Differential Cortical Atrophy in Subgroups of Mild Cognitive Impairment

Differential Cortical Atrophy in Subgroups of Mild Cognitive Impairment

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.

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