Effects of dopamine and amyloid-beta on rest-to-task network reconfiguration in older adults
Poster No:
900
Submission Type:
Abstract Submission
Authors:
Thomas Morin1, Claire Ciampa2, Hsiang-Yu Chen3, Jennifer Crawford3, Jourdan Parent4, Alex Adornato3, Jordyn Cowan3, Katherine O'Malley3, Cristina Cusin4, Ming Hsu5, Jacob Hooker4, William Jagust5, Anne Berry3
Institutions:
1Mass General Hospital, Brandeis University, Boston, MA, 2University of Brandeis, Waltham, MA, 3Brandeis University, Waltham, MA, 4Mass General Hospital, Boston, MA, 5UC Berkeley, Berkeley, CA
First Author:
Co-Author(s):
Introduction:
Functional brain network stability across resting and task states is linked to cognitive performance in young adults (Schultz & Cole, 2016; Thiele et al., 2022), but is reduced in older adults (Hughes et al., 2020) and worsened by Alzheimer's disease (AD) pathology. Separately, the dopamine system has been hypothesized to play a key role in regulating brain network stability and flexibility (Braun et al., 2015, 2021). Recent work from our group has proposed that the dopamine system may offer cognitive resilience to Alzheimer's disease-related pathology (Ciampa et al., 2022). Using multimodal neuroimaging (PET, fMRI) from two longitudinal studies, we examine how age, dopamine, and AD-pathology influence brain network dynamics and cognition.
Methods:
Data were used from two ongoing longitudinal studies: the Berkeley Aging Cohort Study (BACS) (n = 47 older adults; n = 29 younger adults) and the Brandeis Aging Brain Study (BABS) (n = 45 older adults). All older adults were cognitively normal according to neuropsychological testing.
The BACS dataset included fMRI scans acquired during a reward-learning task, and pre- and post-task resting state scans. Older-adult BACS participants also completed PET brain imaging using [11C]Pittsburgh Compound B (PiB) to measure cerebral amyloid-beta plaques. BACS participants were classified as amyloid-positive (PiB+) or amyloid-negative (PiB-) using a distribution volume ratio (DVR) threshold of 1.065 (Villeneuve et al., 2015). The BABS dataset included fMRI scans acquired during a memory encoding task, and pre- and post-task resting state scans. Simultaneous [11C]Raclopride PET data were also acquired to measure striatal dopamine D2/3 receptor binding potential. BABS participants completed the experiment twice, first following placebo, and then following administration of methylphenidate, a dopamine-enhancing drug. Functional connectomes were generated for each resting and task state by extracting the mean denoised BOLD-signal time-course from each cortical region in the Schaefer-400 atlas (Schaefer et al., 2018). Network reconfiguration was quantified as the cosine-distance between functional connectomes generated from resting state and task scans. Linear mixed effects models were used to assess the relationships between network reconfiguration and memory, methylphenidate administration, age, and PiB-status.
The BACS dataset included fMRI scans acquired during a reward-learning task, and pre- and post-task resting state scans. Older-adult BACS participants also completed PET brain imaging using [11C]Pittsburgh Compound B (PiB) to measure cerebral amyloid-beta plaques. BACS participants were classified as amyloid-positive (PiB+) or amyloid-negative (PiB-) using a distribution volume ratio (DVR) threshold of 1.065 (Villeneuve et al., 2015). The BABS dataset included fMRI scans acquired during a memory encoding task, and pre- and post-task resting state scans. Simultaneous [11C]Raclopride PET data were also acquired to measure striatal dopamine D2/3 receptor binding potential. BABS participants completed the experiment twice, first following placebo, and then following administration of methylphenidate, a dopamine-enhancing drug. Functional connectomes were generated for each resting and task state by extracting the mean denoised BOLD-signal time-course from each cortical region in the Schaefer-400 atlas (Schaefer et al., 2018). Network reconfiguration was quantified as the cosine-distance between functional connectomes generated from resting state and task scans. Linear mixed effects models were used to assess the relationships between network reconfiguration and memory, methylphenidate administration, age, and PiB-status.
Results:
In the BACS cohort, older adults showed greater rest-to-task brain network reconfiguration compared to younger adults (b = 0.098, t = 3.64, p < 0.001). Moreover, PiB+ older adults showed increased rest-to-task reconfiguration of the visual networks relative to PiB- older adults (b = 0.063, t = 2.46, p < 0.05) (see Figure 1, top). In the BABS cohort, rest-to-task brain network reconfiguration was not impacted by the administration of methylphenidate (b = 1.33, t = 0.87, p = 0.38) (see Figure 1, bottom). However, we found that lower levels of functional network reconfiguration were associated with better memory scores (b = 0.047, t = 2.42, p = 0.016) and that subjects had better memory for items displayed during the drug session compared to the placebo session (b = 0.080, t = 12.10, p < 0.001). Accordingly, drug-induced [11C]Raclopride binding potential in the dorsal caudate was associated with reduced network reconfiguration for connections within the cognitive control network (b = 0.16, t = 2.28, p < 0.05) and across all connections with the default mode network (b = 0.30, t = 2.26, p < 0.05).
Conclusions:
We replicated previous findings that older adults exhibit reduced brain network stability, and showed that this is worsened by high levels of amyloid beta plaques. In a second study, methylphenidate improved memory, and dorsal caudate dopamine receptor occupancy was linked to the induction of brain network stability. These results suggest that the benefits of dopamine-modulating drugs may be associated with the induction of stable brain states, and may particularly benefit amyloid-positive older adults.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s)
Learning and Memory:
Learning and Memory Other
Lifespan Development:
Aging 1
Modeling and Analysis Methods:
fMRI Connectivity and Network Modeling
Physiology, Metabolism and Neurotransmission:
Pharmacology and Neurotransmission 2
Keywords:
Aging
Cognition
Dopamine
FUNCTIONAL MRI
Memory
Pharmacotherapy
Positron Emission Tomography (PET)
Other - Amyloid Beta
1|2Indicates the priority used for review
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