R.A. van Schijndel

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.

Measuring progression of cerebral white matter lesions on MRI: Visual rating and volumetrics

Objective: To evaluate the concordance of a volumetric method for measuring white matter lesion (WML) change with visual rating scales. Methods: The authors selected a stratified sample of 20 elderly people (mean age 72 years, range 61 to 88 years) with an MRI examination at baseline and at 3-year follow-up from the community-based Rotterdam Scan Study (RSS). Four raters assessed WML change with four different visual rating scales: the Fazekas scale, the Scheltens scale, the RSS scale, and a new visual rating scale that was designed to measure change in WML. The authors assessed concordance with a volumetric method with scatter plots and correlations, and interobserver agreement with intraclass correlation coefficients. Results: For assessment of change in WML, the Fazekas, Scheltens, and periventricular part of the RSS scale showed little correlation with volumetrics, and low interobserver agreement. The authors’ new WML change scale and the subcortical part of the RSS scale showed good correlation with volumetrics. After additional training, the new WML change scale showed good interobserver agreement for measuring WML change. Conclusions: Commonly used visual rating scales are not well suited for measuring change in white matter lesion severity. The authors’ new white matter lesion change scale is more accurate and precise, and may be of use in studies focusing on progression of white matter lesions.

Recommendations to improve imaging and analysis of brain lesion load and atrophy in longitudinal studies of multiple sclerosis

Focal lesions and brain atrophy are the most extensively studied aspects of multiple sclerosis (MS), but the image acquisition and analysis techniques used can be further improved, especially those for studying within-patient changes of lesion load and atrophy longitudinally. Improved accuracy and sensitivity will reduce the numbers of patients required to detect a given treatment effect in a trial, and ultimately, will allow reliable characterization of individual patients for personalized treatment. Based on open issues in the field of MS research, and the current state of the art in magnetic resonance image analysis methods for assessing brain lesion load and atrophy, this paper makes recommendations to improve these measures for longitudinal studies of MS. Briefly, they are (1) images should be acquired using 3D pulse sequences, with near-isotropic spatial resolution and multiple image contrasts to allow more comprehensive analyses of lesion load and atrophy, across timepoints. Image artifacts need special attention given their effects on image analysis results. (2) Automated image segmentation methods integrating the assessment of lesion load and atrophy are desirable. (3) A standard dataset with benchmark results should be set up to facilitate development, calibration, and objective evaluation of image analysis methods for MS.

Corpus callosum size correlates with asymmetric performance on a dichotic listening task in healthy aging but not in Alzheimer's disease

Alzheimers disease (AD) involves not only gray matter but also white matter pathology, as reflected by atrophy of the corpus callosum (CC). Since decreased CC size may indicate reduced functional interhemispheric connectivity, differences in callosal size may have cognitive consequences that may become specifically apparent in neuropsychological tasks that tap hemispheric laterality. In the present study, we examined callosal functioning with a dichotic listening task in 25 Alzheimer patients, 20 healthy elderly and 20 healthy elderly with subjective memory complaints. We found decreased performance, increased ear asymmetry, and decreased callosal size in the AD group compared to healthy elderly. As expected, in the healthy elderly, we found significant negative correlations between ear asymmetry and callosal size, specifically in the anterior and posterior callosal subareas. While the association with the posterior subareas (isthmus and splenium) points at involvement of temporal areas mediating language processing, the association with the anterior subarea (the rostrum and genu) points at involvement of frontal areas mediating attention and executive functions. Remarkably however, in contrast to the healthy elderly, callosal size was not related to ear asymmetry in the AD group. The absence of an association between callosal atrophy and ear asymmetry implies that other pathological processes, next to reduced callosal functioning, attribute to ear asymmetry in AD. Difficulties to attend specifically to the left ear during dichotic listening in some of the AD patients, points at decreased attention and executive functions and suggests that pathology of specifically the frontal areas is involved.

Improved reliability of hippocampal atrophy rate measurement in mild cognitive impairment using fluid registration.

MRI-derived rates of hippocampal atrophy may serve as surrogate markers of disease progression in mild cognitive impairment (MCI). Manual delineation is the gold standard in hippocampal volumetry; however, this technique is time-consuming and subject to errors. We aimed to compare regional non-linear (fluid) registration measurement of hippocampal atrophy rates against manual delineation in MCI. Hippocampi of 18 subjects were manually outlined twice on MRI scan-pairs (interval+/-SD: 2.01+/-0.11 years), and volumes were subtracted to calculate change over time. Following global affine and local rigid registration, regional fluid registration was performed from which atrophy rates were derived from the Jacobian determinants over the hippocampal region. Atrophy rates as derived by fluid registration were computed using both forward (repeat onto baseline) and backward (baseline onto repeat) registration. Reliability for both methods and agreement between methods was assessed. Mean+/-SD hippocampal atrophy rates (%/year) derived by manual delineation were: left: 2.13+/-1.62; right: 2.36+/-1.78 and for regional fluid registration: forward: left: 2.39+/-1.68; right: 2.49+/-1.52 and backward: left: 2.21+/-1.51; right: 2.42+/-1.49. Mean hippocampal atrophy rates did not differ between both methods. Reliability for manual hippocampal volume measurements (cross-sectional) was high (intraclass correlation coefficient (ICC): baseline and follow-up, left and right, >0.99). However, the resulting ICC for manual measurements of hippocampal volume change (longitudinal) was considerably lower (left: 0.798; right: 0.850) compared with regional fluid registration (forward: left: 0.985; right: 0.988 and backward: left: 0.975; right: 0.989). We conclude that regional fluid registration is more reliable than manual delineation in assessing hippocampal atrophy rates, without sacrificing sensitivity to change. This method may be useful to quantify hippocampal volume change, given the reduction in operator time and improved precision.

Location of brain lesions predicts conversion of clinically isolated syndromes to multiple sclerosis

Objectives: To assess in a large population of patients with clinically isolated syndrome (CIS) the relevance of brain lesion location and frequency in predicting 1-year conversion to multiple sclerosis (MS). Methods: In this multicenter, retrospective study, clinical and MRI data at onset and clinical follow-up at 1 year were collected for 1,165 patients with CIS. On T2-weighted MRI, we generated lesion probability maps of white matter (WM) lesion location and frequency. Voxelwise analyses were performed with a nonparametric permutation-based approach (p < 0.05, cluster-corrected). Results: In CIS patients with hemispheric, multifocal, and brainstem/cerebellar onset, lesion probability map clusters were seen in clinically eloquent brain regions. Significant lesion clusters were not found in CIS patients with optic nerve and spinal cord onset. At 1 year, clinically definite MS developed in 26% of patients. The converting group, despite a greater baseline lesion load compared with the nonconverting group (7 ± 8.1 cm3 vs 4.6 ± 6.7 cm3, p < 0.001), showed less widespread lesion distribution (18% vs 25% of brain voxels occupied by lesions). High lesion frequency was found in the converting group in projection, association, and commissural WM tracts, with larger clusters being in the corpus callosum, corona radiata, and cingulum. Conclusions: Higher frequency of lesion occurrence in clinically eloquent WM tracts can characterize CIS subjects with different types of onset. The involvement of specific WM tracts, in particular those traversed by fibers involved in motor function and near the corpus callosum, seems to be associated with a higher risk of clinical conversion to MS in the short term.

Long-Interval T2-Weighted Subtraction Magnetic Resonance Imaging A Powerful New Outcome Measure in Multiple Sclerosis Trials

To compare long‐interval T2‐weighted subtraction (T2w‐Sub) imaging with monthly gadolinium‐enhanced T1‐weighted (Gd‐T1w) imaging for (1) detection of active lesions, (2) assessment of treatment efficacy, and (3) statistical power, in a multiple sclerosis (MS), phase 2, clinical trial setting.

Long-term effects of amyloid, hypometabolism, and atrophy on neuropsychological functions.

Objective: To assess how amyloid deposition, glucose hypometabolism, and cerebral atrophy affect neuropsychological performance in patients with Alzheimer disease (AD) dementia, patients with mild cognitive impairment (MCI), and controls over time. Methods: A total of 41 patients with AD dementia, 28 patients with MCI, and 19 controls underwent [11C]–Pittsburgh compound B (11C-PiB) and [18F]-2-fluoro-2-deoxy-d-glucose (18F-FDG)–PET and MRI scans at baseline. We extracted global binding potential for 11C-PiB, the number of abnormal voxels for 18F-FDG, and gray matter volumes using SIENAX for MRI as measures of amyloid, hypometabolism, and atrophy. In addition, repeat neuropsychological testing was performed, including memory, attention, language, and executive tasks (mean follow-up 2.2 ± 0.7 years). Cross-sectional and longitudinal relationships between imaging markers and cognition were assessed using linear mixed models, including terms for the imaging markers, time, sex, age, diagnosis, and interactions for imaging marker × time and imaging marker × time × diagnosis. Results: Linear mixed models showed that baseline hypometabolism and atrophy were associated with poorer baseline performance on attention and executive functions (p < 0.05), whereas amyloid was not related to baseline cognition. Hypometabolism and amyloid were strongly associated with longitudinal decline in essentially all cognitive domains (pinteraction < 0.05), whereas atrophy was related specifically to future decline in Mini-Mental State Examination and memory (pinteraction < 0.05). Conclusion: Glucose hypometabolism and brain atrophy were associated with concurrent cognitive function, whereas brain amyloid was not. Amyloid deposition and glucose hypometabolism were predictors for decline of a wide variety of cognitive functions, while brain atrophy specifically predicted memory deterioration.

Positional changes of the masseter and medial pterygoid muscles after surgical mandibular advancement procedures: an MRI study.

This study evaluated whether surgical mandibular advancement procedures induced a change in the direction and the moment arms of the masseter (MAS) and medial pterygoid (MPM) muscles. Sixteen adults participated in this study. The sample was divided in two groups: Group I (n=8) with a mandibular plane angle (mpa) <39° and Group II (n=8) with an mpa >39°. Group I patients were treated with a bilateral sagittal split osteotomy (BSSO). Those in Group II were treated with a BSSO combined with a Le Fort I osteotomy. Pre- and postoperative direction and moment arms of MAS and MPM were compared in these groups. Postsurgically, MAS and MPM in Group II showed a significantly more vertical direction in the sagittal plane. Changes of direction in the frontal plane and changes of moment arms were insignificant in both groups. This study demonstrated that bimaxillary surgery in patients with an mpa >39° leads to a significant change of direction of MAS and MPM in the sagittal plane.