Spatial and Temporal Profiles of Cholinergic Degeneration Across the Alzheimer’s Disease Continuum
Poster No:
153
Submission Type:
Abstract Submission
Authors:
Milan Nemy1,2, Fedor Levin3, Martin Dyrba3, Lenka Vyslouzilova1, Zuzana Nedelska4, Emrah Düzel5, Frank Jessen6, Stefan Teipel3, Daniel Ferreira2
Institutions:
1Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University, Prague, Czech Republic, 2Karolinska Institute, Division of Clinical Geriatrics, Stockholm, Sweden, 3German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany, 4Memory Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol Uni, Prague, Czech Republic, 5German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany, 6German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
First Author:
Milan Nemy
Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University|Karolinska Institute, Division of Clinical Geriatrics
Prague, Czech Republic|Stockholm, Sweden
Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University|Karolinska Institute, Division of Clinical Geriatrics
Prague, Czech Republic|Stockholm, Sweden
Co-Author(s):
Lenka Vyslouzilova
Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University
Prague, Czech Republic
Czech Institute of Informatics, Robotics and Cybernetics, Czech Technical University
Prague, Czech Republic
Zuzana Nedelska
Memory Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol Uni
Prague, Czech Republic
Memory Clinic, Department of Neurology, Second Faculty of Medicine, Charles University and Motol Uni
Prague, Czech Republic
Introduction:
The nucleus basalis of Meynert and its cholinergic white matter pathway are vital for cognitive function and disproportionately affected in Alzheimer's disease (AD) (Mesulam, 2013). This study investigates spatial and temporal patterns of cholinergic pathway degeneration across the AD continuum, emphasizing the preclinical phase as a critical window for early intervention. Using advanced diffusion MRI techniques and our established analysis pipeline (Nemy, 2020; Nemy, 2023), we conducted cross-sectional and longitudinal analyses to examine cholinergic integrity throughout stages of cognitive decline. By focusing on preclinical and prodromal stages of AD, this research seeks to enhance the identification of biomarkers for AD, facilitating timely interventions that could improve patient outcomes (Hampel, 2018).
Methods:
Data from the DELCODE study, focusing on subjective cognitive decline (SCD), were utilized alongside individuals with mild cognitive impairment (MCI), AD dementia, and healthy controls (HC). Diffusion MRI data were acquired using a multi-shell protocol (b=700, b=1000 s/mm²).
Cross-sectional analysis included 402 participants: 112 HC, 172 SCD, 66 MCI, and 52 AD dementia. Fiber orientations were estimated using the ball-and-sticks model, while mean diffusivity (MD) and fractional anisotropy (FA) assessed cholinergic integrity. Voxel-wise analyses, corrected via permutation testing (5,000 permutations), identified spatial profiles of degeneration.
The longitudinal subset included 370 participants with at least two annual visits. The average of the maximum follow-up durations across the cohort was 2.80 years. Longitudinal analyses modeled changes in MD and FA over time or as a function of cognitive impairment severity (ADAS-Cog 13 scores). Linear mixed models accounted for clinical stage, age, sex, education, and scanning protocol, incorporating random intercepts and slopes. Statistical maps underwent cluster-based correction using Monte Carlo simulations (FWE < 0.05), providing stage-specific and between-stage estimates.
Cross-sectional analysis included 402 participants: 112 HC, 172 SCD, 66 MCI, and 52 AD dementia. Fiber orientations were estimated using the ball-and-sticks model, while mean diffusivity (MD) and fractional anisotropy (FA) assessed cholinergic integrity. Voxel-wise analyses, corrected via permutation testing (5,000 permutations), identified spatial profiles of degeneration.
The longitudinal subset included 370 participants with at least two annual visits. The average of the maximum follow-up durations across the cohort was 2.80 years. Longitudinal analyses modeled changes in MD and FA over time or as a function of cognitive impairment severity (ADAS-Cog 13 scores). Linear mixed models accounted for clinical stage, age, sex, education, and scanning protocol, incorporating random intercepts and slopes. Statistical maps underwent cluster-based correction using Monte Carlo simulations (FWE < 0.05), providing stage-specific and between-stage estimates.
·Cholinergic White Matter Pathways (Medial and Lateral Pathways)
Results:
Cross-sectional analysis revealed significant increases in MD and decreases in FA in cholinergic pathways at all disease stages, including SCD (p < 0.001), but no significant changes in non-cholinergic control pathways (p > 0.05). Voxel-wise maps highlighted profound MD changes in the retrosplenial and posterior cingulate cortex in SCD (FWE < 0.05), progressing to anterior regions with increasing disease severity.
In the longitudinal analysis, the yearly MD decline was non-significant in the HC group (-0.13 ± 0.17, p > 0.05), but significant in SCD (0.70 ± 0.13), MCI (1.00 ± 0.22), and AD (2.05 ± 0.36) (all p < 0.001, all units ×10−5 mm²/s/year). All longitudinal differences between groups were significant except for SCD-MCI (p > 0.05). Similar trends were observed when modeling changes as a function of ADAS-Cog 13 scores. In voxel-wise analysis, no significant clusters of temporal changes were observed in HC, whereas significant temporal changes appeared in SCD, spanning posterior and mid-anterior cingulate regions. Clusters of longitudinal changes in the basal forebrain became prominent only at the AD dementia stage.
In the longitudinal analysis, the yearly MD decline was non-significant in the HC group (-0.13 ± 0.17, p > 0.05), but significant in SCD (0.70 ± 0.13), MCI (1.00 ± 0.22), and AD (2.05 ± 0.36) (all p < 0.001, all units ×10−5 mm²/s/year). All longitudinal differences between groups were significant except for SCD-MCI (p > 0.05). Similar trends were observed when modeling changes as a function of ADAS-Cog 13 scores. In voxel-wise analysis, no significant clusters of temporal changes were observed in HC, whereas significant temporal changes appeared in SCD, spanning posterior and mid-anterior cingulate regions. Clusters of longitudinal changes in the basal forebrain became prominent only at the AD dementia stage.
·Longitudinal Changes in Cingulum Cholinergic Pathway Mean Diffusivity by Diagnostic Group
Conclusions:
Our study reveals distinct spatial and temporal profiles of cholinergic white matter degeneration across the AD continuum, with selective deterioration visible even in SCD-a stage undetectable by objective cognitive tests and conventional MRI. This finding highlights the critical role of cholinergic pathways in cognitive decline and establishes advanced diffusion MRI techniques as promising biomarkers for early detection. By integrating cross-sectional and longitudinal analyses, we provide new insights into the progressive nature of neurodegeneration, paving the way for innovative intervention strategies. These results not only enhance our understanding of Alzheimer's disease but also invite further exploration into therapeutic approaches targeting cholinergic dysfunction.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Diffusion MRI Modeling and Analysis 2
Keywords:
Acetylcholine
Aging
Degenerative Disease
Tractography
WHITE MATTER IMAGING - DTI, HARDI, DSI, ETC
Other - Alzheimer's Disease; Diffusion MRI; Subjective Cognitive Decline; Longitudinal Analysis; Basal Forebrain; Neuroimaging Biomarkers; Cognitive Decline
1|2Indicates the priority used for review
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Provide references using APA citation style.
Mesulam, M. M. (2013). Cholinergic circuitry of the human nucleus basalis and its fate in Alzheimer's disease. Journal of Comparative Neurology, 521(18), 4124-4144.
Nemy, M. (2020). Cholinergic white matter pathways make a stronger contribution to attention and memory in normal aging than cerebrovascular health and nucleus basalis of Meynert. Neuroimage, 211, 116607.
Nemy, M. (2023). Cholinergic white matter pathways along the Alzheimer's disease continuum. Brain, 146(5), 2075-2088.