As the field inches toward treating Alzheimer’s disease at the preclinical stage, researchers need to find sensitive tests that can tell whether therapies work. Measures that pick up subtle cognitive decline in healthy elderly are coming along, but how to detect changes in people's everyday function is less clear. To this end, the Alzheimer’s Disease Cooperative Study (ADCS) has spent the last 10 years developing the Cognitive Function Instrument (CFI). In the February 23 JAMA Neurology, researchers led by Reisa Sperling at Brigham and Women’s Hospital, Boston, report that the CFI tracks longitudinal decline in people who start out cognitively normal, suggesting it may serve as a good functional outcome measure in prevention trials. “While cognitive outcomes are considered the gold standard, you want to show that a treatment impacts people’s everyday functioning,” said Rebecca Amariglio, first author on the paper. “That’s what matters most to people participating in these studies.”
The most recent draft guidance from the FDA suggests that a treatment can gain provisional approval for preclinical Alzheimer's based on a single cognitive measure, but will eventually have to demonstrate an improvement on function as well (see Mar 2013 news). Unfortunately, most of the tried-and-true functional measures, such as the ADCS Activities of Daily Living, do better at detecting drastic changes during the later stages of disease than subtle changes in people who may be on the cusp.
The CFI survey is administered by mail, over the phone, or online (see paper). It is short, requires no interview, and is relatively inexpensive to use in large trials. Study participants and their partners each answer parallel questions separately, addressing early signs of problems with everyday functions, such as remembering appointments, driving, keeping track of finances, navigating around town, or following news or story plots. The survey also asks about perceived decline, such as whether the person's memory has worsened over the previous year, or whether they repeat questions. Responders answer yes, no, or maybe, to 14 questions to yield a score of 1, 0, or 0.5, respectively. Summed scores generated from the patient and his or her partner can be analyzed separately or together. By assessing subjective functional change, the test complements the modified ADCS Preclinical Alzheimer Cognitive Composite (mADCS-PACC), which detects objective cognitive changes in apparently healthy people (see Jun 2014 news). In the ongoing A4 trial the mADCS-PACC will be used as a primary, and the CFI as a secondary, outcome measure (see Dec 2014 conference story).
To test whether the CFI captures longitudinal change, Amariglio and colleagues enrolled 468 older individuals, average age 79, who were considered cognitively healthy based on the Clinical Dementia Rating Scale (CDR), modified mini-mental state examination (3MSE), and free and cued selective reminding test (FCSRT). During the four-year study, each participant came in for an annual cognitive assessment. A month before each visit, each completed the CFI survey. The researchers sent the parallel version to each person’s study partner. At the end of the study, the researchers correlated changing CFI scores with clinical progression, change on the mADCS-PACC, and ApoE4 status.
People who eventually became impaired, i.e., progressed to a CDR greater than 0, started out with higher CFI scores at baseline than people who remained stable over the four years of study. Since all began with a CDR of 0, it suggests that the survey detects functional problems before the CDR does. During the study, scores worsened on the self, partner, and combined tests for those who declined. The “self plus partner” score best predicted CDR change (see image above), implying that both inputs reinforce each other.
Overall, the scores correlated well with cognitive decline detected by the mADCS-PACC, with higher CFI tallies tracking with worsening cognition. Again, the combined score correlated best, followed by the partner- and self-assessment scores. Both mADCS-PACC and CFI predicted decline independently, but together performed slightly better, hinting that cognitive plus functional measures are most informative, wrote the authors. Since the researchers measured no biomarkers to confirm that Alzheimer's was behind these early changes, they used ApoE4 status as a proxy. While the differences were less stark than between progressors and non-progressors, the partner CFIs did differentiate ApoE carriers and non-carriers by three years into the study.
The CFI could provide an outcome measure in preventative drug trials for AD, allowing scientists to compare subjective cognitive function of treated and untreated groups, said Amariglio. In the future, researchers may also develop this test as a diagnostic tool to pick out people at risk for decline, but more research needs to determine the appropriate cutoffs, she said.
This is a really important contribution to the field,” said Jessica Langbaum of Banner Alzheimer's Institute in Phoenix. That the CFI requires no interview is a major plus, she added. Langbaum and other scientists of the Alzheimer’s Prevention Initiative (API) and Novartis are still deciding which patient-reported outcomes to use in the API ApoE4 trial. Langbaum said it would be interesting to compare the CFI with the more extensive ADCS measure of function, the Activities of Daily Living–Prevention Instrument, which does require a physician interview (see Galasko et al., 2006). The ADL-PI is longer and includes no questions about memory function, which may be important to detect early progression, wrote Amariglio and colleagues. It is also more difficult to score and interpret, said Amariglio. The correlation between CFI and ADL-PI questionnaires is in the range of 0.3 to 0.4, she said.
“There is without doubt a clear need for new measures of functional impairment,” John Harrison of Metis Cognition, Wiltshire, U.K., wrote to Alzforum (see full comment below). “With the interest in AD focused largely on secondary prevention, appropriate and sensitive measures of functional activities are essential. Of course, one of the big questions is whether these scales can capture the effect of pharmaceutical and other interventions."—Gwyneth Dickey Zakaib
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