Multiple Sclerosis Journal - October 2017 - 1472

Multiple Sclerosis Journal 23(11)
summation images in MNI space. The CIC
Neuroanatomical Atlas was non-linearly deformed
into the individual's space, via mapping of
T1-weighted MR imaging data, to obtain a personalised anatomical parcellation of regions of interest,
which were used to generate time-activity curves for
the caudate and voxel-wise for the whole brain. The
whole spectroscopy voxel mask and the WML,
NAWM and grey matter masks within the spectroscopy voxel were rigid registered to the MNI space.
The Logan graphical reference method20 using a reference tissue time-activity curve as the input function
and model fitting performed with linear regression
was used to estimate the distribution volume ratio
(DVR) at the voxel level to produce parametric DVR
maps, relative to the caudate nucleus volume of distribution (VT). All masks were applied to the PET parametric DVR image to obtain the DVR for the
respective regions of interest.
We chose to use a normalised quantitation to allow
studies to be conducted without an arterial line. [11C]
PBR28 VT has a high test-retest variability of approximately 20%, the major contribution to which appears
to come in the blood to tissue transfer modelling.21
Alternatively, reference-based methods show less
test-retest variability (5% or less).21 While TSPO is
expressed throughout the brain, lower levels of specific binding within a proposed pseudo-reference
region do not affect the reliability of the parameter
estimates, although this may lead to underestimation
of relative binding differences between regions of
interest.22 We used the caudate nucleus as a pseudoreference region as relatively lower levels of microglial activity and TSPO expression is found in the
caudate and normalised standardised uptake ratios are
low in caudate compared to other brain regions.12,23
Statistical analyses
Statistical analyses were performed using SPSS software (IBM, SPSS v22). The Shapiro-Wilk test (with
p-value <0.05 considered significant) and Q-Q plots
for normality found that the following variables did not
pass the tests for normality: EDSS (p = 0.008), MSFC
(p = 2 × 10−4), [11C]PBR28 DVR in NAWM (p = 0.04)
and in WML (p = 0.03) of the spectroscopy voxel.
The non-parametric Spearman's correlation coefficient therefore was used for correlational analyses,
unless otherwise stated. Descriptive statistics were
reported as median and range, unless otherwise
stated. A p-value of less than 0.05 was considered
significant for all statistical tests. A multivariate
1472

Table 1. Summary of the clinical disability characteristics,
grey matter volume and positron-emission tomography
(PET) [11C]PBR28 distribution volume ratio for all
multiple sclerosis patients.

EDSS
Disease duration (years)
MSFC (z-score)
25FTW (seconds)
9HPT (seconds)
Whole brain grey matter
volume (cm3)
DVR spectroscopy voxel
Whole voxel
White matter lesions
NAWM
Grey matter

Median

Range

5.0
13
−0.09
7.4
23.3
791

1.0-7.0
1-28
−5.99 to 0.69
3.3-138.4
17.7-75.2
545-946

1.26
0.97
1.10
1.44

0.99-1.79
0.61-1.74
0.79-1.72
1.12-1.87

EDSS: Expanded Disability Status Scale; MSFC: Multiple
Sclerosis Functional Composite; 25FTW: 25 foot timed walk;
9HPT: nine hole peg test; DVR: distribution volume ratio;
NAWM: normal-appearing white matter.

linear regression of clinical scores (EDSS or MSFC
and its components, 25 foot timed walk, nine hole
peg test (9HPT) and three second paced auditory
serial addition test (PASAT-3)) was performed using
a general linear model with normalised whole brain
grey matter volume, TSPO DVR, myo-inositol and
NAA as predictor variables.
Results
A total of 24 people with clinically definite MS underwent [11C]PBR28 PET, single voxel MRS and structural MRI scanning (Table 1, Figure 1). One patient
was excluded from the final analysis because noise
artefacts precluded reliable estimates of metabolite
concentrations. Of the 23 remaining patients (nine
men, median age 48 years, range 22-66 years)
included in the final analysis, 7 had a diagnosis of secondary progressive disease and 16 had relapsingremitting disease. The median EDSS was 5.0 (range,
1.0-7.0). WMLs were found within the spectroscopy
voxel for all patients. None of these lesions was gadolinium enhancing.

Differences in [11C]PBR28 uptake are not
correlated with brain [myo-inositol]
The concentration of myo-inositol in the spectroscopy voxel (expressed as either an absolute concentration or as a ratio to total tissue creatine) was not
significantly correlated to the TSPO binding
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