MRI correlates of neurofibrillary tangle pathology at autopsy: A voxel-based morphometry study
Open accessAbstract
BACKGROUND: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology. METHODS: Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II). RESULTS: In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden. CONCLUSIONS: Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.
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Several studies have reported a strong negative correlation between neuronal counts and NFT number in the CA1 subfield, suggesting that the progression of brain atrophy and the progression of NFT are strongly associated.
“Moreover, several studies have reported a strong negative correlation between neuronal counts and NFT number in the CA1 subfield (Fukutani et al., 2000; Von Gunten et al., 2006) suggesting that the progression of brain atrophy and the progression of NFT are strongly associated (Whitwell et al., 2008).”
From Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia (2013) · cites this paper as Whitwell et al., 2008
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- Authors
- Whitwell, J. L., Josephs, K. A., Murray, M. E., Kantarci, K., Przybelski, S. A., Weigand, S. D., Vemuri, P., Senjem, M. L., Parisi, J. E., Knopman, D. S., Boeve, B. F., Petersen, R. C., Dickson, D. W., & Jack, C. R.
- Affiliations
- Mayo Clinic (US)
- ORCID
- Venue
- Neurology
- Published
- 2008-09-02
- Volume
- 71
- Issue
- 10
- Pages
- 743-749
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- PMC
- PMC2676950
- OpenAlex
- W2068338689
- Cited by
- 376
- References
- 38
- Citations by year
- 2026: 19 · 2025: 23 · 2024: 16 · 2023: 11 · 2022: 15 · 2021: 22 · 2020: 17 · 2019: 21 · 2018: 26 · 2017: 20 · 2016: 23 · 2015: 22 · 2014: 26 · 2013: 29 · 2012: 28
- FWCI
- 13.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Neurology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- National Institutes of Health
- National Institute on Aging (R01AG11378, K23AG030935, P50‐AG16574, U01AG06786, U01AG006786, R01AG011378, P50AG016574)
- National Center for Research Resources (C06RR018898)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD049078, K12 HD 49078)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- neurofibrillary tangles, Alzheimer's disease, Braak staging, tau burden, gray matter atrophy, voxel-based morphometry, medial temporal lobe, lateral temporal lobe, neuropathology
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Autopsy, Brain Mapping, Cognition Disorders, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Psychiatric Status Rating Scales, Neurofibrillary Tangles, tau Proteins, alpha-Synuclein
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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