The demographic data of the study participants are presented in . During the 2 year observation, 8 (33%) out of the 24 evaluable MCI subjects seen at baseline declined to AD and 16 retained the diagnosis of MCI. None of the 21 normal controls changed diagnostic group. There were no significant age, education, or length of observation period differences between the study groups (p
> 0.05; see ). MCI-AD patients had lower MMSE scores than MCI-MCI patients at follow-up (p
< 0 05) and against controls at both baseline and follow-up (p
< 0.01). MCI-AD patients had a higher prevalence of APOE4 carriers than either stable MCI or control (p
< 0.05). Both MCI-AD and control groups demonstrated a higher prevalence of females than MCI-MCI (χ2
< 0.05). As previous brain studies show age effects [23
], age (in addition to APOE genotype and gender) was controlled for in the subsequent analyses.
Demographics of study participants
Voxel-based gray matter concentration results
Univariate ANOVA over the 3 study groups at baseline showed several GMC clusters in the right hemisphere (including MTL, superior, middle and inferior temporal gyri) and in the left (including MTL and posterior cingulate gyrus). Similarly, at follow-up the analysis detected clusters in the right (including MTL, superior and inferior temporal gyri) and in the left hemisphere (including MTL and posterior cingulate gyrus).
Post-hoc analysis showed that MCI-AD subjects as compared with MCI-MCI, at baseline demonstrated reduced GMC bilaterally in MTL and in right inferior temporal gyrus (for local maxima and Brodman areas see , ). Similar effects were found at the follow-up. Comparison of NL-NL with MCI-AD subjects at baseline showed bilateral MTL effects with superior and middle temporal gyri in the right hemisphere and inferior frontal and posterior cingulate gyri in the left hemisphere. Similar effects were found at follow-up (, ). No significant differences in GMC between NL-NL and MCI-MCI groups were detected at either baseline or follow-up.
Voxel-based morphometry: local maxima and Brodman areas (BA) of clusters of significant baseline and follow-up differences in gray matter concentration between MCI-MCI and MCI-AD and between NL-NL and MCI-AD
Voxel-based morphometry results: clusters with significantly different GMC in MCI-MCI subjects vs. MCI-AD subjects (A) and NL-NL subjects vs. MCI-AD subjects (B) at baseline and at follow-up.
The between-group analysis of the differential GMC images (follow-up minus baseline) did not detect differences in GMC. Further, the unprotected paired-t-tests analyses within each study group also failed to reach statistical significance.
In summary, at baseline and follow-up for the VBM analyses, only the MTL showed consistent bilateral effects separating decliners from the other groups.
Longitudinal MRI rBS-determined atrophy rates
Given our hypothesized longitudinal MTL effects, the MTL region was specifically examined with the rBS method. After controlling for confounds, annualized atrophy rates for both the left (F(2,36) = 9.5, p < 0.001) and right rBS-MTL (F(2,36) = 4 4 p < 0.05) differed among three study groups (see and ). Post-hoc analysis showed that atrophy rates in the left MTL were higher in MCI-AD patients than in either NL-NL or MCI-MCI (p < 0.01). Atrophy rates in the right MTL were only higher in MCI-AD patients as compared with NL-NL (p < 0 01) For neither hemisphere were the annual MTL atrophy rates different between MCI-MCI patients and NL-NL (p > 0.05)
Baseline and follow-up measures of CSF biomarkers and annualized rates of change for CSF and MRI measures by diagnostic group
rBS atrophy rates in the left (A) and right (B) MTL region for the three diagnostic outcome groups. The bars represent mean value ± SEM. One star indicates p < 0.05, two stars: p < 0.001.
The rBS showed consistent longitudinal MTL effects distinguishing the decliners from the other groups.
CSF biomarkers analysis: baseline, follow-up and longitudinal results
Across all groups, there were significant baseline effects for all CSF analytes (see ). The MCI-AD patients showed significantly higher values of T-tau, P-tau231 and IP levels, and lower values of Aβ42/Aβ40 ratio when compared with either MCI-MCI patients or with NL-NL (p < 0.05; see ). Similar significant effects were found at the follow-up with exception the Aβ42/Aβ40 ratio (see ). No differences were found between MCI-MCI and NL-NL subjects at baseline, or follow-up.
Analysis of longitudinal changes in CSF biomarker levels showed a trend for overall between-group differences for IP (p = 0.07; see ). Exploratory post-hoc analysis showed that a significantly greater increase in the IP level was found in MCI-AD patients as compared with NL-NL (p < 0.01). No other CSF biomarker showed longitudinal diagnostic group effects.
In summary, consistent baseline and follow-up effects were found in MCI-AD as compared with the other groups for T-tau, P-tau231 and IP levels. Only IP showed a trend towards a longitudinal effect.
The prediction of decline to AD
Logistic regression outcome models classifying MCI-MCI and MCI-AD subjects showed that at baseline, both right and left GMC-MTL values predicted MCI to AD decline with ≥74% accuracy (p < 0.01, see ). All baseline CSF measures discriminated the groups in the logistic regression models (≥70%, p < 0.05, see ).
Significant predictors of MCI to AD decline corrected for confounding measures
Multivariate CSF and MRI models were used to test for incremental prediction effects among the significant baseline measures (see ). The results showed that adding the right GMC-MTL to baseline CSF P-tau231 raised the overall prediction accuracy to 84% (pstep < 0.05). Addition of right GMC-MTL to baseline CSF IP levels increased the prediction accuracies to 78% (pstep < 0.05).
Longitudinal correlates of decline
Longitudinally, atrophy of the left MTL using the rBS method discriminated MCI-MCI from MCI-AD with 74% overall accuracy (p < 0.01). The right rBS-MTL atrophy and longitudinal changes in CSF biomarkers levels were not significant group discriminators (p > 0.05). No longitudinal correlations were observed between the MRI and CSF biomarkers.
Combining the rBS-MTL atrophy rate with the baseline IP level resulted in a significant increment in the correlation with decline (p < 0.05). Combining the rBS-MTL atrophy rate with the IP change did not result in a significant increment in the correlation with decline (p > 0.05).
Follow-up diagnostic classifications
All follow-up CSF measures with the exception of the Aβ42/40 ratio discriminated the groups in the logistic regression models (≥70%,p < 0.05). Similarly, both right and left GMC-MTL at follow-up discriminated the groups in the logistic regression models (≥78%, p < 0.05).