Cobbers on the Brain

Parkinson’s disease….. A very tough disease to deal with. It seems the more you know about this disease the less you do actually know. Upon learning about PD I found myself asking more questions than I had to start. Lets see what you think…..
Parkinson’s Disease is a progressive disorder that affects the movement of person suffering with the disease. Around 1 million people in the United states suffer from Parkinson’s Disease and each year, around 60,000 new cases are diagnosed. The disease is characterized as a loss of dopamine neurotransmission in the human brain. This results in all of the symptoms characterized with PD such as, tremors, slowed movement, rigid muscles, impaired posture and balance, speech difficulties etc. These symptoms come at the cost of decreased dopamine neurotransmission that fuels the neurons and connections in your brain.
The current treatments for Parkinson’s disease are mainly to treat the symptoms of the disease. L-Dopa or levodopa is an amino acid that is a precursor to neurotransmitters dopamine, norepinephrine and epinephrine. It is able to cross the blood brain barrier and subsequently be converted into dopamine. Early studies showed that L-DOPA can cause sever side effects such as nausea and vomiting. These side effects were occurring because the L-DOPA was being converted into dopamine before it was crossing the blood brain barrier. So researchers added inhibitors of dopa-decarboxylase, which is the enzyme responsible for converted levodopa into dopamine; these inhibitors are called carbidopa and benserazide. L-DOPA medication provides relief to the tremors and shakiness symptoms of Parkinson’s disease. However, long-term use of the drug is shown to induce dyskinesia for 80% of patients that use levodopa. Dyskinesia is a disorder characterized by involuntary muscle movement. As patients progress with the treatment of levodopa the drug effects begin to wear off several hours of some or all doses of the medication.  The reasons these motor fluctuations occur is unclear but is thought to be because of uneven changes in the basal ganglia circuitry resulting in the depletion of both dopamine and the drug treatment. Treatment of levodopa-induced dyskinesia is difficult but treatments used for the disease or dopamine agonists and neurosurgery. The main problems with both Parkinson’s disease and LID are the depletion of dopamine or the lack of dopamine circulating throughout the brain.
So what is the cause for this lack of dopamine Neurotransmission? Why do people get Parkinson’s Disease? Several factors point to genes. Specifically the SNCA gene which encodes for a-synuclein protein. A review article in the frontiers in molecular neuroscience journal discusses this very protein and why it is highly involved in Parkinson’s disease. In a general sense, a-synuclein is being turned on in a specific area on the protein called Serine 129 (S129) which is called hyperphosphorylation. This attributes to the formation of Lewy bodies which consequently, cause the cell to die and thus no dopamine present.

The article also goes into detail of different proteins that are related to the mechanism for the hyperphosphorylation of a-synuclein, such as polo-like kinase, casein kinases, and G protein coupled receptor kinase. However, more research needs to go into this mechanism in order to establish more of an understanding of this phenomenon. In addition to the hyperphosphorylation of a-synuclein, other factors such as the dysredulation of kinase proteins are attributed in the pathogenesis of PD. These kinases include proteins called LRRK2 and PINK1. Like the hyperphsophorylation of a-synuclein these are due to genetic factors and more research needs to be done.
Like I said, this disease is very complicated to understand. It seems like the more you know the less. Hoever, I reall think that this disease needs to be researched more and I believe eventually we can come up with an effective way to treat the causality of the disease not just the symptoms.

Many may wonder the rationale behind this title, and indeed it seems a strange connection to make. But the truth of Alzheimer’s disease lies in insulin receptors, and eventually insulin resistance. These receptors are, of course, localized to the brain, and not the pancreas (as in the case of diabetes as we know it). To understand the idea of Alzheimer’s as an insulin disorder, we must initially observe and understand the properties of the receptor on a cell.

Insulin is, at its very simplest, a growth factor. This means, in short, that it promotes cell longevity and proliferation. Growth factors could lead to a plethora of anti-aging medicines. And just so, we can also realize that an enormous risk factor for Alzheimer’s disease is aging. Certainly, if aging is happening, insulin reception is not (or at least not as well as it normally does). This is the first connection of Alzheimer’s with insulin resistance.
But if that were the only connection, it would likely be coincidence. We must delve deeper into the causes of Alzheimer’s, or at least the causes doctors have identified thus far. The beta-amyloid plaque has been used as the sure-sign of Alzheimer’s for decades. This is an aggregation of protein that essentially clogs up neurons and eventually causes their degeneration. But what could these beta-amyloids have to do with insulin resistance? The answer lies in competition.

Many body receptors have a certain ligand/molecule they like to bind to, but nothing is perfect, and other molecules can also bind instead. It has been proposed that beta-amyloid plaques can bind to insulin receptors on neurons and essentially cause them to not recognize when insulin is actually present. This leads to the opposite effect of the insulin “growth factor” and instead causes the cell to degenerate. Even further, since the cell is recognizing that many of these receptors are full of binding molecules, it “decouples” the receptors from the membrane, making insulin signaling even more difficult.
In reverse, studies have indicated that low levels of insulin reception cause levels of beta-amyloid plaques to increase, exacerbating the problem. There is still no consensus on whether low insulin reception initially creates high levels of beta-amyloid, and this feedback causes lower levels of insulin reception, or whether high levels of beta-amyloid begin the process. Either way, this emphasizes the “insulin resistance” that is so common with diabetes.

All of this culminates in the treatment for Alzheimer’s. A newly-prescribed medicine is intranasal insulin spray. By introducing the molecule to the nasal membranes, it quickly makes its way into the brain, increasing insulin levels. These increased levels might be able to “push” the beta-amyloid plaques out of the insulin receptors and allow normal binding and signaling to occur. Whether this is actually the case is unknown, but the medicine shows promising results.
Is this just one more reason to eat a healthy diet and exercise frequently? Perhaps. But in the end, the choice is our own. We must simply realize that our actions today have an effect on us for the rest of our lives.

In the United States there has been much discussion about drug use over the past several decades.  Of course this all started with the War on Drugs which was first mentioned by President Richard Nixon in 1971.  However, the United States has been combating drugs since the Harrison Narcotics Act of 1914.  This ultimately led up to the formation of the Bureau of Narcotics in 1930.  Since then there has been many new drug laws being put on the books.  Ultimately the drug scare arose in the Comprehensive Drug Abuse Prevention and Control Act of 1970.  This led to the first mandatory minimums and some people would argue to the rapid rise of incarceration in the United States.  That is a topic for another post.

In the modern day and age it is estimated in 2013 that approximately 24.6 million Americans (9.4% of the population) had used drugs in the past month, according to the National Institute on Drug Abuse.  This was an increase from the 8.3% of the population in 2002.  However, one important thing to note is that the National Institute on Drug Abuse estimates that the number of people that are dependent on drugs is decreasing.  Even if this is the case it is still important to understand what is occurring in the brain and how someone can get help if they need it.

First it is probably best to explain what occurs in the normal brain.  In the normal brain there are dopamine receptors and glutamate receptors located on medium spiny neurons.  Medium spiny neurons are GABAergic inhibitory neurons that comprise about 95% of all neurons in the striatum/basal ganglia.  The receptors discussed above bind dopamine and glutamate, respectively.  These molecules when released bind to their respective receptor and cause downstream signaling that can lead to memory formation, motivated behavior, reward learning consolidation, and synaptic remodeling.  It is important to remember that this is a natural process and occurs every day.

Now when drugs of abuse enter the body they alter dopamine and glutamate neurotransmission.  The primary receptor targeted is the dopamine receptor because of its primary role in the reward system and their interaction with glutamate receptors to signal reward learning.  Underlying regulatory mechanisms of these receptors become altered and ultimately lead to functional and structural neuroplasticity.  Basically, what I am saying is that drugs can alter the behavior and function of the receptors to promote the addictive state.  This ultimately can lead to hyper-synaptic remodeling, overwhelming reward learning, and uncontrollable drug-seeking and drug-taking.  This leads to a never ending cycle that can cause an addict to have uncontrollable urges to obtain and take drugs.  Inevitably this may lead to such a reliance on the drug that the addict may ultimately die to the body’s dependence on it.  One important thing to note is that since the drug causes structural and functional alterations to the brain, withdrawals can be severe and going “cold turkey” may actually do more harm than good.
If you know anyone that is addicted please reach out to help them to prevent these scenarios.  Get them help and be there for them as support to make it through the process.

Autism spectrum Disorder (ASD) is a mental health disorder that is characterized with the difficulty with social skills, repetitive behaviors, and most forms of communication and uniqueness of strengths. Autism is a disease that has many different forms that are in a range of severity, which is why it is called autism spectrum disorder. The different forms of autism are the result of different combinations of genetic and environmental factors. It is currently accepted that ASD is contracted through polygenic inheritance, meaning that there are multiple genes that can contribute to the formation of the disorder. The disorder is usually diagnosed between 14 months and by age 3. Diagnosing ASD can be very difficult because there is no physical medical test such as a blood screening to validate the presence of the disorder. Diagnosing takes two steps of Developmental Screening and Comprehensive Diagnostic Evaluation. These steps include evaluating their behaviors and progression through development. ASD can include associated neurological disorders such as mood disorders and systemic disorders such as immune dysfunction and GI tract problems. The symptoms of autism are usually lifelong but can be managed to reduce symptoms and improve skills and abilities.

A review Article in the Frontiers of Psychiatry journal discuses more on the factors linked to ASD. Although the polygenic genetic inheritance is predominately responsible for the development of autism it does explain the whole story. The review article discusses the many different environmental factors such as immune system abnormalities and Zinc deficiency. The picture below expresses all of the difficulties and risk factors of Autism.

Immune system abnormalities are linked to prenatal stress, prenatal viral infection, and parental age at the time of pregnancy. During prenatal stress the mother releases corticotrophins from her adrenal gland, which can pass through the placenta and cross the blood brain barrier causing inflammation in the fetus’ hippocampus. Parental age is associated with the increase rick of autoimmune disorders around the age of 30 years old which can affect the fetus and cause immune system abnormalities.
Zinc deficiencies are said to be caused by prenatal malnutrition, heavy metal poisoning, and maternal diabetes. Zinc is a very important molecule that regulates many different functions in the body and is a structural component in the body. Thus, indicating that a deficiency of Zinc could be related to immune deficiency and increase risk of infections.
Although the causes and rick factors for autism have been displayed, the underlying causes and specific biological abnormalities are k=not well known. Many people throughout the world suffer from Autism. Families struggle with finding and adapting to their family member that suffers from the disorder. I believe that more research and more people should investigate the causes and mechanisms that are responsible for autism spectrum disorder.