Using amyloid PET imaging to diagnose Alzheimer’s disease in patients with multiple sclerosis

Abstract

Background
Cognitive dysfunction affects 40–60% of individuals with multiple sclerosis (MS). The neuropsychological profile commonly consists of a subcortical pattern of deficits, although a proportion of patients have a severe progressive cortical dementia. However, patients with MS can be affected by other neurodegenerative diseases, such as Alzheimer’s disease (AD). Little is known about the co-existence of these two conditions but distinguishing dementia due to MS alone from a coexisting neurodegenerative disease is challenging. Amyloid PET imaging has allowed improved AD diagnosis, especially in patients with atypical presentations or multiple possible causes of cognitive impairment. Amyloid PET demonstrates increased cortical signal in AD, whereas reductions in subcortical uptake are associated with demyelination. To the authors knowledge, there are no reports of clinical Amyloid PET use in MS patients with dementia.Methods
Here, three MS patients presenting to the Cognitive Neurology Clinic with progressive cognitive impairment are described. Due to lack of diagnostic clarity from standard investigations, they underwent Amyloid PET Imaging with 18F-florbetapir according to established appropriate use criteria and after review by a multidisciplinary team.ResultsTwo patients were diagnosed with AD based on positive Amyloid PET imaging and were subsequently started on cholinesterase inhibitor treatment. The other patient had a negative scan, leading to further investigations and identification of another potential cause of worsening cognitive impairment.Conclusions
The experience from this case series suggests that Amyloid PET Imaging may be of diagnostic value in selected patients with MS and dementia. In these individuals, it may provide diagnostic clarity and assist with therapeutic decisions.

Full text

Vol:.(1234567890)
Journal of Neurology (2020) 267:3268–3273
https://doi.org/10.1007/s00415-020-09969-z
1 3
ORIGINAL COMMUNICATION
Using amyloid PET imaging todiagnose Alzheimer’s disease
inpatients withmultiple sclerosis
MagdalenaKolanko1,2· ZarniWin3· NevaPatel3· OmarMalik2· ChristopherCarswell2· AnastassiaGontsarova4·
RichardNicholas1,2· RichardPerry1,2· PareshMalhotra1,2,5
Received: 22 January 2020 / Revised: 23 April 2020 / Accepted: 1 June 2020 / Published online: 18 June 2020
© The Author(s) 2020
Abstract
Background Cognitive dysfunction affects 40–60% of individuals with multiple sclerosis (MS). The neuropsychological
profile commonly consists of a subcortical pattern of deficits, although a proportion of patients have a severe progressive
cortical dementia. However, patients with MS can be affected by other neurodegenerative diseases, such as Alzheimer’s
disease (AD). Little is known about the co-existence of these two conditions but distinguishing dementia due to MS alone
from a coexisting neurodegenerative disease is challenging. Amyloid PET imaging has allowed improved AD diagnosis,
especially in patients with atypical presentations or multiple possible causes of cognitive impairment. Amyloid PET dem-
onstrates increased cortical signal in AD, whereas reductions in subcortical uptake are associated with demyelination. To
the authors knowledge, there are no reports of clinical Amyloid PET use in MS patients with dementia.
Methods Here, three MS patients presenting to the Cognitive Neurology Clinic with progressive cognitive impairment
are described. Due to lack of diagnostic clarity from standard investigations, they underwent Amyloid PET Imaging with
18F-florbetapir according to established appropriate use criteria and after review by a multidisciplinary team.
Results Two patients were diagnosed with AD based on positive Amyloid PET imaging and were subsequently started on
cholinesterase inhibitor treatment. The other patient had a negative scan, leading to further investigations and identification
of another potential cause of worsening cognitive impairment.
Conclusions The experience from this case series suggests that Amyloid PET Imaging may be of diagnostic value in selected
patients with MS and dementia. In these individuals, it may provide diagnostic clarity and assist with therapeutic decisions.
Keywords Alzheimer’s disease· Multiple sclerosis· Dementia· PET imaging
Introduction
As the population ages and the treatment of Multiple Sclero-
sis (MS) advances, more individuals with MS will develop
age-related neurodegenerative disorders, including Alz-
heimer’s disease (AD) [10]. However, diagnosing AD in
cognitively impaired MS patients is challenging and little
is known about the coexistence of the two conditions [9].
Cognitive dysfunction is common in MS, affecting
45–65% of patients [14]. Neuropsychological symptoms
include deficits in processing speed, executive function,
episodic memory and visuospatial function. However,
progressive dementia with prominent amnesia and classic
cortical features has also been described [19]. Grey matter
involvement and cortical tissue loss in MS are increasingly
recognised [4] and correlate better with MS-related cogni-
tive impairment than white matter lesion load [2]. Deep grey
* Paresh Malhotra
p.malhotra@imperial.ac.uk
1 Department ofBrain Sciences, Faculty ofMedicine,
Imperial College London, LondonW68RP, UK
2 Department ofNeurology, Imperial College Healthcare NHS
Trust, London, UK
3 Department ofNuclear Medicine, Imperial College
Healthcare NHS Trust, London, UK
4 Department ofRadiology, Imperial College Healthcare NHS
Trust, London, UK
5 UK Dementia Research Institute, Imperial College London,
London, UK
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3269Journal of Neurology (2020) 267:3268–3273
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matter and cortical atrophy appears to be tightly coupled to
cognitive decline in late relapsing–remitting and progres-
sive MS [7], and hence, distinguishing this from coexisting
Alzheimer’s disease using structural imaging alone can be
problematic.
The introduction of two reliable biomarkers for amyloid
pathology, cerebrospinal fluid amyloid β1-42/tau levels and
amyloid PET Imaging (API), has transformed pre-mortem
diagnosis in AD, particularly in patients with atypical pres-
entations or co-morbidities known to impair cognition. Clin-
ical API utilises fluorinated tracers (18F-florbetapir, 18F-flor-
betaben or 18F-flutemetamol) that bind to amyloid beta in
cerebral amyloid plaques, leading to increased cortical signal
in AD. There is a growing research interest in using amyloid
PET as a surrogate marker of MS demyelination–remyelina-
tion, and reductions in white matter tracer uptake have been
demonstrated with demyelination in MS [3]. However, this
is independent of cortical β-amyloid deposition, and tracer
uptake in the cortex in late MS has been found to be no dif-
ferent from age-matched controls [21].
Two recent studies have examined the association
between amyloid PET tracer binding and cognitive function
in MS [11, 21], and a prospective population-based study
used amyloid PET to investigate beta-amyloid accumula-
tion in ageing MS patients and matched controls [20]. Yet,
there are no reports of API to diagnose AD in patients with
established MS and increasing cognitive impairment.
Here, three MS patientspresenting with progressive cog-
nitive impairmentare described. Each had API because of a
lack of diagnostic clarity with standard dementia investiga-
tions. It is highlighted how clinical diagnosis of AD might
be aided by this approach.
Methods
Patients
Patients presented to the Cognitive Neurology clinic at Char-
ing Cross Hospital, London, between 2016 and 2019. Each
was referred with progressive cognitive impairment and had
an established diagnosis of MS.
Decision toinvestigate withamyloid PET imaging
All patients were first clinically assessed by an experienced
cognitive neurologist before structural imaging was dis-
cussed at a Cognitive Neurology and Radiology Multidisci-
plinary meeting. The decision to perform API was made by
consensus among neuroradiologists, nuclear medicine spe-
cialists and cognitive neurologists, according to appropriate
use criteria proposed by the Amyloid Imaging Taskforce
(AIT) [8].
(18)F‑orbetapir imaging
Images were qualitatively read as amyloid positive or nega-
tive by two nuclear medicine radiologists, in accordance
with that outlined in the Amyvid summary of product char-
acteristics (Eli Lilly, 2012), which had been approved by the
FDA in 2012 and EMA in 2013. Positive scans had two or
more brain areas of reduced or absent grey–white differen-
tiation, or one or more areas in which grey matter activity
was intense and clearly exceeded activity in adjacent white
matter.
Results
Case 1
A woman presented with a 6-year history of progressive
amnesia and language impairment that had started in her
mid-60s, followed by a rapid deterioration over a year with
urinary incontinence and self-neglect. She was initially diag-
nosed by a Memory Clinic with dementia secondary to MS.
However, a second opinion was sought in view of her fairly
preserved physical function but rapid worsening in cogni-
tion. She had been diagnosed with MS in 1994 and MRI
imaging at the time had been consistent with demyelination.
She had not had any major relapses since 1997 and was not
on disease modifying treatment. There was a family his-
tory of dementia with the patient’s sister being diagnosed
in her late 60s. On examination, she had severe cognitive
impairment, with difficulty completing the Mini Mental
State Examination. Brain MRI showed a number of inflam-
matory demyelinating lesions (Fig.1a), as well as moderate
global cerebral volume loss (Fig.1b). API, carried out fol-
lowing MDT discussion, was reported as positive (Fig.1c).
The patient was given a diagnosis of AD and started on a
cholinesterase inhibitor, but continued to decline cognitively.
Case 2
A woman in her mid-70s presented with a 5-year history of
gradual cognitive decline with progressive amnesia, inat-
tention, organisational difficulties and spatial disorientation.
She was diagnosed with relapsing–remitting MS in 1994 and
had also been under observation for a parafalcine meningi-
oma since 2008 (Fig.2a). ACE (Addenbrookes Cognitive
Examination)-III score was 87/100, and neuropsychological
assessment showed inefficiencies in inhibition and switch-
ing, non-verbal abstract reasoning, processing speed and
free recall of structured auditory information. Performance
was intact on tasks of language, visuospatial ability, recall
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3270 Journal of Neurology (2020) 267:3268–3273
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of unstructured auditory information, visual memory, sim-
ple attention and working memory. Brain MRI showed MS
changes with little progression when compared to previous
scans (Fig.2b). The meningioma was noted to have evolved
over time with slight increase in size but without associated
oedema (Fig.2a). API was negative (Fig.2d), and it was felt
that she had transitioned to secondary progressive MS with
associated cognitive decline. In view of worsening cogni-
tion (ACE-III score 75/100 (from 87/100)), repeat imaging
was performed, which showed an interval increase in men-
ingioma size with worsening oedema (Fig.2e), potentially
contributing to her cognitive impairment. She was referred
to the neurosurgical team who decided to keep her under
regular review.
Case 3
A woman was referred with a 2-year history of progres-
sive amnesia and concentration problems that had begun
in her late 60s. She had a history of relapsing–remitting
MS, diagnosed in 2000. In 2008, she was diagnosed with
polymyalgia rheumatica for which she had been given Pred-
nisolone followed by steroid-sparing agents (Azathioprine
and Mycophenolate Mofetil, then Methotrexate). ACE-
III score was 87/100, and neuropsychological assessment
demonstrated impairments in executive function, memory
(particularly encoding of new information) and processing
speed. MRI brain showed confluent white matter changes
on MRI, but no significant change in T2 lesion load when
compared to previous imaging (Fig.3a). There was mild
generalised cerebral volume loss, more prominent in both
temporal lobes (Fig.3b). API, carried out after MDT discus-
sion, was positive (Fig.3c) and a diagnosis of AD was made.
Donepezil was commenced with some initial improvement
in symptoms. However, in the longer term, she continued
to deteriorate cognitively with functional consequences,
although her MS remained stable.
Discussion
Cognitive impairment in MS may be related to mood,
fatigue and sleep disturbance as well as strategic lesions [2,
7]. Using clinical assessment and structural imaging, it is
often difficult to differentiate degeneration related to MS
progression from coexisting Alzheimer’s, with the underly-
ing diagnosis only becoming clear following post-mortem
examination [18]. In such situations, API offers non-invasive
detection of beta-amyloid plaques, enabling recognition of
AD in the MS population and earlier introduction of appro-
priate management.
Here, three MS patients, all in their 70s, presenting with
progressive cognitive impairment of unclear aetiology were
described. Following MDT discussion, they underwent API
because of a lack of diagnostic clarity from standard investi-
gations. One patient had a negative amyloid PET scan, while
two were diagnosed with AD based on positive scans. Both
individuals diagnosed with AD were previously thought to
have MS-related cognitive decline. API led to a change in
diagnosis, as well as a change in management, including
initiation of new medication and enrolment into clinical tri-
als. Importantly, patients and their families could also be
providedwith information about the prognosis and appro-
priate support services available to them. This is in keeping
with recent studies examining the wider utility of amyloid
PET imaging [5, 13]. When used in individuals who meet
appropriate criteria [8], API reduces the number of further
investigations and significantly affects clinical management,
in addition to increasing diagnostic certainty.
In MS, which is associated with cortical atrophy [17],
examination of structural imaging for typical AD atrophy
Fig. 1 Case 1. Axial T2-weighted (a) and coronal FLAIR (b) images
through the brain showing typical MS lesions in the periventricular
white matter, perpendicular to the ependymal surface. Note gener-
alised neuroparenchymal loss, with relative sparing of the tempo-
ral lobe white matter (left mesial temporal atrophy score is 2; right
mesial temporal atrophy score is 1). Sagittal and coronal amyloid
PET images (c) demonstrating generalised increased activity within
the cortical grey matter in all lobes with complete loss of grey–white
differentiation consistent with widespread amyloid deposition
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3271Journal of Neurology (2020) 267:3268–3273
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patterns is challenging as the combination of MS- and AD-
related cortical atrophy leads to a less well-defined pattern.
This is illustrated by Cases 1 and 3, where both patients
had a degree of asymmetrical hippocampal atrophy. This
is a relatively typical finding in Alzheimer’s disease and
strongly associated with a positive amyloid PET [1], but
regional hippocampal atrophy has also been found in
patients with MS [16], with some reports also describing
asymmetry [15]. Thus, API may provide key information
regarding the underlying cause of cognitive decline. CSF
examination for amyloid β1-42 and Tau levels is a possible
alternative approach but is invasive with more potential for
adverse effects. Moreover, establishing CSF cut-off points
is difficult, as evidenced by the wide variation in normal
ranges used in different centres. Furthermore, there is evi-
dence that atypical AD syndromes may have less clear-cut
CSF profiles than are normally observed in typical AD
[12].
One potential issue when using API in MS is that the
reduced tracer uptake that has been found in demyelination
might result in a failure to detect clinically relevant amyloid
plaque, generating false-negative results. A recent study
found that cortical β-amyloid deposition measured with API
was lower in ageing MS patients than the controls matched
Fig. 2 Case 2. a Post-contrast
coronal T1-weighted images
through the brain showing
growth of the meningioma in
the left parietal region. Menin-
gioma volumes: 5.5cc in 2008,
5.5cc in 2011, 21cc in 2017.
b Sagittal T2-weighted MRI
images demonstrating stable
lesion load in the periven-
tricular white matter between
2011 and 2017. c Coronal
post-contrast T1-weighted
MRI image demonstrating
normal bilateral hippocampal
volumes at age 76. d Negative
amyloid PET scan, with clear
differentiation between grey
and white matters and absence
of tracer uptake in the cerebral
grey matter. e CT scan showing
an interval increase in size of
the left parasagittal meningi-
oma (4.3 × 3.7 × 3.5cm) with
associated local mass effect and
vasogenic oedema
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3272 Journal of Neurology (2020) 267:3268–3273
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for age, sex and APOE ε4 status [20]. While the authors con-
cluded that MS could be protective of beta‐amyloid pathol-
ogy, this finding may also reflect a loss of tracer binding due
to demyelination, resulting in a falsely low estimation ofcor-
tical amyloid accumulation. Importantly, the research cohort
imaged in this study mainly comprised cognitively unim-
paired MS patients, in contrast to the case series described
here, all of whom had dementia (and in whom ApoE status
was not tested).
Another potential concern is that the proportion of cogni-
tively normal individuals with clinically silent amyloid PET
increases with age, and that any amyloid deposition may
not be responsible for cognitive symptoms. However, these
patients’ subsequent clinical course was in keeping with the
diagnoses made with API.
Furthermore, although AD pathology seems to develop in
MS in a similar incidence to that observed in normal ageing
[6], it may be that individuals with MS are more vulner-
able to the effects of amyloid because of their pre-existing
cortical atrophy, leading to a shorter asymptomatic phase of
AD. Studies such as thatby Zeydan and colleagues which
use modalities that are currently available in the research
setting, such Tau PET imaging, may shed further light on
this. However, given the possible confounds associated with
tracer binding, neuropathological studies are more likely to
be definitive.
In clinical practice, implementation of API in appropriate
MS patients is recommendedthrough a multidisciplinary
approach according to appropriate use criteria in order to
aid diagnosis and management of patients with cognitive
decline. As described here, it may provide diagnostic clar-
ity and assist with therapeutic decisions, while reducing the
overall burden of investigations.
Acknowledgements PM, ZW and RP receive research funding from
the Alzheimer’s Society to explore the clinical utility of clinical Amy-
loid PET. This research is supported by theNIHR Biomedical Research
Centre at Imperial College London
Compliance with ethical standards
Conflicts of interest RP previously sat on an advisory board for Lilly
and currently has no funding or support from any organisation involved
in amyloid PET imaging, and, in particular, no funding or support from
the manufacturer of the only commercially available ligand. ZW was
previously also participated in the Eli Lilly PET advisory board and
was an amyloid PET read trainer. CC has taken part in an advisory
panel for Roche pharmaceuticals. PM has given an educational talk at
a meeting organised by GE.
Ethical approval All procedures performed were in accordance with
the 1964 Helsinki declaration and its later amendments.
Open Access This article is licensed under a Creative Commons Attri-
bution 4.0 International License, which permits use, sharing, adapta-
tion, distribution and reproduction in any medium or format, as long
as you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article are
included in the article’s Creative Commons licence, unless indicated
otherwise in a credit line to the material. If material is not included in
the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will
need to obtain permission directly from the copyright holder. To view a
copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.
Fig. 3 Case 3. Axial FLAIR images through the brain (a) demon-
strating white matter changes over a 3-year interval. Coronal T1- and
T2-weighted images through the brain (b) showing progressive atro-
phy of the brain over the 3-year interval. The most recent scan (right)
shows bilateral medial temporal lobe atrophy, more so on the right.
Amyloid PET imaging (c) was positive with loss of grey–white dif-
ferentiation consistent with widespread amyloid deposition
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3273Journal of Neurology (2020) 267:3268–3273
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