AG081681 worth?

$1,566,000 has been obligated on R21AG081681.

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