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Increased Blood-Brain Barrier Permeability of the Thalamus Correlated With Symptom Severity and Brain Volume Alterations in Patients With Schizophrenia

      Abstract

      Background

      While direct in vivo data from patients is insufficient, cumulative evidence of microvascular dysfunction has shown that the blood-brain barrier (BBB) is disrupted in schizophrenia. In this study, we attempted to test the hypothesis that greater BBB permeability in patients with schizophrenia was associated with clinical characteristics and brain volumetric alterations using dynamic contrast-enhanced magnetic resonance imaging techniques.

      Methods

      Structural magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging data from 29 patients with schizophrenia and 18 age- and sex-matched control subjects were obtained. We calculated the volume transfer constant (Ktrans) value and compared the difference between the 2 groups. The regions with an abnormal Ktrans value were extracted as regions of interest (thalamus), and the correlations with clinical characteristics and gray matter volume were analyzed.

      Results

      The results revealed that Ktrans value of the bilateral thalamus was higher in the schizophrenia group as compared to the healthy control group (p < .001). There were significant positive correlations between thalamic mean Ktrans value with disease duration (p < .05) and symptom severity (p < .001). Analysis of the thalamic subregions revealed that BBB disruption was significant in the pulvinar, especially the medial pulvinar nucleus and lateral pulvinar nucleus (p < .001). The correlation between the Ktrans values and the corresponding volumes was negative for the whole brain, the thalamus, and the thalamic subregions.

      Conclusions

      These results provide the first in vivo evidence of BBB disruption of thalamus in patients with schizophrenia and suggest that BBB dysfunction might contribute to the pathological brain structural alterations in schizophrenia.

      Keywords

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      References

        • Müller N.
        Inflammation in schizophrenia: Pathogenetic aspects and therapeutic considerations.
        Schizophr Bull. 2018; 44: 973-982
        • Marques T.R.
        • Ashok A.H.
        • Pillinger T.
        • Veronese M.
        • Turkheimer F.E.
        • Dazzan P.
        • et al.
        Neuroinflammation in schizophrenia: Meta-analysis of in vivo microglial imaging studies.
        Psychol Med. 2019; 49: 2186-2196
        • Dawidowski B.
        • Górniak A.
        • Podwalski P.
        • Lebiecka Z.
        • Misiak B.
        • Samochowiec J.
        The role of cytokines in the pathogenesis of schizophrenia.
        J Clin Med. 2021; 10: 3849
        • Dobi A.
        • Rosanaly S.
        • Devin A.
        • Baret P.
        • Meilhac O.
        • Harry G.J.
        • et al.
        Advanced glycation end-products disrupt brain microvascular endothelial cell barrier: The role of mitochondria and oxidative stress.
        Microvasc Res. 2021; 133104098
        • Najjar S.
        • Pahlajani S.
        • De Sanctis V.
        • Stern J.N.H.
        • Najjar A.
        • Chong D.
        Neurovascular unit dysfunction and blood-brain barrier hyperpermeability contribute to schizophrenia neurobiology: A theoretical integration of clinical and experimental evidence.
        Front Psychiatry. 2017; 8: 83
        • Pollak T.A.
        • Drndarski S.
        • Stone J.M.
        • David A.S.
        • McGuire P.
        • Abbott N.J.
        The blood-brain barrier in psychosis.
        Lancet Psychiatry. 2018; 5: 79-92
        • Daneman R.
        • Prat A.
        The blood-brain barrier.
        Cold Spring Harb Perspect Biol. 2015; 7: a020412
        • Cai H.Q.
        • Catts V.S.
        • Webster M.J.
        • Galletly C.
        • Liu D.
        • O’Donnell M.
        • et al.
        Increased macrophages and changed brain endothelial cell gene expression in the frontal cortex of people with schizophrenia displaying inflammation.
        Mol Psychiatry. 2020; 25: 761-775
        • Lizano P.
        • Lutz O.
        • Xu Y.
        • Rubin L.H.
        • Paskowitz L.
        • Lee A.M.
        • et al.
        Multivariate relationships between peripheral inflammatory marker subtypes and cognitive and brain structural measures in psychosis.
        Mol Psychiatry. 2021; 26: 3430-3443
        • Uranova N.A.
        • Zimina I.S.
        • Vikhreva O.V.
        • Krukov N.O.
        • Rachmanova V.I.
        • Orlovskaya D.D.
        Ultrastructural damage of capillaries in the neocortex in schizophrenia.
        World J Biol Psychiatry. 2010; 11: 567-578
        • Greene C.
        • Hanley N.
        • Campbell M.
        Blood-brain barrier associated tight junction disruption is a hallmark feature of major psychiatric disorders.
        Transl Psychiatry. 2020; 10: 373
        • Kealy J.
        • Greene C.
        • Campbell M.
        Blood-brain barrier regulation in psychiatric disorders.
        Neurosci Lett. 2020; 726133664
        • Campana M.
        • Strauß J.
        • Münz S.
        • Oviedo-Salcedo T.
        • Fernando P.
        • Eichhorn P.
        • et al.
        Cerebrospinal fluid pathologies in schizophrenia-spectrum disorder-A retrospective chart review.
        Schizophr Bull. 2022; 48: 47-55
        • Schümberg K.
        • Polyakova M.
        • Steiner J.
        • Schroeter M.L.
        Serum S100B is related to illness duration and clinical symptoms in schizophrenia-A meta-regression analysis.
        Front Cell Neurosci. 2016; 10: 46
        • Steiner J.
        • Schiltz K.
        • Walter M.
        • Wunderlich M.T.
        • Keilhoff G.
        • Brisch R.
        • et al.
        S100B serum levels are closely correlated with body mass index: An important caveat in neuropsychiatric research.
        Psychoneuroendocrinology. 2010; 35: 321-324
        • Sourbron S.P.
        • Buckley D.L.
        Tracer kinetic modelling in MRI: Estimating perfusion and capillary permeability.
        Phys Med Biol. 2012; 57: R1-R33
        • Chidambaram S.
        • Pannullo S.C.
        • Roytman M.
        • Pisapia D.J.
        • Liechty B.
        • Magge R.S.
        • et al.
        Dynamic contrast-enhanced magnetic resonance imaging perfusion characteristics in meningiomas treated with resection and adjuvant radiosurgery.
        Neurosurg Focus. 2019; 46: E10
        • Al-Bachari S.
        • Naish J.H.
        • Parker G.J.M.
        • Emsley H.C.A.
        • Parkes L.M.
        Blood-brain barrier leakage is increased in Parkinson’s disease.
        Front Physiol. 2020; 11593026
        • Varatharaj A.
        • Liljeroth M.
        • Darekar A.
        • Larsson H.B.W.
        • Galea I.
        • Cramer S.P.
        Blood-brain barrier permeability measured using dynamic contrast-enhanced magnetic resonance imaging: A validation study [published correction appears in J Physiol 2020; 598:2507].
        J Physiol. 2019; 597: 699-709
        • Kamintsky L.
        • Beyea S.D.
        • Fisk J.D.
        • Hashmi J.A.
        • Omisade A.
        • Calkin C.
        • et al.
        Blood-brain barrier leakage in systemic lupus erythematosus is associated with gray matter loss and cognitive impairment.
        Ann Rheum Dis. 2020; 79: 1580-1587
        • Wang X.
        • Ma L.
        • Luo Y.
        • Yang Y.
        • Upreti B.
        • Cheng Y.
        • et al.
        Increasing of blood brain barrier permeability and the association with depression and anxiety in systemic lupus erythematosus patients.
        Front Med (Lausanne). 2022; 9852835
        • Kamintsky L.
        • Cairns K.A.
        • Veksler R.
        • Bowen C.
        • Beyea S.D.
        • Friedman A.
        • Calkin C.
        Blood-brain barrier imaging as a potential biomarker for bipolar disorder progression.
        NeuroImage Clin. 2020; 26102049
        • Arnone D.
        • Cavanagh J.
        • Gerber D.
        • Lawrie S.M.
        • Ebmeier K.P.
        • McIntosh A.M.
        Magnetic resonance imaging studies in bipolar disorder and schizophrenia: Meta-analysis.
        Br J Psychiatry. 2009; 195: 194-201
        • Haijma S.V.
        • Van Haren N.
        • Cahn W.
        • Koolschijn P.C.
        • Hulshoff Pol H.E.
        • Kahn R.S.
        Brain volumes in schizophrenia: A meta-analysis in over 18 000 subjects.
        Schizophr Bull. 2013; 39: 1129-1138
        • Patlak C.S.
        • Blasberg R.G.
        • Fenstermacher J.D.
        Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data.
        J Cereb Blood Flow Metab. 1983; 3: 1-7
        • Heye A.K.
        • Thrippleton M.J.
        • Armitage P.A.
        • Valdés Hernández M.D.C.
        • Makin S.D.
        • Glatz A.
        • et al.
        Tracer kinetic modelling for DCE-MRI quantification of subtle blood-brain barrier permeability.
        NeuroImage. 2016; 125: 446-455
        • Brookes J.A.
        • Redpath T.W.
        • Gilbert F.J.
        • Murray A.D.
        • Staff R.T.
        Accuracy of T1 measurement in dynamic contrast-enhanced breast MRI using two- and three-dimensional variable flip angle fast low-angle shot.
        J Magn Reson Imaging. 1999; 9: 163-171
        • Rohrer M.
        • Bauer H.
        • Mintorovitch J.
        • Requardt M.
        • Weinmann H.J.
        Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths.
        Invest Radiol. 2005; 40: 715-724
        • Bors L.
        • Tóth K.
        • Tóth E.Z.
        • Á Bajza
        • Csorba A.
        • Szigeti K.
        • et al.
        Age-dependent changes at the blood-brain barrier. A Comparative structural and functional study in young adult and middle aged rats [published correction appears in Brain Res Bull 2020; 155:211–212].
        Brain Res Bull. 2018; 139: 269-277
        • Winkler A.M.
        • Ridgway G.R.
        • Douaud G.
        • Nichols T.E.
        • Smith S.M.
        Faster permutation inference in brain imaging.
        Neuroimage. 2016; 141: 502-516
        • Raja R.
        • Rosenberg G.A.
        • Caprihan A.
        MRI measurements of blood-brain barrier function in dementia: A review of recent studies.
        Neuropharmacology. 2018; 134: 259-271
        • Nakagawa Y.
        • Chiba K.
        Involvement of neuroinflammation during brain development in social cognitive deficits in autism spectrum disorder and schizophrenia.
        J Pharmacol Exp Ther. 2016; 358: 504-515
        • Steullet P.
        Thalamus-related anomalies as candidate mechanism-based biomarkers for psychosis.
        Schizophr Res. 2020; 226: 147-157
        • Zhou Y.-F.
        • Huang J.-C.
        • Zhang P.
        • Fan F.-M.
        • Chen S.
        • Fan H.-Z.
        • et al.
        Choroid plexus enlargement and allostatic load in schizophrenia.
        Schizophr Bull. 2020; 46: 722-731
        • Shepherd A.M.
        • Laurens K.R.
        • Matheson S.L.
        • Carr V.J.
        • Green M.J.
        Systematic meta-review and quality assessment of the structural brain alterations in schizophrenia.
        Neurosci Biobehav Rev. 2012; 36: 1342-1356
        • van Erp T.G.M.
        • Hibar D.P.
        • Rasmussen J.M.
        • Glahn D.C.
        • Pearlson G.D.
        • Andreassen O.A.
        • et al.
        Erratum: Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.
        Mol Psychiatry. 2016; 21: 585
        • Pong S.
        • Karmacharya R.
        • Sofman M.
        • Bishop J.R.
        • Lizano P.
        The role of brain microvascular endothelial cell and blood-brain barrier dysfunction in schizophrenia.
        Complex Psychiatry. 2020; 6: 30-46
        • Coisne C.
        • Engelhardt B.
        Tight junctions in brain barriers during central nervous system inflammation.
        Antioxid Redox Signal. 2011; 15: 1285-1303
        • Dorph-Petersen K.-A.
        • Lewis D.A.
        Postmortem structural studies of the thalamus in schizophrenia.
        Schizophr Res. 2017; 180: 28-35
        • Highley J.R.
        • Walker M.A.
        • Crow T.J.
        • Esiri M.M.
        • Harrison P.J.
        Low medial and lateral right pulvinar volumes in schizophrenia: A postmortem study.
        Am J Psychiatry. 2003; 160: 1177-1179
        • Byne W.
        • Hazlett E.A.
        • Buchsbaum M.S.
        • Kemether E.
        The thalamus and schizophrenia: Current status of research.
        Acta Neuropathol. 2009; 117: 347-368
        • Benarroch E.E.
        Pulvinar: Associative role in cortical function and clinical correlations.
        Neurology. 2015; 84: 738-747
        • Saalmann Y.B.
        • Pinsk M.A.
        • Wang L.
        • Li X.
        • Kastner S.
        The pulvinar regulates information transmission between cortical areas based on attention demands.
        Science. 2012; 337: 753-756
        • Pessoa L.
        • Adolphs R.
        Emotion processing and the amygdala: From a ‘low road’ to ‘many roads’ of evaluating biological significance.
        Nat Rev Neurosci. 2010; 11: 773-783
        • Van Dyken P.
        • Lacoste B.
        Impact of metabolic syndrome on neuroinflammation and the blood-brain barrier.
        Front Neurosci. 2018; 12: 930
        • Khalyfa A.
        • Gozal D.
        • Kheirandish-Gozal L.
        Plasma extracellular vesicles in children with OSA disrupt blood-brain barrier integrity and endothelial cell wound healing in vitro.
        Int J Mol Sci. 2019; 20: 6233
        • Elmorsy E.
        • Elzalabany L.M.
        • Elsheikha H.M.
        • Smith P.A.
        Adverse effects of antipsychotics on micro-vascular endothelial cells of the human blood-brain barrier.
        Brain Res. 2014; 1583: 255-268
        • Dwork A.J.
        Postmortem studies of the hippocampal formation in schizophrenia.
        Schizophr Bull. 1997; 23: 385-402
        • Selvaraj S.
        • Arnone D.
        • Cappai A.
        • Howes O.
        Alterations in the serotonin system in schizophrenia: A systematic review and meta-analysis of postmortem and molecular imaging studies.
        Neurosci Biobehav Rev. 2014; 45: 233-245

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