Giorgos Karas

Global and local gray matter loss in mild cognitive impairment and Alzheimer's disease.

PURPOSE Mild cognitive impairment (MCI) is thought to be the prodromal phase to Alzheimers disease (AD). We analyzed patterns of gray matter (GM) loss to examine what characterizes MCI and what determines the difference with AD. MATERIALS AND METHODS Thirty-three subjects with AD, 14 normal elderly controls (NCLR), and 22 amnestic MCI subjects were included and underwent brain MR imaging. Global GM volume was assessed using segmentation and local GM volume was assessed using voxel-based morphometry (VBM); VBM was optimized for template mismatch and statistical mass. RESULTS AD subjects had significantly (12.3%) lower mean global GM volume when compared to controls (517 +/- 58 vs. 590 +/- 52 ml; P < 0.001). Global GM volume in the MCI group (552 +/- 52) was intermediate between these two: 6.2% lower than AD and 6.5% higher than the controls but not significantly different from either group. VBM showed that subjects with MCI had significant local reductions in gray matter in the medial temporal lobe (MTL), the insula, and thalamus compared to NCLR subjects. By contrast, when compared to subjects with AD, MCI subjects had more GM in the parietal association areas and the anterior and the posterior cingulate. CONCLUSION GM loss in the MTL characterizes MCI, while GM loss in the parietal and cingulate cortices might be a feature of AD.

A comprehensive study of gray matter loss in patients with Alzheimer's disease using optimized voxel-based morphometry.

Voxel-based morphometry (VBM) has already been applied to MRI scans of patients with Alzheimers disease (AD). The results of these studies demonstrated atrophy of the hippocampus, temporal pole, and insula, but did not describe any global brain changes or atrophy of deep cerebral structures. We propose an optimized VBM method, which accounts for these shortcomings. Additional processing steps are incorporated in the method, to ensure that the whole spectrum of brain atrophy is visualized. A local group template was created to avoid registration bias, morphological opening was performed to eliminate cerebrospinal fluid voxel misclassifications, and volume preserving modulation was used to correct for local volume changes. Group differences were assessed and thresholded at P < 0.05 (corrected). Our results confirm earlier findings, but additionally we demonstrate global cortical atrophy with sparing of the sensorimotor cortex, occipital poles, and cerebellum. Moreover, we show atrophy of the caudate head nuclei and medial thalami. Our findings are in full agreement with the established neuropathological descriptions, offering a comprehensive view of atrophy patterns in AD.

Precuneus atrophy in early-onset Alzheimer’s disease: a morphometric structural MRI study

IntroductionAlzheimer’s disease (AD) usually first presents in elderly patients, but may also develop at an earlier age. Patients with an early age at onset tend to present with complaints other than memory impairment, such as visuospatial problems or apraxia, which may reflect a different distribution of cortical involvement. In this study we set out to investigate whether age at onset in patients with AD determines the pattern of atrophy on cerebral MRI scans.MethodsWe examined 55 patients with AD over a wide age range and analyzed their 3-D T1-weighted structural MRI scans in standard space using voxel-based morphometry (VBM). Regression analysis was performed to estimate loss of grey matter as a function of age, corrected for mini-mental state examination (MMSE) scores and sex.ResultsThe VBM analyses identified multiple areas (including the temporal and parietal lobes), showing more atrophy with advancing age. By contrast, a younger age at onset was found to be associated with lower grey matter density in the precuneus. Regionalized volumetric analysis of this region confirmed the existence of disproportionate atrophy in the precuneus in patients with early-onset AD. Application of a multivariate model with precuneus grey matter density as input, showed that precuneal and hippocampal atrophy are independent from each other. Additionally, we found that a smaller precuneus is associated with impaired visuospatial functioning.ConclusionOur findings support the notion that age at onset modulates the distribution of cortical involvement, and that disproportionate precuneus atrophy is more prominent in patients with a younger age of onset.

Patterns of cerebral atrophy in dementia with Lewy bodies using voxel-based morphometry

Previous cross-sectional MRI studies based on region-of-interest analyses have shown that increased cerebral atrophy is a feature of both Dementia with Lewy bodies (DLB) and Alzheimers disease (AD). Relative preservation of the hippocampus and temporal lobe structures in DLB compared to AD has been reported in region-of-interest-based studies. Recently, image processing techniques such as voxel-based morphometry (VBM) have been developed to provide an unbiased, visually informative, and comprehensive means of studying patterns of cerebral atrophy. We report the first study to use the voxel-based approach to assess patterns of cerebral atrophy in DLB compared to control subjects and AD. Regional gray matter volume loss was observed bilaterally in the temporal and frontal lobes and insular cortex of patients with DLB compared to control subjects. Comparison of dementia groups showed preservation of the medial temporal lobe, hippocampus, and amygdala in DLB relative to AD. Significant gray matter loss was also observed in the thalamus of AD patients compared to DLB.

Amnestic Mild Cognitive Impairment : Structural MR Imaging Findings Predictive of Conversion to Alzheimer Disease

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is considered by many to be a prodromal phase of Alzheimer disease (AD). We used voxel-based morphometry (VBM) to find out whether structural differences on MR imaging could offer insight into the development of clinical AD in patients with amnestic MCI at 3-year follow-up. MATERIALS AND METHODS: Twenty-four amnestic patients with MCI were included. After 3 years, 46% had progressed to AD (n = 11; age, 72.7 ± 4.8 years; women/men, 8/3). For 13 patients (age, 72.4 ± 8.6 years; women/men, 10/3), the diagnosis remained MCI. Baseline MR imaging at 1.5T included a coronal heavily T1-weighted 3D gradient-echo sequence. Localized gray matter differences were assessed with VBM. RESULTS: The converters had less gray matter volume in medial (including the hippocampus) and lateral temporal lobe, parietal lobe, and lateral temporal lobe structures. After correction for age, sex, total gray matter volume, and neuropsychological evaluation, left-sided atrophy remained statistically significant. Specifically, converters had more left parietal atrophy (angular gyrus and inferior parietal lobule) and left lateral temporal lobe atrophy (superior and middle temporal gyrus) than stable patients with MCI. CONCLUSION: By studying 2 MCI populations, converters versus nonconverters, we found atrophy beyond the medial temporal lobe to be characteristic of patients with MCI who will progress to dementia. Atrophy of structures such as the left lateral temporal lobe and left parietal cortex may independently predict conversion.

Operational definitions for the NINDS-AIREN criteria for vascular dementia: an interobserver study.

Background and Purpose— Vascular dementia (VaD) is thought to be the most common cause of dementia after Alzheimer’s disease. The commonly used International Workshop of the National Institute of Neurological Disorders and Stroke (NINDS) and the Association Internationale pour la Recherche et l’Enseignement en Neurosciences (AIREN) criteria for VaD necessitate evidence of vascular disease on CT or MRI of the brain. The purposes of our study were to operationalize the radiological part of the NINDS-AIREN criteria and to assess the effect of this operationalization on interobserver agreement. Methods— Six experienced and 4 inexperienced observers rated a set of 40 MRI studies of patients with clinically suspected VaD twice using the NINDS-AIREN set of radiological criteria. After the first reading session, operational definitions were conceived, which were subsequently used in the second reading session. Interobserver reproducibility was measured by Cohen’s &kgr;. Results— Overall agreement at the first reading session was poor (&kgr;=0.29) and improved slightly after application of the additional definitions (&kgr;=0.38). Raters in the experienced group improved their agreement from almost moderate (&kgr;=0.39) to good (0.62). The inexperienced group started out with poor agreement (&kgr;=0.17) and did not improve (&kgr;=0.18). The experienced group improved in both the large- and small-vessel categories, whereas the inexperienced group improved generally in the extensive white matter hyperintensities categories. Conclusions— Considerable interobserver variability exists for the assessment of the radiological part of the NINDS-AIREN criteria. Use of operational definitions improves agreement but only for already experienced observers.

Whole-brain atrophy rate and cognitive decline: Longitudinal MR study of memory clinic patients

PURPOSE To prospectively determine whole-brain atrophy rate in mild cognitive impairment (MCI) and Alzheimer disease (AD) and its association with cognitive decline, and investigate the risk of progression to dementia in initially nondemented patients given baseline brain volume and whole-brain atrophy rate. MATERIALS AND METHODS This study was IRB approved; written informed consent was obtained; and included 65 AD patients (38 women, 27 men; age, 52-81 years), 45 MCI patients (22 women, 23 men; age, 56-80 years), 27 patients with subjective complaints (12 women, 15 men; age, 50-87 years), and 10 healthy controls (six women, four men; age, 53-80 years). Two magnetic resonance (MR) images were acquired at average interval of 1.8 years +/- 0.7 (standard deviation). Baseline brain volume and whole-brain atrophy rates were measured on three-dimensional T1-weighted MR images (1.0 T; single slab, 168 sections; matrix size, 256 x 256; field of view, 250 mm; voxel size, 1 x 1 x 1.5 mm; repetition time msec/echo time msec/inversion time msec, 15/7/300; and flip angle, 15 degrees ). Associations were assessed by using partial-correlations. Cox proportional hazards models were used to estimate risk of developing dementia. RESULTS Baseline brain volume was lowest in AD but did not differ significantly between MCI, subjective complaints, and control groups (P > .38). Whole-brain atrophy rates were higher in AD (-1.9% per year +/- 0.9) than MCI (-1.2% per year +/- 0.9, P = .003) patients, who had higher whole-brain atrophy rates than patients with subjective complaints (-0.7% per year +/- 0.7, P = .03) and controls (-0.5% per year +/- 0.5, P = .05). Whole-brain atrophy rate correlated with annualized Mini-Mental State Examination (MMSE) change (r = 0.48, P < .001), while baseline volume did not (r = 0.11, P = .22). Cox models showed that-after correction for age, sex, and baseline MMSE-a higher whole-brain atrophy rate was associated with an increased risk of progression to dementia (highest vs lowest tertile [hazard ratio, 3.6; 95% confidence interval: 1.2, 11.4]). CONCLUSION Whole-brain atrophy rate was strongly associated with cognitive decline. In nondemented participants, a high whole-brain atrophy rate was associated with an increased risk of progression to dementia.

Feature extraction and strategy of analyzing structural neuroimaging in dementia.

Publisher Summary This chapter describes the first steps of structural neuroimaging with computed tomography (CT) in the 1980s, the introduction of magnetic resonance imaging (MRI) in the 1990s and the current status of computational neuroanatomy. It reviews that the first images produced were two dimensional and of relatively poor quality compared to present-day images. The indication for imaging was initially to exclude treatable causes of dementia. However, it became evident that structural changes in the brain were present in patients with dementia, especially dilatation of the ventricular system. Later the focus shifted towards quantified hippocampal atrophy on MRI, and eventually the hippocampus was signaled as an early marker for Alzheimers disease (AD). In visual rating, for example in a busy clinical setting, the rater compares a single scan to his own reference database and consensus criteria and decides whether the scan is abnormal. Finally, the chapter concludes that the methods of analyzing the brain in dementia are becoming more detailed in scale and in terms of dimensions. The past 25 years have seen a revolution in imaging technology and with it a revolution of in vivo analysis of neuropathological changes.

P1-302: Accelerating regional atrophy rates in the progression from normal aging to Alzheimer's disease

Background: To assess regional lobar atrophy rates, as well as investigate the risk of progression to dementia in initially non-demented elderly, based on these regional atrophy rates. Methods: We included 64 patients with Alzheimer’s (AD), 44 patients with Mild Cognitive Impairment (MCI), and 34 controls, with repeated MR imaging including volumetric imaging (interval 1.8 0.7y). Fluid, a non-linear matching algorithm, was applied to measure longitudinal regional atrophy rates in 6 regions: frontal, medial temporal, remaining part temporal, parietal, occipital, and insular lobe. Results: ANOVA for repeated measures with region as within subjects factor, diagnosis as between subjects factor, and age and sex as covariates, showed significant main effects of diagnosis (p 0.001), and region (p 0.001; figure), and an interaction between diagnosis and region (p 0.001). For MCI patients, the highest atrophy rates were observed in the medial temporal lobe, where atrophy rates were comparable to those of AD patients. With progression of the disease, atrophy spread throughout the brain, as AD patients showed even higher atrophy rates in the remaining part of the temporal lobe. Atrophy rates in the frontal, parietal and occipital lobes were additionally increased in comparison to patients with MCI. Subsequently Cox proportional hazard models, adjusted for age and sex, showed that all regional atrophy rates predicted conversion to AD. Hazard ratio’s varied between 2.6 (95% confidence interval, CI (1.1 6.2)) for occipital lobe, and 15.8 (95% CI (3.5 71.8)) for the medial temporal lobe. When evaluated simultaneously in a stepwise model, medial temporal lobe atrophy rate was the only predictor. Conclusions: These data illustrate how atrophy spreads through the brain with the progression of AD. In MCI, the temporal lobe shows the greatest atrophy rate. In AD patients, the medial temporal lobe shows an atrophy rate comparable to MCI, while the remaining part of the temporal lobe demonstrates an even higher rate of atrophy. Moreover, atrophy also accelerates in parietal, frontal, insular and occipital lobes. Finally, in non-demented elderly medial temporal lobe atrophy was most predictive of progression to AD, demonstrating the importance of this region in the early detection of AD. P1-303 PHASE I STUDY OF THE F-LABELLED BENZOTHIAZOLE DERIVATIVE [F]AH110690 AS A BIOMARKER OF ALZHEIMER’S DISEASE– RELATED BRAIN AMYLOIDOSIS