Volumetric reduction of the corpus callosum in Alzheimer's disease in vivo as assessed with voxel-based morphometry

Several recent magnetic resonance imaging studies have employed voxel-based morphometry (VBM) to detect regional gray matter volume abnormalities in Alzheimer's disease (AD). However, investigations of corpus callosum (CC) abnormalities in AD using this automated methodology have been scarce, and no VBM study investigated correlations between regional CC atrophy and cognitive measurements in AD subjects at mild disease stages. We used VBM to compare the topography of CC volume differences between 14 AD subjects (MMSE 14-25) and 14 healthy volunteers. Images were acquired using a 1.5-Telsa scanner, and were spatially normalized and segmented using optimized VBM. Statistical comparisons were performed using the general linear model. Significant CC atrophy was detected in the antero-superior portion of the splenium, the isthmus, the anterior and posterior portions of the CC body, and the rostral portion of the genu. Voxels showing peak statistical difference were all left-sided (P<0.001, uncorrected for multiple comparisons). A cluster of significant positive correlation with MMSE scores was seen on the left anterior CC body. Our results confirm previous findings of diffuse volumetric CC reductions early in the course of AD, and warrant further evaluation of the relevance of atrophic changes in anterior CC portions to the cognitive impairments that characterize the disorder.     

The cerebellum in mild cognitive impairment and Alzheimer's disease - a structural MRI study

Neuropathological research consistently revealed the cerebellum to undergo degenerative changes in Alzheimer's disease (AD). Whether these alterations affect cerebellar morphology in vivo has not yet been investigated in a comprehensive way. Magnetic resonance imaging was performed in 20 patients with AD, 20 with mild cognitive impairment (MCI), and 20 healthy controls. By manual tracing the cerebellum was divided in four substructures (anterior lobe, superior posterior lobe, inferior posterior lobe and corpus medullare, respectively) on each hemisphere. Posterior cerebellar lobes were significantly smaller in AD patients when compared to healthy controls. In the AD group, atrophy of the posterior cerebellar regions was associated with poorer cognitive performance. Our findings lend further support for cerebellar involvement in AD.     

Corpus callosum atrophy associated with the degree of cognitive decline in patients with Alzheimer's dementia or mild cognitive impairment: A meta-analysis of the region of interest structural imaging studies

Individual structural neuroimaging studies of the corpus callosum (CC) in Alzheimer's disease (AD) and mild cognitive impairment (MCI) with the region of interest (ROI) analysis have yielded inconsistent findings. The aim of this study was to conduct a meta-analysis of structural imaging studies using ROI technique to measure the CC midsagittal area changes in patients with AD or MCI. Databases of PubMed, the Cochrane Library, the ISI Web of Science, and Science Direct from inception to June 2014 were searched with key words “corpus callosum” or “callosal”, plus “Alzheimer's disease” or “mild cognitive impairment”. Twenty-three studies with 603 patients with AD, 146 with MCI, and 638 healthy controls were included in this meta-analysis. Effect size was used to measure the difference between patients with AD or MCI and healthy controls. Significant callosal atrophy was found in MCI patients with an effect size of −0.36 (95% CI, -0.57 to −0.14; P = 0.001). The degree of the CC atrophy in mild AD was less severe than that in moderate AD with a mean effect size −0.69 (95% CI, -0.89 to −0.49) versus −0.92 (95% CI, -1.16 to −0.69), respectively. Comparing with healthy controls, patients with MCI had atrophy in the anterior portion of the CC (i.e., rostrum and genu). In contrast, patients with AD had atrophy in both anterior and posterior portions (i.e., splenium). These results suggest that callosal atrophy may be related to the degree of cognitive decline in patients with MCI and AD, and it may be used as a biomarker for patients with cognitive deficit even before meeting the criteria for AD.     

Strukturelle zerebrale Veränderungen bei Probanden mit leichter kognitiver Beeinträchtigung Eine MR-volumetrische Studie

The aim of the present study was to investigate the morphological changes in subjects with mild cognitive impairment (MCI) revealed by quantitative magnetic resonance imaging (MRI). Twenty-one subjects with cognitive impairment and 22 healthy controls were compared with 12 patients suffering from mild Alzheimer's disease (AD). The volumes of the following brain structures were assessed: total intracranial compartment, cerebrospinal fluid compartment, whole brain, and medial temporal substructures (hippocampus and parahippocampal gyrus). Subjects with mild cognitive impairment showed a significantly reduced volume of the right parahippocampal gyrus over healthy controls. Volumes of the other regions and structures did not differ between the MCI group and controls. The volumetric and neuropsychological findings of the present study support the hypothesis that mild cognitive impairment - at least in some of the affected individuals - can be seen as a preclinical stage of AD and that atrophy of the parahippocampal gyrus might be useful as an early marker of AD.     

Hippocampal atrophy correlates with the severity of cognitive decline

BACKGROUND: The aim of this study is to compare the results of magnetic resonance (MR) imaging, particularly the decline in hippocampal volume, of patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) with healthy age-matched controls, to examine the reliability of hippocampal volumetry in the early diagnosis of AD and the correlation of the severity of hippocampal atrophy with the severity of cognitive decline. METHODS: Twenty-six AD, 22 MCI and 15 normal cognitive status (NCS) patients were scanned with a 3 Tesla MR scanner. Hippocampus volumes were detected manually by Osiris 4.18. RESULTS: Multivariate regression analysis, which was performed to adjust the covariate effects of education, age, gender, hypertension and diabetes mellitus, showed that hippocampal atrophy was correlated with AD and MCI for right hippocampus; AD, MCI and age for left hippocampus independent of other parameters. A second regression analysis revealed that MMSE was correlated with hippocampal volume. CONCLUSIONS: Hippocampal volumetry can be used in early diagnosis of cognitive impairment, as well as grading cognitive decline.     

Voxel-based morphometry in Alzheimer's disease

Recent morphometric MRI studies have investigated brain volume abnormalities associated with the diagnosis of Alzheimer's disease (AD) using voxel-based morphometry (VBM). This technique allows the assessment of gray matter volumes in subjects with AD or related conditions compared with healthy controls in an automated fashion, across the whole brain. This article reviews VBM findings related to different AD stages and its prodrome, mild cognitive impairment. These findings include not only gray matter deficits in medial temporal structures as seen in former MRI studies of AD conducted using manual region-of-interest measurements, but also volume changes in several other brain regions not assessed in previous MRI studies. We also discuss potential applications of VBM to improve AD diagnostic accuracy in routine clinical practice. Finally, we highlight future research directions in this field, including: investigations on the relationship between VBM findings of multifocal gray matter deficits and changes in white matter tracts that interconnect such regions; the need for population-based VBM studies using large AD samples; and the potential of studies combining VBM measurements with other potential biological markers (such as brain imaging indices of amyloid-beta deposition and cerebrospinal fluid AD markers) to further advance our knowledge about the physiopathology of AD.     

Traumatic brain injury and grey matter concentration: a preliminary voxel based morphometry study

BACKGROUND: Magnetic resonance imaging (MRI) studies have shown diffuse cerebral atrophy following traumatic brain injury. In the past, quantitative volumetric analysis of these changes was carried out by manually tracing specific regions of interest. In contrast, voxel based morphometry (VBM) is a fully automated technique that allows examination of the whole brain on a voxel by voxel basis. OBJECTIVE: To use VBM to evaluate changes in grey matter concentration following traumatic brain injury. METHODS: Nine patients with a history of traumatic brain injury (ranging from mild to severe) about one year previously were compared with nine age and sex matched healthy volunteers. T1 weighted three dimensional MRI images were acquired and then analysed with statistical parametric mapping software (SPM2). The patients with traumatic brain injury also completed cognitive testing to determine whether regional grey matter concentration correlated with a measure of attention and initial injury severity. RESULTS: Compared with controls, the brain injured patients had decreased grey matter concentration in multiple brain regions including frontal and temporal cortices, cingulate gyrus, subcortical grey matter, and the cerebellum. Decreased grey matter concentration correlated with lower scores on tests of attention and lower Glasgow coma scale scores. CONCLUSIONS: Using VBM, regions of decreased grey matter concentration were observed in subjects with traumatic brain injury compared with well matched controls. In the brain injured patients, there was a relation between grey matter concentration and attentional ability.     

Differences in grey and white matter atrophy in amnestic mild cognitive impairment and mild Alzheimer's disease

Background:  Grey matter (GM) atrophy has been demonstrated in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD), but the role of white matter (WM) atrophy has not been well characterized. Despite these findings, the validity of aMCI concept as prodromal AD has been questioned.
Methods:  We performed brain MRI with voxel-based morphometry analysis in 48 subjects, aiming to evaluate the patterns of GM and WM atrophy amongst mild AD, aMCI and age-matched normal controls.
Results:  Amnestic mild cognitive impairment GM atrophy was similarly distributed but less intense than that of mild AD group, mainly in thalami and parahippocampal gyri. There were no difference between aMCI and controls concerning WM atrophy. In the mild AD group, we found WM atrophy in periventricular areas, corpus callosum and WM adjacent to associative cortices.
Discussion:  We demonstrated that aMCI might be considered a valid concept to detect very early AD pathology, since we found a close proximity in the pattern of atrophy. Also, we showed the involvement of WM in mild AD, but not in aMCI, suggesting a combination of Wallerian degeneration and microvascular ischaemic disease as a plausible additional pathological mechanism for the discrimination between MCI and AD.     

Structure and function of medial temporal and posteromedial cortices in early Alzheimer's disease

Medial temporal lobe (MTL) atrophy and posteromedial cortical hypometabolism are consistent imaging findings in Alzheimer's disease (AD). As the MTL memory structures are affected early in the course of AD by neurofibrillary tangle pathology, the posteromedial metabolic abnormalities have been postulated to represent remote effects of MTL alterations. In this study, we investigated with functional MRI (fMRI) the structure-function relationship between the MTL and posteromedial regions, including the retrosplenial, posterior cingulate and precuneal cortices, in 21 older controls (OCs), 18 subjects with amnestic mild cognitive impairment (MCI) and 16 AD patients during a word list learning task. In the voxel-based morphometric and volumetric analyses, the MCI subjects showed smaller entorhinal volume than OCs (P = 0.0001), whereas there was no difference in the hippocampal or posteromedial volume. AD patients, as compared with MCI patients, showed pronounced loss of volume in the entorhinal (P = 0.0001), hippocampal (P = 0.01) and posteromedial (P = 0.001) regions. The normal pattern of posteromedial fMRI task-induced deactivation during active encoding of words was observed bilaterally in the OCs, but only in restricted unilateral left posteromedial areas in the MCI and AD patients. Across all subjects, more extensive impairment of the retrosplenial and posterior cingulate function was significantly related to smaller entorhinal (P = 0.001) and hippocampal (P = 0.0002) volume. These findings demonstrate that entorhinal atrophy and posteromedial cortical dysfunction are early characteristics of prodromal AD, and precede and/or overwhelm atrophy of the hippocampus and posteromedial cortices. Disturbances in posteromedial cortical function are associated with morphological changes in the MTL across the continuum from normal aging to clinical AD.     

基于体素的MRI形态学测量对遗忘型轻度认知障碍和轻度阿尔茨海默病脑灰质萎缩的研究

目的：利用磁共振3DT1WI成像研究遗忘型轻度认知障碍（aMCI）、轻度阿尔茨海默病（AD）患者相对于正常老年人灰质体积改变的特点。方法：采用3．0T磁共振,对33例aMCI患者（aMCI组）、32例轻度AD患者（轻度AD组）及31名正常老年人（对照组）进行3DT1WI扫描,利用基于SPM5的DARTEL工具箱对扫描获得的结构图像进行预处理,再对aMCI组、轻度AD组和对照组的全脑灰质体积进行基于体素的统计学比较。结果：与对照组比较,aMCI组左侧海马、海马旁回、舌回、颞上回,双侧岛叶和颞中回等结构的灰质体积萎缩,其差异有显著统计学意义（P〈0．01,FDR corrected,K〉50体素）。轻度AD组的双侧海马、海马旁回及杏仁核、双侧丘脑、双侧颞顶叶皮质等结构灰质体积萎缩,额叶和枕叶皮质也出现灰质萎缩,其差异也有统计学意义（P〈0．05,FDR corrected,K≥50体素）。结论：基于体素的MRI形态学测量能够客观揭示AD早期阶段的脑灰质萎缩改变,对左侧海马萎缩的识别有助于AD的早期诊断。     

Anterior cingulate cortex volume reduction in patients with panic disorder

Aim:  Recent neuroimaging studies have suggested that the anterior cingulate cortex (ACC) has an important role in the pathology of panic disorder. Despite numerous functional neuroimaging studies that have elucidated the strong relationship between functional abnormalities of the ACC and panic disorder and its symptoms and response to emotional tasks associated with panic disorder, there has been no study showing volumetric changes of the ACC or its subregions.
Methods:  To clarify the structural abnormalities of ACC and its subregions, the combination of region of interest (ROI) and optimized voxel-based morphometry (VBM) methods were performed on 26 patients with panic disorder, and 26 age and sex-matched healthy subjects. In the ROI study, ACC was divided into four subregions: dorsal, rostral, subcallosal and subgenual ACC.
Results:  The results of the manually traced ROI volume comparison showed significant volume reduction in the right dorsal ACC. VBM also showed a volume reduction in the right dorsal as well as a part of the rostral ACC as a compound mass.
Conclusions:  Both manual ROI tracing and optimized VBM suggest a subregion-specific pattern of ACC volume deficit in panic disorder. In addition to functional abnormalities, these results suggest that structural abnormalities of the ACC contribute to the pathophysiology of panic disorder.     

Grey-matter atrophy in Alzheimer's disease is asymmetric but not lateralized

In Alzheimer's disease (AD), brain atrophy has been proposed to be left lateralized. Here, we reinvestigated the asymmetry and lateralization (i.e., asymmetry directed toward one hemisphere) of grey-matter (GM) distribution in 35 patients with AD, 24 patients with amnestic mild cognitive impairment (aMCI, a state of increased risk for AD), and 30 age-matched healthy controls (HC). We analyzed GM distribution by applying voxel-based morphometry (VBM) including analyses for asymmetry and lateralization. When comparing MCI with AD patients, VBM revealed GM loss in the entorhinal, temporoparietal, dorsofrontal, and occipital cortices as well as in the precuneus; when comparing HCs with MCI patients, we found similar differences, which were less pronounced especially within the temporoparietal cortex and precuneus. Analyses of regional asymmetry and regional lateralization as well as global lateralization did not yield significant results. However, lobar asymmetry of the temporal, parietal, and occipital lobes increased from HC to AD. Moreover, in aMCI and AD patients, performance of language-based neuropsychological tests correlated with lateralization of GM loss to the left hemisphere. We conclude that, in principle, brain atrophy in AD is asymmetric rather than lateralized. At the individual level however, asymmetry contributes to cognitive deficits.     

The fornix and mammillary bodies in older adults with Alzheimer's disease, mild cognitive impairment, and cognitive complaints: a volumetric MRI study

The fornix and mammillary bodies are important limbic structures that have not been systematically investigated in the earliest stages of preclinical dementia. The present study examined volumetric changes in the fornix and mammillary bodies and improved previously established tracing guidelines to increase reliability and provide more comprehensive measurements. Volumetric measurements were made in euthymic older adults, including 16 patients with mild Alzheimer's disease (AD), 20 patients with amnestic mild cognitive impairment (MCI), 20 individuals with cognitive complaints (CC) but normal neuropsychological test performance, and 20 demographically matched healthy controls (HC). Structural magnetic resonance imaging included a T1-weighted 1.5-mm coronal volume, acquired on a GE 1.5T LX scanner. After adjustment for total intracranial volume (ICV), significant volume reductions were observed in the fornix and mammillary bodies in patients with AD as compared with HC, CC, and MCI participants. No volume differences were seen between the HC, CC, and MCI groups. Study findings are consistent with previous research showing volume decreases of the fornix and mammillary bodies in AD, and provide new data on the relative preservation of these structures in preclinical disease stages. Results suggest that atrophy of the fornix and mammillary bodies becomes apparent at the point of conversion from MCI to AD. Longitudinal assessments are needed to delineate the time course and extent of the observed volumetric changes.     

Intracranial volume in mild cognitive impairment,Alzheimer's disease and vascular dementia: evidence for brain reserve?

OBJECTIVE: The possibility of brain volume reserve effects was examined in a sample of geriatric outpatients with mild cognitive impairment (MCI), Alzheimer's disease (AD) and vascular dementia (VaD). The total intracranial volume (ICV) served as an estimate of the maximum attained brain volume in life. METHODS: Subjects (n = 181, mean age 60.7) were consecutive referrals to a geriatric outpatients clinic (n = 96) and a group of age-matched healthy control subjects (n = 85). ICV and brain volume were attained from T1-weighted magnetic resonance images using a stereological method. Hippocampal atrophy was assessed with a visual rating scale. RESULTS: ICV was significantly smaller in patients with AD and VaD than in control subjects, but effect size was small. After adjusting for age and gender, having ICV in the smallest quartile significantly increased the risk of cognitive impairment (either MCI or dementia). In patients with dementia, but not in MCI, severity of cognitive impairment and ICV were moderately correlated. The effect of ICV on cognition was not mediated by hippocampal atrophy. CONCLUSIONS: These findings are compatible with volume reserve effects that modify the clinical expression of symptoms in both AD and VaD. They may have implications for the design of neuroimaging studies that use ICV for normalization procedures.     

Comparison of Manual and Automated Determination of Hippocampal Volumes in MCI and Early AD

MRI-based hippocampal volume analysis has been extensively employed given its potential as a biomarker for brain disorders such as Alzheimer’s disease (AD), and accurate and efficient determination of hippocampal volumes from brain images is still a challenging issue. We compared an automated method, FreeSurfer (V4), with a published manual protocol for the determination of hippocampal volumes from T1-weighted MRI scans. Our study included MRI data from 125 older adult subjects: healthy controls with no significant cognitive complaints or deficits (HC, n?=?38), euthymic individuals with cognitive complaints (CC, n?=?39) but intact neuropsychological performance, and patients with amnestic mild cognitive impairment (MCI, n?=?37) or a clinical diagnosis of probable AD (AD, n?=?11). Pearson correlations and intraclass correlation coefficients (ICCs) were calculated to evaluate the relationship between results of the manual tracing and FreeSurfer methods and to estimate their agreement. Results indicated that these two methods derived highly correlated results with strong agreement. After controlling for the age, sex and intracranial volume in statistical group analysis, both the manual tracing and FreeSurfer methods yield similar patterns: both the MCI group and the AD group showed hippocampal volume reduction compared to both the HC group and the CC group, and the HC and CC groups did not differ. These comparisons suggest that FreeSurfer has the potential to be used in automated determination of hippocampal volumes for large-scale MCI/AD-related MRI studies, where manual methods are inefficient or not feasible.     

Medial temporal lobe atrophy and memory dysfunction as predictors for dementia in subjects with mild cognitive impairment

To determine whether the medial temporal lobe is atrophic in subjects with mild cognitive impairment, and whether atrophy of this structure is a better predictor of dementia than memory dysfunction. Forty-five noninstitutionalized subjects aged 65–85 years were randomly selected from a population based study to obtain a sample with Alzheimer’s disease (AD; n = 7), and a clinically nondemented sample (n = 38). Twenty of the latter subjects displayed some cognitive impairment and fulfilled CAMDEX criteria for “minimal dementia.” Coronal T1-weighted magnetic resonance imaging was used to visualize the medial temporal lobe. The volume of the parahippocampal gyrus and hippocampus was measured, and medial temporal lobe atrophy was assessed qualitatively. The memory subscore from the CAMCOG was used as a measure of memory functioning. The follow-up period was 3 years. Nine subjects who were diagnosed as being minimally demented at baseline met the criteria for AD during follow-up. At baseline the volume of the parahippocampal gyrus of these subjects was smaller than that of the other subjects with minimal dementia. The memory score was the best predictor of clinical outcome. All medial temporal lobe measures increased the accuracy of prediction compared with only the memory score, by reducing the number of false-negative classifications of dementia. Severe medial temporal lobe atrophy is present even in some subjects with mild cognitive impairment and is an indicator of subsequent AD. The absence of medial temporal lobe atrophy, however, does not exclude the development of dementia. In the majority of subjects memory impairment was a better predictor of dementia than atrophy of the medial temporal lobe. The combination of the two increased predictive accuracy. Nondemented subjects with severe atrophy of the medial temporal lobe could be enrolled in drug trials aimed at slowing the progression of AD. Received: 18 June 1998 Received in revised form: 28 September 1998Accepted: 4 November 1998     

Discriminating accuracy of medial temporal lobe volumetry and fMRI in mild cognitive impairment

We investigated structural and functional changes in the medial temporal lobe (MTL) using magnetic resonance imaging (MRI) and compared the discriminative power of these measures with neuropsychological testing in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Functional MRI (fMRI) was performed in 21 elderly controls, 14 MCI subjects, and 15 mild AD patients during encoding and cued retrieval of word-picture pairs. A region-of-interest-based approach in SPM2 was used to extract the extent of hippocampal activation. The volumes of the hippocampus and entorhinal cortex (EC) were manually outlined from anatomical MR images. Discriminant analyses were conducted to assess the ability of hippocampal fMRI, MTL volumetry, and neuropsychological measures to classify subjects into clinical groups. Entorhinal but not hippocampal volumes differed significantly between the control and MCI subjects. Both entorhinal and hippocampal volumes differed between MCI and AD patients. There were no significant differences in the extent of hippocampal fMRI activation during encoding or retrieval between the groups. Entorhinal volume was the best discriminator with a discriminating accuracy of 85.7% between controls and MCI, 86.2% between MCI and AD, and 97.2% between controls and AD. Delayed recall of a wordlist classified the subjects, second best, with a discriminating accuracy of 81.8% between controls and MCI, 75% between MCI and AD and 93.5% between controls and AD. The accuracy of hippocampal volumetry ranged from 42.9 to 69.4%, and hippocampal fMRI activation during encoding and retrieval had a classification accuracy of only 41.4-57.7% between the groups. Our results suggest that evaluation of entorhinal atrophy, in addition to the prevailing diagnostic criteria, seems promising in the identification of prodromal AD. Future technical improvements may improve the utilization of hippocampal fMRI for early diagnostic purposes.     

轻度认知障碍和轻度Alzeimer病的海马体积MRI测量

目的研究轻度认知功能障碍（mildcognitiveimpairment,MCI）和轻度阿尔兹海默病（A1zheimerdisease,AD）患者的海马体积萎缩情况,评价利用影像学测定海马体积对MCI、AD的诊断价值。方法应用3．0T磁共振分别对20例MCI患者,20例轻度AD患者,20例认知功能正常的对照者的海马体积进行测量,所得数值用头颅体积进行标准化处理。采用计算机SPSS13．0统计学软件进行资料的统计学处理,比较三组之间体积的差异。结果对照组与MCI组,对照组与AD组的两侧海马体积均存在显著的统计学差异,轻度AD与MCI组两侧的海马体积无显著的统计学差异。结论认知功能障碍与海马体积具有一定的相关性,海马萎缩对早期认知障碍有一定的诊断意义。     

Parahippocampal volume deficits in subjects with aging-associated cognitive decline

OBJECTIVE: Neuropathological evidence suggests that the earliest changes in Alzheimer's disease selectively affect the parahippocampal regions of the brain. This study was conducted to determine if otherwise healthy elderly subjects with mild cognitive impairment had structural volume deficits affecting the parahippocampal gyrus. METHOD: Magnetic resonance imaging (MRI) was used to compare global and regional brain volumes in 21 subjects with mild cognitive deficits defined according to the criteria for aging-associated cognitive decline, 22 cognitively intact comparison subjects, and 12 patients with Alzheimer's disease. RESULTS: Compared with the cognitively intact subjects, the subjects with aging-associated cognitive decline had a significantly smaller mean volume of the right parahippocampal gyrus. The subjects with aging-associated cognitive decline had a mean parahippocampal volume that was intermediate between that of the Alzheimer's disease patients and that of the cognitively intact subjects. CONCLUSIONS: Parahippocampal atrophy underlies the observed cognitive deficits in aging-associated cognitive decline. These findings support the hypothesis that aging-associated cognitive decline represents a preclinical stage of Alzheimer's disease.     

Three-dimensional patterns of hippocampal atrophy in mild cognitive impairment

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.