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Cited by 629Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMedical Imaging Techniques and Applications

Prediction of cognitive decline in normal elderly subjects with 2-[ 18 F]fluoro-2-deoxy- d -glucose/positron-emission tomography (FDG/PET)

Open access
de Leon, M. J., Convit, A., Wolf, O. T., Tarshish, C. Y., DeSanti, S., Rusinek, H., Tsui, W., Kandil, E. +11 more·2001·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.191044198PMC PMC58582
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Abstract

Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimer's disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex. Related observations with in vivo imaging have enabled the prediction of dementia from MCI. Although individuals with normal cognition may have focal EC lesions, this anatomy has not been studied as a predictor of cognitive decline and brain change. The objective of this MRI-guided 2-[ 18 F]fluoro-2-deoxy- d -glucose/positron-emission tomography (FDG/PET) study was to examine the hypothesis that among normal elderly subjects, EC METglu reductions predict decline and the involvement of the Hip and neocortex. In a 3-year longitudinal study of 48 healthy normal elderly, 12 individuals (mean age 72) demonstrated cognitive decline (11 to MCI and 1 to Alzheimer's disease). Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender. At baseline, metabolic reductions in the EC accurately predicted the conversion from normal to MCI. Among those who declined, the baseline EC predicted longitudinal memory and temporal neocortex metabolic reductions. At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip. Among those subjects who declined, apolipoprotein E E4 carriers showed marked longitudinal temporal neocortex reductions. In summary, these data suggest that an EC stage of brain involvement can be detected in normal elderly that predicts future cognitive and brain metabolism reductions. Progressive E4-related hypometabolism may underlie the known increased susceptibility for dementia. Further study is required to estimate individual risks and to determine the physiologic basis for METglu changes detected while cognition is normal.

AI snapshot

Written from the paper’s full text.

TL;DR

In a 3-year longitudinal MRI-guided FDG/PET study of 48 healthy normal elderly, baseline entorhinal cortex (EC) glucose metabolism reductions predicted conversion from normal cognition to mild cognitive impairment (MCI). Decliners showed follow-up memory impairment and temporal neocortical/hippocampal hypometabolism, with marked longitudinal temporal neocortex reductions among declining apoE E4 carriers.

Key findings

  • Baseline EC METglu was reduced 18% in subjects who declined relative to those who did not decline (F[1,21] = 29.1, P < 0.001), and EC correctly classified decline outcome with 84% accuracy, 83% sensitivity, and 85% specificity (odds ratio = 1.42, CI = 1.08–1.88).
  • At follow-up, the declining group had lower METglu in EC (17%, F[1,21] = 35.5, P < 0.001), hippocampus (7%, F[1,21] = 4.5, P < 0.05), and lateral temporal lobe (LTL; 8%, F[1,21] = 8.0, P = 0.01).
  • Among decliners, baseline EC predicted longitudinal reductions in LTL (F[1,9] = 5.0, P < 0.05) and orbital frontal lobe (F[1,9] = 6.0, P < 0.05) metabolism.
  • A longitudinal outcome-by-apoE interaction was found for LTL (F[1,21] = 7.2, P = 0.01): E4 carriers who declined showed 13% reductions over time versus 3% in decliners without an E4 allele.

Methods

  • Longitudinal 36-month FDG/PET study with MRI-guided region-of-interest sampling; 48 healthy normal elderly completed the PET evaluation, including 12 analyzed decliners (11 to MCI and 1 to probable AD) and 13 matched nondeclining controls.
  • Inclusion criteria included age 60–80 years, at least 12 years of education, MMSE ≥ 28, and baseline GDS scores of 1 or 2; exclusion criteria included conditions affecting brain structure or function and use of cognitively active medications.
  • Regional METglu was slab-normalized, corrected for CSF partial volume, and analyzed with two-factor ANOVA, repeated-measures models, hierarchical linear/logistic regression, and SPM99 voxel-based analysis.

Limitations

  • The paper states that observations were made with small numbers of subjects under controlled conditions and that clinical application is not yet justified.
  • The paper states that 3 years was not a long enough follow-up interval to observe the hypothesized longitudinal hippocampal involvement, and that MCI etiologic heterogeneity and the mechanism linking AD-related brain changes to METglu are unknown.
  • The paper notes that SPM may not consistently align the EC across individuals because of large anatomical variability; the text also makes evident that only one subject declined to AD, so findings mainly concern conversion to MCI.

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

Integrity signals

Registry

Crossref · 10.1073/pnas.191044198

Cites

Statistics

11 tests recomputed · 0 with the reported and recomputed p on opposite sides of .05

Claims the paper makes

0 of 56 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Results

    The DFL METglu measure did not significantly contribute to the risk for decline.

    “This measure did not significantly contribute to the risk for decline (lower CI limit ≤ 1.00).”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Abstract

    The EC correctly classified decline outcome with 84% accuracy: 83% sensitivity and 85% specificity.

    “At baseline, metabolic reductions in the EC accurately predicted the conversion from normal to MCI.”
    • Also stated in: § Results · plain
      “The EC correctly classified decline outcome with 84% accuracy: 83% sensitivity (those who declined) and 85% specificity (those who did not decline) [X2 (1) = 20.8, P < 0.001; odds ratio = 1.42; confidence interval (CI) = 1.08–1.88].”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    None of the analyses showed an interaction between outcome and apoE groups.

    “None of the analyses showed an interaction between outcome and apoE groups.”
    Quote in the paperNot a substantial claim
  • Findingown data
    § Results

    After removal of the case that later declined to Alzheimer's disease, only the EC outcome group effect remained significant (17% reduction).

    “After removal of the case that later declined to AD, only the EC outcome group effect remained significant (17%, P < 0.001).”
    Quote in the paperSubstantial claim
  • Findingown data
    § Results

    Removing the one case with Alzheimer's disease or correcting for atrophy had little effect on the EC classification (83% and 80%, respectively).

    “Removing the one case with AD or correcting for atrophy had little effect on the EC classification (83 and 80%, respectively).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 31
  • Classified as probably not a substantial claim. 29
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data
    § Methods

    Of 48 subjects, 13 declined (all GDS = 2 at baseline and 4 heterozygote E4 carriers).

    “Of 48 subjects, 13 declined (all GDS = 2 at baseline and 4 heterozygote E4 carriers).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given
    § Methods

    At baseline, none of the subjects demonstrated cognitive or functional deficits and all were diagnosed as normal.

    “At baseline, none of the subjects demonstrated cognitive or functional deficits and all were diagnosed as normal.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    With atrophy correction, the EC outcome group effect (11%) and LTL apoE effect (8%) remained significant, and DFL METglu became significantly reduced in those who declined (10%).

    “With atrophy correction the EC outcome group effect (11%, P < 0.01) and the LTL apoE effect (8%, P < 0.01) remained significant, and the DFL METglu became significantly reduced in those who declined (10%, F[1,21] = 4.7, P < 0.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    At the 36-month follow-up, cognitive decline was seen in 29% of the 105 MRI subjects, comparable to 27% in the 48 PET subjects.

    “At the 36-month follow-up, cognitive decline was seen in 29% of the 105 MRI subjects, which was comparable to the 27% observed in the 48 PET subjects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Both the lateral temporal lobe (LTL) and superior temporal gyrus were reduced in E4 carriers relative to noncarriers (8% and 3%, respectively).

    “Both the LTL and the superior temporal gyrus were reduced in E4 carriers relative to noncarriers (8%, F[1,21] = 6.9, P = 0.05; and 3%, F[1,21] = 4.6, P = 0.05, respectively).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Methods

    Among those who declined, 12 declined to MCI and 1 met criteria for probable Alzheimer's disease (GDS = 5).

    “Among those who declined, 12 declined to MCI and 1 met criteria for probable AD (GDS = 5).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    No significant longitudinal main effects or interactions were found with SPM.

    “No significant longitudinal main effects or interactions were found with SPM.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Abstract

    At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip.

    “At follow-up, those who declined showed memory impairment and hypometabolism in temporal lobe neocortex and Hip.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Methods

    E4 carriers showed 11-17% adjustment as compared with 6-14% in noncarriers.

    “E4 carriers showed 11–17% adjustment as compared with 6–14% in the noncarriers.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    There were no apoE group effects or interactions in the SPM analyses.

    “There were no apoE group effects or interactions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Methods

    The application of atrophy correction increased regional metabolism by 10-21% in those who declined and 5-15% in those who did not decline, with the greatest adjustment seen in EC and DFL.

    “The application of this correction increased regional metabolism by 10–21% in those who declined and 5–15% in those who did not decline, with the greatest adjustment seen in EC and DFL, respectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    No apoE effects or interactions between outcome and apoE groups were found for any neuropsychological measure at baseline.

    “No apoE effects or interactions between outcome and apoE groups were found for any of the measures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    At follow-up, the declining group showed significant reductions in 8/10 neuropsychological measures and a trend toward reduced MMSE performance.

    “At follow-up, the declining group showed significant (P < 0.05) reductions in 8/10 neuropsychological measures and a trend toward reduced MMSE performance (P < 0.1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data
    § Methods

    The greatest adjustments were for the EC.

    “The greatest adjustments were for the EC.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    In a regression model, adding uncorrected baseline EC to the designs test increased the number of cases correctly classified but did not significantly increment the risk for decline (lower CI limit <1.00).

    “In a regression model, adding the uncorrected baseline EC to the designs test increased the number of cases correctly classified but did not significantly increment the risk for decline (lower CI limit < 1.00).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data
    § Results

    Among those who declined, a smaller baseline EC predicted greater longitudinal reduction in LTL METglu (F[1,9]=5.0, P<0.05).

    “Only among those who declined did a smaller baseline EC predict greater longitudinal reduction in the LTL [F(1,9) = 5.0, P < 0.05] and the orbital frontal lobe [F(1,9) = 6.0, P < 0.05].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    At baseline, neither ROI nor SPM identifies neocortical outcome group effects or interactions, but ROI showed small apoE group effects for the temporal neocortex.

    “At baseline, neither approach identifies neocortical outcome group effects or interactions, but the ROI method showed small apoE group effects for the temporal neocortex.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given
    § Discussion

    Correction of regional metabolism samples for partial volume of cerebrospinal fluid generally increased the values.

    “As expected, correction of the regional metabolism samples for the partial volume of cerebrospinal fluid generally increased the values.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    The temporal neocortical effect was more robust than the bilateral hippocampal effect that disappeared after removing the one case that declined to AD.

    “This effect was more robust than the bilateral hippocampal effect that disappeared after removing the one case that declined to AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    At follow-up, both ROI and SPM show comparable neocortical outcome and apoE group effects, but SPM uniquely identified an outcome group difference in the left inferior frontal gyrus.

    “At follow-up, both methods show comparable neocortical outcome and apoE groups effects, but SPM uniquely identified an outcome group difference in the left inferior frontal gyrus, a region not studied with ROI.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    The results show that only the LTL showed the apoE group by outcome group interaction, driven by declining E4 carriers (all heterozygous).

    “The results show that only the LTL showed the interaction, which on closer examination was driven by declining E4 carriers (all heterozygous).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    At follow-up, we did not observe a specific hippocampal stage associated with MCI; instead, we found neocortical temporal lobe hypometabolism and limited hippocampal involvement.

    “However, at follow-up, we did not observe a specific hippocampal stage associated with MCI; instead, we found neocortical temporal lobe hypometabolism and limited hippocampal involvement.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Abstract

    Carriers of an apolipoprotein E (apoE) E4 allele show at younger ages increased neocortical beta amyloid deposits and EC NFTs.

    “Carriers of an apolipoprotein E (apoE) E4 allele show at younger ages increased neocortical beta amyloid deposits (6) and EC NFTs (7).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Schmechel D E, Saunders A M, Strittmatter W J, Crain B J, Hulette C M, Joo S H, Pericak-Vance M A, Goldgaber D, Roses A D. Proc Natl Acad Sci USA. 1993;90:9649–9653. doi: 10.1073/pnas.90.20.9649. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [7] Ghebremedhin E, Schultz C, Braak E, Braak H. Exp Neurol. 1998;153:152–155. doi: 10.1006/exnr.1998.6860. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § Results

    Time to follow-up was equivalent between outcome groups.

    “Time to follow-up was equivalent.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Reduced size or glucose metabolism (METglu) in the EC, Hip, temporal neocortex, and posterior cingulate gyrus have been shown to predict the MCI conversion to Alzheimer's disease.

    “Reduced size or glucose metabolism (METglu) in the EC (10), Hip (11–16), temporal neocortex (17–20), and posterior cingulate gyrus (16) have been shown to predict the MCI conversion to AD.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [10] Killiany R J, Gomez-Isla T, Moss M, Kikinis R, Sandor T, Jolesz F, Tanzi R, Jones K, Hyman B, Albert M S. Ann Neurol. 2000;47:430–439. [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [11] de Leon M J, George A E, Stylopoulos L A, Smith G, Miller D C. Lancet. 1989;2:672–673. doi: 10.1016/s0140-6736(89)90911-2. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [12] de Leon M J, Golomb J, George A E, Convit A, Tarshish C Y, McRae T, De Santi S, Smith G, Ferris S H, Noz M, et al. Am J Neuroradiol. 1993;14:897–906. [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [13] Jack C R, Jr, Petersen R C, Xu Y C, O'Brien P C, Smith G E, Ivnik R J, Boeve B F, Waring S C, Tangalos E G, Kokmen E. Neurology. 1999;52:1397–1403. doi: 10.1212/wnl.52.7.1397. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [14] Visser P J, Scheltens P, Verby F R J, Schmand B, Launer L J, Jolles J, Jonker C. J Neurol. 1999;246:477–485. doi: 10.1007/s004150050387. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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      Not checked in the free run.

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      Not checked in the free run.

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      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data
    § Methods

    One patient with MCI was excluded during data analysis because a small thalamic lacunar infarct was found on the follow-up research MRI.

    “One patient with MCI was excluded during the data analysis because a small thalamic lacunar infarct, not detected on the follow-up clinical MRI, was found on the follow-up research MRI.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data
    § Abstract

    Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender.

    “Nondeclining controls were matched on apolipoprotein E genotype, age, education, and gender.”
    • Also stated in: § Methods · plain
      “From the 35 nondeclining subjects, 13 matched controls (11 GDS 2 and 2 GDS 1) were selected on (descending order of importance): E4 carrier or noncarrier, age, education, and gender (see Table 1).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Abstract

    Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimer's disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex.

    “Neuropathology studies show that patients with mild cognitive impairment (MCI) and Alzheimer's disease typically have lesions of the entorhinal cortex (EC), hippocampus (Hip), and temporal neocortex.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Braak H, Braak E. Acta Neuropathol. 1991;82:239–259. doi: 10.1007/BF00308809. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

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      Not checked in the free run.

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      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Abstract

    Braak and Braak proposed a staging model for brain Alzheimer's disease where the NFT distribution expands from an EC locus to involve the Hip and then the neocortex.

    “Braak and Braak (3) proposed a staging model for brain AD where the NFT distribution expands from an EC locus to involve the Hip and then the neocortex.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Braak H, Braak E. Acta Neuropathol. 1991;82:239–259. doi: 10.1007/BF00308809. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data
    § Results

    The LTL longitudinal interaction remained significant after removal of the case with AD (P=0.05) and after atrophy correction (P=0.01).

    “The LTL interaction was also found after removal of the case with AD (P = 0.05) and after atrophy correction (P = 0.01).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data
    § Methods

    The regional isotope recovery is robust and varies in a narrow (<5% absolute error) range.

    “The results show that the regional isotope recovery is robust and varies in a narrow (<5% absolute error) range.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data
    § Methods

    For MRI, 144 normal community-residing elderly were enrolled at baseline, of whom 105 completed follow-up.

    “For MRI, 144 normal community-residing elderly were enrolled at the baseline of whom 105 completed the follow-up.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § Methods

    We estimated an average registration error of <2 mm.

    “We estimated an average registration error of <2 mm.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data
    § Methods

    At baseline, 67/144 subjects were also enrolled in the PET study, of whom 48 completed the 36-month PET evaluation.

    “At the baseline, 67/144 subjects were also enrolled in the PET study, of whom 48 completed the 36-month PET evaluation (see below).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given
    § Methods

    An informant always corroborated the determination of decline.

    “An informant always corroborated the determination of decline.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    AD neuropathology is known to involve the Hip in MCI patients.

    “and also the Hip in MCI patients (39)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Morris J C, Storandt M, Miller P, McKeel D W, Price J L, Rubin E H, Berg L. Neurology. 2001;58:397–405. doi: 10.1001/archneur.58.3.397. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    These neuropathology findings support the Braak and Braak staging of NFT accumulations.

    “findings supporting the Braak and Braak (3) staging of NFT accumulations.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Braak H, Braak E. Acta Neuropathol. 1991;82:239–259. doi: 10.1007/BF00308809. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Structural imaging studies report useful hippocampal, EC, and combined medial temporal and temporal neocortex predictors for conversion to AD.

    “They report useful hippocampal (11–14), EC (10), and combined medial temporal and temporal neocortex (17) predictors for the conversion.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [11] de Leon M J, George A E, Stylopoulos L A, Smith G, Miller D C. Lancet. 1989;2:672–673. doi: 10.1016/s0140-6736(89)90911-2. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [12] de Leon M J, Golomb J, George A E, Convit A, Tarshish C Y, McRae T, De Santi S, Smith G, Ferris S H, Noz M, et al. Am J Neuroradiol. 1993;14:897–906. [PMC free article] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [13] Jack C R, Jr, Petersen R C, Xu Y C, O'Brien P C, Smith G E, Ivnik R J, Boeve B F, Waring S C, Tangalos E G, Kokmen E. Neurology. 1999;52:1397–1403. doi: 10.1212/wnl.52.7.1397. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [14] Visser P J, Scheltens P, Verby F R J, Schmand B, Launer L J, Jolles J, Jonker C. J Neurol. 1999;246:477–485. doi: 10.1007/s004150050387. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [10] Killiany R J, Gomez-Isla T, Moss M, Kikinis R, Sandor T, Jolesz F, Tanzi R, Jones K, Hyman B, Albert M S. Ann Neurol. 2000;47:430–439. [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [17] Convit A, de Asis J, de Leon M J, Tarshish C, De Santi S, Rusinek H. Neurobiol Aging. 2000;21:19–26. doi: 10.1016/s0197-4580(99)00107-4. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    Among structural imaging studies examining conversion of MCI to AD, there is one longitudinal study and several prediction studies.

    “Among structural imaging studies examining the conversion of MCI to AD, there are one longitudinal (40) and several prediction studies (one scan predicting clinical outcome).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Jack C R, Peterson R C, Xu Y, O'Brien P C, Smith G E, Ivnik R J. Neurology. 2000;55:484–489. doi: 10.1212/wnl.55.4.484. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Others have observed that temporo-parietal METglu deficits predict AD.

    “Others have observed that temporo-parietal METglu deficits predict AD (18–20).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Pietrini P, Azari N P, Grady C L, Salerno J A, Gonzalez-Aviles A, Heston L L, Pettigrew K D, Horwitz B, Haxby J V, Schapiro M B. Dementia. 1993;4:94–101. doi: 10.1159/000107349. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

    • cites [19] Berent S, Giordani B, Foster N, Minoshima S, Lajiness-O'Neill R, Koeppe R, Kuhl D E. J Psychiatr Res. 1999;33:7–16. doi: 10.1016/s0022-3956(98)90048-6. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [20] Arnaiz E, Jelic V, Almkvist O, Wahlund L-O, Winblad B, Valind S, Nordberg A. NeuroReport. 2001;12:851–855. doi: 10.1097/00001756-200103260-00045. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data
    § Discussion

    Although EC pathology may be a specific predictor, it alone does not cause the decline from normal.

    “This result suggests that although EC pathology may be a specific predictor, it alone does not cause the decline from normal.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning
    § Discussion

    From the structural imaging literature, it remains largely unexplored whether neocortical changes in addition to medial temporal changes are necessary for decline to AD.

    “Consequently, from the structural imaging literature, it remains largely unexplored whether neocortical changes in addition to medial temporal changes are necessary for decline to AD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Neuropsychological studies and neuroimaging studies have often suggested that DFL changes underlie age-associated deficits in working memory, psychomotor speed, and attention.

    “Neuropsychological studies (see ref. 46 for review) and neuroimaging studies (47) have often suggested that DFL changes underlie age-associated deficits in working memory, psychomotor speed, and attention.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Tulving E. Am Psychol. 1985;40:385–398. [Google Scholar] source

      Not checked in the free run.

    • cites [47] de Leon M J, George A E, Tomanelli J, Christman D, Kluger A, Miller J, Ferris S H, Fowler J, Brodie J, Klinger A, et al. Neurobiol Aging. 1987;8:319–323. doi: 10.1016/0197-4580(87)90070-4. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Not all subjects with MCI deteriorate to clinical AD.

    “Not all subjects with MCI deteriorate to clinical AD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Kluger A, Ferris S H, Golomb J, Mittelman M S, Reisberg B. J Geriatr Psychiatry Neurol. 1999;12:168–179. doi: 10.1177/089198879901200402. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Estimates based on 4 years of observation suggest that 50-70% of MCI subjects will decline.

    “Estimates based on 4 years of observation suggest that 50–70% will decline (42).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Kluger A, Ferris S H, Golomb J, Mittelman M S, Reisberg B. J Geriatr Psychiatry Neurol. 1999;12:168–179. doi: 10.1177/089198879901200402. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    The conjecture that excess temporal neocortex metabolic reduction in E4 carriers is related to increased β-amyloid deposition is supported by the increased predilection in early AD for β-amyloid to accumulate in the neocortex rather than the hippocampal formation and by reductions in METglu observed in transgenic mouse models overproducing amyloid.

    “This conjecture is supported further by the increased predilection in early AD for β-amyloid to accumulate in the neocortex rather than the hippocampal formation (2, 6) and by reductions in METglu observed in transgenic mouse models overproducing amyloid (44).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Berg L, McKeel D W, Miller P J, Storandt M, Rubin E H, Morris J C, Baty J, Coats M, Norton J, Goate A M, et al. Arch Neurol (Chicago) 1998;55:326–335. doi: 10.1001/archneur.55.3.326. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [6] Schmechel D E, Saunders A M, Strittmatter W J, Crain B J, Hulette C M, Joo S H, Pericak-Vance M A, Goldgaber D, Roses A D. Proc Natl Acad Sci USA. 1993;90:9649–9653. doi: 10.1073/pnas.90.20.9649. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [44] Reiman E M, Uecker A, Gonzalez-Lima F, Minear D, Calloway N P, Berndt J D, Games D. NeuroReport. 2000;11:987–991. doi: 10.1097/00001756-200004070-00018. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation
    § Discussion

    It has been suggested that this association may account for the earlier onset of symptoms in E4 carriers.

    “It has been suggested that this association may account for the earlier onset of symptoms in E4 carriers (21–23).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [21] Small G W, Mazziotta J C, Collins M T, Baxter L R, Phelps M E, Mandelkern M A, Kaplan A, LaRue A, Adamson C F, Chang L, et al. J Am Med Assoc. 1995;273:942–947. [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [22] Reiman E M, Caselli R J, Yun L S, Chen K, Bandy D, Minoshima S, Thibodeau S N, Osborne D. N Engl J Med. 1996;334:752–758. doi: 10.1056/NEJM199603213341202. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [23] Small G W, Ercoli L M, Silverman D H S, Huang S C, Komo S, Bookheimer S, Lavretsky H, Miller K, Siddarth P, Rasgon N L, et al. Proc Natl Acad Sci USA. 2000;97:6037–6042. doi: 10.1073/pnas.090106797. . (First Published May 16, 2000; 10.1073/pnas.090106797) [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation
    § Discussion

    In the absence of a specific diagnostic test, it is unknown what proportion of patients with MCI have AD neuropathological changes; estimates range as high as >80%.

    “Relatedly, in the absence of a specific diagnostic test, it is also unknown what proportion of patients with MCI have AD neuropathological changes [estimates range as high as >80% (39)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Morris J C, Storandt M, Miller P, McKeel D W, Price J L, Rubin E H, Berg L. Neurology. 2001;58:397–405. doi: 10.1001/archneur.58.3.397. [DOI] [PubMed] [Google Scholar]

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    In vitro, β-amyloid has been shown to reduce glucose transport.

    “In vitro, β-amyloid has been shown to reduce glucose transport (43)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Mark R J, Pang Z, Geddes J W, Uchida K, Mattson M P. J Neurosci. 1997;17:1046–1054. doi: 10.1523/JNEUROSCI.17-03-01046.1997. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data
    § Discussion

    The uncorrected data were examined by using both ROI and SPM methods and the results demonstrate partial agreement between them.

    “The uncorrected data were examined by using both ROI and SPM methods and the results demonstrate partial agreement between them.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation
    § Discussion

    Patients with AD show numerous lesions that may explain the hypometabolism-synaptic and neuronal losses and amyloid and NFT depositions.

    “Patients with AD show numerous lesions that may explain the hypometabolism—synaptic and neuronal losses and amyloid and NFT depositions (see ref. 43 for summary).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [43] Mark R J, Pang Z, Geddes J W, Uchida K, Mattson M P. J Neurosci. 1997;17:1046–1054. doi: 10.1523/JNEUROSCI.17-03-01046.1997. [DOI] [PMC free article] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation
    § Discussion

    NFT depositions damage neurons, favor the hippocampal formation over the neocortex in preclinical AD stages, and may be accelerated in E4 carriers.

    “NFT depositions, on the other hand, damage neurons (45), favor the hippocampal formation over the neocortex in preclinical AD stages (3, 4), and may also be accelerated in E4 carriers (7).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [45] Bobinski M, Wegiel J, Tarnawski M, Reisberg B, de Leon M J, Miller D C, Wisniewski H M. J Neuropathol Exp Neurol. 1997;56:414–420. doi: 10.1097/00005072-199704000-00010. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [3] Braak H, Braak E. Acta Neuropathol. 1991;82:239–259. doi: 10.1007/BF00308809. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [4] Arriagada P V, Marzloff K, Hyman B T. Neurology. 1992;42:1681–1688. doi: 10.1212/wnl.42.9.1681. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

    • cites [7] Ghebremedhin E, Schultz C, Braak E, Braak H. Exp Neurol. 1998;153:152–155. doi: 10.1006/exnr.1998.6860. [DOI] [PubMed] [Google Scholar] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data
    § Discussion

    Our observations were made with small numbers of subjects under controlled conditions; clinical application is not yet justified.

    “We caution that our observations were made with small numbers of subjects under controlled conditions; clinical application is not yet justified.”
    Quote in the paperNot a substantial claim
53 of 53

  • The paper relies on this without support.

    The anatomy predicting future memory impairment in normal elderly has not been well characterized.

    “however, the affected anatomy predicting future impairment has not been well characterized.”

  • The paper relies on this without support.

    Longitudinal imaging studies have not investigated the decline from normal cognition.

    “longitudinal imaging studies have not investigated the decline from normal.”

  • The paper relies on this without support.

    A relationship between E4-related hypometabolism and longitudinally observed decline has not been reported.

    “but a relationship to longitudinally observed decline has not been reported.”

  • The paper relies on this without support.

    Focal EC lesions in normal cognition have not been studied as a predictor of cognitive decline and brain change.

    “Although individuals with normal cognition may have focal EC lesions, this anatomy has not been studied as a predictor of cognitive decline and brain change.”

  • The paper relies on this without support.

    The decline from MCI to Alzheimer's disease has been examined only.

    “The decline from MCI to AD has been examined only.”

  • The paper relies on this without support.

    This longitudinal FDG/PET study is the first imaging study to predict future cognitive decline and MCI among normal elderly.

    “This longitudinal FDG/PET study is the first imaging study, to our knowledge, to predict future cognitive decline and MCI among normal elderly.”

  • The paper relies on this without support.

    Very little information is available in vivo about AD neuropathology.

    “However, very little information is available in vivo.”

  • The paper relies on this without support.

    Few imaging studies have examined multiple vulnerable brain regions, and even fewer used longitudinal designs with patients who clinically decline.

    “Few imaging studies have examined multiple vulnerable brain regions, and even fewer studies used longitudinal designs with patients who clinically decline”

  • The paper relies on this without support.

    Imaging outcome measures lack neuropathologic specificity.

    “(necessary because imaging outcome measures lack neuropathologic specificity)”

  • The paper relies on this without support.

    Metabolic prediction imaging studies examining conversion of MCI to AD, with one exception, have not examined the Hip.

    “Metabolic prediction imaging studies examining the conversion of MCI to AD, with one exception, have not examined the Hip.”

  • The paper relies on this without support.

    Etiologic heterogeneity is suspected in MCI.

    “Etiologic heterogeneity is suspected in MCI”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Patients with mild cognitive impairment and Alzheimer's disease exhibit deficits in brain energy metabolism years before symptom onset.

    “Numerous studies show that patients with mild cognitive impairment (MCI) and AD exhibit deficits in brain energy metabolism years before disease symptom onset [8][9][10][11] .”

    From APOE4-drives brain bioenergetic shifts independent of Alzheimer’s disease pathology (2026) · cites this paper as [10]

    The Abstract and Discussion report that reduced entorhinal-cortex glucose metabolism in cognitively normal elderly subjects predicted clinical decline during a three-year follow-up. The study does not establish that patients with MCI and AD generally have metabolic deficits years before symptom onset: 11 participants developed MCI and only one developed AD, and the timing of symptom onset is not specified. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Both mild cognitive impairment and Type 2, as well as Type 1, diabetes are recognized as risk factors for dementia.

    “both mild cognitive impairment and Type 2, as well as Type 1, diabetes are recognized as risk factors for dementia (Ott et al., 1996; de Leon et al., 2001; Haan, 2006).”

    From Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators (2008) · cites this paper as de Leon et al., 2001

  • Decreased glucose metabolism predicts future cognitive decline and mild cognitive impairment among normal elderly individuals in a longitudinal FDG-PET study.

    “De Leon in a longitudinal FDG-PET study prognosticated the future cognitive decline and MCI among normal elderly individuals using decreased glucose metabolism as a predictor of the clinical change [78].”

    From Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery (2021) · cites this paper as [78]

  • Both MCI and type 2, as well as type 1, diabetes are recognized as risk factors for dementia.

    “and both MCI and type 2, as well as type 1, diabetes are recognized as risk factors for dementia.117-119”

    From Protective and damaging effects of stress mediators: central role of the brain (2006) · cites this paper as [119]

Statistics that don’t add up

Each reported p-value recomputed from its test statistic and degrees of freedom.

  • p-value fits an unstated one-tailed test: F(1,9) = 5.0, p < .05

    Minor

    The paper reports p < .05 here; recomputing from the test statistic and its degrees of freedom gives p = .052. The reported value is what a one-tailed test gives, but the paper does not say near this result that a one-tailed test was used.

    Reported p < .05 · recomputed p = .052

1 of 1

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Doesn’t add upF(1, 9) = 5reported p < .05 · recomputed p = .052

    “F(1,9) = 5.0, p < .05”

  • Consistentχ²(1) = 20.8reported p < .001 · recomputed p < .001

    “X2 (1) = 20.8, p < .001”

  • ConsistentF(1, 21) = 7.2reported p = .01 · recomputed p = .014

    “F(1,21) = 7.2, p = .01”

  • ConsistentF(1, 9) = 6reported p < .05 · recomputed p = .037

    “F(1,9) = 6.0, p < .05”

  • ConsistentF(1, 20) = 5.8reported p < .05 · recomputed p = .026

    “F(1,20) = 5.8, p < .05”

  • ConsistentF(1, 20) = 5.3reported p < .05 · recomputed p = .032

    “F(1,20) = 5.3, p < .05”

  • ConsistentF(1, 8) = 13.7reported p < .01 · recomputed p = .006

    “F(1,8) = 13.7, p < .01”

  • ConsistentF(1, 9) = 14reported p < .01 · recomputed p = .005

    “F(1,9) = 14.0, p < .01”

  • ConsistentF(1, 19) = 4.9reported p < .05 · recomputed p = .039

    “F(1,19) = 4.9, p < .05”

  • ConsistentF(1, 8) = 5.7reported p < .05 · recomputed p = .044

    “F(1,8) = 5.7, p < .05”

  • ConsistentF(1, 20) = 8.9reported p < .01 · recomputed p = .007

    “F(1,20) = 8.9, p < .01”

11 of 11

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Conflicting descriptions of follow-up SPM apoE effects

    Minor

    The discussion says both ROI and SPM found neocortical apoE-group effects at follow-up, but the follow-up SPM results explicitly say there were no apoE-group effects.

1 of 1

The citation lists haven’t been fetched yet

References 52 · Cited by 629

Research works printed but not linked: 8

  1. M J de Leon, J Golomb, A E George, A Convit, C Y Tarshish, T McRae, S De Santi, G Smith, S H Ferris, M Noz, et al. Am J Neuroradiol 14, 897–906 (1993).
  2. P Pietrini, N P Azari, C L Grady, J A Salerno, A Gonzalez-Aviles, L L Heston, K D Pettigrew, B Horwitz, J V Haxby, M B Schapiro Dementia 4, 94–101 (1993).
  3. B Reisberg, S G Sclan, E H Franssen, M J de Leon, A Kluger, C L Torossian, E Shulman, G Steinberg, I Monteiro, T McRae, et al. Neurosci Res Commun 13, Suppl. 1, 551–554 (1993).
  4. D Wechsler Wechsler Adult Intelligence Scale–Revised (Harcourt, Brace & Jovanovich, New York, 1981).
  5. R F Main, P J H Jones, R T A McGillivery, D K Banfield J Lipid Res 1991, 183–187 (2000).
  6. B Bendriem, S L Dewey, D J Schlyer, A P Wolf, N D Volkow IEEE Trans Nucl Sci 10, 216–222 (1991).
  7. O G Rousset, Y Ma, A C Evans J Nucl Med 39, 904–911 (1998).
  8. J C Morris, M Storandt, P Miller, D W McKeel, J L Price, E H Rubin, L Berg Neurology 58, 397–405 (2001).

Authors
de Leon, M. J., Convit, A., Wolf, O. T., Tarshish, C. Y., DeSanti, S., Rusinek, H., Tsui, W., Kandil, E., Scherer, A. J., Roche, A., Imossi, A., Thorn, E., Bobinski, M., Caraos, C., Lesbre, P., Schlyer, D., Poirier, J., Reisberg, B., & Fowler, J.
Affiliations
  • New York University School of Medicine, New York, NY 10016; Nathan Kline Institute, Orangeburg, NY 10962; University of Duesseldorf, Duesseldorf D-40225, Germany; Brookhaven National Laboratory, Upton, NY 11973; and McGill University, Montreal, QC, Canada H4H IR3
  • Nathan Kline Institute for Psychiatric Research (US)
  • Brookhaven National Laboratory (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2001-08-28
Volume
98
Issue
19
Pages
10966-10971
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.191044198
PMC
PMC58582
OpenAlex
W2101991516
Semantic Scholar
7d5082b7ad7e8c1cffff9dd59db1cc6527d15871
Cited by
629
References
52
Citations by year
2026: 11 · 2025: 10 · 2024: 13 · 2023: 16 · 2022: 15 · 2021: 16 · 2020: 18 · 2019: 21 · 2018: 20 · 2017: 19 · 2016: 19 · 2015: 16 · 2014: 31 · 2013: 24 · 2012: 26
FWCI
19.11
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer Society
  • National Institutes of Health (AG12101, AG08051)
  • National Institute on Aging (AG03051, R01AG003051, AG 12101, R01AG012101, P30AG008051, AG 08051, R01AG013616, AG 13616)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Medical Imaging Techniques and Applications
Keywords
cognitive decline prediction, entorhinal cortex, FDG-PET hypometabolism, mild cognitive impairment, Alzheimer's disease, hippocampus, temporal neocortex, apolipoprotein E e4, memory impairment, brain glucose metabolism, dementia risk
MeSH terms
Aged, Aged, 80 and over, Apolipoproteins E, Brain, Cognition Disorders, Female, Follow-Up Studies, Hippocampus, Humans, Longitudinal Studies, Magnetic Resonance Imaging, Male, Middle Aged, Predictive Value of Tests, Radiography, Tomography, Emission-Computed, Entorhinal Cortex, Fluorodeoxyglucose F18

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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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.

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