William R. Crum

Patterns of temporal lobe atrophy in semantic dementia and Alzheimer's disease.

Volumetric magnetic resonance imaging analyses of 30 subjects were undertaken to quantify the global and temporal lobe atrophy in semantic dementia and Alzheimers disease. Three groups of 10 subjects were studied: semantic dementia patients, Alzheimers disease patients, and control subjects. The temporal lobe structures measured were the amygdala, hippocampus, entorhinal cortex, parahippocampal gyrus, fusiform gyrus, and superior, middle, and inferior temporal gyri. Semantic dementia and Alzheimers disease groups did not differ significantly on global atrophy measures. In semantic dementia, there was asymmetrical temporal lobe atrophy, with greater left‐sided damage. There was an anteroposterior gradient in the distribution of temporal lobe atrophy, with more marked atrophy anteriorly. All left anterior temporal lobe structures were affected in semantic dementia, with the entorhinal cortex, amygdala, middle and inferior temporal gyri, and fusiform gyrus the most severely damaged. Asymmetrical, predominantly anterior hippocampal atrophy was also present. In Alzheimers disease, there was symmetrical atrophy of the entorhinal cortex, hippocampus, and amygdala, with no evidence of an anteroposterior gradient in the distribution of temporal lobe or hippocampal atrophy. These data demonstrate that there is a marked difference in the distribution of temporal lobe atrophy in semantic dementia and Alzheimers disease. In addition, the pattern of atrophy in semantic dementia suggests that semantic memory is subserved by anterior temporal lobe structures, within which the middle and inferior temporal gyri may play a key role. Ann Neurol 2001;49:433–442

Imaging of onset and progression of Alzheimer's disease with voxel-compression mapping of serial magnetic resonance images

BACKGROUND Early diagnosis and monitoring of the progression of Alzheimers disease is important for the development of therapeutic strategies. To detect the earliest structural brain changes, individuals need to be studied before symptom onset. We used an imaging technique known as voxel-compression mapping to localise progressive atrophy in patients with preclinical Alzheimers disease. METHODS Four symptom-free individuals from families with early-onset Alzheimers disease with known autosomal dominant mutations underwent serial magnetic resonance imaging (MRI) over 5-8 years. All four became symptomatic during follow-up. 20 individuals with a clinical diagnosis of probable Alzheimers disease and 20 control participants also underwent serial MR imaging. A non-linear fluid matching algorithm was applied to register repeat scans onto baseline imaging. Jacobian determinants were used to create the voxel-compression maps. FINDINGS Progressive atrophy was revealed in presymptomatic individuals, with posterior cingulate and neocortical temporoparietal cortical losses, and medial temporal-lobe atrophy. In patients with known Alzheimers disease, atrophy was widespread apart from in the primary motor and sensory cortices and cerebellum, reflecting the clinical phenomenology. INTERPRETATION Voxel-compression maps confirmed early involvement of the medial temporal lobes, but also showed posterior cingulate and temporoparietal cortical losses at presymptomatic stage. This technique could be applied diagnostically and used to monitor the effects of therapeutic intervention.

Automatic differentiation of anatomical patterns in the human brain: Validation with studies of degenerative dementias

We compared voxel-based morphometry (VBM) with independent accurate region-of-interest (ROI) measurements of temporal lobe structures in order to validate the usefulness of this fully automated and unbiased technique in Alzheimers disease (AD) and semantic dementia (SD). In AD, ROI analyses appear more sensitive to volume loss in the amygdalae, whereas VBM analyses appear more sensitive to right middle temporal gyrus and regional hippocampal volume loss. In SD, ROI analyses appear more sensitive to left middle and inferior temporal gyrus volume loss, whereas VBM appears more sensitive to regional hippocampal volume loss. In addition the significance of volume reductions was generally less in VBM owing to more stringent corrections for multiple comparisons. In conclusion, the automated technique detects a general trend of atrophy similar to that of expertly labeled ROI measurements in AD and SD, although there are discrepancies in the ranking of severity and in the significance of volume reductions that are more marked in AD.

Correlation between rates of brain atrophy and cognitive decline in AD.

Article abstract Twenty-nine untreated patients diagnosed with probable AD and 15 control patients underwent two or more clinical and volumetric MRI assessments with intervals ranging from 5 months to 6 years. The change in global cerebral volume for an individual was calculated by a novel method of registration and subtraction of serial scans. Rate of global cerebral volume loss correlated strongly with rate of change in Mini-Mental State Examination scores (r = 0.80, p < 0.001), implying clinical relevance to this marker of progression.

Progressive cerebral atrophy in MS A serial study using registered, volumetric MRI

Objective: To assess the potential of registered volumetric MRI in measuring rates of atrophy in MS. Background: Pathologic and imaging studies suggest that the development of permanent neurologic impairment in MS is associated with progressive brain and spinal cord atrophy. Atrophy has been suggested as a potential marker of disease progression. Conventional atrophy measurements requiring manual outlining are time-consuming and subject to reproducibility problems. Registration of serial MRI may offer a useful alternative in that cerebral losses may be measured directly from automated subtraction of brain volumes. Methods: Twenty-six patients with MS and 26 age- and gender-matched controls had two volumetric brain MR studies 1 year apart. Baseline brain and ventricular volumes were measured using semiautomated techniques, and follow-up scans were registered to baseline. Rates of cerebral atrophy were calculated directly from the registered scans. Results: Baseline brain volumes in the MS group were smaller (mean difference 78 mL [95% CI 13 to 143; p = 0.02]) and ventricular volumes greater (mean difference 12 mL [95% CI 6 to 18; p < 0.001]) than controls. The rate of cerebral atrophy in the MS group (0.8% per year) was over twice that of controls (0.3%), and the rate of ventricular enlargement was five times greater than the controls (1.6 versus 0.3 mL/year). Conclusion: Progressive cerebral atrophy is an important feature of MS. Registration-based measurements are sensitive and reproducible, allowing progressive atrophy to be detected within 1 year and may have potential as a marker of progression in monitoring therapeutic trials.

Progressive brain atrophy on serial MRI in dementia with Lewy bodies, AD, and vascular dementia

The authors determined rates of brain atrophy, as assessed by the boundary shift integral on serial MRI, in patients with dementia with Lewy Bodies (DLB, n = 10), AD (n = 9), vascular dementia (VaD, n = 9), and age-matched controls (n = 20). Mean % ± SD atrophy rates per year were as follows: DLB, 1.4 ± 1.1; AD, 2.0 ± 0.9; VaD, 1.9 ± 1.1; and controls, 0.5 ± 0.7. Dementia subjects had higher rates than controls (p < 0.001), but there were no significant differences between the three dementia groups. The authors found accelerating atrophy with increasing severity of cognitive impairment, further emphasizing the need for early diagnosis and intervention in dementia.

Rates of global and regional cerebral atrophy in AD and frontotemporal dementia

Objective: Serial registered MRI provides a reproducible technique for detecting progressive cerebral atrophy in vivo and was used to determine if there were differences between the rates of cerebral atrophy in AD and frontotemporal dementia (FTD). Methods: Eighty-four patients with dementia (54 AD and 30 FTD) and 27 age-matched control subjects each had at least two volumetric MR scans. Serial scans were positionally matched (registered), and brain volume loss was determined by calculation of the brain boundary shift integral. Results: There was a difference between the rates of whole-brain atrophy in patients (mean annual volume loss 2.7% of total brain volume) and in control subjects (mean annual volume loss 0.5%). AD and FTD were associated with different rates of atrophy (mean annual losses 2.4 and 3.2%). The range of atrophy rates in the FTD group (0.3 to 8.0%) greatly exceeded that in the AD group (0.5 to 4.7%). Frontal-variant FTD was associated with a wider range of atrophy rates than temporal-variant FTD. Analysis of regional brain atrophy rates revealed that there was widespread symmetrically distributed cerebral volume loss in AD, whereas in frontal FTD there was greater atrophy anteriorly and in temporal FTD the atrophy rate was greatest in the left anterior cerebral cortex. Conclusions: Both AD and FTD patients had increased rates of brain atrophy. Whereas the patients with AD were associated with a relatively restricted spread of atrophy rates, the greater spread of rates observed in the patients with FTD may reflect the heterogeneity of disease in FTD, with differences observed between frontal and temporal FTD. Increased rates of whole-brain atrophy did not discriminate AD from FTD, but analysis of regional atrophy rates revealed marked differences between patient groups.

Detection of ventricular enlargement in patients at the earliest clinical stage of MS

Article abstract The aim of this study was to determine whether atrophy could be detected at the earliest clinical stages of MS. Patients were selected from a 1-year follow-up MRI study of clinically isolated syndromes. Nine patients who developed MS were compared with eight matched patients who had no further symptoms. Significant ventricular enlargement occurred in the group that developed MS but not in the other group. Our findings show that atrophy, albeit mild, can be detected early in the course of MS.

Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis

Background: In patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS), the extent of brain magnetic resonance imaging (MRI) lesion load influences the probability and time to development of clinically definite MS. Cerebral atrophy is recognised in established MS, but its time of onset and whether, in early disease, it is related to MRI lesion load or clinical outcome is less certain. Objectives: This study investigated ventricular enlargement over one year in CIS patients and explored its relation with lesion load and clinical outcome. Methods: A semi-automated thresholding technique for measuring ventricular volume (MIDAS) was applied to MRI scans in a cohort of 55 patients with CIS, recruited consecutively and imaged within three months of the onset of symptoms and again after one year. Results: Clinical MS had developed after one year in 16 of 40 patients with an abnormal baseline T2 scan and 2 of 15 with a normal scan. Significant ventricular enlargement was seen in 27 of 55 patients who fulfilled the new McDonald MRI criteria for MS using all available MRI at clinical follow up (median increase 0.3 cm3, p=0.005) Significant increase in ventricular volume was also seen in the 18 of 55 patients who developed clinical MS over the follow up period (median increase 0.5 cm3, p=0.006). There were significant but modest correlations between baseline lesion measures and subsequent ventricular enlargement. Conclusions: (1) Lesions and atrophy are both associated with early relapse leading to a diagnosis of clinical MS; (2) while lesions contribute to the development of atrophy, atrophy may also develop by other mechanisms. This suggests that MR measures have a complementary role in monitoring the course of MS, even from the earliest clinical stage.

Anisotropic multi-scale fluid registration: evaluation in magnetic resonance breast imaging

Registration using models of compressible viscous fluids has not found the general application of some other techniques (e.g., free-form-deformation (FFD)) despite its ability to model large diffeomorphic deformations. We report on a multi-resolution fluid registration algorithm which improves on previous work by (a) directly solving the Navier-Stokes equation at the resolution of the images, (b) accommodating image sampling anisotropy using semi-coarsening and implicit smoothing in a full multi-grid (FMG) solver and (c) exploiting the inherent multi-resolution nature of FMG to implement a multi-scale approach. Evaluation is on five magnetic resonance (MR) breast images subject to six biomechanical deformation fields over 11 multi-resolution schemes. Quantitative assessment is by tissue overlaps and target registration errors and by registering using the known correspondences rather than image features to validate the fluid model. Context is given by comparison with a validated FFD algorithm and by application to images of volunteers subjected to large applied deformation. The results show that fluid registration of 3D breast MR images to sub-voxel accuracy is possible in minutes on a 1.6 GHz Linux-based Athlon processor with coarse solutions obtainable in a few tens of seconds. Accuracy and computation time are comparable to FFD techniques validated for this application.