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Original Contribution |

Three-dimensional Patterns of Hippocampal Atrophy in Mild Cognitive Impairment FREE

James T. Becker, PhD; Simon W. Davis, BA; Kiralee M. Hayashi, BS; Carolyn Cidis Meltzer, MD; Arthur W. Toga, PhD; Oscar L. Lopez, MD; Paul M. Thompson, PhD; Imaging Methods and Analysis in Geriatrics Research Group
[+] Author Affiliations

Author Affiliations: Alzheimer’s Disease Research Center (Drs Becker, Meltzer, and Lopez and Mr Davis) and Departments of Psychiatry (Dr Becker and Mr Davis), Neurology (Drs Becker and Lopez), Psychology (Dr Becker), and Radiology (Dr Meltzer), University of Pittsburgh, Pittsburgh, Pa; and Laboratory of Neuro Imaging, Brain Mapping Division, Department of Neurology, University of California, Los Angeles (Ms Hayashi and Drs Toga and Thompson).


Arch Neurol. 2006;63(1):97-101. doi:10.1001/archneur.63.1.97.
Text Size: A A A
Published online

Objective  To measure hippocampal volumes in patients diagnosed as having subtypes of mild cognitive impairment (MCI) relative to those of elderly control subjects and those of patients with Alzheimer disease (AD) using 3-dimensional mesh reconstructions.

Design  A magnetic resonance imaging volumetric study of MCI subgroups (MCI, amnesic subtype [MCI-A]; and MCI, multiple cognitive domain subtype) using 3-dimensional mesh reconstructions of the structure.

Setting  Referral dementia clinic.

Subjects  Twenty-six subjects with MCI (MCI-A, n = 6; and MCI, multiple cognitive domain subtype, n = 20), 20 subjects with AD, and 20 controls who were equivalent in age, education, and sex distributions.

Main Outcome Measures  Three-dimensional parametric mesh models of the hippocampus and total hippocampal volumes.

Results  The hippocampi of the patients with AD were significantly atrophic relative to those of the healthy controls. The MCI, multiple cognitive domain subtype, group did not differ from the controls, yet was significantly different from the MCI-A and the AD groups. The MCI-A patients had significant hippocampal atrophy compared with the controls, and did not differ significantly from the patients with AD.

Conclusion  These data add to the growing evidence that there are multiple forms of MCI, that they have distinct neuropathological correlates, and that MCI, multiple cognitive domain subtype, is not a more advanced form of the MCI-A subtype.

Figures in this Article

Mild cognitive impairment (MCI) is considered a transitional state between normal cognition and Alzheimer disease (AD).14 Because memory disorders are the core clinical symptom in MCI and AD, and the earliest AD pathological changes have been noted in the entorhinal cortex and hippocampus,5,6 most of the magnetic resonance imaging (MRI) volumetric studies conducted in MCI patients have focused on these brain regions. The hippocampus and entorhinal cortex volumes are smaller than those of healthy individuals, appearing to be somewhere between those of patients with AD and those of healthy individuals,7,8 or as atrophic as those of patients with AD.9,10 Studies1113 that use whole brain techniques find that in addition to the loss of volume in mesial temporal lobe structures, MCI patients have atrophy in the other heteromodal association areas.

We report herein the results of the first study, to our knowledge, to use 3-dimensional surface mesh models to evaluate the structural integrity of the hippocampus in MCI subgroups. This technique has advantages over other methods in that it permits visualization of the spatial profile of any neuropathological abnormalities, offering the possibility of more refined neuroanatomical localization if the changes seen in those with MCI are regionally selective. We analyzed data from healthy elderly control subjects, patients with mild probable AD, and 2 groups of MCI patients. We examined the presence, locus, and extent of hippocampal atrophy in the 3 patient groups, with specific reference to differences between the 2 MCI subgroups.

The data for this study were derived from the archives of the University of Pittsburgh Alzheimer’s Disease Research Center14 and the Mental Health Intervention Research Center for Late-Life Mood Disorders.15 The patients were all examined in the Alzheimer’s Disease Research Center, and the images for the 20 control subjects were obtained through the Late-Life Mood Disorders and the Imaging Methods and Analysis in Geriatrics Research Group data repository. The subjects were selected (blind to imaging findings) to create groups of equivalent age, education, and sex distribution.

The 46 study patients underwent an extensive neuropsychiatric examination,14,16 and all patient records were reviewed at a multidisciplinary clinical consensus conference for assignment of a diagnosis. All patients with AD met the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association criteria for probable AD17; none of the patients with MCI had comorbid conditions that could in and of themselves cause cognitive dysfunction.

The diagnosis of MCI, amnesic subtype (MCI-A), required impairments in delayed recall verbal memory, nonverbal memory, or both, defined as performance greater than 1.5 SDs below that of individuals of comparable age and education with otherwise normal cognitive function. For the diagnosis of the MCI, multiple cognitive domain subtype (MCI-MCD), there was deterioration in at least 1 cognitive domain (not including memory) or 2 abnormal test results in 2 different domains (which could include memory). Selected neuropsychological test data results are given in Table 1. The MRIs were not used to differentiate MCI subtypes. Table 2 shows the demographic and neuropsychiatric characteristics of the patients.

Table Graphic Jump LocationTable 1. Selected Neuropsychological Test Data
Table Graphic Jump LocationTable 2. Subject Demographic and Neuropsychiatric Characteristics*

The MRI data were acquired in 3 dimensions to obtain 124 thin contiguous images throughout the entire brain. The contrast maximized the gray-white matter and cerebrospinal fluid differences (repetition time, 25 milliseconds; echo time, 5 milliseconds; slice thickness, 1.5 mm; 0-mm gap; 40° flip angle; and field of view, 24 × 18 cm). The individual brain volumes were first reoriented into the axial plane, then spatially realigned with the International Consortium for Brain Mapping nonlinear average brain template (ICBM152), using FLIRT (available at http://www.fmrib.ox.ac.uk/fsl/). The hippocampi from each brain were traced using a software program (Tracer) (available at http://www.loni.ucla.edu/Software/Software_Detail.jsp?software_id=10).

The hippocampi were manually traced bilaterally by one of us (S.W.D.), who was blind to diagnosis, sex, and demographics. Anatomical segmentation was performed using a standard neuroanatomical atlas of the hippocampus,18 according to previously described criteria.1921 Hippocampal models were delineated in contiguous coronal brain sections using standard guidelines,22 including the hippocampus proper, dentate gyrus, and subiculum (Figure 1A). The borders of the hippocampus were determined by the temporal horn, the choroidal fissure, the uncal and ambient cisterns, and the gray-white junction between the subiculum and parahippocampal gyrus.

Place holder to copy figure label and caption
Figure 1.

The boundary of the hippocampus traced in consecutive coronal magnetic resonance imaging sections (A); 3-dimensional parametric surface created using anatomical surface modeling software (B); the surface of the hippocampus, which is composed of discrete triangular tiles that are spatially uniform and can be averaged across subjects (C); and an average anatomical model for a group, produced from the triangular tiles (D). A 3-dimensional medial curve is derived from each individual hippocampus (arrows in part B), and the distance from this axis to the surface is the dependent variable in a regression analysis. See the “Methods” section of the text for details.

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Anatomical mesh modeling methods23,24 matched equivalent hippocampal surface points across subjects and groups.25 The manually derived contours were made uniform by modeling them as a 3-dimensional variable surface mesh (Figure 1B),23,24 allowing measurements to be made at corresponding surface locations in each subject (Figure 1C and D). This procedure also allows the averaging of hippocampal surface morphological features across all individuals belonging to a group and the recording of the amount of variation between corresponding surface points relative to the group averages.

To assess global hippocampal atrophy, the volumes of these 3-dimensional models were measured in cubic millimeters. To measure local atrophy, a medial 3-dimensional curve was derived from each hippocampus down the central axis (Figure 1B). The distance of each surface point from this center line measures the radial size of the hippocampus. Regressions were performed at each surface point to map linkages between radial size and as many as 3 covariates. The resulting maps were visualized, and their significance was assessed by permutation to correct for multiple comparisons within each statistical map.24

At a global level, the total volume of the hippocampus differed significantly between controls and all MCI and AD subjects (F2,63 = 13.54, P<.001, η2 = 0.30). The total volume of the hippocampus was significantly smaller in the patients with AD compared with the controls (least significant difference test, P<.001) and with all of the MCI patients (P<.001). The hippocampi of the MCI patients, as a group, did not differ from those of controls (P = .09). When we examined the 2 MCI subgroups, there were significant differences among the study groups in terms of the volumes of the right side of the hippocampus (F3,65 = 11.4, P<.001, η2 = 0.36), the left side of the hippocampus (F3,65 = 6.46, P = .001, η2 = 0.23), and the total hippocampus (bilateral) (F3,65 = 9.97, P<.001, η2 = 0.32) (Figure 2 and Table 3).

Place holder to copy figure label and caption
Figure 2.

The mean ± SEM total volume of the 2 sides of the hippocampus in each subject group (see also Table 3). HC indicates healthy control; AD, Alzheimer disease; MCI-A, mild cognitive impairment, amnesic subtype; and MCI-MCD, mild cognitive impairment, multiple cognitive domain subtype.

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Table Graphic Jump LocationTable 3. Hippocampal Volumes by Study Group*

Significant local atrophy in the hippocampus in the patients with AD compared with the controls is shown in Figure 3A on the right (P<.001 by permutations tests) and left (P<.001) sides. By contrast, there was only a small amount of local atrophy in the hippocampi of the MCI patients (as a group) compared with the controls (Figure 3B).

Place holder to copy figure label and caption
Figure 3.

Statistical 3-dimensional maps showing local differences in hippocampal structures between patients with Alzheimer disease and control subjects (A) and between all patients with mild cognitive impairment and control subjects (B). The right hippocampus is on the left side of the figure.

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The MCI-MCD patients did not have significant volume loss in the hippocampus, examined either on the maps (all permutation tests, P>.05) or by the measured volumes (η2<0.05, P>.25 for all values). Compared with the patients with AD, the MCI-MCD patients showed significant sparing of the hippocampi on the maps (left side, P = .002; and right side, P = .002) and by the measured volumes (right side, P<.001; left side, P = .001; and total, P<.001; η2>0.25).

The MCI-A patients had significant atrophy on the inferior hippocampal surface (left side, P = .02; and right side, P = .03), but there was no difference vs the patients with AD (P>.05 for all). The overall volumes showed a similar pattern; there was significant atrophy on the right side and in total hippocampal volume measures compared with the controls (right side, P = .01 [η2 = 0.21]; left side, P = .14 [η2 = 0.11]; and total, P<.03 [η2 = 0.19]) and no differences vs the patients with AD (right side, P = .25; left side, P = .20; and total, P = .20) (Figure 4).

Place holder to copy figure label and caption
Figure 4.

Statistical 3-dimensional maps showing local hippocampal atrophy in patients with mild cognitive impairment (MCI) compared with control subjects. The right hippocampus is on the left side of the figure. A, Patients with MCI, multiple cognitive domain subtype, vs controls (P>.05 for all). B, Patients with MCI, amnesic subtype (MCI-A), vs controls. C, Patients with MCI-A vs controls, showing bottom sections of the map (P<.03 for all).

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These data show that there are neuropathological differences (reflected as MRI measured volumes) between MCI as an idiopathic amnesia (MCI-A) and the MCI that includes other cognitive deficits (MCI-MCD), supporting the clinical differentiation of the 2 subgroups. Furthermore, these data and those of others11 demonstrate that MCI-MCD is not a more advanced stage of MCI-A. The lack of extensive hippocampal atrophy and the presence of significant cortical atrophy in those with MCI-MCD means that the starting point for the 2 syndromes differs. However, only longitudinal data will be able to compare and contrast the trajectories of the cerebral atrophy over time. Finally, these data emphasize the importance of careful clinical characterization of MCI. Differences in the method of case ascertainment, the extent of the neuropsychological examination, and the use of subgroup analysis may explain the discrepancies among clinical and neuroimaging studies of MCI.2,4,11,13,2630

Our clinical definition of MCI was based on the nature and extent of neuropsychological impairment; in the case of MCI-A, cognitive dysfunction was limited to memory. By contrast, the MCI-MCD patients, while often having mild memory impairments, also had deficits in other domains. Although the entire MCI group had only a small degree of hippocampal atrophy, this was an artifact of combining the 2 subgroups. The MCI-MCD group had no atrophy, masking the shrinkage in the MCI-A group. The focal nature of the cognitive loss in MCI-A patients is, thus, consistent with the focal atrophy within the hippocampal complex.

Our analysis was aided by the fact that these cases were taken from a referral-based clinic. In all cases, someone (patient, family member, or physician) believed that there was a significant change in cognition and, consequently, the MCI patients studied herein are likely “closer” to conversion to clinical AD than they might be otherwise. Were we to study patients from a population study without such referral bias, we would be able to evaluate central nervous system structural changes before their clinical expression, and then the locus and extent of atrophy might differ from what was observed herein.

These data provide further evidence for the existence of subtypes of MCI, and they are also consistent with the parsimonious explanation that MCI represents a mild form of AD that has yet to convert to the full expression of a dementia syndrome. The differences among the subtypes of MCI are a consequence of different patterns of atrophy, which express themselves as different patterns of neuropsychological dysfunction.

Correspondence: James T. Becker, PhD, Neuropsychology Research Program, 3501 Forbes Ave, Suite 830, Pittsburgh, PA 15213 (beckerjt@upmc.edu).

Accepted for Publication: September 16, 2005.

Author Contributions:Study concept and design: Becker, Davis, Meltzer, Toga, and Lopez. Acquisition of data: Becker and Davis. Analysis and interpretation of data: Becker, Davis, Hayashi, Meltzer, and Thompson. Drafting of the manuscript: Becker, Davis, and Lopez. Critical revision of the manuscript for important intellectual content: Becker, Hayashi, Meltzer, Toga, Lopez, and Thompson. Statistical analysis: Becker, Davis, and Thompson. Obtained funding: Becker, Meltzer, Toga, and Thompson. Administrative, technical, and material support: Becker, Meltzer, Toga, Lopez, and Thompson. Study supervision: Thompson.

Funding/Support: This study was supported in part by grants AG05233 and AG20098 from the National Institute on Aging; grant LM05639 from the National Library of Medicine; resource grant RR013642 from the National Center for Research Resources; and center grant RR021813 from the National Center for Research Resources and the National Institute of General Medical Sciences, all part of the National Institutes of Health, Bethesda, Md. Dr Becker was the recipient of a level 2 Research Scientist Development Award (MH01077).

Imaging Methods and Analysis in Geriatrics Research Group

University of Pittsburgh, Pittsburgh, Pa: H. Aizenstein, MD, PhD; J. T. Becker, PhD; M. A. Butters, PhD; S. Derbyshire, PhD; M. Gach, PhD; W. Klunk, MD; O. L. Lopez, MD; C. Mathis, PhD; C. C. Meltzer, MD; J. Price, PhD; C. Rosano, MD; J. Spears, MS; S. Ziolko, MS; F. Boada, PhD; R. Jennings, PhD; R. Nebes, PhD; E. Nozfinger, MD. Carnegie Mellon University, Pittsburgh: O. Carmichael, PhD; Y. Liu, PhD.

Bowen  JTeri  LKukull  WMcCormick  WMcCurry  SMLarson  EB Progression to dementia in patients with isolated memory loss. Lancet 1997;349763- 765
PubMed Link to Article
Petersen  RCSmith  GEWaring  SCIvnik  RJTangalos  EGKokmen  E Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56303- 308
PubMed Link to Article
Morris  JCStorandt  MMiller  JP  et al.  Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001;58397- 405
PubMed
Lopez  OLJagust  WJDeKosky  ST  et al.  Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study: part 1. Arch Neurol 2003;601385- 1389
PubMed Link to Article
Gomez-Isla  TPrice  JLMcKeel  DWMorris  JCGrowdon  JHHyman  BT Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 1996;164491- 4500
PubMed
Braak  HBraak  E Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 1991;82239- 259
PubMed Link to Article
Pennanen  CKivipelto  MTuomainen  S  et al.  Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiol Aging 2004;25303- 310
PubMed Link to Article
Killiany  RJHyman  BTGomez-Isla  T  et al.  MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 2002;581188- 1196
PubMed Link to Article
Dickerson  BCSalary  DHBates  JF  et al.  Medial temporal lobe function and structure in mild cognitive impairment. Ann Neurol 2004;5627- 35
PubMed Link to Article
Wu  CCMungas  DPetkov  CI  et al.  Brain structure and cognition in a community sample of elderly Latinos. Neurology 2002;59383- 391
PubMed Link to Article
Bell-McGinty  SLopez  OLMeltzer  CC  et al.  Differential cortical atrophy in subgroups of mild cognitive impairment. Arch Neurol 2005;621393- 1397
PubMed Link to Article
Karas  GBScheltens  PRombouts  SA  et al.  Global and local gray matter loss in mild cognitive impairment and Alzheimer’s disease. Neuroimage 2004;23708- 716
PubMed Link to Article
Chetelat  GDesgranges  Bde la Sayette  VViader  FEustache  FBaron  JC Mapping gray matter loss with voxel-based morphometry in mild cognitive impairment. Neuroreport 2002;131939- 1943
PubMed Link to Article
Lopez  OLBecker  JTKlunk  W  et al.  Research evaluation and diagnosis of possible Alzheimer’s disease over the last two decades: II. Neurology 2000;551863- 1869
PubMed Link to Article
Mulsant  BHPollock  BGNebes  RD  et al.  A double-blind randomized comparison of nortriptyline and paroxetine in the treatment of late-life depression: 6-week outcome. J Clin Psychiatry 1999;60(suppl 20)16- 20
PubMed
Lopez  OLBecker  JTSweet  RA Non-cognitive symptoms in mild cognitive impairment subjects. Neurocase 2005;1165- 71
PubMed Link to Article
McKhann  GDrachman  DAFolstein  MFKatzman  RPrice  DLStadlan  E Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34939- 944
PubMed Link to Article
Duvernoy  H The Human Hippocampus: An Atlas of Applied Anatomy.  Munich, Germany: JF Bergman Verlag; 1988
Narr  KLThompson  PMSharma  T  et al.  Three-dimensional mapping of temporo-limbic regions and the lateral ventricles in schizophrenia: gender effects. Biol Psychiatry 2001;5084- 97
PubMed Link to Article
Narr  KLThompson  PMSzeszko  P  et al.  Regional specificity of hippocampal volume reductions in first-episode schizophrenia. Neuroimage 2004;211563- 1575
PubMed Link to Article
Watson  CAndermann  FGloor  P  et al.  Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging. Neurology 1992;421743- 1750
PubMed Link to Article
Pantel  JCretsinger  KKeefe  H  et al Hippocampus tracing guidelines.  Available at: http://www.psychiatry.uiowa.edu/mhcrc/pdf/papers/hippocampus.pdf. Accessed November 1, 2005
Thompson  PMSchwartz  CToga  AW High-resolution random mesh algorithms for creating a probabilistic 3D surface atlas of the human brain. Neuroimage 1996;319- 34
PubMed Link to Article
Thompson  PMSchwartz  CLin  RTKhan  AAToga  AW 3D statistical analysis of sulcal variability in the human brain. J Neurosci 1996;164261- 4274
PubMed
Thompson  PMHayaski  KMSowell  ER  et al.  Mapping cortical changes in Alzheimer’s disease, brain development, and schizophrenia. Neuroimage 2004;23(suppl 1)S2- S18
PubMed Link to Article
Ritchie  KArtero  STouchon  J Classification criteria for mild cognitive impairment: a population-based validation study. Neurology 2001;5637- 42
PubMed Link to Article
Schroder  JKratz  BPantel  JMinnemann  ELehr  USauer  H Prevalence of mild cognitive impairment in an elderly community sample. J Neural Transm Suppl 1998;5451- 59
PubMed
Convit  Ade Asis  Jde Leon  MJTarshish  CYDe Santi  SRusinek  H Atrophy of the medial occipitotemporal, inferior, and middle temporal gyri in non-demented elderly predict decline to Alzheimer’s disease. Neurobiol Aging 2000;2119- 26
PubMed Link to Article
Killiany  RJGomez-Isla  TMoss  M  et al.  Use of structural magnetic resonance imaging to predict who will get Alzheimer’s disease. Ann Neurol 2000;47430- 439
PubMed Link to Article
Visser  PJScheltens  PVerhey  FR  et al.  Medial temporal lobe atrophy and memory dysfunction as predictors for dementia in subjects with mild cognitive impairment. J Neurol 1999;246477- 485
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

The boundary of the hippocampus traced in consecutive coronal magnetic resonance imaging sections (A); 3-dimensional parametric surface created using anatomical surface modeling software (B); the surface of the hippocampus, which is composed of discrete triangular tiles that are spatially uniform and can be averaged across subjects (C); and an average anatomical model for a group, produced from the triangular tiles (D). A 3-dimensional medial curve is derived from each individual hippocampus (arrows in part B), and the distance from this axis to the surface is the dependent variable in a regression analysis. See the “Methods” section of the text for details.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

The mean ± SEM total volume of the 2 sides of the hippocampus in each subject group (see also Table 3). HC indicates healthy control; AD, Alzheimer disease; MCI-A, mild cognitive impairment, amnesic subtype; and MCI-MCD, mild cognitive impairment, multiple cognitive domain subtype.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Statistical 3-dimensional maps showing local differences in hippocampal structures between patients with Alzheimer disease and control subjects (A) and between all patients with mild cognitive impairment and control subjects (B). The right hippocampus is on the left side of the figure.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Statistical 3-dimensional maps showing local hippocampal atrophy in patients with mild cognitive impairment (MCI) compared with control subjects. The right hippocampus is on the left side of the figure. A, Patients with MCI, multiple cognitive domain subtype, vs controls (P>.05 for all). B, Patients with MCI, amnesic subtype (MCI-A), vs controls. C, Patients with MCI-A vs controls, showing bottom sections of the map (P<.03 for all).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Selected Neuropsychological Test Data
Table Graphic Jump LocationTable 2. Subject Demographic and Neuropsychiatric Characteristics*
Table Graphic Jump LocationTable 3. Hippocampal Volumes by Study Group*

References

Bowen  JTeri  LKukull  WMcCormick  WMcCurry  SMLarson  EB Progression to dementia in patients with isolated memory loss. Lancet 1997;349763- 765
PubMed Link to Article
Petersen  RCSmith  GEWaring  SCIvnik  RJTangalos  EGKokmen  E Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56303- 308
PubMed Link to Article
Morris  JCStorandt  MMiller  JP  et al.  Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001;58397- 405
PubMed
Lopez  OLJagust  WJDeKosky  ST  et al.  Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study: part 1. Arch Neurol 2003;601385- 1389
PubMed Link to Article
Gomez-Isla  TPrice  JLMcKeel  DWMorris  JCGrowdon  JHHyman  BT Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer’s disease. J Neurosci 1996;164491- 4500
PubMed
Braak  HBraak  E Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol (Berl) 1991;82239- 259
PubMed Link to Article
Pennanen  CKivipelto  MTuomainen  S  et al.  Hippocampus and entorhinal cortex in mild cognitive impairment and early AD. Neurobiol Aging 2004;25303- 310
PubMed Link to Article
Killiany  RJHyman  BTGomez-Isla  T  et al.  MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 2002;581188- 1196
PubMed Link to Article
Dickerson  BCSalary  DHBates  JF  et al.  Medial temporal lobe function and structure in mild cognitive impairment. Ann Neurol 2004;5627- 35
PubMed Link to Article
Wu  CCMungas  DPetkov  CI  et al.  Brain structure and cognition in a community sample of elderly Latinos. Neurology 2002;59383- 391
PubMed Link to Article
Bell-McGinty  SLopez  OLMeltzer  CC  et al.  Differential cortical atrophy in subgroups of mild cognitive impairment. Arch Neurol 2005;621393- 1397
PubMed Link to Article
Karas  GBScheltens  PRombouts  SA  et al.  Global and local gray matter loss in mild cognitive impairment and Alzheimer’s disease. Neuroimage 2004;23708- 716
PubMed Link to Article
Chetelat  GDesgranges  Bde la Sayette  VViader  FEustache  FBaron  JC Mapping gray matter loss with voxel-based morphometry in mild cognitive impairment. Neuroreport 2002;131939- 1943
PubMed Link to Article
Lopez  OLBecker  JTKlunk  W  et al.  Research evaluation and diagnosis of possible Alzheimer’s disease over the last two decades: II. Neurology 2000;551863- 1869
PubMed Link to Article
Mulsant  BHPollock  BGNebes  RD  et al.  A double-blind randomized comparison of nortriptyline and paroxetine in the treatment of late-life depression: 6-week outcome. J Clin Psychiatry 1999;60(suppl 20)16- 20
PubMed
Lopez  OLBecker  JTSweet  RA Non-cognitive symptoms in mild cognitive impairment subjects. Neurocase 2005;1165- 71
PubMed Link to Article
McKhann  GDrachman  DAFolstein  MFKatzman  RPrice  DLStadlan  E Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of the Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 1984;34939- 944
PubMed Link to Article
Duvernoy  H The Human Hippocampus: An Atlas of Applied Anatomy.  Munich, Germany: JF Bergman Verlag; 1988
Narr  KLThompson  PMSharma  T  et al.  Three-dimensional mapping of temporo-limbic regions and the lateral ventricles in schizophrenia: gender effects. Biol Psychiatry 2001;5084- 97
PubMed Link to Article
Narr  KLThompson  PMSzeszko  P  et al.  Regional specificity of hippocampal volume reductions in first-episode schizophrenia. Neuroimage 2004;211563- 1575
PubMed Link to Article
Watson  CAndermann  FGloor  P  et al.  Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging. Neurology 1992;421743- 1750
PubMed Link to Article
Pantel  JCretsinger  KKeefe  H  et al Hippocampus tracing guidelines.  Available at: http://www.psychiatry.uiowa.edu/mhcrc/pdf/papers/hippocampus.pdf. Accessed November 1, 2005
Thompson  PMSchwartz  CToga  AW High-resolution random mesh algorithms for creating a probabilistic 3D surface atlas of the human brain. Neuroimage 1996;319- 34
PubMed Link to Article
Thompson  PMSchwartz  CLin  RTKhan  AAToga  AW 3D statistical analysis of sulcal variability in the human brain. J Neurosci 1996;164261- 4274
PubMed
Thompson  PMHayaski  KMSowell  ER  et al.  Mapping cortical changes in Alzheimer’s disease, brain development, and schizophrenia. Neuroimage 2004;23(suppl 1)S2- S18
PubMed Link to Article
Ritchie  KArtero  STouchon  J Classification criteria for mild cognitive impairment: a population-based validation study. Neurology 2001;5637- 42
PubMed Link to Article
Schroder  JKratz  BPantel  JMinnemann  ELehr  USauer  H Prevalence of mild cognitive impairment in an elderly community sample. J Neural Transm Suppl 1998;5451- 59
PubMed
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