A composite score for the CERAD neuropsychological battery was recently developed6
, but until now the utility of the Total Score had not been examined in terms of AD progression. As expected, AD subjects showed significantly greater annual change in Total Scores than NC subjects. In order to establish a meaningful degree of cognitive change, the annual Change Scores of the AD and NC groups were compared. According to the 90% CI established by the RCI, CERAD Change Scores should exceed at least ± 10.51 points in order to represent clinically meaningful change. This threshold provided by the RCI increases the likelihood that an individual's change in performance reflects an actual change in cognitive abilities rather than extraneous factors such as subject variability. The mean annualized rate of AD progression as measured by the CERAD battery was determined to be -7.2 points, and it was not until Visit 3 that the majority of AD subjects exhibited a clinically significant decline in their performance as determined by the calculated RCIs.
Several factors were examined to better understand the lack of clinically significant change in years 1 and 2 (based on the RCI). To assess the potential impact of dementia severity, change scores were reviewed based on CDR at baseline and no differences were seen when comparing those with baseline CDRs of 1 versus 2. This was surprising given the substantial amount of research identifying dementia severity as a key factor in AD progression.12
Although the mild severity group (CDR Stage ≤ 1; N=411) had significantly better CERAD and MMSE total scores than the moderate to severe group (CDR Stage ≥ 2; N=244) at baseline and last visit, there was no significant difference in the rate of decline. However, it should be noted that the range of CDR scores was restricted at baseline (.5 – 3.0) and the majority of subjects (59%) were classified at CDR Stage 1, limiting the number of subjects in other stages that were available for comparison. Since the AD sample's CERAD performance was fairly impaired at baseline there may not have been much room for further decline, resulting in floor effects.
The potential impact of selective attrition on CERAD Change Scores was also examined to identify if lower-functioning individuals with AD may have dropped out earlier in the study than less-affected individuals, thus biasing the remaining sample with a disproportionate contribution from comparatively higher-functioning individuals. In fact, comparison of the average baseline CERAD performance of subjects with no follow-up data to those with at least one follow-up assessment revealed that those individuals who dropped out were significantly more impaired (CERAD M (SD) = 30.78 (14.07); MMSE M (SD) = 13.71 (6.72) than those who remained in the study (CERAD M (SD) = 39.46 (12.97); MMSE M (SD) = 18.50 (5.10). For the 64 AD subjects who had follow-up data at each time interval, the mean annualized decline was -5.4 (3.69), which is 1.8 points less than the mean of the larger sample (N = 655). These results provide some support for the idea that subjects who were experiencing less pronounced dementia remained in the study longer, which suggests that the progression rates found in the current study may not apply as readily to individuals with more severe dementia.
The annual CERAD Change Score was compared to the annual rate of change in the MMSE, CDR Sum of Boxes, and BDRS, which are established measures of cognitive decline.13, 14, 15
The mean annualized rate of change in the AD sample was -7.20 (6.93)
on the CERAD, -3.43 (3.33)
on the MMSE, 2.28 (2.13)
on the CDR, and 1.89 (1.54)
on the BDRS. The mean rates of change for the MMSE and BDRS are in keeping with prior research.16, 17, 18
The CERAD Change Score was significantly and moderately correlated with each measure with the exception of the BDRS, which fell slightly short of the 0.4 – 0.6 range (r
= -.38), likely due to the fact that the BDRS is based upon caregiver report of functioning rather than an objective assessment of cognitive functioning per se. These results support the concurrent validity of the CERAD neuropsychological battery in measuring AD progression and provide comparative data for annualized change in the CERAD Total Score and other common measures.
This study was subject to the inherent limitations of longitudinal designs, namely, selective attrition that resulted in successively smaller ns and inconsistency in the subjects returning at each visit. However, when comparing subjects with consistent annual follow-ups to the total sample, the results were similar, as shown in . This study was limited to Caucasian and African-American subjects, so the CERAD Total Score's utility as a measure of progression among other ethnic populations is unknown. As reflected in the composition of the CERAD registry, this sample has a relatively high level of education (M = 13.3 years). It is possible that the progression of individuals with limited education may manifest differently than the results reported here.
The RCI method of determining clinically significant change in scores utilized in this study is well researched; however, it is relatively conservative.19
As such, it may have provided overly wide confidence intervals that required AD subjects to exhibit a larger degree of change in order to be categorized as “meaningful.” Therefore, Change Scores that do not exceed the specified confidence interval may not necessarily be insignificant but should be interpreted within the context of other sources of clinical information.19
Although the confidence interval provided by RCIs is useful, once the degree of change extends beyond the critical range it does not provide information regarding the relative magnitude of the change.11
Given that in a sample of AD affected individuals each annual assessment would be expected to reveal significant change in cognitive performance, it may be that the RCI method is in fact too conservative for this population in assessing cognitive progression. Furthermore, while the RCI method takes into account standard error of measurement, it only measures one point in time and may miss variability that occurred between assessments.
The current study establishes the CERAD Total Score as a measure of AD progression comparable to other common measures such as the MMSE, CDR, and BDRS. Additional research geared toward exploring the utility of the CERAD Total Score in the staging of AD would be valuable. The establishment of cut-off scores for mild, moderate, and severe impairment would allow the CERAD battery to be used more precisely as a dementia staging tool. In addition, the CERAD battery could be utilized as a measure of change in intervention studies with dementia populations by examining the change in CERAD Total Score to assess the effectiveness of pharmacological or other interventions.