Alberto Beltramello

Detection of grey matter loss in mild Alzheimer's disease with voxel based morphometry

Objectives: To test the applicability of an automated method of magnetic resonance image analysis (voxel based morphometry) to detect presence and severity of regional grey matter density reduction—a proxy of atrophy—in Alzheimers disease. Methods: Twenty nine probable Alzheimers patients and 26 non-demented controls (mini-mental state examinations mean (SD) 21 (4) and 29 (1)) underwent high resolution 3D brain magnetic resonance imaging. Spatial normalisation to a stereotactic template, segmentation into grey matter, white matter, and cerebrospinal fluid, and smoothing of the grey matter were carried out based on statistical parametric mapping (SPM99) algorithms. Analyses were carried out: (a) contrasting all Alzheimers patients with all controls (p<0.05 corrected for multiple comparisons); (b) contrasting the three Alzheimers patients with mini-mental state of 26 and higher with all controls (p<0.0001 uncorrected); and (c) correlating grey matter density with mini-mental state score within the Alzheimers group (p<0.0001 uncorrected). Results: When all Alzheimers patients were compared with controls, the largest atrophic regions corresponded to the right and left hippocampal/amygdalar complex. All parts of the hippocampus (head, body, and tail) were affected. More localised atrophic regions were in the temporal and cingulate gyri, precuneus, insular cortex, caudate nucleus, and frontal cortex. When the mildest Alzheimers patients were contrasted with controls, the hippocampal/amygdalar complex were again found significantly atrophic bilaterally. The mini-mental state score correlated with grey matter density reduction in the temporal and posterior cingulate gyri, and precuneus, mainly to the right. Conclusions: Voxel based morphometry with statistical parametric mapping is sensitive to regional grey matter density reduction in mild Alzheimers disease.

Hippocampal and entorhinal cortex atrophy in frontotemporal dementia and Alzheimer’s disease

Objective: To describe atrophic changes of the hippocampus and entorhinal cortex in frontotemporal dementia (FTD) and compare them with those of AD. Background: The medial temporal lobe shows atrophic changes early in the course of AD, but whether these changes are specific to AD or occur in other degenerative dementias, and to what extent, is unclear. Methods: The authors measured the volumes of the left and right hippocampus and entorhinal cortex from MR images (1.5 T, 2-mm–thick slices) in 12 patients with FTD, 30 with AD, and 30 elderly control subjects. Results: In FTD patients, the left and right hippocampus (16% and 21% tissue loss) and the entorhinal cortex (28% and 27% loss) were more atrophic than the control subjects. Atrophy of the hippocampus in FTD was less severe than in AD, but atrophy of the entorhinal cortex was equally severe. Greater hippocampal and entorhinal cortex atrophy was present in the most severe patients in both groups (as high as a 49% tissue loss). The sensitivity of the hippocampus and the entorhinal cortex to discriminate FTD patients from control subjects was low (49% and 52%, respectively; specificity set at 90%), whereas hippocampal volumes could better differentiate AD patients from control subjects (80% sensitivity). Conclusions: At variance with AD, detectable in vivo atrophy of the hippocampus might not be an early event in FTD. Differential patterns of atrophy might help in the diagnostic process of the degenerative dementias.

Structural correlates of early and late onset Alzheimer’s disease: voxel based morphometric study

Objective: To examine the brain structural correlates of age at onset in patients with Alzheimer’s disease. Methods: We studied nine patients with early onset (age ⩽65 years), nine with late onset (age >65) Alzheimer’s disease (EOAD and LOAD, respectively) of mild-moderate severity, and 26 controls who were stratified into younger (YC, age ⩽65, n = 9) and older (OC, age >65, n = 17) subjects. The patients were closely matched for clinical severity: 3/2/3/1 patients had clinical dementia rating of 0.5/1/2/3, respectively, in both the groups. High resolution magnetic resonance images of the brain of the EOAD and YC groups and the LOAD and OC groups were compared on a voxel by voxel basis with statistical parametric mapping to detect areas specifically atrophic. Results: The patients with EOAD showed greater neocortical atrophy at the temporoparietal junction while the patients with LOAD showed greater hippocampal atrophy. The results could not be accounted for by the apolipoprotein E genotype. Conclusions: Since genetic factors are believed to play a relevant pathogenetic role in EOAD and environmental factors in LOAD, genetic and environmental factors may differentially predispose the neocortical and limbic areas to the development of Alzheimer’s neuropathology.

Hippocampus and entorhinal cortex in frontotemporal dementia and Alzheimer's disease: a morphometric MRI study.

BACKGROUND Magnetic resonance imaging (MRI) of hippocampal atrophy is a sensitive but not specific method to support the clinical diagnosis of early Alzheimers disease (AD). We recently described our findings that atrophy of the entorhinal cortex (ERC) in frontotemporal dementia (FTD) is equal to that found in AD but that hippocampal atrophy in FTD is less than that found in AD. The MRI volumes of these structures provide a topographic representation of the region of interest. We hypothesized that two different dementias with distinct histopathologic and clinical features might, in addition to quantitative patterns, display topographically different patterns of atrophy. METHODS We adopted a morphometric approach to monitor the pattern of atrophy of the hippocampus and the ERC by computing two-dimensional profiles from MRI volumes of the structures in control subjects and patients with FTD and AD. RESULTS Compared with control subjects, atrophy of the hippocampus in patients with AD was diffuse. In patients with FTD, atrophy of the hippocampus was localized predominantly in the anterior hippocampus, suggesting a different pattern of hippocampal atrophy in FTD compared with AD. The amount and pattern of atrophy of the entorhinal cortex was virtually equal in both demented groups. CONCLUSIONS This study provides novel data on the nature of medial temporal lobe atrophy in FTD. Morphometric MRI may be a useful technique for characterizing different patterns of atrophy in primary degenerative dementias in vivo.

A comparison between the accuracy of voxel-based morphometry and hippocampal volumetry in Alzheimer's disease

To compare the accuracy of voxel‐based morphometry (VBM) and region of interest (ROI)‐based hippocampal volumetry to detect medial temporal lobe atrophy in Alzheimers disease (AD).

APOE-ε4 is associated with less frontal and more medial temporal lobe atrophy in AD

Objective: To test the hypothesis that the ε4 allele of APOE is associated with a region-specific pattern of brain atrophy in AD. Methods: Volumes of the hippocampi, entorhinal cortices, and anterior temporal and frontal lobes were measured in 28 mild to moderate AD patients and 30 controls using MRI. Within the AD group, 14 patients were noncarriers (−/−), 9 were heterozygous (ε4/−), and 5 were homozygous (ε4/4) for the ε4 allele. Dementia severity was similar across the three AD groups. Results: Smaller volumes were found with increasing dose of the ε4 allele in the hippocampus, entorhinal cortex, and anterior temporal lobes in AD patients. When compared with controls, the volume loss in the right and left temporal regions ranged from −15.3 to −22.7% in the −/− AD group, from −26.2 to −36.0% in the ε4/− group, and from −24.0 to −48.0% in the ε4/4 group (p < 0.0005). In contrast, larger volumes were found in the frontal lobes with increasing ε4 gene dose. When compared with controls, volume differences of the right frontal lobe were −11.8% in the −/− AD group, −8.5 in the ε4/− group, and −1.4% in the ε4/4 group (p = 0.03). Conclusions: We found smaller volumes in the temporal lobe regions but larger volumes in the frontal lobes with increasing APOE-ε4 gene dose in AD patients. These data suggest a region-specific biological effect of the ε4 allele in the brains of AD patients.

Frontotemporal dementia as a neural system disease

Some brain structures atrophic in frontotemporal dementia (FTD) belong to the rostral limbic system (RLS), that regulates context-dependent behaviors after evaluation of the motivational content of stimuli. The clinical manifestations of FTD are consistent with its impairment. Aim of this study was to assess whole brain morphology in FTD using magnetic resonance imaging (MRI) and voxel-based morphometry with statistic parametric mapping (SPM99) to test the hypothesis that the RLS might be specifically targeted by FTD. Nine FTD patients and 26 healthy controls underwent high resolution 3D MRI. SPM99 performed (a) spatial normalization to a customized template, (b) segmentation, (c) smoothing, (d) voxel-by-voxel comparison of gray matter between cases and controls. P was set at 0.05 corrected for multiple comparisons. All but one regions of the RLS (the periaqueductal gray) were atrophic in FTD. At P<0.001 uncorrected also the periaqueductal gray was atrophic. Atrophy outside the RLS was confined to a few voxels in the frontal and temporal gyri. FTD might be a neural-system disease where the RLS is predominantly damaged.

Apolipoprotein E genotype and hippocampal asymmetry in Alzheimer's disease: a volumetric MRI study

Asymmetry of brain structures is common to many species and is even present in utero. Some developmental, pathological, and dementing diseases are associated with alterations in normal anatomical asymmetries. Anatomical asymmetries, however, have been only superficially studied in Alzheimers disease. Recent evidence indicates that the allele ε4 of the apolipoprotein E (ApoE), a well known risk factor for Alzheimers disease, might play a part in determining some brain morphological changes both in normal carriers and in patients with Alzheimers disease. This study evaluated the effect of the ApoE genotype on hippocampal asymmetry in patients with Alzheimers disease carrying 0, 1, and 2 copies of the allele. Volumetric right-left differences of the hippocampi were computed in 28 right handed patients with Alzheimers disease (14 -/-, 9 ε4/-, and 5 ε4/4) and 30 controls without detectable cognitive deficit. In controls, the right hippocampus was larger than the left, whereas in patients with Alzheimers disease this asymmetry was progressively reduced with increasing gene dose of the ε4 allele, and the asymmetry was reversed in the ε4/4 Alzheimers disease group. The mean right-left volume differences were: 1.2, 0.7, 0.2, and -1.0 in controls, -/-, ε4/-, and ε4/4 patients, respectively (sex adjusted p for trend=0.017). The data indicate a dose dependent effect of the ApoE ε4 allele on hippocampal volume asymmetry in Alzheimers disease.

Brain atrophy in frontotemporal dementia.

OBJECTIVES--To evaluate the pattern of regional brain atrophy in patients with frontotemporal dementia by comparing it with that in patients with Alzheimers disease and normal controls. METHODS--Fourteen patients with frontotemporal dementia, 13 with moderate, and 33 with mild Alzheimers disease, and 31 controls were studied. Atrophy was evaluated with linear measures in the anterior brain, medial temporal lobe, and hippocampal formation regions using MRI. RESULTS--Patients with frontotemporal dementia had greater atrophy in the anterior brain regions than patients with Alzheimers disease or controls. Atrophy of the hippocampal formation, which best discriminates Alzheimers disease from controls, was present also in patients with frontotemporal dementia. By contrast, atrophy of the medial temporal lobe, which is also present in Alzheimers disease, was absent in frontotemporal dementia. CONCLUSION--A pattern of atrophy in the frontal lobes and hippocampal formation with sparing of the medial temporal lobe might be distinctive of frontotemporal dementia. Hippocampal involvement might not be specific for Alzheimers disease and specific patterns of atrophy might be distinctive of some forms of degenerative dementia.

The MRI pattern of frontal and temporal brain atrophy in fronto-temporal dementia

OBJECTIVE To compare patterns of brain atrophy in fronto-temporal dementia (FTD) and Alzheimers disease (AD) since atrophy in individual areas may not be sufficiently specific as diagnostic marker. METHODS Frontal, temporal and hippocampal atrophy was measured from MRI of 10 FTD patients, 27 AD, and 27 controls. Corrected atrophy and asymmetry were computed (W-scores). RESULTS FTD had mild atrophy in the hippocampus (average W-score=-1.3), severe in the frontal (W-score=-2.4) and very severe in the temporal lobes (W-score=-2.9). AD had moderate atrophy in the hippocampus and temporal lobes (W-score=-1.8 and -1.9, respectively), and very mild frontal atrophy (W-score=-0.9). Atrophy was more asymmetrical in FTD (left more atrophic) than in AD patients, particularly in the temporal lobes. A discriminant function including the asymmetry values of frontal and temporal regions could separate FTD from AD with 90% sensitivity and 93% specificity. CONCLUSIONS FTD is characterized by a specific pattern of atrophy, more useful than atrophy of single regions in the differential diagnosis.