Piero Calvini

Hippocampal perfusion in mild Alzheimer's disease

Perfusion and metabolic studies in patients with Alzheimers disease (AD) have so far yielded conflicting results on the functional status of the hippocampal region, whose deep location in the brain makes it critical to optimize the image-reconstruction technique employed in emission tomography. We used a brain-dedicated device (CERASPECT) to perform single photon emission computed tomography (SPECT) studies with 99mTc-hexamethylpropylene-amine-oxime in 22 consecutive patients (mean age: 74+/-6.5 years) with mild [mini-mental status examination (MMSE) score > or =15, mean 20.8+/-3.2], probable AD. The control subjects were 11 healthy elderly people (mean age: 70.5+/-6.5 years). In patients, the total score on the selective reminding test (SRT) was used as an index of memory function. Counts from a hippocampal and a temporoparietal region of interest in each hemisphere were referred to the average thalamic counts. To optimize SPECT images, we used conventional filtered back-projection (FBP) reconstruction and a new iterative method of conjugate gradients (CG), which takes into account the geometrical and physical characteristics of the gamma-camera. Hippocampal perfusion in the two hemispheres was significantly lower in patients than in control subjects, regardless of which reconstruction method was used, and correlated with the MMSE score. The correlation between hippocampal perfusion and the SRT score was significantly (bootstrap procedure) higher with the CG method than with the FBP method (CG: r=0.52 and 0.54; FBP: r=0.39 and 0.47, for the right and left hemisphere, respectively). These results show hippocampal hypoperfusion in patients with mild AD, a correlation between hippocampal perfusion and the severity of cognitive impairment, and enhanced identification of these subtle perfusional changes with the use of an alternative image-reconstruction method that improves the spatial resolution of SPECT images.

Brain SPECT in subtypes of mild cognitive impairment Findings from the DESCRIPA multicenter study

The Development of Screening Guidelines and Clinical Criteria of Predementia Alzheimer’s Disease (DESCRIPA) multicenter study enrolled patients with MCI or subjective cognitive complaints (SUBJ), a part of whom underwent optional brain perfusion SPECT. These patients were classified as SUBJ (n = 23), nonamnestic MCI (naMCI; n = 17) and amnestic MCI (aMCI; n = 40) based on neuropsychology. Twenty healthy subjects formed the control (CTR) group. Volumetric regions of interest (VROI) analysis was performed in six associative cortical areas in each hemisphere. ANOVA for repeated measures, corrected for age and center, showed significant differences between groups (p = 0.01) and VROI (p < 0.0001) with a significant group-region interaction (p = 0.029). In the post hoc comparison, SUBJ did not differ from CTR. aMCI disclosed reduced uptake in the left hippocampus and bilateral temporal cortex (compared with CTR) or in the left hippocampus and bilateral parietal cortex (compared with SUBJ). In the naMCI group, reduced VROI values were found in the bilateral temporal cortex and right frontal cortex. In the comparison between aMCI and naMCI, the former had lower values in the left parietal cortex and precuneus. Discriminant analysis between SUBJ/CTR versus all MCI patients allowed correct allocations in 73 % of cases. Mean VROI values were highly correlated (p < 0.0001) with the learning measure of a verbal memory test, especially in the bilateral precunei and parietal cortex and in the left hippocampus. In a subset of 70 patients, mean VROI values showed a significant correlation (p < 0.05) with the white matter hyperintensities score on MRI. In conclusion, MCI subtypes have different perfusion patterns. The aMCI group exhibited a pattern that is typical of early Alzheimer’s disease, while the naMCI group showed a more anterior pattern of hypoperfusion. Instead, a homogeneous group effect was lacking in SUBJ.

Automatic Lung Segmentation in CT Images with Accurate Handling of the Hilar Region

A fully automated and three-dimensional (3D) segmentation method for the identification of the pulmonary parenchyma in thorax X-ray computed tomography (CT) datasets is proposed. It is meant to be used as pre-processing step in the computer-assisted detection (CAD) system for malignant lung nodule detection that is being developed by the Medical Applications in a Grid Infrastructure Connection (MAGIC-5) Project. In this new approach the segmentation of the external airways (trachea and bronchi), is obtained by 3D region growing with wavefront simulation and suitable stop conditions, thus allowing an accurate handling of the hilar region, notoriously difficult to be segmented. Particular attention was also devoted to checking and solving the problem of the apparent ‘fusion’ between the lungs, caused by partial-volume effects, while 3D morphology operations ensure the accurate inclusion of all the nodules (internal, pleural, and vascular) in the segmented volume. The new algorithm was initially developed and tested on a dataset of 130 CT scans from the Italung-CT trial, and was then applied to the ANODE09-competition images (55 scans) and to the LIDC database (84 scans), giving very satisfactory results. In particular, the lung contour was adequately located in 96% of the CT scans, with incorrect segmentation of the external airways in the remaining cases. Segmentation metrics were calculated that quantitatively express the consistency between automatic and manual segmentations: the mean overlap degree of the segmentation masks is 0.96 ± 0.02, and the mean and the maximum distance between the mask borders (averaged on the whole dataset) are 0.74 ± 0.05 and 4.5 ± 1.5, respectively, which confirms that the automatic segmentations quite correctly reproduce the borders traced by the radiologist. Moreover, no tissue containing internal and pleural nodules was removed in the segmentation process, so that this method proved to be fit for the use in the framework of a CAD system. Finally, in the comparison with a two-dimensional segmentation procedure, inter-slice smoothness was calculated, showing that the masks created by the 3D algorithm are significantly smoother than those calculated by the 2D-only procedure.

Resting SPECT-neuropsychology correlation in very mild Alzheimer's disease

OBJECTIVE To investigate the relationships between brain function and some of the most frequently impaired cognitive domains in the first stages of Alzheimers disease (AD), we searched for correlation between the scores on 3 neuropsychological tests and brain perfusion, assessed by single photon emission computed tomography (SPECT) in patients with very mild AD. METHODS Twenty-nine consecutive outpatients (mean age 78.2+/-5.5) affected by probable AD in the very mild phase (i.e. with a score > or =20 on the mini-mental state examination, MMSE) underwent brain SPECT with (99m)Tc-ethylcisteinate dimer. For correlative purposes, word list learning (by the selective reminding test, SRT), constructional praxis test (CPT) and visual search test (VST) were chosen a priori out of an extended battery employed to diagnose AD at first patient evaluation. Voxel-based correlation analysis was achieved by statistical parametric mapping (SPM99) with a height threshold of P=0.005. Age, years of education and the MMSE score were inserted in the correlative analysis as confounding variables. RESULTS The SRT score showed correlation with brain perfusion in 3 clusters of the left hemisphere, including the post-central gyrus, the parietal precuneus, the inferior parietal lobule and the middle temporal gyrus, and in one cluster in the right hemisphere including the middle temporal gyrus and the middle occipital gyrus. The CPT score was significantly correlated with brain perfusion in the parietal precuneus and the posterior cingulate gyrus in the left hemisphere, whereas the VST score gave a significant correlation with brain perfusion in a left cluster including the parietal precuneus and the superior temporal gyrus. CONCLUSIONS Cognitive impairment in very mild AD is reflected by brain dysfunction in posterior associative areas, with peculiar topographical differences proper of each domain. The parietal precuneus was a common site of correlation of all 3 neuropsychological tests. This region, together with the posterior cingulate and the superficial posterior temporal-parietal cortex, is thought to be affected by disconnection from the mesial temporal lobe, besides being directly affected by increased oxidative stress and by atrophy as well. The impairment of these areas is thought to contribute to cognitive decline in verbal memory, constructional praxis and visual sustained attention which are indeed among the earliest signs of cognitive impairment in AD. SIGNIFICANCE Assessing the relationships between neuropsychology and brain functional imaging is a key approach to clarify the pathophysiology of cognitive failure in AD; the specificity of these findings in AD remains to be proven through comparison with correlation achieved in matched controls.

Quantitative EEG and perfusional single photon emission computed tomography correlation during long-term donepezil therapy in Alzheimer's disease

OBJECTIVE There is an increasing interest in the effects of the acetylcholinesterase inhibitors (AChEIs) in Alzheimers disease (AD), as investigated by means of objective, neurophysiological tools. In an open-label study, we evaluated the neurophysiological effects of chronic administration of donepezil to AD patients, by means of a correlative approach between quantitative EEG (qEEG) and perfusional brain single photon emission computed tomography (SPECT). METHODS Sixteen patients (mean age: 74.8+/-7.9 years) with mild to moderate AD (MMSE score >13, mean: 20.7+/-4.6) underwent qEEG and SPECT examinations at the time of diagnosis (t0) and after approximately 1 year of donepezil therapy (t1). The brain SPECT (99mTc-hexamethylpropyleneamine oxime) was performed by means of a high-resolution SPECT camera; the qEEG was recorded from 19 scalp electrodes by average reference and digitized at 512 Hz. The mean frequency (MF) value of the mean power spectrum (fast Fourier transform) from 4 brain regions (one frontal and one temporal-parietal in each hemisphere) was chosen for statistical analysis. Changes in MMSE score and qEEG-MF values between t0 and t1 were assessed by analysis of variance. SPECT differences between t0 and t1, as well as the relationships between SPECT and qEEG changes, were assessed by statistical parametric mapping (SPM 99; height threshold: P=0.001 at cluster level). RESULTS Between t0 and t1, the MMSE score significantly (P<0.05) decreased (from 20.7+/-4.64 to 19.1+/-5.09; 95% confidence interval: 1.14) and qEEG was unchanged. There was no regional perfusion decrease; a small area of relative perfusion increase was observed, including the right occipital cuneus and the left lingual gyrus. A positive correlation was found between the right frontal MF and brain perfusion in the left superior parietal lobule. A post hoc SPM analysis (height threshold: P=0.01) showed a positive correlation between brain perfusion and each of the 4 qEEG MF values in the left parietal lobe, including the precuneus, the superior parietal lobule, and the post-central gyrus. CONCLUSIONS The posterior parietal region, which is involved in memory and attention, is often affected by hypoperfusion in AD, as a likely consequence of disconnection from the atrophic mesial temporal cortex. Metabolic activation induced by AChEIs may especially influence this disconnected but still not grossly impaired area, which could be one of the pathophysiological substrates of the cognitive effects of AChEIs. The modest topographical sensitivity of qEEG, reflecting the rather diffuse changes in AD, is further confirmed.

Fusion of the MR image to SPECT with possible correction for partial volume effects

Low spatial resolution and the related partial volume effects limit the diagnostic potential of brain single photon emission computed tomography (SPECT) imaging. As a possible remedy for this problem we propose a technique for the fusion of SPECT and MR images, which requires for a given patient the SPECT data and the T1-weighted MR image. Basically, after the reconstruction and coregistration steps, the high-frequency part of the MR, which would be unrecoverable by the set SPECT acquisition system + reconstruction algorithm, is extracted and added to the SPECT image. The tuning of the weight of the MR on the resulting fused image can be performed very quickly, any iterative reconstruction algorithm can be used and, in the case that the SPECT projections are not available, the proposed technique can also be applied directly to the SPECT image, provided that the performance of the scanner is known. The procedure has the potential of increasing the diagnostic value of a SPECT image. Even in the locations of SPECT-MR mismatch it does not significantly affect quantitation over regions of interest (ROIs) whose dimensions are decidedly larger than the SPECT resolution distance. On the other hand, appreciable corrections for partial volume effects are expected in the locations where the contrast in the structural MR matches the corresponding contrast in functional activity.

Clinical correlative evaluation of an iterative method for reconstruction of brain SPECT images

BACKGROUND Brain SPECT and PET investigations have showed discrepancies in Alzheimers disease (AD) when considering data deriving from deeply located structures, such as the mesial temporal lobe. These discrepancies could be due to a variety of factors, including substantial differences in gamma-cameras and underlying technology. Mesial temporal structures are deeply located within the brain and the commonly used Filtered Back-Projection (FBP) technique does not fully take into account either the physical parameters of gamma-cameras or geometry of collimators. In order to overcome these limitations, alternative reconstruction methods have been proposed, such as the iterative method of the Conjugate Gradients with modified matrix (CG). However, the clinical applications of these methods have so far been only anecdotal. The present study was planned to compare perfusional SPECT data as derived from the conventional FBP method and from the iterative CG method, which takes into account the geometrical and physical characteristics of the gamma-camera, by a correlative approach with neuropsychology. METHODS Correlations were compared between perfusion of the hippocampal region, as achieved by both the FBP and the CG reconstruction methods, and a short-memory test (Selective Reminding Test, SRT), specifically addressing one of its function. A brain-dedicated camera (CERASPECT) was used for SPECT studies with 99mTc-hexamethylpropylene-amine-oxime in 23 consecutive patients (mean age: 74.2 +/- 6.5) with mild (Mini-Mental Status Examination score > or =15, mean 20.3 +/- 3), probable AD. Counts from a hippocampal region in each hemisphere were referred to the average thalamic counts. RESULTS Hippocampal perfusion significantly correlated with the MMSE score with similar statistical significance (p < 0.01) between the two reconstruction methods. Correlation between hippocampal perfusion and the SRT score was better with the CG method (r = 0.50 for both hemispheres, p < 0.01) than with the FBP method (r = 0.37 and 0.43, respectively for the right and left hemisphere, p < 0.05 and p < 0.02). The bootstrap procedure showed that such correlation indexes were statistically different both in the right (p < 0.01) and in the left (p < 0.05) hemisphere. CONCLUSION These results are interpreted as a better performance of the CG reconstruction method in correctly detecting counts from hippocampal ROI. By using the same gamma-camera or collimator, alternative methods for brain SPECT reconstruction may improve quality of data and then help SPECT diagnostic accuracy.

Global cognitive impairment should be taken into account in SPECT-neuropsychology correlations: the example of verbal memory in very mild Alzheimer's disease

PurposeTo examine the impact of severity of global cognitive impairment on SPECT–neuropsychology correlations, we correlated a verbal memory test with brain perfusion in patients with very mild Alzheimer’s disease (AD), taking into account the Mini-Mental State Examination (MMSE) score as an index of global cognitive impairment.MethodsTwenty-nine outpatients (mean age 78.2±5.5 years) affected by very mild, probable AD underwent brain SPECT with 99mTc-ethylcysteinate dimer and a word list learning test. SPM99 was used for voxel-based correlation analysis after normalisation to mean cerebellar counts (height threshold: p<0.01). In a first analysis, only age and years of education were inserted as nuisance covariates, while in a second analysis the MMSE score was inserted as well.ResultsIn the first analysis, two clusters of significant correlation were found in both hemispheres, mainly including regions of the right hemisphere, such as the inferior parietal lobule, the middle temporal gyrus and the posterior cingulate. Significant correlation in the left hemisphere was observed in the lingual lobule, the parietal precuneus and the posterior cingulate. After taking into consideration the MMSE, the largest cluster of correlation was found in the left hemisphere, including the parietal gyrus angularis, the posterior cingulate and the middle temporal gyrus.ConclusionThe wide differences observed between the correlations achieved with and without taking into account the MMSE score indicate that severity of global cognitive impairment should be considered when searching for brain perfusion–neuropsychology correlations. In the present case, this strategy resulted in correlations that more closely matched neuropsychological models of verbal memory deficit.

Right hemispheric dysfunction in a case of pure progressive aphemia: fusion of multimodal neuroimaging

This article describes the unusual case of a 60-year-old woman suffering from pure progressive aphemia. The fusion of multimodal neuroimaging (MRI, perfusion SPECT) implicated the right frontal lobe, especially the inferior frontal gyrus. This area also showed the greatest functional MRI activation during the performance of a covert phonemic fluency task. Results are discussed in terms of bihemispheric language representation. The fusion of three sets of neuroimages has aided in the interpretation of the patients cognitive brain dysfunction.

Automatic localization of the hippocampal region in MR images to asses early diagnosis of Alzheimer’s disease in MCI patients

Atrophy and other brain changes, which are typical of aging, generate wide inter-individual variability of morphology in the medial temporal lobe (MTL), including the hippocampal formation. Starting from a sample population of 133 MR images we developed a procedure that extracts from each MR two sub images, containing the hippocampal formations plus a portion of the adjacent tissues and cavities. Then, a small number of templates is selected among the previously obtained sub images, able to describe the morphological variability present in the whole population. Finally an automatic procedure is prepared which, on the basis of the given set of templates, is able to find both hippocampal formations in any new MR image. MR images ranging from normalcy to extreme atrophy can be successfully processed. The proposed approach, besides being a preliminary step towards the unsupervised segmentation of the hippocampus, extracts from the MR image information useful for diagnostic purposes and, in particular, could give the possibility of performing morphometric studies on the medial temporal lobe in an automated way. The automated analysis of MTL atrophy in the segmented volume is readily applied to the early assessment of Alzheimer Disease (AD), leading to discriminating converters from Mild Cognitive Impairment (MCI) to AD with an average three years follow-up. This procedure can quickly and reliably provide additional information in early diagnosis of AD.