Characterization and localization of microstructural changes in brain tissue in Neuropsychiatric Systemic Lupus Erythematosus (NPSLE)

SLE is an autoimmune disease with a prevalence of 1:2000 characterized by the
production of various antibodies, such as anti-double strand DNA,
anti-erythrocyte, anti-cardiolipin, and anti-neuronal antibodies. Many (75%)
SLE patients develop neurological and psychiatric (NP) symptoms or signs of
cognitive decline during the course of the disease, which are the most feared
complications of the disease among SLE patients. These signs and symptoms can
be manifestations of involvement of the central nervous system by SLE (primary
NPSLE), or they can be secondary to side effects of medication or based on
metabolic disorders due to involvement of other organs than the brain
(secondary NPSLE). The diagnosis of primary NPSLE is an important one, since it
has grave consequences for patients. Since primary NPSLE is a disease that
requires aggressive treatment with serious side effects, the indication for and
choice of therapy should be well founded to prevent unnecessary suffering from
side effects on the one hand and suffering from inadequate treatment on the
other hand. In a given SLE patient with NP symptoms the first question is
whether the symptoms are based on secondary or primary NPSLE, conditions that
may require different treatment. The second question is whether the symptoms
are based on ischemia due to a disturbed coagulation system requiring
anticoagulation therapy, or whether the symptoms are based on an inflammatory
response requiring aggressive treatment with steroids or even cytostatic
therapy. Currently, answering these questions is often very difficult due to a
lack of diagnostic clues to differentiate between the different underlying
pathomechanisms.

The American College of Rheumatologists (ACR) advocates conventional MRI (cMRI)
for the diagnosis of NPSLE. Cerebral changes are frequently detected on cMRI in
SLE patients with NP symptoms, but very often these changes are non-specific
and do not provide an explanation for the symptoms. This clinico-radiological
paradox is most pronounced in SLE patients with diffuse NP symptoms, who often
have a normal cMRI examination. Over the past few years quantitative MRI (qMRI)
tools, such as magnetization transfer imaging (MTI), diffusion weighted imaging
(DWI) and MR spectroscopy (MRS), have diminished this paradox. From the
preliminary work that has been carried out in our center and elsewhere, there
is a significant amount of evidence that NPSLE is accompanied by
microstructural changes in brain tissue, both in gray matter and in white
matter, as evidenced by global histograms of MTR values and of ADC values
derived from DWI experiments. It has been thus shown that MTI and DWI, the very
basic MR methods sensitized to microstructural features of neural tissue, were
able to detect changes that correlated with the diseased state significantly
more so than the standard relaxation-based contrast (T1W, T2W and FLAIR), which
in many instances did not show any abnormalities in symptomatic subjects.

Thus far, qMRI has been used in a volumetric way, which only provides
measurements that permit assessing the presence of changes in compartments such
as the whole brain, or the white matter (WM) and gray matter (GM) compartments.
This approach does not provide images that allow assessing the regional
distribution of changes, whereas such patterns contain a wealth of information
on the nature of the underlying disease. Furthermore, thus far the qMRI methods
that have been applied in NPSLE are sensitive for the presence of brain damage,
but they do not allow identifying the nature of the underlying histological
changes, which further limits their diagnostic value.

Recently, new qMRI methods have been developed that are not only significantly
more sensitive to subtle changes in tissue microstructure, but also help reveal
in more detail the underlying histological changes. Methods such as q-space
imaging have been shown to be particularly sensitive to microstructural changes
in white matter in multiple sclerosis, and help classify and characterize
lesions caused by the disease. MRS relaxometry picks up subtle changes in
neuronal structure in bipolar disorder, a disease that shows almost no visible
sign on any MR modality. Diffusion tensor spectroscopy (DTS) has been shown to
be extremely sensitive to sizes of axons in the human brain. It is thus
hypothesized, that similarly to what has been shown in other neurological
disorders, e.g. multiple sclerosis, the use of more sophisticated MR modalities
sensitized to microstructural characteristics of neural tissue will enable a
more sensitive and more specific characterization of these changes that are
associated with NPSLE.

The combination of MR tools we propose will take advantage of the increased
sensitivity of q-MRI methods such as magnetization transfer to disturbances in
tissue structure in primary NPSLE, and with the incorporation of additional
tools such as q-space imaging, will be able to provide a better localization of
the tissue damage. The combination of MR tools will reflect changes in specific
brain tissue components and will be able to offer a better characterization to
the nature of the brain lesions caused by NPSLE, both those that are currently
detectable with cMRI and those that appear as normal brain tissue in cMRI.

• To increase the sensitivity of the current MRI methods for detecting the
changes caused by NPSLE through the scans made on the 7 Tesla scanner, since
the higher field strength will lead to a higher signal to noise ratio and
higher resolution.

• To increase the specificity of the current MRI methods for NP involvement by
distinguishing the changes due to NPSLE from the ones due to SLE.

• To investigate and localize the microstructural changes in the brain tissue
due to the histopathology of NPSLE through a multimodal analysis of the data
obtained from different MRI tools.

• To increase the understanding of underlying pathophysiology of the brain
lesions caused by NPSLE by taking the measurements from these lesions and
comparing them with the measurements from normal appearing brain regions.

We will perform a single center cross-sectional case-control study to compare
NPSLE patients with age and gender matched controls. The control group consists
of healthy subjects and SLE patients without NP complaints. The inclusion of
SLE patients is necessary to specify whether the observed changes are caused by
SLE itself or specific to NPSLE. In order to have a better explanation about
the nature of the focal lesions and compare them with diffuse lesions in normal
appearing brain tissue, we will examine NPSLE patients with and without focal
lesions visible on cMRI. The study will consist of MRI scans performed on 3
Tesla (3T) and 7 Tesla (7T) Philips scanners at LUMC. The scan protocol in 7T
will be complementary to the one in 3T in order to provide an increased
specificity and sensitivity. A total of 120 subjects (30 NPSLE with focal
lesions, 30 NPSLE without focal lesions 30 SLE and 30 healthy) will participate
on the study. The NPSLE patients will be asked before their visit whether or
not they are interested to participate in our study. In case that they want to
participate, their consent will be taken to access their most recent 3T scans
that have been made by the patient care or during follow-up study. These 3T
scans will be used as a part of our data analysis procedure. The NPSLE patients
will only undergo the scan in 7T Philips MR scanner for our study. SLE patients
without NP symptoms and the healthy volunteers will be asked to undergo both 3T
and 7T scans. The 3T scan protocol used for these subjects will be similar to
the one used for scanning the NPSLE patients in patient care and during
follow-up study. The study will take place at LUMC. From the starting point of
the study, 2-3 scans will be made each week. Each MRI scan will last about 60
minutes. The duration of the study will be about 80-84 weeks.

The risks of this study are the standard risks related to MRI. These risks will
be minimized by screening the subjects through a questionnaire for MRI safety
prior to the examination. The questionnaire will cover the risk factors
associated with MRI. Based on the answers, the subject will be allowed or not
allowed to go into the scanner. There is no direct benefit of the study to the
subjects. However, the outcomes of the study may contribute to the future
diagnostic value of the quantitative MRI methods in NPSLE.