Clinical Utility of Amyloid PET Imaging in the Differential
Diagnosis of Atypical Dementias and Its Impact on Caregivers
Mémoire
Mohamed Réda Bensaïdane
Maîtrise en médecine expérimentale
Maître ès sciences (M. Sc.)
Québec, Canada
© Mohamed Reda Bensaïdane, 2016
Clinical Utility of Amyloid PET Imaging in the Differential
Diagnosis of Atypical Dementias and Its Impact on Caregivers
Mémoire
Mohamed Réda Bensaïdane
Sous la direction de :
Robert Laforce Jr – Directeur de recherche
III
RÉSUMÉ
La maladie d'Alzheimer (MA) se caractérise pathologiquement par l'accumulation de plaques amyloïde
dans le cerveau. La tomographie par émission de positrons (TEP) permet d'imager les plaques amyloïde in
vivo. Le but de ce projet est d’évaluer le rôle de la TEP amyloïde dans le processus diagnostique de la MA
dans des cas de démences atypiques. Le deuxième but de ce projet est de déterminer l'impact de la
révélation d’un diagnostic plus certain chez les proches aidants. 28 patients sans diagnostic malgré une
investigation exhaustive ont été sélectionnées et imagées avec le traceur amyloïde 18F-NAV4694 (âge 59,3
ans, é-t. 5,8; MMSE 21.4, é-t 6.0). Les neurologues référents documentaient par la suite tout changement
de niveau de certitude, de diagnostic, de traitement et/ou de prise en charge. Les proches aidants
consentants ont été rencontrés subséquemment, et un questionnaire avec une échelle de Likert a été utilisé
afin de documenter l’impact de l’imagerie leur perception de la maladie. Notre cohorte a été également
divisée entre amyloïde positifs (14/28) et négatifs (14/28). Un changement de diagnostic a lieu dans 9/28
cas (32,1% :17.8% ont changé de MA à non-MA, 14,3% de non-MA à MA). Il y avait une augmentation
significative (p<0,05) de 44% dans la certitude du neurologue suite à cet examen. Un changement de prise
en charge a été obtenu dans 20/28 (71,4%) des cas. Bien que non significatifs statistiquement, un impact
favorable sur les proches-aidants a été noté. Cette étude suggère que l’imagerie amyloïde a un rôle
bénéfique dans les cas de démences atypiques n’ayant pu être élucidés avec les techniques
d’investigations actuellement recommandées. De plus, le processus a été perçu positivement par les
proches aidants, notamment en encourageant du temps de qualité avec leurs personnes chères. Ceci illustre
un rôle prometteur des biomarqueurs, qui sont de plus en plus explorés.
IV
ABSTRACT
Recent studies have supported a role for amyloid PET imaging in distinguishing Alzheimer’s disease
(AD) pathology from other pathological protein accumulations leading to dementia. We investigated the
clinical utility of amyloid PET in the differential diagnosis of atypical dementia cases and its impact on
caregivers. Using the amyloid tracer 18F-NAV4694, we prospectively scanned 28 patients (mean age 59.3
y, s.d. 5.8; mean MMSE 21.4, s.d. 6.0) with an atypical dementia syndrome. Following a comprehensive
diagnostic workup (i.e., history taking, neurological examination, blood tests, neuropsychological
evaluation, MRI and FDG-PET), no certain diagnosis could be arrived at. Amyloid PET was then
conducted and classified as positive or negative. Attending physicians were asked to evaluate whether this
result led to a change in diagnosis or altered management. They also reported their degree of confidence in
the diagnosis. Caregivers were met after disclosure of amyloid PET results and completed a
questionnaire/interview to assess the impact of the scan. Our cohort was evenly divided between positive
(14/28) and negative (14/28) 18F-NAV4694 cases. Amyloid PET resulted in a diagnostic change in 9/28
cases (32.1%: 17.8% changed from AD to non-AD, 14.3% from non-AD to AD). There was a 44%
increase in diagnostic confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of
amyloid status improved caregivers’ outcomes in all domains (anxiety, depression, disease perception,
future anticipation, and quality of life). This study suggests a useful additive role for amyloid PET in
atypical cases with an unclear diagnosis beyond the extensive workup of a tertiary memory clinic.
Amyloid PET increased diagnostic confidence and led to clinically significant alterations in management.
The information gained from that test was well received by caregivers and encouraged spending quality
time with their loved ones. This study underscores the promising role of biomarkers in the study of
dementias.
V
TABLE DES MATIÈRES
RÉSUMÉ ................................................................................................................................................................... III
ABSTRACT ............................................................................................................................................................... IV
TABLE DES MATIÈRES ........................................................................................................................................ V
DÉDICACE .............................................................................................................................................................. VII
REMERCIEMENTS .............................................................................................................................................VIII
AVANT-PROPOS .................................................................................................................................................... IX
INTRODUCTION ..................................................................................................................................................... 1 Background Theory ............................................................................................................................................................ 1 Objectives ................................................................................................................................................................................ 3
METHODS .................................................................................................................................................. 5 Patients and diagnostic procedures ........................................................................................................... 5 Amyloid PET imaging and interpretation ................................................................................................ 6 Assessment of the impact of amyloid PET on the diagnostic process ............................................ 7 Assessment of the impact on caregivers’ life .......................................................................................... 7 Statistical analysis ............................................................................................................................................ 8
RESULTS ..................................................................................................................................................... 9 Subjects ................................................................................................................................................................. 9 Illustrative case example................................................................................................................................ 9 Amyloid status .................................................................................................................................................. 10 Change in diagnosis and diagnostic confidence following amyloid PET ..................................... 10 Effect on treatment and patient management ...................................................................................... 11 Impact on caregivers ...................................................................................................................................... 12
DISCUSSION ............................................................................................................................................ 14 Impact on caregivers ...................................................................................................................................... 15 Limits ................................................................................................................................................................... 16
CONCLUSION ......................................................................................................................................................... 18
REFERENCES ......................................................................................................................................................... 20
ANNEXES ................................................................................................................................................................ 24 TABLES .................................................................................................................................................................................. 24
Table 1. Patient characteristics. ............................................................................................................................. 24 Table 2. Diagnostic change following amyloid PET scan. ........................................................................... 25 Table 3. Effect of amyloid scan on treatment and patient management. ............................................. 26 Table 4. Most polarized answers on the caregiver questionnaire. ......................................................... 27
FIGURES ................................................................................................................................................................................ 28 Figure 1 ............................................................................................................................................................................ 28
VI
Figure 2. Assessment of the impact of amyloid imaging on the diagnostic process and main caregiver. ......................................................................................................................................................................... 29 Figure 3. Positive amyloid-PET study using NAV4694. ...................................................................................... 30 Figure 4. Global Aβ burden with NAV4694 in our 28 participants. ........................................................ 31 Figure 5. Change in diagnostic confidence following amyloid scan. ...................................................... 32 Figure 6. Impact of amyloid imaging on caregivers. ..................................................................................... 33
LIST OF ABBREVIATIONS ............................................................................................................................................. 34 SUPPLEMENTARY MATERIAL .................................................................................................................................... 34
Caregiver Questionnaire ........................................................................................................................................... 34
* Les parties en gras sont les sections qui proviennent de manière
quasi-intégrale de l’article que nous avons publié dans le « Journal of
Alzheimer’s Disease » (voir section Avant-Propos)
VII
DÉDICACE
À mes parents, ma sœur, mes grands-parents, mes
oncles et ma tante.
Pour m’avoir toujours poussé à me dépasser.
VIII
REMERCIEMENTS
J’aimerais tout d’abord remercier Dr. Robert Laforce, pour tout l’enseignement qu’il m’a offert et pour
m’avoir transmis sa passion pour les sciences neurologiques.
Mes remerciements vont également à Mme. Audrey Paradis et M. André Boucher pour leur inestimable
aide à la coordination tout au long de l’étude.
Tous mes remerciements à Dr Jean-Mathieu Beauregard, Dr Stéphane Poulin, Dr François-Alexandre
Buteau, Dr Jean Guimond, David Bergeron, Dr Louis Verrt, Dre Marie-Pierre Fortin, Dre Michèle Houde,
Dr Rémi W. Bouchard et Dr Jean-Paul Soucy pour leurs conseils, leurs encouragements, et leur
contribution à la réalisation du projet.
Je remercie aussi Navidea pour avoir facilité notre projet, notamment M. Stephen Haber, ainsi que Dr.
Gassan Massaraweh et l’équipe au McConnell Brain Imaging Center pour la synthèse du ligand amyloïde.
Également, remerciements à M. Benoît Galarneau et M. René Rebeaud de Hermes Medical Solutions,
pour nous avoir donné accès au logiciel d’analyse d’images. Finalement, je remercie La Société Alzheimer
de Québec, La fondation du CHUL de Québec, Les Fonds sur la Maladie d’Alzheimer de l’Université
Laval, et Le Réseau de Bio-Imagerie du Québec, pour leurs supports financiers.
IX
AVANT-PROPOS
Ce mémoire de maîtrise est fait sur un projet effectué à la Clinique Interdisciplinaire de Mémoire, du
Centre Hospitalier Universitaire (CHU) de Québec. Le projet a ultimement a été soumis au « Journal of
Alzheimer’s Disease » et a été officiellement publié le 18 avril 2016 (PUBMED ID : 27104896).
Une large partie de ce mémoire est basé sur l’article. Plus précisément, les sections MÉTHODS,
RESULTS, DISCUSSION sont identiques à celle du mémoire. L’introduction et la conclusion sont
différentes, et ont été faites afin de fournir une vision encore plus globale que celle publiée ; publiée dans
un journal que lisent déjà des experts du domaine. Afin d’avoir un texte continu, tout le mémoire a été
rédigé en anglais, langue originale de l’article.
Les auteurs de l’article sont les suivants : Dr. Robert Laforce (neurologue), Dre Marie-Pierre Fortin
(Gériatre), Dr Jean-Mathieu Beauregard (radiologiste nuclésite), Dr. Stéphane Poulin (psychiatre), Dr.
François-Alexandre Buteau (radiologiste nucléiste), Dr. Jean Guimond (radiologiste nucléiste), Dr Louis
Verret (neurologue), Dre Michèle Houde (gérontopsychiatre), Dr. Rémi W Bouchard (neurologue), Dr
Jean-Paul Soucy (radiologiste nucléiste), David Bergeron (étudiant MD-Ph.D) et moi-même. Ces
personnes ont tous été nécessaires à la réalisation du projet ; soit en référant des patients, en interprétant
des images radiologiques, ou en donnant des conseils qui ont bénéficié à la bonne réalisation du projet.
Dans cet article, j’ai été premier auteur et j’ai entrepris, sous les corrections et la supervision du Dr
Laforce, la rédaction de l’article. Les co-auteurs ont tous approuvé l’article avant sa publication et ont
permis d’apporter des commentaires qui ont augmenté la qualité du rapport. Évidemment, chaque auteur a
accepté à ce qu’une partie majeure de l’article soit inséré dans ce mémoire.
En espérant le tout à votre convenance, je vous invite à vous plonger dans le monde fascinant des
démences atypiques par la lecture de ce mémoire.
Réda Bensaïdane
1
INTRODUCTION
Background Theory Dementias are a group of neurodegenerative diseases characterized by a significant dysfunction of
cognitive function associated with impairment in functionality (McKhann, 2011). Since age is the
most important risk factor for dementia (van der Flier, 2005), it is important to acknowledge the
increasing prevalence of the disease in today’s ageing society (Lobo, 2000; Fratiglioni, 2000). In
fact, over 750 000 Canadians are living with a dementing disorder, and this number is expected to
double to 1.4 million by 2031 (Alzheimer Society of Canada, 2012). On a more global scale, over
40 million individuals are living with dementia and this has humongous economic impacts, as over
1% of the global gross domestic product (GDP) is dedicated to health-related costs of such
conditions (Prince, 2013). While Alzheimer’s disease (AD) is the most common cause of dementia,
accounting for about 40-60% (World Health Organization, 2012), other causes include
frontotemporal lobar degeneration (FTLD), vascular dementia, Lewy Body dementia, and
Parkinson disease with dementia (Caselli, 2003).
AD was first described by German psychiatrist, Alois Alzheimer, who examined the brain of a
cognitively impaired patient that fascinated him (Cipriani, 2011). He showed the histological
features that are today associated with AD: amyloid beta senile plaques and neurofibrillary tangles
(NFTs). The former is an accumulation of a constitutively generated peptide, named amyloid beta,
formed from the cleavage of amyloid precursor protein. The extra and intracellular accumulation of
this peptide has been shown to be toxic to neurons. However, several studies have showed, through
its complex uptake and breakdown pathways, that amyloid beta is not just a toxic protein but that it
may have a physiological role that is yet to be fully understood (Pearson, 2006). NFTs are
intracellular microtubule-associated aggregations of hyperphosphorilated tau protein. In addition to
being toxic to synaptic function (Spires-Jones, 2014), they are highly correlated in their spatial
distribution with the cortical atrophy observed in AD (Braak, 1991) and are correlated in an
inversely proportional manner to cognitive performance (Nelson, 2012). Whether these two
pathological entities are related or independent is still a matter of debate, and their review exceeds
the objectives of this introduction. However, let us underscore an important study, conducted by
Jack and colleagues, which had major impacts on the field and that allows us to see the big picture
(Jack, 2010; Jack, 2013). Indeed, they suggested a model in which there is a temporal ordering of
2
AD biomarkers: first appear amyloid plaques, several years before symptom onset; then appear tau
protein abnormalities causing neuronal injury. It is not until after brain structure begins to
significantly alter, as objectified with magnetic resonance imaging (MRI), that early AD symptoms
begin.
Until recently, AD was considered to be a homogenous entity that required distinctive memory
impairment, as it was indicated in the 1984 criteria (McKhann, 1984). It is now clear that AD
includes several distinct cognitive profiles, ranging from the typical late-onset amnestic AD to more
focal syndromes (Galton, 2000; Alladi, 2007; Lam, 2013; Warren, 2012; Bergeron, 2015). Briefly,
these include language variants of AD, a condition with different variants called primary
progressive aphasia (PPA) (Mesulam, 1982; Gorno-Tempini, 2011), behavioural-executive variant
(Taylor, 2008; Ossenkoppele, 2015), and visuospatial variant, also known as posterior cortical
atrophy (Crutch, 2012). For this, new criteria have been developed, which not only take in account
nonamnestic presentations, but can also incorporate biomarkers (McKhann, 2011). Despite such
definitions, AD diagnosis remains challenging especially in younger patients with atypical
symptoms or comorbid conditions (Vandenberghe R, 2013). Indeed, trained physicians can
diagnose “probable AD” with a sensitivity and specificity of only 71% when compared to
pathology, and up to 39% of patients diagnosed with non-AD dementia show postmortem AD-
histopathological features (Beach, 2010). In addition, misdiagnosis rates are higher in complex,
atypical patients with an uncertain diagnosis, approaching 30% (Grundman, 2013; Wolk, 2012).
In Canada, dementia diagnosis follows the recommendations of 4th Canadian Consensus
Conferences on the Diagnosis and Treatment of Dementia (CCCDTD4) (Gauthier, 2012). In these,
structural imaging, using MRI, is reserved for young patients (< 60 years) or for those with
unexplained symptomatology despite a thorough history, physical examination and basic laboratory
tests. Nuclear imaging, using fluorodeoxyglucose (FDG) positron emission tomography (PET), is
reserved for patients who have undergone structural brain imaging and who have been evaluated by
a dementia specialist but whose diagnosis remains unclear. FDG-PET can show distinctive patterns
of hypometabolism, all depending on the different underlying pathologies (Schöll, 2014). It can
significantly aid in the differential diagnosis of complex/atypical dementing disorders with
accuracies varying between 79 and 93% (Jagust, 2007; Laforce, 2011; Soucy, 2013).
Because of its high sensitivity and specificity for the detection of neuritic plaque densities
associated with AD (Klunk, 2004; Clark, 2012; Curtis, 2015; Sabri, 2015), amyloid PET imaging
3
(or amyloid PET) has recently been shown by several studies to be useful in the differential
diagnosis of atypical dementias (Wolk, 2012; Ossenkoppele, 2013; Bensaïdane, 2014; Sanchez-
Juan, 2014; Zannas, 2014; Mitsis, 2014). When compared to FDG-PET in discriminating AD
(n=62) from FTLD (n=45), it was shown to have higher sensistivity and inter-rater agreement in the
diangosis of FTLD (90%, k=0.96, vs. 78% and k=0.72, p<0.05) (Rabinovici, 2011). In another
effort where amyloid accuracy was assessed against pathologically confirmed cases (n=37),
negative predictive value was 100%, along with excellent sensitvity and specificy, being 90% and
100% respectively (Rabinovici, 2014). Furthermore, in a major study in which authors recruited 229
patients from 19 clinical sites (Grundman, 2013), amyloid PET was found to change diagnosis in
54.6% of cases, increase diagnostic confidence by 21.6%, and to significantly alter care
management. Intended acetylcholinesterase inhibitors (ACheI) or memantine treatment increased by
17.7% with positive scans and decreased by 23.3% with negative scans. Similar findings were
reported by another group (Zwan, 2015), which studied 211 early-onset dementia patients (aged
≤70 years) with an MMSE ≥18, and in whom diagnostic confidence was <90% after routine
diagnostic work-up. After disclosure of PET results, change in diagnosis occurred in 19% of cases,
diagnostic confidence increased from 69% to 88%, and here again PET led to a significant change
in patient management. Altogether, this has major implications for a cohort of individuals who are
often younger than 65 years old and still active in the workforce. In those patients, an accurate
diagnosis can help direct therapy, determine a better care plan, and enable patients to participate in
legal and financial planning that will directly affect them.
Objectives
Beyond converging evidence for the clinical utility of amyloid imaging in complex cases, two
particular issues remain poorly studied. First, definitions of what constitutes a “complex
atypical/unclear dementia case” vary among authors. For some, this would be a case where age,
symptoms and/or standard diagnostic evaluation do not fit a recognizable pattern while for others it
would be a case where diagnosis is confounded by comorbid psychiatric issues and/or
polypharmacy. Moreover, the sequence of investigations which leads to amyloid imaging can be
very different from one center to another, some having access to hippocampal volumetry and FDG-
PET, while others must rely on more limited techniques. Second, to our knowledge, none of these
studies have addressed the impact of a more definitive pre-mortem diagnosis on caregivers.
Caregivers constitute an essential part of the care of patients with early-onset atypical dementias,
yet no authors have explored their emotional reaction to the results from an amyloid imaging study.
4
Clinicians find it to be beneficial because it helps them arrive at a more definite diagnosis, but how
is this viewed from the caregiver perspective? Would they do it again? Does it impact quality of
life, and how so?
The main goal of this study was therefore to investigate the clinical utility of amyloid PET imaging
in the differential diagnosis of early-onset atypical cases. It is different from previous work in two
distinct ways. First, we followed appropriate use criteria for amyloid imaging (Johnson, 2013)
which recommend using it only in cases where three prerequisites are met: (1) there is an
objectively confirmed cognitive impairment, (2) AD is a possible diagnosis but it remains
unconfirmed after a comprehensive assessment, and (3) evidence of increased levels of amyloid in
the brain is expected to increase diagnostic certainty and alter management. We defined
“comprehensive assessment” as the combination of history taking, neurological examination, basic
blood tests, detailed neuropsychological examination, magnetic resonance imaging (MRI) –
dementia protocol (see below) – and FDG-PET. The important nuance here is that we recruited
highly atypical cases, assuming from previous literature and clinical experience that the sequence of
testing described above should have a sensitivity and specificity well above 90% (Jagust, 2007;
Laforce, 2010; Rabinovici, 2011). Yet, none of the patients included in this study had a clear
diagnosis, and therefore were considered to be highly complex/atypical cases. The second way in
which our study differed from previous work is that we specifically addressed impact on caregiver
by exposing them to the results of the amyloid PET and measuring a number of key variables using
a 21-item Likert scale questionnaire along with a 1-hour interview. Based on recent literature we
hypothesized that amyloid imaging would provide important added clinical information in atypical
cases with an unclear diagnosis beyond the detailed workup of a tertiary memory clinic, and that the
overall process would have a positive impact on caregivers’ life.
5
METHODS
Patients and diagnostic procedures Patients were recruited from La Clinique Interdisciplinaire de Mémoire du CHU de Québec
(www.cliniquedememoire.ca), one of the oldest tertiary memory clinics in Canada, which relies on
the expertise of six dementia specialists (3 behavioral neurologists [RWB, LV, RL], 1 geriatrician
[MPF], 1 geriatric psychiatrist [MH], and 1 neuropsychiatrist [SP]). This clinic is visited by an
average of 1,000 patients per year, referred from Eastern Quebec, generally for further evaluation
after an inconclusive initial assessment.
Compliance with guidelines on human experimentation was enforced at all phases of the study and
protocol approval by our local Institutional Review Board was obtained. Each patient and caregiver
provided written consent.
Prospective recruitment took place between January 1st 2013 and September 1st 2015. During that
period, a total of 3,542 patients were seen at our clinic. All patients were assessed according to the
“Recommendations of the 4th Canadian Consensus Conference on the Diagnosis and Treatment of
Dementia” (Gauthier, 2012). Following history taking, detailed neurological examination, basic
blood tests (complete blood count, ions, TSH, B12, Ca/Mg/Ph, Rapid Plasma Reagin for screening
of syphilis), comprehensive neuropsychological evaluation (Trail Making Test A and B, Stroop
Color-Word Test, Consonant Trigrams, IVA Continuous Performance Test, Wechsler Adult
Intelligence Scale-III, Controlled Oral Word Association Test, Boston Naming Test, Clock Drawing
test, Rey Complex Figure [copy], Hooper Visual Organizational Test, Wisconsin Card-Sorting Test,
Wechsler Memory Scale-III, California Verbal Learning Test, ABC 15 items, Beck Depression
Inventory), and MRI (dementia protocol – includes axial and coronal T2/FLAIR, axial SWI and
diffusion, and 3-D T1 sequences with detailed atrophy measures using Scheltens scale and grading
of white matter changes using Fazekas scale interpreted by a neuroradiologist with expertise in
dementia [MB]), only a limited number of cases remained unclear (n=270). In such a situation, our
investigative sequence is to request an FDG-PET scan, which is covered by the Quebec public
health insurances. Cerebrospinal fluid (CSF) analyses were not covered at the time of the study and
therefore were only very rarely used. Among the 270 FDG-PET scans that were requested during
that period (and interpreted by nuclear medicine specialists with expertise in dementia [FAB, JMB,
JPS, JG]), 30 cases corresponded to our inclusion and exclusion criteria, which are: inclusion
6
criteria: 1) ≤ 65 years old, 2) an atypical/unclear case with no specific diagnosis despite history
taking, neurological examination, neuropsychological assessment, MRI, and FDG-PET; exclusion
criteria: 1) typical dementia syndrome (see Figure 1), and 2) absence of FDG-PET. Of note, one
patient was cancelled twice because of unavailability of the tracer and decided to withdraw.
Another patient was deemed typical after blinded review of the FDG-PET by one of the co-authors
(JPS). Consequently, a total of 28 patients underwent an amyloid scan.
---------------------------------------------
Insert Figure 1 here
---------------------------------------------
Amyloid PET imaging and interpretation
Patients underwent amyloid imaging using 18F-NAV4694 (NAV4694; Navidea
Biopharmaceuticals, Dublin, OH, USA). Authorization was obtained from Health Canada to use this
non-approved tracer in a research protocol. This fluorine-based ligand was shown to be equivalent
to the reference standard carbon-11 (11C)-labeled Pittsburgh Compound B (PiB), but with a 110
minutes half-life (Jereus, 2010; Cselenyi, 2012; Rowe, 2013), it has the added advantage of much
more flexible scanning scheduling. NAV4694 was radiolabeled at the PET Unit, McConnell Brain
Imaging Centre (McGill University, Montreal [QC], Canada). Briefly, it was produced by
radiofluorination of the corresponding N-Boc–protected nitro precursor, followed by acidic
deprotection with hydrochloric acid. Average radiochemical yield is 16% after a synthesis time of
65 min, with radiochemical purity greater than 98% and an average specific activity of 555 ± 230
GBq/μmol.
PET scans were acquired in 3-D mode on a Siemens Biograph 6 PET/CT scanner (Siemens Medical
Solutions, Erlangen, Germany) at our PET unit, CHU de Québec, Québec City (QC), Canada. After
the intravenous injection of 200 to 370 MBq of NAV4694, an uptake period of 40 minutes was
observed. A low-dose, non-contrast CT of the head was acquired for attenuation correction and
anatomical correlation, followed by a 30 minutes dynamic PET acquisition. Three 10-minute frames
were reconstructed using 3-D ordered subset expectation maximization with a point-spread function
(Siemens HD-PET) with a 256 x 256 matrix. Analysis was performed with automated Brass
software (Hermes Medical Solutions, Stockholm, Sweden), which co-register the PET images to an
atlas and segment the brain in standard regions of interest (ROIs) to generate standardized uptake
7
value ratios (SUVRs) referenced to the cerebellar cortex, a region relatively unaffected by dense Aβ
plaques in sporadic AD, for NAV4694. Global Aβ burden was expressed as the average SUVR of
the mean of the following cortical ROIs: frontal (consisting of dorsolateral prefrontal, ventrolateral
prefrontal, and orbitofrontal regions), superior parietal, lateral temporal, lateral occipital, and
anterior/posterior cingulate and precuneus. As in previous studies using NAV4694 (Jereus, 2010;
Cselenyi, 2012; Rowe, 2013), SUVR cutoff was set at 1.50. In addition to quantitative interpretation
using SUVRs, images were qualitatively interpreted by two highly trained nuclear medicine
physicians (JPS, JMB). These clinicians were blinded to clinical information and performed their
readings independently. In the end, each amyloid PET scan was judged as either positive or
negative based on qualitative and quantitative reads.
Assessment of the impact of amyloid PET on the diagnostic process
Amyloid PET was presented to both the patient and the caregiver as an additional test that was part
of a research protocol and that could help clarify the diagnosis. Following each amyloid PET, the
principal investigator (RL) of the study met with the patient and family to disclose amyloid status
(either positive or negative) and further inquire about any side effects or discomfort associated with
the process. The amyloid PET image was shown to each case. Amyloid status was then disclosed to
the patient’s treating dementia expert who scheduled another appointment to discuss the most recent
diagnostic opinion. Each physician filled a questionnaire detailing pre-scan and post-scan diagnoses
with their corresponding confidence levels. Confidence level was assessed on a scale of 5 where 1 =
very weak, 2 = weak, 3 = average, 4 = high, and 5 = very high. Treatment changes and altered
management following scan were also documented in this questionnaire. Physicians were asked to
explain in what way the amyloid scan had contributed to the overall assessment process.
Assessment of the impact on caregivers’ life
All participating caregivers were very close to the patients and aware of each step of the diagnostic
process. They were present at each appointment with their treating physician, and for this reason
had access to the same information as the patient prior to the amyloid scan. Amyloid PET was
presented as an additional test that could help clarify the diagnosis (the sequence of events that led
to disclosure of amyloid status is detailed in the section above).
Consenting caregivers were met at least 30 days after disclosure of amyloid status by their treating
dementia expert. A 21-item Likert scale questionnaire along with a 1-hour interview designed to
assess the impact of the amyloid scan results was then administered (see Supplementary Material –
8
Caregiver Questionnaire). More specifically, the purpose of this interview was to go over each
question individually, and, by taking in account the caregivers’ psychosocial contexts, try to
understand the reasons that motivated his or her answers. This was done in order to try and correct
for the different interpretations that may have the caregivers of the different statements.
The questionnaire and interview covered the following domains: anxiety, depression, disease
perception, future anticipation, and quality of life. In fact, 4 questions assessed “Anxiety” (e.g. I am
more afraid of developing a neurodegenerative disease since the diagnosis has become more
certain), 4 assessed “Depression” (e.g. I sleep better since my loved one’s condition is known), 6
assessed “Disease perception” (e.g. The family atmosphere is better since the precise diagnosis of
my loved one has become clearer), 4 assessed “Future anticipation” (e.g. Better assessment has
allowed us to better plan for the future) and 3 assessed general “Quality of life” (e.g. I appreciate
more every moment with my loved one since clarification of the diagnosis). In some cases, more
than one caregiver was interviewed (e.g. both parents, or spouse and daughter). Figure 2
recapitulates the sequence of events that occurred following amyloid PET scan.
---------------------------------------------
Insert Figure 2 here
---------------------------------------------
Statistical analysis
Independent sample t-tests were used to assess group differences. Paired-sample t-tests were used to
assess change in diagnostic certainty before and after amyloid PET scan. Pearson χ2 tests were used
to assess differences in patient management plan.
9
RESULTS
Subjects
Patient characteristics are shown in Table 1. Treating physicians’ hypotheses (AD vs. non-AD) of
the 28 participants with complex/atypical dementias are listed in Table 1. There were a total of 16
AD diagnoses; 8 amnestic AD, 3 behavioral/dysexecutive AD, 3 language variant AD/logopenic
variant of primary progressive aphasia, 1 visual variant AD/posterior cortical atrophy and 1
corticobasal syndrome. A total of 12 cases were judged non-AD; 3 behavioral variant
frontotemporal dementia, 2 corticobasal degeneration, 1 non-fluent/agrammatic variant primary
progressive aphasia, and 6 of other causes (psychiatric condition, intellectual deficiency, etc.).
Diagnostic confidence of attending physicians in their hypotheses before amyloid scanning (scale 1-
5) is also listed in Table 1.
---------------------------------------------
Insert Table 1 here
---------------------------------------------
Illustrative case example
A 65-year-old woman was referred to our Memory Clinic for complaints of progressive memory
difficulties. No changes in behavior were noted. Memory problems were combined with increasing
functional difficulties. Neurological examination documented the absence of eye movement
irregularities as well as of extrapyramidal signs. Initial blood tests were non-contributory.
Neuropsychological evaluation showed spared verbal episodic memory but impaired visual memory
along with visuospatial deficits. There were impairments in lexical verbal fluency as well. MRI did
not show any specific pattern of focal atrophy or significant vascular burden. Given the atypical
nature of her deficits, her young age and the functional impact of her symptoms, FDG-PET was
ordered. This test showed diffuse fronto-parieto-temporal hypometabolism with a frontal
predominance and sparing of the posterior portions of the cingulate gyri, suggestive of
frontotemporal lobar degeneration (FTLD). The treating behavioral neurologist (LV) explained to
the family that there was a discrepancy between the clinical presentation and the results of the
investigation, and suggested further imaging. Amyloid imaging revealed high deposition of amyloid
10
plaques with an average SUVR of 2.15 (figure 3) with a positive read from two different nuclear
medicine specialists blinded to clinical data. A diagnosis of Alzheimer’s disease was announced
with greater confidence. The full one-hour interview with the primary caregiver revealed that family
members were glad to be finally clear on diagnosis, as they had been seeking answers for over a
year at that time.
---------------------------------------------
Insert Figure 3 here
---------------------------------------------
Amyloid status
Based on qualitative (visual interpretation) and quantitative (SUVR > 1.5 means positive) blinded
reads by 2 independent expert nuclear medicine specialists, half of our patients (n=14) had a
positive amyloid scan (see Figure 4). No significant differences were found between amyloid-
positive and amyloid-negative groups in terms of age, gender, education, disease duration and
MMSE scores. The average SUVRs were 2.12 (± 0.19 ; 1.80 – 2.51) and 0.97 (± 0.85; 0.84 – 1.19)
in the amyloid-positive and amyloid-negative groups, respectively. Therefore, no overlap was
found, and the difference between the highest SUVR value of the negative group and the lowest
SUVR value of the positive group was quite large. The concordance rate between our two nuclear
medicine specialists was 100%. Of interest, 3 patients (2 amyloid-positive and 1 amyloid-negative)
also had lumbar punctures with analysis of Aβ1-42, total tau and p-tau, and their CSF levels were
consistent with amyloid PET scan results.
---------------------------------------------
Insert Figure 4 here
---------------------------------------------
Change in diagnosis and diagnostic confidence following amyloid PET
Table 2 indicates the changes in diagnosis following the amyloid scan. Overall, diagnostic changes
occurred in 9 (32.1%) cases and were found slightly more often in the direction from AD to non-
AD (17.8%) then the opposite (14.3%). Diagnostic change occurred in 28.6% and 35.7% in amyloid
positive and amyloid negative groups respectively. There were no statistical differences between
11
these 2 groups in terms of diagnostic change.
---------------------------------------------
Insert Table 2 here
---------------------------------------------
Amyloid imaging generated a significant increase (p<0.05) of 44% in diagnostic confidence from
pre- to post-amyloid scanning (see Figure 5). This did not significantly differ between the amyloid-
positive and amyloid-negative groups (p=0.169).
---------------------------------------------
Insert Figure 5 here
---------------------------------------------
Effect on treatment and patient management
A total of 11/28 patients saw their medication changed (initiation of an ACheI, change in dosage or
molecule, or discontinuation of the treatment) following amyloid PET (see Table 3). All amyloid-
positive patients who saw their diagnosis changed also had a change in medication (initiation or
modification, but no discontinuation). Amongst the patients who were amyloid-negative and saw
their diagnosis changed from AD to non-AD, 3 did not have medication change because they were
not previously on an ACheI. The other two patients were previously on such medication, which was
discontinued.
Changes in patient management (or care plan) are also shown in Table 3. This excludes medication
changes and includes, but is not limited to, registration to a vaccine trial, lumbar puncture for CSF
analysis, referral to a speech therapist and/or referral to a psychologist. The amyloid-negative group
showed the most care plan changes (57% vs. 21%; p=0.120 by chi-square test). When there was a
negative amyloid scan and no diagnostic change, the care plan changed most often (67%). This
proportion approached significance when compared to the amyloid-positive group without change
in diagnosis (67% vs. 20%; p=0.07 by 2-sided chi-square test).
---------------------------------------------
Insert Table 3 here
12
---------------------------------------------
Impact on caregivers
A total of 23 caregivers were met. All participating caregivers completed the 21-item Likert scale
questionnaire as well as the 1-hour interview. Figure 6 illustrates the impact of amyloid imaging on
various variables. There were no statistically significant differences between the amyloid-positive
and amyloid-negative groups.
---------------------------------------------
Insert Figure 6 here
---------------------------------------------
An in-depth and purely qualitative exploration of the most polarized answers from the questionnaire
revealed interesting characteristics (see Table 4). Most importantly, and not surprisingly, different
questions were understood differently by caregivers depending on their standpoint and life situation
(for example, in one instance the caregiver was the 82-year-old father of the patient).
---------------------------------------------
Insert Table 4 here
---------------------------------------------
The 1-hour interview with caregivers provided a different perspective on things. Caregivers
expressed in their own words the impact of amyloid PET results on their overall appreciation of life.
First and foremost, caregivers reported a better understanding of their loved one’s condition. They
consistently described their state of mind prior to amyloid imaging, all of them reporting many
periods of confusion and frustration towards unexplainable behavioral and cognitive changes seen
in their loved ones. They expressed frustration towards the difficulty physicians showed in
providing appropriate answers to their questions. Amyloid imaging was correctly perceived as the
final test that was meant to indicate if Alzheimer’s disease was the causal pathology. Generally,
after amyloid imaging, caregivers felt more confident as to the next steps ahead. For example, in
question #10 of the questionnaire “I appreciate every instant with my beloved one even more since
we know the precise diagnosis”, some caregivers described how they stopped working in order to
spend more time with their loved one now that the diagnosis was clear and that the reserved
13
prognosis of the disease was clarified. Examples of future plans were given as well (buying plane
tickets for vacations and making sure that wills and testaments were completed). For such reasons,
despite remaining saddened by the incurable nature of neurodegenerative diseases, they all saw
themselves as having a better acceptance of the disease.
14
DISCUSSION
This study investigated the clinical utility of amyloid PET imaging in the differential diagnosis of
early-onset atypical cases of dementia. It demarcated itself from previous work in two ways. First,
by defining ‘uncertainty after a comprehensive assessment’ (see AUC criteria (Johnson, 2013)) as
an “uncertain diagnosis after history taking, neurological examination, blood tests, comprehensive
neuropsychological examination, MRI – dementia protocol and FDG-PET”, therefore recruiting the
most challenging atypical cases. Second, it addressed impact on caregivers using a 21-item Likert
scale questionnaire and a 1-hour interview specifically designed for this study. Amyloid PET was
associated with a diagnostic change in 9/28 cases (32.1%). There was a 44% increase in diagnostic
confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of amyloid status
improved caregivers’ outcomes in all domains (anxiety, depression, disease perception, future
anticipation, and quality of life). Altogether, our results suggested a useful and additive role for
amyloid PET in atypical cases with an unclear diagnosis beyond the detailed workup of a tertiary
memory clinic. Amyloid PET increased diagnostic confidence and generated clinically significant
alterations in management. The overall process was positive for caregivers notably by making it
easier to spend quality time with their loved ones.
Usefulness of amyloid imaging in cases where diagnostic confidence is low has been reported in
several studies (Grundman, 2010; Ossenkoppele, 2013; Zannas, 2013; Wolk, 2013), and our results
are consistent with those findings. Indeed, a total of 32.1% of the subjects had a diagnosis change
following amyloid PET scan. Despite this, amyloid imaging did not replace clinical judgment. In
some instances, ACheI treatment was maintained in the presence of a negative amyloid scan
because of a lack of negative impact on the patient. Most often, however, acetylcholinesterase
treatment was initiated in patients thought to have AD pathology and stopped in FTLD cases. This
is relevant because FTLD patients were shown to have worsening of their symptoms following
acetylcholinesterase treatment (Mendez, 2007; Boxer, 2013; Arciniegas, 2013).
Clinically significant alterations in management have been defined in various ways by authors. The
most obvious problem regarding this claim is what is significant exactly? In all cases, the pre-test
diagnosis was an incurable dementia and neurodegenerative disease, as was the post-test diagnosis.
Does a change in cholinesterase inhibitor use really indicate a significant alteration in therapy?
15
Nonetheless, it is important to try and quantify this concept. The definition of altered management
used in our study excluded medication changes and included registration to a vaccine trial, lumbar
puncture for CSF analysis, referral to a speech therapist and/or referral to a psychologist, as well as
other similar interventions. Although it failed to reach statistical significance, we found a change in
careplan (or management) in up to 11/28 (39.2%) of our cohort.
Interestingly, the group that had the most careplan/management changes (excluding medication
change according to the definition used in the current study) was the group with a negative amyloid
PET and no change in diagnosis. In that group, 2 patients were referred to speech-therapy, 1 for
psychotherapy, 1 was encouraged to focus on a number of compensatory strategies, and 2 had
lumbar puncture for further investigations. This opposes our amyloid positive group without
diagnosis change where out of all patients in this group, the only management change included 2
patients referred for vaccine protocol trials. The most likely explanation for this could be that non-
AD entities appear to have more components where clinicians can intervene. For example, non-AD
cases can benefit from speech therapy, when appropriate. Our pseudo-dementia case could benefit
from psychotherapy but no amyloid positive AD got such referral because of lack of expected
benefit from psychotherapy. Another explanation could be that once clinicians eliminate the
possibility of prescribing acetylcholinesterase inhibitors; they take an extra step in attempting to
help their patients. This could explain why 2 patients had lumbar puncture for more advanced
analyses.
There was a 100% inter-rater agreement in the readings of amyloid scans in this study. The experts’
interpretations also matched with quantitative (SUVR) results 100% of the time. This has also been
reported previously in the literature. For instance, a major multicenter study identified an overall
agreement of 93% between 3 independent readers (Barthel, 2011). The higher agreement in our
study may reflect the quality of the ligand, as NAV4694 has less white matter binding than other
fluorine-based compounds commonly used (Rowe, 2013). Consequently, images are easier to
interpret. SUVRs in our study followed a bimodal distribution with no borderline cases approaching
recommended threshold. This certainly made the cases easier for the nuclear medicine physicians to
interpret.
Impact on caregivers
Caregivers constitute an essential part of the care of patients with early-onset atypical dementias,
yet no authors have explored their emotional reaction to the results of an amyloid scan in the
16
context of a tertiary memory clinic investigation. Clinicians believe it is beneficial because it helps
them establish a diagnosis but we wished to explore how this is viewed from the caregiver’s
perspective. In a study where participants were asked whether they wanted or not to know if they
had AD pathology, older adults with subjective memory complaints had two kinds of reactions:
there were those who did not want to know, who stated it would create anxiety, whereas those who
wanted to know reported several potential benefits (Elson, 2006). Amongst those were developing
plans for the future, considering early treatment, facilitating psychological adjustments, enabling
family members to understand behaviours, and the desire to be kept informed. Another study
suggests that disclosure of AD status could help patients deal with anxiety (Mormont, 2014).
Overall, these results suggest a benefit in the disclosure of a correct diagnosis. However, no study
had investigated the impact of a more confident AD diagnosis on caregivers, particularly when their
loved ones present with an atypical syndrome. Since no disease-modifying treatments are available
yet for AD, we believe that it is of the uttermost importance to assess the impact of a correct
diagnosis on caregivers. Hence, the second objective of this study was to see the impact on
caregivers of disclosure of diagnosis following amyloid imaging.
Overall, we found a clear qualitative improvement in the variables assessed namely anxiety,
depression, disease perception, anticipation of the future, and quality of life following disclosure of
the amyloid scan findings. However, none of these trends reached statistical significance. This
could be biased by the fact that, at the end of the day, one can be informed with greater confidence
about a diagnosis but the fact remains that a young individual is faced with a progressive and
irreversible neurodegenerative disease. This can never be a source of joy. Following amyloid PET,
caregivers appreciated more each moment with their loved ones and were better able to make plans
for the future, as shown in Table 4. Most reported they did not regret going through all of the
investigations. Furthermore, there were no differences between amyloid-positive and amyloid-
negative groups with respect to caregiver impact. Nevertheless, those with a negative scan often had
a more nebulous understanding of the disease and of its natural history.
Limits
This study has limitations. First, it was conducted on a small sample of 28 patients without
pathological confirmation. However, this sample was carefully selected by experienced experts in
the field of behavioral neurology. It is also unique in that contrary to previous reports, it addressed
the value of amyloid imaging in the most atypicals among atypicals. Second, the questionnaire used
17
to assess impact on caregivers was not validated and only reflected the general feelings of the
caregivers. A difficulty that was encountered with our questionnaire is variable interpretations of
the same statement. Caregivers sometimes showed problems relating to how they actually felt at the
moment when the diagnosis was announced. In other words, caregivers tended sometimes to answer
the questions relating to how they lived through their loved one’s disease in general, instead of
concentrating on what happened at the point in time where they obtained a more accurate diagnosis.
A possible way to prevent this type of confusion would have been to perform the questionnaire
before the amyloid PET, and to re-perform it after the amyloid PET. Third, those with a negative
scan often had a more nebulous understanding of the disease and of its natural history. Fourth, this
study was conducted in young dementia patients in whom the prevalence of “age-related” amyloid
pathology is less likely to be present compared to older patients in whom (mixed) amyloid
pathologies are more frequently found. Finally, all were recruited from a tertiary memory clinic,
which may not reflect the impact of amyloid PET in a general, often older aged population.
However, it supports the usefulness of appropriate use criteria for amyloid PET imaging, which
describe a potential added value in patients with early-onset dementia with unclear clinical
presentations (Johnson, 2013; Dubois, 2015; Laforce, 2016)
18
CONCLUSION
Our findings support an additive value to amyloid PET imaging in the context of a comprehensive
tertiary memory clinic work-up in patients suspected of early-onset atypical dementia. This has an
impact on clinical diagnosis, it increases overall diagnostic confidence and alters patient
management plan. In these patients, an accurate diagnosis can help direct therapy (i.e. avoid
unnecessary or undesired ACheI or memantine prescriptions), determine a better care plan (which
considers patient safety and minimizes the risk of preventable complications), and enable patients to
participate in legal and financial planning. The information gained from this technique is well
received by caregivers and encouraged spending quality time with their loved ones.
Since our main inclusion criteria was that our patients did not have a clear diagnosis despite a
thorough investigation, our results provide additional evidence for the recommendations put
forward in the appropriate use criteria for amyloid PET in clinical practice (Johnson, 2013; Laforce,
2016). As previously mentioned in the introduction, these criteria are: (1) there is an objectively
confirmed cognitive impairment, (2) AD is a possible diagnosis but it remains unconfirmed after a
comprehensive assessment, and (3) evidence of increased levels of amyloid in the brain is expected
to increase diagnostic certainty and alter management. Such evidence-based criteria are important
because amyloid imaging can be harmful if not used properly. A recent cross-sectional study which
measured amyloidosis and neurodgeneration in 985 cognitively normal participants aged 50-89
years old, it was demonstrated that amyloid inveitably acumulates with age. Yet, many people
retain normal cognivitve function despite this substantial amyloid burden (Jack, 2014). Despite
some evidence suggesting that participants who are APOE e4 positive (an allele known to be a risk
factor for AD) and have high amyloid beta burden on amyloid PET show the highest cognitive
decline on MMSE, these are merely risk factors for developping the disease (Mormino, 2014).
Thus, inappropriate amyloid imaging can lead to disclosure of results that can create distress and be
harmful.
Our study can be continued as part of doctoral studies and could investigate the overall use of
biomarkers in atypical dementias. Recent advances in neurosciences have led to a better
understanding of neurodegenerative diseases’ pathophysiological processes, and have resulted in
the incorporation of biomarker evidence as part of some disorders’ criteria (see updated McKhann
criteria for AD for example). However, the combined use of these biomarkers in a large (>100)
19
cohort of atypical dementias has never been studied. Such biomarkers not only include amyloid
imaging, but also CSF analyses, and tau imaging, whose clinical role is still ambiguous. Subgroups
analyses can then be performed to compare each biomarker and better define their roles and
limitations within a complete clinical setting that assesses every variable, from the diagnosis to the
management of patients.
Furthermore, much is expected from the recently launched Imaging Dementia – Evidence for
Amyloid Scanning (IDEAS) Study, a $100M open-label longitudinal cohort effort on approximately
18,500 US Medicare beneficiaries. In this venture, diagnostically uncertain cases of mild cognitive
impairment and atypical dementia will be referred by physicians of all specialities, including those
in primary care, to be scanned to determine whether knowledge of amyloid status leads to
significant changes in patient management and if this translates into improved medical outcomes.
In addition to enhancing the diagnostic process of atypical dementing syndromes and allowing
earlier treatment, we can expect amyloid imaging to be a major contributor to future advancements
and discoveries in the field of Alzheimer disease and the natural evolution of dementias. For
example, amyloid imaging has served as a secondary outcome measure in Alzheimer disease
clinical trials with disease-modifying agents such as the anti-amyloid monoclonal antibodies
bapineuzemab and solanezumab. Recently, a study has shown brain amyloid reduction and slowing
of cognitive decline after one year of treatment with aducanumab, a human IgG1 monoclonal
antibody against a conformational epitope found on Aβ (Keller, 2015). Hence, confirming the
amyloid-positive status of patients in clinical trials (e.g., the Anti-Amyloid Treatment in
Asymptomatic Alzheimer’s Disease (A4) Study) will be of the uttermost importance for validation
of therapies.
20
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24
ANNEXES
TABLES
Table 1. Patient characteristics.
Abbreviations: AD: Alzheimer’s disease; CDR: Clinical dementia rating; CDR-SB: Clinical
dementia rating – Sum of boxes; MMSE: Mini-Mental State Examination; SD: Standard deviation.
*AD means: 8 amnestic AD, 3 behavioral/dysexecutive AD, 3 language variant AD (or logopenic
variant of primary progressive aphasia), 1 visual variant AD (or posterior cortical atrophy) and 1
corticobasal syndrome.
‡Non-AD means: 3 behavioral variant frontotemporal dementia, 2 corticobasal degeneration, 1 non-
fluent/agrammatic variant primary progressive aphasia, and 6 of other causes (psychiatric condition,
intellectual deficiency, etc.).
§Confidence level was assessed on a scale of 1-5.
Age (mean ± SD; range) 59.3 ± 5.8; 48 – 68
Gender (% female) 13 (46.4%)
Education (mean ± SD; range) 13.3 ± 3.4; 8 – 23
Disease duration (mean ± SD; range) 3.0 ± 1.5; 1 – 6
MMSE (mean ± SD; range) 21.4 ± 6.0; 9 – 29
CDR (mean ± SD) 1.1 ± 0.6
CDR-SB (mean ± SD) 5.9 ± 4.2
Pre-amyloid diagnosis
AD*
Non-AD‡
16 (57.1%)
12 (42.9%)
Confidence level in pre-amyloid diagnosis§ (mean ± SD) 3 ± 0.90
25
Table 2. Diagnostic change following amyloid PET scan.
No change Diagnostic change
from AD to non-AD
Diagnostic change
from non-AD to AD
All patients (n=28) 19 (67.9%) 5 (17.8%) 4 (14.3%)
Amyloid-positive
patients (n=14) 10 (71.4%) 0 (0%) 4 (28.6%)
Amyloid-negative
patients (n=14) 9 (64.3%) 5 (35.7%) 0 (0%)
26
Table 3. Effect of amyloid scan on treatment and patient management. Amyloid + (n=14) Amyloid – (n=14)
Change in
diagnosis
(n=4)
No change in
diagnosis
(n=10)
Change in
diagnosis
(n=5)
No change in
diagnosis
(n=9)
No change in medication 0 5 (50%) 3 (60%) 9 (100%)
Change in
medication
Initiation 2 (50%) 3 (30%) 0 (0%) 0 (0%)
Modification 2 (50%) 2 (20%) 0 (0%) 0 (0%)
Discontinuation 0 (0%) 0 (0%) 2 (40%) 0 (0%)
Care plan change 1 (25%) 2 (20%) 2 (40%) 6 (67%)
27
Table 4. Most polarized answers on the caregiver questionnaire.
Question Global result (mean ± SD; range) Answer
I appreciate every instant with my beloved one
even more since we know the precise diagnosis. *4.13 ± 0.92; 2 – 5
11/23 strongly agreed, 7/23 agreed and only 1/23
disagreed.
In hindsight, I would have preferred if we didn't
go through all of the investigations to determine
the diagnosis of my beloved person.
1.26 ± 0.54 ; 1 – 3
18/23 strongly disagreed, 1 caregiver neither
agreed nor disagreed, and no caregiver was in
agreement with this statement.
It scares me to develop a neurodegenerative
disease even more now that we know the
diagnosis of my beloved one.
1.78 ± 0.90; 1 – 4
Only 1/23 agreed with this statement. When asked
about it, he said that if something happens to him,
his wife would not be there for him and he would
not be there for her. 4/23 neither agreed nor
disagreed with this statement.
If I had an uncurable neurodegenerative disease,
I'd rather not go through all of the investigations
(including amyloid imaging) to know what my
diagnosis is.
1.70 ± 0.82; 1 – 4
Only 1/23 agreed with this statement. His reason
was that it is uncurable so there is no use. This
caregiver was the father of the patient, and he was
82 years old.
Scores on the Likert scale were as follows:
1 = strongly disagree; 2 = disagree; 3 = neither agree nor disagree; 4 = agree; 5 = strongly agree.
28
FIGURES Figure 1. Proposed investigative sequence in complex/atypical dementia cases.
*Brain FDG-PET is covered by the provincial public health insurances in Quebec (QC), Canada.
Cerebrospinal fluid analyses were not covered at the time of the study.
Abbreviations: FDG-PET: 18F-fluorodeoxyglucose positron emission tomography; MRI: magnetic
resonance imaging.
History taking, neurological examination, blood tests, neuropsychological evaluation and MRI
Unclear diagnosis?
FDG-PET*
Unclear diagnosis and 65 years old
Amyloid imaging
29
Figure 2. Assessment of the impact of amyloid imaging on the diagnostic process and main caregiver.
*In 46.4% of the cases included in this study, the Principal Investigator (RL) was also the treating
physician.
‡Caregiver evaluations were conducted by a graduate student blinded to the clinical context and were two-
fold: 1) Structured one-hour interview, and 2) 21-item Likert scale questionnaire. Both were designed to
assess the impact of the amyloid scan.
Amyloid imaging
Disclosure of amyloid status by the Principal Investigator (RL)*
Caregiver evaluations‡:
- Levels of anxiety and depression
- Disease perception
- Future anticipation
- Quality of life
Treating physicians' evaluations:
- Diagnostic impact
- Change in diagnostic confidence
- Treatment changes
- Management changes
30
Figure 3. Positive amyloid-PET study using NAV4694. This test shows significant deposition of fibrillary amyloid plaques in the cingulate cortex (A) as well as diffusely throughout the brain (B).
31
Figure 4. Global Aβ burden with NAV4694 in our 28 participants.
Horizontal line denotes 1.50 threshold between high and low radiotracer binding.
Abbreviation: SUVR: Standard Uptake Value Ratio.
SU
VR
Amyloid PET result
Negative Positive
32
Figure 5. Change in diagnostic confidence following amyloid scan.
Scores on the diagnostic confidence scale were as follow: 1= very weak, 2=weak, 3=average, 4=high,
5=very high.
*Change is significant by paired-sample t test (p<0.05)
0
1
2
3
4
5
6
All subjects (n=28) Amyloid + (n=14) Amyloid - (n=14)
Dia
gn
ost
ic c
on
fid
ence
(S
cale
1-5
)
Pre amyloid scan
Post amyloid scan
* *
*
33
Figure 6. Impact of amyloid imaging on caregivers.
Scores are taken from a 21-item Likert-scale questionnaire. A score approaching 5 suggests a strong
impact on “Anxiety” or “Depression” and therefore less symptoms. On the contrary, a score closer to 1
suggests minimal impact and therefore more anxiety or depressive symptomatology. For the variable
“Disease perception”, a score closer to 5 suggests a better understanding of the nature of the disease and
its natural history. For the variable “Future anticipation”, a score closer to 5 suggests a positive attitude
towards future issues. A score approaching 5 on “Quality of life” highlights better quality time (in general
and with the loved one). Finally, the global score is an average of the scores on all variables.
1
2
3
4
5
Anxiety Depression Disease
perception
Future
anticipation
Quality of
life
Global
Impac
t
34
LIST OF ABBREVIATIONS ACheI: acetylcholinesterase inhibitor AD: Alzheimer’s disease CSF: cerebrospinal fluid FDG: fluorodeoxyglucose FTLD: frontotemporal lobar degeneration GDP: Gross domestic product MRI: magnetic resonance imaging NFG: neurofibrillary tangles PET: positron-emission tomography PiB: Pittsburgh compound B ROI: region of interest SUVR: standard uptake value ratio
SUPPLEMENTARY MATERIAL
Caregiver Questionnaire
Patient Name: ____________________________
Date: ____________________________
Caregiver Name: ____________________________ Age: _____________
Relation (circle): Parent Husband/Wife Sibling Friend
Stepbrother/Stepsister Cousin Uncle/aunt Son/Daughter
The purpose of the following questions is to assess your perceptions concerning your beloved person's
disease since the disclosure of amyloid imaging results. After answering the questionnaire, each question
will be discussed with the interviewer in order for us to have the most accurate representation of your
situation.
A. Please answer the following questions by checking the appropriate box. Note that when we ask "since
you know the diagnosis", we are referring to the very last meeting with your treating dementia expert
following the amyloid PET scan, and not since the beginning of the disease.
1 – Strongly disagree 2 – Tend to disagree 3 – Neither agree nor disagree
35
4 – Tend to agree 5 – Strongly agree
# Question 1 2 3 4 5
1 I am more anxious since we know the diagnosis of my beloved one. (A)
2 I sleep better since I know that my loved one's condition is known. (D)
3 The family atmosphere is better since we know the diagnosis of my beloved one (S).
4 A new technique like amyloid PET shows me that there is hope in scientific progress.
(P)
5 I spend more quality time with my beloved one since we know the diagnosis. (H)
6 Since we know the diagnosis of my beloved one, I sometimes have palpitations
and/or tremors. (A)
7 The revelation of the diagnosis had made me more depressed. (D)
8 I am reassured to know the exact diagnosis of my beloved one. (S)
9 The revelation of the diagnosis has allowed me to make future plans (financial
decision, travel, etc.) (P)
10 I appreciate every instant with my beloved one even more since we know the precise
diagnosis. (H)
11 It scares me to develop a neurodegenerative disease even more now that we know
the diagnosis of my beloved one. (A)
12 Since we know the diagnosis, I often feel guilty when I think of my dear person's
disease. (D)
13 In hindsight, I would have preferred if we didn't go through all of the investigations to
determine the diagnosis of my beloved person. (S)
14 I feel like the future scares me less since we know the precise diagnosis. (P)
15 My life (social activities, work, hobbies) is better since we know the precise diagnosis.
(H)
16 Since the revelation of the diagnosis, I feel like I can lose control even more. (A)
17 I lost interest in many activities since I know the precise diagnosis of my beloved one.
(D)
18 If I had an untreatable neurodegenerative disease, I'd rather not go through all of the
investigations (including amyloid imaging) to know what my diagnosis is. (S)
19 I understand the course of the disease of my beloved one better now that we know
36
the precise diagnosis. (P)
20 I find that my beloved one's disease is even harder for me to accept since we know
the exact diagnosis. (S)
21 My perception of my beloved one's disease has not changed since we know the
precise diagnosis. (S)
Note for interviewer: (A) = anxiety, (D) = depression, (P) = future anticipation, (S) = disease perception,
and (H) = quality of life.
37
B. The purpose of the following questions is to determine what you think of your beloved one's condition
SINCE the disclosure of the amyloid imaging results.
1 – Strongly disagree 2 – Tend to disagree 3 – Neither agree nor disagree
4 – Tend to agree 5 – Strongly agree
# Question 1 2 3 4 5
1 My beloved one seems saddened since the revelation of the diagnosis.
2 My beloved one seems to understand his or her disease better since the revelation of
the diagnosis.
3 I noticed an overall improvement in my beloved one's condition since we know the
diagnosis.
4 In general, I think that my beloved one seems to have been affected negatively by the
announcement of his or her diagnosis.
38
C. Please answer the following questions by checking YES, NO, or DO NOT KNOW.
# Question YES NO DO NOT
KNOW
1 Did your beloved one attend support groups (ex. Alzheimer's association) BEFORE
the diagnosis was known?
2 Did your beloved one attend support groups (ex. Alzheimer's association) AFTER the
diagnosis was known?
3 If you answered YES to question #1 or #2, please answer this question. Otherwise, go directly to
question #4.
Going to support groups makes a difference in your beloved one's perception of his
or her disease.
4 Are there any changes in your beloved one's habits and lifestyle since the diagnosis
is precisely known?
If you answered YES to question #4, please circle how did his/her habits change?
Nutrition Physical exercise Cognitive exercise Other
Specify: _______________________________________________________________________
5 Are there changes in your own habits and lifestyle since the diagnosis is precisely
known?
If you answered YES to question #4, please circle how did his or her habits change?
Nutrition Physical exercise Cognitive exercise Other
Specify:: _______________________________________________________________________