MRI‐assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction

Elman, Jeremy A.; Puckett, Olivia K.; Beck, Audrey N.; Fennema‐Notestine, Christine; Cross, Latonya K.; Dale, Anders M.; Eglit, Graham M.L.; Eyler, Lisa T.; Gillespie, Nathan A.; Granholm, Eric; Gustavson, Daniel E.; Hagler, Donald J.; Hatton, Sean N.; Hauger, Richard L.; Jak, Amy J.; Logue, Mark W.; McEvoy, Linda K.; McKenzie, Ruth; Neale, Michael C.; Panizzon, Matthew S.; Reynolds, Chandra A.; Sanderson‐Cimino, Mark; Toomey, Rosemary; Tu, Xin; Whitsel, Nathan; Williams, McKenna E.; Xian, Hong; Lyons, Michael J.; Franz, Carol E.; Kremen, William S.

doi:10.1002/alz.12261

Cited by 48 publications

(53 citation statements)

References 55 publications

(115 reference statements)

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“…As a result, functions associated with the LC-NA system, such as modulating cognition, could be disrupted. Consistent with this, LC structural integrity in later life has been linked with outcomes across cognitive domains such as verbal fluency and intelligence (Elman et al, 2021;Liu et al, 2020), learning and memory , and emotional memory (Hämmerer et al, 2018).…”

Section: Introductionmentioning

confidence: 54%

Behavioral and fMRI evidence that arousal enhances bottom-up attention and memory selectivity in young but not older adults

Bachman

et al. 2021

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During a challenge or emotional experience, increases in arousal help us focus on the most salient or relevant details and ignore distracting stimuli. The noradrenergic system integrates signals about arousal states throughout the brain and helps coordinate this adaptive attentional selectivity. However, age-related changes in the noradrenergic system and attention networks in the brain may reduce the efficiency of arousal to modulate selective processing in older adults. In the current neuroimaging study, we examined age differences in how arousal affects bottom-up attention to category-selective stimuli differing in perceptual salience. We found a dissociation in how arousal modulates selective processing in the young and older brain. In young adults, emotionally arousing sounds enhanced selective incidental memory and brain activity in the extrastriate body area for salient versus non-salient images of bodies. Older adults showed no such advantage in selective processing under arousal. These age differences could not be attributed to changes in the arousal response or less neural distinctiveness in old age. Rather, our results suggest that, relative to young adults, older adults become less effective at focusing on salient over non-salient details during increases in emotional arousal.

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Section: Introductionmentioning

confidence: 54%

Behavioral and fMRI evidence that arousal enhances bottom-up attention and memory selectivity in young but not older adults

Bachman

et al. 2021

Preprint

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“…In particular, the LC is a key structure involved in arousal and modulation of cognitive function. For example, our previous work in this sample showed that people with lower rostral LC integrity had greater daytime sleep-related dysfunction [21] – a symptom frequently reported in people with chronic pain [19]. Furthermore, people with chronic pain have worse cognitive performance than those without chronic pain [6,7].…”

Section: Discussionmentioning

confidence: 98%

“…Furthermore, people with chronic pain have worse cognitive performance than those without chronic pain [6,7]. Our prior work has shown better rostral LC integrity may be related to better cognitive performance and reduced risk of amnestic mild cognitive impairment [21]. In other studies, lower LC integrity has also been associated with major depressive disorder [45], a condition more common in people with chronic pain.…”

Section: Discussionmentioning

confidence: 99%

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Locus Coeruleus Integrity in Older Adults with and without Chronic Pain

Bell

Franz

Eyler

et al. 2021

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The locus coeruleus (LC) is a brainstem region involved in regulating pain. Chronic pain is common in older adulthood, but no studies have examined its association with the LC in humans. We used neuromelanin-sensitive imaging to study differences in LC integrity in older adults with and without chronic pain. Chronic pain was assessed in community-dwelling men from the Vietnam Era Twin Study of Aging (VETSA) in 3 study waves covering an average of 12 years. Pain was self-reported on the SF-36 Bodily Pain Scale. Chronic pain was defined as moderate to severe pain severity at the current and at least one prior wave; 17% had chronic pain (n=80). At the third wave, 481 participants (mean age=67.57) underwent neuromelanin-sensitive MRI scans from which we calculated an LC contrast-to-noise ratio (LCCNR) – an index of LC integrity. We examined associations between chronic pain and LCCNR (in the rostral LC and caudal regions) with generalized estimating equations after adjusting for age, race, education, depressive symptoms, medical comorbidities, and opioid medication use. Individuals with chronic pain had .35 standard deviation lower rostral LCCNR (95% CI: -.62 to -.05) compared to those without chronic pain. No differences in the caudal LCCNR were detected. Chronic pain was associated with decreased rostral LC integrity in older adults. Differences in the rostral LC, rather than caudal LC, suggest the association between lower LC integrity and chronic pain may be related to pain processing in cortical regions where rostral LC projections typically connect.

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“…2,[8][9][10][11][12][13][14][15][16][17][18][19][20] Both imaging and postmortem studies indicate that volumetric reduction, neuronal loss, and neuropathology in LC predict the rate of cognitive decline, attentional and executive function deficits, and Tau burden in humans, suggesting an important role in cognitive resilience and abnormal protein aggregation. 16,[21][22][23][24][25] Hyperphosphorylated Tau, a "pretangle" form of the protein prone to aggregation, appears in the LC before any other area of the brain, and is now considered the earliest detectable Alzheimer's disease-like neuropathology, evident even in young and middle-aged adults. 14,[26][27][28][29][30][31][32] The connectivity of the LC provides a neuroanatomical substrate that may mediate the spread of pathological Tau seeds to the forebrain.…”

Section: Introductionmentioning

confidence: 99%

A Phase II Study Repurposing Atomoxetine for Neuroprotection in Mild Cognitive Impairment

Levey

Qiu

Zhao

et al. 2021

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The locus coeruleus (LC) is the initial site of Alzheimer’s disease neuropathology, with hyperphosphorylated Tau appearing in early adulthood followed by neurodegeneration in dementia. LC dysfunction contributes to Alzheimer’s pathobiology in experimental models, which can be rescued by increasing norepinephrine (NE) transmission. To test NE augmentation as a potential disease-modifying therapy, we performed a biomarker-driven phase II trial of atomoxetine, a clinically-approved NE transporter inhibitor, in subjects with mild cognitive impairment due to Alzheimer’s disease.The design was a single-center, 12-month double-blind crossover trial. Thirty-nine participants with mild cognitive impairment (MCI) and biomarker evidence of Alzheimer’s disease were randomized to atomoxetine or placebo treatment. Assessments were collected at baseline, 6- (crossover) and 12-months (completer). Target engagement was assessed by CSF and plasma measures of NE and metabolites. Prespecified primary outcomes were CSF levels of IL1α and Thymus-Expressed Chemokine. Secondary/exploratory outcomes included clinical measures, CSF analyses of Aβ42, Tau, and pTau181, mass spectrometry proteomics, and immune-based targeted inflammation-related cytokines, as well as brain imaging with MRI and FDG-PET.Baseline demographic and clinical measures were similar across trial arms. Dropout rates were 5.1% for atomoxetine and 2.7% for placebo, with no significant differences in adverse events. Atomoxetine robustly increased plasma and CSF NE levels. IL-1α and Thymus-Expressed Chemokine were not measurable in most samples. There were no significant treatment effects on cognition and clinical outcomes, as expected given the short trial duration. Atomoxetine was associated with a significant reduction in CSF Tau and pTau181 compared to placebo, but not associated with change in Aβ42. Atomoxetine treatment also significantly altered CSF abundances of protein panels linked to brain pathophysiologies, including synaptic, metabolism, and glial immunity, as well as inflammation-related CDCP1, CD244, TWEAK, and OPG proteins. Treatment was also associated with significantly increased BDNF and reduced triglycerides in plasma. Resting state fMRI showed significantly increased inter-network connectivity due to atomoxetine between the insula and the hippocampus. FDG-PET showed atomoxetine-associated increased uptake in hippocampus, parahippocampal gyrus, middle temporal pole, inferior temporal gyrus, and fusiform gyrus, with carry-over effects six months after treatment.In summary, atomoxetine treatment was safe, well tolerated, and achieved target engagement in prodromal Alzheimer’s disease. Atomoxetine significantly reduced CSF Tau and pTau, normalized CSF protein biomarker panels linked to synaptic function, brain metabolism, and glial immunity, and increased brain activity and metabolism in key temporal lobe circuits. Further study of atomoxetine is warranted for repurposing the drug to slow Alzheimer’s disease progression.

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MRI‐assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction

Cited by 48 publications

References 55 publications

Behavioral and fMRI evidence that arousal enhances bottom-up attention and memory selectivity in young but not older adults

Behavioral and fMRI evidence that arousal enhances bottom-up attention and memory selectivity in young but not older adults

Locus Coeruleus Integrity in Older Adults with and without Chronic Pain

A Phase II Study Repurposing Atomoxetine for Neuroprotection in Mild Cognitive Impairment

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