Does Loss of Integrity of the Cingulum Bundle Link Amyloid-β Accumulation and Neurodegeneration in Alzheimer’s Disease?

Article type: Research Article

Authors: Vlegels, Naomi^{a; *} | Ossenkoppele, Rik^{b; c} | van der Flier, Wiesje M.^{b; d} | Koek, Huiberdina L.^e | Reijmer, Yael D.^a | Wisse, Laura EM^f | Biessels, Geert Jan^a | the Alzheimer’s Disease Neuroimaging Initiative¹

Affiliations: [a] Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands | [b] Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands | [c] Clinical Memory Research Unit, Lund University, Lund, Sweden | [d] Department of Epidemiology and Data Science, VU University Medical Center, Amsterdam, The Netherlands | [e] Department of Geriatrics, University Medical Center Utrecht, Utrecht, The Netherlands | [f] Department of Diagnostic Radiology, Lund University, Lund, Sweden

Correspondence: [*] Correspondence to: Naomi Vlegels, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. Tel.: +31 88 75 568 66; E-mail: n.vlegels@umcutrecht.nl.

Note: [1] Data used in preparation of this article were obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (https://adni.loni.usc.edu/). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. A complete listing of ADNI investigators can be found at: https://adni.loni.usc.edu/wp-content/uploads/how_to_apply/ADNI_Acknowledgement_List.pdf

Abstract: Background:Alzheimer’s disease is characterized by the accumulation of amyloid-β (Aβ) into plaques, aggregation of tau into neurofibrillary tangles, and neurodegenerative processes including atrophy. However, there is a poorly understood spatial discordance between initial Aβ deposition and local neurodegeneration. Objective:Here, we test the hypothesis that the cingulum bundle links Aβ deposition in the cingulate cortex to medial temporal lobe (MTL) atrophy. Methods:21 participants with mild cognitive impairment (MCI) from the UMC Utrecht memory clinic (UMCU, discovery sample) and 37 participants with MCI from Alzheimer’s Disease Neuroimaging Initiative (ADNI, replication sample) with available Aβ-PET scan, T1-weighted and diffusion-weighted MRI were included. Aβ load of the cingulate cortex was measured by the standardized uptake value ratio (SUVR), white matter integrity of the cingulum bundle was assessed by mean diffusivity and atrophy of the MTL by normalized MTL volume. Relationships were tested with linear mixed models, to accommodate multiple measures for each participant. Results:We found at most a weak association between cingulate Aβ and MTL volume (added R2 <0.06), primarily for the posterior hippocampus. In neither sample, white matter integrity of the cingulum bundle was associated with cingulate Aβ or MTL volume (added R2 <0.01). Various sensitivity analyses (Aβ-positive individuals only, posterior cingulate SUVR, MTL sub region volume) provided similar results. Conclusion:These findings, consistent in two independent cohorts, do not support our hypothesis that loss of white matter integrity of the cingulum is a connecting factor between cingulate gyrus Aβ deposition and MTL atrophy.

Keywords: Alzheimer’s disease, amyloid-β, diffusion tensor imaging, medial temporal lobe, neurodegeneration, PET, white matter integrity

DOI: 10.3233/JAD-220024

Journal: Journal of Alzheimer's Disease, vol. 89, no. 1, pp. 39-49, 2022