Plasma tau as a window to the brain—negative associations with brain volume and memory function in mild cognitive impairment and early alzheimer's disease

Neurofibrillary tangles are associated with cognitive dysfunction, and hippocampal atrophy with increased CSF tau markers. However, the plasma tau levels of Alzheimer's disease (AD) have not been well studied. We investigated plasma tau by using an immunomagnetic reduction assay in 20 patients with mild cognitive impairment (MCI) due to AD, 10 early AD dementia, and 30 healthy elders (HE). All received a 3D‐brain MRI scan and a set of cognitive function test. We explored their relationships with both brain structure and cognitive functions. Images were analyzed to determine the brain volumes and gray matter densities. Patients with MCI or early AD had significantly increased plasma tau levels compared with HE. Plasma tau levels were negatively associated with the performance of logical memory, visual reproduction, and verbal fluency; also negatively associated with volume of total gray matter, hippocampus, amygdala; and gray matter densities of various regions. Regression analyses indicated that logical memory explained 0.394 and hippocampus volume predicted .608 of the variance of plasma tau levels, both P < 0.001. Education years were negatively associated with the gray matter densities of the supramarginal (r = ?0.407), middle temporal gyrus (r = ?0.40) and precuneus (r = ?0.377; all P < 0.05) in HE; and negatively associated with plasma tau levels in patients (r = ?0.626). We propose that plasma tau may serve as a window to both structure and function of the brain. Higher education is a protective factor against AD and is associated with lower plasma tau levels in patients. Hum Brain Mapp 35:3132–3142, 2014. © 2013 Wiley Periodicals, Inc.     

Impact of leptin on memory function and hippocampal structure in mild cognitive impairment

Metabolic changes have been suggested to contribute to dementia and its precursor mild cognitive impairment (MCI), yet previous results particularly for the “satiety hormone” leptin are mixed. Therefore, we aimed to determine if MCI patients show systematic differences in leptin, independent of sex, adipose mass, age, and glucose and lipid metabolism, and whether leptin levels correlated with memory performance and hippocampal integrity. Forty MCI patients (20 females, aged 67 years ± 7 SD) were compared to 40 healthy controls (HC) that were pair‐wise matched for sex, age, and body fat. Memory performance was assessed using the auditory verbal learning test. Volume and microstructure of the hippocampus were determined using 3T‐neuroimaging. Fasting serum markers of leptin, glucose and lipid metabolism, and other confounding factors were assayed. MCI patients, compared with HC, showed lower serum leptin, independent of sex, age, and body fat (P < 0.001). Glucose and lipid markers did not attenuate these results. Moreover, MCI patients exhibited poorer memory and lower volume and microstructural integrity within hippocampal subfields. While leptin and memory were not significantly correlated, mediation analyses indicated that lower leptin contributed to poorer memory through its negative effect on right hippocampus volume and left hippocampus microstructure. We demonstrated that MCI is associated with lower serum leptin independent of sex, age, body fat, glucose, and lipid metabolism. Our data further suggest that inefficient leptin signaling could partly contribute to decreases in memory performance through changes in hippocampus structure, a hypothesis that should now be verified in longitudinal studies. Hum Brain Mapp 37:4539–4549, 2016. © 2016 Wiley Periodicals, Inc.     

A Meta‐Analysis of fMRI Activation Differences during Episodic Memory in Alzheimer's Disease and Mild Cognitive Impairment

Functional MRI (fMRI) has the potential to be used as a tool to detect biomarkers related to classifying Alzheimer's disease (AD) and its prodromal stage, mild cognitive impairment (MCI). Previous meta‐analyses suggest that during episodic memory tasks, MCI patients exhibit hyperactivation in the medial temporal lobe (MTL) while AD patients exhibit hypoactivation, compared to healthy older adults (HOAs). However, these previous studies have methodological weaknesses that limit the generalizability of the results. This quantitative meta‐analysis re‐examines the activation associated with episodic memory in AD and MCI as compared to cognitively normal populations to assess these commonly cited activation differences. A whole‐brain activation likelihood estimation based meta‐analysis was conducted on fMRI studies that examined episodic memory in HOA (n = 200), MCI (n = 131), and AD populations (n = 89; total n = 409). Diffuse activation was exhibited in the HOA sample, while activation was more limited in the clinical populations. Additionally, the HOA sample showed more activation in the right hippocampus compared to the AD sample. The MCI studies showed greater activation in the cerebellum compared to the HOA sample, potentially indicating a compensatory mechanism for verbal encoding. MTL hypoactivation in the AD sample is consistent with previous studies, but more evidence of MCI hyperactivation is needed before considering MTL activation as an early biomarker for the AD disease process.     

Association between fully automated MRI-based volumetry of different brain regions and neuropsychological test performance in patients with amnestic mild cognitive impairment and Alzheimer’s disease

Fully automated magnetic resonance imaging (MRI)-based volumetry may serve as biomarker for the diagnosis in patients with mild cognitive impairment (MCI) or dementia. We aimed at investigating the relation between fully automated MRI-based volumetric measures and neuropsychological test performance in amnestic MCI and patients with mild dementia due to Alzheimer’s disease (AD) in a cross-sectional and longitudinal study. In order to assess a possible prognostic value of fully automated MRI-based volumetry for future cognitive performance, the rate of change of neuropsychological test performance over time was also tested for its correlation with fully automated MRI-based volumetry at baseline. In 50 subjects, 18 with amnestic MCI, 21 with mild AD, and 11 controls, neuropsychological testing and T1-weighted MRI were performed at baseline and at a mean follow-up interval of 2.1 ± 0.5 years (n = 19). Fully automated MRI volumetry of the grey matter volume (GMV) was performed using a combined stereotactic normalisation and segmentation approach as provided by SPM8 and a set of pre-defined binary lobe masks. Left and right hippocampus masks were derived from probabilistic cytoarchitectonic maps. Volumes of the inner and outer liquor space were also determined automatically from the MRI. Pearson’s test was used for the correlation analyses. Left hippocampal GMV was significantly correlated with performance in memory tasks, and left temporal GMV was related to performance in language tasks. Bilateral frontal, parietal and occipital GMVs were correlated to performance in neuropsychological tests comprising multiple domains. Rate of GMV change in the left hippocampus was correlated with decline of performance in the Boston Naming Test (BNT), Mini-Mental Status Examination, and trail making test B (TMT-B). The decrease of BNT and TMT-A performance over time correlated with the loss of grey matter in multiple brain regions. We conclude that fully automated MRI-based volumetry allows detection of regional grey matter volume loss that correlates with neuropsychological performance in patients with amnestic MCI or mild AD. Because of the high level of automation, MRI-based volumetry may easily be integrated into clinical routine to complement the current diagnostic procedure.     

The new Alzheimer’s criteria in a naturalistic series of patients with mild cognitive impairment

To test the validity of the new diagnostic criteria for Alzheimer’s disease (AD) in a naturalistic series of patients with mild cognitive impairment (MCI). Ninety consecutive MCI patients were enrolled in a longitudinal study on the natural history of cognitive impairment. Medial temporal (MT) atrophy on MRI was defined as hippocampal volume below the fifth percentile of the distribution in healthy elders, abnormal CSF was based on Sjogren’s cutoffs for Abeta42 and tau, and temporoparietal hypometabolism on 18F-FDG PET based on Herholz’s t sum score. Patients were followed clinically to detect conversion to AD (MCI-AD), non-AD dementia (MCI-nAD), or no conversion (MCI-NC). The 24 MCI-AD and 15 MCI-nAD patients had sociodemographic, clinical, and neuropsychological baseline features similar to the 51 MCI-NC patients. All MCI patients with MT atrophy converted to AD, as did all those with abnormal CSF, but only 48 and 35% of those without MT atrophy or abnormal CSF converted (p on logrank test = 0.0007 and 0.001). Prediction of AD conversion was enhanced when positivity to either MT atrophy or abnormal CSF was considered, with only 15% of those MCI patients negative on both converting to AD (p < 0.0005). Markers were not predictive of non-AD dementia conversion. The accuracy of either MT atrophy or abnormal CSF in discriminating MCI-AD from MCI-NC was good (AUC 0.82, 95% CI 0.70–0.95). MT atrophy and abnormal CSF are the single most robust predictors of conversion to AD in MCI patients, and their combination enhances prediction. AD markers are not predictive of conversion to non-AD dementia.     

Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: insights from functional MRI studies

Functional MRI (fMRI) studies of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have begun to reveal abnormalities in memory circuit function in humans suffering from memory disorders. Since the medial temporal lobe (MTL) memory system is a site of very early pathology in AD, a number of studies, reviewed here, have focused on this region of the brain. By the time individuals are diagnosed clinically with AD dementia, the substantial memory impairments appear to be associated with not only MTL atrophy but also hypoactivation during memory task performance. Prior to dementia, when individuals are beginning to manifest signs and symptoms of memory impairment, the hippocampal formation and other components of the MTL memory system exhibit substantial functional abnormalities during memory task performance. It appears that, early in the course of MCI when memory deficits and hippocampal atrophy are less prominent, there may be hyperactivation of MTL circuits, possibly representing inefficient compensatory activity. Later in the course of MCI, when considerable memory deficits are present, MTL regions are no longer able to activate during attempted learning, as is the case in AD dementia. Recent fMRI data in MCI and AD are beginning to reveal relationships between abnormalities of functional activity in the MTL memory system and in functionally connected brain regions, such as the precuneus. As this work continues to mature, it will likely contribute to our understanding of fundamental memory processes in the human brain and how these are perturbed in memory disorders. We hope these insights will translate into the incorporation of measures of task-related brain function into diagnostic assessment or therapeutic monitoring, such as for use in clinical trials.     

Hippocampal volume and asymmetry in mild cognitive impairment and Alzheimer's disease: Meta‐analyses of MRI studies

Numerous studies have reported a smaller hippocampal volume in Alzheimer's disease (AD) patients than in aging controls. However, in mild cognitive impairment (MCI), the results are inconsistent. Moreover, the left‐right asymmetry of the hippocampus receives less research attention. In this article, meta‐analyses are designed to determine the extent of hippocampal atrophy in MCI and AD, and to evaluate the asymmetry pattern of the hippocampal volume in control, MCI, and AD groups. From 14 studies including 365 MCI patients and 382 controls, significant atrophy is found in both the left [Effect size (ES), 0.92; 95% confidence interval (CI), 0.72–1.11] and right (ES, 0.78; 95% CI, 0.57–0.98) hippocampus, which is lower than that in AD (ES, 1.60, 95% CI, 1.37–1.84, in left; ES, 1.52, 95% CI, 1.31–1.72, in right). Comparing with aging controls, the average volume reduction weighted by sample size is 12.9% and 11.1% in left and right hippocampus in MCI, and 24.2% and 23.1% in left and right hippocampus in AD, respectively. The findings show a bilateral hippocampal volume loss in MCI and the extent of atrophy is less than that in AD. By comparing the left and right hippocampal volume, a consistent left‐less‐than‐right asymmetry pattern is found, but with different extents in control (ES, 0.39), MCI (ES, 0.56), and AD (ES, 0.30) group. © 2009 Wiley‐Liss, Inc.     

Genetic influence of apolipoprotein E4 genotype on hippocampal morphometry: An N = 725 surface‐based Alzheimer's disease neuroimaging initiative study

The apolipoprotein E (APOE) e4 allele is the most prevalent genetic risk factor for Alzheimer's disease (AD). Hippocampal volumes are generally smaller in AD patients carrying the e4 allele compared to e4 noncarriers. Here we examined the effect of APOE e4 on hippocampal morphometry in a large imaging database—the Alzheimer's Disease Neuroimaging Initiative (ADNI). We automatically segmented and constructed hippocampal surfaces from the baseline MR images of 725 subjects with known APOE genotype information including 167 with AD, 354 with mild cognitive impairment (MCI), and 204 normal controls. High‐order correspondences between hippocampal surfaces were enforced across subjects with a novel inverse consistent surface fluid registration method. Multivariate statistics consisting of multivariate tensor‐based morphometry (mTBM) and radial distance were computed for surface deformation analysis. Using Hotelling's T² test, we found significant morphological deformation in APOE e4 carriers relative to noncarriers in the entire cohort as well as in the nondemented (pooled MCI and control) subjects, affecting the left hippocampus more than the right, and this effect was more pronounced in e4 homozygotes than heterozygotes. Our findings are consistent with previous studies that showed e4 carriers exhibit accelerated hippocampal atrophy; we extend these findings to a novel measure of hippocampal morphometry. Hippocampal morphometry has significant potential as an imaging biomarker of early stage AD. Hum Brain Mapp 35:3903–3918, 2014. © 2014 Wiley Periodicals, Inc .     

Lesion patterns and mechanism of cerebral infarction caused by severe atherosclerotic intracranial internal carotid artery stenosis

The hippocampus is believed to have close relationship with many cerebral cortexes and constitute memory network to modulate and facilitate communication, which makes it especially interesting and meaningful in the study of functional connectivity in mild cognitive impairment (MCI). However, functional connectivity between the hippocampus and other brain regions remains unclear in MCI. Furthermore, the longitudinal changes of the hippocampal connectivity have not been reported. In the study, resting state functional MRI (fMRI) was used to examine changes in hippocampal connectivity comparing 14 patients and 14 healthy age-matched controls. We found that functional connectivity between the hippocampus and a set of regions was disrupted in MCI, these regions are: the right frontal lobe, the bilateral temporal lobe and the right insular. While, the left posterior cingulate cortex, precuneus, hippocampus, caudate and right occipital gyrus showed increased connectivity to the hippocampus in MCI. Additionally, we traced the seven MCI patients and compared the hippocampal connectivity in initial stage and 3 years later stage. Several regions presented decreased connectivity to the hippocampus after 3 years. Finally, the hippocampal connectivity with some regions showed significant correlation with the cognitive performance of patients. Based on these findings, the decreased hippocampal connectivity might indicate reduced integrity of hippocampal cortical memory network in MCI. In addition, the increased hippocampal connectivity suggested compensation for the loss of memory function. With the development of the disease, the hippocampal connectivity may lose some compensation and add some more disruption due to the pathological changes.     

Cholinergic plasticity in hippocampus of individuals with mild cognitive impairment: correlation with Alzheimer's neuropathology

Several recent studies indicate that activity of cholinergic enzymes in the cortex of people with mild cognitive impairment (MCI) and early Alzheimer's disease (AD) are preserved. We correlated levels of hippocampal choline acetyltransferase (ChAT) activity with the extent of AD lesions in subjects from the Religious Order Study, including cases with no cognitive impairment (NCI), MCI, and with mild to moderate AD. Hippocampal ChAT activity levels were also determined in a group of end-stage AD patients who were enrolled in the University of Pittsburgh Alzheimer's Disease Research Center. MCI subjects were characterized with increased hippocampal ChAT activity. This elevation was no longer present in mild AD cases, which were not different from NCI subjects. Severe AD cases showed markedly depleted hippocampal ChAT levels. In NCI, MCI, and mild-moderate AD, there was a positive correlation between hippocampal ChAT activity levels and progression of neuritic plaque pathology in entorhinal cortex and hippocampus. A significant elevation of hippocampal ChAT in the MCI group was found selectively in the limbic (i.e., entorhinal-hippocampal, III/IV) Braak stages. We hypothesize that cholinergic changes in the hippocampus of MCI subjects reflect a compensatory response to the progressive denervation of the hippocampus by lost entorhinal cortex input. Moreover, the present findings suggest that the short-term memory loss observed in MCI is not caused by cholinergic deficits; it more likely relates to disrupted entorhinal-hippocampal connectivity.     

Altered memory‐related functional connectivity of the anterior and posterior hippocampus in older adults at increased genetic risk for Alzheimer's disease

The hippocampal complex is affected early in Alzheimer's disease (AD). Increasingly, altered functional connectivity of the hippocampus is recognized as an important feature of preclinical AD. Carriers of the APOE?4 allele are at an increased risk for AD, which could lead to altered hippocampal connectivity even in healthy older adults. To test this hypothesis, we used a paired‐associates memory task to examine differences in task‐dependent functional connectivity of the anterior and posterior hippocampus in nondemented APOE?4 carriers (n = 34, 18F) and noncarriers (n = 46, 31F). We examined anterior and posterior portions of the hippocampus separately to test the theory that APOE?4‐mediated differences would be more pronounced in the anterior region, which is affected earlier in the AD course. This study is the first to use a psychophysiological interaction approach to query the context‐dependent connectivity of subregions of the hippocampus during a memory task in adults at increased genetic risk for AD. During encoding, APOE?4 carriers had lower functional connectivity change compared to baseline between the anterior hippocampus and right precuneus, anterior insula and cingulate cortex. During retrieval, bilateral supramarginal gyrus and right precuneus showed lower functional connectivity change with anterior hippocampus in carriers. Also during retrieval, carriers showed lower connectivity change in the posterior hippocampus with auditory cortex. In each case, APOE?4 carriers showed strong negative connectivity changes compared to noncarriers where positive connectivity change was measured. These differences may represent prodromal functional changes mediated in part by APOE?4 and are consistent with the anterior‐to‐posterior theory of AD progression in the hippocampus. Hum Brain Mapp 37:366–380, 2016. © 2015 Wiley Periodicals, Inc.     

Altered resting state networks in mild cognitive impairment and mild Alzheimer's disease: an fMRI study

Activity and reactivity of the default mode network in the brain was studied using functional magnetic resonance imaging (fMRI) in 28 nondemented individuals with mild cognitive impairment (MCI), 18 patients with mild Alzheimer's disease (AD), and 41 healthy elderly controls (HC). The default mode network was interrogated by means of decreases in brain activity, termed deactivations, during a visual encoding task and during a nonspatial working memory task. Deactivation was found in the default mode network involving the anterior frontal, precuneus, and posterior cingulate cortex. MCI patients showed less deactivation than HC, but more than AD. The most pronounced differences between MCI, HC, and AD occurred in the very early phase of deactivation, reflecting the reactivity and adaptation of the network. The default mode network response in the anterior frontal cortex significantly distinguished MCI from both HC (in the medial frontal) and AD (in the anterior cingulate cortex). The response in the precuneus could only distinguish between patients and HC, not between MCI and AD. These findings may be consistent with the notion that MCI is a transitional state between healthy aging and dementia and with the proposed early changes in MCI in the posterior cingulate cortex and precuneus. These findings suggest that altered activity in the default mode network may act as an early marker for AD pathology.     

Supporting evidence for using biomarkers in the diagnosis of MCI due to AD

The aim of this study is to support the use of biomarkers in the diagnosis of mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) according to the revised NIA-AA diagnostic criteria. We compared clinical features and conversion to AD and other dementias among groups of MCI patients with different abnormal biomarker profiles. In this study, we enrolled 58 patients with MCI, and for each of them AD biomarkers (CSF Abeta42 and tau, temporoparietal hypometabolism on 18F-FDG PET, and hippocampal volume) were collected. Patients were divided into three groups: (i) no abnormal biomarker, (ii) AD biomarker pattern (including three subgroups of early = only abnormal Abeta42, intermediate = abnormal Abeta42 and FDG PET or tau, and late = abnormal Abeta42, FDG PET or tau, and HV), and (iii) any other biomarker combination. MCI patients with AD biomarker pattern had lower behavioural disturbances than patients with any other biomarker combination (p < 0.0005). This group also showed lower performance on verbal and non-verbal memory than the other two groups (p = 0.07 and p = 0.004, respectively). Within the three subgroups with AD biomarker patterns we observed a significant trend toward a higher rate of conversion to dementia (p for trend = 0.006). With regard to dementia conversion, 100 % of patients with an AD biomarker pattern developed AD, but none of the patients with no abnormal biomarker and 27 % of patients with any other biomarker combination (p = 0.002) did so. We also described some clinical cases representative for each of these three groups. The results of this study provide evidence in favour of the use of biomarkers for the diagnosis of MCI due to AD, in line with recently published research criteria.     

The role of neuroimaging in mild cognitive impairment

The main purposes of neuroimaging in Alzheimer's disease (AD) have been moved from diagnosis of advanced AD to diagnosis of very early AD at a prodromal stage of mild cognitive impairment, prediction of conversion from mild cognitive impairment (MCI) to AD, and differential diagnosis from other diseases causing dementia. Structural MRI studies and functional studies using F‐18 fluorodeoxyglucose‐positron emission tomography (FDG‐PET) and brain perfusion single‐photon emission computed tomography (SPECT) are widely used in diagnosis of AD. Outstanding progress in diagnostic accuracy of these neuroimaging modalities has been obtained using statistical analysis on a voxel‐by‐voxel basis after spatial normalization of individual scans to a standardized brain‐volume template instead of visual inspection or a conventional region of interest technique. In a very early stage of AD, this statistical approach revealed gray matter loss in the entorhinal and hippocampal areas and hypometabolism or hypoperfusion in the posterior cingulate cortex and precuneus. These two findings might be related in view of anatomical knowledge that the regions are linked through the circuit of Papez. This statistical approach also offers prediction of conversion from MCI to AD. Presence of hypometabolism or hypoperfusion in parietal association areas and entorhinal atrophy at the MCI stage has been reported to predict rapid conversion to AD.     

The role of volumetric MRI in understanding mild cognitive impairment and similar classifications

We review nineteen empirical studies of mild cognitive impairment (MCI), age-associated memory impairment (AAMI) and related classifications reporting volumetric data on the hippocampus, entorhinal cortex and amygdala. Studies varied considerably in terms of the selection of participants, sample characteristics, the definitions of regions of interest and normalization techniques. Effect sizes for differences in left hippocampal volume and right hippocampal volumes of AAMI, MCI and pre-clinical dementia groups compared with controls ranged from 0.47 to 1.34. Effect sizes for left and right hippocampal volumes for Alzheimer's disease (AD) versus control were 1.88 and 1.75 respectively. Longitudinal results confirm that initial hippocampal volume is predictive of conversion to AD. Greater standardization in methodology and the development of normative age-referenced databases of regional brain volumes is required.     

Classification of Alzheimer's disease based on hippocampal multivariate morphometry statistics

Background

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline, and mild cognitive impairment (MCI) is associated with a high risk of developing AD. Hippocampal morphometry analysis is believed to be the most robust magnetic resonance imaging (MRI) markers for AD and MCI. Multivariate morphometry statistics (MMS), a quantitative method of surface deformations analysis, is confirmed to have strong statistical power for evaluating hippocampus.

Aims

We aimed to test whether surface deformation features in hippocampus can be employed for early classification of AD, MCI, and healthy controls (HC).

Methods

We first explored the differences in hippocampus surface deformation among these three groups by using MMS analysis. Additionally, the hippocampal MMS features of selective patches and support vector machine (SVM) were used for the binary classification and triple classification.

Results

By the results, we identified significant hippocampal deformation among the three groups, especially in hippocampal CA1. In addition, the binary classification of AD/HC, MCI/HC, AD/MCI showed good performances, and area under curve (AUC) of triple-classification model achieved 0.85. Finally, positive correlations were found between the hippocampus MMS features and cognitive performances.

Conclusions

The study revealed significant hippocampal deformation among AD, MCI, and HC. Additionally, we confirmed that hippocampal MMS can be used as a sensitive imaging biomarker for the early diagnosis of AD at the individual level.     

CERAD test performances in amnestic mild cognitive impairment and Alzheimer's disease

OBJECTIVES: The aim of the study was to examine the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) test performances cross-sectionally in patients suffering from amnestic mild cognitive impairment (MCI) and mild Alzheimer's disease (AD). Moreover, we wanted to determine the sensitivity to amnestic MCI and mild AD, as well as the specificity of different CERAD subtests in our study groups. MATERIAL AND METHODS: Fifteen healthy elderly individuals, 15 amnestic MCI patients and 15 probable AD patients suffering from mild dementia were tested with the CERAD neurocognitive dementia screening test. RESULTS: Significant differences were found in all CERAD tests except Constructional praxis (copy) and Clock drawing between the controls and the AD group. The MCI group was differentiated from the controls only in the Wordlist learning test. In the language tests the sensitivity to MCI and AD was quite low and the specificity very high. In the savings scores the sensitivity to AD was high, but the specificity rather low. The Wordlist recognition test screened no false positives using the current cut-off score and the sensitivity to AD was 0.6, but only one MCI patient was detected using the current cut-off score. Raising the cut-off score also raised the sensitivity to MCI without dramatic loss of specificity. Cut-off scores for the Wordlist learning test and Wordlist delayed recall, which have been found to differentiate normal aging from dementia, are lacking in the Finnish CERAD. The current data indicates that the Wordlist learning test might be relatively sensitive to MCI. CONCLUSIONS: The results indicate that the Finnish CERAD test battery with its current cut-off scores has low sensitivity to MCI, and using it as a sole cognitive screening instrument for MCI and preclinical dementia might result in false negatives.     

Automated 3D mapping of hippocampal atrophy and its clinical correlates in 400 subjects with Alzheimer's disease,mild cognitive impairment,and elderly controls

We used a new method we developed for automated hippocampal segmentation, called the auto context model, to analyze brain MRI scans of 400 subjects from the Alzheimer's disease neuroimaging initiative. After training the classifier on 21 hand‐labeled expert segmentations, we created binary maps of the hippocampus for three age‐ and sex‐matched groups: 100 subjects with Alzheimer's disease (AD), 200 with mild cognitive impairment (MCI) and 100 elderly controls (mean age: 75.84; SD: 6.64). Hippocampal traces were converted to parametric surface meshes and a radial atrophy mapping technique was used to compute average surface models and local statistics of atrophy. Surface‐based statistical maps visualized links between regional atrophy and diagnosis (MCI versus controls: P = 0.008; MCI versus AD: P = 0.001), mini‐mental state exam (MMSE) scores, and global and sum‐of‐boxes clinical dementia rating scores (CDR; all P < 0.0001, corrected). Right but not left hippocampal atrophy was associated with geriatric depression scores (P = 0.004, corrected); hippocampal atrophy was not associated with subsequent decline in MMSE and CDR scores, educational level, ApoE genotype, systolic or diastolic blood pressure measures, or homocysteine. We gradually reduced sample sizes and used false discovery rate curves to examine the method's power to detect associations with diagnosis and cognition in smaller samples. Forty subjects were sufficient to discriminate AD from normal and correlate atrophy with CDR scores; 104, 200, and 304 subjects, respectively, were required to correlate MMSE with atrophy, to distinguish MCI from normal, and MCI from AD. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

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。