Abstract
INTRODUCTION:
Recent studies suggest that AD biomarker disclosure has no discernable psychological impact on cognitively healthy persons. Far less is known about how such results affect symptomatic individuals and their caregivers.
METHODS:
RCT of 82 MCI patient and caregiver dyads (total n=164) to determine the effect of receiving amyloid PET results on understanding of, and perceived efficacy to cope with, mild cognitive impairment (MCI) over 52 weeks of follow-up.
RESULTS:
Gains in the primary outcomes were not consistently observed. Amyloid negative patients reported greater perceived ambiguity regarding MCI at follow-up, while moderate and sustained emotional distress was observed in patients, and to a lesser extent, caregivers of those who were amyloid positive. There was no corresponding increase in depressive symptoms.
DISCUSSION:
These findings point to the possibility that both MCI patients and caregivers may need emotional support following the disclosure of amyloid scan results.
Keywords: mild cognitive impairment, amyloid PET, biomarker disclosure, caregiving, ethics
1. Introduction
Biomarker tests of Alzheimer’s disease (AD) pathology can provide critical insights into the etiology of cognitive decline,1–3 and sharing such information with patients and families affected by mild cognitive impairment (MCI) could lessen their sense of ambiguity regarding the syndrome.
We tested the hypotheses that, irrespective of scan results, giving patients the opportunity to learn their brain amyloid status would enhance understanding of and decrease perceived ambiguity regarding MCI, and empower both patients with MCI and their family caregivers to cope more effectively with its challenges.
2. Methods
2.1. Design and Participants
The Return of Amyloid Imaging Scan Results (RAISR) Study enrolled participants from the University of Pittsburgh Alzheimer Disease Research Center (ADRC) between September of 2014 and September of 2018. Eligible participants and their family caregivers were allocated as dyads in a 1:1 ratio to a scan group or comparison group (Figure 1). Details of the study design and protocols for MCI education (comparison group) and pre-testing counseling (scan group), amyloid PET results disclosure, and adverse event monitoring have been previously described.4–6 Briefly, we included patients with all MCI subtypes and excluded those with active untreated mood disorders. Caregivers were 18 years of age or older. All participants provided written informed consent and demonstrated decisional capacity.
Figure 1.
Consort diagram. ADRC, Alzheimer Disease Research Center (University of Pittsburgh); PT, patient; CG,caregiver *N=12 patients had previously undergone a research PET amyloid scan under a protocol that precluded results disclosure. The randomization process was overridden in these cases and participants were assigned to the scan group, with the opportunity to undergo a new amyloid PET scan and results disclosure. This deviation did not impact the balance of the study groups (including the subgroups of amyloid positive and negative cases) on key baseline characteristics or primary outcomes measures.
RAISR was approved by the University of Pittsburgh Institutional Review Board and registered at ClinicalTrials.gov.
2.2. Intervention:
Scan group dyads received pre-test counseling including content on normal aging, MCI, and AD, amyloid PET, and information about the limitations of knowledge to be gained. Participants were encouraged to consider possible reactions to potential scan result scenarios before deciding whether to proceed. Comparison group dyads received an MCI education session with no option of amyloid PET. PET scans were acquired using a standard florbetapir F18 injection protocol7 and rated using a validated binary visual read method.8,9
The disclosure protocol included: verbal and visual presentations of scan results using “significant amyloid buildup,” or lack thereof, to describe positive and negative scans; short-term risk estimates for conversion to AD; brain health information; and follow-up monitoring instructions.4 Participants were randomly assigned to one of three clinically licensed, formally trained results disclosers. Disclosure sessions were audited for protocol adherence and participants’ comprehension of information presented was verified.4
2.3. Primary Outcomes
Outcomes measures were administered at baseline and weeks 4, 24, and 52 post-disclosure (scan group) or MCI education session (comparison group). Objective knowledge of MCI was measured using the MCI/AD Knowledge Assessment from the REVEAL IV protocol.10 Perceived ambiguity about what MCI means was measured using the Illness Coherence Subscale of the Revised Illness Perception Questionnaire (IPQ-R).1 Self-efficacy for coping was measured by the Coping Self-Efficacy Scale (CSE).12
2.4. Psychological Safety
Depressive symptoms were measured by the Center for Epidemiological Studies Depression Scale (CESD).13 State anxiety was measured by the Spielberger State Anxiety Inventory (STAI).14 Emotional impact was measured by the 15-item Impact of Event Scale (IES).15 The Distress and Positive Impact subscales of the Impact of Genetic Testing-Alzheimer’s Disease (IGT-AD) were also administered,16 substituting “test result” for “genetic test.”
2.5. Statistical Analyses
Intention-to-treat (ITT) analyses of primary outcomes were conducted based on an a priori power analysis indicating that 40 subjects per group would yield 80% power to detect a medium effect size of 0.64 (from a behavioral science perspective) at a two-tailed significance level of .05. This estimation is conservative given RAISR’s repeated measures design which can detect effect sizes as small as 0.32.
After screening, transformations were applied to normalize skewed residuals where encountered (e.g., CESD, STAI). Group comparisons of participant characteristics were performed using two-sample t-tests (or Mann-Whitney U-tests) and chi-square tests (or Fisher exact tests). Linear mixed modeling with fixed effects for group and time and their interaction, and random effects for participant, were used to examine change in the dependent variables. Least squares means and their corresponding standard errors were reported by group and time point along with means and standard errors from within-group linear contrasts. Linear mixed modeling was also used to examine psychological safety by scan result. All 164 participants were included and the significance level was set at p<0.05 for two-sided hypothesis testing. Results based on untransformed dependent variables are reported as findings were similar using transformed data.
3. Results
The sample included 164 individuals (n=82 patients; n=82 caregivers) who completed baseline data collection before allocation to the scan opportunity (n=42 dyads) or comparison condition (n=40 dyads). Characteristics of the sample are shown in Table 1. Most patients were highly interested (M=9.2 on a 10-point scale) in learning their brain amyloid status upon enrollment. Of the 39 scan group patients who completed pre-test counseling, 37 proceeded with the scan, and 36 received results. Reasons for declining included concerns about radiation exposure and the potential for a negative emotional reaction.
Table 1.
Sample characteristics by study group*
| Patient participants | Caregiver participants | |||||
|---|---|---|---|---|---|---|
| Variable | All patient (N=82) | Scan opportunity (n=42) | Comparison (n=40) | All Caregiver (N=82) | Scan opportunity (n=42) | Comparison (n=40) |
| Mean age in years (SD) | 72.6 (8.80) | 73.2 (8.19) | 72.0 (9.47) | 66.8 (12.56) | 67.8 (11.59) | 65.8 (13.58) |
| Education, n (%) | ||||||
| < High school | 1 (1%) | 0 (0%) | 1 (2%) | 1 (1%) | 1 (2%) | 0 (0%) |
| High school/GED | 13 (16%) | 7 (17%) | 6 (15%) | 15 (18%) | 5 (12%) | 10 (25%) |
| Technical school or College | 23 (28%) | 10 (24%) | 13 (33%) | 38 (46%) | 18 (43%) | 20 (50%) |
| Graduate school | 45 (55%) | 25 (59%) | 20 (50%) | 28 (34%) | 18 (43%) | 10 (25%) |
| Gender, n (%) | ||||||
| Female | 33 (40%) | 19 (45%) | 14 (35%) | 62 (76%) | 31 (74%) | 31 (77%) |
| Male | 49 (60%) | 23 (55%) | 26 (65%) | 20 (24%) | 11 (26%) | 8 (23%) |
| Race/ethnicity, n (%) | ||||||
| White/Caucasian | 75 (92%) | 37 (88%) | 38 (95%) | 74 (90%) | 37 (88%) | 37 (92%) |
| Black/African American | 6 (7%) | 4 (10%) | 2 (5%) | 5 (6%) | 4 (9.5%) | 1 (3%) |
| Asian/Pacific Islander | 1 (1%) | 1 (2%) | 0 (0%) | 1 (1%) | 1 (2%) | 0 (0%) |
| Multiracial | 0 (0%) | 0 (0%) | 0 (0%) | 2 (2%) | 0 (0%) | 2 (5%) |
| MCI subtype, n (%) | ||||||
| Amnestic | 71 (87%) | 37 (88%) | 34 (85%) | n/a | n/a | n/a |
| Non-amnestic | 11 (13%) | 5 (12%) | 6 (15%) | |||
| Relationship, n (%) | ||||||
| Spouse/partner | 60 (73%) | 28 (67%) | 32 (87%) | |||
| Adult child | n/a | n/a | n/a | 9 (11%) | 7 (17%) | 2 (5%) |
| Other | 13 (16%) | 7 (17%) | 6 (15%) | |||
| Mean interest in amyloid PET at baselinea (SD) | 9.2 (1.59) | 9.0 (1.96) | 9.4 (1.06) | 8.9 (2.50) | 8.6 (2.65) | 9.1 (2.35) |
| Mean UBACCb score (SD) | 18.9 (1.43) | 18.9 (1.32) | 18.9 (1.56) | 19.1 (1.43) | 18.8 (1.51) | 19.3 (1.31) |
Abbreviations: GED, general education diploma; MCI, mild cognitive impairment; PET, positron emission tomography; UBACC, University of San Diego Brief Capacity to Consent;
rating of interest in PET amyloid PET on 10-point scale;
p>.05 difference between scan and comparison groups using chi-square or t-test; post-hoc comparisons of demographic characteristics of amyloid negative and amyloid positive scan group participants were also non-significant
3.1. Primary Outcomes
Among patient participants, there were no significant time or group by time effects for any of the three primary endpoints (Table 2). Findings were similar among caregivers. However, a time effect was observed for objective knowledge of MCI/AD, with scores increasing from baseline among caregivers in both groups (FT=5.12, p=0.002). A within group time effect was observed for self-efficacy for coping with MCI; caregivers in the scan group reported decreased self-efficacy for coping with their relatives’ MCI at 4 weeks post results disclosure (mean difference=−12.35±−5.12; p<.05), with the decrease persisting at week 52 (mean difference=−14.98±−6.67; p<.05).
Table 2.
Primary outcomes
| Patient | Caregiver | |||||
|---|---|---|---|---|---|---|
| Variable | Scan Opportunity (n=42) | Comparison (n=40) | Scan Opportunity (n=42) | Comparison (n=40) | ||
| mean±SE | mean±SE | F-value, p-value | mean±SE | mean±SE | F-value, p-value | |
| IPQ Coherence | FG=0.00, p=.955 | FG=0.00, p=.947 | ||||
| Baseline (T1) | 14.69±0.57 | 14.03±0.58 | FT=0.96, p=.412 | 12.38±0.49 | 12.65±0.50 | FT=1.54, p=.207 |
| 4 weeks (T2) | 14.39±0.59 | 14.27±0.60 | FG×T=1.21, p=.306 | 13.26±0.52 | 12.55±0.53 | FG×T=0.82, p=.486 |
| 24 weeks (T3) | 13.77±0.62 | 14.57±0.62 | 11.85±0.55 | 12.26±0.55 | ||
| 52 weeks (T4) | 13.72±0.59 | 13.86±0.60 | 12.43±0.53 | 12.31±0.53 | ||
| Change (T2-T1) | −0.30±0.52 | 0.25±0.53 | 0.87±0.53 | −0.10±0.54 | ||
| Change (T3-T1) | −0.92±0.55 | 0.54±0.55 | −0.54±0.56 | −0.39±0.55 | ||
| Change (T4-T1) | −0.97±0.52 | −0.16±0.53 | −0.05±0.54 | −0.34±0.54 | ||
| Knowledge | FG=1.64, p=.204 | FG=0.03, p=.871 | ||||
| Baseline (T1) | 8.90±0.22 | 8.90±0.22 | FT=0.25, p=.863 | 8.79±0.23 | 8.80±0.24 | FT=5.12, p=.002 |
| 4 weeks (T2) | 8.75±0.23 | 9.34±0.24 | FG×T=1.38, p=.249 | 9.29±0.24 | 9.47±0.25 | FG×T=0.91, p=.436 |
| 24 weeks (T3) | 8.90±0.24 | 9.00±0.25 | 9.43±0.26 | 9.14±0.26 | ||
| 52 weeks (T4) | 8.65±0.23 | 9.19±0.24 | 9.15±0.25 | 9.43±0.25 | ||
| Change (T2-T1) | −0.16±0.25 | 0.44±0.26 | 0.51±0.24* | 0.67±0.24** | ||
| Change (T3-T1) | 0.00±0.26 | 0.10±0.27 | 0.64±0.25* | 0.34±0.25 | ||
| Change (T4-T1) | −0.26±0.25 | 0.29±0.26 | 0.37±0.24 | 0.63±0.24** | ||
| Coping Self-Efficacy | FG=0.37, p=.543 | FG=0.04, p=.852 | ||||
| Baseline (T1) | 204.92±5.12 | 202.13±5.25 | FT=0.14, p=.936 | 204.05±4.99 | 200.76±6.50 | FT=2.19, p=.100 |
| 4 weeks (T2) | 205.45±5.27 | 202.02±5.39 | FG×T=0.66, p=.578 | 191.70±7.42 | 191.13±10.61 | FG×T=1.33, p=.274 |
| 24 weeks (T3) | 205.91±5.41 | 204.57±5.52 | 196.64±6.47 | 195.23±9.35 | ||
| 52 weeks (T4) | 208.73±5.3 | 199.91±5.39 | 189.07±8.44 | 201.23±6.97 | ||
| Change (T2-T1) | 0.53±3.83 | −0.11±3.91 | −12.35±5.12* | −9.63±8.26 | ||
| Change (T3-T1) | 0.99±4.03 | 2.45±4.08 | −7.41±4.52 | −5.53±7.90 | ||
| Change (T4-T1) | 3.81±3.87 | 2.22±3.91 | −14.98±6.67* | 0.47±5.06 | ||
Abbreviations: SE, standard error; IPQ, Illness Perception Questionnaire;
p<.05;
p<.01
3.2. Safety Outcomes and Subgroup Analyses
There were no consistent differences in depressive symptoms in either patients or caregivers, and patients’ ratings of state anxiety were stable over time across groups (Figure 2). Caregivers’ state anxiety levels were increased from baseline at both 4 and 24 weeks of follow-up, returning to baseline at week 52 (FT=3.16, p=0.031). Mean scores on both the depression and anxiety measures were below cut-points for clinical significance across all participant groupings and time points (Table 1, Supplement).
Figure 2.
Psychological safety. Measures of mood over time CESD, Center for Epidemiological Studies Depression Scale; STAI, Speilberger State Anxiety Inventory; Aβ, amyloid beta.
Subgroup analyses showed increasing perceived ambiguity about MCI among amyloid negative patients (p<.05) and revealed that decreased self-efficacy for coping was most pronounced among caregivers of amyloid positive individuals at 4 weeks post disclosure (mean difference=−14.83±−7.72; p<.05), and those of amyloid negative patients at 24 weeks post disclosure (mean difference=−12.22±5.83; p<.05).
At all follow-up assessments, IES ratings were higher among amyloid positive patients versus amyloid negative patients. These scores declined over time (FT=5.42, p=0.008), but between group differences persisted (Figure 3). Similar patterns were observed on IGT-AD distress ratings, with the greatest difference at week 4 where amyloid positive patients had mean IGT-AD scores averaging three times higher than amyloid negative patients. IGT-AD positive scores were elevated and stable among amyloid positive patients, but increased at each follow-up point among amyloid negative patients, whose scores grew closer to those of the amyloid positive patients over time (Supplement).
Figure 3.
Post-disclosure impact of event scores over time. IES, Impact of Events Scale; IGT, Impact of Genetic Testing Scale; Aβ, amyloid beta An IES total score cut-off point of 26 is noted by a dashed line above which a moderate or severe impact may be indicated
Analyses of caregiver post-disclosure distress revealed group differences on the IGT-AD distress and positive subscales, with caregivers of amyloid positive individuals reacting more negatively to test results (Figure 3).
4. Discussion
We hypothesized that, irrespective of scan results, having the opportunity to learn more about the potential etiology of cognitive symptoms would improve patients’ and caregivers’ overall understanding of, and self-efficacy for coping with, MCI. However, learning one’s brain amyloid status was no more effective than an MCI education session for increasing caregivers’ knowledge about MCI, and patients’ knowledge scores were unchanged regardless of group assignment. Subgroup analysis showed that perceived ambiguity regarding MCI increased in amyloid negative patients, suggesting that such individuals likely understood that their symptoms remained unexplained.
Contrary to our hypothesized increase, we observed decreased self-efficacy for coping with MCI among caregivers of scan group participants, a finding which was present, at varying time points, among caregivers of participants with both positive and negative results. This unstable decrease in self-efficacy could potentially reflect feelings of unpreparedness regarding the prospect of one’s relative progressing to AD (amyloid-positive group) as well as increased uncertainty about the cause of the symptoms (amyloid-negative group).
Although emerging literature suggests that disclosing brain amyloid status to cognitively normal adults and those with subjective cognitive impairment has no discernable effect on psychological well-being, evidence in overtly symptomatic populations and family caregivers is limited.17 Consistent with prior investigations of unimpaired persons18, we found no significant differences in mood between amyloid positive and negative individuals. However, we observed significant and sustained levels of event-related distress among MCI care dyads who learned of amyloid positivity, with ratings notably higher than those reported in asymptomatic samples.
Overall, our findings raise the possibility that emotional support interventions may be indicated upon biomarker testing in MCI, although needs may vary depending on one’s perspective (patient or caregiver) and scan result.
Given the self-selection bias associated with ADRC participation, there is a critical need for additional studies with more diverse samples who may be less receptive, or may respond differently, to AD biomarker testing. Importantly, RAISR excluded individuals with active untreated mood disorders, which are prevalent among cognitively impaired individuals. Therefore, our exploratory findings regarding psychological safety may not extend to all MCI patients meeting Appropriate Use Criteria for amyloid PET.19,20
Supplementary Material
Acknowledgments
The authors gratefully acknowledge the participants who volunteered for this research. We also Thank Drs. Meghan Mattos, Jonna Morris and Ms. Sarah Goldberg for their efforts as pre-test counselors. This study was supported by NIH/NIA R01AG046906–01, NIH/NIA, P50 AG05133, and NIH/NIA P30 AG053760. Florbetapir F 18 Injection doses in this study are supplied at no cost by Avid Radiopharmaceuticals a wholly owned subsidiary of Eli Lily, Inc. The week-4 follow-up data reported in this manuscript were first presented at the 2019 Alzheimer’s Association International Conference.
Footnotes
Conflict of Interest Statement: Florbetapir F 18 Injection doses in this study are supplied at no cost by Avid Radiopharmaceuticals a wholly owned subsidiary of Eli Lily, Inc. Dr. Lopez provides consultation to Grifols, Inc.
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