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Figure 1.  Flowchart of Patient Inclusion
Flowchart of Patient Inclusion

MCI indicates mild cognitive impairment; PET, positron emission tomography; VUMC, VU University Medical Center; UMCU, University Medical Center Utrecht.

Figure 2.  Pre- and Post-Positron Emission Tomography (PET) Levels of Anxiety and Uncertainty
Pre- and Post-Positron Emission Tomography (PET) Levels of Anxiety and Uncertainty

Pre- and post-PET changes in anxiety and uncertainty scores (mean [SD]). A, Pre- and post-PET anxiety in patients for whom the PET result was disclosed (n = 41). B, Pre- and post-PET anxiety in patients for whom the PET result was not disclosed (n = 21). C, Pre- and post-PET uncertainty in patients for whom the PET result was disclosed (n = 35; P < .05). D, Pre- and post-PET uncertainty in patients for whom the PET result was not disclosed (n = 19). MUIS indicates Mishel Uncertainty in Illness Scale; STAI, State-Trait Anxiety Inventory.

Table 1.  Demographic and Clinical Characteristics According to Syndrome Diagnosis Before 18F-florbetaben PETa
Demographic and Clinical Characteristics According to Syndrome Diagnosis Before 18F-florbetaben PETa
Table 2.  Association of 18F-florbetaben PET with Changes in Clinical Diagnosis, Confidence in Diagnosis, and Patient Treatment According to Clinical Diagnosis Before PETa
Association of 18F-florbetaben PET with Changes in Clinical Diagnosis, Confidence in Diagnosis, and Patient Treatment According to Clinical Diagnosis Before PETa
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Original Investigation
September 2018

Association of Amyloid Positron Emission Tomography With Changes in Diagnosis and Patient Treatment in an Unselected Memory Clinic Cohort: The ABIDE Project

Author Affiliations
  • 1Department of Neurology & Alzheimer Center, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
  • 2Department of Epidemiology & Biostatistics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
  • 3Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands
  • 4Department of Radiology & Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands
  • 5Department of Medical Psychology, Amsterdam Neuroscience, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands
  • 6Institutes of Neurology and Healthcare Engineering, University College London, London, England
  • 7Piramal Imaging GmbH, Berlin, Germany
  • 8BV Cyclotron, Amsterdam, the Netherlands
JAMA Neurol. 2018;75(9):1062-1070. doi:10.1001/jamaneurol.2018.1346
Key Points

Question  What is the association between amyloid positron emission tomography (PET) and changes in clinical diagnosis and patient treatment in an unselected memory clinic cohort?

Findings  In this prospective cohort study, the etiological diagnosis changed for 25% of patients after amyloid PET, more often due to a negative than a positive PET result. Diagnostic confidence increased, and for several patients, there was a change in the treatment received by patients post-PET.

Meaning  Amyloid-positive and amyloid-negative results were associated with changes in diagnosis and treatment, both for patients with and without dementia.

Abstract

Importance  Previous studies have evaluated the diagnostic effect of amyloid positron emission tomography (PET) in selected research cohorts. However, these research populations do not reflect daily practice, thus hampering clinical implementation of amyloid imaging.

Objective  To evaluate the association of amyloid PET with changes in diagnosis, diagnostic confidence, treatment, and patients’ experiences in an unselected memory clinic cohort.

Design, Setting, and Participants  Amyloid PET using fluoride-18 florbetaben was offered to 866 patients who visited the tertiary memory clinic at the VU University Medical Center between January 2015 and December 2016 as part of their routine diagnostic dementia workup. Of these patients, 476 (55%) were included, 32 (4%) were excluded, and 358 (41%) did not participate. To enrich this sample, 31 patients with mild cognitive impairment from the University Medical Center Utrecht memory clinic were included. For each patient, neurologists determined a preamyloid and postamyloid PET diagnosis that existed of both a clinical syndrome (dementia, mild cognitive impairment, or subjective cognitive decline) and a suspected etiology (Alzheimer disease [AD] or non-AD), with a confidence level ranging from 0% to 100%. In addition, the neurologist determined patient treatment in terms of ancillary investigations, medication, and care. Each patient received a clinical follow-up 1 year after being scanned.

Main Outcomes and Measures  Primary outcome measures were post-PET changes in diagnosis, diagnostic confidence, and patient treatment.

Results  Of the 507 patients (mean [SD] age, 65 (8) years; 201 women [39%]; mean [SD] Mini-Mental State Examination score, 25 [4]), 164 (32%) had AD dementia, 70 (14%) non-AD dementia, 114 (23%) mild cognitive impairment, and 159 (31%) subjective cognitive decline. Amyloid PET results were positive for 242 patients (48%). The suspected etiology changed for 125 patients (25%) after undergoing amyloid PET, more often due to a negative (82 of 265 [31%]) than a positive (43 of 242 [18%]) PET result (P < .01). Post-PET changes in suspected etiology occurred more frequently in patients older (>65 years) than younger (<65 years) than the typical age at onset of 65 years (74 of 257 [29%] vs 51 of 250 [20%]; P < .05). Mean diagnostic confidence (SD) increased from 80 (13) to 89 (13%) (P < .001). In 123 patients (24%), there was a change in patient treatment post-PET, mostly related to additional investigations and therapy.

Conclusions and Relevance  This prospective diagnostic study provides a bridge between validating amyloid PET in a research setting and implementing this diagnostic tool in daily clinical practice. Both amyloid-positive and amyloid-negative results had substantial associations with changes in diagnosis and treatment, both in patients with and without dementia.

Introduction

The accumulation of brain amyloid-β is one of the neuropathological hallmarks of Alzheimer disease (AD).1-3 The introduction of carbon 11–labeled Pittsburgh compound B ([11C]PIB) enabled the detection of brain amyloid-β deposition in vivo using positron emission tomography (PET).4 Amyloid PET has now been incorporated in research criteria for diagnosing AD.5-7 Furthermore, the approval by the US Food and Drug Administration, Health Canada, and the European Medicine Agency of 3 fluoride-18–(F-18) labeled amyloid PET tracers allowed for the widespread use of amyloid PET based on the longer half-life of F-18 (110 minutes).8-12 As a result, amyloid PET has gained a prominent role in research, although not yet in daily clinical practice. Appropriate use criteria for amyloid imaging have been developed to provide guidance on its clinical use.13 However, these criteria are based solely on clinical experience and are not guided by empirical evidence.

Previous studies have investigated the clinical effects of amyloid imaging and their results are pooled in a recent review with a reported mean weighted change in diagnosis of 29% and a change in patient treatment of 64%.14 However, all published studies included selected research populations, not reflecting daily practice and thus hampering clinical use of amyloid imaging. Therefore, studies with large, unselected cohorts that evaluate how amyloid PET can be integrated in routine clinical practice are warranted.15 Moreover, to our knowledge, none of these former studies assessed patients’ experiences with amyloid imaging.

We aimed to evaluate the association of amyloid PET that was embedded in routine clinical practice using an unselected memory cohort with changes in diagnosis, diagnostic confidence, and patient treatment. In addition, we assessed patients’ experienced burden and their levels of anxiety and uncertainty before and after undergoing PET.

Methods
Design

As part of the Alzheimer Biomarkers in Daily Practice (ABIDE) project, we offered amyloid PET to all patients who were visiting the memory clinic of the VU University Medical Center (VUMC) between January 2015 and December 2016 and embedded it into the routine diagnostic workup.16 To enrich the sample for mild cognitive impairment (MCI), we additionally included patients with MCI from the University Medical Center Utrecht (UMCU) memory clinic.

At the VUMC, patients received a letter with written study information 6 weeks before their visit. Subsequently, patients were called to ask them to provide verbal consent and if they had study-related questions. Amyloid PET was planned either during the 1-day routine diagnostic workup day or shortly thereafter (median [interquartile range], 2 [4] weeks). Patients with MCI from the UMCU were recruited either directly after they had visited the geriatric memory clinic in the UMCU or indirectly when they were referred to UMCU for participation in research by local memory clinics in the Utrecht region. All patients underwent a standard diagnostic dementia evaluation that consisted of their medical and informant-based history as well as results from neurological examinations, neuropsychological testing, basic laboratory testing, and magnetic resonance imaging (MRI).17,18 A lumbar puncture (amyloid-β 1–42, total tau, and p-tau) was performed for research purposes.

Clinical diagnoses were established by a consensus at weekly multidisciplinary meetings using conventional clinical criteria without knowledge of amyloid PET or cerebrospinal fluid results.5,6,19-24 For the purpose of this study, the results of the lumbar puncture were not disclosed to the neurologists before the association of the PET results had been assessed. The amyloid PET scans were provided by the VUMC and UMCU as a research procedure. In general, the neurologists disclosed amyloid PET results to patients with dementia but not to patients with MCI and subjective cognitive decline (SCD) unless patients specifically asked for their individual results. In clinical practice, most patients with MCI were interested in learning their results, whereas patients with SCD were not. Before disclosing results, the advantages and disadvantages of knowing were discussed by the neurologist. The medical ethics review committees of both VUMC and UMCU approved the study. All participating patients gave their written informed consent.

Patients

We invited 866 patients at the VUMC to participate, of whom 476 were included, 32 were excluded, and 358 did not participate (Figure 1). The total number available for analysis was 507 (VUMC,476 [93.9%]; UMCU, 31 [6.1%]). Compared with the nonparticipants, participating patients tended to be older (mean [SD] age, 65 [8] vs 62 [9] years; P = .09), more often male (306 [60%] vs 195 [50%]; P < .01), have a higher Mini-Mental State Examination score (mean [SD], 25 [3] vs 23 [6]; P < .01), and a positive family history of dementia (235 [46%] vs 152 [39%]; P < .01).

Clinical Diagnosis, Diagnostic Confidence, and Patient Management Plan

During multidisciplinary meetings (before the PET result disclosure), the neurologist (F.B. or G.J.B.) determined the clinical syndrome (dementia, MCI, or SCD) and the suspected etiology (AD, vascular, frontotemporal dementia, Lewy body dementia, other neurodegenerative disease, or non-neurodegenerative). Neurologists then estimated their level of diagnostic confidence in the suspected etiology on a visual analoge scale that ranged from 0% to 100%. In addition, they determined patient treatment in terms of (1) ancillary investigations (eg, fludeoxyglucose (18F) PET scan, dopamine transporter scan, and genetic testing), (2) initiation or withdrawal of AD medication (ie, cholinesterase inhibitors and trial referral), and (3) initiation or withdrawal of care. After disclosing the PET results to the neurologists, they reevaluated the syndrome diagnosis, suspected etiological diagnosis, and patient treatment. Changes in patient treatment were verified with hospital medical records.

Exploratory Substudy on Patient-Centered Outcomes
Patients’ Motivations and Experiences

Halfway through the study, we added an exploratory substudy on patient-centered outcomes. At T1 (pre-PET), we assessed patients’ reasons to participate with the following answering options: (1) I hope to contribute to science, (2) I want to learn more about my diagnosis, (3) I find it comforting to undergo extra diagnostic tests, and (4) other (check all that apply). At T1 and T2 (post-PET), we assessed whether patients expected and/or experienced the PET scan procedure to be burdensome (yes/no), and if yes, because of (1) the duration, (2) a fear of small spaces (claustrophobia), (3) a fear of needle punctures, (4) a fear of experiencing adverse effects, or (5) other reasons (check all that apply). Of 311 patients, 259 (83.3%) filled out T1, and 275 (88.4%) filled out T2.

Patients’ Anxiety and Uncertainty

In addition, we measured anxiety and uncertainty at T1 and T2, but only in patients who underwent amyloid PET on the same day as their standardized diagnostic workup. For anxiety, we used the State-Trait Anxiety Inventory, which consists of 6 statements and is scored on a 4-point Likert scale (total score: 6-24).25 We used the Mishel Uncertainty in Illness scale for uncertainty, which consists of 6 statements and is scored on a 5-point Likert scale (total score: 6-30).26 Of all 116 eligible patients, 71 (61%) filled out the questionnaire at both T1 and T2. Scales with 3 or fewer statements were excluded from the analysis, leaving 62 anxiety and 54 uncertainty scales available for analysis. When patients filled out 4 to 5 statements, we used the mean of these statements to impute the remaining ones. Forty-two patients (36.2%) received their PET result from the neurologist.

Amyloid PET Scan Procedure and Visual Reading

All procedures regarding the amyloid PET procedure using 18F-florbetaben have been described in detail elsewhere.16 A whole-brain visual assessment was performed by 1 nuclear medicine physician (B.N.vB.), who was masked to clinical information. In case of serious doubt of a PET result, we consulted with Piramal Enterprises Ltd for a second reading.

Statistical Analysis

We assessed differences in baseline characteristics between diagnostic groups using analysis of variance, Kruskal-Wallis tests, and Pearson χ2 tests when appropriate. We used analyses of variance to assess differences in confidence level prior to PET between etiological diagnoses. We assessed change in diagnostic confidence levels after PET using paired sample t tests. We used χ2 tests to assess differences in the patient treatment plan. We assessed differences between pre- and post-PET anxiety and uncertainty using a paired sample t test. We set the level of significance at P < .05.

Results
Demographic and Clinical Characteristics

Patients with dementia and MCI were older and had lower Mini-Mental State Examination scores than patients with SCD (Table 1). Patients with dementia had lower education levels and were more often apolipoprotein E (APOE) e4 positive than those with SCD. The suspected pre-PET etiological diagnosis was predominantly AD in dementia and MCI, and most often non-neurodegenerative in SCD.

Prevalence of Positive Amyloid PET Results

Amyloid PET was positive in 242 patients (48%), with the highest prevalence of amyloid positivity in dementia (128 [78%]) and MCI (45 [63%]) with suspected AD etiology (Table 2). Many patients with suspected non-AD etiology had a positive amyloid PET result (63 [25%]). Of patients who had a positive amyloid PET result, 145 (67%) were APOE e4–positive, compared with 73 (29%) of patients who were amyloid-negative.

Change in Clinical Diagnosis

Amyloid PET results contributed to a change in suspected etiological diagnosis for 125 patients (25%) (Table 2). Diagnoses changed more often because of a negative (82 of 265 [31%]) than a positive (43 of 242 [18%]) PET result (P < .01). There was no difference in the proportion of changes in etiological diagnosis between patients with dementia (50 of 234 [21%]) and without dementia (75 of 273 [28%]; P > .05). Post-PET changes in the suspected etiology occurred more frequently in older (>65 years) than younger (<65 years) patients (74 of 257 [29%] vs 51 of 250 [20%]; P < .05). A negative amyloid PET scan in patients with suspected AD etiology, almost invariably and independently of syndrome diagnosis, led to a change in suspected etiological diagnosis (97%).

Diagnostic Confidence

Overall, mean confidence levels (SD) in etiological diagnosis increased from 80% (13%) to 89% (13%) (P < .001), both as a result of positive (from 80% [13%] to 92% [11%]; P < .001) and negative (from 79% [14%] to 87% [15%]; P < .001) scan results (Table 2). The highest increases in diagnostic confidence were observed in groups in which amyloid PET was compatible with a clinical diagnosis for patients with MCI with a pre-PET suspected AD etiology and positive PET result (n = 45; mean [SD], 20% [13%]) and patients with MCI with a pre-PET suspected non-AD etiology and negative PET result (n = 32; mean [SD], 18 [16]). Most diagnostic changes occurred when the diagnostic confidence was less than 90% (111 [87%]).

Patient Treatment

Amyloid PET results led to a change in patient treatment for 123 patients (24%) (Table 2). The patient treatment plan altered more often for patients with a positive (81 of 242 [33%]) scan than for those with a negative PET scan (42 of 265 [16%]) (P < .001). A positive amyloid PET scan mainly led to changes in the medication prescribed, consisting of the start of cholinesterase inhibitors (12 [15%]), a clinical trial referral (52 [64%]), or both (7 [9%]). After a negative PET result, neurologists primarily performed ancillary investigations, such as fluorodeoxyglucose PET (16 [38%]), genetic screening (6 [14%]), referral to a psychiatrist (5 [12%]), multiple investigations (9 [21%]), or other (6 [14%]). It should be noted that even in patients with SCD, amyloid PET led to changes in patient treatment for 17 or 159 (11%) (eg, fluorodeoxyglucose PET, genetic screening). When we reran the analyses restricted to the VUMC sample (excluding 31 UMCU patients), the results were essentially similar (data not shown).

Patients’ Motivations and Experiences

Patients indicated that the most common motivations to participate in the trial were to learn more about their diagnosis (139 [54%]) and to contribute to science (123 [47%]). Most patients (215 [83%]) expected the PET procedure not to be burdensome. Afterwards, 222 patients (81%) reported that the PET scan was not as burdensome, whereas the remainder (19%) reported discomfort due to the long scan duration (n = 17), claustrophobia (n = 16), fear of needle puncture (n = 4), fear of experiencing adverse effects (n = 3), or other (n = 13).

Patients’ Anxiety and Uncertainty

Pre- and post-PET levels of anxiety and uncertainty are depicted in Figure 2. Anxiety levels (SD) did not change after amyloid PET (pre-PET: 12 [3]; post-PET: 13 [4]; P = .15), irrespective of whether the PET result was disclosed to the patient. Mean levels of uncertainty (SD) decreased significantly from 19 (4) pre-PET to 16 (6) post-PET (P < .01). This effect was attributable to a decrease in uncertainty in patients for whom the neurologist disclosed the PET results (n = 35; 19 [4] to 14 [6], P < .01), irrespective of whether the PET result was positive or negative, while uncertainty levels remained similar in patients for whom PET results were not disclosed (n = 19; 19 [5] to 19 [5]; P > .99).

Discussion

We found in a large and unselected memory clinic cohort that both amyloid-positive and amyloid-negative results led to changes in etiological diagnosis, diagnostic confidence, and patient treatment. The association of amyloid PET was observed in all diagnostic groups, encompassing the spectrum of dementia, MCI, and SCD. Disclosing the amyloid PET results resulted in a decrease in uncertainty, whereas anxiety did not increase.

Recently, the Geneva Road Maps were published, evaluating progress in the validation of the clinical usefulness of AD biomarkers.28 For biomarkers to be used rationally and cost-effectively in clinical care, several gaps in the evidence on how to use them must be filled. In the context of AD, to our knowledge, no biomarker has completed the proposed 5-phase roadmap for clinical validation. For amyloid PET, its rationale, discriminative ability, and capacity to detect the earliest disease stages have been largely established.15 However, prospective diagnostic studies that investigate the usefulness of amyloid imaging in patients whose diagnosis and treatment are based on amyloid PET status are lacking. Here, we studied the clinical utility of amyloid imaging incorporated in routine daily practice of a memory clinic (phase 4). Our results demonstrate that amyloid imaging has additional value in routine clinical practice. Currently, several large-scale studies investigating the clinical utility of amyloid PET are underway. In the United States, the Imaging Dementia—Evidence for Amyloid Scanning (IDEAS) study closed to new patient accrual as of December 7, 2017, and in Europe, the Amyloid Imaging to Prevent Alzheimer Disease (AMYPAD) study has started enrollment. These studies will expand observations on a larger scale and will be very useful in quantifying the cost-effectiveness of amyloid imaging.

Former studies investigating the clinical utility of amyloid imaging reported changes in diagnosis that varied from 9% to 69%.29-44 The average increases in diagnostic confidence varied from 16% to 26%.33,36,39,41,42,45 The changes in patient treatment varied from 29% to 87%.29,33-36,38,41-44 In this study, we found a change in clinical diagnosis in 25% of patients, with an average increase (SD) in diagnostic confidence of 10% (15%) and a change in patient treatment in 24% of patients. The difference between the relatively small proportion of changes in diagnosis and patient treatment observed in this study and the larger number reported in earlier studies may be due to differences in study samples and settings. In former studies with selected research populations, the pre-PET diagnostic certainty was by definition low, and high rates of changes in diagnosis, diagnostic confidence, and patient treatment could be expected. We used an unselected memory clinic sample rather than basing inclusion on the appropriate use criteria or diagnostic uncertainty, and this may explain the lower proportional change.

This study goes beyond previous findings, as we also assessed patient-reported outcomes. More than 80% of patients experienced the PET scan as not burdensome. One-fifth of patients expected the PET scan to be burdensome and a similar fraction, looking back, said to have experienced the PET scan as burdensome. Notably, the concordance between pre-PET expectations and post-PET experiences was low, implying that there is room for improving communication about amyloid PET. Whether to disclose an amyloid PET result to patients with MCI and cognitively normal individuals is controversial given the current lack of understanding of the predictive value of an amyloid PET result at an individual level. In addition, it is unknown whether disclosure could lead to psychological harm.46-50 To our knowledge, only a few former studies have addressed the safety of disclosure of amyloid imaging results to cognitively healthy participants in a trial setting, and those studies found that disclosure infers only a low risk of psychological harm.46,51 In this study, we asked a subset of patients about their levels of anxiety and uncertainty before and after undergoing amyloid PET. Their levels of anxiety did not increase after disclosure, whereas their levels of uncertainty decreased, which was attributable to a decrease in uncertainty in patients for whom the neurologist disclosed the PET results. These preliminary results suggest that amyloid PET result disclosure in a clinical setting does not seem harmful to patients in terms of anxiety or uncertainty.

The appropriate use criteria for amyloid imaging predefines certain scenarios in which amyloid PET would be justified. One of the preambles is that knowledge of the result is expected to increase diagnostic certainty and alter treatment. In support of these criteria, 87% of diagnostic changes occurred when the diagnostic confidence was less than 90%. Patients who fulfill core clinical criteria for AD and have a typical age at onset of 65 years are considered not appropriate. The observation that diagnostic changes occurred more frequently in older (>65 years) than in younger (<65 years) patients, primarily due to a negative amyloid PET result for patients with dementia and patients with MCI with a suspected AD etiology, shows that other patient groups may benefit as well and that appropriate use criteria may actually benefit from refinement based on empirical data. Further, the observed increase in trial referrals after amyloid PET is potentially very valuable given the current challenges in trial recruitment and could be argued to reflect an “appropriate” outcome. Patients with SCD are not part of the appropriate use criteria, yet they represent almost 1 of 4 patients in memory clinics. These patients are worried and demand information from their physicians. The setup of this study provided us with a unique opportunity to investigate what amyloid PET could mean for this group of memory clinic patients. Notably, even in this group, in which amyloid PET was not warranted under the current guidelines, the suspected etiology changed in 23% of cases, while the treatment plan changed in 11% of cases. With amyloid PET becoming increasingly available, it seems important to gather evidence on its clinical value in these individuals with SCD. Currently, there is insufficient longitudinal data to interpret the predictive value of amyloid PET in SCD. Long-term follow-up is needed to evaluate how amyloid PET can help predict clinical outcomes, especially given the evidence that amyloid-positive patients with SCD have a higher risk of progressing to dementia.52-54 To date, cognitively normal individuals can already participate in clinical trials, and in such a research context their amyloid status is being disclosed.55 It is imperative that, within the context of clinical practice, recommendations for use and disclosure of amyloid PET for this group of patients are developed.48,56 Especially in view of a future in which antiamyloid disease-modifying drugs become available, amyloid PET in patients with SCD will become highly relevant.

Limitations

This study has some limitations. First, the main outcome measure was change in diagnosis. Because postmortem verification was not available, this outcome measure reflects, at least in part, the clinicians’ beliefs. However, the observed proportional change in diagnosis was lower than in former studies, rendering it less likely that this has driven the results. Clinical follow-up of the population might yield long-term insights on the association of amyloid PET with diagnostic and patient treatment parameters. We are currently following patients without dementia to empirically validate clinical outcomes. Second, being a tertiary referral center, the routine diagnostic workup is quite extensive, including neuropsychological testing, MRI, and electroencephalography. This may have led to an underestimation of the association of amyloid PET. Third, most patients were included in a tertiary referral center, with a high proportion of young patients with often complex clinical presentations. This may hamper the translation to primary care and local memory clinics, as their populations are often older, more advanced, and more straightforward. However, one might argue that amyloid PET should only be performed in complex cases, and therefore it is more likely to be performed in a tertiary setting. Fourth, our study setup deviates from regular clinical practice in several important ways, as we offered amyloid PET to all patients rather than diagnostically uncertain cases, the primary neurologist may or may not have seen the patient, results were not always disclosed to patients, and patients had no financial liability (which deviates from practices in some health systems). Finally, patients were included in this study based on self-selection instead of a randomization process. However, it is unlikely that this has affected the results significantly, as there were only minor differences in baseline characteristics between included and nonincluded patients.

Conclusions

In this prospective diagnostic study, we attempted to bridge the gap between validating amyloid PET in a research setting and implementing this diagnostic tool in daily clinical practice. We offered amyloid PET to all patients who visited the memory clinic and observed that both amyloid-positive and amyloid-negative results had an important association with changes in diagnosis and treatment in patients with and without dementia.

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Article Information

Accepted for Publication: February 16, 2018.

Corresponding Author: Arno de Wilde, MD, Alzheimer Center and Department of Neurology, VU University Medical Center, PO Box 7057, 1007 MB, Amsterdam, the Netherlands (a.dewilde@vumc.nl).

Published Online: June 11, 2018. doi:10.1001/jamaneurol.2018.1346

Author Contributions: Dr de Wilde and Prof van der Flier had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: de Wilde, van der Flier, Bouwman, Kunneman, Smets, van Lier, Van Berckel, Scheltens.

Acquisition, analysis, or interpretation of data: de Wilde, van der Flier, Pelkmans, Bouwman, Verwer, Groot, van Buchem, Zwan, Ossenkoppele, Yaqub, Kunneman, Barkhof, Lammertsma, Stephens, Biessels, Van Berckel, Scheltens.

Drafting of the manuscript: de Wilde, van der Flier, van Buchem, Stephens, Scheltens.

Critical revision of the manuscript for important intellectual content: de Wilde, van der Flier, Pelkmans, Bouwman, Verwer, Groot, Zwan, Ossenkoppele, Yaqub, Kunneman, Smets, Barkhof, Lammertsma, Stephens, van Lier, Biessels, Van Berckel, Scheltens.

Statistical analysis: de Wilde, van der Flier, van Buchem.

Obtained funding: van der Flier, Smets, Stephens, Scheltens.

Administrative, technical, or material support: de Wilde, Pelkmans, Verwer, Zwan, Ossenkoppele, Yaqub, Barkhof, Lammertsma, van Lier, Scheltens.

Supervision: van der Flier, Bouwman, Smets, Lammertsma, Van Berckel, Scheltens.

Conflict of Interest Disclosures: Dr Lammertsma is currently the principal investigator of a study sponsored by Avid. Research programs of Dr van der Flier have been funded by ZonMW, the Netherlands Organization of Scientific Research, Seventh European Framework Programme, Alzheimer Nederland, Cardiovascular Onderzoek Nederland, Stichting Dioraphte, Gieskes-Strijbis fonds, Boehringer Ingelheim, Piramal Imaging, Roche BV, Janssen Stellar, and Combinostics. All funding is paid to her institution. Dr Barkhof is a consultant for Biogen-Idec, Janssen Alzheimer Immunotherapy, Bayer-Schering, Merck-Serono, Roche, Novartis, Genzume, and Sanofi-Aventis; has received sponsoring from European Commission–Horizon 2020, National Institute for Health Research–University College London Hospitals Biomedical Research Centre, Scottish Multiple Sclerosis Register, TEVA, Novartis, and Toshiba; is supported by the University College London Hospitals NHS Foundation Trust Biomedical Research Center; and serves on the editorial boards of Radiology, Brain, Neuroradiology, Multiple Sclerosis Journal, and Neurology. Dr Stephens is a full-time employee of Piramal Imaging GmbH and owns stock. Dr van Lier is a full-time employee of BV Cyclotron VU. Dr Scheltens has acquired grant support (for the institution) from GE Healthcare, Danone Research, Piramal, and Merck. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham, and EIP Pharma. No other disclosures are reported.

Funding/Support: The VU University Medical Center (VUMC) Alzheimer Center is supported by Alzheimer Nederland and Stichting VUMC funds. This study was performed within the framework of the Dutch ABIDE project and was supported by a ZonMW-Memorabel grant (project No 733050201) in the context of the Dutch Deltaplan Dementie and through a grant of Piramal Imaging (positron emission tomography scan costs) to the Stichting Alzheimer & Neuropsychiatrie, Amsterdam. Research of the VUMC Alzheimer Center is part of the neurodegeneration research program of Amsterdam Neuroscience. The clinical database structure was developed with funding from Stichting Dioraphte.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the following members of the ABIDE Study Group: Alzheimer Center and Department of Neurology, Amsterdam Neuroscience, VU University Medical Center: Wiesje M. van der Flier, PhD, Philip Scheltens, MD, PhD, Femke H. Bouwman, MD, PhD, Marissa D. Zwan, PhD, Ingrid S. van Maurik, MSc, Arno de Wilde, MD, Wiesje Pelkmans, MSc, Colin Groot, MSc, and Ellen Dicks, MSc, Els Dekkers; Department of Radiology and Nuclear Medicine, Amsterdam Neuroscience, VU University Medical Center: Bart N.M. van Berckel, MD, PhD, Frederik Barkhof, MD, PhD, and Mike P. Wattjes, MD, PhD; Neurochemistry laboratory, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center: Charlotte E. Teunissen, PhD, Eline A. Willemse, MSc; Department of Medical Psychology, University of Amsterdam, Academic Medical Center: Ellen M. Smets, PhD, Marleen Kunneman, PhD, Sanne Schepers, MSc (BV Cyclotron) E. van Lier, MSc, and Niki M. Schoonenboom, MD, PhD; Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht: Geert Jan Biessels, MD, PhD, and Jurre H. Verwer, MSc; Department of Geriatrics, University Medical Center Utrecht: Dieneke H. Koek, MD, PhD; Department of Radiology and Nuclear Medicine: Monique G. Hobbelink, MD; Vilans, Center of Expertice: Mirella M. Minkman, PhD, Cynthia S. Hofman, PhD, Ruth Pel, MSc; Espria: Esther Kuiper, MSc; Piramal Imaging GmbH: Andrew Stephens, MD, PhD; Roche Diagnostics International Ltd: Richard Bartra-Utermann, MD. We also thank the members of the Memory Clinic Panel: Spaarne Gasthuis: Niki M. Schoonenboom, MD, PhD; Medisch Centrum Leeuwarden: Barbera van Harten, MD, PhD, Niek Verwey, MD, PhD, Peter van Walderveen, MD, and Liesbeth Hempenius, MD; Admiraal de Ruyter Ziekenhuis: Ester Korf, MD, PhD; Sint Elisabeth Ziekenhuis: Gerwin Roks, MD, PhD; Onze Lieve Vrouwe Gasthuis: Bertjan Kerklaan, MD, PhD; Medisch Centrum Alkmaar: Leo Boelaarts, MD; Diaconessenhuis: Annelies. W.E. Weverling, MD; Jeroen Bosch Ziekenhuis: Rob J. van Marum, MD, PhD; Tergooi Ziekenhuis: Jules J. Claus, MD, PhD; Catherina Ziekenhuis: Koos Keizer, MD, PhD; Reiner de Graaf Gasthuis: Marlijn de Beer, MD, PhD; LangeLand Ziekenhuis: Mariska Kleier, MD. These individuals were not compensated for their contributions.

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