Medial Temporal Lobe MRIBased Volume Measurements at Mayo

In order to more thoroughly assess the possible utility of MR-based volume measurements of anteromedial temporal lobe neuroanatomic structures in the diagnosis of AD we undertook a study which employed a large number of control and AD patients, state-of-the-art image acquisition and image-processing techniques, and well-accepted neuroanatomic boundary criteria for the various medial temporal lobe structures that were measured (58). MR-based volume measurements of the hippocampus, parahippocampal gyrus

(PHG), and amygdala were performed in 126 cognitively normal elderly controls and 94 patients with probable AD. These three medial temporal lobe neu-roanatomic structures were selected because these areas are involved early in the course of the disease, and are depicted with a high level of anatomic clarity with an appropriately performed MRI study. The clinical characteristics of the 220 study subjects are found in Table 2. The control and AD groups were well matched with respect to gender distribution and education, and fairly well matched with respect to age. AD patients as expected scored substantially lower on cognitive measures. Disease severity in AD patients was assessed by the Clinical Dementia Rating (CDR) scale: very mild, CDR 0.5; mild, CDR 1; moderate, CDR 2 (59). An important distinction is made between establishing a diagnosis of AD and ranking its severity. The former was done according to NINCDS-ADRDA criteria, which emphasize a decline in cognitive performance over time as an important benchmark in establishing a diagnosis of AD. The CDR score was used as a staging instrument to rank disease severity at a specific point in time. It was therefore possible for patients to meet NINCDS-ADRA criteria for AD and also be ranked as only very mildly demented (CDR 0.5).

As mentioned previously, cerebral atrophy is a negative phenomenon that must be assessed by comparing the volumes of the medial temporal lobe structures of interest in affected individuals with a normal reference population. The first aim of this study was therefore to characterize volumetric changes in the hippocampus, amygdala, and PHG in normal aging in both men and women. These volumes were then characterized in patients with AD, and we then assessed the ability of these measures to discriminate between AD and normal aging.

Controls

In the group of 126 cognitively normal controls, the volume of each structure declined with increasing age and did so in parallel for men and women. The mean nonnormalized volumetric decline in cubic millimeters per year of age was 45.63 for hippocampus; 46.65 for the PHG; 20.75 for amygdala. The data in Table 3 indicate that in normal elderly individuals both age and gender affect the volume of the hippocampus, amygdala, and PHG. A third important variable that independently affects the volume of these medial temporal lobe structures is head size. Larger people have larger cranial volumes, and in turn have larger brain volumes including the three medial temporal lobe structures of interest in this study. A method for controlling or normalizing the individual medial temporal lobe structure volumes for interindividual variation in head size was therefore necessary, and this was ac-

Table 2

Characterization of Subjects

Table 2

Characterization of Subjects

Controls, CDR= 0

CDR

= 0.5

CDR

=1

CDR

=2

(N = 126)

(N =

36)

(N =

43)

(N =

15)

Variable

Mean ± SD

Mean

± SD

Mean

± SD

Mean

± SD

Age

79.15 ± 6.73

72.92

t 8.43

73.47 ±

9.68

75.87 ±

8.71

Education

13.43 ± 2.96

13.33

2.91

12.98 ±

2.69

12.38 ±

2.47

MMSE*

28.60 ± 1.26

21.60

4.36

18.16 ±

4.47

13.93 ±

5.99

DRS*j

135.14 ± 6.95

112.79

13.72

101.33 ±

20.75

89.62 ±

25.58

CDR, Clinical Dementia Rating; MMSE, Mini-Mental State Examination; DRS, Dementia Rating Scale.

*One case in each CDR group with missing values.

fOne control, three cases in CDR = 0.5, four cases in CDR = 1, two cases in CDR = 2 with missing values.

CDR, Clinical Dementia Rating; MMSE, Mini-Mental State Examination; DRS, Dementia Rating Scale.

*One case in each CDR group with missing values.

fOne control, three cases in CDR = 0.5, four cases in CDR = 1, two cases in CDR = 2 with missing values.

complished by dividing the medial temporal lobe structure volume by the measured total intracranial volume of each individual subject (60,61). Mean total intracranial volume in controls was 1393 cm3(+/-SD 133 mm3).

Patients With AD

A decline in normalized medial temporal lobe volumes with age was observed among patients with AD, which paralleled the decline seen among control subjects (Table 3 and Fig. 3). Individual volume measurements in control subjects and in patients were affected by the subjects' age and gender in addition total intracranial volume (Table 3). In order to isolate the relationship between disease status (control vs AD) and structure volume, normalized volumetric percentiles in controls specific for age and gender were calculated for each of the three medial temporal lobe structures of interest (62). Age and gender-specific normalized volumetric percentiles among AD patients were then determined and converted to W scores using the inverse of the standard normal distribution (a percentile value of .95 corresponding to a W score of 1.645, for example). Thus, a W of zero indicates that volume is equal to that expected for a normal subject after adjustment for age and gender. A value of —1.96 corresponds to a value which is at the 2.5 percentile of normals. W scores were significantly lower than zero among AD patients (p < 0.001) (Table 4). The differences among hippocampus, PHG, and amygdala were significant (p < 0.001 ANOVA), and all pairwise comparisons (paired t tests) were also significant (hippocampus vs amygdala, p < 0.001;

Table 3.

Relationship Between Normalized Volume, Age, and Gender in Control Subjects and AD patients

Table 3.

Relationship Between Normalized Volume, Age, and Gender in Control Subjects and AD patients

Controls

AD Patients

Normalized Structure

Intercept

Age

Gender (M = 0, F = 1)

Intercept

Age (M

Gender = 0, F = 1)

Volume

B0

B1

B2

B0

B1

B2

Uo N

Hippocampus Amygdala Parahippocampal gyrus

6.359 2.414

-0.0371***

-0.025***

0.250*

Values are derived from the following regression equation:

Values are derived from the following regression equation:

where V = normalized MTL structure volume in mm3/ccm3 B0 = intercept

B1 = the calculated regression coefficient associated with age B2 = the calculated regression coefficient associated with gender

Fig. 3. Normalized hippocampal volume by age in control subjects and patients with AD. Regression of the mean-normalized hippocampal volume by age in male (A) and female (B) control subjects and patients with AD. The upper and lower limits, dashed lines, represent the 75th and 25th percentile values for each group. Hippocampal volumes of AD patients are smaller than those of age-matched controls. Volumes in both groups decline linearly and in parallel with advancing age. For clinical purposes the position of a memory impaired elderly subject may be plotted and compared to age- and gender-matched controls and AD patients.

Fig. 3. Normalized hippocampal volume by age in control subjects and patients with AD. Regression of the mean-normalized hippocampal volume by age in male (A) and female (B) control subjects and patients with AD. The upper and lower limits, dashed lines, represent the 75th and 25th percentile values for each group. Hippocampal volumes of AD patients are smaller than those of age-matched controls. Volumes in both groups decline linearly and in parallel with advancing age. For clinical purposes the position of a memory impaired elderly subject may be plotted and compared to age- and gender-matched controls and AD patients.

Table 4

W Scores* in Patients With Alzheimer's Disease

Variable Mean W Value SD Mean W Value SD Mean W Value SD

Total hippocampus -1.752 0.939 -1.989 1.193 -2.225 1.183

10 Parahippocampal gyrus -0.874 1.035 -0.996 1.101 -0.512 1.344

The W score is the normal deviate relative to controls, adjusted for age and gender. All mean W scores were significantly different from 0 (the expected value for normal subjects), p < 0.001.

hippocampus vs PHG, p < 0.001, amygdala vs PHG, p = 0.006) (Table 4). The mean TIV of AD patients, 1369 cm3 (± SD 138 cm3), was not significantly different from that of controls.

Discrimination Between Control Subjects and AD Patients of Varying Severity

Using stepwise linear discriminant analysis (including age, gender, and TIV-normalized volumes as independent variables) to predict AD, the only variables that appeared in the final model were hippocampal volume, hippocampal volume squared, and age. Although all these terms were significant at the 0.02 level, the predication equation was dominated by the hippocampal volume term, and the accuracy of the prediction was identical to that obtained using hippocampal W scores alone. The sensitivity of hippocampal volumes to distinguish AD patients from control subjects was assessed by computing the percentage of AD patients with W scores at selected percentiles among control subjects (Table 5). For example, at a fixed specificity of 80%, the sensitivity of hippocampal volumetric measurements in discriminating control subjects from patients was 77.8% for CDR 0.5, 83.7% for CDR 1, and 86.7% for CDR 2. Discrimination between control subjects and AD patients was roughly equivalent among the three AD severity groups at the 50th and 20th percentiles of normal. Discrimination was greater for CDRs 1 and 2 than CDR 0.5 patients at the 10th and 5th percentile of normal. At the first percentile of normal, discrimination improved as the patient's disease severity (CDR score) increased. Hippocampal W values progressively decline (increasing atrophy) with increasing CDR score in Table 4, which suggests that hippocampal volumetric measurements are a sensitive marker of the degenerative neuroanatomic substrate of the progressively more severe memory impairment seen with advancing CDR scores in AD. The most encouraging finding in this study was the ability of hippocampal volumetric measurements to discriminate between control subjects and AD patients with very mild disease. The mean hippocampal volume in very mild (CDR 0.5) AD patients was 1.75 SD below the control mean, and 97.2% of all CDR 0.5 AD patients had hippocampal volumes below the 50th percentile of normal. These data, derived from a large number of subjects, demonstrate that MRI volumetric measurements of hippocampal atrophy are a sensitive marker of the pathology of AD in its most mild form.

The sensitivity and specificity of hippocampal volume measurements in discriminating between controls and AD patients this study is lower than was described in several of the initial studies assessing the efficacy of volume measurements of medial temporal lobe structures in making the diagnosis of AD (48-57). Because of the large number of study subjects involved, the sensitivity

Table 5

Diagnostic Discrimination of Normalized Total Hippocampal Volume Adjusted for Age and Gender*

Indicated Percentile of Normal

Table 5

Diagnostic Discrimination of Normalized Total Hippocampal Volume Adjusted for Age and Gender*

AD Patients

50%

20%

10%

5%

1%

CDR 0.5 (N = 36)

97.2

77.8

72.2

58.3

36.1

CDR 1 (N = 43)

90.7

83.7

81.4

67.4

53.5

CDR 2 (N = 15)

93.3

86.7

80.0

66.7

66.7

Overall (N = 94)

93.6

81.9

77.7

63.8

48.9

♦Percentage of Alzheimer's disease (AD) patients below indicated percentile of normal. CDR = Clinical Dementia Rating.

♦Percentage of Alzheimer's disease (AD) patients below indicated percentile of normal. CDR = Clinical Dementia Rating.

and specificity reported here are probably more representative of that which can be expected in a more generalized clinical setting. We believe that this type of MR-based hippocampal volume measurement has sufficient sensitivity and specificity to be a useful clinical adjunct, although it is not 100% accurate and therefore will not be an absolute diagnostic test. A comparison of the normalized hippocampal volume measurements of an individual patient with age and gender specific normal percentiles as illustrated in Table 6 would provide a clinically useful assessment of the presence and severity of hippocampal atrophy. Despite the overlap in hippocampal volume measurements between probable AD patients and elderly controls, a volume assessment of hippocampal atrophy should still be clinically useful in assessing the possibility of AD in individual subjects. For example, given an elderly patient complaining of a memory impairment, if hip-pocampal volume measurements in that patient fell into the AD range, then a clinical diagnosis of probable AD might be more strongly entertained, whereas if the hippocampal volume measurements fell into the control range, a diagnosis of AD might be considered less likely. There has been growing interest in measuring volumetric changes in individuals wth "mild cognitive impairment" (MCI). Early reports suggest that elders with MCI exhibit diminished hip-pocampal or medial temporal volumes compared to cognitively healthy normal controls (62a,62b). Elders with MCI may account for some of the observed overlap between nondemented elders and patients with a diagnosis of AD.

The sensitivity and specificity of MRI measures of medial temporal lobe atrophy as a marker of AD generally have been assessed by comparing volume measurements in patients with a clinical diagnosis of probable AD to a matched control population. While estimates of the statistical sensitivity and specificity of the discriminatory power of these measurements may be assessed in this fashion, the "clinical" specificity of MRI measures of medial

Table 6

Age and Gender-Specific Normal Percentiles for Normalized Hippocampal Volume

Normal Percentiles

Table 6

Age and Gender-Specific Normal Percentiles for Normalized Hippocampal Volume

Normal Percentiles

Age

Gender

1

5

10

25

50

50

M

3.7364

3.9526

4.0593

4.2426

4.4906

F

3.9998

4.2159

4.3226

4.5059

4.7539

60

M

3.3790

3.5952

3.7019

3.8851

4.1332

F

3.6424

3.8585

3.9652

4.1485

4.3965

70

M

3.0216

3.2378

3.3445

3.5277

3.7757

F

3.2850

3.5011

3.6078

3.7911

4.0391

80

M

2.6642

2.8804

2.9871

3.1703

3.4183

F

2.9275

3.1437

3.2504

3.4337

3.6817

89

M

2.3426

2.5587

2.6654

2.8487

3.0967

F

2.6059

2.8220

2.9287

3.1120

3.3600

Values in the body of the table represent age and gender-specific mean-normalized hippocampal volume in controls. The units are mm3/cm3 X 103. The 1st, 5th, 10th, 25th, and 50th percentile values in controls are reported. The presence of hippocampal atrophy in an individual patient can be assessed by comparing the normalized hippocampal volumes of that patient against those of age- and gender-matched controls reported in this table.

Values in the body of the table represent age and gender-specific mean-normalized hippocampal volume in controls. The units are mm3/cm3 X 103. The 1st, 5th, 10th, 25th, and 50th percentile values in controls are reported. The presence of hippocampal atrophy in an individual patient can be assessed by comparing the normalized hippocampal volumes of that patient against those of age- and gender-matched controls reported in this table.

temporal lobe atrophy as a marker of AD can only be assessed by comparing these volume measurements among different patient groups; for example, AD vs frontal dementia, or AD vs normal pressure hydrocephalus. Few studies of this type have been done. Hippocampal volume measurements have been shown to discriminate AD patients from patients with dementia due to normal pressure hydrocephalus (63). The clinical specificity of medial temporal volume measurements in discriminating among different conditions that share medial temporal lobe atrophy as a common pathological feature is likely to be low. Medial temporal lobe volume measurements are specific for neuro-anatomic degeneration of this region of the brain, but are not disease specific.

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