Subtle changes in several different indicators can be investigated through the use of advanced MR techniques.
Molecular and metabolic imaging with MR spectroscopy quantifies several biochemical markers. AD is associated with decreased metabolism of the brain. MR spectroscopy (Fig. 17.2) shows a reduction of W-acetyl-aspartate over time before volume reduction occurs [28-31], and an increase in myo-inositol [32, 33], suggesting these markers are predictors of cognitive impairment . However, MRS techniques are limited by poor spatial resolution, and precise quantification is cumbersome. In addition, unless absolute quantification is performed, no references exist and the voxel values are expressed through ratios within and between voxels.
Diffusion weighted imaging depicts random motion of water molecules, which varies according to the num ber of microscopic structures hindering this motion. Diffusion is restricted in cytotoxic oedema, in which water goes from interstitium to intracellular spaces, where diffusion is hindered, reducing the size of the in-terstitium. Diffusion is abnormal in AD due to neuronal loss [35, 36], although this finding has not always been confirmed . In addition to simple quantification of water motion, gradient-encoded sequences measure water diffusion in several directions. Using these spatially encoded diffusion weighted images, preferential diffusion direction (diffusion anisotropy) can be obtained. From these data, a diffusion tensor for each voxel can be generated. This technique is called diffusion tensor imaging and is the basis of fibre tracking techniques. Fibre tracking techniques reconstruct nervous pathways by connecting tensors, assuming that preferential direction of water diffusion is parallel to nervous bundles. In degenerative diseases, diffuse degeneration has at least two effects. The first is to reduce the size of the nerve bundles, which are then represented using a lower number of „virtual fibres". The second is that interstitial space size is slightly increased, thus reducing structure density, causing anisotropic diffusion. In AD diffusion anisotropy is reduced . The reduction of diffusion anisotropy reduces the capability of fibre tracking to identify pathways and to connect cerebral areas. In other words, connectivity measured through fibre tracking techniques may represent a surrogate indicator of brain connectivity . Theoretically, after functional impairment, microanatomical connectivity between cerebral regions is the next alteration before clear cerebral atrophy occurs.
Magnetic resonance perfusion is based on signal changes during the passage of contrast material or
spin-labelled protons through a slice with a T2* weighted scan. A significant blood flow reduction has been observed in AD patients in respect to healthy controls [40,41].
Several other MR techniques might be useful indicators of microstructural changes. Magnetization transfer is based on signal loss induced by macromolecules. MT ratios in the hippocampus and cortical grey matter are significantly lower in patients with AD than in those with non-AD dementia and in control subjects [35, 42-44].
Absolute T1 and T2 maps may be useful to increase reproducibility and to perform comparisons over time. In addition, relaxation values have been used for automatic segmentation of brain structures, which is particularly useful for quantifying atrophy
Estimation of brain atrophy and volume of entorhi-nal cortex, hippocampus and amygdala have been extensively investigated though a variety of techniques [45-50]. In fact, this is a post-analysis technique, requiring a suitable image data set. These data sets are represented by conventional morphological high resolution images. Three-dimensional gradient echo-based sequences are used. Image weightening varies according to the structure being studied. For instance, amygdala has been defined on high-resolution T1-, T2- or diffusion weighted images; these latter have been shown to be the most suitable ones for identifying the layers of this small inner structure . Manual segmentation is practical for assessing the volume of amygdala, which is reduced in AD. Semiautomatic and automatic segmentation procedures are under investigation in order to increase reproducibility [52, 53]. There is a very high correlation between hippocampal volumes measured through MR and neuronal numbers in histology, showing that accurate volumetric measurements of the whole hippocampal formation can be obtained by using MR . Voxel-based morphometry (VBM), based on T1 images (MPRAGE sequence), estimates, using a statistical approach, areas in which neuronal loss is prominent by comparing patients with a reference control group . In addition, patients can be monitored over time in order to assess atrophy progression rate [56-58]. Components of the brain (white matter, grey matter, cerebrospinal fluid and other tissues) are segmented automatically and relative volume loss is assessed for brain areas [59-61]. Corrections with intracranial total volume can be done in order to reduce interindividual variability, although intracrani-al volume is not associated with AD [62, 63]. Estimation of brain atrophy can help to predict conversion from MCI to AD [57, 64]. Comparison over time of atrophy after registration of serial MRI has been shown to be a potentially powerful method with which to monitor progression of AD in clinical trials [65, 66]. Cortical pattern matching (CPM) is a more accurate method, in which homologous areas of the brain are compared between two groups. CPM uses brain sulci as references for defining homologous areas of the brain, overcoming interindividual variability of brain anatomy .
Differences of extension and signal intensity of cortical activation in fMRI were observed between MCI, AD patients and control groups [68, 69], and between groups of patients with different phenotypes [8, 70]. Functional MRI might provide substantial information for assessing disease progression in groups and predicting neuromodulation and effects of drugs. However, group analysis results can hardly be transferred in single individuals for clinical routine. Hardware should be suitable for such investigations, operators should be experienced in fMRI, and image scanning and analysis are expensive for uncertain responses.
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