ORIGINAL CONTRIBUTION Differential Cortical Atrophy in Subgroups of Mild Cognitive Impairment Sandra Bell-McGinty, PhD; Oscar L. Lopez, MD; Carolyn Cidis Meltzer, MD; Joelle M. Scanlon, PhD; Ellen M. Whyte, MD; Steven T. DeKosky, MD; James T. Becker, PhD Objective: To compare gray matter brain volumes in jects. Compared with patients with MCI-MCD, patients patients diagnosed with subtypes of mild cognitive im- with MCI-A had significant volume loss of the left ento- pairment (MCI) (those with a focal amnestic disorder and rhinal cortex and inferior parietal lobe. Compared with those with more diffuse cognitive dysfunction) with those patients with MCI-A, patients with MCI-MCD had sig- of elderly controls. nificantly reduced volume of the right inferior frontal gy- rus, right middle temporal gyrus, and bilateral superior Design: Magnetic resonance imaging volumetric study temporal gyrus. Patients with MCI who progressed to Alz- of MCI subgroups (MCI-amnestic [MCI-A], and MCI- heimer disease during follow-up (mean interval 2 years, multiple cognitive domain [MCI-MCD]) using a whole maximum 4.5 years), showed greater atrophy in the left brain voxel-based analysis. entorhinal cortex, bilateral superior temporal gyri, and right inferior frontal gyrus compared with those who did Setting: Referral dementia clinic. not progress. Patients: Thirty-seven patients with MCI (age range, Conclusions: These data provide evidence of distinct 49-85 years; MCI-A, n=9; MCI-MCD, n=28) and 47 con- brain structural abnormalities in 2 groups of patients with trol subjects (age range, 55-81 years). MCI. While both have mesial temporal and cortical vol- ume loss, those with a focal memory deficit have more Main Outcome Measures: Volumetric anatomical mag- involvement of the mesial temporal structures and less netic resonance imaging differences between MCI sub- involvement of the neocortical heteromodal association groups and normal controls, and between patients with areas than those patients with MCI with diffuse cogni- MCI who progressed to dementia. Magnetic resonance tive dysfunction. Thus, MCI may represent a more het- imaging scans were analyzed using statistical software erogeneous group than currently conceived, possibly re- SPM99. flecting 2 different etiological processes to dementia. These data also suggest that these structural abnormalities pre- Results: Overall, the patients with MCI had signifi- cede the development of Alzheimer disease. cantly decreased volume in the hippocampus and middle temporal gyrus, bilaterally, compared with control sub- Arch Neurol. 2005;62:1393-1397 HE TRANSITIONAL STATE BE- particularly severe among those patients tween normal aging and with MCI who progress to AD compared Author Affiliations: 6,8 Departments of Psychiatry Alzheimer disease (AD), with those who do not. (Drs Bell-McGinty, Lopez, mild cognitive impair- Even though MCI diagnosis relies pri- Meltzer, Scanlon, Whyte, ment (MCI), has become a marily on the presence of memory dysfunc- DeKosky, and Becker), Tfocus of research owing to the develop- tion, a growing number of studies have con- Neurology (Drs Lopez, ment of effective pharmacotherapy aimed cluded that performance in other cognitive DeKosky, and Becker), at altering the natural history of the dis- domains is often not entirely normal.1,9 Radiology (Dr Meltzer), and ease.1,2 A number of brain structural ab- While some patients exhibit an isolated Psychology (Dr Becker), normalities have been identified among pa- memory problem, others can have altered Neuropsychology Research tients with MCI with abnormal memory, neuropsychological test performance in Program, Functional Imaging including significant reduction in the vol- multiple cognitive areas.1,9 The purpose of Research Program, and the ume of the hippocampus,3,4 medial occipi- this study was to compare regional gray Mental Health Intervention 5 Research Center for Late-Life totemporal lobe, parahippocampal gy- matter brain volumes in 2 subtypes of pa- Mood Disorders, University of rus, entorhinal cortex, superior temporal tients with MCI using a whole brain voxel- Pittsburgh Medical Center, gyrus, and anterior cingulate gyrus.6,7 based analysis.10 This approach is not bi- Pittsburgh, Pa. These morphological abnormalities are ased to a specific brain region and permits (REPRINTED) ARCH NEUROL / VOL 62, SEP 2005 WWW.ARCHNEUROL.COM 1393 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 1. Demographic Characteristics of Patients With MCI and Control Subjects MCI Subgroups Controls All MCI MCI-A MCI-MCD No. of patients 47 37 9 28 Mean age ± SD (range), y 66.9 ± 7.3 (55-81) 71.9 ± 7.6 (49-85)* 73.4 ± 4.3 (66-78)† 71.5 ± 8.4 (49-85) Men (%) 27 (57) 17 (46) 4 (44) 13 (46) Caucasian (%) 42 (89) 31 (84) 9 (100) 22 (46) Mean educational level ± SD, y 15.7 ± 2.7 14.1 ± 3.9 13.7 ± 2.1 14.6 ± 4.4 Mean baseline MMSE ± SD 29.4 ± .4 25.5 ± 3.2* 23.1 ± 3.8† 26.3 ± 2.6† Mean baseline MDRS ± SD ‡ 133.7 ± 7.9 130.7 ± 7.5† 134.7 ± 7.9 Abbreviations: MCI, mild cognitive impairment; MCI-A, mild cognitive impairment–amnestic; MCI-MCD, mild cognitive impairment–multiple cognitive domain; MDRS, Mattis Dementia Rating Scale; MMSE, Mini-Mental State Examination. *Patients with MCI were older (t = - 3.04, P = .003) and had lower MMSE scores (t = - 5.86, P = .001) than controls. †Controls vs MCI subtypes; age was different among the 3 groups (F = 4.84, P = .01); patients with MCI-A and MCI-MCD were older than controls; the MMSE scores were different among the 3 groups (F = 3.8, P = .02); patients with MCI-A had lower scores than those with MCI-MCD (t = - 2.85, P = .01); patients with MCI-A had lower MDRS scores than those with MCI-MCD (t = 2.32, P = .02). ‡The MDRS was not administered to the comparison subjects from outside the Alzheimer’s Disease Research Center. identification of potential unsuspected brain structure ab- main (not including memory), without sufficiently severe cog- normalities,10 allowing for a more comprehensive descrip- nitive impairment or loss of daily living skills to constitute tion of the differences between MCI subtypes. dementia, or 2 abnormal tests in 2 different domains.16 METHODS MRI ACQUISITION AND ANALYSIS Magnetic resonance imaging scans were conducted using a Signa PATIENTS 1.5 Tesla scanner (GE Medical Systems, Milwaukee, Wis). The MRI of the brain was done within 6 months after the initial evalu- Thirty-seven patients from a group of 200 who met criteria for ation. The spoiled gradient-recalled sequence was designed to MCI, as described below, underwent a volumetric spoiled gra- maximize contrast between gray and white matter (echo time=5 dient-recalled magnetic resonance imaging (MRI) scan. Each 11 milliseconds, repetition time=25 milliseconds, 1.5-mm sec- patient received an extensive evaluation, and was reevalu- tion, 0-mm intersection interval, 40° flip angle). ated on an annual basis with regard to neuropsychiatric status All MRI data were processed using Statistical Parametric Map- to determine whether there was a change in diagnosis. ping (SPM99; Wellcome Department of Cognitive Neurology, Volumetric MRI scans were obtained on 47 older compari- London, England) running in MATLAB (Mathworks, Sher- son subjects from 3 ongoing studies, including the Alzhei- 11 born, Mass). The spoiled gradient recalled images were spa- mer’s Disease Research Center (n=28), the University of tially normalized (Montreal Neurological Institute coordinate Pittsburgh’s Mental Health Intervention Research Center for system; McGill University, Montreal, Quebec), and the tissue Late-Life Mood Disorders,12 and a study of cognitive and cere- 13 segmented using a modified mixture model cluster analysis tech- brovascular consequences of hypertension (n=19). None of nique.17 The segmented gray matter images were then smoothed the controls converted to dementia or MCI within 5 years of using an 8-mm isotropic gaussian kernel. A more complete de- the scan. scription of voxel-based morphometry method can be found in Good et al18 and Ashburner et al.17 NEUROPSYCHOLOGICAL EVALUATION RESULTS 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, vi- The demographic characteristics of all subjects and MCI suospatial/visuoconstructional, and attention/executive func- subgroups are shown in Table 1. Fourteen patients with tions. Details of the neuropsychological battery have been de- MCI (38%) converted to AD during follow-up (mean±SD scribed elsewhere.16 The results of the cognitive tests were follow-up: 45.7±26.5 months). The proportion of pa- classified normal or abnormal (Ͼ1.5 below that of subjects of tients with MCI-A (44%) and MCI-MCD (36%) who con- comparable age and education) based on normative data ob- verted to AD was similar between groups (␹2=0.65, P=.41). tained from the Alzheimer’s Disease Research Center normal The baseline demographic characteristics of those who con- control sample. verted to AD are shown in Table 2. Overall, those who converted to AD did have lower MMSE (t=3.2, P=0.01) MCI CRITERIA and Mattis Dementia Rating Scale (t=4.15, P=.004) scores at the time of study entry compared with nonconverters. Patients with MCI-amnestic (MCI-A) (n=9) required memory deficits, with otherwise normal cognitive function. These pa- tients must have impairments in delayed recall verbal memory, VOXEL-BASED MORPHOMETRY nonverbal memory, or both.16 Patients with MCI-multiple cognitive domain (MCI- Patients with MCI, as a group, had significantly de- MCD) (n=28) required deterioration in at least 1 cognitive do- creased volume in the hippocampus and middle tempo- (REPRINTED) ARCH NEUROL / VOL 62, SEP 2005 WWW.ARCHNEUROL.COM 1394 ©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 2.