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

Donepezil Improves Dementia With Lewy Bodies

Dementia with Lewy bodies (DLB) is a type of dementia less common than Alzheimer's disease.  However, Lewy bodies (brain neuron deposits of the proteins alpha-synuclean and ubiquitin) are found in up to 10 to 15% of individuals dying of dementia.

DLB is known to deplete brain acetylcholine and dopamine neurotransmitter levels in the brain.  This leads to a clinical syndrome characterized by both cognitive decline and motor symptoms similar to Parkinson's disease.

DLB may be difficult to distinguish from Alzheimer's disease but typically exhibits fluctuations in cognitive function, visual hallucinations, visuoperceptual impairment and concurrent motor symptoms.

Few clinical trials have targeted DLB due to it's relative infrequency and diagnostic classification.  A Japanese study of 148 subjects with DLB recent found support for the effectiveness of the Alzheimer's drug donepezil.

Mori and colleagues conducted a randomized clinical trial with the following key elements in the research design:

• Subjects: Met probable DLB diagnosis using structured criteria, no Parkinson's disease diagnosis more than one year before onset of dementia, no evidence of focal vascular disease on CT or MRI
• Drug administration: Double-blind randomization of donepezil 3 mg, 5 mg, 10 mg or placebo for 12 weeks
• Outcome measures: Minimental state exam (MMSE) scores, attention, executive function and visuoperceptual cognitive function from the Wechsler Memory Scale-Revised (WMS-R), tests for verbal fluency and agnosia.  Ten behavioral domains were also assessed.  Clinicians blind to treatment rated global clinical status.  Caregivers rated burden of care.  Motor symptoms were assessed using the Unified Parkinson's Disease Rating Scale.
• Statistical analysis: Last observation carried forward analysis on all subjects with at least one valid post-treatment measurement

This trial found significant therapeutic effects for donepezil across a variety of DLB disease domains (doses statistically associated with improvement compared to placebo)

• Minimental status exam: 5 and 10 mg
• Clinician global improvement scores: 3, 5 and 10 mg
• Behavioral scores for hallucinations, cognitive fluctuation, delusions, apathy and depression: 5 and 10 mg
• Caregiver burden scores: 10 mg

Photo of two brain Lewy Bodies 

Donepezil was fairly well tolerated in this study sample with 3 to 8% of the active drug groups discontinued due to adverse effects.  This rate was not different than placebo withdrawals.

The authors conclude that their study provides support for the effectiveness of donepezil across a variety of clinical domains.  They note the study supports using a 10 mg dose if tolerated.  

Recruiting clinical sample sizes sufficient to study treatment options in DLB is not easy.  This makes the current study an important one.  Additional clinical trials have also found support for rivastigmine, galantamine and memantine for DLB.  However, there is likely to be a paucity of clinical trials for DLB in the future relative to the number of trials in Alzheimer's dementia. 

Individuals with additional interest in this clinical trial can access the free full-text of the study by clicking on the PMID link below.

Photo of cinnamon teal duck is from the author's files.

Photo of Lewy bodies from the Wikipedia Commons file authored by Dr. Andreas Becker

Mori E, Ikeda M, Kosaka K, & Donepezil-DLB Study Investigators (2012). Donepezil for dementia with Lewy bodies: a randomized, placebo-controlled trial. Annals of neurology, 72 (1), 41-52 PMID: 22829268

Oxytocin and Grandparent Attachment

I a previous post I summarized a review of the emerging research field of oxytocin and human attachment.

This research supports a key role for oxytocin in reproduction and parental infant bonding.   The above mentioned review emphasized the important role of gender, genetic and early environment in the effect individual human variation in oxytocin response.

One additionally related important research topic relates to the effect of ageing on oxytocin-related systems.  Huffmeijer and colleagues from Leidenand Eramus University recently published a review on this topic in the journal Gerontology.

The authors of this review note the importance of oxytocin in parent-infant bonding and argue by extension this system is probably important in grandparent-grandchild bonding.

However, the review notes there is a paucity of research focusing on the age-related effects on the human oxytocin system.  There is extensive data linking oxytocin with prosocial maternal and paternal behavior towards infants.  There is no research examining the role of the oxytocin system in grandparents.

The limited study of the animal human oxytocin system and ageing points to a few key findings:

• Animal studies support a decreased level of oxytonergic activity with age--the results in humans on this area have been mixed
• Older animals with reduced oxytocin activity still have a prosocial response to exogenously administered oxytocin
• The brain amygdala-limbic system has rich neural connections with oxytocin-related neurons but  amygdala volumes decline with age (this effect is more pronounced in Alzheimer's disease)
• With ageing, amygdala connectivity increases with frontal regions but decreases with posterior brain regions
• Age-related amygdala changes may contribute to the decline in emotional recognition with age seen in humans

The authors conclude that the effect of oxytocin in older humans cannot simply be assumed to be the same as in younger adults.   Due to the effects of ageing, oxytocin response (and adverse effects) may be quite different in elderly humans.

Oxytocin research needs to include a focus on the elderly including grandparent-grandchild bonding.  Many children are primarily raised by their grandparents.  Understanding the dynamics of the oxytocin system in the elderly has practical implications for many families.

Readers with more interest in this topic are directed to the free full text manuscript that can be accessed by the PMID

Photo of reddish egret from the author's files.

Huffmeijer R, van Ijzendoorn MH, & Bakermans-Kranenburg MJ (2013). Ageing and oxytocin: a call for extending human oxytocin research to ageing populations - a mini-review. Gerontology, 59 (1), 32-9 PMID: 22922544

Oxytocin and Human Attachment

In a previous post, I summarized a recent review on the neuroscience of human attachment. 

This review highlighted research related to the human bonding and social interactions.  Attachment ability shows significant variability in humans with insecure attachment styles contributing to risk for some mental disorders.     

The neuroanatomical framework for social processing is being investigated with brain imaging techniques.

Hormonal factors including the role of oxytocin also play a key role in social processing.  

Kai MacDonald recently published a review of the prosocial role of oxytocin in attachment.  This review highlighted individual factors that influence variability in oxytocin response.

Molecular Model of Oxytocin

Oxytocin is a central nervous system nine amino acid peptide that has both central and peripheral effects.   Oxytocin can be administered through intranasal mist administration.

The biological effects of oxytocin are complex and include stimulation of uterine contraction during labor, stimulation of breast milk letdown during nursing and modulation of sexual arousal and response.

The effects of oxytocin in social interactions include:

• increases in strength of human bonding
• decreases in anxiety in social situations
• increases in the trust in others 
• increases in calmness and contentment in the presence of a mate

MacDonald notes that individuality in response to oxytocin can be separated into three categories.

Gender: Women appear to be more responsive to the effects of oxytocin.  This may be due to the role of estrogen.  The presence of estrogen upregulates oxytocin and oxytocin receptor production.  Oxytocin response in women is dependent on female hormonal phase with more response during periods of higher estrogen levels.  Administration of intranasal oxytocin has a stronger effect on increasing prosocial behavior in women compared to men. 

Genetic Variation in Oxytocin Receptor Gene and CD38: Genetic variability in the oxytocin receptor gene modulate response to oxytocin with some alleles linked to stronger and weaker responses.  Additionally, genetic variation in the ectoenzyme CD38 have similar effects.  CD38 contributes to the biologic process of oxytocin secretion.  Specific combinations of oxytocin receptor and CD38 genes may contribute to clinical deficits in attachment, stress response and anxiety.

Early Childhood Attachment Environment: Early traumatic experiences appear to impair the development of the oxytocin system.  This may be due to more general adverse effects on neuroplasticity.  Parents with a personal history of childhood abuse are less responsive to the prosocial effects of intranasal oxytocin.  Early traumatic experience may unfortunately contribute to lifelong attachment impairment through this epigenetic effect.

Future research in the role of oxytocin and the oxytocin receptor in a variety of mental disorders will be important.  Intranasal oxytocin clinical trials will be coming in anxiety disorders, stress disorders and disorders of social interaction such as autism and schizophrenia.  Understanding the factors associated with variability in oxytocin response will be key in interpreting the results of future research.

Readers with more interest in this topic can access the free full-text manuscript by clicking the PMID link below. 

Photo of blue heron from the author's files.

Molecular model from the Wikipedia Commons File authored by MindZiper.

Macdonald KS (2012). Sex, receptors, and attachment: a review of individual factors influencing response to oxytocin. Frontiers in neuroscience, 6 PMID: 23335876

Neuroscience of Human Attachment

Attachment is the ability to form human relationship bonds.  Individuals vary in their ability to develop social relationships.  The ability to form secure human relationships plays a key role in successful personal and occupational development.

Attachment theory evolved over 50 years ago.  This theory proposes all humans have an innate biological mechanism that supports social engagement.  This engagement is necessary during infancy to encourage nurturance and provision of a safe environment.

Bowlby is credited with describing attachment theory and he proposed three developmental styles of attachment.  These three attachment styles included:

• Secure attachment: an ability to easily seek and obtain support from others.  This style promotes strong bonds with parents, siblings, friends and later in life allows for bonding with a mate.
• Anxious attachment: a insecure attachment style where emotional support has often been inconsistent during childhood.  Individuals with anxious attachment develop hypersensitivity to interpersonal rejection and have anxiety in social environments.  They may develop a needy approach to relationships constantly seeking reassurance of the strength of social supports.
• Avoidant attachment: an insecure attachment style that may have been characterized by early social adverse environments.  Individuals with insecure attachment style built a wall around their life denying a need or interest in human interactions.

Emerging research in social neuroscience is providing a better understanding of brain mechanisms related to human attachment.  Vrticka and Vuilleumier of the University of Geneva in Switzerland recently published an excellent review of the neuroscience of human attachment in the journal Frontiers in Human Neuroscience.

The authors of this review begin by noting research showing attachment has profound effects in the domains of emotion processing, selective attention and memory.  Insecure attachment individuals are hypersensitive to changes in the expression of emotions in others.   Anxious attachments individuals have enhanced attention to threatening cues.  Avoidant attachment individuals inhibit the memory processing of distressful information.

The authors note social approach behavior appears regulated in specific brain regions including the ventral tegmental area, pituitary, striatum and ventral medial orbitofrontal cortex.  Social aversion appears to be regulated through the amygdala, hypothalamus, insula, anterior cingulate and anterior temporal poles.

Social behavior appears to regulated through both affective evaluation (emotional mentalization) and cognitive control systems (cognitive mentalizations).  These systems interact with hormonal and neurotransmitter domains in influencing social interactions.

The neuroscience of human attachment includes emerging research showing the importance of mental state representation of others (theory of mind).  Mothers with high sensitivity to the cries of their own infants during the post partum period show increased gray matter and fMRI BOLD responses in the prefrontal cortex, superior temporal sulcus and fusiform gyrus.  These regions have been identified as key components engaged in being aware of the emotional states of others.

The authors conclude that the neuroscience of human attachment is beginning to outline key common and distinct elements in avoidant and anxious attachment styles.  Attachment styles appear to be influenced by both environmental history as well as neurobiological factors, some of which may have strong genetic contributions.

Future neuroscience of research will need to move experiments into the "real world" and not be limited to task in brain scanners.  Additionally, future research needs to target early intervention studies in children with attachment problems to find the most effective methods to improve social outcomes.

Readers with more interest in this review are directed to the DOI link below where the free full text manuscript can be found.

Photo of great white egret from the author's files.

Vrtička, P., & Vuilleumier, P. (2012). Neuroscience of human social interactions and adult attachment style Frontiers in Human Neuroscience, 6 DOI: 10.3389/fnhum.2012.00212

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

Lifestyle Factors and Risk of Alzheimer's Dementia

The number of individuals suffering from Alzheimer's disease is rapidly increasing throughout the developed world.

A significant portion of this increase is explained by demographic trends as the Baby Boomer generation progresses through the high-risk age categories for Alzheimer's and other dementia.

It is important to understand potentially modifiable lifestyle risk factors that may stimulate a valid public health prevention program.

An important recent study examined lifestyle factors and risk for dementia among a cohort of Japanese American men.  

Gelber and colleagues followed a cohort of 3468 men over a period of 25 years.  The study focussed on the emergence of dementia including both Alzheimer's disease and vascular dementia.

The key components of the study design in this study included:

• Cohort characteristics: Men of Japanese ancestry born between 1900 through 1919 living in Oahu, Hawaii
• Dementia diagnosis: The cohort received regular neuropsychological screening with cognitive deficits prompting neurologist referral.  The study neurologist and two physicians made decisions about a diagnosis of Alzheimer's disease or vascular dementia using clinical information, neuropsychological testing, blood tests and brain imaging (CT or MRI) results. 
• Modifiable risk factor variables: BMI category, smoking status, physical activity level, dietary intake and alcohol consumption.  A global lifestyle low-risk group was identified that demonstrated the presence of a low risk on all four modifiable risk factors: BMI less than 22.6, never smoking, 3 or more hours per week of physical activity and high dietary score (more vegetable/fruit intake and moderate alcohol intake).

A total of 223 cases of dementia were identified during the follow up period.  The majority were assigned a diagnosis of Alzheimer's dementia (n=117), with vascular dementia a close second in frequency (n=78).  Twenty eight cases were given another cause for dementia.

High BMI, smoking and low physical activity all increased risk for overall dementia diagnosis with the following estimates for odds ratio of those with risk factor compared to those without:

• BMI: Odds ratio= 1.87
• Smoking: Odds ratio= 1.48
• Low physical activity: Odds ratio= 1.59

Diet score did not show a statistically significant association with overall dementia risk.

However, when specific type of dementia was examined, none of the individual lifestyle factors proved to be statistically associated with Alzheimer's disease risk.  BMI, smoking status and low physical activity were individually linked to increased risk for vascular dementia at odds ratios estimated at high levels than in the overall dementia group.

Men positive for all four lifestyle factors showed a 64% reduction in dementia risk, but this was primarily in reduction of risk for vascular dementia.

Finding no association between lifestyle factors and risk for Alzheimer's disease is somewhat discouraging.  It suggests that genetic factors, i.e. APOE gene status, may be resistant to the moderating effects of lifestyle changes.  

However, the study supports promotion of a healthy lifestyle approach in mid-life to reduce risk of vascular dementia.  Adopting all four factors in a healthy lifestyle promotes a significantly reduced risk of later dementia diagnosis.

Readers with a more detailed interest in the study can access the free full text article by clicking on the PMID link below.

Photo of burrowing owl from the author's files. 

Gelber RP, Petrovitch H, Masaki KH, Abbott RD, Ross GW, Launer LJ, & White LR (2012). Lifestyle and the risk of dementia in Japanese-american men. Journal of the American Geriatrics Society, 60 (1), 118-23 PMID: 22211390