In vivo cortical diffusion imaging relates to Alzheimer's disease neuropathology
Open accessAbstract
Abstract Background There has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer’s disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated. Methods Forty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer’s Coordinating Center and Alzheimer’s Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC—the “ABC score” from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies—Lewy body disease and TAR DNA-binding protein 43 (TDP-43)—on cortical microstructure was assessed. Results Cortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology. Conclusions Cortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.
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Most prior work has focused on DTI metrics and linear associations, which may not fully capture compartment-specific microstructural changes.
“most prior work has focused on DTI metrics and linear associations, 39 , 40 , 41 , 42 which may not fully capture compartment‐specific microstructural changes.”
From Diffusion MRI reveals amyloid plaque–associated cellular signatures through spatial transcriptomic integration (2026) · cites this paper as [41]
The Methods (MRI analysis; Statistical analyses) show that this study used DTI-derived metrics and linear models for regional associations, so it supports an example of that approach. The paper does not establish that most prior work used it or say that such analyses fail to capture compartment-specific microstructural changes. (LLM, conf=0.83)
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- Authors
- Torso, M., Ridgway, G. R., Valotti, M., Hardingham, I., Chance, S. A., for the National Alzheimer’s Coordinating Center, Brewer, J., Lopez, O., Hyman, B., Grabowski, T., Sano, M., Chui, H., Albert, M., Morris, J., Kaye, J., Wisniewski, T., Small, S., Trojanowski, J., DeCarli, C., Saykin, A., Bennett, D., Rosenberg, R., Kowall, N., Vassar, R., LaFerla, F., Petersen, R., Reiman, E., Miller, B., Levey, A., Van Eldik, L., Asthana, S., Swerdlow, R., Golde, T., Strittmatter, S., Henderson, V., Craft, S., Paulson, H., Seshadri, S., Roberson, E., Sabbagh, M., Rosenberg, G., Jefferson, A., Whitson, H., Leverenz, J., & Initiative, T. A. D. N.
- Corresponding author
- Torso, Mario
- ORCID
- Torso, Mario
- Ridgway, Gerard R.
- Chance, Steven A.
- Hyman, Bradley
- Grabowski, Thomas
- Sano, Mary
- Chui, Helena
- Albert, Marilyn
- Morris, John
- Kaye, Jeffrey
- Small, Scott
- Trojanowski, John
- DeCarli, Charles
- Saykin, Andrew
- Bennett, David
- Kowall, Neil
- Vassar, Robert
- LaFerla, Frank
- Petersen, Ronald
- Reiman, Eric
- Miller, Bruce
- Levey, Allan
- Asthana, Sanjay
- Swerdlow, Russell
- Golde, Todd
- Strittmatter, Stephen
- Henderson, Victor
- Craft, Suzanne
- Paulson, Henry
- Seshadri, Sudha
- Roberson, Erik
- Sabbagh, Marwan
- Rosenberg, Gary
- Jefferson, Angela
- Whitson, Heather
- Leverenz, James
- Venue
- Alzheimer's Research & Therapy
- Published
- 2023-10-04
- Volume
- 15
- Issue
- 1
- Pages
- 165-165
- ISSN
- 1758-9193 (ISSN-L)
- PMC
- PMC10548768
- OpenAlex
- W4387336768
- Cited by
- 16
- References
- 48
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 5 · 2023: 1
- FWCI
- 3.24
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- en
- Open access
- gold
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- U.S. Department of Defense (U01 AG024904, P50 AG005138, W81XWH, W81XWH-12-2-, W81XWH1220012, AG024904)
- Alzheimer's Association (P30 AG013854, P30AG010124, P50 AG023501, P50 AG025688, AG010129, P30AG035982, P50 AG005681, P30 AG053760, P30 AG010161, U01 AG024904, P50 AG008702, P30 AG049638, P30 AG010133, P50 AG005136, W81XWH-12-2-0012, P50 AG005146)
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- Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
- University of Southern California (P50AG005142, W81XWH-12-2-0012, U01 AG024904)
- F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
- Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
- Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, P30 AG010129)
- BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
- Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012, P30 AG010129)
- Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
- Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
- H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
- IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
- National Institutes of Health (AG028 383, 3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, AG016574, AG049638, AG016573, AG010124, AG023501, U01-AG024904, AG005138, AG005133, AG005131, AG008017, AG010129, AG008051, AG024904, AG005681, AG019610, AG035982, AG047270, AG005134, AG047366, AG053760, AG010161, AG013854, AG025688, AG013846, AG047266, AG068077, AG005136, AG033514, AG008702)
- Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
- University of California, San Diego (P50-AG005131, P50 AG005133)
- Canadian Institutes of Health Research (U01 AG024904, W81XWH-12-2-0012, P50 AG016574, P30 AG010129)
- National Institute on Aging (U01-AG-024904, AG 005138, AG-028383, AG066546, AG010133, P30AG053760, P30AG010129, P30AG010133, P30AG066512, AG-016573, AG008051, AG005134, P30AG049638, AG047366, W81XWH-12-2–0012, AG-010124, P30AG028383, P30AG012300, AG-005133, AG 025688, AG016574, AG008017, P50AG005133, AG 024904, P50AG005131, AG-013854, AG035982, AG049638, P50AG005138, AG019610, AG010161, P20AG068053, P30AG010124, AG047266, P50AG016573, AG072959, P50AG047366, AG010129, P30AG008017, P20AG068024, AG-033514, P30AG010161, AG005131, P30AG008051, P50AG008702, P50AG033514, AG023501, P30AG035982, AG013846, P20AG068077, P50AG005681, P50AG005142, P50AG047270, P30AG019610, P50AG005146, AG068082, AG068024, AG047270, P30AG013846, P50AG005136, P20AG068082, P50AG005134, P30AG013854, AG053760, P50AG025688, P50AG047266, AG005681, P30AG072972, P30AG072959, P30AG066514, P30AG066509, P30AG072958, U24AG072122, P30AG072946, P30AG072977, P30AG072947, P30AG066546, P50AG023501, P50AG016574)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, cortical microstructure, diffusion MRI, mean diffusivity, Braak stages, amyloid plaques, tau pathology, ABC score, Lewy body disease, TDP-43, white matter rarefaction, cerebral amyloid angiopathy, co-pathology, neurodegeneration
- MeSH terms
- Alzheimer Disease, Atrophy, Brain, DNA-Binding Proteins, Humans, Lewy Body Disease
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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