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Kynurenine pathway and white matter
microstructure in bipolar disorder
Abstract
Decreased availability of serotonin in the central nervous system has been suggested to be a
central factor in the pathogenesis of depression. Activation of indoleamine 2–3 dioxygenase
following a pro-inflammatory state could reduce the amount of tryptophan converted to serotonin
and increase the production of tryptophan catabolites such as kynurenic acid, an antagonist of
ionotropic excitatory aminoacid receptors, whose levels are reduced in bipolar disorder.
Abnormalities in white matter (WM) integrity have been widely reported in BD. We then
hypothesized that metabolites involved in serotoninergic turnover in BD could influence DTI
measures of WM microstructure. Peripheral levels of tryptophan, kynurenine, kynurenic acid, 3hydroxy-kynurenine, and 5-HIAA were analysed in 22 patients affected by BD and 15 healthy
controls. WM microstructure was evaluated using diffusion tensor imaging and tract-based
spatial statistics with threshold-free cluster enhancement only in bipolar patients. We observed
that kynurenic acid and 5-HIAA were reduced in BD and associated with DTI measures of WM
integrity in several association fibres: inferior and superior longitudinal fasciculus, cingulum
bundle, corpus callosum, uncus, anterior thalamic radiation and corona radiata. Our results seem
to suggest that higher levels of 5-HIAA, a measure of serotonin levels, and higher levels of
kynurenic acid, which protects from glutamate excitotoxicity, could exert a protective effect on
WM microstructure. Reduced levels of these metabolites in BD thus seem to confirm a crucial
role of serotonin turnover in BD pathophysiology.
Introduction
The neurotransmitter serotonin (5-HT) has been suggested to be involved in the pathogenesis of
depression [39]. In bipolar disorder (BD), gene variants of 5-HT transporter and receptors
influence stress sensitivity [13, 14], onset of illness [78], response to several antidepressants [3,
26, 42, 67, 68, 79, 99], suicidality [44], and white matter (WM) microstructure [12]. 5-HT is
derived from the essential amino acid tryptophan (Trp), and its synthesis in the brain is highly
dependent on the bio-availability of Trp in the plasma. Catabolism via the so-called kynurenine
pathway following indoleamine 2–3 dioxygenase (IDO) activation may divert Trp from the 5-HT
synthetic route. IDO can be activated by a pro-inflammatory state; following its activation, this
enzyme converts Trp to kynurenine (Kyn) [30, 72] in extrahepatic tissues, such as lungs,
placenta, kidneys, spleen, blood, and the brain [33, 49], thus shifting the tryptophan metabolism
away from the liver [53]. While in the physiological condition, the kynurenine pathway in the
brain may serve mainly for glycogen storage and synthesis of small amounts of nicotinamide
adenine dinucleotide required for the central nervous system [41]; following immune activation,
an enhanced IDO activity lead to increased consumption of Trp through the Kyn pathway, thus
reducing the availability of serotonergic neurotransmission, as well as inducing the production of
detrimental tryptophan catabolites with neurotoxic effects [54, 56]. Kynurenine is again
metabolized into 3-hydroxy-kynurenine (3HK) which is finally converted to quinolinic acid, the
excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist [76], and to kynurenic acid (KynA),
the antagonist of all three ionotropic excitatory aminoacid receptors [64]. An elevated Trp
breakdown index, which indirectly indicate the activity of IDO, was found in the plasma of
bipolar patients [59], confirming a decreased availability of serotonin in the central nervous
system which has been suggested to be a central factor in the pathogenesis of depression [39].
The enhanced IDO activity which follows the immune activation has a twofold effect: it
increases the breakdown of tryptophan, which is the precursor of serotonin, and the breakdown
of serotonin into anthraniloylalkylamine fragments [88] thus inducing serotonin depletion.
Hypofunction of the serotonin system, indicated by lower levels of 5-hydroxyindole acetic acid
(5-HIAA) in the cerebrospinal fluid, is associated with suicidal behaviour and suicide risk in
mood disorders [4, 37, 61]. Lastly, 5-HIAA levels in the cerebrospinal fluid have been suggested
to represent a predictor of lethality of suicide attempts in patients with BD [77].
Using diffusion tensor imaging (DTI) techniques, recent studies in patients with BD reported
widespread signs of disrupted WM microstructure independent of drug treatment. Increased
unconstrained mean (MD) and radial diffusivity (RD) with reduced fractional anisotropy (FA)
have been consistently found in BD, suggesting significant demyelination/dysmyelination or
reduced bundle coherence without axonal loss [1, 15, 43, 62, 86]. The capability of neurons
located in different brain areas to efficiently communicate with each other depends on changes in
myelination and integrity of myelin sheaths over the lifetime, which influence signal speed [7,
65]. Reduction in myelin integrity or bundle coherence could lead to the development of the
cognitive and behavioural deficits characteristic of BD [6, 66].
We then hypothesized that metabolites involved in serotoninergic turnover in BD could influence
DTI measures of WM microstructure, and we tested this hypothesis in a homogeneous sample of
patients with BD.
Sample
The sample included 22 biologically unrelated inpatients with a diagnosis of bipolar disorder I
(DSM-IV criteria, SCID-I interview) in course of a depressive episode. Severity of depression
was rated on the 30 item Inventory of Depressive Symptomatology-clinician version (IDS-C)
[70, 71]. Handedness was assessed with the Edinburgh inventory [63]. Exclusion criteria were:
additional diagnoses on axis I, mental retardation on axis II, pregnancy, major medical and
neurological disorders, history of drug or alcohol abuse or dependency and inflammatory
diseases. Seventeen per cent of patients had been taking lithium from at least 6 months. No
patients had received electroconvulsive therapy (ECT) within 6 months prior to study enrolment.
Fifteen healthy subjects with no previous history of psychiatric, neurological, and systemic
disorders served as control subjects for metabolites analyses. Only patients underwent MRI
scanning. The study was performed within the frame of the MOODINFLAME study
(http://moodinflame.eu/), a large-scale European medical scientific project aiming to advance
early diagnosis, treatment, and prevention of mood disorders targeting the activated
inflammatory response system. Additional MOODINFLAME exclusion criteria were
inflammation-related symptoms including fever and infectious or inflammatory disease;
uncontrolled systemic disease; uncontrolled metabolic disease or other significant uncontrolled
somatic disorder known to affect mood; somatic medications known to affect mood or the
immune system such as corticosteroids, non-steroidal anti-inflammatory drugs, and statins.
Physical examinations, laboratory tests, and electrocardiograms were performed at admission.
After complete description of the study to the subjects, a written informed consent was obtained.
All the research activities were approved by the local ethical committee.
Analyses of tryptophan metabolites
Tryptophan metabolites in the serum were analysed using high-performance liquid
chromatography (HPLC). Kyn was detected spectrophotometrically at 365 nm. KynA was
detected fluorimetrically at an excitation wavelength of 334 nm and an emission wavelength of
388 nm. KynA was analysed in plasma that was deproteinized using perchloric acid. 3HK was
measured at a wavelength of 365 nm by UV detection. All of the analyses were conducted using
HPLC with a reverse phase c-18 column. The 3HK analysis method has been validated showing
an absolute recovery of 85.8 %, intra-day precision of 3.9 %, and inter-day precision of 7.5 %;
time series demonstrated perfect stability of the analyte 3HK during our extraction and analysis
steps; the result of the analysis was even stable up to three times repeated freezing/thawing
cycles. Thus, we could ensure the validity of the analysis in samples that had already been
thawed and frozen again. All of these methods have been standardized by a quarterly external
quality assurance scheme amongst 6 universities worldwide under the European collaborative
project MOODINFLAME and the Bundesministerium fuer Bildung und Forschung project,
which contributed independently to this study. Standards were prepared for each calibration
curve, and appropriate internal standards were used for analyses of all metabolites. Data are
shown in nmol/l. The intra- and inter-assay coefficients of variation ranged from 5 to 7 % for all
of the metabolites.
Image acquisition
Diffusion tensor imaging was performed on a 3.0 Tesla scanner (Gyroscan Intera, Philips,
Netherlands) using SE echo-planar imaging (EPI) with the following parameters:
TR/TE = 8753.89/58 ms, FoV (mm) 231.43 (ap), 126.50 (fh), 240.00 (rl); acquisition matrix
2.14 × 2.71 × 2.31; 55 contiguous, 2.3-mm-thick axial slices reconstructed with in-plane pixel
size 1.88 × 1.87 mm; SENSE acceleration factor = 2; 1 b0 and 35 non-collinear directions of the
diffusion gradients; b value = 900 s/mm2. Fat saturation was performed to avoid chemical shift
artefacts. On the same occasion and using the same magnet 22 Turbo Spin Echo (TSE), T2 axial
slices (TR = 3000 ms; TE = 85 ms; flip angle = 90°; turbo factor 15; 5-mm-thick, axial slices
with a 512 × 512 matrix and a 230 × 230 mm2 field of view) were acquired to rule out brain
lesions.
Data processing and analyses
Image analyses and tensor calculations were performed using the “Oxford Centre for Functional
Magnetic Resonance Imaging of the Brain Software Library” (FSL 5.0;
www.fmrib.ox.ac.uk/fsl/index.html) [82, 96]. First, each of the 35 DTI volumes was affine
registered to the T2-weighted b = 0 volume using FLIRT (FMRIB’s Linear Image Registration
Tool) [36]. This is corrected for motion between scans and residual eddy current distortions
present in the diffusion-weighted images. Anisotropy can be estimated through the application of
diffusion-sensitizing gradients and the calculation of elements of the diffusion tensor matrix, i.e.
the three eigenvalues λ1, λ2 and λ3 [8, 40, 91]. The tendency to diffuse along the principal
direction of the fibre (AD) is the principal diffusion eigenvalue (λ1) and reflects the integrity of
axons and myelin sheaths, and the bundle coherence of WM tracts [17]. An increase in radial
diffusivity (RD, the average of λ2 and λ3), perpendicular to axonal walls suggests disrupted
myelination [85]. Mean diffusivity (MD, average of λ1, λ2 and λ3) is a measure of the average
molecular motion, independent of tissue directionality. Fractional anisotropy (FA) is the square
root of the sum of squares (SRSS) of the diffusivity differences, divided by the SRSS of the three
diffusivities. After removal of non-brain tissue [80], least square fits were performed to estimate
the FA, eigenvector, and eigenvalue maps.
Next, all individuals’ volumes were skeletonized and transformed into a common space as used
in tract-based spatial statistics (TBSS) [81, 83]. TBSS focuses on the centres of all fibre bundles
that are common to the participants (the most compact WM skeleton), thus improving the
probability that the given spatial voxels contain data from the same part of the same WM tract of
each participant. Briefly, all volumes were nonlinearly warped to the FMRIB58_FA template
supplied with FSL (http://www.fmrib.ox.ac.uk/fsl/tbss/FMRIB58_FA.html) and normalized to
the Montreal Neurological Institute space, by use of local deformation procedures performed by
FMRIB’s Non-Linear Image Registration Tool (www.fmrib.ox.ac.uk/fsl/fnirt/index.html), a
nonlinear registration toolkit using a b-spline representation of the registration warp field [69].
Next, a mean FA volume of all subjects was generated and thinned to create a mean FA skeleton
representing the centres of all common tracts. We thresholded and binarized the mean skeleton at
FA > 0.20 to reduce the likelihood of partial voluming in the borders between tissue classes,
yielding a mask of 137,833 WM voxels. Individual FA values were warped onto this mean
skeleton mask by searching for maximum FA values perpendicular from the skeleton. Using
maximum FA values from the centres of the tracts further minimizes confounding effects
attributable to partial voluming [81]. The resulting tract invariant skeletons for each participant
were fed into voxelwise permutation-based cross-subject statistics. Similar warping and analyses
were used on MD, AD, and RD data sampled from voxels with FA > 0.20.
Voxelwise DTI analyses were performed using nonparametric permutation-based testing [60] as
implemented in Randomise in FSL. We tested for linear effects of Trp, Kyn, Kyn/Trp, KynA, 3HK, and 5-HIAA, and severity of illness was assessed with IDS-C on FA, MD, AD, and RD
across the WM skeleton with the general linear model. We accounted for the effects of the
following nuisance covariates which could influence WM structure: age [38], sex [32], and
lithium treatment [11]. Threshold-free cluster enhancement (TFCE) [84] was used to avoid
defining arbitrary cluster-forming thresholds and smoothing levels. TFCE is particularly useful
when the spatial correlation length of signal exceeds that of noise, as it is expected when
studying WM tracts. This can be seen as a generalization of the cluster mass statistics [18], using
spatial neighbourhood information in a nonlinear image processing to increase sensitivity and
boosting the height of spatially distributed signals, without changing the location of their
maxima. Voxelwise levels of significance, corrected for multiple comparisons, were then
calculated with a standard permutation testing by building up the null distribution (across
permutation of the input data) of the maximum (across voxels) TFCE scores and then using the
95th percentile of the null distribution to threshold signals at corrected p < 0.05 in a minimum
cluster size of k = 100. The data were tested against an empirical null distribution generated by
5000 permutations for each contrast, thus providing statistical maps fully corrected for multiple
comparisons across space.
Results
Clinical and demographic characteristics of the sample, together with the statistics on the
plasma Trp, Kyn, KynA, 3-HK, and 5-HIAA and the breakdown index of Trp (Kyn/Trp) are shown
in Table 1. Only 5-HIAA differed between patients and controls with bipolar patients showing
significantly lower levels (t = 4.22; p = 0.001). In a multivariate analysis controlled for age and
gender, bipolar patient showed significant lower concentrations of Trp (F = 7.77; p = 0.009), Kyn
(F = 6.18; p = 0.018), KynA (F = 5.44; p = 0.026), and 5-HIAA (F = 14.77; p = 0.038). Finally no
differences were found in the breakdown index of Trp calculated as the serum Kyn to Trp ratio.
Among the metabolites linked to 5-HT turnover, KynA and 5-HIAA associated with changes in
DTI measures of WM microstructure. In bipolar patients, KynA was negatively associated with
RD and MD in the uncinate fasciculus, forceps minor, anterior thalamic radiation, anterior
corona radiata, corpus callosum, superior longitudinal fasciculus, inferior fronto-occipital
fasciculus, and cingulum (Table 1; Fig. 1). 5-HIAA was positively associated with AD, RD, and
MD in the body of corpus callosum, inferior longitudinal fasciculus, corticospinal tract, forceps
minor, superior longitudinal fasciculus, and superior corona radiata (Table 1; Figs. 2, 3). No
effect of severity of illness (IDS-C) was observed on WM integrity.
Discussion
The main finding of the present study is that metabolites associated with 5-HT turnover such as
KynA and 5-HIAA influence WM microstructure in bipolar patients. Lower levels of KynA
associated with higher RD and MD and higher levels of 5-HIAA associated with increased AD,
RD, and MD in several WM tracts. While a decrease in AD suggests axonal injury, an increase
of RD, perpendicular to the main axis of the WM tract, is thought to indicate an increased space
between fibres, therefore suggesting demyelination or dysmyelination [85]. However, AD and
RD might depend on independent processes (coherence and directionality of axonal structure,
and fibre myelination), the changes of which should not be a priori interpreted as detrimental.
Considering the present findings, 5-HIAA could be associated with increased structural integrity
and directionality of axons, including their intra-cellular microtubular structure (higher AD); and
changes of myelination, possibly including remodelling of myelin sheaths and remyelination
(increased RD). An increased myelin repair/remyelination could indeed be expected to reduce
the thickness of myelin and increase intra-axonal space and thus increasing both RD and AD as
observed in the present study.
Few studies investigated Trp levels in BD with contrasting results. Both reduced [58] and
unchanged [35] Trp levels have been reported during the manic phase, while no difference was
found between depressed bipolar patients and controls [73]. However, Trp depletion was
demonstrated to increase depressive symptoms [25] and improve manic symptoms [2]. Patients
with BD also show a reduction in the levels of Kyn and KynA compared to controls, which is in
agreement with the literature [57] while, to our best knowledge, no data exist on 5-HIAA levels
in BD, although a reduction in 5-HIAA levels has been reported in major depression compared to
controls [55]. Finally, contrary to previous studies, no difference in the Trp breakdown index
was found between patients and controls.
These data seem to confirm an inefficient serotonin turnover in BD which, however, does not
seems to follow an increased Trp breakdown, but to a reduced amount of Trp in the blood of
these patients instead. Indeed, while no reduction in the Trp breakdown index was observed,
patients with BD showed reduced levels of KynA and 5-HIAA. Our findings suggest that these
metabolites have a protective role on WM microstructure. KynA seem to exert a protective effect
on WM microstructure reducing demyelination or dysmyelination. Since kynurenic acid is
protective against excitotoxicity induced by quinolinic acid, it could be hypothesized that a
decrease in the number of protective metabolites formed in the Trp metabolism in BD patients is
associated with reductions in myelin integrity. Furthermore, our findings of increased AD, RD,
and MD suggest that 5-HIAA could protect against axonal loss and possibly promote
remyelination processes.
These effects were observed in WM tracts, which have been previously associated with BD and
which are central to cortical functions such as corona radiata [15], anterior thalamic radiation
[47, 89], and superior and inferior longitudinal fasciculus [15, 20, 43, 94, 100]. Furthermore,
impaired WM microstructure in BD was observed in cingulum bundle [10] and the uncinate
fasciculus [10, 47, 89]. These tracts are crucial for both motivational and emotional aspects of
behaviour which have been considered at the core of mood dysregulation in BD [24], mood
regulation, emotional processing, and in the comprehension and regulation of emotional
responses to auditory stimuli [75]. Finally, abnormal myelination and morphometry of corpus
callosum have been consistently associated with BD [9, 15], and with dimensions of BD
psychopathology such as aggression [74] and suicide [46]. These abnormalities persist in
euthymic conditions [27], when patients show signs of reduced fibre density [92].
5-HT exposure was shown to lead to disturbance in cultured oligodendrocytes development, with
reduced myelin proteins expression and with increasing suscep ...
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