Stem Cell Research Provides New Approach to Study Bipolar Disorder

 

Researchers have detected mitochondrial abnormalities, and differences in neuronal firing, in young neurons from patients with bipolar disorder by using induced pluripotent stem-cell (iPSC) technology. These stem cells are created from patient’s skin cells (fibroblasts) or from patient’s white blood cells (lymphocytes). It is possible to take skin cells or white blood cells and reverse engineer them back to the state where they have the ability to grow into different types of cells (basically back to the very early embryo state when the original template cells are just beginning to turn into different types of cells.)  Then these stem cells can be grown in the lab and encouraged to become neurons. By imaging these created neurons from people with and without bipolar disorder, researchers have seen a difference in neuron firing between people who respond to lithium treatment vs those who don’t respond to treatment. This hyperexcitability activity of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment.

Mitochondria are structures found within all cell types, and they are the organelles that help provide energy for the cells, along with other important functions. Mitochondria contain their own DNA separate from the cell’s nuclear DNA. Mitochondria DNA is mainly inherited from the egg, therefore the maternal side of the family. In one study, in about 80% of the bipolar patients, hippocampal mitochondria were smaller than even the smallest of the control subjects’ mitochondria. The hippocampus is the elongated ridges on the floor of each lateral ventricle of the brain, thought to be the center of emotion, memory, and the autonomic nervous system. Differences in expression of the genes in the mitochondria were also found between subjects and controls. Is it possible then that a greater predisposition to bipolar disorder could be influenced by the maternal family side?

Brain research is complicated because tissue is difficult and dangerous to extract, and studying brain tissue after death doesn’t give us a good picture of cause and effect across the lifetime. In post-morteum brain tissue, abnormalities could be due to a number of different environmental exposures (such as drug treatment) or trauma such as concussions that are difficult to control in living subjects. A model that does not use living subjects is difficult to create.

However,  researchers have been able to use stem cell from patients to create tissue in the lab for study.  They can take stem cells and “engineer” them to create many different types of tissues; in this study they use patients’s stem cells to create neurons. The hyperexcitability of the neurons is one early indicator of bipolar disorder, and this model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

Here is a link to the study in Nature:

https://www.ncbi.nlm.nih.gov/pubmed/28242870

And a link to one of the earlier studies:

https://www.nature.com/nature/journal/v527/n7576/full/nature15526.html

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C4 and Schizophrenia

When I hear “C4” I immediately think of the television series “Lost” and explosive material. C4 is also the shortened name of Complement component 4- one of a group of proteins that work together to make the immune system.  The C4 gene that codes for this protein is on Chromosome 6, and everyone has different variations in this gene, referred to alleles. Researchers from the Broad Institute, Harvard Medical School and Boston Children’s Hospital, recently published a study with a hypothesis that a key cause of schizophrenia involves different alleles of this gene. The researchers noted that people who had schizophrenia were more likely to have a certain variation that promotes neural “pruning.”

Pruning is part of normal brain development during childhood, and especially during adolescence. Pruning is the process where synapses in the brain are eliminated. It is believed that the purpose of synaptic pruning is to remove unnecessary neuronal structures from the brain; as the human brain develops, the need to understand more complex structures becomes much more pertinent, and simpler associations formed at childhood are thought to be replaced by complex structures.

It may be that different alleles cause different amounts of pruning. Perhaps less pruning, which could lead to too much information being retained, could be a risk factor for mental health.  This could be one of the factors contributing to schizophrenia- there are likely many genetic and environmental factors. More knowledge of these mechanisms may be helpful in creating or refining treatment.

Here is the link to the study’s abstract:

http://www.nature.com/nature/journal/v530/n7589/full/nature16549.html#access

Microbiome and Major Depression (i.e. Bacteria and Mood)

probiotics

Embryos develop from a small ball of cells to a flat sheet of cells. This sheet rolls up into a tube. One end of the tube becomes the brain, the other end becomes the digestive tract.

There is communication along this brain-gut axis via nerves, hormones and the immune system (via the blood). And I’m probably not the only person who asked out loud for my stomach to stop growling, so there’s a cognitive connection too :).

There is some evidence that our intestinal micro biota, the bacteria that we harbor that aids in digestion, actually communicates with our brain via the immune system. Scientists are also investigating the hypothesis that modification of microbial ecology, for example by supplements containing microbial species (probiotics), may be used therapeutically to modify stress responses and symptoms of anxiety and depression.

A recent study from the Netherlands reported the first evidence that the intake of probiotics may help reduce negative thoughts associated with sad mood and suggest that probiotics supplementation warrants further research as a potential preventive strategy for depression.

The study was small, 40 people total for cases and controls, but it certainly works as a pilot study for more research.

The study was published with open access- you can read it here:

http://www.sciencedirect.com/science/article/pii/S0889159115000884

This also adds to the evidence that chocolate is good for us! Also, probiotics do not have to be taken as supplements. Besides chocolate, probiotics are found in fermented foods such as kim chi, and in yogurt.

http://www.webmd.com/digestive-disorders/features/what-are-probiotics

23andMe Ordered by FDA to Stop Marketing Genetic Tests

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I’ve been on the fence about 23andMe’s personalized genetic tests.I like that it’s a cheap way to access your own DNA- which many of us may never have the opportunity to do. On the other hand, many of the gene allele interpretations are based on very small research studies that may not apply to the general population. The test has risk predictors for mental health conditions like schizophrenia, bipolar disorder, depression and alcholism. I have looked at the studies that 23andMe bases their intrepretations on, and I find them lacking. I would not recommend that anyone make decisions on treatment, medication, or personal life decisions such as having children, on such results.

23andMe is backed by Google, so obviously there is a lot of money behind the company. I think it is very important that the FDA takes this stand, and demonstrates to the American public that profit has to take a backseat to safety.

Alberto Gutierrez, director of the FDA’s Center for Devices and Radiological Health, said in a letter to the company made public on Monday that 23andMe had failed to address concerns raised on multiple occasions since the agency began working with it on compliance in July 2009. He commented that the the FDA does not have any assurance that the firm has analytically or clinically validated the tests for its intended uses.

23andMe responded  “We recognize that we have not met the FDA’s expectations regarding timeline and communication regarding our submission,” the company said in a statement. “Our relationship with the FDA is extremely important to us and we are committed to fully engaging with them to address their concerns.”

23andMe has plans to start markeing to the public via televison. As far as I can see from the report, they will not be able to do this immediately.

Here is a link to more information:

http://www.theguardian.com/science/2013/nov/25/genetics-23andme-fda-marketing-pgs-screening

 

Do People With Mental Illness Age Faster Than People Who Are Unaffected?

Last week I attended a talk by Dr. Owen Wolkowitz, psychiatrist and professor at UCSF Langley Porter Institute.  His answer to this question is “yes.”  He refers to mental illness as “disorders of the whole body.”

There is data that people with mental illness die, on an average, 25 years earlier than people in the general population.  30-40% of people with mental illness die of suicide or accidents, but the remaining 60% die of natural causes earlier than the general population.

There are some obvious reasons as to why:

1)      Poor lifestyle – smoking , drinking, illicit drug use, bad nutrition

2)      Poor access to healthcare, poor medication compliance, homelessness

3)      Medication side effects such as obesity, increased lipids

Less obvious are some of the behind the scenes factors, such as inflammation due to stress.

It is also possible that mental illness actually changes our DNA, in particular our telomeres. Telomeres are the pieces of DNA at the ends of the chromosomes. Each time a cell divides, it duplicates its chromosomes, and a little bit of the end of the chromosome is lost. At some point, too much information is lost, and instead of dividing, the cell dies. This is the aging process in a nutshell. We can’t have cells that live forever (that’s what happens in cancer, the mechanism gets screwed up and the cell keeps dividing forever.)  Telomerase, the enzyme that adds the telomeres to the end of the chromosome, can be measured in the blood, and can be used as a marker for aging.

telemore-image2

Studies have been done on telomeres of people with mental illness. Studies of people with depression show telomere shortening. Adults with early life trauma have shorter telomeres, demonstrating perhaps a “scar in the brain.”  There’s evidence that people with schizophrenia who take anti-psychotic meds have longer telomeres than people with schizophrenia who aren’t taking any medication- demonstrating a potential benefit of medication. It’s possible that anti-psychotics can have an effect by reducing inflammation and oxidative stress.

The good news is that telomeres can lengthen. Factors known to extend telomere length to a healthy level include exercise, dietary restraint, multivitamins, folate, Omega 3’s, stress management, statins, estrogen and social support. So while good nutrition, good sleep, exercise and avoidance of illicit drugs are good plans for everyone, they are especially important for people with mental illness, or people at risk for mental illness.

Link to article on telemore shortening:

http://www.sciencedirect.com/science/article/pii/S0006322306001363

New Clues to the Cause of Schizophrenia

nerve-6

A research study published Aug 25th on Nature Genetics online has found 22 genetic risk loci for schizophrenia, 13 of which are new discoveries. Genes at these loci suggest involvement of two pathways- the calcium signaling pathway and the “micro-RNA 137” pathway. Calcium plays a major role in normal cell functioning. It is a signaling molecular involved in synaptic activity (the junction between nerve cells where neurotransmitters like serotonin are released), cell to cell communication and cell adhesion. In the brain, calcium is fundamental in the control of synaptic activity and memory formation. Calcium signaling disturbances are already known to be involved in different brain diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. The Micro-RNA 137 pathway is involved in neuronal development. This association of development and regulation of brain nerve cell genes with schizophrenia may further understanding and help with new treatments for the disease.

The lead author of the study, Patrick F. Sullivan, MD , commented:

“This study gives us the clearest picture to date of two different pathways that might be going wrong in people with schizophrenia,” Sullivan said. “Now we need to concentrate our research very urgently on these two pathways in our quest to understand what causes this disabling mental illness.”

The link to the study is here:

http://www.nature.com/ng/journal/vaop/ncurrent/full/ng.2742.html

Can We Predict Who Will Attempt Suicide?

suicide

 

Scientists at the Indiana University School of Medicine are looking to answer this question by analyzing proteins in the blood of patients who have mood disorders such as bipolar disorder and schizophrenia/schizoaffective disorder.  They looked at the amount of these proteins in the blood when the person was in a suicidal state vs. a non-suicidal state. A significant difference in expression was found for proteins coded for by the genes SAT1, PTEN, MARCKS and MAP3K3.  SAT1 is involved in the Omega-3 signaling pathway. MARCKS is involved in sleep–wake cycles, as well as mood regulation. PTEN is involved in regulation of the cell cycle and MAP3K3 directly regulates the stress-activated protein kinase SAPK.

Their conclusion was that “suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptosis.” Apoptosis is the natural programmed cycle of cell death. The researchers wrote “our results have implications for the understanding of suicide, as well as for the development of objective laboratory tests and tools to track suicidal risk and response to treatment.” At some point this information could be used to predict and differentiate future and past hospitalizations due to suicidality in patients with bipolar disorder and psychosis (schizophrenia/schizoaffective disorder).

 

The link to the complete article is here:

http://www.nature.com/mp/journal/vaop/ncurrent/full/mp201395a.html