Cognitive Change in Prodromal Alzheimer's Disease
In this clinical prospective study of 212 MCI individuals, we provide rational explanations for selecting neuropsychological tests for the longitudinal identification and follow-up of subjects with prodromal AD. These explanations are based on the analysis of the sensitivity of neuropsychological tests to detect cognitive changes due to prodromal AD and on the description of the metrological properties of these tests (ie, variable sensitivity to cognitive change, floor and ceiling effect).
A major result of this study is the identification of tests that are sensitive to the cognitive change due to prodromal AD. Some tests present a poor sensitivity to cognitive change and seem, therefore, of limited interest in the context of research or clinical care for a longitudinal follow-up, namely, Baddeley's double task, the TMT-B and the WAIS similarities. Conversely, among the 13 scores analysed, six showed a significant decrease over time in the prodromal AD patients, and a substantial difference in their evolution compared with MCI non-AD subjects: the 3 FCSRT scores, the semantic verbal fluency, the Deno100 and the SDOT. These results are consistent with the neuroanatomic distribution of histopathological abnormalities reported in the mildest stages of AD, which overlaps, at least partially, with the regions implicated in these tests. For example, the neuropathological changes in the early stage of AD begin primarily in medial temporal regions (hippocampus, entorhinal cortex), which are known to be critical for episodic memory function. Consequently, an impaired ability to learn and retain new information (ie, an episodic memory deficit) is usually the earliest and most prominent feature of AD. The decrease over time of both free recall and total recall scores (FCSRT) is therefore consistent with the aggravation of the amnesic syndrome of the medial temporal type. Among other tests, the observed decline of the verbal fluency (category) test and the Deno100 illustrates the early impairment of access to semantic memory due to the temporal neocortical damage that occurs in AD. The greater impairment in semantic fluency rather than in letter fluency has been previously reported in Mild AD. A potential limitation of this study is that it included subjects with MCI defined according criteria dating from 1999. The use of other criteria to define MCI or the carrying out of a similar study in the general population could have led to different results. Another point is that subjects were followed over a limited period of 3 years, and it is possible that some AD occurred after the third year of follow-up. However, considering the decreasing incidence of AD during the follow-up, with only five cases diagnosed during the last visit (figure 2), it is likely that this number is low and that this information bias is minimal.
With regards to the metrological properties of the tests, our results suggest a potential interest of selecting neuropsychological tests for a longitudinal follow-up according to the initial cognitive level of the target population (in a research setting) or of the patient (in a clinical setting). Some tests should be chosen for evaluating cognitive changes at high levels of cognition (FCSRT free recall score/delayed free recall score and verbal fluency 'category '), whereas others should be avoided because of their ceiling effect (FCSRT total recall, Deno100). Conversely, some tests seem more useful for evaluating cognitive changes at low levels of cognition (FCSRT total recall score), while some should be avoided (WAIS-DST, TMT-A, SDOT). Another result of this study is that a majority of the scores exhibited strong curvilinearity. This curvilinearity could have consequences on the results of intervention trials or in epidemiological research, and thus, has to be taken into account in the analysis. In addition, this curvilinearity partly explains the remaining difficulties in providing a cut-off value for cognitive decline in the diagnosis of prodromal AD. Indeed, for most of the tests, a decrease of a given number of points will not have the same meaning according to the initial value of the score. Thus it could be interesting to create an algorithm that would include different scores and/or different cut-off values to provide a prediction of the probability of developing AD rather than use a single test with a single cut-off value.
The improvement observed for some tests in MCI non-AD patients (FCRST, BVRT, Deno100) is probably due to practice and/or learning effects. This kind of effect has been extensively documented in healthy participants for tasks assessing different cognitive functions including verbal episodic memory. Contrary to some studies, the observed improvement was not limited to the second testing but was observed during the entire study (data not shown). This effect is generally considered as an interfering variable complicating the interpretation of results. However, it could also be considered as an interesting property that could help to differentiate the normal ability of an individual to learn and adjust with practice from the pathological process of an individual with prodromal AD.
Our statistical methodology has several advantages. It can handle unbalanced repeated measurements and bounded quantitative outcomes, and it can take into account and describe the metrological properties of neuropsychological tests. However, it is worth noting that the LCP in this model is necessarily defined according to the pool of psychometric tests used in the analysis. In this study, we used a large battery of neuropsychological tests that assessed several cognitive domains. Therefore, the modelled LCP could reasonably be interpreted as a global cognitive factor. However, a limitation of this study is that it was not designed to compare numerous different measures of a specific cognitive domain (like episodic memory), and hence, cannot reasonably highlight one measure over others that were not tested.
Our study provides rational explanations for the selection of neuropsychological tests for the cognitive follow-up of patients with MCI in a clinical care context (for diagnostic or prognostic purposes of prodromal AD) or research context (to identify a target population or as an outcome for the effect of an early intervention in prodromal AD). The tests that can be recommended are those that actually demonstrate a decline at the stage of prodromal AD (the three FCSRT scores, the semantic verbal-fluency, the SDOT and the Deno100), and which are able to measure cognitive changes in the range of cognitive levels of the targeted population. In the current study, the free recall, the delayed free recall score (FCSRT) and the semantic verbal fluency test cover a wide cognitive range and seem to be adapted for the follow-up of subjects with an initial medium or high level of cognition. Conversely, the total recall score (FCSRT) suffered from a very considerable ceiling effect, but appeared to be the best score for following up subjects with an initial low cognitive level. For future research, comparing several neuropsychological tests (or score) within a specific cognitive domain (particularly verbal episodic memory and language) using the same methodology could be of great interest for refining the choice of cognitive tests to be used.
Discussion
In this clinical prospective study of 212 MCI individuals, we provide rational explanations for selecting neuropsychological tests for the longitudinal identification and follow-up of subjects with prodromal AD. These explanations are based on the analysis of the sensitivity of neuropsychological tests to detect cognitive changes due to prodromal AD and on the description of the metrological properties of these tests (ie, variable sensitivity to cognitive change, floor and ceiling effect).
A major result of this study is the identification of tests that are sensitive to the cognitive change due to prodromal AD. Some tests present a poor sensitivity to cognitive change and seem, therefore, of limited interest in the context of research or clinical care for a longitudinal follow-up, namely, Baddeley's double task, the TMT-B and the WAIS similarities. Conversely, among the 13 scores analysed, six showed a significant decrease over time in the prodromal AD patients, and a substantial difference in their evolution compared with MCI non-AD subjects: the 3 FCSRT scores, the semantic verbal fluency, the Deno100 and the SDOT. These results are consistent with the neuroanatomic distribution of histopathological abnormalities reported in the mildest stages of AD, which overlaps, at least partially, with the regions implicated in these tests. For example, the neuropathological changes in the early stage of AD begin primarily in medial temporal regions (hippocampus, entorhinal cortex), which are known to be critical for episodic memory function. Consequently, an impaired ability to learn and retain new information (ie, an episodic memory deficit) is usually the earliest and most prominent feature of AD. The decrease over time of both free recall and total recall scores (FCSRT) is therefore consistent with the aggravation of the amnesic syndrome of the medial temporal type. Among other tests, the observed decline of the verbal fluency (category) test and the Deno100 illustrates the early impairment of access to semantic memory due to the temporal neocortical damage that occurs in AD. The greater impairment in semantic fluency rather than in letter fluency has been previously reported in Mild AD. A potential limitation of this study is that it included subjects with MCI defined according criteria dating from 1999. The use of other criteria to define MCI or the carrying out of a similar study in the general population could have led to different results. Another point is that subjects were followed over a limited period of 3 years, and it is possible that some AD occurred after the third year of follow-up. However, considering the decreasing incidence of AD during the follow-up, with only five cases diagnosed during the last visit (figure 2), it is likely that this number is low and that this information bias is minimal.
With regards to the metrological properties of the tests, our results suggest a potential interest of selecting neuropsychological tests for a longitudinal follow-up according to the initial cognitive level of the target population (in a research setting) or of the patient (in a clinical setting). Some tests should be chosen for evaluating cognitive changes at high levels of cognition (FCSRT free recall score/delayed free recall score and verbal fluency 'category '), whereas others should be avoided because of their ceiling effect (FCSRT total recall, Deno100). Conversely, some tests seem more useful for evaluating cognitive changes at low levels of cognition (FCSRT total recall score), while some should be avoided (WAIS-DST, TMT-A, SDOT). Another result of this study is that a majority of the scores exhibited strong curvilinearity. This curvilinearity could have consequences on the results of intervention trials or in epidemiological research, and thus, has to be taken into account in the analysis. In addition, this curvilinearity partly explains the remaining difficulties in providing a cut-off value for cognitive decline in the diagnosis of prodromal AD. Indeed, for most of the tests, a decrease of a given number of points will not have the same meaning according to the initial value of the score. Thus it could be interesting to create an algorithm that would include different scores and/or different cut-off values to provide a prediction of the probability of developing AD rather than use a single test with a single cut-off value.
The improvement observed for some tests in MCI non-AD patients (FCRST, BVRT, Deno100) is probably due to practice and/or learning effects. This kind of effect has been extensively documented in healthy participants for tasks assessing different cognitive functions including verbal episodic memory. Contrary to some studies, the observed improvement was not limited to the second testing but was observed during the entire study (data not shown). This effect is generally considered as an interfering variable complicating the interpretation of results. However, it could also be considered as an interesting property that could help to differentiate the normal ability of an individual to learn and adjust with practice from the pathological process of an individual with prodromal AD.
Our statistical methodology has several advantages. It can handle unbalanced repeated measurements and bounded quantitative outcomes, and it can take into account and describe the metrological properties of neuropsychological tests. However, it is worth noting that the LCP in this model is necessarily defined according to the pool of psychometric tests used in the analysis. In this study, we used a large battery of neuropsychological tests that assessed several cognitive domains. Therefore, the modelled LCP could reasonably be interpreted as a global cognitive factor. However, a limitation of this study is that it was not designed to compare numerous different measures of a specific cognitive domain (like episodic memory), and hence, cannot reasonably highlight one measure over others that were not tested.
Our study provides rational explanations for the selection of neuropsychological tests for the cognitive follow-up of patients with MCI in a clinical care context (for diagnostic or prognostic purposes of prodromal AD) or research context (to identify a target population or as an outcome for the effect of an early intervention in prodromal AD). The tests that can be recommended are those that actually demonstrate a decline at the stage of prodromal AD (the three FCSRT scores, the semantic verbal-fluency, the SDOT and the Deno100), and which are able to measure cognitive changes in the range of cognitive levels of the targeted population. In the current study, the free recall, the delayed free recall score (FCSRT) and the semantic verbal fluency test cover a wide cognitive range and seem to be adapted for the follow-up of subjects with an initial medium or high level of cognition. Conversely, the total recall score (FCSRT) suffered from a very considerable ceiling effect, but appeared to be the best score for following up subjects with an initial low cognitive level. For future research, comparing several neuropsychological tests (or score) within a specific cognitive domain (particularly verbal episodic memory and language) using the same methodology could be of great interest for refining the choice of cognitive tests to be used.