CSF biomarkers are differentially linked to brain areas high and low in noradrenaline, dopamine and serotonin across the Alzheimer’s disease spectrum

Neurotransmitter systems of noradrenaline, dopamine, serotonin and acetylcholine are implicated in cognitive functions such as memory, learning and attention and are known to be altered in neurodegenerative diseases like Alzheimer's disease. Specific brain structures involved in these systems, e.g. the locus coeruleus, the main source of noradrenaline in the cortex, are in fact affected earliest by Alzheimer's disease tau pathology. Preserved volumetric neurotransmitter specific brain areas could therefore be an important neural resource for cognitive reserve in aging. The aim of this study was to determine whether volumes of brain areas known to be high in neurotransmitter receptors are relatively preserved in individuals with lower levels of Alzheimer's disease pathology. Based on the Human Protein Atlas for neurotransmitter receptor distribution, we distinguished between 'areas high and low' in noradrenaline, dopamine, serotonin and acetylcholine and assessed associations of atrophy in those areas with CSF amyloid-ß 42/40, CSF phosphorylated tau protein and cognitive function across healthy controls (<i>n</i> = 122), individuals with subjective cognitive decline (<i>n</i> = 156), mild cognitive impairment or mild Alzheimer's disease dementia (<i>n</i> = 126) using structural equation modelling. CSF pathology markers were inversely correlated and showed a stronger association with disease severity, suggesting distinguishable interrelatedness of these biomarkers depending on the stage of Alzheimer's disease dementia. Across groups, amyloid pathology was linked to atrophy in areas high as well as low in neurotransmitter receptor densities, while tau pathology did not show any significant link to brain area volumes for any of the neurotransmitters. Within disease severity groups, individuals with more amyloid pathology showed more atrophy only in 'areas high in noradrenaline', whereas for dopamine tau pathology was linked to higher volumes in areas low in receptor density possibly indicating compensatory mechanisms. Furthermore, individuals with more tau pathology showed a selective decrease in memory function while amyloid pathology was related to a decline in executive function and language capacity as well as memory function. In summary, our analyses highlight the benefits of investigating disease-relevant factors in Alzheimer's disease using a multivariate multigroup approach. Assessing multivariate dependencies in different disease stages and across individuals revealed selective links of pathologies, cognitive decline and atrophy in particular for areas modulated by noradrenaline, dopamine and serotonin.

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Journal
Brain Communications
Published
2024-12-24
DOI
https://doi.org/10.1093/braincomms/fcaf031
Citations
2
Primary Topic
Dementia and Cognitive Impairment Research
Type
article
Field-Weighted Citation Impact
0.77

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article

CSF biomarkers are differentially linked to brain areas high and low in noradrenaline, dopamine and serotonin across the Alzheimer’s disease spectrum

Emrah Düzel, Jens Wiltfang, Ayda Rostamzadeh, Lukas Preis et al.
2 citations
Brain Communications
Dementia and Cognitive Impairment Research
0.77
article

CSF biomarkers are differentially linked to brain areas high and low in noradrenaline, dopamine and serotonin across the Alzheimer’s disease spectrum

Emrah Düzel, Jens Wiltfang, Ayda Rostamzadeh, Lukas Preis, Robert Perneczky, Annika Spottke, Oliver Peters, Stefan Johannes Teipel, Lena Haag, Gabriel Ziegler, Frederic Brosseron, Yeo‐Jin Yi, Alfredo Ramı́rez, Boris‐Stephan Rauchmann, Klaus Scheffler, Christoph Laske, Renat Yakupov, Luca Kleineidam, Michael Ewers, Michael Wagner, Katharina Büerger, Elisa Lancini, Klaus Fließbach, Josef Priller, Matthew J. Betts, Steffen Wolfsgruber, Frank Jessen, Stefan Hetzer, Daniel Janowitz, Ingo Kilimann, Anja Schneider, Michael T. Heneka, Slawek Altenstein, Luisa‐Sophie Schneider, Niels Hansen, Wenzel Glanz, Matthias H. Munk, Nina Roy‐Kluth, Xiao Wang, Falk Lüsebrink, Peter Dechent, Dorothea Hämmerer, Eike Jakob Spruth, Doreen Göerß
article en
2 citations

Abstract

Neurotransmitter systems of noradrenaline, dopamine, serotonin and acetylcholine are implicated in cognitive functions such as memory, learning and attention and are known to be altered in neurodegenerative diseases like Alzheimer's disease. Specific brain structures involved in these systems, e.g. the locus coeruleus, the main source of noradrenaline in the cortex, are in fact affected earliest by Alzheimer's disease tau pathology. Preserved volumetric neurotransmitter specific brain areas could therefore be an important neural resource for cognitive reserve in aging. The aim of this study was to determine whether volumes of brain areas known to be high in neurotransmitter receptors are relatively preserved in individuals with lower levels of Alzheimer's disease pathology. Based on the Human Protein Atlas for neurotransmitter receptor distribution, we distinguished between 'areas high and low' in noradrenaline, dopamine, serotonin and acetylcholine and assessed associations of atrophy in those areas with CSF amyloid-ß 42/40, CSF phosphorylated tau protein and cognitive function across healthy controls (<i>n</i> = 122), individuals with subjective cognitive decline (<i>n</i> = 156), mild cognitive impairment or mild Alzheimer's disease dementia (<i>n</i> = 126) using structural equation modelling. CSF pathology markers were inversely correlated and showed a stronger association with disease severity, suggesting distinguishable interrelatedness of these biomarkers depending on the stage of Alzheimer's disease dementia. Across groups, amyloid pathology was linked to atrophy in areas high as well as low in neurotransmitter receptor densities, while tau pathology did not show any significant link to brain area volumes for any of the neurotransmitters. Within disease severity groups, individuals with more amyloid pathology showed more atrophy only in 'areas high in noradrenaline', whereas for dopamine tau pathology was linked to higher volumes in areas low in receptor density possibly indicating compensatory mechanisms. Furthermore, individuals with more tau pathology showed a selective decrease in memory function while amyloid pathology was related to a decline in executive function and language capacity as well as memory function. In summary, our analyses highlight the benefits of investigating disease-relevant factors in Alzheimer's disease using a multivariate multigroup approach. Assessing multivariate dependencies in different disease stages and across individuals revealed selective links of pathologies, cognitive decline and atrophy in particular for areas modulated by noradrenaline, dopamine and serotonin.

Brain CommunicationsVol. 7(1)
University of Bonn (DE), The University of Texas at San Antonio Health Science Center (US), University of Cologne (DE), University of Luxembourg (LU), Universität Innsbruck (AT), University Hospital Bonn (DE), German Center for Neurodegenerative Diseases (DE), LMU Klinikum (DE), Humboldt-Universität zu Berlin (DE), Munich Cluster for Systems Neurology (DE), UK Dementia Research Institute (GB), Center for Behavioral Brain Sciences (DE), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Hertie Institute for Clinical Brain Research (DE), Bernstein Center for Computational Neuroscience Berlin (DE), University Hospital Cologne (DE), University College London (GB), University of Rostock (DE), Imperial College London (GB), University of Aveiro (PT), Technical University of Munich (DE), University of Göttingen (DE), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), University of Tübingen (DE), Ludwig-Maximilians-Universität München (DE), University of Sheffield (GB), University of Edinburgh (GB)
Deutsche Forschungsgemeinschaft, Bundesministerium für Bildung und Forschung, National Institutes of Health
Openalex Percentile: Top 24%
Dementia and Cognitive Impairment Research
0.77
DOIOpen Access PDFOpenAlex
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