Absolute diffusivities define the landscape of white matter degeneration in Alzheimer’s disease
Abstract
Recent imaging evidence in Alzheimer's disease suggests that neural involvement in early-stage disease is more complex than is encapsulated in the commonly held position of predominant mesial temporal lobe degeneration-there is also early posterior cingulate cortex and diencephalic damage. These findings suggest that early clinical Alzheimer's disease is underpinned by damage to an inter-connected network. If correct, this hypothesis would predict degeneration of the white matter pathways that connect this network. This prediction can be tested in vivo by diffusion magnetic resonance imaging. Most diffusion tensor imaging studies of white matter in neurodegenerative disorders such as Alzheimer's disease have concentrated on fractional anisotropy reductions and increased 'apparent' diffusivity; however, there is a lack of empirical biological evidence to assume that fractional anisotropy changes will necessarily capture the full extent of white matter changes in Alzheimer's disease. In this study, therefore, we undertook a comprehensive investigation of diffusion behaviour in Alzheimer's disease by analysing each of the component eigenvalues of the diffusion tensor in isolation to test the hypothesis that early Alzheimer's disease is associated with degeneration of a specific neural network. Using tract-based spatial statistics, we performed voxel-wise analyses of fractional anisotropy, axial, radial and mean diffusivities in 25 Alzheimer's disease patients compared with 13 elderly controls. We found that increased absolute (axial, radial and mean) diffusivities in Alzheimer's disease were concordant in a distribution consistent with the network hypothesis, highly statistically significant and far more sensitive than fractional anisotropy reductions. The former three measures identified confluent white matter abnormalities in parahippocampal gyrus and posterior cingulum, extending laterally into adjacent temporo-parietal regions as well as splenium and fornix. The caudal occipital lobe, temporal pole, genu and prefrontal white matter were relatively preserved. This distribution is highly consistent with expected predictions of tract degeneration from grey matter lesions identified by fluorodeoxyglucose positron emission tomography and structural magnetic resonance imaging. Concordant with results from these other imaging modalities, this pattern predominantly involves degeneration of the tracts connecting the circuit of Papez. These findings also highlight that early neuropathological processes are associated with changes of the diffusion ellipsoid that are predominantly proportional along all semi-principal axes.
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Tensor limitations have likely confounded previous diffusion studies of cognitive decline that have found little or no effects with FA.
“suggesting that tensor limitations have likely confounded previous diffusion studies of cognitive decline that have found little or no effects with FA (Acosta-Cabronero et al., 2010).”
From Diffusion MRI Indices and Their Relation to Cognitive Impairment in Brain Aging: The Updated Multi-protocol Approach in ADNI3 (2019) · cites this paper as Acosta-Cabronero et al., 2010
The Discussion (page not available in our copy) explains that FA can miss proportional changes in diffusion and reports that FA was less sensitive than absolute diffusivity measures in this Alzheimer’s disease study. It does not establish that this limitation confounded previous studies of cognitive decline that found little or no FA effect; the authors caution that its relevance beyond Alzheimer’s disease needs to be demonstrated. (LLM, conf=0.84)
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Vuoksimaa, E., Panizzon, M. S., Hagler Jr, D. J., Hatton, S. N., Fennema‐Notestine, C., Rinker, D., Eyler, L. T., Franz, C. E., Lyons, M. J., Neale, M. C., et al. (2017) · Human Brain Mapping · doi:10.1002/hbm.23502 · Cited by 58 · see citing works
Daianu, M., Mendez, M. F., Baboyan, V. G., Jin, Y., Melrose, R. J., Jimenez, E. E., & Thompson, P. M. (2016) · Brain Imaging and Behavior · doi:10.1007/s11682-015-9458-5 · Cited by 64 · see citing works
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Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis
Al-Amin, M. M., Grandjean, J., Klohs, J., & Kim, J. (2020) · doi:10.1101/2020.04.27.064634 · Cited by 2 · see citing works
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40 Years of diffusion MRI in the brain: From history to emerging frontiers
Le Bihan, D. (2026) · Imaging Neuroscience · doi:10.1162/imag.a.1365
“…diffusivity measures may be more sensitive than fractional anisotropy, whereas increasing radial diffusivity and declining fractional anisotropy may better track disease severity longitudinally ( Acosta-Cabronero et al., 2010, 2012; Chen et al., 2023; Fu et al., 2014; Lo Buono et al., 2020).”
- Authors
- Acosta-Cabronero, J., Williams, G. B., Pengas, G., & Nestor, P. J.
- Affiliations
- University of Cambridge (GB)
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2009-11-13
- Volume
- 133
- Issue
- 2
- Pages
- 529-539
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- OpenAlex
- W2107169104
- Cited by
- 393
- References
- 51
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 13 · 2023: 10 · 2022: 10 · 2021: 15 · 2020: 21 · 2019: 21 · 2018: 19 · 2017: 30 · 2016: 31 · 2015: 39 · 2014: 34 · 2013: 39 · 2012: 47
- FWCI
- 22.42
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Brain (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0508-10327)
- NIHR Cambridge Biomedical Research Centre
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, white matter degeneration, fractional anisotropy, Papez circuit, posterior cingulate cortex, parahippocampal gyrus, fornix, splenium, diffusion MRI
- MeSH terms
- Aged, Alzheimer Disease, Female, Humans, Male, Middle Aged, Nerve Degeneration, Nerve Fibers, Myelinated, Diffusion Magnetic Resonance Imaging, Diffusion Tensor Imaging
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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