Analysis of Psychological Symptoms Following Disclosure of Amyloid–Positron Emission Tomography Imaging Results to Adults With Subjective Cognitive Decline

Key Points Question What are the psychological symptoms following disclosure of a positive amyloid–positron emission tomography (PET) imaging result on patients with subjective cognitive decline? Findings This study of 105 patients found that the disclosure of a positive amyloid-PET result was associated with a greater psychological changes, yet such changes did not reach the threshold for clinical concern. Meaning These findings suggest that the disclosure of a positive amyloid-PET result in patients with subjective cognitive decline was not associated with clinically meaningful psychological risk.


Introduction
Amyloid deposition in the brain is considered as the strongest risk factor for Alzheimer disease (AD), 1 and is often also observed in patients with other neurodegenerative diseases 2 and in cognitively unimpaired individuals. 3 It can be assessed in vivo through positron emission tomography (PET) imaging. The use of amyloid-PET in clinical practice is recommended only for some categories of patients with objective cognitive impairment, although it is discouraged in cognitively unimpaired older individuals. 4,5 However, consistent evidence suggests that individuals with subjective cognitive decline (SCD), a category of patients representing 21% to 29% of a general memory clinic population, 6,7 are at higher risk of developing dementia in the upcoming years (incidence of dementia: 20.1/1000 person-years in SCD population vs 14.2/1000 person-years in controls 8 ).
Moreover, some additional clinical features further increase the likelihood of preclinical AD, defining the so-called subjective cognitive decline plus (SCD+) construct. 9 Furthermore, the risk of progression to dementia is substantially increased in case of the presence of amyloid deposition (ie, a hazard ratio of 17.0 compared with SCD with normal AD biomarkers 10 ). For these reasons, individuals with SCD are increasingly targeted in research and prevention initiatives, 11 and are frequently included in research studies involving amyloid-PET (eg, ABIDE, 12 AMYPAD-DPMS, 13,14 DELCODE, 15 SCIENCe, 16 COSCODE, 17 ALFA+ 18 ). Previous studies have shown that amyloid-PET has substantial clinical consequences in terms of diagnostic change and improvement of diagnostic confidence in SCD, 19,20 and many of these individuals are proactively seeking medical advice and information about their amyloid status. 11 Although cognitively unimpaired individuals receiving a negative amyloid-PET result are relieved as they can reinterpret their subjective memory impairment as normal aging, individuals who are amyloid-positive perceive the result as more serious and sensitive than other examinations given its implications for identity, self-determination, and stigma. 21 Moreover, individuals without cognitive impairment who are amyloid-positive reported to contemplate and make more changes to health behaviors and future plans after disclosure than individuals who are amyloid negative. 21,22 Nevertheless, it has been reported that the prognostic uncertainty of amyloid-PET is correctly understood by two-thirds of patients. 23 The psychological outcomes of the amyloid-PET result disclosure in cognitively unimpaired individuals has been assessed by some previous studies. For example, one of these studies showed no association with depression and minor increases in disclosure-related distress and anxiety that are mild and well-tolerated over 6 months. 24 Another study found that individuals who were cognitively unimpaired and receiving a positive amyloid-PET result disclosure were no more likely to experience short-term increases in anxiety, depression, or suicidality than those receiving a negative amyloid-PET result disclosure. 25 Taken together, these results suggest that, in a research setting, the disclosure of the amyloid status in cognitively unimpaired individuals is associated with a low risk of psychological harm. 22,24-28 As these studies mostly took place in research settings, evidence on the impact of the amyloid-PET result disclosure in clinical settings is currently missing. Moreover, to the best of our knowledge, no studies have empirically assessed which variables may facilitate a safer disclosure of a positive amyloid-PET result.
The aims of this study were to assess (1) the psychological outcomes of the amyloid-PET result disclosure in a memory clinic population of individuals with SCD+ and (2) which variables may facilitate a safer disclosure in individuals with amyloid-positive SCD+.

Study Design
This study was carried out in the context of AMYPAD-DPMS. AMYPAD-DPMS is a European, multicenter, prospective, and randomized clinical study implementing amyloid-PET in clinical practice. 13 A total of 840 memory clinic patients with variable disease stage (ie, 244 SCD+, 341 mild cognitive impairment, and 255 dementia) were recruited in 8 European memory clinics from April 16, 2018 to October 30, 2020, 14 and allocated into 3 study groups: (1) ARM1, amyloid-PET was performed early in the diagnostic workup (ie, within 1 month from baseline); (2) ARM2, amyloid-PET was performed late in the diagnostic workup (ie, after 8 months from baseline); and (3) ARM3, amyloid-PET was performed if and when the managing physician chooses to request it (free-choice group). According to the study design, the AMYPAD-DPMS participants underwent up to 5 clinical visits: screening (baseline), 3-month, 6-month, 13-month, and 18-month (only for group 1, not mandatory) visits. 13,14 In the present observational study, we assessed the study outcomes irrespective of participants' randomization into the study groups (assuming that the disclosure of the amyloid-PET result has a similar outcome at different moments [eg, early or late] in the diagnostic workup, and so that randomization does not influence the outcomes of the present study).

Participants
In the present study, participants were memory clinic patients with SCD+ who underwent amyloid-PET as part of AMYPAD-DPMS 13,14 and who were asked to take part in an add-on study on the disclosure of the amyloid-PET result. These participants were enrolled from the 5 AMYPAD-DPMS recruiting memory clinics that accepted to participate in this study: (1) University and adapted from those used in the A4 trial 29 and a brochure template (eTable 2 in Supplement 1) to support managing physicians in the disclosure process. Nevertheless, managing physicians may or may not have followed the disclosure guidelines, and delivered, all or in part, information outlined in the disclosure brochure template. Moreover, we recorded whether it was communicated that SCD+ is a risk condition for the future development of cognitive impairment or dementia, whether the amyloid-PET result was disclosed in person (face-to-face) or over the phone, and the disclosure duration by using an ad hoc questionnaire.

Outcomes
In the present study we assessed: (1) the psychological outcomes after the amyloid-PET result disclosure in a memory clinic population of SCD+ individuals, and (2) which variables were associated with a safer disclosure in patients with amyloid-positive SCD+. The psychological outcomes after the amyloid-PET result disclosure were defined as disclosure-related distress, assessed using the Impact of Event Scale-Revised (IES-R); and anxiety and depression, assessed using the Hospital Anxiety and Depression scale (HADS).
IES-R a 22-item self-report measure assessing subjective distress caused by traumatic events (ie, the amyloid-PET result disclosure in this case) that occurred in the past 7 days, and consists of 1 total score (0 to 88) and 3 average subscores (0 to 4): avoidance (avoidance of thoughts, feelings, memories or situations), intrusions (intrusive memories, thoughts, or feelings causing distress), and hyperarousal (hypervigilance, feeling watchful and on guard, difficulty concentrating), with higher scores meaning more symptoms. The IES-R total score is normally used to support a clinical diagnosis of posttraumatic stress disorder (PTSD; greater than or equal to 33: probable presence of a PTSD). 30 In previous studies, the IES-R total score has been used to assess the presence of PTSD-like symptoms in the context of medical bad news delivery (eg, cancer diagnosis 31 ), and also to assess the disclosure-related distress in patients undergoing amyloid-PET. 22,27,28 The IES-R was administered to all participants included in this study 1 to 3 days after the amyloid-PET result disclosure.
HADS is a 14-item self-report screening scale containing two 7-item scales: one for anxiety and one for depression, both with a score range of 0 to 21, with higher scores meaning higher levels of anxiety or depression. 32 Items referring to symptoms that may have a physical cause (eg, insomnia and weight loss) are not included in the scale, so the HADS is considered to be unbiased by coexisting general medical conditions. 33 HADS has 2 distinct subscales (HADS Anxiety and HADS Depression) and scores of at least 15 indicate the probable presence of severe mood disorder symptoms, and scores of at least 8 indicate mild symptoms. 34 HADS was administered to all participants at different times during the study. For the present study, we used HADS scores collected at baseline and after the amyloid-PET result disclosure (the time interval between the baseline and the follow-up HADS administrations is not consistent among participants). Deltas (follow-up HADS score minus the baseline HADS score) were used to assess changes in anxiety and depression after amyloid-PET. For participants who underwent amyloid-PET before the 3-month visit, we also assessed anxiety and depression after 13 months (ie, the last visit in which HADS was administered).
In order to assess which variables were associated with a safer amyloid-PET result disclosure in individuals with amyloid-positive SCD+, we assessed the association of age, sex, education (years), global cognition (MMSE score), communication that SCD+ is a risk condition, disclosure type (face-toface vs phone), disclosure duration, and presence of study partner (independent variables) with IES-R total and subscale scores, and HADS Anxiety and Depression (dependent variables).

Statistical Analysis
Continuous variables are described as median and IQR, and categorical variables as percentages (raw numbers). Between-group differences were assessed using Wilcoxon rank sum test for continuous variables, or test for equality of proportions for categorical variables. Significance was set at 2-tailed P < .05, and post hoc pairwise comparisons (Dunn all-pairs rank comparison test for continuous variables, or pairwise comparisons for proportions) were adjusted using Bonferroni correction.
Associations between continuous variables were assessed using Spearman correlations (ρ). All  Table 1 illustrates the disclosure modalities in the whole group and by amyloid status. In 94% of participants with SCD+ (99 of 105), it was communicated that SCD+ is a risk condition for the future development of cognitive impairment or dementia. Among those to whom it was not communicated that SCD+ is a risk condition (n = 6), reasons for not communicating were available only for 5 participants (who were all amyloid negative): amyloid-PET was negative (n = 3), amyloid-PET was negative and the medial temporal lobe atrophy scale score was 0 (n = 1), there was a clear psychosocial factor for the SCD (n = 1).

Association of Amyloid-PET Disclosure and Distress, Anxiety, and Depression
After disclosure, patients with amyloid-positive SCD+ had significantly higher median (IQR) IES-R total score (   No participants with amyloid-positive SCD+ showed probable presence of PTSD (ie, IES-R total score at least 33) (Figure 1), or severe anxiety or depression symptoms (ie, HADS score at least 15) at follow-up ( Figure 2 Figure 2).

Variables Facilitating a Safer Disclosure in Amyloid-Positive Individuals
In participants with amyloid-positive SCD+ (n = 27), the presence of study partner was associated with higher IES-R total score (W = 7.5; P = .03). Higher education was associated with lower IES-R hyperarousal (ρ = -0.43, P = .02) ( Table 2 and Figure 3).

Discussion
Our results found that the disclosure of a positive amyloid-PET result to individuals with SCD+ was associated with a greater change in psychological well-being than a negative amyloid-PET result, but this change did not reach the threshold for clinical concern. Specifically, patients with amyloidpositive SCD+ experienced higher levels of avoidance, intrusion, and hyperarousal than amyloidnegative patients directly after disclosure. In contrast, the disclosure of the amyloid-PET result had no statistically significant differences for anxiety and depression in individuals with amyloid-positive and amyloid-negative SCD+ (also in a subgroup of participants with a longer follow-up at 13 months).
Finally, in individuals with SCD+ receiving a positive amyloid-PET result, we observed that higher education was associated with lower hyperarousal symptoms (hypervigilance, feeling watchful and on guard, difficulty concentrating), and that disclosure-related distress was higher when a study partner was present.
Our results are in line with previous studies demonstrating that the disclosure of a positive amyloid-PET result does not cause significant psychological risk. Moreover, to the best of our knowledge, this is the first study exploring which variables may facilitate a safer disclosure of a positive amyloid-PET result. In particular, higher education might help participants elaborate and interpret the meaning of a positive biomarker result, and cope with its psychological consequences.
Thus, special attention should be paid to individuals with lower education levels during the

Limitations
The main limitations of the present study are the lack of long-term assessment of health-related outcomes (eg, quality of life) and the lack of follow-up on the psychological outcomes of amyloid-PET disclosure. Indeed, the absence of follow-up data prevents us from alleging that the disclosure of a positive amyloid-PET does not cause significant psychological risk in the long term. Another issue is the relatively small sample size, possibly resulting in insufficient power to detect small associations and preventing us from drawing strong conclusions. Moreover, only some of the multiple aspects of psychological risk have been assessed (ie, distress, depression, and anxiety), possibly neglecting relevant issues such as suicidal ideation, which is a potential negative outcome reported in previous studies of risk disclosure.

Conclusions
This study found that the disclosure of a positive amyloid-PET result to participants with SCD+ was associated with greater psychological changes, yet such changes did not reach the threshold for clinical concern. This study adds evidence to previous studies showing that the disclosure of the amyloid-PET result is associated with a low risk of psychological harm.