CoChat
Sign Up
Cited by 159Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsMemory and Neural Mechanisms

Atrophy of presubiculum and subiculum is the earliest hippocampal anatomical marker of Alzheimer's disease

Open access
Carlesimo, Giovanni A., Piras, Fabrizio, Orfei, Maria Donata, Iorio, Mariangela, Caltagirone, Carlo, Spalletta, Gianfranco·2015·Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
DOI 10.1016/j.dadm.2014.12.001PMC PMC4876901
Open this paper in CoChat — free accountOpen PDF

Abstract

Background: There is no consensus about which hippocampal subfields become atrophic earliest in the course of Alzheimer's disease (AD). Methods: Thirty AD patients, 41 mild cognitive impairment (MCI) patients, and 38 healthy controls (HCs) underwent cerebral magnetic resonance imaging (with an automated segmentation protocol for the volumetric analysis of hippocampal subfields) and a test of immediate and delayed recall of a 15‐word list. Results: The volumes of the presubiculum and subiculum presented the most remarkable reduction in the patient's groups. In the MCI group, only the volumes of presubiculum and subiculum predicted performance on the memory tests. In AD patients, the volumes of all hippocampal subfields (with the notable exception of the CA1) predicted memory scores. Conclusions: Our data point to a prevalent atrophy of the presubicular‐subicular complex from the early phases of AD. This finding is consistent with neuropathological observations in AD patients and probably reflects the severe degeneration of the perforant pathway while penetrating the hippocampus through the subicular field in its course from the entorhinal cortex to the dentate gyrus.

AI snapshot

Written from the paper’s full text.

TL;DR

In a cross-sectional comparison of 30 AD, 41 amnestic MCI, and 38 healthy controls, hippocampal subfield volumetry showed the presubiculum and subiculum had the most marked atrophy and were the only subfields that significantly discriminated AD from MCI. These volumes also predicted verbal memory in MCI, suggesting the presubicular-subicular complex is an early anatomical marker of AD.

Key findings

  • Presubiculum and subiculum volumes showed the most remarkable reduction in patient groups; in AD versus MCI, only presubiculum (P = .02) and subiculum (P = .05) had significantly larger volume decrease, whereas CA1 (P = .74), CA2-3 (P = .20), and CA4-DG (P = .11) did not.
  • In MCI, only presubiculum and subiculum volumes predicted performance on the memory tests; in AD, all hippocampal subfields except CA1 predicted memory scores.
  • ROC analyses found the presubiculum produced the largest area under the curve and highest diagnostic sensitivity/specificity, followed by subiculum, overall hippocampal volume, CA4-DG, CA3-DG, and CA1; only presubiculum and subiculum significantly discriminated AD from MCI.
  • In the genetic subsample (12 AD, 34 MCI), the APOE ε4 allele was present in 17% of AD patients and 38% of MCI patients; no genetic data were available for HCs.

Methods

  • Cross-sectional study of 109 individuals: 30 with probable AD, 41 with single-domain amnestic MCI, and 38 healthy matched controls; AD and MCI patients were consecutively recruited from specialist dementia clinics at Santa Lucia Foundation, Rome.
  • Participants underwent 3-T MRI with FreeSurfer whole-hippocampus segmentation followed by Bayesian subfield segmentation; left and right volumes were averaged for CA1, CA2/3, CA4/dentate gyrus, presubiculum, subiculum, and total hippocampus.
  • Memory was assessed with immediate and 15-minute delayed recall of a 15-word list; analyses included ANOVAs/ANCOVAs with education as covariate, two-way ANCOVA on standardized z values, ROC analyses, and partial correlations controlling for education separately by group.

Limitations

  • Stated: image resolution was 1 × 1 × 1 mm versus the original 0.38 × 0.38 × 0.8 mm used by van Leemput et al.; the interpolation step could introduce bias, though segmentation is carried out on higher-resolution reference images and the original sequence was impractical clinically.
  • Stated: inclusion was restricted to amnestic MCI for homogeneity; APOE data were available only for a subsample; future longitudinal studies are needed to test whether this atrophy pattern predicts conversion from MCI to AD.
  • Evident: the cross-sectional design cannot establish temporal progression or MCI-to-AD conversion; HCs had no genetic data, and the APOE subsample was small.

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

Integrity signals

Registry

Crossref · 10.1016/j.dadm.2014.12.001

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 72 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    AD patients had reduced volumes of the presubiculum and subiculum with respect to MCI patients.

    “patients with AD had reduced volumes of the presubiculum and subiculum with respect to MCI patients.”
    Quote in the paperSubstantial claim
  • Findingown data

    The significant group × hippocampal subfield interaction reflected nonhomogeneous volume decrease in AD versus MCI across the different subfields.

    “Instead, the significant group × hippocampal subfield interaction reflected the nonhomogeneous volume decrease in the AD with respect to the MCI group across the different subfields.”
    Quote in the paperSubstantial claim
  • Findingown data

    Both patient groups significantly differed from HCs for volumes of CA2-3, CA4-DG, presubiculum, subiculum, and overall hippocampus.

    “Post hoc analyses documented that although both groups of patients significantly differed from HCs for volumes of the CA2-3, CA4-DG, presubiculum, subiculum, and overall hippocampus”
    Quote in the paperSubstantial claim
  • Findingown data

    Volumes of all subfields and total hippocampal volume discriminated AD patients and HCs at a significant level.

    “Volumes of all subfields and total hippocampal volume discriminated AD patients and HCs at a significant level”
    Quote in the paperSubstantial claim
  • Findingown data

    Presubiculum and subiculum were the only subfields that showed a significantly larger reduction in AD than in MCI group.

    “they were also the only ones that showed a significantly larger reduction in the AD than in the MCI group.”
    Quote in the paperSubstantial claim
  • May combine two claims. 34
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Findingown data

    Planned comparisons confirmed a nonsignificant difference in volume reduction in CA1, CA2-3, and CA4-DG but a significantly larger volume decrease in AD than in MCI in presubiculum and subiculum.

    “Indeed, planned comparisons confirmed a nonsignificant difference in volume reduction in the CA1 (P = .74), CA2-3 (P = .20), and CA4-DG (P = .11) subfields but a significantly larger volume decrease in the AD than in the MCI group in the presubiculum (P = .02) and subiculum (P = .05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    With the exception of CA1, the volume of all other hippocampal subfields, as well as the entire hippocampus, significantly differed among groups.

    “One-way ANOVAs documented that, with the exception of CA1, the volume of all the other subfields, as well as of the entire hippocampus, significantly differed among groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The three groups differed on both immediate and delayed recall of the 15-word list, with AD patients scoring worse than MCI patients who, in turn, scored worse than HCs.

    “The three groups differed on both the immediate and delayed recall test, with AD patients scoring worse than MCI patients who, in turn, scored worse than HCs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The significant effect of hippocampal subfield was due to a volume reduction relative to HCs that was minimal in CA1, progressively larger in CA2-3 and CA4-DG, and maximal in presubiculum and subiculum.

    “In particular, the significant effect of the hippocampal subfield was due to a volume reduction (with respect to HCs) that was minimal in the CA1 subfield, progressively larger in the CA2-3 and CA4-DG subfields, and maximal in the presubiculum and subiculum”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The two-way ANOVA showed a nonsignificant main effect of group, a highly significant effect of hippocampal subfield, and a significant group × hippocampal subfield interaction.

    “The two-way ANOVA documented a nonsignificant main effect of the group (F = 2.0; P = .17) but highly significant effects of hippocampal subfield (F = 35.0; P < .001) and of the group × hippocampal subfield interaction (F = 4.2; P = .002).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CA1 subfield was least involved in AD-related atrophy; its size did not significantly differ among HCs, MCI, and AD.

    “The CA1 subfield was the one least involved in the AD-related atrophy. Its size did not significantly differ in HCs, patients in the initial phases of the Alzheimer's degeneration, and patients with fully developed AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In AD group, several subfields and overall hippocampus correlated with memory scores; CA1 was the only subfield without significant correlation with verbal memory measures.

    “Conversely, in the AD group, several subfields and the overall hippocampus correlated with memory scores. Notably, the only subfield that did not show any significant correlation with verbal memory measures was the CA1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In AD and MCI groups, all correlation coefficients between hippocampal volumes and memory scores were positive, indicating reduced volumes associated with reduced memory performance.

    “Although in the HC group several correlation coefficients were negative, in the AD and MCI groups, all correlation coefficients were positive, indicating that in these patients, reduced anatomical volumes were consistently associated with reduced memory performance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In ROC analyses, presubiculum produced the largest area under the curve and highest diagnostic sensitivity/specificity, followed by subiculum, overall hippocampal volume, CA4-DG, CA3-DG, and CA1.

    “In all cases, the presubiculum produced the largest area under the curve and the highest diagnostic sensitivity/specificity values, followed by the subiculum, the overall hippocampal volume, the CA4-DG, CA3-DG, and finally, the CA1 subfield.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CA2-3 and CA4-DG subfields presented atrophic changes that remained substantially stable during progression of AD pathology; volumes were smaller in AD and MCI vs HC but did not differ between patient groups.

    “The CA2-3 and CA4-DG subfields presented atrophic changes that remained substantially stable during the progression of AD pathology. Indeed, CA2 and CA3 volumes were significantly smaller in the AD and MCI groups with respect to the HC group but did not significantly differ between the patients' groups.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    This discriminative pattern was true both for HCs vs patients and for MCI vs AD.

    “This was true both when we considered HCs with respect to individuals in the two patients' groups and when we contrasted MCI versus AD patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The present data point to a nonhomogeneous pattern of atrophy in the hippocampus of AD patients, with prevalent involvement of the presubicular-subicular complex from the very early phases of the disease that is still evident in the most advanced phases.

    “In conclusion, our data point to a nonhomogeneous pattern of atrophy in the hippocampus of AD patients, with prevalent involvement of the presubicular-subicular complex from the very early phases of the disease that is still evident in the most advanced phases.”
    • Also stated in: § Discussion · hedged
      “Our data point to a prevalent atrophy of the presubicular-subicular complex from the early phases of AD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductown data

    The three groups (AD, MCI, and HC) did not differ for sex distribution or age.

    “As can be seen in Table 1, the three groups (AD, MCI, and HC) did not differ for sex distribution or age.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    There is no consensus about which hippocampal subfields become atrophic earliest in AD or which neuropathological change is primarily implicated in volume reduction.

    “There is no consensus about which hippocampal subfields become atrophic earliest in the course of Alzheimer's disease (AD).”
    • Also stated in: § Introduction · plain
      “There is no consensus about which subfields become atrophic earliest in the disease course or which neuropathological change is primarily implicated in volume reduction.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [11] West M.J. Coleman P.D. Flood D.G. Troncoso J.C. Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease Lancet 344 1994 769 772 7916070 source

      Not checked in the free run.

    • cites [13] Simić G. Kostović I. Winblad B. Bogdanović N. Volume and number of neurons of the human hippocampal formation in normal aging and Alzheimer's disease J Comp Neurol 379 1997 482 494 9067838 source

      Not checked in the free run.

    • cites [15] Mizutani T. Kasahara M. Hippocampal atrophy secondary to entorhinal cortical degeneration in Alzheimer-type dementia Neurosci Lett 222 1997 119 122 9111743 source

      Not checked in the free run.

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

    Study design and conductcitation

    The Dice overlap measures between manual and automated segmentation methods were approximately 0.7 for all the substructures.

    “The Dice overlap measures between manual and automated segmentation methods were approximately 0.7 for all the substructures [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Van Leemput K. Bakkour A. Benner T. Wiggins G. Wald L.L. Augustinack J. Automated segmentation of hippocampal subfields from ultra-high resolution in vivo MRI Hippocampus 19 2009 549 557 19405131 PMC2739884 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neuroradiological indexes of hippocampal atrophy and episodic memory deficits are among the most powerful diagnostic indexes of AD from the very early phases.

    “neuroradiological indexes of hippocampal atrophy [3], [4] and, consistent with the well-known role of the hippocampus in human declarative memory [5], episodic memory deficits [6], [7] are among the most powerful diagnostic indexes of AD from the very early phases, corresponding to the clinical condition of amnestic mild cognitive impairment (MCI).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Frisoni G.B. Fox N.C. Jack C.R. Jr. Scheltens P. Thompson P.M. The clinical use of structural MRI in Alzheimer disease Nat Rev Neurol 6 2010 67 77 20139996 PMC2938772 source

      Not checked in the free run.

    • cites [4] Petrella J.R. Coleman R.E. Doraiswamy P.M. Neuroimaging and early diagnosis of Alzheimer disease: a look to the future Radiology 226 2003 315 336 12563122 source

      Not checked in the free run.

    • cites [6] Salmon D.P. Thomas R.G. Pay M.M. Booth A. Hofstetter C.R. Thal L.J. Alzheimer's disease can be accurately diagnosed in very mildly impaired individuals Neurology 59 2002 1022 1028 12370456 source

      Not checked in the free run.

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

    Study design and conductown data

    The three groups differed for years of formal education, with AD patients significantly less educated than MCI and HC participants.

    “Instead, they differed for years of formal education, with AD patients significantly less educated than MCI and HC participants.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The hippocampus is not a unitary anatomical formation; several subfields have been identified, differentiable on histological grounds and by functional role in memory encoding and retrieval.

    “The hippocampus is not, however, a unitary anatomical formation. Several subfields have been identified, which can be differentiated on both histological grounds [2], [8] and according to their functional role in memory encoding and retrieval [9], [10].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [2] Braak H. Braak E. Evolution of the neuropathology of Alzheimer's disease Acta Neurol Scand 165 Suppl 1 1996 S3 S12 8740983 source

      Not checked in the free run.

    • cites [8] Duvernoy H.M. The human hippocampus: functional anatomy, vascularization and serial sections with MRI 2005 Springer-Verlag Berlin, Heidelberg source

      Not checked in the free run.

    • cites [9] Carr V.A. Rissman J. Wagner A.D. Imaging the human medial temporal lobe with high-resolution fMRI Neuron 65 2010 298 308 20159444 PMC2844113 source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The three groups differed for mean MMSE adjusted score; AD patients scored worse than MCI and HC, and MCI patients scored worse than HCs.

    “The three groups also differed for the mean MMSE adjusted score. Indeed, AD patients scored worse than the other two groups and patients with MCI scored worse than HCs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The volume of the CA3 and CA4 subfields was found in the normal range in most studies using manual segmentation and 3D surface reconstruction but was invariably atrophic in studies based on automated segmentation procedures.

    “Conversely, the volume of the CA3 and CA4 subfields was found in the normal range in most of the studies that used manual segmentation [34], [35] and 3D surface reconstruction and shape analysis [36] but was invariably atrophic in studies based on automated segmentation procedures [31], [33].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [34] Mueller S.G. Schuff N. Raptentsetsang S. Elman J. Weiner M.W. Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T Neuroimage 42 2008 42 48 18534867 PMC2597377 source

      Not checked in the free run.

    • cites [31] Lim H.K. Hong S.C. Jung W.S. Ahn K.J. Won W.Y. Hahn C. Automated segmentation of hippocampal subfields in drug-naïve patients with Alzheimer disease AJNR Am J Neuroradiol 34 2013 747 751 23042923 PMC7964501 source

      Not checked in the free run.

    • cites [33] Li Y.D. Dong H.B. Xie G.M. Zhang L.J. Discriminative analysis of mild Alzheimer's disease and normal aging using volume of hippocampal subfields and hippocampal mean diffusivity: an in vivo magnetic resonance imaging study Am J Alzheimers Dis Other Demen 28 2013 627 633 23813689 PMC10852725 source

      Not checked in the free run.

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

    Premisecitation

    According to Hyman et al., episodic memory deficit in AD results from anatomical and functional segregation of hippocampus from associative sensory inputs due to degeneration of perforant pathway.

    “Indeed, according to Hyman et al. [29], [30], the episodic memory deficit in AD patients results from the anatomical and functional segregation of the hippocampus from associative sensory inputs due to degeneration of the perforant pathway.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [29] Hyman B.T. Van Hoesen G.W. Damasio A.R. Memory-related neural systems in Alzheimer's disease: an anatomic study Neurology 40 1990 1721 1730 2234428 source

      Not checked in the free run.

    • cites [30] Hyman B.T. Van Hoesen G.W. Kromer L.J. Damasio A.R. Perforant pathway changes and the memory impairment of Alzheimer's disease Ann Neurol 20 1986 472 481 3789663 source

      Not checked in the free run.

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

    Premisecitation

    Mizutani and Kasahara noted that atrophic subiculum showed marked loss of pyramidal neurons, whereas hippocampus proper showed only slight loss.

    “Mizutani and Kasahara [15] also noted that the atrophic subiculum showed marked loss of pyramidal neurons, whereas the hippocampus proper showed only a slight loss of neurons.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Mizutani T. Kasahara M. Hippocampal atrophy secondary to entorhinal cortical degeneration in Alzheimer-type dementia Neurosci Lett 222 1997 119 122 9111743 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both degeneration of perforant pathway and loss of pyramidal neurons would account for our finding that subicular volume predicts severity of verbal memory deficit in AD patients.

    “Both degeneration of the perforant pathway and loss of pyramidal neurons would account for our finding that subicular volume predicts the severity of the verbal memory deficit in AD patients.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Mizutani and Kasahara reported disproportionate atrophy in subicular complex with respect to Ammon's horn fields and dentate gyrus in AD.

    “These authors investigating an autoptical series of AD patients reported disproportionate atrophy in the subicular complex with respect to Ammon's horn fields (CA1, 2, 3, and 4) and the dentate gyrus.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Mizutani T. Kasahara M. Hippocampal atrophy secondary to entorhinal cortical degeneration in Alzheimer-type dementia Neurosci Lett 222 1997 119 122 9111743 source

      Not checked in the free run.

    • cites [16] Mizutani T. Kasahara M. Degeneration of the intrahippocampal routes of the perforant and alvear pathways in senile dementia of Alzheimer type Neurosci Lett 184 1995 141 144 7724049 source

      Not checked in the free run.

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

    Premisecitation

    Normal volume of the CA1 subfield was reported by Lim et al. and by Kerchner et al.

    “Normal volume of the CA1 subfield was reported by Lim et al. [31], who used the same automated segmentation protocol used in the present study, and by Kerchner et al. [32], who inferred volume by measuring the thickness of the CA1 subfield”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Lim H.K. Hong S.C. Jung W.S. Ahn K.J. Won W.Y. Hahn C. Automated segmentation of hippocampal subfields in drug-naïve patients with Alzheimer disease AJNR Am J Neuroradiol 34 2013 747 751 23042923 PMC7964501 source

      Not checked in the free run.

    • cites [32] Kerchner G.A. Hess C.P. Hammond-Rosenbluth K.E. Xu D. Rabinovici G.D. Kelley D.A. Hippocampal CA1 apical neuropil atrophy in mild Alzheimer disease visualized with 7-T MRI Neurology 75 2010 1381 1387 20938031 PMC3013485 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Results document progressive hippocampal atrophy in different phases of AD that is not homogeneous across subfields.

    “Results of the present study document progressive hippocampal atrophy in the different phases of AD that is not homogeneous across the various subfields.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cross-sectional differences in hippocampal subfield volumes between MCI and AD patients reflect the temporal progression of atrophy within individuals.

  • Classified as probably not a substantial claim.

    Premisecitation

    Previous neuroimaging studies obtained contrasting data regarding the pattern of hippocampal subfield atrophy in AD patients.

    “Previous neuroimaging studies obtained contrasting data regarding the pattern of hippocampal subfield atrophy in AD patients.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [31] Lim H.K. Hong S.C. Jung W.S. Ahn K.J. Won W.Y. Hahn C. Automated segmentation of hippocampal subfields in drug-naïve patients with Alzheimer disease AJNR Am J Neuroradiol 34 2013 747 751 23042923 PMC7964501 source

      Not checked in the free run.

    • cites [33] Li Y.D. Dong H.B. Xie G.M. Zhang L.J. Discriminative analysis of mild Alzheimer's disease and normal aging using volume of hippocampal subfields and hippocampal mean diffusivity: an in vivo magnetic resonance imaging study Am J Alzheimers Dis Other Demen 28 2013 627 633 23813689 PMC10852725 source

      Not checked in the free run.

    • cites [34] Mueller S.G. Schuff N. Raptentsetsang S. Elman J. Weiner M.W. Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T Neuroimage 42 2008 42 48 18534867 PMC2597377 source

      Not checked in the free run.

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

    Premisecitation

    Mizutani and Kasahara attributed severe volume loss of these structures to isomorphic fibrillary gliosis resulting from early and severe degeneration of the perforant pathway while penetrating the hippocampus through the subicular field.

    “They attributed the particularly severe volume loss of these structures to isomorphic fibrillary gliosis resulting from early and severe degeneration of the perforant pathway while penetrating the hippocampus through the subicular field, in its course from the entorhinal cortex to the dentate gyrus.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Mizutani T. Kasahara M. Hippocampal atrophy secondary to entorhinal cortical degeneration in Alzheimer-type dementia Neurosci Lett 222 1997 119 122 9111743 source

      Not checked in the free run.

    • cites [16] Mizutani T. Kasahara M. Degeneration of the intrahippocampal routes of the perforant and alvear pathways in senile dementia of Alzheimer type Neurosci Lett 184 1995 141 144 7724049 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The volume of the subiculum was reported to be normal in MCI in a manual segmentation study and an automated segmentation study but significantly reduced in two other studies using manual or automated segmentation.

    “Thus, for example, the volume of the subiculum was reported to be normal in MCI in a study that relied on manual segmentation [35] and in another study that used an automated segmentation method [38] but was significantly reduced in two other studies that also used a method of manual [39] or automated segmentation [40].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Mueller S.G. Weiner M.W. Selective effect of age, Apo e4, and Alzheimer's disease on hippocampal subfields Hippocampus 19 2009 558 564 19405132 PMC2802542 source

      Not checked in the free run.

    • cites [38] Pluta J. Yushkevicha P. Dasa S. Wolkc D. In vivo analysis of hippocampal subfield atrophy in mild cognitive impairment via semi-automatic segmentation of T2-weighted MRI J Alzheimers Dis 31 2012 85 99 22504319 PMC3391337 source

      Not checked in the free run.

    • cites [39] La Joie R. Perrotin A. de La Sayette V. Egret S. Doeuvre L. Belliard S. Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia Neuroimage Clin 14 2013 155 162 24179859 PMC3791274 source

      Not checked in the free run.

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

    Premisecitation

    Among individuals with late-onset AD, the ε4 allele is present at a two- to threefold higher rate compared to the general population, and some studies indicate up to 65% of clinically diagnosed cases carry at least one ε4 allele.

    “In fact, among individuals that manifest late-onset AD, the ε4 allele is present at a two- to threefold higher rate compared to the general population, and some studies indicate up to 65% of clinically diagnosed cases carry at least one ε4 allele [45].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Bekris L.M. Yu C.E. Bird T.D. Tsuang D.W. Genetics of Alzheimer disease J Geriatr Psychiatry Neurol 23 2010 213 227 21045163 PMC3044597 source

      Not checked in the free run.

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

    Premisecitation

    Not all ε4 carriers develop AD, and not all AD patients are ε4 carriers; the ε2 allele seems to play a protective role.

    “However, not all ε4 carriers develop AD, and not all AD patients are ε4 carriers; rather, the ε2 allele seems to play a protective role [45], [46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Bekris L.M. Yu C.E. Bird T.D. Tsuang D.W. Genetics of Alzheimer disease J Geriatr Psychiatry Neurol 23 2010 213 227 21045163 PMC3044597 source

      Not checked in the free run.

    • cites [46] Khachaturian A.S. Corcoran C.D. Mayer L.S. Zandi P.P. Breitner J.C. Apolipoprotein E epsilon4 count affects age at onset of Alzheimer disease, but not lifetime susceptibility: The Cache County Study Arch Gen Psychiatry 61 2004 518 524 15123497 source

      Not checked in the free run.

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

    Premisereasoning

    Controversial data were obtained particularly in studies that relied on manual versus automated segmentation methods.

    “As for the second point of concern, controversial data were obtained particularly in studies that relied on manual versus automated segmentation methods.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Li Y.D. Dong H.B. Xie G.M. Zhang L.J. Discriminative analysis of mild Alzheimer's disease and normal aging using volume of hippocampal subfields and hippocampal mean diffusivity: an in vivo magnetic resonance imaging study Am J Alzheimers Dis Other Demen 28 2013 627 633 23813689 PMC10852725 source

      Not checked in the free run.

    • cites [35] Mueller S.G. Weiner M.W. Selective effect of age, Apo e4, and Alzheimer's disease on hippocampal subfields Hippocampus 19 2009 558 564 19405132 PMC2802542 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    In recruiting MCI patients, the authors adhered closely to diagnostic criteria for single-domain amnestic MCI.

    “in recruiting MCI patients, we adhered closely to diagnostic criteria for single-domain amnestic MCI [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Petersen R.C. Morris J.C. Mild cognitive impairment as a clinical entity and treatment target Arch Neurol 62 2005 1160 1163 16009779 source

      Not checked in the free run.

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

    Interpretationreasoning

    Inconsistencies might be due to dementia severity in AD patients and criteria adopted for defining MCI.

    “Regarding the first issue, inconsistencies might be due to the dementia severity in the group of AD patients and the criteria adopted for defining MCI.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    There were differences in defining the CA1 and subiculum in previous studies.

    “Indeed, there were differences in defining the CA1 and subiculum in previous studies.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Mueller S.G. Schuff N. Raptentsetsang S. Elman J. Weiner M.W. Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T Neuroimage 42 2008 42 48 18534867 PMC2597377 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Literature on individuals with MCI is more controversial, with discrepant data resulting from adoption of the same subfield segmentation procedure.

    “Analogous literature on individuals with MCI is still more controversial, with discrepant data resulting from adoption of the same subfield segmentation procedure.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [35] Mueller S.G. Weiner M.W. Selective effect of age, Apo e4, and Alzheimer's disease on hippocampal subfields Hippocampus 19 2009 558 564 19405132 PMC2802542 source

      Not checked in the free run.

    • cites [38] Pluta J. Yushkevicha P. Dasa S. Wolkc D. In vivo analysis of hippocampal subfield atrophy in mild cognitive impairment via semi-automatic segmentation of T2-weighted MRI J Alzheimers Dis 31 2012 85 99 22504319 PMC3391337 source

      Not checked in the free run.

    • cites [39] La Joie R. Perrotin A. de La Sayette V. Egret S. Doeuvre L. Belliard S. Hippocampal subfield volumetry in mild cognitive impairment, Alzheimer's disease and semantic dementia Neuroimage Clin 14 2013 155 162 24179859 PMC3791274 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 conductreasoning

    One step of the segmentation procedure interpolates input images to the reference ones at 0.38×0.38×0.8 mm, so segmentation is carried out with more resolved images and the discrepancy between the two resolutions is minimized.

    “Although this difference exists, it must be noted that one of the steps of the segmentation procedure is the interpolation of input images to the reference ones at 0.38 × 0.38 × 0.8 mm. Thus, the segmentation is carried out with more resolved images, and the discrepancy between the two resolutions is minimized.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All AD patients included in the present study were in the mild phase of the disease.

    “All the AD patients included here were in the mild phase of the disease”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Dementia severity in AD patients and the pattern of cognitive deficits in MCI patients have a great impact on the expected pattern of hippocampal regional atrophy.

    “It seems quite obvious that both the dementia severity in AD patients and the pattern of cognitive deficits in MCI patients (only amnestic, amnestic plus other domains, or not amnestic at all [41]) have a great impact on the expected pattern of hippocampal regional atrophy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Winblad B. Palmer K. Kivipelto M. Jelic V. Fratiglioni L. Wahlund L.O. Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment J Intern Med 256 2004 240 246 15324367 source

      Not checked in the free run.

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

    Study design and conductreasoning

    The difference in resolution between the present study's images (1×1×1 mm) and those originally used by van Leemput et al. (0.38×0.38×0.8) is a critical aspect.

    “First, a critical aspect is the difference in resolution between our images (1 × 1 × 1 mm) and those originally used by van Leemput et al. [28] (0.38 × 0.38 × 0.8).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Van Leemput K. Bakkour A. Benner T. Wiggins G. Wald L.L. Augustinack J. Automated segmentation of hippocampal subfields from ultra-high resolution in vivo MRI Hippocampus 19 2009 549 557 19405131 PMC2739884 source

      Not checked in the free run.

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

    Premisecitation

    Mueller et al. chose the border because it could be easily and reliably identified although parts of the presubiculum and subiculum proper were counted towards CA1.

    “as acknowledged by Mueller et al. [34], the border used in that study was chosen “because it could be easily and reliably identified although by doing so, parts of the presubiculum and subiculum proper were counted towards CA1” (p. 45).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Mueller S.G. Schuff N. Raptentsetsang S. Elman J. Weiner M.W. Selective effect of Apo e4 on CA3 and dentate in normal aging and Alzheimer's disease using high resolution MRI at 4 T Neuroimage 42 2008 42 48 18534867 PMC2597377 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The most critical issues explaining contrasting data regard the diagnostic criteria adopted in sample selection and the reliability of segmentation techniques for discriminating between individual hippocampal subfields.

    “Probably, the most critical issues regard the diagnostic criteria adopted in sample selection and the reliability of the segmentation techniques used for discriminating between individual hippocampal subfields.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [33] Li Y.D. Dong H.B. Xie G.M. Zhang L.J. Discriminative analysis of mild Alzheimer's disease and normal aging using volume of hippocampal subfields and hippocampal mean diffusivity: an in vivo magnetic resonance imaging study Am J Alzheimers Dis Other Demen 28 2013 627 633 23813689 PMC10852725 source

      Not checked in the free run.

    • cites [35] Mueller S.G. Weiner M.W. Selective effect of age, Apo e4, and Alzheimer's disease on hippocampal subfields Hippocampus 19 2009 558 564 19405132 PMC2802542 source

      Not checked in the free run.

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

    Premisereasoning

    The original MRI sequence used by van Leemput et al. was about 35 minutes long, making it useless in clinical settings, especially for degenerative diseases, due to unfitness for patients and proneness to movement artifacts.

    “Although we are aware that this step could introduce some biases, it should be outlined that the original MRI sequence used by van Leemput et al. [28] was about 35 minutes long. This makes it useless in clinical settings, especially in the framework of degenerative diseases, given its unfitness for patients and its proneness to movement artifacts.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Van Leemput K. Bakkour A. Benner T. Wiggins G. Wald L.L. Augustinack J. Automated segmentation of hippocampal subfields from ultra-high resolution in vivo MRI Hippocampus 19 2009 549 557 19405131 PMC2739884 source

      Not checked in the free run.

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

    Premisecitation

    Automated methods used geometric rules as criteria for defining subfields, whereas manual segmentation and 3D surface reconstruction methods used anatomical points derived from central nervous system atlases.

    “Automated methods used geometric rules as the criteria for defining subfields, whereas manual segmentation and 3D surface reconstruction methods used anatomical points derived from central nervous system atlases (e.g., [8]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [8] Duvernoy H.M. The human hippocampus: functional anatomy, vascularization and serial sections with MRI 2005 Springer-Verlag Berlin, Heidelberg source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    There is no consensus about which hippocampal subfields become atrophic earliest in the course of AD or which neuropathological change is primarily implicated in volume reduction.

    “There is no consensus about which hippocampal subfields become atrophic earliest in the course of Alzheimer's disease (AD) or which neuropathological change is primarily implicated in volume reduction.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Most works support the hypothesis that amnestic subtype of MCI is more likely to subsequently convert to AD, although this is still debated.

    “Most of works support the hypothesis that amnestic subtype of MCI is more likely to subsequently convert to AD [43], although this is still a debated issue [44].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Landau S.M. Harvey D. Madison C.M. Reiman E.M. Foster N.L. Aisen P.S. Comparing predictors of conversion and decline in mild cognitive impairment Neurology 75 2010 230 238 20592257 PMC2906178 source

      Not checked in the free run.

    • cites [44] Baars M.A. van Boxtel M.P. Dijkstra J.B. Visser P.J. van den Akker M. Verhey F.R. Predictive value of mild cognitive impairment for dementia. The influence of case definition and age Dement Geriatr Cogn Disord 27 2009 173 181 19202336 source

      Not checked in the free run.

46 of 46

  • The paper relies on this without support.

    MCI patients in this study have underlying Alzheimer's disease pathology (i.e., amnestic MCI represents early AD).

    “episodic memory deficits [6], [7] are among the most powerful diagnostic indexes of AD from the very early phases, corresponding to the clinical condition of amnestic mild cognitive impairment (MCI).”

  • The paper relies on this without support.

    Cross-sectional differences in hippocampal subfield volumes between MCI and AD patients reflect the temporal progression of atrophy within individuals.

    “Results of the present study document progressive hippocampal atrophy in the different phases of AD that is not homogeneous across the various subfields.”
    “atrophic changes in the presubiculum and subiculum progressively worsened passing from the MCI to the AD group.”

  • The paper relies on this without support.

    Healthy controls are free of Alzheimer's disease pathology.

    “None of them showed cognitive problems or evidence of cognitive deficits on neuropsychological testing.”

  • The paper relies on this without support.

    Automatic procedures offer comparable results to manual techniques, are bias free, tracer independent, and allow processing a large amount of data within a relatively brief period of time.

    “Although automatic procedures offer comparable results to manual techniques, they are bias free, tracer independent, and allow processing a large amount of data within a relatively brief period of time (i.e., 8–16 subjects per day, depending on the computational power of available computers).”

  • The paper relies on this without support.

    Imaging studies have been limited by the fact that manual work was required to outline the subfield borders.

    “imaging studies have been limited by the fact that manual work was required to outline the subfield borders.”
5 of 5

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?

The citation lists haven’t been fetched yet

References 50 · Cited by 159

Authors
Carlesimo, G. A., Piras, F., Orfei, M. D., Iorio, M., Caltagirone, C., & Spalletta, G.
Affiliations
  • University of Rome Tor Vergata (IT)
  • Fondazione Santa Lucia (IT)
  • Baylor College of Medicine (US)
Corresponding author
Carlesimo, Giovanni A.
ORCID
Venue
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring
Publisher
Wiley
Published
2015-03
Volume
1
Issue
1
Pages
24-32
ISSN
2352-8729 (ISSN-L)
DOI
10.1016/j.dadm.2014.12.001
PMC
PMC4876901
OpenAlex
W2154763875
Semantic Scholar
bf25f63a73a415b9347f892b2d6035ff881d2da0
Cited by
159
References
50
Citations by year
2026: 11 · 2025: 22 · 2024: 16 · 2023: 17 · 2022: 18 · 2021: 19 · 2020: 16 · 2019: 14 · 2018: 18 · 2017: 4 · 2016: 3 · 2015: 1
FWCI
7.03
Type
journal article
Language
en
Open access
Licence
Locations
  • Alzheimer s & Dementia Diagnosis Assessment & Disease Monitoring (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Italian Ministry of Health (RC 10-11-12-13-14/A, RF 13, RF 2011)
  • Novartis Farma SpA Italia
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 › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
Alzheimer's disease, presubiculum, subiculum, hippocampal subfields, hippocampal atrophy, mild cognitive impairment, memory impairment, perforant path, entorhinal cortex, dentate gyrus

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 2026-10-10.

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

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 ›

Are you an author, or do you see a problem with this page? Request a review