Cholinergic white matter pathways along the Alzheimer’s disease continuum

Milan Nemy, Martin Dyrba, Frederic Brosseron, Katharina Buerger, Peter Dechent, Laura Dobisch, Michael Ewers, Klaus Fliessbach, Wenzel Glanz, Doreen Goerss, Michael T. Heneka, Stefan Hetzer, Enise I. Incesoy, Daniel Janowitz, Ingo Kilimann, Christoph Laske, Franziska Maier, Matthias H. Munk, Robert Perneczky, Oliver PetersLukas Preis, Josef Priller, Boris Stephan Rauchmann, Sandra Röske, Nina Roy, Klaus Scheffler, Anja Schneider, Björn H. Schott, Annika Spottke, Eike J. Spruth, Michael Wagner, Jens Wiltfang, Renat Yakupov, Maria Eriksdotter, Eric Westman, Olga Stepankova, Lenka Vyslouzilova, Emrah Düzel, Frank Jessen, Stefan J. Teipel, Daniel Ferreira

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Previous studies have shown that the cholinergic nucleus basalis of Meynert and its white matter projections are affected in Alzheimer’s disease dementia and mild cognitive impairment. However, it is still unknown whether these alterations can be found in individuals with subjective cognitive decline, and whether they are more pronounced than changes found in conventional brain volumetric measurements. To address these questions, we investigated microstructural alterations of two major cholinergic pathways in individuals along the Alzheimer’s disease continuum using an in vivo model of the human cholinergic system based on neuroimaging. We included 402 participants (52 Alzheimer’s disease, 66 mild cognitive impairment, 172 subjective cognitive decline and 112 healthy controls) from the Deutsches Zentrum für Neurodegenerative Erkrankungen Longitudinal Cognitive Impairment and Dementia Study. We modelled the cholinergic white matter pathways with an enhanced diffusion neuroimaging pipeline that included probabilistic fibre-tracking methods and prior anatomical knowledge. The integrity of the cholinergic white matter pathways was compared between stages of the Alzheimer’s disease continuum, in the whole cohort and in a CSF amyloid-beta stratified subsample. The discriminative power of the integrity of the pathways was compared to the conventional volumetric measures of hippocampus and nucleus basalis of Meynert, using a receiver operating characteristics analysis. A multivariate model was used to investigate the role of these pathways in relation to cognitive performance. We found that the integrity of the cholinergic white matter pathways was significantly reduced in all stages of the Alzheimer’s disease continuum, including individuals with subjective cognitive decline. The differences involved posterior cholinergic white matter in the subjective cognitive decline stage and extended to anterior frontal white matter in mild cognitive impairment and Alzheimer’s disease dementia stages. Both cholinergic pathways and conventional volumetric measures showed higher predictive power in the more advanced stages of the disease, i.e. mild cognitive impairment and Alzheimer’s disease dementia. In contrast, the integrity of cholinergic pathways was more informative in distinguishing subjective cognitive decline from healthy controls, as compared with the volumetric measures. The multivariate model revealed a moderate contribution of the cholinergic white matter pathways but not of volumetric measures towards memory tests in the subjective cognitive decline and mild cognitive impairment stages. In conclusion, we demonstrated that cholinergic white matter pathways are altered already in subjective cognitive decline individuals, preceding the more widespread alterations found in mild cognitive impairment and Alzheimer’s disease. The integrity of the cholinergic pathways identified the early stages of Alzheimer’s disease better than conventional volumetric measures such as hippocampal volume or volume of cholinergic nucleus basalis of Meynert.

Original languageEnglish
Pages (from-to)2075-2088
Number of pages14
JournalBrain
Volume146
Issue number5
DOIs
StatePublished - 1 May 2023
Externally publishedYes

Keywords

  • Alzheimer’s disease
  • CSF markers
  • MRI
  • cholinergic system
  • nucleus basalis of Meynert

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