Of the 142 healthy elderly subjects included in this study, there were 67 females and 75 males, the mean age was 75 years (range 59 to 90), the mean education 16 years (range 6 to 20), and 40 were carriers of the APOE ε4 allele. The mean MMSE at baseline was 29.22 (range 25 to 30) and the mean ADAS-cog at baseline was 5.89 (range 1 to 16.33).
On three of the four memory-specific neuropsychological assessments, subjects showed a slight mean improvement with repeat testing over the course of two years. The two-year mean change on LM delayed recall (maximum score 25) was an improvement of 0.64 points (range 10-point decline to 9-point improvement), the mean change on LM retention (maximum score 1) was a decline of 0.05 points (range 0.93-point decline to 0.43-point improvement), the mean change on AVLT sum (maximum score 105) was an improvement of 1.20 points (range 42-point decline to 30-point improvement), and the mean change on AVLT delayed recognition (maximum score 15) was an improvement of 0.09 points (range 11-point decline to 10-point improvement).
There was significant evidence of medial temporal atrophy over a six-month period (). Although not all subjects had measurable atrophy, there was a mean loss of subcortical volume and cortical thickness in all regions of interest, with the exception of the inferior lateral ventricles, which expanded. There were mean decreases in the volumes of the left and right hippocampus (-1.02 and -0.98 %, respectively) and mean decreases in the thicknesses of the left and right middle temporal gyri (both -0.64%), left and right inferior temporal gyri (-0.55 and -0.65%), left and right entorhinal cortices (-0.45 and -0.43 %), and left and right fusiform gyri (-0.55 and -0.50 %, respectively). There were mean expansions in the volumes of the left and right inferior lateral ventricles (1.74 and 1.90 %, respectively). Additionally, there was a mean loss of volume in the whole brain (-0.31%) and a mean gain in volume in all ventricles (1.73%).
Figure 1 Neuroanatomical change between baseline and 6-month follow-up visits across medial temporal lobe (MTL) regions. All volumes were normalized to baseline. Data points represent mean volumes for all subjects who retained a diagnosis of cognitively normal (more ...)
Univariate regression analysis revealed that six-month neurodegenerative change in several medial temporal regions significantly predicted two-year cognitive decline at a significance level α < .01 (). The multivariate regression models designated three of these regions as the best predictors of cognitive decline when compared to other risk factors such as age, education and APOE ε4 carrier status. A decrease in the thickness of the right fusiform gyrus predicted decline on LM delayed recall (p = .001), with a 1% decrease in thickness corresponding to a 1.22 ± 0.35 point decline. Expansion of the right inferior lateral ventricle was a significant predictor of decline on LM retention (p = .002), with an expansion of 10% corresponding to a decline in the retention ratio by 0.09 ± 0.03. A decrease of thickness in the right inferior temporal gyrus predicted decline on AVLT sum (p = .004), with a 1% decrease in thickness corresponding to a 2.57 ± .43 point decline. Additionally, a decrease in whole brain volume predicted decline on AVLT delayed recognition (p=.009) with a 1% decrease in volume corresponding to a 1.39 ± .53 point decline. Age, sex, education and APOE ε4 carrier status were not significant predictors of cognitive decline.
Variables of significance in univariate and multivariate regression models
When baseline ADAS-cog scores and six-month change in ADAS-cog, and MMSE scores were entered into the regression model as independent variables, they failed to be significant predictors of two-year cognitive decline and the regression models did not change. Six-month change on AVLT sum did predict change on AVLT sum over the subsequent eighteen months (p=.000), and six-month change on AVLT delayed recognition predicted change on AVLT delayed recognition over the subsequent eighteen months (p=.000). In addition, six-month change on AVLT sum predicted two-year change on LM delayed recall (p=.007).
Data from two subjects who converted to MCI during the two-year follow-up period were found to exert undue influence in the regression models for LM delayed recall and LM retention. When these subjects were removed from the regression analyses, neither the right fusiform nor the right inferior lateral ventricle were significant predictors at p < .01, although the right fusiform remained significant at p < .05. Change in the right fusiform predicted decline on LM delayed recall (p = .016), with a 1% decrease in thickness corresponding to a 0.92 ± 0.38 point decline. Additionally, change in the left hippocampus became significant (p = .012) with a 1% decrease in thickness corresponding to a decline in the retention ratio by 0.39 ± .15.
During the two-year follow-up period, a total of seven subjects converted to MCI. The subjects who converted were not significantly different at baseline in age, education or MMSE than those who retained a normal diagnosis. However, the converters had a significantly higher frequency of the APOE ε4 allele (0.71 vs 0.26, p = .049) and significantly more impaired ADAS-cog scores at baseline (mean 9.19 vs. 5.72, p = .030).
In a secondary regression analysis, data from the seven subjects who converted to MCI, including the two subjects mentioned above who exerted undue influence in the regression models, were weighted twice as heavily as data from all other subjects in order to create a prediction model biased toward identifying changes in the brain that predict conversion to MCI (). Change in the right fusiform became a more significant predictor (p < .001) of decline on LM delayed recall, with a 1% decrease in thickness corresponding to a 1.46 ± .33 point decline. Additionally, change in the right fusiform became a significant predictor (p = .005) of AVLT delayed recognition, with a 1% decrease in volume corresponding to a .83 ± .29 point decline. Expansion of the right inferior lateral ventricle also became a more significant predictor (p < .001) of decline on LM retention, with a 10% increase corresponding to a decline in the ratio by 0.10 ± 0.03. No regions remained significant predictors of decline on AVLT sum at the α = .01 level, but there was a trend toward change in the left entorhinal cortex predicting decline on AVLT sum (p = .017), with a 1% decrease in thickness corresponding to a 1.34 ± .55 point decline.
Variables of significance in regression analysis after weighting data from subjects who converted to MCI a
Among the nine subjects with the greatest composite neuroanatomical change (defined as being greater than one standard deviation relative to our sample), two converted to a diagnosis of MCI, and five had cognitive change greater than the mean for the group. In no case did a subject above the 93rd percentile for composite neuroanatomical change fail to have greater than average decline on the composite memory measure. Further, in no case did a subject below the 32nd percentile for composite neuroanatomical change convert to a diagnosis of MCI.