Diagnostic and Prognostic Value of the Combination of Two Measures of Verbal Memory in Mild Cognitive Impairment due to Alzheimer’s Disease

INTRODUCTION

Mild cognitive impairment (MCI) is a broad, heterogeneous clinical syndrome that can include multiple neurodegenerative and non-neurodegenerative conditions [1]. The increasing use of biomarkers in recent years has enabled the identification of a subgroup of MCI patients with underlying Alzheimer’s disease (AD). Imaging and cerebrospinal fluid (CSF) biomarkers, in particular, have shown to be excellent tools for the diagnosis of MCI due to AD (MCI-AD) and both have been incorporated into current diagnostic criteria [2, 3].

The core feature of typical AD is episodic memory impairment. This deficit can be assessed by episodic memory tests, [4] but studies comparing their diagnostic performance in biomarker-supported or autopsy-proven patient samples are scarce [5, 6].

One of the most commonly used tests world-wide is the Free and Cued Selective Reminding Test (FCSRT). The FCSRT is considered a typical episodic memory test that ensures encoding by semantic cueing and has been particularly recommended for the diagnosis of prodromal AD [7]. Other tests that use verbal word lists are the Consortium to Establish a Registry for Alzheimer’s Disease (abbreviated herein as CERAD-WL) or the Rey Auditory Verbal Learning Test (RAVLT). The CERAD-WL test includes a delayed recognition task which has been tightly related to the integrity of the entorhinal and perirhinal cortex, regions known to be selectively vulnerable to AD [8]. Although the current evidence indicate that these tests are reliable tools for the early diagnosis of AD, there is insufficient data about their direct comparison [9]. Some studies claim the use of the FCSRT based on longitudinal studies in subjects with MCI [10–13]. However, in these studies the progression to AD dementia was assessed during a short follow-up [10–13]. This approach has two major limitations: first, a limited follow-up may underestimate the full clinical spectrum of AD as some cases may not have the time to progress to the dementia stage. In addition, MCI-AD is heterogeneous and multiple patterns of neurodegeneration and longitudinal trajectories have been recognized [14]. Second, the sensitivity for the diagnosis of AD dementia based only on clinical criteria is limited, as up to a third of the patients may have non-AD pathologies or insufficient AD-related neuropathological changes at autopsy [15, 16]. Thus, we believe that it is necessary to explore the diagnostic accuracy of verbal memory tests in biomarker-supported MCI studies. In this study, we compared the diagnostic accuracy of two commonly used verbal memory tests, the FCSRT and CERAD-WL to predict MCI-AD defined by CSF biomarkers. Importantly, we further provide information about follow-up and the impact of verbal memory profiles on the progression to AD dementia. We hypothesized that the combination of FCSRT and CERAD-WL measures could improve the prediction of MCI-AD and define different prognostic profiles as it would unveil a more accurate picture of verbal memory disintegration along the heterogeneous MCI-AD continuum [14]. This information is crucial to select candidates for biomarker testing in clinical practice and clinical trials [17].

MATERIALS AND METHODS

RESULTS

Use of FCSRT and CERAD-WL to predict conversion to AD dementia in MCI-AD

Of the 163 patients selected for longitudinal analysis, 78 (47.8%) had an AD CSF profile (MCI-AD). After a mean follow-up of 34.2±24.2 months, almost half of these patients (35/78, 44.9%) had progressed to AD dementia. Four patients labeled as MCI nonAD (2.4%) at baseline converted to AD dementia during follow-up (two had borderline Aβ_1 - 42 levels and two had a CSF profile compatible with suspected non-Alzheimer disease pathophysiology (SNAP) (for a detailed description of patients’ characteristics see Supplementary Table 4). As shown in Fig. 1, the combination of FCSRT and CERAD-WL subtests defined different prognostic profiles in MCI-AD patients. After adjusting for age, sex, and education, MCI-AD patients who failed both FCSRT delayed free recall and CERAD-WL recall had a faster progression to AD dementia than patients who failed only one test (HR = 4.7; p = 0.018). Similarly, patients who failed both FCSRT delayed total recall and CERAD-WL recognition tests had a faster progression to AD dementia than patients who failed only one test (HR = 2.39; p = 0.019, Supplementary Table 5). As shown in Fig. 1, amnestic profiles did not differ in the non-amnestic global z-scores, suggesting that progression rates to AD dementia were not driven by global cognitive impairment (data not shown).

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Fig.1

Survival plots for the progression to AD dementia in MCI-AD. A) Survival plots of FCSRT delayed free recall and CERAD-WL delayed recall amnestic profiles; B) Survival plots of FCSRT delayed total recall and CERAD-WL recognition amnestic profiles; ^*, p < 0.05 (Mantel-Cox); ns, no statistically significant difference; +, abnormal result according to the calculated cut-off; -, normal result according to the calculated cut-off; MCI-AD, mild cognitive impairment due to Alzheimer’s disease; FCSRT, Free and Cued Selective Reminding Test; CERAD-WL, Word list of the Consortium to Establish a Registry for Alzheimer’s Disease.

DISCUSSION

In this study, we found that the combination of FCSRT and CERAD-WL measures improves the identification of subjects with MCI-AD defined by CSF biomarkers. In addition, the combination of a semantically-cued test and a free list-learning test with a recognition task defined distinct prognostic profiles in MCI-AD.

We found a relatively low agreement between FCSRT and CERAD-WL, indicating that each of these tests measures different but overlapping aspects of declarative memory [4]. Although both tests evaluate free retrieval, the FCSRT could more closely reflect the hippocampal-mediated consolidationprocess because registration is ensured by semantic cueing. The CERAD-WL test, in contrast, includes a recognition task that implies both recollection and familiarity, functions that depend more on extra-hippocampal areas [8]. Previous studies have examined the neural substrate of the different components of episodic verbal memory using the RAVLT, a non-cued list-learning test with a delayed recognition task [8]. A study using MRI found a close relationship between RAVLT recognition and atrophy in perirhinal and entorhinal regions [33], while a study based on ¹⁸F-fluoro-D-glucose positron emission tomography found that the delayed recall performance was associated with hypometabolism in orbitofrontal, cingulate-precuneus, and parietal areas [34]. Conversely, other imaging studies have shown that cued-recall measures of the FCSRT are related to medial temporal lobe atrophy, although other temporal and parietal regions have been also involved [6, 36]. Moreover, a recent study has highlighted heterogeneity in amnestic FCSRT profiles among MCI-AD patients as defined by CSF core AD biomarkers [37]. Taken together, these data indicate that different verbal memory tests capture different aspects of episodic memory that reflect interrelated but distinct neural circuits.

Comparative data are scarce with regard to the diagnostic performance of verbal memory tests in biomarker-supported or autopsy-proven patient samples and most studies have relied on clinical diagnosis [10–13]. In the only comparable study so far, the authors found that the FCSRT test performed better than the CERAD-WL test to predict MCI-AD [5]. Their sample size (185 patients) was similar to ours (202 patients) and they used a similar broad definition of MCI, but we were unable to replicate their findings. However, we identified some methodological differences that might explain the discrepant results. First, in our study we added both true positive and true negative responses to the CERAD-WL recognition final score, while Wagner et al. considered only true positive responses. Second, we included the CERAD-WL trial 3 score in the analysis but Wagner et al. did not. It is of note that both these subtests appeared to be important predictors of MCI-AD in our study.

We observed that the FCSRT showed a slightly higher sensitivity than CERAD-WL in the diagnosis of MCI-AD (specially, FCSRT total free recall and FCSRT total recall) but both tests had low specificities, reinforcing the notion that MCI is a heterogeneous syndrome [38, 39]. It is known that MCI can be caused by pathophysiological processes other than AD that target the medial temporal lobe structures. Hippocampal sclerosis, TDP-43 pathology, primary age-related tauopathy, and other non-neurodegenerative conditions may explain some of these MCI-nonAD cases [40–42]. Our results could have implications for clinical practice and clinical trials. In clinical practice, when selecting MCI patients for biomarker testing, FCSRT could be used first and then CERAD-WL could be applied if FCSRT is normal. This would maximize the sensitivity to detect MCI-AD in clinical practice. In a clinical trial, measures with high specificity, such as CERAD-WL recognition, could be used in order to minimize the number of screening failures due to biomarker negative results. Further studies are needed to test if the addition of a delayed recognition task to the FCSRT may help increasing specificity for the diagnosis of MCI-AD.

The progression rates to AD dementia during the longitudinal follow up of the patients were similar to those in previous large collaborative studies [23, 43]. Of note, 4 patients with MCI-nonAD converted to AD dementia during follow-up, possibly due to an atypical CSF biomarker AD profile (SNAP or borderline Aβ_1–42 levels) or phenocopies due to non-AD conditions [23, 41].

It is also of note in our study that MCI-AD patients with deficits in both FCSRT and CERAD-WL progressed to dementia faster than those with deficits in only one memory test. These data is in agreement with other previous studies that have described different patterns of neurodegeneration in MCI-AD [14, 39]. We speculate that because FCSRT and CERAD-WL reflect slightly different neural substrates, MCI patients with deficits in both tests may have a higher pathology burden in AD-related structures and their disorder could therefore be at a more advanced stage in the disease continuum. Further imaging studies are needed to confirm this hypothesis.

This study has several limitations. First, we did not analyze measures of visual memory and we acknowledge that the combination of verbal and visual memory measures could further increase the ability to detect MCI-AD [17]. Second, the inclusion of a second verbal memory test could have caused interference when administering the two tests. To minimize this effect, however, we allowed a minimum time between both memory tests and included a non-verbal task. Nonetheless, interference is a potential limitation of all studies that introduce multiple declarative memory tests. Third, we defined MCI-AD using the t-Tau/Aβ_1–42 ratio instead of decreased Aβ_1–42 levels together with increased t-Tau or p-Tau. Our decision to do so was based on large neuropathological series where t-Tau/Aβ_1–42 ratio has proven to be the most sensitive CSF biomarker for AD [26, 44]. Finally, the fact that we used broad criteria to define MCI could be seen as a limitation in a heterogeneous syndrome such as MCI. However, the frequency of MCI-AD being consistent with previous CSF-based studies on MCI population [23, 43] suggests that the MCI sample in our study is comparable to many previous studies.

In summary, we provide evidence that the classification of MCI-AD can be improved by combining FCSRT and CERAD-WL. The diagnostic performance of each test should be considered when MCI-AD is suspected and when selecting patients for biomarker testing in clinical trials. Importantly, the combination had prognostic implications. Our findings highlight the heterogeneity of the amnestic syndrome in the earliest symptomatic phase of AD and reinforce the need to use pathophysiological markers to diagnose AD at this stage.