Cited by 1,132Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsFunctional Brain Connectivity Studies

The DOI matches its Crossref record; 104 of the 105 references it cites were found in a registry or an index; none of the 58 sources its claims cite is checked for support yet.

Dynamics of Gray Matter Loss in Alzheimer's Disease

Open access

Abstract

We detected and mapped a dynamically spreading wave of gray matter loss in the brains of patients with Alzheimer's disease (AD). The loss pattern was visualized in four dimensions as it spread over time from temporal and limbic cortices into frontal and occipital brain regions, sparing sensorimotor cortices. The shifting deficits were asymmetric (left hemisphere > right hemisphere) and correlated with progressively declining cognitive status ( p < 0.0006). Novel brain mapping methods allowed us to visualize dynamic patterns of atrophy in 52 high-resolution magnetic resonance image scans of 12 patients with AD (age 68.4 ± 1.9 years) and 14 elderly matched controls (age 71.4 ± 0.9 years) scanned longitudinally (two scans; interscan interval 2.1 ± 0.4 years). A cortical pattern matching technique encoded changes in brain shape and tissue distribution across subjects and time. Cortical atrophy occurred in a well defined sequence as the disease progressed, mirroring the sequence of neurofibrillary tangle accumulation observed in cross sections at autopsy. Advancing deficits were visualized as dynamic maps that change over time. Frontal regions, spared early in the disease, showed pervasive deficits later (>15% loss). The maps distinguished different phases of AD and differentiated AD from normal aging. Local gray matter loss rates (5.3 ± 2.3% per year in AD v 0.9 ± 0.9% per year in controls) were faster in the left hemisphere ( p < 0.029) than the right. Transient barriers to disease progression appeared at limbic/frontal boundaries. This degenerative sequence, observed in vivo as it developed, provides the first quantitative, dynamic visualization of cortical atrophic rates in normal elderly populations and in those with dementia.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This longitudinal MRI study mapped a dynamically spreading wave of cortical gray matter loss in Alzheimer’s disease, from temporal/limbic regions into frontal and occipital cortex while sparing sensorimotor areas. Loss was asymmetric (left faster than right) and correlated with declining MMSE scores.

Key findings

  • In 12 patients with AD versus 14 controls, AD showed significant gray matter deficits in bilateral temporal and parietal cortices (baseline permutation p < 0.00495 left, p < 0.0154 right; follow-up p < 0.00027 left, p < 0.00056 right), with deficits exceeding 15% in most affected regions and relative sparing of sensorimotor cortex (0–5% loss).
  • Frontal cortex was initially only mildly affected (6–10% loss) but became severely affected later (>15% everywhere) as MMSE declined from 17.7 ± 1.9 to 12.9 ± 2.5 (mean change 5.5 ± 1.9; p < 0.00054); controls remained stable at MMSE 29.5 ± 0.3.
  • Local gray matter loss rates were 5.03 ± 2.28% per year in AD versus 0.91 ± 0.92% per year in controls; left hemisphere loss was faster in AD by 0.79% per year (p < 0.04). Whole-brain atrophy was 5.22 ± 2.04% per year in AD versus 0.88 ± 0.15% per year in controls (p < 0.003 group difference).
  • Lower MMSE scores were linked to greater gray matter deficits in temporal-parietal and limbic cortices, but not in sensorimotor cortex; correlation maps were significant by permutation (e.g., p < 0.0013 left, p < 0.0028 right when mean MMSE was 18).

Methods

  • Longitudinal MRI study: 12 AD patients (six men, six women; mean age 68.4 ± 1.9 years at first scan) and 14 elderly controls (seven men, seven women; mean age 71.4 ± 0.9 years), each scanned twice. Methods report mean interscan intervals of 1.5 ± 0.3 years for AD and 2.6 ± 0.3 years for controls; the abstract reports an overall interscan interval of 2.1 ± 0.4 years.
  • Image processing included bias correction, stereotaxic registration, tissue classification, 3D cortical surface extraction, and cortical pattern matching using 72 sulcal landmarks per brain (30 sulci traced per hemisphere). Gray matter density was measured as the proportion of gray matter within 15 mm of each cortical point.
  • Statistical maps used pointwise multiple regression across the cortex and permutation testing (1 million permutations) with a primary threshold of p = 0.01 and corrected map-wise p values; left and right hemispheres were assessed separately.

Limitations

  • Stated in the paper: only two time points per subject were used, forcing the assumption of linear loss during the interscan interval; future studies with multiple time points are needed to test whether AD accelerates or progresses nonlinearly.
  • Evident from the text: the sample is small (12 AD patients and 14 controls), limiting generalizability and power for subgroup analyses.
  • Evident from the text: reported interscan intervals differ between the abstract (2.1 ± 0.4 years overall) and the Methods (AD 1.5 ± 0.3 years; controls 2.6 ± 0.3 years), which may affect rate estimates.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1523/jneurosci.23-03-00994.2003

Cites

104 of 104 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

82 Own result · 34 Not checked yet · 23 Own interpretation · 13 Own method · 2 No basis given

Verify all 58 references — free account

Show all 89 claims

  • It may state two separate claims as one. 50
  • Probably not a substantial claim. 24
  • The quote only partly states this claim. 1
65 of 65
  • The paper relies on this without support.

    MRI-visible gross atrophy reflects the neuronal loss caused by AD pathology.

    “The result-ing neuronal loss is observable as gross atrophy with magnetic resonance imaging (MRI).”
  • The paper relies on this without support.

    In early AD, neurofibrillary tangles accumulate inside neurons.

    “In early AD, intraneuronal filamentous deposits, or neurofibrillary tangles (NFTs), accumulate within neurons.”
  • The authors state this as an assumption.

    Gray matter loss is linear during the interval between scans.

    “which forces us to assume linear loss during the interscan interval.”
3 of 3

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3 of 3

Citations

Cites

Show all 105 references

Research works printed but not linked: 2

  1. Ashburner J, Csernansky J, Davatzikos C, Fox NC, Frisoni G, Thompson PM (2003) Computational neuroanatomy: towards a computer-assisted diagnosis of degenerative brain diseases based on magnetic resonance imaging. Lancet Neurol, in press.
  2. Kaye, 1999, The rate of brain volume loss accelerates as Alzheimer's disease progresses from a presymptomatic phase to frank dementia., Neurology, 52[Suppl], A569

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Metadata

Authors
Thompson, P. M., Hayashi, K. M., de Zubicaray, G., Janke, A. L., Rose, S. E., Semple, J., Herman, D., Hong, M. S., Dittmer, S. S., Doddrell, D. M., & Toga, A. W.
Affiliations
  • University of California, Los Angeles (US)
  • The University of Queensland (AU)
  • GlaxoSmithKline (United Kingdom) (GB)
Venue
The Journal of Neuroscience
Published
2003-02-01
Volume
23
Issue
3
Pages
994-1005
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2153996202
Cited by
1,132
References
105
Citations by year
2026: 17 · 2025: 50 · 2024: 32 · 2023: 42 · 2022: 33 · 2021: 49 · 2020: 56 · 2019: 34 · 2018: 43 · 2017: 38 · 2016: 43 · 2015: 53 · 2014: 51 · 2013: 62 · 2012: 63
FWCI
27.01
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • QUT ePrints (Queensland University of Technology) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • GlaxoSmithKline
  • National Institute of Mental Health (P01MH052176, P01 MH52176)
  • National Institute on Drug Abuse
  • U.S. National Library of Medicine (LM 05639, R01LM005639, R01 LM05639)
  • National Center for Research Resources (LM05639, P41RR013642, (M01 RR00865), RR 13642, RR00865, M01RR000865, P41 RR13642)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
Keywords
Alzheimer's disease, cortical atrophy, gray matter loss, atrophy progression, hemispheric lateralization, temporal lobe, limbic cortex, frontal cortex, occipital cortex, neurofibrillary tangles, cognitive decline, normal aging, dementia
MeSH terms
Aged, Aging, Alzheimer Disease, Atrophy, Brain, Brain Mapping, Cognition Disorders, Humans, Image Processing, Computer-Assisted, Longitudinal Studies, Magnetic Resonance Imaging, Neuropsychological Tests, Reference Values, Time, Disease Progression, Internet

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