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Amariglio RE, Donohue MC, Marshall GA, Rentz DM, Salmon DP, Ferris SH, Karantzoulis S, Aisen PS, Sperling RA, Alzheimer’s Disease Cooperative Study. Tracking early decline in cognitive function in older individuals at risk for Alzheimer disease dementia: the Alzheimer's Disease Cooperative Study Cognitive Function Instrument. JAMA Neurol. 2015 Apr;72(4):446-54. PubMed.
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Metis Cognition Ltd.
There is without doubt a clear need for new measures of functional impairment. As the authors rightly point out, with the interest in AD focused largely on secondary prevention, appropriate and sensitive measures of functional activities are essential. Established measures such as the DAD and ADCS-ADL have rather shown their age with regard to content, and have been prone to ceiling effects in these early stage patients. The Clinical Dementia Rating (CDR) scale has become a popular alternative selection. Whilst the CDR can be a very useful staging instrument, many in the AD community, including the EMA, have expressed concerns about its utility as an outcome measure.
I think the appeal of the CDR has been that because it is a semi-structured interview, any comment made by a patient or their informant can be considered in scoring the patient’s levels of performance. These comments might reflect items not included on traditional ADL measures. Fixed item scales, which have focused on activities most commonly reported as being problematic, but not the entirety of function, are not as flexible, and that is challenging. Good examples of gaps with traditional measures would be buying things online, or organizing a tour-style vacation, etc. These have become relatively common activities and it is good to see that some elements of these issues have been incorporated in the CFI.
Personal performance on ADL items can also be idiosyncratic and especially influenced by cultural factors. I think by asking about change across a one year period this has been well-managed by the authors, because if the item is not appropriate then a ‘no change’ judgment can be selected. The challenge of having adopted this approach is whether the reporting of patients and informants can be considered accurate. This has long been an issue in the self-reporting capacities of patients’ who might exhibit anosognosia, possibly as an early consequence of AD. In this context it is interesting to see the authors state that the perceived change in function across 48 months by partners was more than twice that reported by patients.
Capturing levels of functional capacity has been a significant challenge for research in a number of CNS indications. An exciting development to have grown out of the ‘quantified self’ movement is the possibility of using mobile apps and ‘always-on’ gadgets to track and analyze people’s activities. I think this approach has great promise, but is very much in its infancy. In the meantime we will be largely reliant on patient and informant report measures. Recent innovations such as the CFI and the Amsterdam IADL scale are promising developments in an area with clear unmet need. Of course, one of the big questions is whether these scales can capture the effect of pharmaceutical and other interventions. I have found that sponsors have been unwilling to move away from scales like the DAD and CDR. However, it seems unlikely that these scales can capture interventional benefit, so arguably there is nothing to lose from trying newer, promising measures. It is worth mentioning that in contrast to the CDR, the CFI and AIADL can be administered by competent non-specialists. This is a clear benefit because the lack of appropriate CDR raters has been a major challenge in successfully running early stage AD clinical drug trials.
University of Cape Town
Tracking Early Decline with the CFI
The need for functional scales as outcomes for AD prevention trials has been identified. There are other scales available (ADL and iADL), but this one has the advantage of being able to be completed at home and returned by mail/email, by telephone, or face-to-face. For lengthy intervention trials in those at very early stages of cognitive decline, this is an obvious advantage over scales that only can be administered face-to-face. However, to provide reliable results, these sorts of questionnaires rely on the participants being honest, relatively well-educated, and not severely cognitively impaired.
The CFI does not attempt to replace cognitive outcome measures for trials, and in fact correlates well with the ADCS cognitive instrument (mADCS-PACC). Cognition will need to be assessed; however, interventions to improve cognition need to show efficacy for behavioral outcomes as well, to show that they are making a difference with activities of daily living.
The CFI was shown to predict cognitive decline to MCI and dementia over a four-year period. Its sensitivity to decline was only detectable after 12 months follow-up for both the partner report and when the self-report and partner-report scores were combined. Self-report only reached significance at 24 months. The self-report was reportedly more reliable in the earlier phase of decline (approximately between 24-36 months), while the partner report became more reliable when functional decline was more obvious (48 months). This is expected, because self-awareness of memory decline is better before decline is too marked, while a partner or informant may not be aware of early, subtle decline.
Overall, the differences in scores between those who progressed to MCI or mild dementia (CDR-G 0.5 or higher) are relatively small from a clinical perspective for the self-report (2.13 points in 48 months), although “self plus partner” reached a good degree of separation between the groups (7.5 points in 48 months). The problem is that not many trials of 48 months are easily affordable and compliance may fall and drop-outs increase. However, from a statistical analysis of trial efficacy, it looks as though trials of 24-36 months may also be long enough to show significant change.
The authors used modelling to test the scales as predictors of decline. This is not the same as testing improvement or maintenance of function due to intervention. However, the trajectories of decline that have been established will be useful as baselines for assessment of change due to interventions. The rate of change that can be expected with an intervention is therefore unknown, but would be expected to be less than the rate of decline, unless the intervention can completely restore the global function to normal (e.g. CDR-G = 0).
Another difficulty in a clinical trial is that the baseline cognitive/functional status of those randomized may not all be at the same level, especially in trials for those already experiencing memory complaints or who have MCI, thus change over time will be more variable.
The CFI does allow for inexpensive monitoring of reported functional ability, which will go a long way to making long-term AD prevention trials more feasible. The best results will be obtained with both self- and partner-report scores combined. Whether this scale will be sufficient, with other measures (cognitive, clinical etc.) only taken at baseline and trial end, remains to be seen. Alternatively, an intervention may be stopped after a period (for instance two years) with all measures done, and the CFI used in follow up to assess longer term benefits of the intervention.
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