Medial Temporal Lobe Atrophy

Although almost every study in which imaging measures of global or hemispheric atrophy have been employed has identified a statistically significant difference between the mean value found in AD patients and that found in control subjects, invariably substantial overlap exists between individual members of these two populations which in turn limits the clinical utility of this approach for diagnosis in individual patients (20). It is highly likely that this overlap between controls and AD patients is due in part to the manner in which normal aging is defined when selecting subjects to serve as controls. Most studies have employed as controls individuals who would fall into the category of typical aging. The result is that most elderly control populations in imaging studies include subjects with conditions that predispose toward cerebral atrophy such as hypertension, and some may be in the preclinical stages of dementia. Much better separation between AD patient and controls would be expected if the control group was restricted to "supernormal" or "healthy-aging" individuals.

In an attempt to increase the sensitivity of image derived neuroanatomic measures of cerebral atrophy as a diagnostic marker of AD, a number of investigators in recent years have focused on detecting regional brain atrophy in the medial temporal lobe regions. The rationale for this focus on the medial temporal lobe in AD is the following:

1. A decline in declarative memory is a hallmark of AD.

2. The neuroanatomic substrate for declarative memory is the limbic medial tempo ral lobe, particularly the hippocampus and anatomically related areas such as the entorhinal cortex (33). 3. Cell loss and atrophy are consistent features of AD and the limbic anteromedial temporal lobe, particularly the entorhinal cortex and the hippocampus, is involved earliest and most severely by the neurofibrillary pathology of AD (34-38)(Fig 2).

Several investigators have employed qualitative ranking (39-41) or linear measurements (43,44) of anteromedial temporal lobe atrophy on CT scans to effectively separate AD patients from elderly controls. More recently a great deal of interest has arisen in employing MR-based measures of anteromedial temporal lobe atrophy in the diagnosis of AD. The rationale for employing MR (as opposed to CT) to evaluate neuroanatomic changes in this region of the brain is: superior soft tissue contrast with MR; MR does not suffer from beam hardening artifacts in this region of the brain as does CT; and the mul-tiplanar capability of MR which permits the optimal anatomic display of this region of the brain in the coronal plane.

As with quantitative measures of hemispheric atrophy, investigators have employed linear, area, and volume measures of anteromedial temporal lobe atrophy. An example of quantitative MR-based linear measurements of medial temporal lobe atrophy is the interuncal distance (45,46). Seab and colleagues (47) described area measures of several neuroanatomic structures from a single MR slice, the most effective measurement at separating controls from AD patients was the area of the hippocampus. Finally, in the past several years a number of investigators have reported MR-based measurements of the volume of various anteromedial temporal lobe structures to assess the atrophy associated with AD (48-57). A variety of structures have been measured. The most common has been the hippocampus, but other neuroanatomic structures which have been employed include the parahippocampal gyrus, temporal horn, amygdala, parahippocampal CSF spaces, and the anterior temporal lobe (48-57) (Table 1). A number of these initial studies describing MR-based volume measurements of the medial temporal lobe have reported extremely high sensitivity in separating patients with AD from elderly control individuals. Based on these initial studies, MR-based volume measurements of medial temporal lobe structures have been proposed as a clinically useful test for the diagnosis of AD. However, the published literature does not unequivocally validate the utility of MR-based volume measurements of the medial temporal lobe in AD because:

1. The method of image acquisition varied among some of the reported studies, and the earliest studies were performed during a period of rapid technical evolution of MRI with methods that are no longer state-of-the-art.

Fig. 2. Selective anteromedial temporal lobe atrophy in AD. (A) Axial T1-weighted MR images of two subjects—a 70-year-old woman with probable AD in the column on the right and a 70-year-old cognitively normal woman in the column on the left. From top to bottom the axial images progress from superior to inferior. Note the minimal difference in the appearance of the brain (i.e., presence of cerebral atrophy) between the two subjects in the two more cephalic axial sections through the cerebral hemispheres, and the markedly more striking atrophy particularly of the hippocampus in the patient with AD compared to the control (arrows) in the two basal sections through the temporal lobes.

Fig. 2. Selective anteromedial temporal lobe atrophy in AD. (A) Axial T1-weighted MR images of two subjects—a 70-year-old woman with probable AD in the column on the right and a 70-year-old cognitively normal woman in the column on the left. From top to bottom the axial images progress from superior to inferior. Note the minimal difference in the appearance of the brain (i.e., presence of cerebral atrophy) between the two subjects in the two more cephalic axial sections through the cerebral hemispheres, and the markedly more striking atrophy particularly of the hippocampus in the patient with AD compared to the control (arrows) in the two basal sections through the temporal lobes.

Fig. 2. (cont.) (B) Coronal T1-weighted MR images of the same two patients in Figure 2A. Note the pronounced atrophy of the hippocampus (arrows) in the patient with AD on the right compared to the age-and gender-matched control.

Table 1

Volume Measurements of Medial Temporal Lobe Atrophy in AD

Table 1

Volume Measurements of Medial Temporal Lobe Atrophy in AD

Structure

N

Sens/Spec (Acc)*

Ref.

Hipp/PHG

15

49

Hippocampus

44

(85%)

50

Hipp, T Horn

15

100%/100%

56

Amygdala/PHG

31

100%/100%

54

Hipp/CSF

(80%)

55

Amygdala

17

57

Hipp, amygdala

26

100%/100%

51

Hipp, amygdala

48

(92%)j

52

RT L, T Horn

60

100%/100%

53

Hipp, amygdala, whole brain,

30

(85%)j

48

fontal lobes, temporal lobes

Hipp, amygdala, PHG

220

82%/80%|

58

The neuroanatomic structures measured in each study are indicated: Hipp, hippocampus; PHG, parahippocampal gyrus; T horn, temporal horn; ATL, anterior temporal lobe; CSF, cerebrospinal fluid; N, the total number of subjects in each study.

*The sensitivity and specificity or accuracy (in parentheses) when cited, in discriminating AD patients from controls on the basis of the volume measurements in first column. (Pearlson and colleagues employed SPECT scans in addition to MRI-based volume measurements.)

fAccuracy figure refers to measurements of the right amygdala-hippocampal complex. ¿Sensitivity and specificity figures refer to hippocampal volume measurements.

The neuroanatomic structures measured in each study are indicated: Hipp, hippocampus; PHG, parahippocampal gyrus; T horn, temporal horn; ATL, anterior temporal lobe; CSF, cerebrospinal fluid; N, the total number of subjects in each study.

*The sensitivity and specificity or accuracy (in parentheses) when cited, in discriminating AD patients from controls on the basis of the volume measurements in first column. (Pearlson and colleagues employed SPECT scans in addition to MRI-based volume measurements.)

fAccuracy figure refers to measurements of the right amygdala-hippocampal complex. ¿Sensitivity and specificity figures refer to hippocampal volume measurements.

2. Anatomic boundary criteria for the various medial temporal lobe structures varied significantly among the different studies.

3. Different structures or combinations of medial temporal lobe structures were evaluated in the studies.

4. Most importantly, the studies published before 1997 contain relatively small numbers of subjects. In many cases the control and patient subjects were highly selected, which makes extrapolation of the results to the diagnosis of AD in a general setting problematic.

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