Two-hundred-twenty subjects are included in this report—126 controls and 94 AD patients (). The control and AD patients were well matched on education and gender distribution with approximately a 2:1 female to male ratio in both groups. The age range of controls was 51-89 years and AD patients 50-89 years. Forty-four of the 126 controls were men; 16 of the 36 CDR=0.5 AD patients were men; 10 of the 43 CDR=1 patients were men; 7 of the 15 CDR=2 patients were men. As expected, Dementia Rating Scale(39
) and Mini-Mental State Exam (40
) scores declined with increasing CDR grade in AD patients.
Characterization of Subjects
The results from this study are discussed in three parts: 1) descriptive statistics of the control subjects which characterize the relationship between normal aging, gender, and MTL volumes; 2) similar descriptive statistics of the AD patients which are compared to those in controls; 3) analysis of the ability of MTL volume measurements to discriminate between controls and AD subjects with varying disease severity.
Normalized MTL volumes declined with age in a linear fashion(, ). The segment of the hippocampus that demonstrated the greatest decline with age was the head. No significant hemispheric differences in volume loss with age were observed in any MTL structure, except the PHG where the age related volume loss was greater on the left than the right side (P = .024). The mean non-normalized volumetric decline with age was 45.63 mm3/year for the total hippocampus; 27.43 for the hippocampal head; 8.84 for the hippocampal body; 9.68 for the hippocampal tail; 46.65 for the PHG; and 20.75 for the amygdala. Mean total intracranial volume in controls was 1393cm3 (SD 133cm3).
Relationship between normalized volume, age, and gender in controls and AD patients.
Normalized Hippocampal Volume by Age in Control Subjects and AD Patients
The unnormalized MTL structure volumes of men were generally larger than those of women, while the normalized MTL volumes of women were generally larger than those of men (, ). That is, these MTL limbic structures occupied a larger percentage of TIV in women than men. The decline in volume associated with age did not differ significantly between men and women. These associations were used to estimate age and gender specific normal percentiles for TIV-normalized MTL volumes().
Age & Gender Specific Normal Percentiles for Hippocampal Volume Normalized by TIV
Alzheimer's Disease Patients
A decline in normalized MTL volumes with age was observed among AD patients. The slopes of the age-volume regression lines were not significantly different between patients and controls over the age range studied (, ). As with controls, unnormalized volumes were generally larger among men than women, while larger normalized volumes were observed among female AD patients. Associations between MTL volume and age were linear, and did not differ between men and women. The segment of the hippocampus showing the greatest decline with age was the head.
Age and gender specific percentiles for normalized volumes were computed for each of the AD patients, and these were converted to W scores (corresponding to a normal distribution)(). Thus, values of W below 0 indicate that volume is less than the mean value 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 among normals.
W Scores* in Alzheimer's Disease Patients
We assessed the extent to which cases differed from controls, and, for each anatomic structure W scores were significantly less than 0 among AD patients, (P<.001). As would be expected from , the deficit in volumes relative to controls was not associated with age or gender. We also assessed whether the magnitude of the volumetric deficit in cases relative to controls was greater in some structures than others. The differences among hippocampus, PHG, and amygdala were significant (P = <.001, ANOVA), and all pairwise comparisons (paired t-tests) were also significant (hippocampus vs. amygdala, P<.001; hippocampus vs. PHG, P<.001, amygdala vs. PHG, P=.006)(). Within the hippocampus, volumes differed significantly among the head, body, and tail (P = <.001, ANOVA), and pairwise differences between the head and body, and body and tail were also significant (P<.001, paired t-tests). The mean TIV of AD patients, 1369 cm3 (SD 138cm3), was not significantly different from that of controls.
When AD patients were categorized by disease severity into those with very mild, mild, or moderate disease, W scores within each group remained significantly less than 0, (P <.001)(). The MTL structure with the lowest W scores was the hippocampus for all 3 AD groups. Within the hippocampus, W values were most negative for the head().W scores for the total hippocampus (P <0.05) and hippocampal head (P<0.001) were significantly different among AD patients of different CDR severity grades (Spearman Rank Correlation). Pairwise comparison of the W scores were also significant for the total hippocampus—CDR 0.5 vs 1.0 (P < 0.01), CDR 1.0 vs 2.0 (P < 0.01) (Rank Sum Test).
Discrimination Between Controls 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 which appeared in the final model were hippocampal volume, hippocampal volume squared, and age. Although all these terms were significant at the .02 level, the prediction equation was dominated by the linear 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 controls was assessed by computing the percentage of AD patients with W scores at selected percentiles among controls(). For example, at a fixed specificity of 80% the sensitivity of hippocampal volume measurements in discriminating controls from cases was 77.8% for CDR=0.5; 83.7% CDR=1; and 86.7% for CDR=2. Discrimination between controls and AD patients was roughly equivalent among the three AD severity groups at the 50th and 20th percentile of normal; discrimination was greater for CDR 1 and 2 than CDR 0.5 patients at the 10th and 5th percentile of norma; and, at the 1st percentile of normal, discrimination improved as patient's disease severity (CDR score) increased.
Diagnostic Discrimination of Normalized Total Hippocampal Volume Adjusted for Age and Gender*