Interferon-induced Depression: Genetics

Photo of a pair of green wing teal

Interferon remains a key first line treatment for treatment of hepatitis C.  However, interferon has significant neuropsychiatric effects including risk for depression and even suicide in rare individuals.

Some individuals with hepatitis C are unable to complete a course of interferon because of induced depression.  This makes understanding this phenomenon important to develop prevention and treatment strategies.

Understanding how interferon induces depression in some individuals and not other may provide insight into some of the core mechanisms involved in mood disorders.

Joerg Schlaak and colleagues from Germany recently published an important manuscript on gene expression in interferon treated humans.  

The key elements of design in their study included:
Subject characteristics: 50 subjects with hepatitis C followed prospectively while receiving antiviral therapy (interferon alpha and ribavirin), 22 psychiatric patients hospitalized for severe depression and 11 controls without hepatitis C or depression
Gene expression analysis: Total RNA isolation, DNA microarray analysis, real time detection gene expression using PCR
Statistical analysis: group comparisons using T-test or Mann-Whitney U test

Eleven subjects (22%) in the prospective interferon/ribavirin hepatitis C trial developed significant depression.  Fifteen genes were identified in these interferon-induced depression subjects that were "hyper-responsive" to the interferon alpha compared to the response in subjects that did not develop depression.  Six genes identified in this study have previously been identified as important in depression and neuron development:

• DISC1: linked to schizophrenia, hippocampus, neuron migration
• DYNLT1: linked to hippocampus neuron development
• GCH1: linked to bipolar disorder, depression, dopamine metabolism
• TOR1B: linked to major depression, neurotransmitter regulation
• MEF2A: linked to neuronal and hippocampal development
• ST3GAL: linked to a form of epilepsy and hippocampal cell apoptosis

Cells from psychiatric patients with major depression were exposed to interferon alpha in vitro.  The authors were able to demonstrate a statistically higher induction rate for DISC1, DYNLT1, GCH1 and TOR1B in these cell lines.  MEF2A and ST3GAL5 showed a statistical trend for higher induction in psychiatric major depression subjects compared to controls.

Molecular Structure Interferon Alpha

Additionally, psychiatric inpatient depression in this study showed enhanced production of endogenous interferons.  

Interestingly, all eleven subjects developing depression during interferon alpha treatment responded to initiation of selective serotonin reuptake drug treatment (citalopram).

The authors conclude dysregulation of cytokine inflammatory pathways appear to be working in both interferon-induced depression and depression in psychiatric inpatients.  This dysregulation may be acting through the specific genes identified in this study. 

The link of interferon-induced depression with several genes related to the hippocampus is also intriguing.  The authors note hippocampus neuron loss is found in depression and that antidepressants and lithium stimulate neurogenesis.

Further study of interferon-induced depression is a promising strategy in understanding psychiatric depression.  This approach may yield development of novel drug treatments for the mood disorders.

Photo of green winged teal from the author's files.

Graphic of interferon alpha is from a Wikipedia Commons file authored by Nevit Dilmen. 

Schlaak JF, Trippler M, Hoyo-Becerra C, Erim Y, Kis B, Wang B, Scherbaum N, & Gerken G (2012). Selective hyper-responsiveness of the interferon system in major depressive disorders and depression induced by interferon therapy. PloS one, 7 (6) PMID: 22701688

Fat Gene (FTO) Linked to Alzheimer's Disease Risk

The relationship between obesity and risk for Alzheimer's disease is a controversial area of research.

Several studies have found a prospective increase in risk for Alzheimer's disease in those with obesity.  However, the association has been inconsistent.  Some studies have even found a reduced risk of later Alzheimer's disease in overweight populations.

One method to further investigate the possible obesity-Alzheimer's risk association is through direct genetic studies of genes known to be related to obesity.

Christiane Reitz and colleagues from the U.S. National Institute on Aging recently published this type of study in the journal PLOS One.

They focused on polymorphisms of the Fat and Obesity-Associated (FTO) gene.  The FTO gene is located on the q arm of human chromosome 15.  Polymorphisms associated with FTO intron 1, intron 2 and exon 2 have been linked to increased rates for obesity and also have some evidence of being linked to risk for Alzheimer's disease.

To study this issue in more detail, Reitz and colleagues conducted a single nucleotide protein (SNP) analysis of the FTO gene in Alzheimer's disease subjects and controls.  Two independent samples with a combined sample size approaching 3000 subjects were used in the SNP analysis. Additionally, they conducted a FTO gene expression analysis of Alzheimer's disease cases that had been confirmed by brain neuropathological analysis. 

The key finds from this genetic study were:

• Eight FTO SNP regions were linked to variation in risk for Alzheimer's disease
• Eleven FTO haplotypes were identified that significantly contributed to risk for Alzheimers's disease
• Gene expression studies in brain tissue of Alzheimer's disease subjects showed lower FTO gene expression compared to controls

The authors note their study findings "confirm the association between genetic variation in Intron 1, Exon 2 or Intron 2 in the FTO gene and AD".  (AD=Alzheimer's disease).

They propose several mechanisms for this association.  FTO gene status increases risk for hyperinsulinemia and type II diabetes, known risk factors for Alzheimer's disease.  They note a second potential mechanism where FTO gene status contributes to Alzheimer's disease by a vascular pathology (i.e. hypertension, lipid dysregulation, atherosclerosis).  Finally, they note obesity increases inflammatory markers by increasing adipokines and cytokines that may contribute to risk or severity of Alzheimer's disease.

This is an important study in the ongoing search to understand the effect of obesity on Alzheimer's disease risk.  Exploring genetic mechanisms is a promising approach to complement  epidemiological risk factor studies to advance our understanding of Alzheimer's disease. 

Photo of willet from the author's files. 

Reitz C, Tosto G, Mayeux R, Luchsinger JA, & the NIA-LOAD/NCRAD Family Study Group and the Alzheimer's Disease Neuroimaging Initiative (2012). Genetic Variants in the Fat and Obesity Associated (FTO) Gene and Risk of Alzheimer's Disease. PloS one, 7 (12) PMID: 23251365

Early Brain Inflammation in Lupus (SLE)

I previously reviewed a brain research imaging study of patients with systemic lupus erythematosis (SLE).  This study found evidence of disruption of brain connectivity markers even before any clinical brain symptoms.

SLE is a multi-organ disease known to produce significant neuropsychiatric symptoms.  These symptoms do not affect all patients with SLE as the brain effects are highly variable in this disorder.  Studying patients with early SLE without brain-related symptoms provides insight into the timing, course and prevalence of brain pathophysiology.

A second study from the University of Texas Health Sciences Center at San Antonio, School of Medicine, Research Imaging Institute lends support to the early effect of SLE on the brain.

In this study, 85 subjects with SLE underwent brain positron emission tomography (PET).  PET imaging is a sensitive tool to assess brain glucose metabolism and brain inflammation.

The key elements of the design of this study included:

• Case identification: Newly diagnosed SLE (within 9 months of initial diagnosis) with SLE disease severity measured by the SLE Disease Activity Index (SLEDAI)
• Clinical presentation: Potential subjects with stroke were eliminated, 19 of the remaining sample had neuropsychiatric symptoms (anxiety, depression, psychosis, mononeuropathy or headache symptoms) and 17 had abnormal white matter hyperintensities or atrophy on magnetic resonance imaging (MRI).
• Imaging parameters: Fluoro-deoxy-glucose (FDG) PET imaging analysis by visual inspection and statistical analysis by SLEDIA severity scores

The key findings from the study included:

• 36 of 85 subjects (42%) showed abnormal PET images (decreased glucose uptake) on visual ratings localized to the frontal and parietal brain cortex
• Disease activity ratings correlated with white matter increases in FDG uptake in multiple brain regions including: frontal, parietal and occipital regions, subcortical temporal regions, limbic regions, cerebellar white matter and brain stem areas
• Subjects with neuropsychiatric symptoms showed hypermetabolism in frontal regions and subcortical white matter regions most notably in the corpus callosum regions
• Subjects without neuropsychiatric symptoms showed hypermetabolism that was limited to frontal lobe, anterior cingulate and corpus callosum regions

It is interesting that the study was able to identify specific brain regions (corpus callosum noted in figure to the right) of white matter inflammation in those with anxiety, depression and other neuropsychiatric symptoms.  This supports a specific regional effect of the SLE disease process on production of psychiatric symptoms commonly found in the disorder. 

The author note their study is the first study that demonstrates a "strong association between SLE disease activity and increased FDG uptake indicating inflammation of white matter of newly diagnosed SLE patients".  They argue that this finding suggest that primary brain pathology in SLE is inflammation targeting white matter vascular and microglial structures. 

This is an important study using brain imaging to better understand the mechanisms related to the neuropathology of SLE.  The study supports an early onset of brain inflammation in SLE, often before any neuropsychiatric symptoms.  

For interested readers the complete text article can be accessed by selecting the PMID link below.

Photo of eclectus parrot from the author's files. 

Ramage, A., Fox, P., Brey, R., Narayana, S., Cykowski, M., Naqibuddin, M., Sampedro, M., Holliday, S., Franklin, C., Wallace, D., Weisman, M., & Petri, M. (2011). Neuroimaging evidence of white matter inflammation in newly diagnosed systemic lupus erythematosus Arthritis & Rheumatism, 63 (10), 3048-3057 DOI: 10.1002/art.30458

Can Exercise Reduce Stroke Damage?

This is the fourth and final post is a series focusing on exercise and the brain.  In the first post, I reviewed research documenting the brain's role in exercise fatigue.  The second post examined the hypothesis that aerobic physical activity had a key evolutionary role in the growth of brain size in humans.  The third post focused on animal study research supporting a role for exercise in reducing vulnerability to anxiety by changes in the 5-HT2C serotonin receptor.

In this post, I will review a provocative study suggesting that physical fitness and it's effect on brain vascular health, may limit the brain damage produced by stroke.

Dunn and colleagues at the University of Calgary in Canada conducted an experiment in rats that has recently been published in the journal PLOS ONE.  They noted that in the mammalian brain a chemical called hypoxia inducible factor, or HIF-1alpha, exists that improves "the capacity of tissue to survive low oxygen conditions".   They hypothesized that manipulation of environmental factors that increase HIF-1alpha may serve as a potential mechanism to reduce the brain damage associated with hypoxic events.

In their study, rather than exercise, they exposed rats to hypoxia by placing them in a 1/2 atmosphere environment for three weeks.  This results in brain changes that can also be seen with aerobic exercise including:

• Increase in capillary density by up to 30%
• Increase in brain oxygen partial pressure by up to 40%

The hypoxia-exposed experimental rat group was then compared to a group of control rats following stroke simulation by occlusion of the middle cerebral artery for one hour.  They then compared the stroke outcome of the case and control groups and noted the following key findings:

• Case rats had an increase in total hemoglobin, total hematocrit, capillary density and brain tissue oxygen level prior to the stroke simulation
• Absolute brain volume of stroke damage assessed by magnetic resonance imaging was reduced by 52% in the case group compared to controls
• Case rats showed no motor behavioral deficits 48 hours after the stroke simulation while control rats showed continued motor deficits
• Case rats showed a reduction in brain inflammation post stroke simulation measured by levels of lymphocyte infiltration and number of macrophages

The authors note in their discussion, that one clinical implication from their study relates to humans living in high altitudes under chronic acclimation to hypoxia.  They note there is limited study of stroke in these populations.  There is some human research showing that chronic high-altitude hypoxia with increased hemoglobin and hematocrit might actually lead to a higher incidence of stroke.  However, individuals living at high-altitude might be expected to have a better stroke outcome due to other adaptive brain mechanisms associated with acclimation to hypoxia.

The authors also note their study supports additional research in humans for ways to increase brain neuroplasticity through stimulation of HIF-1alpha.  This might be accomplished by a high baseline rate of aerobic exercise or use of pharmacological agents such as desferoxamine.

Such interventions in high-risk stroke populations (i.e. those who have had a transient ischemic attack) may lead to reduction in brain damage related to future stroke events. 

For the general population, this study suggests one benefit of aerobic exercise might include reduction in both the risk for stroke and a better outcome if one occurs.

For free access to this study, select the PMID link from the reference below. 

Photo of blue jay is from the author's files.

Dunn JF, Wu Y, Zhao Z, Srinivasan S, & Natah SS (2012). Training the brain to survive stroke. PloS one, 7 (9) PMID: 23028788