Background
Cytokines such as tumor necrosis factor (TNF) α have been implicated in neurodegeneration
relevant to various neuropsychiatric disorders. Little is known about the genetic
predisposition to neurodegenerative properties of cytokine genes on brain function
and on hippocampus (HC) function in particular. In this study we investigate the neurodegenerative
role of TNF polymorphisms on brain morphology in healthy individuals.
Methods
Voxel-based morphometry was used in a large sample of healthy individuals (n = 303) to analyze the associations between genetic variants of TNF (rs1800629; rs361525) and brain morphology (gray matter concentration).
Results
In a region of interest analysis of the HC, for rs1800629, we observed a strong genotype
effect on bilateral HC gray matter concentration. Carriers of one or two A-alleles
had significantly smaller volumes compared with GG-homozygotes. For rs361525, a similar
effect was observed at almost the same location, with the A-allele resulting in smaller
HC volumes compared with GG homozygotes.
Conclusions
The findings suggest a neurodegenerative role of the A-alleles of the TNF single nucleotide polymorphisms rs1800629 (-308G/A) and rs361525 (-238G/A) on hippocampal
volumes in healthy individuals. Future imaging studies on the role of these single
nucleotide polymorphisms in psychiatric populations of diseases with neurodegenerative
components are warranted.
Key Words
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References
- Immune modulation of learning, memory, neural plasticity and neurogenesis.Brain Behav Immun. 2011; 25: 181-213
- Cytokine and growth factor involvement in long-term potentiation.Mol Cell Neurosci. 1999; 14: 273-286
- Evidence for a cytokine model of cognitive function.Neurosci Biobehav Rev. 2009; 33: 355-366
- From inflammation to sickness and depression: When the immune system subjugates the brain.Nat Rev Neurosci. 2008; 9: 46-56
- Inflammatory blockade restores adult hippocampal neurogenesis.Science. 2003; 302: 1760-1765
- Cumulative depression episodes predict later C-reactive protein levels: A prospective analysis.Biol Psychiatry. 2012; 71: 15-21
- Reduced expression of glucocorticoid-inducible genes GILZ and SGK-1: High IL-6 levels are associated with reduced hippocampal volumes in major depressive disorder.Translational Psychiatry. 2012; 8: e88https://doi.org/10.1038/tp.2012.1014
- Stress and inflammation reduce brain-derived neurotrophic factor expression in first-episode psychosis: A pathway to smaller hippocampal volume.J Clin Psychiatry. 2011; 72: 1677-1684
- Neurobehavioral alterations in developing transgenic mice expressing TNF-alpha in the brain.Brain Behav Immun. 1996; 10: 126-138
- Cognitive dysfunction in mice deficient for TNF- and its receptors.Am J Med Genet B Neuropsychiatr Genet. 2008; 147B: 1056-1064
- Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice.J Immunol. 1997; 158: 438-445
- Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression.Biol Psychiatry. 2009; 65: 732-741
- Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions.J Clin Invest. 1991; 87: 949-954
- Cytokine polymorphisms and Alzheimer disease: Possible associations.Neurol Sci. 2010; 31: 321-325
- [Association of the polymorphisms in the promoter region of tumor necrosis factor alpha and interleukin 6 genes with schizophrenia].Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2011; 28: 427-431
- Cytokine signals propagate through the brain.Mol Psychiatry. 2000; 5: 604-615
- “Inflammatory” cytokines: Neuromodulators in normal brain?.J Neurochem. 2000; 74: 457-471
- Cytokines and the central nervous system.Brain Res Bull. 2001; 54: 329-338
- Neuromodulative actions of cytokines.Yale J Biol Med. 1990; 63: 133-146
- Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system.Exp Physiol. 2005; 90: 663-670
- Control of synaptic strength by glial TNFalpha.Science. 2002; 295: 2282-2285
- Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha.J Neurosci. 2005; 25: 3219-3228
- The roles of TNF in brain dysfunction and disease.Pharmacol Ther. 2010; 128: 519-548
- Divergent roles for tumor necrosis factor-alpha in the brain.J Neuroimmune Pharmacol. 2007; 2: 140-153
- Pro-inflammatory cytokines and their effects in the dentate gyrus.Prog Brain Res. 2007; 163: 339-354
- TNF-alpha-secreting monocytes are recruited into the brain of cholestatic mice.Hepatology. 2006; 43: 154-162
- The effects of TNF deficiency on age-related cognitive performance.Psychoneuroendocrinology. 2009; 34: 615-619
- Association between genetic variants of IL-1beta, IL-6 and TNF-alpha cytokines and cognitive performance in the elderly general population of the MEMO-study.Psychoneuroendocrinology. 2008; 33: 68-76
- Double dissociated effects of the functional TNF-alpha −308G/A polymorphism on processes of cognitive control.Neuropsychologia. 2011; 49: 196-202
- Associations between the tumor necrosis factor alpha gene (−308G→A) and event-related potential indices of attention and mental rotation.Neuroscience. 2010; 170: 742-748
- Variations in the TNF-alpha gene (TNF-alpha −308G→A) affect attention and action selection mechanisms in a dissociated fashion.J Neurophysiol. 2010; 104: 2523-2531
- The hippocampus in major depression: Evidence for the convergence of the bench and bedside in psychiatric research?.Mol Psychiatry. 2010; 16: 252-264
- Evidence for acquired pregenual anterior cingulate gray matter loss from a twin study of combat-related posttraumatic stress disorder.Biol Psychiatry. 2008; 63: 550-556
- Limbic scars: Long–term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging.Biol Psychiatry. 2011; 71: 286-293
- Tumour necrosis factor-α selectively upregulates nuclear factor κb expression in hippocampal sub-neuronal populations.Proc Br Pharmacol Soc. 2006; 3: 113
- The BDNF Val66Met polymorphism impacts parahippocampal and amygdala volume in healthy humans: Incremental support for a genetic risk factor for depression.Psychol Med. 2009; 39: 1831-1839
- Association of the brain-derived neurotrophic factor Val66Met polymorphism with reduced hippocampal volumes in major depression.Arch Gen Psychiatry. 2007; 64: 410-416
- Reduced hippocampal volumes associated with the long variant of the serotonin transporter polymorphism in major depression.Arch Gen Psychiatry. 2004; 61: 177-183
- No effect of 5HTTLPR or BDNF Val66Met polymorphism on hippocampal morphology in major depression.Genes Brain Behav. 2011; 10: 756-764
- ZNF804A risk allele is associated with relatively intact gray matter volume in patients with schizophrenia.Neuroimage. 2011; 54: 2132-2137
- Diagnostic and Statistical Manual of Mental Disorders.4th ed. American Psychiatric Association, Washington, DC1994
- SKID-I.Hogrefe, Göttingen, Germany1997
- Mehrfachwahl-Wortschatz-Intelligenztest MWT-B [in German].Hogrefe, Göttingen, Germany1995
- Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation.Proc Natl Acad Sci U S A. 1997; 94: 3195-3199
- TNFalpha signaling in depression and anxiety: Behavioral consequences of individual receptor targeting.Biol Psychiatry. 2006; 59: 775-785
- Tumor necrosis factor-alpha-238G>A promoter polymorphism is associated with increased risk of new hemorrhage in the natural course of patients with brain arteriovenous malformations.Stroke. 2006; 37: 231-234
- Functional analysis of a new polymorphism in the human TNF alpha gene promoter.Scand J Immunol. 1995; 42: 501-504
- iPLEX Assay: Increased Plexing Efficiency and Flexibility for MassARRAY System Through Single Base Primer Extension with Mass-Modified Terminators.(Accessed December 12, 2011)
- Case-control studies.(Accessed December 12, 2011)
- Unified segmentation.NeuroImage. 2005; 26: 839-851
- Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.Neuroimage. 2002; 15: 273-289
- An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets.Neuroimage. 2003; 19: 1233-1239
- Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): Use of a cluster-size threshold.Magn Reson Med. 1995; 33: 636-647
- Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: Intersubject variability and probability maps.Anat Embryol (Berl). 2005; 210: 343-352
- A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data.Neuroimage. 2005; 25: 1325-1335
- TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways.Cell. 1996; 84: 299-308
- Cooperation of both TNF receptors in inducing apoptosis: Involvement of the TNF receptor-associated factor binding domain of the TNF receptor 75.J Immunol. 1998; 161: 390-399
- Differential role of tumor necrosis factor receptors in mouse brain inflammatory responses in cryolesion brain injury.J Neurosci Res. 2005; 82: 701-716
- Differential expression, cytokine modulation, and specific functions of type-1 and type-2 tumor necrosis factor receptors in rat glia.J Neuroimmunol. 1997; 75: 104-112
- Evolution of cerebral tumor necrosis factor-alpha production during human ischemic stroke.Stroke. 2001; 32: 1750-1758
- Neurodegenerative and neuroprotective effects of tumor Necrosis factor (TNF) in retinal ischemia: Opposite roles of TNF receptor 1 and TNF receptor 2.J Neurosci. 2002; 22: RC216
- Cellular expression of tumor necrosis factor α and its receptors in human ischemic stroke.Clin Neuropathol. 2003; 22: 35-40
- Exclusive tumor necrosis factor (TNF) signaling by the p75TNF receptor triggers inflammatory ischemia in the CNS of transgenic mice.Proc Natl Acad Sci U S A. 2003; 100: 709-714
- TNF-alpha stimulates caspase-3 activation and apoptotic cell death in primary septo hippocampal cultures.J Neurosci. 2001; 64: 121-131
- TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: Neuroprotection by NF kappa B inhibition.Brain Res. 2005; 1034: 11-24
- Tumor necrosis factor alters synaptic transmission in rat hippocampal slices.Neurosci Lett. 1992; 146: 176-178
- Interleukin-1 beta (IL-1 beta) and tumour necrosis factor (TNF) inhibit long-term potentiation in the rat dentate gyrus in vitro.Neurosci Lett. 1996; 203: 17-20
- Dissection of TNF-a inhibition of LTP reveals a p38 MAPK-dependent mechanism which maps to early but not late-phase LTP.Neuroscience. 2004; 124: 319-326
- The inhibitory effect of tumour necrosis factor-a on long-term potentiation is attenuated by type 1 metabotropic glutamate receptor blockade.J Physiol. 2004; 560P: C23
- Neuroinflammation and regulation of glial glutamate uptake in neurological disorders.J Neurosci Res. 2007; 85: 2059-2070
- Modulation of astrocytic metabolic phenotype by proinflammatory cytokines.Glia. 2008; 56: 975-989
- Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present.J Neurosci. 2008; 28: 5321-5330
- Glial reduction in amygdala in major depressive disorder is due to oligodendrocytes.Biol Psychiatry. 2004; 55: 563-569
- Glial reduction in the subgenual prefrontal cortex in mood disorders.Proc Natl Acad Sci U S A. 1998; 95: 13290-13295
- A pathophysiological framework of hippocampal dysfunction in ageing and disease.Nat Rev Neurosci. 2011; 12: 585-601
- Functional connectivity bias of the orbitofrontal cortex in drug-free patients with major depression.Biol Psychiatry. 2010; 67: 161-167
- Interactions between BDNF Val66Met polymorphism and early life stress predict brain and arousal pathways to syndromal depression and anxiety.Mol Psychiatry. 2009; 14: 681-695
- Specifying the neuropsychology of affective disorders: Clinical, demographic and neurobiological factors.Neuropsychol Rev. 2011; 21: 337-359
- Reduced hippocampal volumes and memory loss in patients with early- and late-onset depression.Br J Psychiatry. 2005; 186: 197-202
- Acute psychosocial stress reduces cell survival in adult hippocampal neurogenesis without altering proliferation.J Neurosci. 2007; 27: 2734-2743
- Cell proliferation in adult hippocampus is decreased by inescapable stress: Reversal by fluoxetine treatment.Neuropsychopharmacology. 2003; 28: 1562-1571
- Repeated restraint stress suppresses neurogenesis and induces biphasic PSA-NCAM expression in the adult rat dentate gyrus.Eur J Neurosci. 2003; 17: 879-886
- Circuits and systems in stress.Depress Anxiety. 2002; 15: 126-147
- Lower hippocampal volume in patients suffering from depression: A meta-analysis.Am J Psychiatry. 2004; 161: 598-607
- Hippocampal volume and depression: A meta-analysis of MRI studies.Am J Psychiatry. 2004; 161: 1957-1966
- Structural neuroimaging studies in major depressive disorder.Arch Gen Psychiatry. 2011; 68: 675-690
- Hippocampal atrophy in first episode depression: A meta-analysis of magnetic resonance imaging studies.J Affect Disord. 2011; 134: 483-487
- Polymorphisms of the human TNF-alpha promoter - random variation or functional diversity?.Mol Immunol. 1999; 36: 1017
- [Tumor necrosis factor alpha genetic polymorphism as a risk factor in disease].Rev Med Chil. 2002; 130: 1043-1050
- The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: A meta-analysis.Neuropsychopharmacology. 2011; 36: 2452-2459
- Citalopram reduces endotoxin-induced fatigue.Brain Behav Immun. 2011; 25: 256-259
- Pro-inflammatory biomakers in depression: Treatment with venlafaxine.World J Biol Psychiatry. 2009; 10: 313-323
- Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans.Proc Natl Acad Sci U S A. 2011; 108: 9262-9267
- Defining the human hippocampus in cerebral magnetic resonance images—an overview of current segmentation protocols.Neuroimage. 2009; 47: 1185-1195
- Can voxel based morphometry, manual segmentation and automated segmentation equally detect hippocampal volume differences in acute depression?.Neuroimage. 2009; 45: 29-37
- Liefern HAWIE-R, WST und MWT-B vergleichbare IQ-Werte?.Zeitschrift für Differentielle und Diagnostische Psychologie. 2002; 23: 159-170
Article info
Publication history
Published online: May 04, 2012
Accepted:
April 5,
2012
Received in revised form:
March 20,
2012
Received:
January 19,
2012
Footnotes
Authors BTB and CK contributed equally to this work.
Identification
Copyright
© 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
