Discussion
heterogenous, cognitive impairment, MCI disease, MCI, dementia, amnestic MCI, COA, aMCI
DISEASE, PATHOLOGY
The aim of this study was the evaluation of the psychometric properties of the ADCS-ADL-MCI, a functional evaluation scale assessing aMCI patients' ability to perform ADLs as reported by an informant/carer. This psychometric evaluation included aspects of reliability, validity, and responsiveness examined using data from 769 adults with amnestic MCI who had participated in the ADC-008 trial of the ADCS [While a single timepoint is frequently used to evaluate psychometric properties, we observed a somewhat narrow range of impairments in the population recruited into the ADC-008 study and valued including the more heterogenous and advanced MCI disease presentation observed in the cohort evaluated at the 36-month time point. Further, as evaluation of an instrument’s measurement properties is not related to the biologic reasons underlying disease process, we determined it appropriate to use both placebo- and experimental-treated patients at the 36-month timepoint. With the totality of these data, we found good evidence of psychometric validity for the ACDS-ADL-MCI in this cohort of amnestic MCI patients.Item-level analysis indicated that ceiling effects on the ADCS-ADL-MCI total score were not apparent, while examining individual items indicated some isolated ceiling effects. Given the relatively mild condition of this cohort of patients, the findings are likely due to the relatively low impairment level of the cohort rather than the instrument's limitations. This is supported by the observation that fewer item-level ceiling effects were observed at month 36 compared to baseline. Interestingly, outcomes that may be attributed to sex differences were observed on some items, particularly the activities that may have sex-specific roles for some participants, as may be associated with the generation of patients represented in this study (e.g., cleaning and laundry). This finding suggests these questions were not assessing abilities but rather usual activities.The ADCS-ADL-MCI demonstrated moderate evidence of internal consistency. While item-total correlations were overall acceptable at month 36, at baseline there were generally poor correlations for most items. These findings were anticipated as variability in responses are known to increase with increasing disease severity and items with higher response variability are expected to show stronger correlations with the total score [Further, items with strong sex effects (e.g., items 4 and 7) also had low item-total correlations (< 0.30), indicating that they behave systematically different from the other items. Finally, the Cronbach’s alpha measure of internal consistency was acceptable, with a Cronbach's alpha of 0.64 at baseline, and 0.87 at month 36 [Reproducibility, defined by test–retest ICC, of the ADCS-ADL-MCI was moderate to good, especially as the timeframe between screening and baseline assessments (up to 6 months) was longer than typically desired (e.g., two weeks). In general, the ICC was higher when using the MCI-CGIC, GDS and CDR-SB vs. MMSE to define stability. One reason may be that the MMSE has higher variability in the MCI population than the other measure. Nonetheless, given the widespread use of the MMSE in this population, it was deemed important to explore 'stability' according to the MMSE as well.The convergent validity of the ADCS-ADL-MCI with other relevant COA measures defined a priori showed moderate to high correlations. The ADCS-ADL-MCI was moderately correlated with the CDR-SB total score in the baseline measurement cohort. At month 36, strong correlations were observed between the ADCS-ADL-MCI total score and all the COA instruments evaluated, except for the BDI, Qol-AD-Informant total score, and NYU delayed paragraph recall test (moderate correlations observed). While a few of these results were contrary to expectations (i.e., we had expected weaker correlations with the NYU paragraph recall test and Symbol Digit Modalities Test), they indicate that functional, behavioral, and cognitive symptoms are all affected by (mild) cognitive impairment, particularly in a cohort with increased variability in disease presentation. Further, The ADCS-ADL-MCI likely had the strongest correlations with the CDR-SB as both measures assess functional aspects, whereas the MMSE and ADAS-Cog address predominantly cognitive aspects.Further strong support was found for the known-groups validity of the ADCS-ADL-MCI, which is in line with previous publications [Finally, there was good support for the responsiveness of the ADCS-ADL-MCI, i.e., the instrument was adequately responsive in patients who indicated change in other instruments; and it was adequately stable in patients who did not show change in other instruments (CDR-SB and global CDR). Curiously, the 'improved' group according to CDR functional domain showed a marginal decrease in ADCS-ADL-MCI scores. Further, for the GDS, the two categories' improved' and 'no change' showed decreases in ADCS-ADL-MCI scores, with the former group showing even larger reductions than the latter group. Given that no confirmation of underlying AD or other neurodegenerative pathology was confirmed in this trial, it is plausible that some participants who meet criteria for MCI could subsequently “revert” to normal cognition. However, MCI patients reverting back to normal still remain at higher risk of progressing to dementia [Strengths of the study include a relatively large sample size that enabled us to carry out all psychometric tests planned and trust that results are robust, especially given that the sample was based on a diverse population in terms of age, education, and years since disease onset. Besides that, the ADC-008 trial dataset included an extensive range of COA instruments that enabled us to use these as reference instruments to assess various psychometric properties. Further, given that the study used data from an interventional clinical trial, tests of sensitivity to change over time were possible as the objective change had occurred in many trial participants over the 36-month duration of the trial.The present study also has some limitations. For example, our target instrument was assessed at baseline, while some of the reference COA instruments had only been assessed at the screening assessment. Hence, while it is not expected that large changes occurred between these two time points, for the purpose of our project, it would have been preferable to have all COAs assessed at the same time point. However, we responded to this potential limitation by using 36-month data for our psychometric tests as well. The 36-month timepoint has limitations in that it only includes the aMCI patients who have not progressed to dementia, e.g., a more slowly progressing population. Thus, while the sensitivity to change reported herein may represent a conservative estimate, this reflects somewhat of a strength in that the psychometric property is shown in a more conservative sample. Given that Further, the two-step response process to most ADCS-ADL-MCI items poses some challenges for psychometric evaluation. For example, scale-level tests such as factor analysis on gated items are more challenging than those on questions with thoroughly graded responses. Therefore, we could not confirm nor deny the unidimensionality assumption of the ADCS-ADL-MCI. However, our results suggest that the ADCS-ADL-MCI performs well across multiple psychometric tests despite this limitation. The diversitiy of the enrolled clinical cohort was poor, with 92% of the cohort “white, not of Hispanic Origin”. While the inclusion criteria for the study was extensive to confirm amnestic MCI, subjects were not required to have evidence of amyloid or tau pathology, thus the application of these findings to MCI patients on the AD continuum can be considered an extrapolation on the basis that a clinical diagnosis of amnestic MCI is the same regardless of the underlying disease pathology. It is nonetheless important to note that patients with MCI may not necessarily have underlying AD. Finally, a caveat to the use of informant-based methods is reliance on the caregiver’s knowledge about patient’s daily activities. As such, the accuracy of these reports is somewhat limited to the amount of care provided by the informant.Overall, findings from this study suggest that the ADCS-ADL-MCI is reliable, valid and responsive to change in an amnestic MCI population. However, further investigation is needed in this sample, and a comparison of performance-based measures, self-report and informant-report measures may help define functional impairment in MCI (in terms of quanitifable cut-off scores) more precisely.