title: Cholinergic basal forebrain structure influences the reconfiguration of white matter connections to support residual memory in mild cognitive impairment.
abstract: The fornix and hippocampus are critical to recollection in the healthy human brain. Fornix degeneration is a feature of aging and Alzheimer's disease. In the presence of fornix damage in mild cognitive impairment (MCI), a recognized prodrome of Alzheimer's disease, recall shows greater dependence on other tracts, notably the parahippocampal cingulum (PHC). The current aims were to determine whether this shift is adaptive and to probe its relationship to cholinergic signaling, which is also compromised in Alzheimer's disease. Twenty-five human participants with MCI and 20 matched healthy volunteers underwent diffusion MRI, behavioral assessment, and volumetric measurement of the basal forebrain. In a regression model for recall, there was a significant group × fornix interaction, indicating that the association between recall and fornix structure was weaker in patients. The opposite trend was present for the left PHC. To further investigate this pattern, two regression models were generated to account for recall performance: one based on fornix microstructure and the other on both fornix and left PHC. The realignment to PHC was positively correlated with free recall but not non-memory measures, implying a reconfiguration that is beneficial to residual memory. There was a positive relationship between realignment to PHC and basal forebrain gray matter volume despite this region demonstrating atrophy at a group level, i.e., the cognitive realignment to left PHC was most apparent when cholinergic areas were relatively spared. Therefore, cholinergic systems appear to enable adaptation to injury even as they degenerate, which has implications for functional restoration.
authors.affiliation: Department of Basic and Clinical Neuroscience and.
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Ray
authors.affiliation: Cardiff University Brain Research Imaging Centre, School of Psychology, and Neuroscience and Mental Health Research Institute, Cardiff, CF10 3AT, United Kingdom.
authors.forename: Claudia
authors.identifier: http://orcid.org/0000-0002-8646-1144
authors.initials: C
authors.lastname: Metzler-Baddeley
authors.affiliation: Biostatistics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London SE5 8AF, United Kingdom.
authors.forename: Mizanur R
authors.initials: MR
authors.lastname: Khondoker
authors.affiliation: Department of Psychosomatic Medicine, University Medicine Rostock, D-18147 Rostock, Germany, and.
authors.forename: Michel J
authors.identifier: http://orcid.org/0000-0003-2600-9022
authors.initials: MJ
authors.lastname: Grothe
authors.affiliation: German Center for Neurodegenerative Diseases Rostock/Greifswald, D-18471 Rostock, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Teipel
authors.affiliation: Department of Basic and Clinical Neuroscience and.
authors.forename: Paul
authors.identifier: http://orcid.org/0000-0001-5297-6257
authors.initials: P
authors.lastname: Wright
authors.affiliation: Laboratory of Morphological Brain Research, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University of Würzburg, D-97080 Würzburg, Germany.
authors.forename: Helmut
authors.identifier: http://orcid.org/0000-0002-4688-4441
authors.initials: H
authors.lastname: Heinsen
authors.affiliation: Cardiff University Brain Research Imaging Centre, School of Psychology, and Neuroscience and Mental Health Research Institute, Cardiff, CF10 3AT, United Kingdom.
authors.forename: Derek K
authors.initials: DK
authors.lastname: Jones
authors.affiliation: Cardiff University Brain Research Imaging Centre, School of Psychology, and Neuroscience and Mental Health Research Institute, Cardiff, CF10 3AT, United Kingdom.
authors.forename: John P
authors.initials: JP
authors.lastname: Aggleton
authors.affiliation: Department of Basic and Clinical Neuroscience and Cardiff University Brain Research Imaging Centre, School of Psychology, and Neuroscience and Mental Health Research Institute, Cardiff, CF10 3AT, United Kingdom, mike.osullivan@kcl.ac.uk.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: O'Sullivan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D060825:Cognitive Dysfunction / Q000503:physiopathology*; D005260:Female; D020712:Fornix, Brain / Q000503:physiopathology; D006801:Humans; D008297:Male; D061212:Memory, Episodic; D011939:Mental Recall; D008875:Middle Aged; D008959:Models, Neurological; D016548:Prosencephalon / Q000473:pathology / Q000503:physiopathology*; D066127:White Matter / Q000503:physiopathology*
keywords: cholinergic system; diffusion; episodic memory; fornix; mild cognitive impairment; white matter