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Figure.
Statistical software SPM99 results, controlling for current chronological age (P<.001), showing regions of reduced gray matter volume in patients with MCI-A (A) and patients with MCI-MCD compared with the comparison subjects (B), controlling for current age. The top rows show results projected onto an averaged template brain. The bottom rows show results projected in the coronal plane onto a mean image of 37 patients with MCI (A, Bottom left image = right hippocampus, y = - 23; bottom right image = right entorhinal/amygdala, y = - 4. B, Bottom left image = bilateral hippocampus, y = - 18; bottom right image = bilateral middle temporal and right inferior frontal, y = - 5). Images are displayed in neurological convention.

Statistical software SPM99 results, controlling for current chronological age (P<.001), showing regions of reduced gray matter volume in patients with MCI-A (A) and patients with MCI-MCD compared with the comparison subjects (B), controlling for current age. The top rows show results projected onto an averaged template brain. The bottom rows show results projected in the coronal plane onto a mean image of 37 patients with MCI (A, Bottom left image = right hippocampus, y = - 23; bottom right image = right entorhinal/amygdala, y = - 4. B, Bottom left image = bilateral hippocampus, y = - 18; bottom right image = bilateral middle temporal and right inferior frontal, y = - 5). Images are displayed in neurological convention.

Table 1. 
Demographic Characteristics of Patients With MCI and Control Subjects
Demographic Characteristics of Patients With MCI and Control Subjects
Table 2. 
Demographic and Cognitive Characteristics of Patients With MCI Who Converted to AD and Those Who Did Not
Demographic and Cognitive Characteristics of Patients With MCI Who Converted to AD and Those Who Did Not
Table 3. 
Gray Matter Atrophy in MCI and MCI Subgroups Compared With Normal Controls
Gray Matter Atrophy in MCI and MCI Subgroups Compared With Normal Controls
Table 4. 
Comparison of Gray Matter Atrophy Between MCI Subgroups
Comparison of Gray Matter Atrophy Between MCI Subgroups
Table 5. 
Locations of Significant Differences in Gray Matter Volume Between MCI Converters and Nonconverters
Locations of Significant Differences in Gray Matter Volume Between MCI Converters and Nonconverters
1.
Petersen  RCSmith  GEWaring  SCIvnik  RJTangalos  EGKokmen  E Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56303- 308
PubMedArticle
2.
Morris  JCStorandt  MMiller  JP  et al.  Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001;58397- 405
PubMed
3.
Wolf  HGrunwald  MKruggel  F  et al.  Hippocampal volume discriminates between normal cognition: questionable and mild dementia in the elderly. Neurobiol Aging 2001;22177- 186
PubMedArticle
4.
Soininen  HSPartanen  KPitkanen  A  et al.  Volumetric MRI analysis of the amygdala and the hippocampus in subjects with age-associated memory impairment: correlation to visual and verbal memory. Neurology 1994;441660- 1668
PubMedArticle
5.
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
PubMedArticle
6.
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
PubMedArticle
7.
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
PubMedArticle
8.
Visser  PJVerhey  FRHofman  PAScheltens  PJolles  J Medial temporal lobe atrophy predicts Alzheimer's disease in patients with minor cognitive impairment. J Neurol Neurosurg Psychiatry 2002;72491- 497
PubMed
9.
Hanninen  THallikainen  MKoivisto  K  et al.  Decline of frontal lobe functions in subjects with age-associated memory impairment. Neurology 1997;48148- 153
PubMedArticle
10.
Ashburner  JFriston  KJ Voxel-based morphometry: the methods. Neuroimage 2000;11805- 821
PubMedArticle
11.
Lopez  OLBecker  JTKlunk  W  et al.  Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades: I. Neurology 2000;551854- 1862
PubMedArticle
12.
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
13.
Jennings  JRMuldoon  MFRyan  CM  et al.  Cerebral blood flow in hypertensives: an initial report of reduced and compensatory blood flow responses during performance of two cognitive tasks. Hypertension 1998;311216- 1222
PubMedArticle
14.
Folstein  MFFolstein  SEMcHugh  PR Mini-mental state: a practical method grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMedArticle
15.
Mattis  S Mental status examination for organic mental syndrome in the elderly patient.  In: Bellak  L, Karuso  TB, eds. Geriatric Psychiatry. New York, NY: Grune & Stratton; 1976
16.
Lopez  OLBecker  JTSweet  RA Non-cognitive symptoms in mild cognitive impairment subjects. Neurocase 2005;1165- 71
PubMedArticle
17.
Ashburner  JFriston  K Multimodal image coregistration and partitioning: a unified framework. Neuroimage 1997;6209- 217
PubMedArticle
18.
Good  CDJohnsrude  ISAshburner  JHenson  RNFriston  KJFrackowiak  RS A voxel-based morphometric study of aging in 465 normal adult human beings. Neuroimage 2001;1421- 36
PubMedArticle
19.
Killiany  RJHyman  BTGomez-Isla  T  et al.  MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 2002;581188- 1196
PubMedArticle
20.
Price  JLMorris  JC Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol 1999;45358- 368
PubMedArticle
21.
Kordower  JHChu  YStebbins  GT  et al.  Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 2001;49202- 213
PubMedArticle
22.
Klunk  WEEngler  HNordberg  A  et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compond-B. Ann Neurol 2004;55306- 319
PubMedArticle
Original Contribution
September 2005

Differential Cortical Atrophy in Subgroups of Mild Cognitive Impairment

Author Affiliations

Author Affiliations: Departments of Psychiatry (Drs Bell-McGinty, Lopez, Meltzer, Scanlon, Whyte, DeKosky, and Becker), Neurology (Drs Lopez, DeKosky, and Becker), Radiology (Dr Meltzer), and Psychology (Dr Becker), Neuropsychology Research Program, Functional Imaging Research Program, and the Mental Health Intervention Research Center for Late-Life Mood Disorders, University of Pittsburgh Medical Center, Pittsburgh, Pa.

Arch Neurol. 2005;62(9):1393-1397. doi:10.1001/archneur.62.9.1393
Abstract

Objective  To compare gray matter brain volumes in patients diagnosed with subtypes of mild cognitive impairment (MCI) (those with a focal amnestic disorder and those with more diffuse cognitive dysfunction) with those of elderly controls.

Design  Magnetic resonance imaging volumetric study of MCI subgroups (MCI-amnestic [MCI-A], and MCI-multiple cognitive domain [MCI-MCD]) using a whole brain voxel-based analysis.

Setting  Referral dementia clinic.

Patients  Thirty-seven patients with MCI (age range, 49-85 years; MCI-A, n = 9; MCI-MCD, n = 28) and 47 control subjects (age range, 55-81 years).

Main Outcome Measures  Volumetric anatomical magnetic resonance imaging differences between MCI subgroups and normal controls, and between patients with MCI who progressed to dementia. Magnetic resonance imaging scans were analyzed using statistical software SPM99.

Results  Overall, the patients with MCI had significantly decreased volume in the hippocampus and middle temporal gyrus, bilaterally, compared with control subjects. Compared with patients with MCI-MCD, patients with MCI-A had significant volume loss of the left entorhinal cortex and inferior parietal lobe. Compared with patients with MCI-A, patients with MCI-MCD had significantly reduced volume of the right inferior frontal gyrus, right middle temporal gyrus, and bilateral superior temporal gyrus. Patients with MCI who progressed to Alzheimer disease during follow-up (mean interval 2 years, maximum 4.5 years), showed greater atrophy in the left entorhinal cortex, bilateral superior temporal gyri, and right inferior frontal gyrus compared with those who did not progress.

Conclusions  These data provide evidence of distinct brain structural abnormalities in 2 groups of patients with MCI. While both have mesial temporal and cortical volume loss, those with a focal memory deficit have more involvement of the mesial temporal structures and less involvement of the neocortical heteromodal association areas than those patients with MCI with diffuse cognitive dysfunction. Thus, MCI may represent a more heterogeneous group than currently conceived, possibly reflecting 2 different etiological processes to dementia. These data also suggest that these structural abnormalities precede the development of Alzheimer disease.

The transitional state between normal aging and Alzheimer disease (AD), mild cognitive impairment (MCI), has become a focus of research owing to the development of effective pharmacotherapy aimed at altering the natural history of the disease.1,2 A number of brain structural abnormalities have been identified among patients with MCI with abnormal memory, including significant reduction in the volume of the hippocampus,3,4 medial occipitotemporal lobe,5 parahippocampal gyrus, entorhinal cortex, superior temporal gyrus, and anterior cingulate gyrus.6,7 These morphological abnormalities are particularly severe among those patients with MCI who progress to AD compared with those who do not.6,8

Even though MCI diagnosis relies primarily on the presence of memory dysfunction, a growing number of studies have concluded that performance in other cognitive domains is often not entirely normal.1,9 While some patients exhibit an isolated memory problem, others can have altered neuropsychological test performance in multiple cognitive areas.1,9 The purpose of this study was to compare regional gray matter brain volumes in 2 subtypes of patients with MCI using a whole brain voxel-based analysis.10 This approach is not biased to a specific brain region and permits identification of potential unsuspected brain structure abnormalities,10 allowing for a more comprehensive description of the differences between MCI subtypes.

METHODS
PATIENTS

Thirty-seven patients from a group of 200 who met criteria for MCI, as described below, underwent a volumetric spoiled gradient-recalled magnetic resonance imaging (MRI) scan. Each patient received an extensive evaluation,11 and was reevaluated on an annual basis with regard to neuropsychiatric status to determine whether there was a change in diagnosis.

Volumetric MRI scans were obtained on 47 older comparison subjects from 3 ongoing studies, including the Alzheimer's Disease Research Center (n = 28),11 the University of Pittsburgh’s Mental Health Intervention Research Center for Late-Life Mood Disorders,12 and a study of cognitive and cerebrovascular consequences of hypertension (n = 19).13 None of the controls converted to dementia or MCI within 5 years of the scan.

NEUROPSYCHOLOGICAL EVALUATION

The neuropsychological evaluation included the Mini-Mental State Examination (MMSE),14 the Mattis Dementia Rating Scale,15 and measures of 4 cognitive domains: memory, language, visuospatial/visuoconstructional, and attention/executive functions. Details of the neuropsychological battery have been described elsewhere.16 The results of the cognitive tests were classified normal or abnormal (>1.5 below that of subjects of comparable age and education) based on normative data obtained from the Alzheimer's Disease Research Center normal control sample.

MCI CRITERIA

Patients with MCI-amnestic (MCI-A) (n = 9) required memory deficits, with otherwise normal cognitive function. These patients must have impairments in delayed recall verbal memory, nonverbal memory, or both.16

Patients with MCI-multiple cognitive domain (MCI-MCD) (n = 28) required deterioration in at least 1 cognitive domain (not including memory), without sufficiently severe cognitive impairment or loss of daily living skills to constitute dementia, or 2 abnormal tests in 2 different domains.16

MRI ACQUISITION AND ANALYSIS

Magnetic resonance imaging scans were conducted using a Signa 1.5 Tesla scanner (GE Medical Systems, Milwaukee, Wis). The MRI of the brain was done within 6 months after the initial evaluation. The spoiled gradient-recalled sequence was designed to maximize contrast between gray and white matter (echo time = 5 milliseconds, repetition time = 25 milliseconds, 1.5-mm section, 0-mm intersection interval, 40° flip angle).

All MRI data were processed using Statistical Parametric Mapping (SPM99; Wellcome Department of Cognitive Neurology, London, England) running in MATLAB (Mathworks, Sherborn, Mass). The spoiled gradient recalled images were spatially normalized (Montreal Neurological Institute coordinate system; McGill University, Montreal, Quebec), and the tissue segmented using a modified mixture model cluster analysis technique.17 The segmented gray matter images were then smoothed using an 8-mm isotropic gaussian kernel. A more complete description of voxel-based morphometry method can be found in Good et al18 and Ashburner et al.17

RESULTS

The demographic characteristics of all subjects and MCI subgroups are shown in Table 1. Fourteen patients with MCI (38%) converted to AD during follow-up (mean ± SD follow-up: 45.7 ± 26.5 months). The proportion of patients with MCI-A (44%) and MCI-MCD (36%) who converted to AD was similar between groups (χ2 = 0.65, P = .41). The baseline demographic characteristics of those who converted to AD are shown in Table 2. Overall, those who converted to AD did have lower MMSE (t = 3.2, P = 0.01) and Mattis Dementia Rating Scale (t = 4.15, P = .004) scores at the time of study entry compared with nonconverters.

VOXEL-BASED MORPHOMETRY

Patients with MCI, as a group, had significantly decreased volume in the hippocampus and middle temporal gyrus, bilaterally. In addition, the left inferior parietal, left middle frontal, and right superior frontal volumes were also reduced in patients with MCI compared with control subjects (Table 3).

Patients with MCI-A had significantly reduced volume of the mesial temporal lobe on the right, including the hippocampus, entorhinal cortex, and amygdala (Figure, A) compared with control subjects. In addition, reduced volume was observed in the left inferior parietal, inferior and middle frontal, and superior temporal gyri. Patients diagnosed with MCI-MCD had significant bilateral volume loss of the hippocampus, middle and superior temporal, and inferior frontal gyri compared with controls (Figure, B). In addition, the left inferior parietal gyrus and the right superior frontal gyrus were significantly decreased in patients with MCI-MCD compared with controls (Table 3).

Compared with patients with MCI-MCD, patients with MCI-A had significantly greater volume loss in the left inferior parietal lobe (P<.001) and the left entorhinal/perirhinal cortex (P<.01). By contrast, compared with patients with MCI-A, patients with MCI-MCD had significantly greater volume loss in the right inferior frontal gyrus, right middle temporal gyrus, and superior temporal gyrus, bilaterally (Table 4).

Among all patients with MCI who progressed to AD, there was greater baseline atrophy in the left entorhinal cortex, bilateral superior temporal gyri, and right inferior frontal gyrus (Table 5). Partial correlation analyses, controlling for age, showed significant positive correlations between the MMSE score and the volumes of the left entorhinal cortex (r = 0.35; df = 34; P = .04) and right inferior frontal gyrus (r = 0.36; df = 34; P = .03).

COMMENT

The present study demonstrates distinct brain structural abnormalities in 2 subgroups of patients with MCI. Specifically, patients with MCI-A have atrophy in the hippocampus and entorhinal cortex, as expected,37 as well as in the amygdala, and in the neocortex. Patients with MCI-MCD showed more diffuse and extensive volume loss in the neocortical heteromodal association, with less involvement of the medial temporal lobe structures compared with those diagnosed with MCI-A. The MCI subgroups share a region of atrophy in the inferior frontal cortex, specifically BA 44/45, suggesting that this region may be important in the clinical presentation of MCI, and perhaps, reflecting the impending defect in retrieval from semantic memory.

Our data also suggest that atrophy in specific cortical regions precede the development of dementia in patients with MCI. Specifically, patients who developed AD during follow-up had significantly decreased volume of the left entorhinal cortex, bilateral superior temporal gyri, and right inferior frontal gyrus at study entry. Volume reduction of the entorhinal cortex and superior temporal gyrus has been noted in recent studies;6,19 however, our findings suggest additional structural abnormalities within the inferior frontal cortex of those patients with MCI who progress to AD. The degree of cognitive impairment, as measured by the MMSE, appears to be associated with decreased volume in both the frontal and entorhinal areas.

The structural changes associated with the MCI syndrome are more diffuse than previously thought. Although the hippocampus has been the most studied area in MCI cases, more recent studies have shown that structural lesions (eg, neurofibrillary tangles, neuritic plaques) are more widely distributed in MCI, and include the neocortex and limbic areas.20,21 Furthermore, amyloid deposits were identified in vivo in the frontal and parietal lobes in patients with mild AD, and practically no amyloid was seen in the medial temporal lobe structures.22 Therefore, the structural abnormalities in MCI cases, especially in those who progress to AD, are not limited to the mesial temporal areas.

This study is limited by the small sample of MCI subtypes, particularly those who progressed to AD. Nevertheless, our study shows that there are at least 2 subtypes of MCI, those with the more traditionally defined memory deficit and those with more diffuse cognitive impairment, each presenting with distinct brain structural abnormalities. The therapeutic implications of our findings need to be explored, as differences in brain abnormalities may be associated with variations in disease course and treatment response. Better understanding of these subtypes may enhance our knowledge of the relationship between normal aging and dementia.

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Article Information

Correspondence: Oscar L. Lopez, MD, Neuropsychology Research Program, Suite 830, Oxford Bldg, 3501 Forbes Ave, Pittsburgh, PA 15213 (lopezol@upmc.edu).

Accepted for Publication: January 4, 2005.

Author Contributions:Study concept and design: Bell-McGinty, Lopez, Meltzer, Scanlon, DeKosky, and Becker. Acquisition of data: Bell-McGinty, Lopez, Meltzer, and Becker. Analysis and interpretation of data: Bell-McGinty, Lopez, Meltzer, Scanlon, Whyte, DeKosky, and Becker. Drafting of the manuscript: Bell-McGinty, Lopez, DeKosky, and Becker. Critical revision of the manuscript for important intellectual content: Bell-McGinty, Meltzer, Scanlon, Whyte, DeKosky, and Becker. Statistical analysis: Lopez and Becker. Obtained funding: Bell-McGinty and DeKosky. Administrative, technical, and material support: Bell-McGinty, Meltzer, and DeKosky. Study supervision: Lopez, Meltzer, DeKosky, and Becker.

Funding/Support: This research was supported in part by grants AG05133 and AG20098 from the National Institute on Aging, Bethesda, Md; and HL57529 from the National Heart, Lung, and Blood Institute, Bethesda. Drs Bell-McGinty, Scanlon, and Whyte are postdoctoral research fellows in the Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, Pa (T32 MH19986). Dr Becker is the recipient of a Research Scientist Development Award, Level-II (K02 MH01077).

References
1.
Petersen  RCSmith  GEWaring  SCIvnik  RJTangalos  EGKokmen  E Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56303- 308
PubMedArticle
2.
Morris  JCStorandt  MMiller  JP  et al.  Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol 2001;58397- 405
PubMed
3.
Wolf  HGrunwald  MKruggel  F  et al.  Hippocampal volume discriminates between normal cognition: questionable and mild dementia in the elderly. Neurobiol Aging 2001;22177- 186
PubMedArticle
4.
Soininen  HSPartanen  KPitkanen  A  et al.  Volumetric MRI analysis of the amygdala and the hippocampus in subjects with age-associated memory impairment: correlation to visual and verbal memory. Neurology 1994;441660- 1668
PubMedArticle
5.
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
PubMedArticle
6.
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
PubMedArticle
7.
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
PubMedArticle
8.
Visser  PJVerhey  FRHofman  PAScheltens  PJolles  J Medial temporal lobe atrophy predicts Alzheimer's disease in patients with minor cognitive impairment. J Neurol Neurosurg Psychiatry 2002;72491- 497
PubMed
9.
Hanninen  THallikainen  MKoivisto  K  et al.  Decline of frontal lobe functions in subjects with age-associated memory impairment. Neurology 1997;48148- 153
PubMedArticle
10.
Ashburner  JFriston  KJ Voxel-based morphometry: the methods. Neuroimage 2000;11805- 821
PubMedArticle
11.
Lopez  OLBecker  JTKlunk  W  et al.  Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades: I. Neurology 2000;551854- 1862
PubMedArticle
12.
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
13.
Jennings  JRMuldoon  MFRyan  CM  et al.  Cerebral blood flow in hypertensives: an initial report of reduced and compensatory blood flow responses during performance of two cognitive tasks. Hypertension 1998;311216- 1222
PubMedArticle
14.
Folstein  MFFolstein  SEMcHugh  PR Mini-mental state: a practical method grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12189- 198
PubMedArticle
15.
Mattis  S Mental status examination for organic mental syndrome in the elderly patient.  In: Bellak  L, Karuso  TB, eds. Geriatric Psychiatry. New York, NY: Grune & Stratton; 1976
16.
Lopez  OLBecker  JTSweet  RA Non-cognitive symptoms in mild cognitive impairment subjects. Neurocase 2005;1165- 71
PubMedArticle
17.
Ashburner  JFriston  K Multimodal image coregistration and partitioning: a unified framework. Neuroimage 1997;6209- 217
PubMedArticle
18.
Good  CDJohnsrude  ISAshburner  JHenson  RNFriston  KJFrackowiak  RS A voxel-based morphometric study of aging in 465 normal adult human beings. Neuroimage 2001;1421- 36
PubMedArticle
19.
Killiany  RJHyman  BTGomez-Isla  T  et al.  MRI measures of entorhinal cortex vs hippocampus in preclinical AD. Neurology 2002;581188- 1196
PubMedArticle
20.
Price  JLMorris  JC Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease. Ann Neurol 1999;45358- 368
PubMedArticle
21.
Kordower  JHChu  YStebbins  GT  et al.  Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment. Ann Neurol 2001;49202- 213
PubMedArticle
22.
Klunk  WEEngler  HNordberg  A  et al.  Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compond-B. Ann Neurol 2004;55306- 319
PubMedArticle
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