Multiple Sclerosis Journal - October 2017 - 1476

Multiple Sclerosis Journal 23(11)
significant correlations between either the whole
brain normalised grey matter volume and the whole
brain [11C]PBR28 DVR (ρ = −0.236, p = 0.278) or
the grey matter fraction and the [11C]PBR28 DVR
within the voxel (ρ = 0.07, p = 0.75).
Imaging measures and disability
Disability measured by MSFC was correlated with
normalised grey matter volume (ρ = 0.535, p = 0.009).
We found within a general linear model that a large
component of disability, as measured by MSFC, was
explained by normalised grey matter volume (F = 19.5,
p = 2 × 10−4). This relationship was driven predominantly by lower and upper limb motor scores (25 foot
timed walk, F = 18.8, p = 0.007; 9HPT, F = 11.6,
p = 0.003). We further tested for additional explanatory power from measures here by including the [11C]
PBR28 DVR, myo-inositol and NAA, but did not find
that they added further to the model. We also did not
find significant relationships between any of these
measures and EDSS.
Discussion
Increased brain TSPO uptake with non-malignant
brain pathology could be attributed to either an
increased density of activated microglia or to
increased astrocytes, as TSPO expression can be
elevated in both cell types.7 Histopathological studies in MS have shown that the [myo-inositol]
detected by MRS signal corresponds to astrocyte
activation4 and that increased TSPO expression colocalises with activated microglia.12 We have been
able to test the independence of these markers in
vivo for the first time in a group of MS patients with
a range of inflammatory loads. We did not find a
meaningful correlation between MRS [myo-inositol]
and PET [11C]PBR28 uptake. We propose that
changes in the two measures in this population are
related to distinct processes or to elements of a common process with different time courses. Similar
findings were reported for HIV-positive patients
studied using the first-generation PET radioligand
[11C]PK11195 in conjunction with MRS for [myoinositol].24 The results support interpretation of
TSPO PET primarily as a marker of activated microglia/macrophages in MS.
Activated astrocytes and microglia are found within
and outside lesions at all stages of MS.25 Brex et al.26
highlight the heterogeneity of changes in MRS neurodegenerative and inflammatory markers among
lesions and between patients. In our exploratory
analyses, we found that under some conditions there
1476

may be parallel activation of microglia, reflected in
the PET TSPO signal, and astrocyte activation,
reflected by MRS [myo-inositol]. In this study, in
patients with a higher inflammatory load, MRS
[myo-inositol] and PET [11C]PBR28 uptake in WML
were correlated, providing evidence in vivo for the
joint activation of astrocytes and microglia under
some conditions. Similar observations were made in
a study that found the [myo-inositol] was associated
with higher levels of brain inflammatory pathology
in Alzheimer's disease.27
Grey matter volume and MRS NAA are both markers
of neurodegeneration.4,6 In this study, we found that
higher TSPO uptake within T2 WMLs was correlated
with both reduced NAA and grey matter volume. We
suggest that this provides evidence that the microglial activation found within T2 WMLs is associated
with neurodegeneration, although we cannot infer
causation from this cross-sectional study. This is consistent with histopathological findings in MS in
which microglial activation is associated with grey
matter neurodegeneration28,29 In vivo clinical studies
have shown an association of increased PET [11C]
PK11195 uptake in NAWM with greater brain atrophy.2 Both populations of glial cells could contribute
to axonal damage.5 However, the lack of a relationship between brain [myo-inositol] and measures of
neurodegeneration in this study again supports that
the TSPO PET and MRS measure are reporting
largely independent phenomena or phenomena with
different time courses. There is some evidence that
astrocyte activation could be antecedent to neurodegeneration with a longer time course.30
We did not find relationships between disability and
the inflammatory marker measures, although a wellprecedented31 correlation between grey matter atrophy and disability measured with MSFC was
observed, despite the limited study power. However,
PET TSPO and MRS, as measures of inflammatory
state, may be potentially predictive of future change
rather than neurodegenerative processes.32,33 This is
supported by in vivo PET [11C]PK11195 studies
showing correlations between PET TSPO radioligand
uptake and measures of disability or likelihood of a
diagnosis of clinically definite MS after presentation
with the clinically isolated syndrome.33,34 However, a
complication of following how baseline brain inflammation relates to future neurodegenerative and disability is that there appear to be different delays
between regional brain inflammatory changes and
these other processes in patients with MS.25,30,34
Future, longer term longitudinal studies combining
MRS and PET TSPO imaging could evaluate their
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Table of Contents for the Digital Edition of Multiple Sclerosis Journal - October 2017
