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Increased cerebrospinal fluid albumin and immunoglobulin A fraction forecast cortical atrophy and longitudinal functional deterioration in relapsing-remitting multiple sclerosis


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Background: Currently, no unequivocal predictors of disease evolution exist in patients with multiple sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disability. Objective: Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical atrophy and clinical disability from cerebrospinal fluid (CSF) markers. Methods: We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF to serum quotients. Results: Widespread atrophy was highly associated with increased baseline CSF concentrations and quotients of albumin and IgA. Patients with increased CSFIgA and CSFIgM showed higher functional disability at follow-up. Conclusion: CSF markers of blood–brain barrier integrity and specific immune response forecast emerging grey matter pathology and disease progression in MS
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Multiple Sclerosis Journal
1 –6
DOI: 10.1177/
© The Author(s), 2017.
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Multiple sclerosis (MS) is a chronic neuroinflamma-
tory disease of the central nervous system (CNS) that
leads to progressive disability. Recent neuroimaging,
immunological, and histopathological studies have
provided valuable insights into the mechanisms of the
disease.1,2 Development of novel biomarkers is, how-
ever, essential since they should serve as optimized
predictors for the disease course. Cortical atrophy
represents an important magnetic resonance imaging
(MRI)-based biomarker that is closely associated with
emerging clinical disability.3 However, there are cur-
rently no unequivocal non-invasive predictors of
ongoing neuroinflammation and damage in the
The blood–brain barrier (BBB) plays an important
role in MS pathogenesis, being the selective gate-
keeper for immunoinflammatory responses in the
CNS and the target of present and future drug devel-
opments.4 Cellular and molecular immune system
components can cross the pathologically permeable
BBB and trigger distinct inflammatory activity in dif-
ferent CNS compartments. BBB disruption has been
attested not only in acute lesions, but also in normal-
appearing gray and white matter.5,6
Increased cerebrospinal fluid albumin
and immunoglobulin A fractions forecast
cortical atrophy and longitudinal functional
deterioration in relapsing-remitting multiple
Julia Kroth, Dumitru Ciolac, Vinzenz Fleischer, Nabin Koirala, Julia Krämer,
Muthuraman Muthuraman, Felix Luessi, Stefan Bittner, Gabriel Gonzalez-Escamilla,
Frauke Zipp, Sven G. Meuth and Sergiu Groppa
Background: Currently, no unequivocal predictors of disease evolution exist in patients with multiple
sclerosis (MS). Cortical atrophy measurements are, however, closely associated with cumulative disabil-
Objective: Here, we aim to forecast longitudinal magnetic resonance imaging (MRI)-driven cortical
atrophy and clinical disability from cerebrospinal fluid (CSF) markers.
Methods: We analyzed CSF fractions of albumin and immunoglobulins (Ig) A, G, and M and their CSF
to serum quotients.
Results: Widespread atrophy was highly associated with increased baseline CSF concentrations and quo-
tients of albumin and IgA. Patients with increased CSFIgA and CSFIgM showed higher functional disability
at follow-up.
Conclusion: CSF markers of blood–brain barrier integrity and specific immune response forecast emerg-
ing gray matter pathology and disease progression in MS.
Keywords: Multiple sclerosis, cerebrospinal fluid albumin, cerebrospinal fluid immunoglobulins, cortical
gray matter, atrophy rate
Date received: 15 August 2017; revised: 20 October 2017; accepted: 7 November 2017
Correspondence to:
S Groppa
Department of Neurology,
Focus Program Translational
Neuroscience (FTN),
Research Center for
Immunology (FZI), Rhine-
Main Neuroscience Network
(rmn²), University Medical
Center of the Johannes
Gutenberg University Mainz,
Langenbeckstraße 1, Mainz
55131, Germany.
Julia Kroth
Vinzenz Fleischer
Nabin Koirala
Muthuraman Muthuraman
Felix Luessi
Stefan Bittner
Gabriel Gonzalez-Escamilla
Frauke Zipp
Sergiu Groppa
Department of Neurology,
Focus Program Translational
Neuroscience (FTN),
Research Center for
Immunology (FZI), Rhine-
Main Neuroscience Network
(rmn2), University Medical
Center of the Johannes
Gutenberg University Mainz,
Mainz, Germany
Dumitru Ciolac
Department of Neurology,
Focus Program Translational
Neuroscience (FTN),
Research Center for
Immunology (FZI), Rhine-
Main Neuroscience Network
(rmn2), University Medical
Center of the Johannes
Gutenberg University Mainz,
Mainz, Germany/Department
of Neurology, Institute
of Emergency Medicine,
Laboratory of Neurobiology
and Medical Genetics,
Nicolae Testemiţanu State
University of Medicine
and Pharmacy, Chisinau,
748474MSJ0010.1177/1352458517748474Multiple Sclerosis JournalJ Kroth, D Ciolac
Original Research Paper
Multiple Sclerosis Journal 00(0)
Under physiological conditions, only low amounts of
albumin and certain immunoglobulin (Ig) types cross
the BBB. Albumin quotient (i.e. cerebrospinal fluid
(CSF) albumin/serum albumin ratio) can therefore be
considered a marker of BBB permeability.7,8 Addressing
BBB integrity and longitudinal gray matter processes
could translate inflammatory activity to focal and
global brain atrophy, the latter being an accepted bio-
logical hallmark of the clinical long-term outcome.
Here, we investigate the connection between cortical
atrophy and the presence of CSF markers of BBB per-
meability/integrity. We observed a significant correla-
tion between CSF albumin and IgA and the rate of
cortical atrophy over 12 months. We propose that
elevated baseline levels of CSF albumin and IgA can
serve as markers of early cortical atrophy and rapid
disease progression in MS.
Seventy-one relapsing-remitting multiple sclerosis
(RRMS) patients (mean age ± standard deviation
(SD) 31.2 ± 9.4 years, 25 males) were included in this
longitudinal study. RRMS diagnosis was established
accordingly to the 2010 revised McDonald diagnostic
criteria.9 All patients underwent comprehensive clini-
cal, laboratory, and neuroimaging evaluation through
a standardized protocol.10 All patients were rescanned
with the same protocol after 12 ± 1 months. The sus-
tained Expanded Disability Status Scale (EDSS)
score (confirmed after 3 months) at the second time
point has been used as a clinical outcome measure to
quantify clinical disability. We opted to use an EDSS
score of 2 as a cut-off, since an EDSS score of <2.0
with at least 10 years of disease duration seems to be
the most appropriate criterion in identifying patients
with benign MS (Glad et al., 2010). Clinical disease
activity was defined as a clinical relapse, while radio-
logical activity was defined as the appearance of new/
enlarging hyperintense lesions or gadolinium-enhanc-
ing lesions. Of 71 patients, 63 patients (89%) were
receiving different disease-modifying treatment
(DMT) and 8 patients were not on DMT. Informed
consent was obtained from all patients and the study
was approved by the local ethics committee.
CSF variables examination
CSF and serum samples were obtained from each
patient at the time of first clinical event and CSF con-
centrations of albumin (CSFAlb), IgA (CSFIgA), IgG
(CSFIgG), and IgM (CSFIgM) were determined with
immunonephelometry. Quotients of albumin (QAlb),
IgA (QIgA), IgG (QIgG), and IgM (QIgM) were defined
as the ratios of CSF concentrations to the correspond-
ing serum concentrations of these fractions; reference
values were considered according to Berlit.11 Since
QAlb is age-sensitive, increased QAlb was considered
in relation to reference ranges depending on the age of
the patients: 6.5–8 for patients aged <40 years (55
patients) and 8.0 for patients aged 40 years (16
patients).12 To detect patients with intrathecal synthe-
sis of IgA, IgG, and IgM, hyperbolic functions for
each Ig type were applied as follows
Ig QIgabQ
where Igloc is local Ig synthesis, Q(Ig) is Ig quotient,
QAlb is albumin quotient, and a, b, and c are empirical
MRI acquisition
Structural MRI images were acquired using a 3T
Magnetom Tim Trio scanner (Siemens Medical
Solutions, Erlangen, Germany) with a 32-channel
head coil, according to a standardized protocol10 at the
Neuroimaging Centre (NIC) Mainz, Germany. This
imaging protocol comprises sagittal three-dimensional
T1- and T2-weighted fluid-attenuated inversion recov-
ery (FLAIR) sequences. T1-weighted magnetization-
prepared rapid gradient echo (MP-RAGE) sequence
included the following acquisition parameters: repeti-
tion time (TR) = 1900 ms, echo time (TE) = 2.52 ms,
inversion time (TI) = 900 ms, echo train length (ETL)
= 1, flip angle = 9°, matrix size = 256 × 256, field of
view (FOV) = 256 × 256 mm, slice thickness = 1 mm,
voxel size = 1 × 1 × 1 mm; FLAIR sequence: TR =
5000 ms, TE = 388 ms, TI = 1800 ms, ETL = 848,
matrix size = 256 × 256, FOV = 256 × 256 mm, slice
thickness = 1 mm, voxel size = 1 × 1 × 1 mm.
T1-weighted, T2-FLAIR, and contrast-enhanced T1
images were analyzed by an experienced neuroradiol-
ogist for the detection of new and contrast-enhancing
Initially, lesion maps were drawn on T2-weighted 3D
FLAIR images using the MRIcron software (http://
Using the lesion segmentation toolbox (LST) which is
part of the statistical parameter mapping (SPM8) soft-
ware, 3D FLAIR images were co-registered to 3D T1
images and bias corrected. After partial volume esti-
mation (PVE), lesion segmentation was performed
with 20 different initial threshold values for the lesion
growth algorithm.14 By comparing automatically and
Julia Krämer
Sven G. Meuth
Department of Neurology,
University of Munster,
Munster, Germany
J Kroth, D Ciolac et al. 3
manually estimated lesion maps, the optimal thresh-
old (ĸ value, dependent on image contrast) was deter-
mined for each patient and an average value for all
patients was calculated. Afterward, for automatic
lesion volume estimation and filling of 3D T1 images,
a uniform ĸ value of 0.1 was applied for all patients.
Subsequently, the filled 3D T1 images as well as the
native 3D T1 images were segmented into gray mat-
ter, white matter, and CSF and normalized to Montreal
Neurological Institute (MNI) space. Finally, the qual-
ity of the segmentations was visually inspected.
MRI data processing: cortical thickness
T1-weighted images were analyzed using FreeSurfer
software (v5.3.0,
for longitudinal cortical thickness (CT) and thalamic
volume estimation in a fully automated fashion. In
brief, after individual surface reconstruction, an unbi-
ased within-subject template was created.15,16 The
unbiased template served for initialization of skull
stripping, normalization, atlas registration, and par-
cellation of individual time points.17 Surface maps of
regional atrophy rates were computed as (thickness2
– thickness1)/(time2 – time1) and smoothed with a 10
mm full width at half maximum (FWHM) Gaussian
kernel for further correlation with CSF variables and
their quotients. Statistical maps of significant correla-
tions were corrected for multiple comparisons using
false discovery rate (FDR, p < 0.05) with a minimum
cluster size of 100 mm2.
Statistical analysis
SPSS 23.0 software (IBM, Armonk, NY, USA) was
used to perform statistical analyses. The data were
checked for normal distribution using the Shapiro–
Wilk test. Summary statistics are presented as mean
± SD, median, and percentage, where applicable.
Standard and stepwise linear regression analyses
were performed to assess the relative contributions of
baseline quotients (QAlb, QIgA, QIgG, and QIgM) in pre-
dicting the rate of cortical atrophy at 1-year follow-
up. Adjusted R2 values are reported. One-sided paired
student’s t-test was used to evaluate the differences in
variables. P-values less than 0.05 were considered
statistically significant. To account for a possible
influence on cortical atrophy rates, age and gender of
the patients were included as covariates.
Baseline characteristics of the patients are reported in
Table 1. In 68 patients, the CSF was positive for oligo-
clonal bands (OCB); two patients were OCB negative.
During the 1-year follow-up, 18 patients (25.4%) pre-
sented a clinical relapse, 22 (31.0%) had MRI activity,
and 11 (15.5%) presented both; the remaining patients
(28.1%) were clinically and radiologically stable. Two
patients exhibited new cortical lesions (precuneus and
frontal). At follow-up, mean CT (2.52 ± 0.1 mm) and
thalamus volume (8954.9 ± 1255.7 mm3) were signifi-
cantly smaller in comparison to baseline values (2.53
Table 1. Baseline demographic, clinical, and CSF data of RRMS patients.
Parameter Mean ± SD Reference range
Age (years) 31.2 ± 9.4
Male/female: number (%) 25 (35%)/46 (65%)
Age at diagnosis (years) 30.7 ± 9.6
Disease duration (years) 1.5 ± 3.4
EDSS 1.5 ± 1.4
CSF albumin (CSFAlb) 234.1 ± 123.7 mg/L 110–350 mg/L
CSF IgA (CSFIgA) 3.2 ± 3.2 mg/L 1.5–6 mg/L
CSF IgG (CSFIgG) 58.0 ± 36.8 mg/L <40 mg/L
CSF IgM (CSFIgM) 1.1 ± 1.8 mg/L <1 mg/L
Albumin quotient (QAlb) 5.3 ± 2.7 6.5 (<40 years)
8 (>40 years)
IgA quotient (QIgA) 1.6 ± 1.4 1.3
IgG quotient (QIgG) 5.1 ± 2.9 2.3
IgM quotient (QIgM) 1.1 ± 1.8 0.3
SD: standard deviation; EDSS: Expanded Disability Status Scale; CSF: cerebrospinal fluid; Ig: immunoglobulin; Q: quotient;
Ig: immunoglobulin.
Multiple Sclerosis Journal 00(0)
± 0.1 mm, p = 0.04 and 9030.9 ± 1211.1 mm3, p =
0.006; respectively).
QAlb, QIgA, and cortical atrophy rate
The rate of cortical atrophy over 1 year was highly
associated with QAlb and QIgA. Significant correlations
between atrophy rates and both baseline QAlb and
baseline QIgA were found in the precuneus (PrC),
rostral middle frontal (rMF), precentral (PC), and
inferior parietal (IP) gyri of both hemispheres
(Figure 1). Specific anatomic locations of these clus-
ters are reported in Supplementary Table 1. The
regions with the highest association between baseline
QAlb and cortical atrophy rate were the right PrC (R2 =
0.364, p < 0.001) and left fusiform gyrus (R2 = 0.290,
p < 0.001). Bilateral PrC had the highest associations
with QIgA (R2 = 0.415 for left and R2 = 0.503 for right
hemispheres, p < 0.0001).
QAlb, QIgA, and thalamic atrophy rate
No significant associations between the addressed
quotients and the annual rate of thalamus atrophy
were detected.
QIgM, QIgG, and cortical atrophy rate
Cortical atrophy rates were also associated with QIgG
(R2 = 0.259, p = 0.02, pars opercularis) and QIgM (R2 =
0.358, p = 0.04, precentral cortex), although with a
weaker effect size. Additional associations with QIgG
were found in the right parietal and occipital lobes,
while QIgM correlated with the atrophy rate in the left
parietal region.
CSF fractions and cortical atrophy
Higher values of CSFAlb and CSFIgA were mirrored by
increased regional gray matter loss. The annual rate of
cortical atrophy correlated with CSFAlb (R2 = 0.17, p <
0.001, precuneus bilateral), CSFIgA (R2 = 0.12, p =
0.001), and to a lesser extent with CSFIgG (R2 = 0.12,
p = 0.02) and CSFIgM (R2 = 0.21, p = 0.04)
(Supplementary Figure 1).
CSF variables and EDSS
CSFIgA and CSFIgM significantly differed between
patients with mild disability (EDSS 0–1.5) and those
with an EDSS score between 2 and 6 at the second
time point (IgA: 1.67 ± 0.69 mg/L vs 2.03 ± 0.71
mg/L, IgM: 9.87 ± 2.38 mg/L vs 11.5 ± 2.03 mg/L, p
= 0.04 and p = 0.003, respectively). CSFAlb, CSFIgG,
and the quotients showed no further correlations with
the EDSS scores at the first or second time points.
Identification of reliable early diagnostic immuno-
logical candidates that mirror ongoing disease activity
and the long-term outcome in patients with MS is
essential for therapeutic decisions in the era of rapidly
increasing options for immune modulation. Here, we
Figure 1. Clusters of significant associations between cortical atrophy rates and (A, B) albumin quotient (QAlb) and (C, D)
IgA quotient (QIgA). Lateral and medial views of right (RH) and left (LH) hemispheres are shown. All labeled clusters were
significant after FDR correction (p < 0.05). The color bar represents the statistical significance of the association.
J Kroth, D Ciolac et al. 5
identified increased CSFAlb and CSFIgA in patients
with RRMS as early markers of cortical atrophy and
emerging clinical disability. As these variables
strongly reflect BBB integrity, we clearly demonstrate
the link of ongoing inflammatory disease activity and
cortical degeneration.
Histopathological analyses have confirmed the
occurrence of BBB damage, inflammatory activity,
and demyelination within the cortex in early MS
patients, even preceding white matter lesions.18
Increased CSFAlb and QAlb have been previously pos-
tulated to be indicators of BBB permeability.19 Our
results show an association between CSFAlb, QAlb,
and cortical atrophy, and an even stronger effect for
CSFIgA and QIgA. Based on the topological similarity
of cortical atrophy patterns for CSFAlb, CSFIgA, and
their quotients, common mechanisms reflecting BBB
disruption can be assumed. A disrupted BBB that
permits albumin transition into the CNS could fur-
ther impact the course of MS given its ability to
induce astrocyte and microglia activation, leading to
an increased synthesis of glutamate or affecting
potassium homeostasis, all potentially leading to
functional and structural alterations of cortical cir-
cuits.20 Hence, higher CSFAlb might not only indicate
BBB permeability alterations, but may also induce a
further deleterious cascade for the long-term out-
come of MS patients. Another IgA-dependent mech-
anism might be driven through meningeal mast cells
that enhance via interleukin-6 the proliferation of B
lymphocytes and induce their differentiation toward
IgA-secreting plasma cells.21
In contrast to our results, a study by Uher et al.8 did not
find any association between QAlb after the first clinical
MS episode and the reduction of global normalized
cortical volume (from 1.5T MRI) 48 months after dis-
ease onset. This discrepancy can be attributed to sev-
eral factors. First, the assessment of global cortical
volume is less sensitive to regional cortical reorganiza-
tion processes. Moreover, the estimation of brain vol-
umes depends on the MRI technical parameters (1.5T
vs 3T) and the type of postprocessing algorithm used,
since the segmentation-based algorithm FSL-SIENAX
applied by Uher et al. shows more heterogeneous
results in brain volume changes than the FreeSurfer-
based analysis of CT22 adapted in our study.
Like QAlb and QIgA, QIgG was also associated with corti-
cal atrophy rates, but showing fewer significant clus-
ters. The pathogenic role of IgG in MS remains unclear,
IgG OCB-positive MS patients having higher global
and regional brain atrophy than IgG OCB-negative
patients.23 Rojas et al.24 reported that the presence of
IgG OCB in CSF at MS onset is associated with the
presence of brain volume reduction, mainly in neocor-
tical GM regions, independent of lesion load and other
clinical parameters. Due to the inclusion of a dispro-
portionately large number of OCB-positive patients,
analysis of the regional cortical differences depending
on IgG OCB status was not possible.
Cortical remodeling is an important characteristic of
evolving MS pathology mirroring the long-term pro-
gress of the disease.25 We have recently shown gray mat-
ter network reorganization with a strengthening of local
and modular cortical connectivity.1 Divergent reorgani-
zation patterns of gray and white matter were associated
with clinical impairment. Here, we detected cortical
thinning in a regional pattern with maxima in the precu-
neus and parieto-occipital cortex. The precuneus is a
central region for a large spectrum of neurocognitive
functions, presenting a wide range of connections to
middle frontal gyrus, amygdala, hippocampus, and thal-
amus.26 The depicted structural alterations in these
regions could be linked to emerging functional cognitive
deficits in MS patients with conscious information pro-
cessing or episodic memory alterations.
We did not find any correlation between CSF variables
and the rate of thalamus atrophy. Since thalamic atro-
phy is detectable early in RRMS patients, a different
and possibly BBB-albumin- and IgA-independent alter-
ation of microstructural integrity can be postulated.27
We determined that increased CSF concentrations of
albumin, IgA, and IgM are associated with regional
cortical atrophy and increased disability in patients
with early MS and demonstrated a link between spe-
cific markers of immune response in the CSF, BBB
function, and disease course.
J.K., D.C., F.Z., S.G.M., and S.G. contributed equally
to this work. We thank Cheryl Ernest for proofreading
the manuscript.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of inter-
est with respect to the research, authorship, and/or
publication of this article.
The author(s) disclosed receipt of the following
financial support for the research, authorship, and/or
publication of this article: This study has been sup-
ported by the German Research Foundation (DFG;
Multiple Sclerosis Journal 00(0)
CRC-TR-128) and the Federal Ministry for Education
and Research (BMBF; KKNMS).
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... A growing body of evidence suggests that the disability accumulation may result from insidious neurodegeneration within the GM 6,17,18 . Early neuroinflammatory activity in GM (and WM) is accompanied by glial activation 19 and blood-brain barrier (BBB) dysfunction 20 , which play an important role in neurodegeneration from early stages onward. Although the effects of neurodegeneration in GM are becoming widely recognized, the underlying mechanisms are intensely debated. ...
... Since the meningeal membrane of the brain is essential to maintain GM integrity, inflammatory processes or evolving meningeal damage may mirror or potentiate GM functional abnormalities. Concordantly BBB abnormalities and, infiltration of adaptive immune cells have been shown as indicators of cortical GM pathology 20,30 . In this line, a recent study on human tissue samples showed that meningeal inflammation induces the microglia to acquire two distinct phenotypes that differentially associate with neurodegeneration in the progressive MS cortex in a time-dependent manner, and that microglia eventually lose its initial protective properties contributing to neuronal damage 31 . ...
Full-text available
Inflammatory demyelination characterizes the initial stages of multiple sclerosis, while progressive axonal and neuronal loss are coexisting and significantly contribute to the long-term physical and cognitive impairment. There is an unmet need for a conceptual shift from a dualistic view of MS pathology, involving either inflammatory demyelination or neurodegeneration, to integrative dynamic models of brain reorganization, where, glia-neuron interactions, synaptic alterations, and grey matter pathology are longitudinally envisaged at the whole-brain level. Functional and structural MRI can delineate network hallmarks for relapses, remissions or disease progression, which can be linked to the pathophysiology behind inflammatory attacks, repair, and neurodegeneration. Here, we aim to unify recent findings of grey matter circuits dynamics in multiple sclerosis within the framework of molecular and pathophysiological hallmarks combined with disease-related network reorganization, while highlighting advances from animal models (in vivo and ex vivo) and human clinical data (imaging and histological). We propose that MRI-based brain networks characterization is essential for better delineating ongoing pathology and elaboration of particular mechanisms that may serve for accurate modelling and prediction of disease courses throughout disease stages.
... Although interactions between the intestinal microbiota and the immune system are thought to play a critical role in MS (11), the relevance of IgA immune responses to organ-specific autoimmune diseases such as MS is not well understood (31)(32)(33)(34)(35)(36)(37). To determine how IgA immune responses affect MS disease activity, we classified patients into MS inactive (remission) versus MS active (relapse) using clinical and radiological metadata and measured IgA and IgG levels in both blood and cerebrospinal fluid (CSF; Fig. 2A, fig. ...
... Our observations therefore provide the rationale for further evaluating CSF IgA as a marker for acute inflammation in MS and other inflammatory diseases. Future studies will have to clarify the role of IgA as a predictor for MS disease course (32,33). ...
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Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA ⁺ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota–specific IgA ⁺ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.
... At the same time, markers predicting the favorable response to a specific DMD are under meticulous development but are not yet validated for clinical pathways. Mainly, MRI parameters are regarded as surrogate measures of treatment response to DMDs, although cerebrospinal fluid (CSF) or peripheral blood immune response may also be a valuable biomarker (10). In this respect, treatment response to dimethyl fumarate (DMF) was reflected by reduced counts of CD4+ and CD8+ T cells in patients without disease activity (11)(12)(13). ...
... Thus, individual patients' stratification to therapy response or failure is warranted. Importantly, easy to obtain and measure immunological markers of therapy response are extremely necessary to minimize tissue damage and longterm functional impairment (10,32). Therefore, here the goal was to stratify patients as responders to DMF therapy by linking cellular responses to clinical, structural MRI and brain network dynamics. ...
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Background: Efficient personalized therapy paradigms are needed to modify the disease course and halt grey (GM) and white matter (WM) damage in patients with multiple sclerosis (MS). Presently, promising disease-modifying drugs show impressive efficiency, however, tailored markers of therapy responses are required. Here, we aimed to detect in a real-world setting patients with a more favorable brain network response and immune cell dynamics upon dimethyl fumarate (DMF) treatment. Methods: In a cohort of 78 MS patients we identified two thoroughly matched groups, based on age, disease duration, disability status and lesion volume, receiving DMF (n = 42) and NAT (n = 36) and followed them over 16 months. The rate of cortical atrophy and deep GM volumes were quantified. GM and WM network responses were characterized by brain modularization as a marker of regional and global structural alterations. In the DMF group, lymphocyte subsets were analyzed by flow cytometry and related to clinical and MRI parameters. Results: Sixty percent (25 patients) of the DMF and 36% (13 patients) of the NAT group had disease activity during the study period. The rate of cortical atrophy was higher in the DMF group (-2.4%) compared to NAT (-2.1%, p < 0.05) group. GM and WM network dynamics presented increased modularization in both groups. When dividing the DMF-treated cohort into patients free of disease activity (n = 17, DMFR) and patients with disease activity (n = 25, DMFNR) these groups differed significantly in CD8+ cell depletion counts (DMFR: 197.7 ± 97.1/µl; DMFNR: 298.4 ± 190.6/µl, p = 0.03) and also in cortical atrophy (DMFR: -1.7%; DMFNR: -3.2%, p = 0.01). DMFR presented reduced longitudinal GM and WM modularization and less atrophy as markers of preserved structural global network integrity in comparison to DMFNR and even NAT patients. Conclusions: NAT treatment contributes to a reduced rate of cortical atrophy compared to DMF therapy. However, patients under DMF treatment with a stronger CD8+ T cell depletion present a more favorable response in terms of cortical integrity and GM and WM network responses. Our findings may serve as basis for the development of personalized treatment paradigms.
... The involvement of IgA in inflammatory disease pathology is presumably not exclusive to IBD. IgA autoantibodies, increased IgA, or aberrant IgA immune complexes are found in several diseases, including celiac disease [64,65], IgA nephropathy [66][67][68], multiple sclerosis [69], IgA blistering diseases [70], and linear IgA bullous disease (LABD) [71]. The pathological contribution of auto-IgA antibodies was recently demonstrated in an LABD in vivo model. ...
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Patients with inflammatory bowel disease (IBD) produce enhanced immunoglobulin A (IgA) against the microbiota compared to healthy individuals, which has been correlated with disease severity. Since IgA complexes can potently activate myeloid cells via the IgA receptor FcαRI (CD89), excessive IgA production may contribute to IBD pathology. However, the cellular mechanisms that contribute to dysregulated IgA production in IBD are poorly understood. Here, we demonstrate that intestinal FcαRI-expressing myeloid cells (i.e., monocytes and neutrophils) are in close contact with B lymphocytes in the lamina propria of IBD patients. Furthermore, stimulation of FcαRI-on monocytes triggered production of cytokines and chemokines that regulate B-cell differentiation and migration, including interleukin-6 (IL6), interleukin-10 (IL10), tumour necrosis factor-α (TNFα), a proliferation-inducing ligand (APRIL), and chemokine ligand-20 (CCL20). In vitro, these cytokines promoted IgA isotype switching in human B cells. Moreover, when naïve B lymphocytes were cultured in vitro in the presence of FcαRI-stimulated monocytes, enhanced IgA isotype switching was observed compared to B cells that were cultured with non-stimulated monocytes. Taken together, FcαRI-activated monocytes produced a cocktail of cytokines, as well as chemokines, that stimulated IgA switching in B cells, and close contact between B cells and myeloid cells was observed in the colons of IBD patients. As such, we hypothesize that, in IBD, IgA complexes activate myeloid cells, which in turn can result in excessive IgA production, likely contributing to disease pathology. Interrupting this loop may, therefore, represent a novel therapeutic strategy.
... IgA autoantibodies, increased IgA or aberrant IgA immune complexes are found in several diseases, such as celiac disease (13,14), IgA nephropathy (15)(16)(17), IgA vasculitis (18), rheumatoid arthritis (19), multiple sclerosis (20) and IgA blistering diseases (21). The potential role of IgA autoantibodies in pathogenesis is, however, mostly ignored, which may be due to the lack of suitable mouse models. ...
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Immunoglobulin A (IgA) is generally considered as a non-inflammatory regulator of mucosal immunity, and its importance in diversifying the gut microbiota is increasingly appreciated. IgA autoantibodies have been found in several autoimmune or chronic inflammatory diseases, but their role in pathophysiology is ill-understood. IgA can interact with the Fc receptor FcαRI on immune cells. We now established a novel IgA autoimmune blistering model, which closely resembles the human disease linear IgA bullous disease (LABD) by using genetically modified mice that produce human IgA and express human FcαRI. Intravital microscopy demonstrated that presence of IgA anti-collagen XVII, - the auto-antigen in LABD-, resulted in neutrophil activation and extravasation from blood vessels into skin tissue. Continued exposure to anti-collagen XVII IgA led to massive neutrophil accumulation, severe tissue damage and blister formation. Importantly, treatment with anti-FcαRI monoclonal antibodies not only prevented disease, but was also able to resolve existing inflammation and tissue damage. Collectively, our data reveal a novel role of neutrophil FcαRI in IgA autoantibody-mediated disease and identify FcαRI as promising new therapeutic target to resolve chronic inflammation and tissue damage.
... Whether the ChP is a more sensitive and earlier marker of MS disease severity than other imaging markers and whether ChP enlargement is a consequence or an immediate cause of MS pathophysiology remains to be clarified. In MS, focal inflammation is known to be associated with widespread white matter pathology and brain topological reorganization (63,64) as well as gray matter pathology (46,65). Here, we extend previous observations by focusing on one of the key barriers, the BCSFB, compared to established surrogate markers of neuroinflammation in MS. ...
Significance Neuroinflammation is a hallmark of multiple sclerosis and is linked to neurodegeneration. This study provides pathophysiological insights into the cross-dependency between neuroinflammation and choroid plexus characteristics in both mice and humans. Our work relates an enlargement of choroid plexus volume to ongoing neuroinflammation and emerging clinical disability in two large cohorts of multiple sclerosis patients as well as in two mouse models, the cuprizone diet-related demyelination and the experimental autoimmune encephalomyelitis. Choroid plexus characterization as measured by high-resolution MRI thus represents a reliable and translatable interspecies marker for the quantification of neuroinflammation and disease trajectories that is strongly associated with functional outcomes.
... Supporting such an association between CNS damage and changes in BBB permeability, it has been observed that high QAlb and other CSF markers of compromised BBB integrity in patients with MS are accompanied by brain atrophy and faster increase in disability. 7,8 To better understand BBB permeability in MS and its putative association with CNS damage and systemic inflammation, we performed a detailed characterization of CSF and paired blood samples that included immunophenotyping and lipidomics. ...
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Objective: CNS damage can increase the susceptibility of the blood-brain barrier (BBB) to changes induced by systemic inflammation. The aim of this study is to better understand BBB permeability in patients with MS and to examine whether compromised BBB integrity in some of these patients is associated with CNS damage and systemic inflammation. Methods: Routine CSF measurements of 121 patients with MS were analyzed including number and type of infiltrating cells, total protein, lactate, and oligoclonal bands, as well as intrathecal production of immunoglobulins and CSF/serum quotients for albumin, immunoglobulins, and glucose. In addition, in a subcohort of these patients, we performed ex vivo immunophenotyping of CSF-infiltrating and paired circulating lymphocytes using a panel of 13 monoclonal antibodies, we quantified intrathecal neurofilament light chain (NF-L) and chitinase 3-like 1 (CHI3L1), and we performed intrathecal lipidomic analysis. Results: Patients with MS with abnormal high levels of albumin in the CSF showed a distinct CSF cell infiltrate and markers of CNS damage such as increased intrathecal levels of NF-L and CHI3L1 as well as a distinct CSF lipidomic profile. In addition, these patients showed higher numbers of circulating proinflammatory Th1 and Th1* cells compatible with systemic inflammation. Of interest, the abnormally high levels of albumin in the CSF of those patients were preserved over time. Conclusions: Our results support the hypothesis that CNS damage may increase BBB vulnerability to systemic inflammation in a subset of patients and thus contribute to disease heterogeneity.
... (Deppe et al., 2014). GM atrophy was demonstrated to be frequent and widespread not only in neocortical areas (Kroth et al., 2017), but also in the hippocampus, cerebellum, and in SDGM structures, starting in the SDGM and then progressively extending to the cortical GM (Rocca et al., 2017). ...
Magnetic resonance imaging (MRI) is the most important tool for diagnosing multiple sclerosis (MS). However, MRI is still unable to precisely quantify the specific pathophysiological processes that underlie imaging findings in MS. Because autopsy and biopsy samples of MS patients are rare and biased towards a chronic burnt-out end or fulminant acute early stage, the only available methods to identify human disease pathology are to apply MRI techniques in combination with subsequent histopathological examination to small animal models of MS and to transfer these insights to MS patients. This review summarizes the existing combined imaging and histopathological studies performed in MS mouse models and humans with MS (in vivo and ex vivo), to promote a better understanding of the pathophysiology that underlies conventional MRI, diffusion tensor and magnetization transfer imaging findings in MS patients. Moreover, it provides a critical view on imaging capabilities and results in MS patients and mouse models and for future studies recommends how to combine those particular MR sequences and parameters whose underlying pathophysiological basis could be partly clarified. Further combined longitudinal in vivo imaging and histopathological studies on rationally selected, appropriate mouse models are required.
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Background Graph theoretical network analysis with structural magnetic resonance imaging (MRI) of multiple sclerosis (MS) patients can be used to assess subtle changes in brain networks. However, the presence of multiple focal brain lesions might impair the accuracy of automatic tissue segmentation methods, and hamper the performance of graph theoretical network analysis. Applying “lesion filling” by substituting the voxel intensities of a lesion with the voxel intensities of nearby voxels, thus creating an image devoid of lesions, might improve segmentation and graph theoretical network analysis. This study aims to determine if brain networks are different between MS subtypes and healthy controls (HC) and if the assessment of these differences is affected by lesion filling. Methods The study included 49 MS patients and 19 HC that underwent a T1w, and T2w-FLAIR MRI scan. Graph theoretical network analysis was performed from grey matter fractions extracted from the original T1w-images and T1w-images after lesion filling. Results Artefacts in lesion-filled T1w images correlated positively with total lesion volume ( r = 0.84, p < 0.001) and had a major impact on grey matter segmentation accuracy. Differences in sensitivity for network alterations were observed between original T1w data and after application of lesion filling: graph theoretical network analysis obtained from lesion-filled T1w images produced more differences in network organization in MS patients. Conclusion Lesion filling might reduce variability across subjects resulting in an increased detection rate of network alterations in MS, but also induces significant artefacts, and therefore should be applied cautiously especially in individuals with higher lesions loads.
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The hippocampus is an anatomically compartmentalized structure imbedded in highly wired networks that are essential for cognitive functions. Hippocampal vulnerability has been postulated in acute and chronic neuroinflammation in multiple sclerosis, while the patterns of occurring inflammation, neurodegeneration or compensation have not yet been described. Besides focal damage to hippocampal tissue, network disruption is an important contributor to cognitive decline in multiple sclerosis patients. We postulate sex-specific trajectories in hippocampal network reorganization and regional integrity, and address their relation to markers of neuroinflammation, cognitive/memory performance, and clinical severity. In a large cohort of multiple sclerosis patients (n = 476; 337 females, age 35 ± 10 years, disease duration 16 ± 14 months) and healthy subjects (n = 110, 54 females; age 34 ± 15 years), we utilized MRI at baseline and at 2-year follow-up to quantify regional hippocampal volumetry and reconstruct single-subject hippocampal networks. Through graph analytical tools we assessed the clustered topology of the hippocampal networks. Mixed-effects analyses served to model sex-based differences in hippocampal network and subfield integrity between multiple sclerosis patients and healthy subjects at both time points and longitudinally. Afterwards, hippocampal network and subfield integrity were related to clinical and radiological variables in dependency of sex attribution. We found a more clustered network architecture in both female and male patients compared to their healthy counterparts. At both time points, female patients displayed a more clustered network topology in comparison to male patients. Over time, multiple sclerosis patients developed an even more clustered network architecture, though with a greater magnitude in females. We detected reduced regional volumes in most of the addressed hippocampal subfields in both female and male patients compared to healthy subjects. Compared to male patients, females displayed lower volumes of para- and presubiculum but higher volumes of molecular layer. Longitudinally, volumetric alterations were more pronounced in female patients, which showed a more extensive regional tissue loss. Despite a comparable cognitive/memory performance between female and male patients over the follow-up period, we identified a strong interrelation between hippocampal network properties and cognitive/memory performance only in female patients. Our findings evidence a more clustered hippocampal network topology in female patients with a more extensive subfield volume loss over time. A stronger relation among cognitive/memory performance and the network topology in female patients suggests a greater entrainment of brain’s reserve. These results may serve to adapt sex-targeted neuropsychological interventions.
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Significance Multiple sclerosis (MS) is an inflammatory disorder characterized by multifocal lesions in the central nervous system. These lesions are caused by infiltrating leukocytes that take advantage and/or actively participate in the disruption of the blood–brain barrier (BBB). In this study, the specific role of the adhesion molecule ALCAM (activated leukocyte cell adhesion molecule) present on BBB endothelial cells was assessed. We demonstrated that ALCAM knockout mice develop a more severe experimental autoimmune encephalomyelitis, the mouse model of MS, due to an increased permeability of the BBB. This phenotypic change is caused by a dysregulation of junctional molecules with which ALCAM indirectly binds, suggesting that in addition to its role in leukocyte transmigration, ALCAM regulates and maintains tight junction stability by acting as an adaptor molecule.
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Background: The pathology of multiple sclerosis (MS) consists of demyelination and neuronal injury, which occur early in the disease; yet, remission phases indicate repair. Whether and how the central nervous system (CNS) maintains homeostasis to counteract clinical impairment is not known. Objective: We analyse the structural connectivity of white matter (WM) and grey matter (GM) networks to understand the absence of clinical decline as the disease progresses. Methods: A total of 138 relapsing–remitting MS patients (classified into six groups by disease duration) and 32 healthy controls were investigated using 3-Tesla magnetic resonance imaging (MRI). Networks were analysed using graph theoretical approaches based on connectivity patterns derived from diffusiontensor imaging with probabilistic tractography for WM and voxel-based morphometry and regional-volume- correlation matrix for GM. Results: In the first year after disease onset, WM networks evolved to a structure of increased modularity, strengthened local connectivity and increased local clustering while no clinical decline occurred. GM networks showed a similar dynamic of increasing modularity. This modified connectivity pattern mainly involved the cerebellum, cingulum and temporo-parietal regions. Clinical impairment was associated at later disease stages with a divergence of the network patterns. Conclusion: Our findings suggest that network functionality in MS is maintained through structural adaptation towards increased local and modular connectivity, patterns linked to adaptability and homeostasis.
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Leakage of the blood–brain barrier (BBB) is a common pathological feature in multiple sclerosis (MS). Following a breach of the BBB, albumin, the most abundant protein in plasma, gains access to CNS tissue where it is exposed to an inflammatory milieu and tissue damage, e.g., demyelination. Once in the CNS, albumin can participate in protective mechanisms. For example, due to its high concentration and molecular properties, albumin becomes a target for oxidation and nitration reactions. Furthermore, albumin binds metals and heme thereby limiting their ability to produce reactive oxygen and reactive nitrogen species. Albumin also has the potential to worsen disease. Similar to pathogenic processes that occur during epilepsy, extravasated albumin could induce the expression of proinflammatory cytokines and affect the ability of astrocytes to maintain potassium homeostasis thereby possibly making neurons more vulnerable to glutamate exicitotoxicity, which is thought to be a pathogenic mechanism in MS. The albumin quotient, albumin in cerebrospinal fluid (CSF)/albumin in serum, is used as a measure of blood-CSF barrier dysfunction in MS, but it may be inaccurate since albumin levels in the CSF can be influenced by multiple factors including: 1) albumin becomes proteolytically cleaved during disease, 2) extravasated albumin is taken up by macrophages, microglia, and astrocytes, and 3) the location of BBB damage affects the entry of extravasated albumin into ventricular CSF. A discussion of the roles that albumin performs during MS is put forth.
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In individuals with multiple sclerosis, physical and cognitive disability progression are clinical and pathophysiological hallmarks of the disease. Despite shortcomings, particularly in capturing cognitive deficits, the Expanded Disability Status Scale is the assessment of disability progression most widely used in clinical trials. Here, we review treatment effects on disability that have been reported in large clinical trials of disease-modifying treatment, both among patients with relapsing–remitting disease and among those with progressive disease. However, direct comparisons are confounded to some degree by the lack of consistency in assessment of disability progression across trials. Confirmed disability progression (CDP) is a more robust measure when performed over a 6-month than a 3-month interval, and reduction in the risk of 6-month CDP in phase III trials provides good evidence for the beneficial effects on disability of several high-efficacy treatments for relapsing–remitting disease. It is also becoming increasingly clear that therapies effective in relapsing–remitting disease have little impact on the course of progressive disease. Given that the pathophysiological mechanisms, which lead to the long-term accrual of physical and cognitive deficits, are evident at the earliest stages of disease, it remains a matter of debate whether the most effective therapies are administered early enough to afford patients the best long-term outcomes.
Purpose To perform a direct metabolic comparison of chronic lesions and diffusely injured normal-appearing white matter (NAWM) in multiple sclerosis (MS). Materials and Methods In this institutional review board-approved study, with the written informed consent of all patients, two-dimensional magnetic resonance spectroscopic imaging data in 46 patients with relapsing-remitting MS (median disease duration, 0.8 year) were analyzed by using the spectral quantification tool LCModel. Metabolic patterns were evaluated for non-gadolinium-enhancing chronic lesions and the corresponding contralateral NAWM. The sensitivity of the method was assessed by reproducing the known metabolic differences between cortical gray matter (GM) and NAWM. In addition to individual spectra, averaged spectra were calculated by accumulating free induction decays over all subjects to yield an increased signal-to-noise ratio (SNR), and in turn, to allow improved curve fitting as demonstrated by lower error bounds for low-concentration metabolites. Metabolite concentrations were statistically tested for intraindividual differences (paired t tests) to avoid effects resulting from variations in disease severity or treatment. Results Differences between the metabolite concentrations in the NAWM and the cortical GM were highly significant (P < .001), demonstrating the reliability of the spectral analysis used here. The spectral patterns of the individual and averaged spectra of chronic lesions and NAWM were qualitatively very similar at visual inspection. Furthermore, in the quantitative comparison, the estimated metabolite concentrations showed only slight differences (P > .07). Owing to increased SNRs in the averaged spectra compared with individual spectra (eg, for chronic lesions, 63 vs 28.4 ± 4.1), it was possible to reliably (Cramér-Rao lower bound [CRLB], <20%) estimate scyllo-inositol levels with a CRLB of 14%. Conclusion These findings revealed that NAWM exhibits the same metabolic changes as chronic white matter lesions, even very early in the disease course, further supporting the view that such lesions may not be as relevant as widely assumed. (©) RSNA, 2016.
Recent studies on patients with clinically isolated syndrome (CIS) and multiple sclerosis (MS) demonstrated thalamic atrophy. Here we addressed the following question: Is early thalamic atrophy in patients with CIS and relapsing-remitting MS (RRMS) mainly a direct consequence of white matter (WM) lesions-as frequently claimed-or is the atrophy stronger correlated to "silent" (nonlesional) microstructural thalamic alterations? One-hundred and ten patients with RRMS, 12 with CIS, and 30 healthy controls were admitted to 3 T magnetic resonance imaging. Fractional anisotropy (FA) was computed from diffusion tensor imaging (DTI) to assess thalamic and WM microstructure. The relative thalamic volume (RTV) and thalamic FA were significantly reduced in patients with CIS and RRMS relative to healthy controls. Both measures were also correlated. The age, gender, WM lesion load, thalamic FA, and gray matter volume-corrected RTV were reduced even in the absence of thalamic and extensive white matter lesions-also in patients with short disease duration (≤24 months). A voxel-based correlation analysis revealed that the RTV reduction had a significant effect on local WM FA-in areas next to the thalamus and basal ganglia. These WM alterations could not be explained by WM lesions, which had a differing spatial distribution. Early thalamic atrophy is mainly driven by silent microstructural thalamic alterations. Lesions do not disclose the early damage of thalamocortical circuits, which seem to be much more affected in CIS and RRMS than expected. Thalamocortical damage can be detected by DTI in normal appearing brain tissue. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
Background: The utility of blood-brain barrier (BBB) biomarkers for clinical and magnetic resonance imaging progression in multiple sclerosis (MS) has not been extensively investigated. Objectives: To determine whether cerebrospinal fluid (CSF) measures of BBB at clinical onset predict radiological and clinical deterioration over 48 months. Methods: This longitudinal study included 182 patients after first clinical event suggestive of MS treated with weekly intramuscular interferon beta-1a. CSF and serum samples were analyzed for leukocytes, total protein, albumin, immunoglobulins, and oligoclonal bands. Optimal thresholds for the albumin quotient (QAlb) were determined. Mixed-effect model analyses, adjusted for age, gender, and treatment escalation, were used to analyze relationship between CSF measures and disease activity outcomes over 48 months of follow-up. Results: Increased QAlb at clinical onset was associated with enlargement of lateral ventricles (p = .001) and greater whole brain (p = .003), white matter (p < .001), corpus callosum (p < .001), and thalamus (p = .003) volume loss over 48 months. Higher QAlb was associated with higher Expanded Disability Status Scale score over 48 months (p = .002). Conclusions: Increased QAlb at clinical onset is associated with increased brain atrophy and greater disability in patients after first clinical event suggestive of MS.
Multi-centre MRI studies of the brain are essential for enrolling large and diverse patient cohorts, as required for the investigation of heterogeneous neurological and psychiatric diseases. However, the multi-site comparison of standard MRI data sets that are weighted with respect to tissue parameters such as the relaxation times (T1, T2) and proton density (PD) may be problematic, as signal intensities and image contrasts depend on site-specific details such as the sequences used, imaging parameters, and sensitivity profiles of the radiofrequency (RF) coils. Water or gel phantoms are frequently used for long-term and/or inter-site quality assessment. However, these phantoms hardly mimic the structure, shape, size or tissue distribution of the human brain. The goals of this study were: (1) to validate the long-term stability of a human post-mortem brain phantom, performing quantitative mapping of T1, T2, PD, and the magnetization transfer ratio (MTR) over a period of 18months; (2) to acquire and analyse data for this phantom and the brain of a healthy control (HC) in a multi-centre study for MRI protocol standardization in four centres, while conducting a voxel-wise as well as whole brain grey (GM) and white matter (WM) tissue volume comparison. MTR, T2, and the quotient of PD in WM and GM were stable in the post-mortem brain with no significant changes. T1 was found to decrease from 267/236ms (GM/WM) to 234/216ms between 5 and 17weeks post embedment, stabilizing during an 18-month period following the first scan at about 215/190ms. The volumetric measures, based on T1-weighted MP-RAGE images obtained at all participating centres, revealed inter- and intra-centre variations in the evaluated GM and WM volumes that displayed similar trends in both the post-mortem brain as well as the HC. At a confidence level of 95%, brain regions such as the brainstem, deep GM structures as well as boundaries between GM and WM tissue were found to be less reproducible than other brain regions in all participating centres. The results demonstrate that a post-mortem brain phantom may be used as a reliable tool for multi-centre MR studies. Copyright © 2015. Published by Elsevier Inc.