Visualizing brain amyloid-beta pathology
de Wilde, Arno
2021
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de Wilde, A. (2021). Visualizing brain amyloid-beta pathology: Toward implementation of amyloid imaging in
daily memory clinic practice.
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VISUALIZING BRAIN AMYLOID-β PATHOLOGY
BRAIN
AMYLOID-β P
ATHOLOGY
Arno de
Wilde
VISUALIZING BRAIN AMYLOID-β PATHOLOGY
VISU
ALIZING BRAIN
AMYL
OID
-β
P
ATHOL
OG
Y
Arno de
Wilde
Toward implementation of amyloid imaging
in daily memory clinic practice
and partially at the University Medical Center Utrecht, Utrecht, the Netherlands. Part of the research described in this thesis was supported Alzheimer Nederland and Stichting VUMC funds. Several studies were 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 Life Molecular Imaging (former Piramal Imaging). Printing of this thesis was supported by Alzheimer Nederland and Stichting Alzheimer and Neuropsychiatry Foundation.
Cover design: Cor Simon, Joël Kortes and Arno de Wilde
Print: ProefschriftMaken | www.proefschriftmaken.nl
ISBN: 978-94-6423-144-1
© A. de Wilde, Amsterdam, the Netherlands, 2021
All rights reserved. No parts of this publication may be reproduced, stored or transmitted in any way or by any means without the prior permission of the copyright holder, or, when applicable, with permission of the publishers of the scientific journals.
VISUALIZING BRAIN AMYLOID-β PATHOLOGY
Toward implementation of amyloid imaging
in daily memory clinic practice
ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam,
op gezag van de rector magnificus prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie
van de Faculteit der Geneeskunde op woensdag 17 maart 2021 om 11.45 uur
in de aula van de universiteit, De Boelelaan 1105
door Arno de Wilde geboren te Barneveld
prof.dr. B.N.M. van Berckel prof.dr. W.M. van der Flier
When life gives you
lemons
make
margaritas
Chapter I Introduction 9 Chapter II Alzheimer’s Biomarkers In Daily practicE (ABIDE) project:
rationale and design 21
Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring (2017)
Chapter III Association of amyloid positron emission tomography with changes in diagnosis and patient treatment in an unselected
memory clinic cohort: the ABIDE project 39
JAMA Neurology (2018)
Chapter IV Assessment of the appropriate use criteria for amyloid PET in an
unselected memory clinic cohort: the ABIDE project 61
Alzheimer’s & Dementia (2019)
Chapter V Disclosure of amyloid positron emission tomography results to
individuals without dementia: a systematic review 85
Alzheimer’s Research and & Therapy (2018)
Chapter VI Applying the ATN schema in a memory clinic population: the
ABIDE project 109
Neurology (2019)
Chapter VII Discordant amyloid-β PET and CSF Biomarkers and its Clinical Consequences 131
Alzheimer’s Research & Therapy (2019)
Chapter VIII Summary and general discussion 159
Addendum Alzheimer center hall of fame 183
List of publications 188
2 3 4 5 6 7 8
Chapter I
I
INTRODUCTION
Alzheimer’s disease
Alzheimer’s disease (AD) is the main cause of dementia, accounting for 50-70% of cases. In 2015, approximately 47 million persons worldwide were thought to be affected
by dementia, at an estimated cost of $818 million (US) dollar.1,2 Currently incurable,
finding a disease-modifying treatment for AD and other dementias has been declared as a global public health priority by the World Health Organization, and governments across the world increasingly prioritize dementia in their national health-care policies.3,4 In 1906, the Bavarian psychiatrist and neuropathologist, Alois Alzheimer (1864 –
1915), was the first to describe the disease that would later be named after him.5 AD is
characterized clinically by progressive cognitive impairment and behavioural changes, and neuropathologically by accumulation of (i) extraneuronal plaques, consisting of amyloid-beta (Aβ) proteins, and (ii) intraneuronal neurofibrillary tangles, consisting
of hyperphosphorylated tau protein.6 According to the leading amyloid cascade
hypothesis, the accumulation of these proteins sets in action a complex chain of events that cause downstream neuronal death, resulting in cognitive decline and ultimately
dementia.7–9 The onset of Aβ accumulation precedes the first clinical symptoms up to
two decades.10,11 The two major risk factors for AD are age and presence of the risk
gene-allele apolipoprotein E (APOE) ε4.12–15
From clinical syndrome to biomarker-driven diagnosis
The first set of clinical criteria for diagnosing AD were proposed in 1984, and these criteria were based on clinical symptoms only, since biomarkers that could demonstrate
AD pathology in vivo had not yet been developed.16 A definite diagnosis of AD could
only be made after confirmation of Aβ plaques and tau tangles during post-mortem neuropathological examination. The development of AD biomarkers allowed in vivo detection of AD pathology and consequently initiated a paradigm shift from defining AD as a clinical syndrome towards a biological definition, demonstrated by the latest diagnostic criteria that integrate biomarker evidence in their diagnostic formulations.17–19 The most recent NIA-AA research diagnostic framework, not (yet) intended to be used in clinical practice, takes biomarker evidence a step further and defines AD by its
underlying pathologic processes as measured in vivo using biomarkers.20 According to
this disease definition, a diagnosis of AD requires the presence of both Aβ pathology and fibrillar tau. The presence of Aβ pathology by itself is not sufficient for a diagnosis of AD but is considered to be the start of the Alzheimer’s continuum. For the purpose of this thesis, we will focus on Aβ pathology, in particular as measured using amyloid
Diagnosing AD and biomarker classification system
Currently, a diagnosis of AD dementia in daily clinical practice is mainly based on clinical parameters, including medical and informant-based-history, neurological examination and neuropsychological testing, and includes ancillary investigations such as basic laboratory testing and structural imaging of the brain. In case of diagnostic uncertainty and depending on the local preferences, knowledge and availability of tests, additional biomarker tests are considered to increase the accuracy of a diagnosis. The major AD biomarkers are divided into three binary categories: Aβ pathology (A), tau pathology (T), and neurodegeneration (N), a marker of neuronal death. These biomarkers
can be used to classify patients for research purposes.21 In parallel to this biomarker
classification, individuals can be staged according to where they are in the cognitive continuum. Syndrome diagnosis could be: cognitively unimpaired, mild cognitive impairment (cognitive impairment below expected range) and dementia (substantial cognitive impairment resulting in a clear functional impact on daily life).20 However, it is unclear how to optimally use of biomarkers and their classification systems in daily clinical practice.
Detecting brain Aβ pathology in clinical practice
There are currently two established methods for detecting presence of Aβ pathology
in vivo, i.e., reduced concentrations of Aβ 1–42 (Aβ1-42) in cerebrospinal fluid (CSF)
CSF and increased cerebral retention of Aβ PET tracers.22,23 These biomarkers have
been incorporated in research and diagnostic criteria.17–20 Aβ PET can both localize and
quantify cortical amyloid-beta pathology. Three Aβ-specific PET ligands have received approval from the US Food and Drug Administration and European Medicines Agency to be used in clinical practice for excluding the presence of amyloid-beta pathology
in individuals with cognitive decline.23 These ligands have a similar sensitivity and
specificity that exceeds 90% in the detection of histo-pathologically confirmed Aβ.23–26
A lumbar puncture is a more indirect method to detect Aβ pathology, since soluble
forms of Aβ1-42 are detected in the CSF surrounding the brain and spinal cord. The
concentration of Aβ1-42 in CSF is lower in patients with AD compared to cognitively
normal controls, and CSF Aβ1-42 levels correlate with Aβ plaque load observed at
autopsy.27–30 Using different Aβ PET ligands, the correlation between in vivo cerebral
Aβ load and low CSF Aβ1-42 has consistently found to be high.27,31–35 It is therefore
assumed in these guidelines that CSF Aβ1-42 and Aβ PET can be used interchangeably.
Nonetheless, 10–20% of study participants have discordant results (i.e., CSF+/PET− or CSF−/PET+). Discordance in Aβ PET and CSF biomarkers potentially has important ramifications for their application in clinical, research, or trial settings. Whether and how Aβ biomarker discordance affects clinical progression of patients or diagnostic changes is not yet known.
I
Clinical utility of Aβ PET
The regulatory (US Food and Drug Administration and European Medicine Agency) approval of Aβ PET tracers for clinical practice between 2012-2014 allowed for their widespread use. However, their approval was based on results from phase 1-3 trials in populations that do not accurately reflect the anticipated clinical use of Aβ PET. Data that assessed the clinical utility of Aβ PET were not required for regulatory approval,
and thus not available.36 While Aβ PET rapidly gained a prominent role in research
since its advent in 2004, its implementation in clinical practice lagged behind.37 Studies that did assess the clinical utility of Aβ imaging were performed in highly selected research populations, not reflecting daily practice and hampering translation to clinical
use of Aβ imaging.23 Before Aβ PET can be implemented in daily practice, its feasibility
of integrating the modality in the diagnostic process and clinical impact in a relevant population needs to be assessed.
Appropriate use criteria for Aβ to guide clinical use
Against the backdrop of a lack of Aβ PET clinical utility studies and within the context of upcoming decisions on reimbursement of Aβ PET by insurance third party payers, appropriate use criteria (AUC) for amyloid imaging were formulated to guide its clinical
use.38 The Amyloid Imaging Taskforce (AIT) that proposed the AUC emphasized
that the formulated criteria were mainly based on expert opinion given the limited experience with clinical use of amyloid PET at that time. Amyloid PET was considered appropriate for use by dementia experts only and limited to cognitively impaired patients to retrieve the underlying cause of cognitive decline after a standard diagnostic evaluation. The few studies that evaluated the usefulness of the AUC consistently found high proportions of changes in diagnosis and patient management, in both patients
consistent and inconsistent with the AUC.39–42 However, these studies included selected
patient populations, whereas a robust evaluation of AUC would require an unselected sample to begin with.
Disclosure of Aβ PET results
Disclosing Aβ PET results to patients with dementia is rather straightforward, as its result provides an explanation for the underlying cause of the clinical syndrome. However, given the lack of understanding of the predictive value of Aβ PET in individuals who are not demented (yet), communicating a PET result to Aβ-positive individuals creates an ethical dilemma in clinical practice: neither disclosure nor not sharing results feels unambiguously comfortable. Withholding information that could potentially impact diagnosis and prognosis conflicts with the principle of patient autonomy, while
mild cognitive impairment (MCI), and result disclosure is a necessity of design.43,44 In addition, appropriate use criteria for clinical use of Aβ PET indicate that patients with MCI could be considered for amyloid imaging to identify the underlying etiology, while CN individuals are considered inappropriate to scan given the limited prognostic value
of PET.38,45 Taken together, amyloid PET is increasingly being used in both research and
clinical practice despite the ethical dilemma of whether or not to disclose its results, and evidence on its impact and safety is lagging behind.15,46–51
Thesis aims
The general aim of this thesis was to develop a deeper understanding of the applicability and utility of Aβ PET use in daily practice in a tertiary memory clinic setting. More specifically, we focused on assessing the impact of Aβ PET on the diagnostic process and patient treatment. In addition, we assessed the clinical impact of applying the ATN biomarker scheme and the clinical consequences of having a discordant ‘A’ (Aβ biomarker).
Thesis outline
In this thesis we studied the impact of the use of Alzheimer’s disease biomarker on the diagnostic process in a memory clinic, with a central role for Aβ PET. Chapter II outlines the study design of the Alzheimer’s Biomarkers In Daily practicE (ABIDE) project, which was designed to translate knowledge on biomarkers tests (including Aβ PET and CSF) to daily clinical practice in a memory clinic. The overarching ABIDE project provided the foundation for this thesis, and the substudy that focused on the clinical utility of Aβ PET - chapter III - is the ‘de facto’ starting point of this thesis. In this large prospective real-world memory clinic cohort, we implemented Aβ PET in the diagnostic process and assessed its association with changes in diagnosis, change in diagnostic confidence, and patient management. The practical use of Aβ PET in daily clinic directly led to two additional practical questions: (i) which patients have the most clinical benefit from Aβ PET to scan and (ii) can we safely disclose Aβ PET results to patients? To answer the first question, we retrospectively studied the usefulness of the appropriate use criteria for Aβ imaging in chapter IV. Our exploration of the second question led to our systematic literature review of the current knowledge on and the effects of disclosure of Aβ PET results in non-demented individuals in chapter V. In chapter VI we retrospectively studied the feasibility and impact of the novel ATN biomarker scheme for Alzheimer’s disease in a memory clinic population, in which markers for Aβ play a disease-defining role. As Aβ can be measured using two different diagnostic tools sometimes gives different information, we finally retrospectively investigated the discordance between two measures for cerebral Aβ in patients across the spectrum of dementia and how discordance affects clinical trajectories (chapter VII). We end this thesis by summarizing our main findings, followed by a general discussion and recommendations for future research.
I
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Distinguish Postmortem-Confirmed Alzheimer’s Disease from Other Dementias and Healthy Controls in the OPTIMA Cohort. J Alzheimer’s Dis 2015; 44: 525–39.
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33. Palmqvist S, Zetterberg H, Mattsson N, et al. Detailed comparison of amyloid PET and CSF biomarkers for identifying early Alzheimer disease. Neurology 2015; 85: 1240–9. 34. Mattsson N, Insel PS, Donohue M, et al. Independent information from cerebrospinal
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38. Johnson KA, Minoshima S, Bohnen NI, et al. Appropriate Use Criteria for Amyloid PET: A Report of the Amyloid Imaging Task Force, the Society of Nuclear Medicine and Molecular Imaging, and the Alzheimer’s Association. Journal of Nuclear Medicine 2013; 54: 476–90.
40. Apostolova LG, Haider JM, Goukasian N, et al. Critical review of the Appropriate Use Criteria for amyloid imaging: Effect on diagnosis and patient care. Alzheimer’s &
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42. Shea Y-F, Barker W, Greig-Gusto MT, Loewenstein DA, Duara R, DeKosky ST. Impact of Amyloid PET Imaging in the Memory Clinic: A Systematic Review and Meta-Analysis.
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44. Cummings J, Lee G, Mortsdorf T, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2017. Alzheimer’s Dementia Transl Res Clin Interventions 2017; 3: 367–84.
45. Grill JD, Apostolova LG, Bullain S, et al. Communicating mild cognitive impairment diagnoses with and without amyloid imaging. Alzheimer’s Research & Therapy 2017; 9: 35. 46. Vos SJ, Xiong C, Visser P, et al. Preclinical Alzheimer’s disease and its outcome: a
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47. Rossum IA van, Vos SJ, Burns L, et al. Injury markers predict time to dementia in subjects with MCI and amyloid pathology. Neurology 2012; 79: 1809–16.
48. Dubois B, Hampel H, Feldman HH, et al. Preclinical Alzheimer’s disease: Definition, natural history, and diagnostic criteria. Alzheimer’s & Dementia 2016; 12: 292–323. 49. Martínez G, Vernooij RW, Padilla P, Zamora J, Flicker L, Cosp X. 18F PET with
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50. Martínez G, Vernooij RW, Padilla P, Zamora J, Cosp X, Flicker L. 18F PET with florbetapir for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database of Systematic Reviews 2017; 11: CD012216.
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3 4 5 6 7 8
1
de Wilde A., van Maurik I.S., Kunneman M., Bouwman F., Zwan M., Willemse E.A.J., Biessels G.J., Minkman M., Pel R., Schoonenboom N.S.M.,
Smets E.M.A., Wattjes M.P., Barkhof F., Stephens A., van Lier E.J., Batrla-Utermann R., Scheltens Ph., Teunissen C.E., van Berckel B.N.M.,
van der Flier W.M.
Alzheimer’s Biomarkers In Daily
practicE (ABIDE) project:
rationale and design
ABSTRACT
Introduction: The Alzheimer’s biomarkers in daily practice (ABIDE) Study is designed to translate knowledge on novel diagnostic tests (MRI, CSF and amyloid PET) to daily clinical practice with a focus on mild cognitive impairment (MCI).
Methods: ABIDE is a 3-year project with a multi-facetted design and is structured into interconnected sub-studies using both quantitative and qualitative research methods.
Results: Based on retrospectively available data, we develop personalized risk estimates for MCI patients. Prospectively, we collect MRI and CSF data from 200 patients from local memory clinics and amyloid PET from 500 patients in a tertiary setting, to optimize application of these tests in daily practice. Furthermore, ABIDE will develop strategies for optimal patient-clinician conversations.
Discussion: Ultimately, this will result in a set of practical tools for clinicians to support the choice of diagnostic tests and facilitate the interpretation and communication of their results. Results will be implemented in clinical practice of local memory clinics.
II
INTRODUCTION
The advent of magnetic resonance imaging (MRI) and the discovery of cerebrospinal fluid (CSF) biomarkers and amyloid positron emission tomography (PET) are amongst the greatest successes in Alzheimer’s Disease (AD) research, allowing an AD diagnosis in an earlier stage of disease.1–5 Despite a wealth of literature on AD biomarkers, there is a gap between the published value and the actual utilization of biomarkers in daily clinical practice.6,7
Structural MRI biomarkers incorporated in the NIA-AA diagnostic criteria for AD
include atrophy, e.g. of the medial temporal lobe, as marker for neurodegeneration.8
The criteria however lack recommendations for preferred methods to establish atrophy (quantitavely versus qualitatively), nor do they provide cut-offs. CSF biomarkers, amyloid-beta 1-42 (Aβ42), total tau (tau) and phosphorylated tau (p-tau), discriminate AD patients from persons with normal ageing with high accuracy and predict dementia
in patients with mild cognitive impairment (MCI.9–11 However, there is considerable
inter- and intra-variability in the measured levels between the manually operated CSF
platforms, which limits comparability between centres and establishing cut-off values.12
Automated platforms are now being developed, and this is expected to reduce analytical
variability.13 The introduction of amyloid PET in 2004 allowed visualization of amyloid
pathology in vivo and the subsequent development of 18F-labeled tracers enabled
widespread implementation in memory clinics.1,14 Appropriate use criteria for amyloid
imaging have been published, but at that time experience with amyloid PET was limited and based on data from highly selected research populations, so it remains unclear which
patients benefit most from costly amyloid PET imaging in the diagnostic tree.15
Furthermore, MRI, CSF and amyloid PET predict progression from MCI to dementia,
but most available literature is based on group-level data.16–19 Translating results to
individual patients in daily practice is difficult, as the prognostic value of each biomarker may vary with e.g. age, gender and cognitive status. Moreover, when combining biomarkers, interpretation of results becomes complicated, especially when they are not clearly positive, negative or even conflicting. Also, little is known about patients’ preferences towards diagnostic testing and best ways of communicating test results with patients and their caregivers. Such conversations about initiating diagnostic testing or communicating test results are challenging for both patients and clinicians. To date it remains unknown how these conversations are conducted in the clinical routine setting, and how patients and clinicians experience and value these conversations.
The Alzheimer’s Biomarkers In Daily practicE (ABIDE) project has been designed to address the need for a translation of the scientific value of AD biomarkers to actual daily utilization in local memory clinics. Figure 1 describes the current patient journey of someone attending a regular memory clinic and provides an overview of how ABIDE
Specific objectives include: (1) To decide on the most useful application of specific AD diagnostic tests in clinical practice (Figure 1B; displayed in orange), including (A) comparison of visual rating and volumetric MRI markers of whole brain atrophy and atrophy of the medial temporal lobe, (B) comparison of manual and automated CSF biomarker platforms, and (C) identify patients that benefit most from amyloid PET. (2) To (A) develop personalized risk estimates in MCI patients for (time to) progression to dementia, and (B) to develop personalized risk estimates in MCI patients for (time to) progression to dementia (displayed in red). (3) To identify optimal strategies, tailored to patients’ characteristics, to effectively involve patients in the decision about diagnostic testing (shared decision making) and communicate results of diagnostic tests (displayed in blue). (4) To develop a tool with algorithms for diagnostic testing and personalized risk estimates, and to facilitate communication about test results (not displayed).
Figure 1. Patient journey in memory clinics
Clinician interprets test results Clinician selects ancillary tests Clinician communicates test results Patient management Ancillary tests
(CSF, MRI & PET) Memory clinic A Clinician [ 3 ] Communication of results Patient management [ 2B ] Personalized risk estimates [ 2A ]
Decision rule for tests
[ 1A, B, C ] Application of MRI, CSF & PET [ 3 ] Shared decision making Memory clinic B Clinician Patient
(A) Current patient journey in memory clinics. (B) ABIDE patient journey in memory clinics. Abbreviations: ABIDE, Alzheimer’s biomarkers in daily practice; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PET, positron emission tomography.
II
METHODS
Study design
ABIDE is a 3-year project which has been funded in the context of the Dutch national dementia plan (https://www.deltaplandementie.nl/en; project number: 733050201). ABIDE has a multi-facetted design and is structured into five sub-studies each with their own objective, design, patient sample and data collection. Figure 2 shows the structure of ABIDE and demonstrates how results from one objective feeds into the next. Below, we describe the sub-studies separately. Table 1 provides an overview of the link between objectives, design, patient samples, and outcome measures.
Figure 2. Hierarchy of ABIDE objectives
Objective 4. Implementation in Dutch Network of Memory Clinics Objective 2B. Personalized risk estimates Objective 2A.
Decision rule for diagnostic testing Objective 3. Patient-clinician communication Objective 4. E-based practical tool for clinicians
Objective 1B. Clinical application of CSF Objective 1A. Clinical application of MRI Objective 1C. Clinical application of amyloid PET
Abbreviations: ABIDE, Alzheimer’s biomarkers in daily practice; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PET, positron emission tomography.
Table 1. ABIDE sub-studies and corresponding objectives and patient cohorts
Sub-study
Objective Cohort Data collection
Sample Measures
No. of
patients Setting Population MRI CSF PET CON
1 1A, B Prospective
Cross-sectional n=200 Local Mixed √ √
2 1C Prospective Longitudinal n=450 Tertiary Mixed √ √ √
2 1C Prospective Longitudinal n=50 Tertiary MCI √ √ √
3 2A, B Retrospective Longitudinal n=400 Tertiary MCI √ √
4 3 Prospective
Cross-sectional n=120 Local Mixed (√) (√) √
Abbreviations: ABIDE, Alzheimer’s biomarkers in daily practice; CON, memory clinic consultation between clinician and patient and caregiver; CSF, cerebrospinal fluid; MCI, mild cognitive impairment; PET, positron emission tomography.
Sub-study 1 - Application of MRI and CSF biomarkers (Objective 1A & 1B)
Patients and design
In this cross-sectional multicenter study designed to compare different measurement methods of MRI and CSF biomarkers, we include 200 patients with subjective cognitive decline (SCD), MCI or dementia from ten Dutch local memory clinics. Clinical assessment is according to local practice, including at least medical and informant history, physical examination and cognitive testing. All patients who are offered MRI and/or lumbar puncture for diagnostic purposes are eligible for the study.
Methods – clinical data
We collect basic demographic and clinical information including age, gender, medical history, use of medication, clinical diagnosis, MMSE, neuropsychological evaluation, and CDR. We use OpenClinica open source software, version 3.1 (Copyright © OpenClinica LLC and collaborators, Waltham, MA, USA) for data management. In addition, we use The Older Persons and Informal Caregivers Survey Minimal DataSet (TOPICS-MDS) instrument, which feeds into a uniformly collected public data repository that contains information on the physical and mental health and wellbeing
of older persons and informal caregivers across the Netherlands.20
Methods – MRI
Structural MRI is performed according to local acquisition protocols and includes at least 3D T1-weighted imaging. Scans are collected centrally at the VU University Medical Center (VUmc). After a quality check, we obtain visual and volumetric measures of medial temporal lobe atrophy, posterior cortical atrophy and global cortical atrophy.21–23 MRIs will also be visually assessed for white matter hyperintensities, number of infarcts,
lacunes and microbleeds.24 We derive quantitative measures of atrophy via the software
package SIENAX (Structural Image Evaluation using Normalization of Atrophy
II
tool, FSL 4.15) will be used to estimate volumes of grey matter structures including the hippocampus.
Methods – CSF
CSF is collected in polypropylene tubes of 10 ml (Sarstedt) after lumbar puncture between L3/L4 or L4/L5 intervertebral space by a needle and syringe. CSF is centrifuged and then divided into 2 new polypropylene tubes (2.5 ml in one, remainder in other). The tubes are sent to the VUmc Neurochemistry Laboratory, department of Clinical Chemistry at the VUmc. CSF is frozen at -80°C until analysis of the biomarkers (Aβ1-42, tau and p-tau). CSF samples will be analyzed using the manually operated
Innotest ELISA.26,27 In addition, we use a novel Roche automated platform, Elecsys
immunoassays.28
Statistics
We will compare (i) visual and volumetric MRI measures and (ii) CSF measurements from both platforms using Spearman’s rank correlation and concordance measures. For CSF platform comparison, we will use Passing Bablok regression analysis. Accuracy, sensitivity, specificity and negative and positive predictive value will be compared.
Sub-study 2 - Application of amyloid PET (Objective 1C)
Patients and design
In this prospective observational study, we offer amyloid PET to all patients visiting our tertiary referral center for one year (n=450) to assess its diagnostic value in an unselected sample of memory clinic patients. Standard diagnostic work-up at the memory clinic of the VUmc Alzheimer Center includes medical history, neurological examination,
neuropsychological evaluation, basic laboratory testing and MRI.29 Additionally, we
enrol 50 MCI patients with similar diagnostic work-up from the University Medical Center Utrecht (UMCU) to enrich the cohort for MCI. We will follow all patients for one year, to verify diagnosis (dementia) or to assess clinical progression (SCD and MCI). Primary outcome measures are change in diagnosis, change in confidence in diagnosis and change in planned patient management following amyloid PET results.
Methods
At the VUmc, amyloid PET scans are made with 3Tesla Philips Ingenuity TF PET/ MR, Philips Ingenuity TF PET/CT and Philips Gemini TF PET/CT scanners. UMCU uses a Siemens Biograph 40 MCT scanner. Before and after scanning, patients fill out a questionnaire regarding their expectations and perceptions of amyloid PET. Patients
are injected with a tracer dose of approximately 300 MBq ± 20% [18F]florbetaben
(NeuraceqTM). The image acquisition window extends from 90 to 110 minutes
For each patient, a pre- and post-amyloid PET diagnosis is obtained with a level of confidence indicated by the neurologist (FB at the VUmc and GJB and the UMCU) varying from 0-100%. Also, the neurologists are asked about patient management before and after amyloid PET scan results are revealed, to assess a change in ancillary investigations, care and medication.
Statistics
We will assess change of syndrome diagnosis and suspected underlying pathophysiology. To assess differences in change of diagnostic confidence among diagnostic groups, we will use ANOVA for repeated measures with group as between subjects variable and (change in) diagnostic confidence as within subjects variable. Finally, we will evaluate whether the appropriate use criteria for amyloid imaging select those patients that are affected most by amyloid PET, in terms of change in diagnosis and change of planned management.
Sub-study 3 - Algorithms for diagnostic testing and personalized risk
estimates (Objective 2A & 2B)
Patients and design
In this retrospective, longitudinal study designed to develop individualized risk estimates, we include MCI patients with baseline MRI and/or CSF and at least one year of clinical
follow-up from the Amsterdam Dementia Cohort.29 Clinical diagnoses of MCI were
made in a multidisciplinary team according to international guidelines.6,30 Progression
to AD dementia at clinical follow-up is the outcome measure.8
Methods – personalized risk estimates
We will use Cox proportional hazards analyses to develop prognostic models for MRI biomarkers (ordinal), for CSF biomarkers (continuous) and for the two combined. To account for patient diversity, we will explicitly take gender, age, and MMSE into
account.31,32 The resulting models will allow to derive individual risk estimates and
confidence intervals (95%CI) for a patient with any given age, gender, MMSE and biomarkers result (MRI and/or CSF). In addition, we will obtain estimates of probability of progression, within one year and within three years, facilitating translation of these risk scores to the clinical setting. Five-fold cross validated Harrell’s concordance index will be used to validate the models.
Methods – algorithms for diagnostic testing
To develop algorithms for selection of diagnostic tests, i.e. MRI and CSF, we will perform an extensive literature search on the diagnostic and prognostic value of individual and
combined tests, taking special care to account for patient diversity.33 We will combine
the literature search results with the retrospective cohort data to develop algorithms for selection of tests. Subsequently, we will validate these rules in the prospective sample of local memory clinics (see objective 1).
II
Sub-study 4 - Identifying optimal strategies for shared decision making
and communication of test results (Objective 3)
Patients, design and methods
We will use qualitative and quantitative research methods to study shared decision making and patient-clinician communication. First, to identify which diagnostic dilemmas occur in the consultation room, we will organize separate focus groups for clinicians, patients and caregivers (n=10 per focus group). Participants will be asked to share their views, experiences, and perceived dilemmas regarding diagnostic testing and communication of test results. Focus group discussions will be audiotaped, transcribed and coded using MAXQDA-software.
Second, we will perform an observational audiotaping study in the routine diagnostic work-up of dementia. We will assess patient-clinician communication in both pre- and post-diagnostic testing consultations in 12 memory clinics (n=10 per clinician, n=240 consultations in total). After each consultation, patients and their caregivers will receive a brief questionnaire on their views and experiences. Based on insights gained from the consultations and focus groups we will extract a set of recommendations on how to effectively involve patients and caregivers in deciding about diagnostic testing, and on how to best discuss the results of such diagnostic tests.
Sub-study 5 - Practical e-based tools and implementation (Objective 4)
Ultimately, to facilitate communication about diagnostic tests in the daily routine of memory clinics, we aim to develop tools that can be used by clinicians in daily practice. We will combine our results from the best application of MRI, CSF and amyloid PET biomarkers (objective 1) with the developed algorithms for diagnostic testing, personalized risk estimates (objective 2) and recommendations for patient-clinician communication (objective 3) to create practical tools that can be used in the care process (Figure 2).
To prepare for the implementation and test phase of these tools, we will develop training sessions for clinicians. We will prospectively pilot and validate the tools in the panel of participating local memory clinics. To provide an infrastructure for nation-wide implementation of ABIDE results in the Netherlands, we recently established the Dutch Memory Clinic Network. This network aims to provide a platform for clinicians working at the more than 90 memory clinics in the Netherlands, enabling them to share new knowledge, harmonize diagnostic and treatment protocols and facilitate participation in research.
EXPECTED RESULTS
ABIDE officially started on December 1st, 2014 and is a four-year project (end date:
November 30th, 2018). In the first year, we obtained Institutional Review Board approval for the different sub-studies. Subsequently, we started with the inclusion of patients for the different sub-studies (Table 1). To date, at the end of the second project year, inclusion targets for substudies 1, 2 and 3 have largely been reached. In sub-study 1, we collected n=202 patients with MRI (target: n=200) and n=135 with CSF (target: n=200) from local memory clinics. In sub-study 2, we collected n=495 memory clinic patients with amyloid PET (target: n=450 mixed memory clinic + n=50 MCI). The retrospective data collected from the Amsterdam Dementia Cohort for sub-study 3 includes n=525 MCI patients (mean age 67 (± 8) years; 60% males; mean MMSE 27 (± 2); mean follow-up duration 2.4 (± 1.6) years). Finally, for sub-study 4 we held focus groups to identify and discuss diagnostic dilemmas with professionals, patients and caregivers and conducted an online survey amongst almost 100 memory clinic professionals. We are currently conducting the audiotape study and have included n=65 of pre- and post-diagnostic audiotaped consultations from local memory clinics (target n=120). Data lock for sub-studies 1 and 2 is expected in Q1 of 2017 and for sub-study 4 in Q3 2017. In the third project year, we will finish data collection, perform statistical analyses, create a prototype of the practical e-based tool (sub-study 5), and publish first results. The fourth and final year will consist of finalising data analyses, publishing results and pilot and validate the practical e-based tool in local memory clinics.
An important milestone was the launch of the Dutch Memory Clinics Network (Nederlands Geheugenpoli Netwerk (NGN); www.geheugenpoliklinieken.nl), linking the more than 90 memory clinics in the Netherlands. This network will facilitate the exchange of knowledge and resources, harmonize diagnostic and treatment protocols and facilitate participation in research. In addition, we will use this network for dissemination of ABIDE results.
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DISCUSSION
The major research advances in AD biomarkers (MRI, CSF and amyloid PET) have led to earlier and more accurate diagnoses, but these developments come with new challenges. First, the availability of biomarker tests poses the clinician for the challenge to select the right tests for each patient. Second, effectively communicating with patients and deciding mutually whether or not to use certain tests is difficult, especially in view of the cognitive deficits that come with (prodromal) AD. Third, biomarker results could affect (future) choices made by patients and their caregivers, especially when it concerns demented patients. With the advent of AD biomarkers, their disclosure to non-demented patients in clinical practice is therefore an emerging topic in research. Fourth, from an economic perspective, biomarkers should only be applied if the results are useful, for example when changing patient management or preventing crises later in the disease process. The ABIDE study aims to address the practical use of AD biomarkers by the clinician and how to take patients’ preferences towards testing and communication of test results into account.
In contrast to amyloid PET, MRI and CSF biomarkers are already widely used in clinical practice. Nonetheless, even for these tests, a lot of work still needs to be done to translate research findings to daily practice as clinicians vary greatly in their knowledge of these markers. In this context of clinical use of AD biomarkers, ABIDE is aligned with several ongoing research initiatives. For example, the Geneva Task Force for the Roadmap of Alzheimer’s Biomarkers works on a plan of actions that are needed to accelerate the
implementation of AD biomarkers in daily practice.34,35 ABIDE adds to this study by
prospectively evaluating the use of MRI and CSF in local memory clinics. When it comes to amyloid PET, its use is self-evident with respect to clinical trials in AD (e.g. Generation (NCT02565511), Early (NCT02569398), and A4 (NCT02008357)), but clinical utility still has to be established.36,37 Currently, the Imaging Dementia – Evidence for Amyloid Scanning (IDEAS) study (www.ideas-study.org) in the United States and the Amyloid Imaging to Prevent Alzheimer’s Disease (AMYPAD) study (http://www. amypad.eu) in Europe assess the clinical utility of amyloid PET in the diagnostic work-up of AD. ABIDE adds to these initiatives by including an unselected memory clinic cohort. This will allow us to empirically evaluate the appropriate use criteria for amyloid imaging.
The decision for clinicians whether to initiate diagnostic testing and choosing a test is still quite novel, so it is not yet common practice to involve patients and their caregivers in their diagnostic dilemma’s. ABIDE will provide insight in the degree of shared decision making during the diagnostic dementia work-up and will help identify roadblocks for the involvement of patients and their caregivers. By translating this knowledge into recommendations for best practice, we can facilitate patients and clinicians to engage in a conversation and work together in choosing care that fits the individual patient. This
the European Prevention of Alzheimer’s Dementia (EPAD) will address ethical aspects of risk disclosure.42 However, none of these studies focuses on disclosure of test results to non-demented patients in the clinical setting. ABIDE adds to these ongoing initiatives, as we focus on diagnostic dilemma’s in daily clinical routine and will deliver practical support to facilitate communication of test results in the clinical setting.
The worldwide costs of dementia care keep rising, and treatments that prevent or delay
AD are not yet available so far.43 Diagnosing patients in an early stage of disease is
important instrument to manage the impact of dementia, but also comes with costs.44
Early diagnosis might reduce costs later on in the disease process, as a well-informed patient is less likely to experience crisis situations or premature institutionalization. ABIDE attempts to harmonize and improve the diagnostic work-up with the ultimate goal of patient centered diagnostic care, based on current scientific knowledge, clinician expertise and patient preferences. Evaluation whether such strategies are cost-efficient will be a necessary next step.45
ABIDE attempts to take the next step in the dementia workup by considering what specific test results imply for individual patients. We will incorporate the developed individualized risk models in practical tools, which will facilitate the use of these diagnostic tests by clinicians in daily practice. By involving the main stakeholders of these novel diagnostic tests, i.e. patients, caregivers and professionals working in local memory clinics, ABIDE attempts to truly translate findings from research to the clinic, with the ultimate goal to improve the quality of diagnostic care.
ACKNOWLEDGEMENTS
Research of the VUmc Alzheimer Center is part of the neurodegeneration research program of Amsterdam Neuroscience. The VUmc Alzheimer Center is supported by Alzheimer Nederland and Stichting VUmc fonds. This study is funded by ZonMW-Memorabel (ABIDE; project No 733050201), a project in the context of the Dutch Deltaplan Dementie.
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APPENDIX
ABIDE study group
Amsterdam, the Netherlands (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, 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, 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; Haarlem, the Netherlands (Spaarne Gasthuis) Niki M. Schoonenboom, MD, PhD; Utrecht, the Netherlands (Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center Utrecht) Geert Jan Biessels, MD, PhD, 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 in long term care) Mirella M. Minkman, PhD, Cynthia S. Hofman, PhD, Ruth Pel, MSc; Meppel, the Netherlands (Espria) Esther Kuiper, MSc; Berlin, Germany (Piramal Imaging GmbH) Andrew Stephens, MD, PhD; Rotrkreuz, Switzerland (Roche Diagnostics International Ltd.) Richard Bartra-Utermann, MD.
Memory clinic panel
The members of the memory clinic panel are: Niki M. Schoonenboom, MD, PhD (Spaarne Gasthuis, Haarlem); Barbera van Harten, MD, PhD, Niek Verwey, MD, PhD, Peter van Walderveen, MD (Medisch Centrum Leeuwarden, Leeuwarden); Ester Korf, MD, PhD (Admiraal de Ruyter Ziekenhuis, Vlissingen); Gerwin Roks, MD, PhD (Sint Elisabeth Ziekenhuis, Tilburg); Bertjan Kerklaan, MD, PhD (Onze Lieve Vrouwe Gasthuis, Amsterdam); Leo Boelaarts, MD (Medisch Centrum Alkmaar, Alkmaar); Annelies. W.E. Weverling, MD (Diaconessenhuis, Leiden); Rob J. van Marum, MD, PhD (Jeroen Bosch Ziekenhuis, ‘s-Hertogenbosch); Jules J. Claus, MD, PhD (Tergooi Ziekenhuis, Hilversum); Koos Keizer, MD, PhD (Catherina Ziekenhuis, Eindhoven).
2
3
4 5 6 7 8
1
de Wilde A., van der Flier W.M., Pelkmans W., Bouwman F., Verwer J., Groot C., van Buchem M.M., Zwan M., Ossenkoppele R., Yaqub M., Kunneman M., Smets E.M.A., Barkhof F., Lammertsma A.A., Stephens A.,
van Lier E., Biessels G.J., van Berckel B.N.M., Scheltens Ph.
Association of amyloid positron
emission tomography with changes in
diagnosis and patient treatment in an
unselected memory clinic cohort: the
ABIDE project
ABSTRACT
Importance: Previous studies have evaluated the diagnostic impact of amyloid PET in selected research cohorts. These research populations, however, do not reflect daily practice, thus hampering clinical implementation of amyloid imaging.
Objective: The aim of this study was to evaluate the impact of amyloid PET on diagnosis, diagnostic confidence, patient management and patients’ experiences in an unselected memory clinic cohort.
Design, setting, and participants: We offered amyloid PET using [18F]florbetaben to all patients (n=866) visiting our tertiary memory clinic between January 2015 and December 2016, as part of their routine diagnostic dementia work-up. Of these patients, 476 (55%) were included, 32 (4%) were excluded, and 358 (41%) did not participate. For each patient, neurologists determined a pre- and post-amyloid PET diagnosis, existing of both a clinical syndrome (dementia, mild cognitive impairment (MCI), or subjective cognitive decline (SCD)), and a suspected etiology (AD; non-AD), with a confidence level ranging from 0-100%. In addition, the neurologist determined patient management, in terms of ancillary investigations, medication, and care. There will be a clinical follow-up after one year.
Main outcomes and measures: Primary outcome measures were post-PET change in diagnosis, diagnostic confidence, and patient management.
Results: We included 507 patients (age: 65±8, 39% female, MMSE: 25±4): 164 (32%) had AD dementia, 70 (14%) non-AD dementia, 114 (23%) MCI, and 159 (31%) SCD. Amyloid PET was positive in 242 (48%) patients. Suspected etiology changed in 125 (25%) patients after amyloid PET, more often due to a negative (82/265, 31%) than a positive (43/242, 18%) PET result (P<.01). Post-PET changes in suspected etiology occurred more frequently in older (>65 years) than younger (<65 years) patients (74/257 (29%) vs. 51/250 (20%), P<.05). Diagnostic confidence increased from 80±13 to 89±13% (P<.001). In 123 (24%) patients, there was a change in patient management 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 impact on diagnosis and management, both in demented and non-demented patients.
III
INTRODUCTION
Accumulation of brain amyloid-β is one of the neuropathological hallmarks of
Alzheimer’s disease (AD).1–3 The introduction of 11C-labeled Pittsburgh Compound B
([11C]PIB) enabled the detection of brain amyloid-β deposition in vivo using 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 (FDA), Health Canada, and the European Medicine Agency (EMA) of three F-18 labeled amyloid PET tracers allowed for more 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, though not yet in daily clinical practice. Appropriate use criteria for amyloid
imaging have been developed to provide guidance on its clinical use.13 These criteria,
however, are based solely on clinical experience and not guided by empirical evidence. Previous studies have investigated the clinical impact 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 management of 64%.14 However, all published studies
included selected research populations, not reflecting daily practice, thus hampering clinical implementation of amyloid imaging. Therefore, studies with large, unselected cohorts evaluating how amyloid PET can be integrated in routine clinical practice are
warranted.15 Moreover, none of these former studies assessed patients’ experiences with
amyloid imaging.
We aimed to evaluate the impact of amyloid PET, embedded in routine clinical practice, using an unselected memory cohort, on diagnosis, diagnostic confidence, and patient management. In addition, we assessed patients’ experienced burden and their levels of anxiety and uncertainty before and after PET.
