The probable AD, MCI converter, MCI stable, and NC groups’ demographic characteristics, clinical ratings, and memory test scores, and their proportion of APOE ε4 homozygotes, heterozygotes and non-carriers are shown in . The groups did not differ in their mean age, gender distribution or educational level. As expected, the groups differed in their clinical ratings, memory test scores, and proportion of number APOE ε4 alleles.
Subject Characteristics, Clinical Ratings, Memory Test Scores and HCIs
As shown in and , HCIs were different in the four subject groups (p=8.6e-17) and were associated with categorical clinical disease severity (linear trend p=3.1e-18). In the post hoc pair-wise comparisons, the probable AD, MCI converter and MCI stable groups each had higher HCIs than the NC group (P=5e-13, 2e-8 and 0.01, respectively), the probable AD and MCI converter groups each had higher HCIs than the MCI non-converter group (P=8e-10 and 2e-4,), and HCIs in the probable AD and MCI converter groups were not different (P=0.74). As shown in , the locations of the voxels that contributed to a high HCI score for an AD patient (and therefore contributed to the between-group differences) are in temporal, occipital and parietal area which is consistent of the areas known to be affected by AD.
Hypometabolic Convergence Index (Mean±SD) in normal controls, MCI stable subjects, MCI converters, and probable AD patients
Figure 2 An example of the brain regions where A) an individual AD patient and B) a normal control subject shows the presence/absence of consistent hypometabolic pattern with AD. For illustration purposes, the overlap display was created with a cut-off of the (more ...)
As shown in , HCIs were correlated with ratings of clinical disease severity and cognitive test scores (even after Bonferroni correction), with the exception of Digit Span Forward and Backward. In addition, HCIs were correlated with smaller baseline hippocampal volumes and each CSF measurement of Aβ and/or tau pathology.
Biomarker correlations with HCIs, clinical ratings, and memory test scores
As shown in , MCI patients who converted to probable AD within 18 months after baseline were distinguished from the stable MCI patients by significantly higher HCIs, smaller hippocampal volumes, higher ADAS-cog, CDR-SB ratings and lower AVLT-LTM scores. While there were fewer MCI patients with CSF assays, there were non-significant trends for lower Aβ1–42 levels and higher p-tau181/Aβ1–42 ratios in the MCI converters than in the MCI stable group. After controlling for higher ADAS-cog scores, the MCI converters continued to be distinguished from the stable MCI by higher HCIs (p=0.0001) and hippocampal volume (p=0.02), but not by any of the other measurements (p-value range 0.09 to 0.9).
Clinical Ratings, Memory Test Scores and Biomarker Measurements in MCI Converters and Stable MCIs.
The biomarker, clinical rating, and memory test cut-off values, area-under-curves (AUC) and their 95% confidence interval found using ROC analyses to distinguish with optimal sensitivity and specificity those MCI patients who did or did not convert to probable AD within 18 months after baseline are shown in . For further performance comparison, ROCs of HCI and hippocampal volume are shown in . Using those cut-offs to sub-divide the MCI patients into those with and without positive scores, shows the estimated hazard risk of converting to probable AD in those MCI patients who were positive on each of the measurements. When each of the candidate predictors was analyzed independently, the MCI patients with a positive (i.e., higher) HCI or positive (i.e., smaller) hippocampal volume had the highest HRs of converting to probable AD within 18 months after baseline (7.38, 95% CI=2.48–21.98 and 6.34, 95% CI=2.32–17.36, respectively). When all of the candidate predictors were included in the same model, only the HCI and hippocampal volume remained significantly associated with a higher HR of conversion to probable AD.
The biomarker, clinical rating, and memory test cut-off values found using ROC analyses to distinguish with optimal sensitivity and specificity those MCI patients who did or do not convert to probable AD within 18 months
Receiver Operating Curves showing the sensitivity and 1-specificity of the HCI and hippocampal volume
Estimated risk of 18-month conversion to probable AD in MCI patients with positive versus negative test measurements
After the non-significant predictors were removed and the multivariate model was refitted, 26 MCI patients with a higher HCI (27% of MCI patients) had an HR of 6.55 (95% CI=2.19–19.61) of conversion to probable AD within 18 months after baseline (), 21 MCI patients with a smaller hippocampal volume (22%) had an HR of 5.60 (95% CI=2.04–15.41) (), and 13 MCI patients with both a higher HCI and smaller hippocampal volume (13%) had an HR of 36.72 (95%CI=4.46–302.34) compared to those with both a lower HCI and larger hippocampal volume (20 and 38 MCI patients or 21% and 39% of the MCI patients) (). In comparison with all of the MCI participants, those with both a higher HCI and hippocampal volume had an HR of 10.17 times (95% CI=4.17–24.86) ().
Figure 4 Kaplan-Meier curves showing the probability of an MCI patient not converting to probable AD within 18 months from baseline in a) the 26 MCI patients with a higher HCI versus the 71 MCI patients with a lower HCI, b) the 21 MCI patients with a smaller hippocampal (more ...)
When the analyses were performed iteratively using training set data to characterize the cut-off values and independent test set data to characterize HRs, the findings were generally consistent with our original analysis: the MCI patients with a higher HCI (average HR=5.32) or smaller hippocampal volume (average HR=4.77) had the highest average HRs of converting to probable AD within 18 months after baseline. Average HRs were 1.54 for those with lower Aβ1–42 levels, 1.62 for t-tau levels, 3.11 for p-tau181 levels, 1.29 for t-tau/Aβ1–42 ratios, 2.44 for p-tau181/Aβ1–42 ratios, 3.58 for ADAS-cog scores, 2.40 for CDR-SB scores, 2.55 for AVLT-LTM scores, and 2.14 for APOE ε4 carriers.
Because there was concern of including subjects who subsequently converted to MCI in the normal database, we re-computed the HCIs without these 4 subjects in the normal database and compared the results to those with the 4 subjects included. The re-computed HCIs were highly correlated to the original HCI computed with the 4 subjects (Pearson correlation r>0.9999), suggesting that to some degree, the HCI is robust to changes in the normal database.