Measures of Cerebral Atrophy

Both computed tomography (CT) and magnetic resonance imaging (MRI) have been employed extensively as cross-sectional imaging modalities in the study of AD. Both of these modalities contain two primary types of information—voxel intensity information and information about gross neuroanatomic structure. Pathological changes in the voxel intensity of brain tissue are most commonly associated with the status of tissue hydration. Tissue damage (cerebral edema, demyelination, astrogliosis) will produce an increase in unbound or free tissue water, which in turn manifests itself as increased signal on T2-weighted MR images, decreased signal on Tl-weighted MR images, or decreased intensity on CT images. The association between pathological alterations in tissue intensity and forms of brain injury such as infarction, trauma, and demyelination are well established. Although a number of investigators have attempted to link such signal intensity changes to the primary neurodegenerative pathology found in AD, a consensus has not been reached as to the validity of such a link (20-23). On the other hand, the second basic type of information contained in both MR and CT images—depiction of gross neuroanatomy—has been convincingly linked with the primary neurodegen-erative pathology of AD in a consistent and universally recognized fashion. Although deposition of amyloid plaques and neurofibrillary tangles in excess of that expected for age are the pathological hallmarks of AD, cerebral atrophy is a widely recognized concomitant of the primary pathology of AD. The ability of cross-sectional imaging techniques (MR and CT) to accurately depict neuroanatomic structure, and thus accurately identify the cerebral atrophy associated with the disease process in AD, has been confirmed in numerous studies (20).

Because the cerebral atrophy that occurs as part of the primary pathology of AD is a negative phenomenon, it must be characterized as a loss of tissue relative to "normal" elderly individuals. A number of different techniques have been employed to accomplish this. Approaches to the characterization of global or hemispheric cerebral atrophy can be divided into those which employ categorization of MR or CT scans by means of visual ranking, and those which employ a continuous quantitative measure of a particular anatomic feature such as sulcal or ventricular size. In its most rigorous implementation the former approach is accomplished by collecting a battery of example cases, which are representative of the various levels of atrophy (sulcal/ventricular enlargement) into which the study scans will be grouped (24,25). For example, each study scan may be assigned to one of four levels of atrophy: none, mild, moderate, or severe. A finer gradation scale with a greater number of categories to which individual study scans are assigned may also be employed. For this type of visual ranking approach, a panel of expert raters is employed to rank the individual study scans. Quality control is assessed by monitoring measures of inter- and intrarater consistency in ranking scans.

The second general approach to evaluating the cerebral atrophy which occurs in AD is quantitative. The rationale for quantitation is that disease related cerebral atrophy exists along a continuum from mild to moderate to severe (Fig. 1). Because cerebral atrophy exists in nature as a continuous variable, it is logical that a continuous radiological descriptor (quantitative measurement) is better suited to characterize this phenomenon than a categorical radiological descriptor (visual ranking into mild, moderate, or severe categories). In addition, cerebral atrophy has also been identified as a feature of "normal" aging. Although this is not universally accepted, a number of studies have clearly established that age-related cerebral atrophy often occurs in nondemented elderly individuals (26-29). The topic of "normal" aging often involves semantic issues (30). One can consider normal as "typical" aging whereby patients may have comorbidities that are felt to be commonly encountered in aging but not felt to affect cognition. This is in contrast to what some refer to as "supernormal" or optimal aging with virtually no co-morbidities. The latter individuals are, however, uncommon. A problem that has plagued attempts at using imaging measures of cerebral atrophy as a marker of AD is distinguishing "pathological" atrophy of AD from the atrophy associated with "normal" aging. The pathological cerebral atrophy associated with the disease process of AD itself is modeled as an additional atrophic burden which is superimposed on the cerebral atrophy that occurs as a feature of "normal" aging. Quantitative approaches lend themselves to separating the effects of normal from pathologic aging because quantitative age-specific levels of cerebral atrophy in "typical aging" can be established for comparison with patients. Several quantitative measures have been employed as markers of the hemispheric atrophy which occur in AD. These can be categorized as linear, area, or volume measurements. These quantitative measures of hemispheric cerebral atrophy were initially employed with CT scanning and later adapted to MR. Because the cerebral hemispheres are morphologically complicated three-dimensional structures, one might assume a priori that greater sensitivity and specificity would be found with volumetric as opposed to more simple linear measurements. In general such a hierarchy has been found with volume measurements outperforming area measurements, which in turn outperform linear measurements (20). Examples of linear measurements made from CT are the width of the frontal horns, width of the third ventricle, and widths of various cortical sulci.

Fig. 1. Cognitive and morphologic continuum. Like cognition in the elderly, cerebral morphology exists in nature as a continuum, without discrete categorization into mild, moderate, or severe atrophy. Furthermore, both normal aging and AD are associated with cerebral atrophy in a continuous, not a discrete, manner.

Fig. 1. Cognitive and morphologic continuum. Like cognition in the elderly, cerebral morphology exists in nature as a continuum, without discrete categorization into mild, moderate, or severe atrophy. Furthermore, both normal aging and AD are associated with cerebral atrophy in a continuous, not a discrete, manner.

Examples of area measurements made from single CT slices are measures of the area of the lateral ventricles, frontal horn, third ventricle, and interhemi-spheric fissures. Volume measurements of ventricular size and subarachnoid space size have been made as well (20). More recently MR has been employed as the imaging modality of choice from which measures of brain volume, ventricular volume, total CSF volume, and hemispheric gray and white matter volume are made (31,32).

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