Monthly Archives: August 2016

Book Review: “The Brain That Changes Itself”

“The Brain That Changes Itself” is a nonfiction book written by psychiatrist Dr. Norman Doidge. The book is focused around the topic of neuroplasticity, the ability of the brain to rewire itself in order to adapt to changing situations. Doidge writes largely in a biographical style, providing rich detail about the lives and careers of some of the field’s most prominent researchers, many of whom were initially rejected by their peers for their controversial research. As Doidge describes, it took nearly a century for neuroscience to transition from believing the brain was static after birth to the now-accepted knowledge that the adult brain continues to reform its neural connections every day. In addition to humanizing the field’s researchers, Doidge also chronicles the stories of patients who have used the power of neuroplasticity to improve their neurological conditions, including stroke, learning disorders, phantom limb syndrome, and more.

The informal and personable style of Doidge’s writing makes the book very pleasant to read. The book has an unusual mix of clinical case studies, scientific research, and personal biography. All information is given at a level that the average reader could easily understand and even apply to their own life. I don’t entirely buy into Doidge’s very Freudian views on psychoanalysis, but this didn’t distract me too much from the main thread of the book. After reading “The Brain That Changes Itself,” I felt more empowered than ever in my ability to control my brain through daily actions. This would be a great read for anyone who is affected by a neurological condition, as it demonstrates the amazing power of neuroplastic therapy to improve neurological symptoms.

Overall rating: 4.5 stars

 

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Immune System Protein Reverses Alzheimer’s Disease in Mice

Background

The immune system is closely involved with the pathology of Alzheimer’s disease. In healthy brains, immune cells called microglia work to destroy or clear away harmful substances in the brain. However, the gradual accumulation of a toxic protein called amyloid-beta can disrupt microglial function, causing them to release potentially-harmful inflammatory molecules. The inflammatory pathways activated by microglial signaling contribute to the development and progression of Alzheimer’s disease. A 2012 study showed that inhibiting some of these pathways can combat Alzheimer’s in animal models.

A protein called interleukin-33 (IL-33) is an important mediator of inflammation and is involved with multiple infections and autoimmune diseases. Genetic studies have demonstrated that people with certain variants in the IL-33 gene have an increased risk of Alzheimer’s. Additionally, the brains of people with Alzheimer’s have decreased levels of IL-33 gene expression compared to healthy brains. This has led some to speculate that lower levels of IL-33 may promote the buildup of amyloid-beta that occurs in Alzheimer’s disease.

New Study

Research published recently in the journal PNAS attempted to address whether IL-33 could be a therapeutic target for Alzheimer’s. The researchers used mice that were genetically designed to simulate Alzheimer’s pathology and injected them with the IL-33 protein. After two days of injections, the mice showed significantly improved long-term potentiation, the process strengthening connections between neurons that is critical for learning and memory. After seven days, the mice also had an improved response to fear conditioning, a test of contextual memory retrieval. Additionally, the mice had approximately 20% lower levels of amyloid-beta plaques in their brains. The researchers demonstrated that this reduction was due to the activation of alternate inflammatory pathways, which enhanced the ability of microglia to destroy the plaques.

Additional research is needed to determine the mechanism by which IL-33 improves Alzheimer’s symptoms in these mice. It is also unclear whether these results will generalize to humans, as the mouse models are more similar to human early-onset Alzheimer’s disease and bear significant differences from the more common late-onset form. However, the research presents an intriguing new approach to combatting Alzheimer’s by enhancing the brain’s own immune system.

 

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The Genetics of Alzheimer’s Disease

If you’d asked me at age sixteen what my life’s dream was, I’d say it was to discover the Alzheimer’s gene. Statements like that one would make any geneticist cringe, or chuckle, or both. It’s a common misconception that one “bad” gene causes Alzheimer’s disease, and that discovering this gene would lead to a cure. The fact of the matter is that Alzheimer’s disease, and most other diseases, are so much more complicated than a single gene. There are a multitude of genes involved, as well as an entire spectrum of non-genetic influences. To try and make sense of this confusing topic, I’ve written this article as a brief overview of the genetics of Alzheimer’s disease.

Note: If you’re not familiar with the science of Alzheimer’s, you may want to look at Alzheimer’s Disease: A general overview to provide a bit of background.

The Amyloid-Beta Protein

Genes encode proteins, and so to understand the role of genetics in Alzheimer’s, we need to first look at the proteins involved. Senile plaques are considered one of the main hallmarks of Alzheimer’s disease. These toxic protein clumps accumulate in the brain over many years and eventually lead to the death of neurons, causing the brain to physically shrink. They form when a protein called amyloid-beta becomes “sticky” and begins to adhere to itself, forming large star-shaped clumps.

Amyloid-beta begins as a longer protein called amyloid precursor protein (APP). APP is usually cut by enzymes called secretases to form a non-sticky version of amyloid-beta that is 40 amino acids long. However, if APP is cut by a different set of secretases, a longer version of amyloid-beta with 42 amino acids is formed. This longer form is what sticks together to form senile plaques in Alzheimer’s disease [1].

Abeta

Formation of the longer amyloid-beta protein by beta-secretase and gamma-secretase. Source: https://www.rndsystems.com

Familial Alzheimer’s Disease

Alzheimer’s disease is divided into two forms. Approximately 5% of cases are of the familial, early-onset form. This type of Alzheimer’s typically affects individuals in their mid-forties and fifties. There are three genes known to be involved with familial Alzheimer’s disease: APP, PSEN1, and PSEN2. APP, as I described above, is the precursor to amyloid-beta, and so certain mutations can make it prone to the cleavage pathway that results in the sticky 42-length protein. Similarly, PSEN1 and PSEN2 are believed to affect the gamma-secretase complex that cleaves APP into amyloid-beta.

Mutations in these three genes are autosomal dominant. This means that only one copy of the mutation is needed to cause the disease, and that carriers have a fifty-percent chance of passing on the gene to each of their children. The mutations also tend to have high penetrance, meaning that their effects cannot be readily altered by environmental factors–i.e., having the mutation nearly always leads to the disease [2], [3].

Sporadic Alzheimer’s Disease

In contrast to the relatively simple genetics of familial Alzheimer’s, late-onset sporadic Alzheimer’s disease (which makes up 95% of cases) is far more complex. The only gene that has been conclusively identified as a risk factor is apolipoprotein E, abbreviated as apoE. We still aren’t sure exactly how apoE affects the brain, but the main hypothesis is that it’s involved with clearing away amyloid-beta before it can accumulate to toxic levels. There are three major versions of this gene: apoE2, apoE3, and apoE4. Having one copy of the apoE4 allele increases the risk of Alzheimer’s by 3 times, while having two copies increases the risk by nearly 15 times. Conversely, having at least one copy of the apoE2 allele reduces the risk of Alzheimer’s [2][4].

It is important to note that unlike the genes involved with familial Alzheimer’s, the apoE alleles are not highly penetrant. Approximately 1 in 5 people have at least one copy of apoE4, yet the majority of them never develop Alzheimer’s. Additionally, there are many people who develop Alzheimer’s without possessing apoE4. The allele increases the risk of developing the disease but is far from a guarantee [2][4]. Overall, it’s estimated that apoE accounts for less than 20% of the genetic risk for sporadic Alzheimer’s [5], [6].

So where does the other 80% come from? The answer gets even more complicated here. There are dozens of genes that are weakly correlated with overall risk, age of onset, rate of progression, or other disease variables. Individually, each of these genetic variants has only a tiny effect, but when combined, each person’s unique combination of variants creates a genetic profile that influences his or her risk of developing the disease (see A New Approach to Predicting Risk of Alzheimer’s Disease). The majority of these weakly-associated genetic variants have yet to be identified [3].

Non-Genetic Factors

In familial Alzheimer’s, there is little that a person can do to prevent the disease if he or she has inherited the gene. However, only 24-33% of a person’s risk for sporadic Alzheimer’s disease is attributable to genetics alone [5], [6].  The remaining risk is modulated by non-genetic factors, including medical conditions, diet, and lifestyle choices. A recent meta-analysis identified 13 non-genetic factors that significantly increase the risk for Alzheimer’s disease, including smoking, being overweight in midlife, cardiovascular disease, low education, and depression. In addition, they identified 23 factors that reduce the risk of Alzheimer’s, including a healthy diet, physical activity, mental stimulation, and certain medical conditions [7].

F3.large

Non-genetic protective and risk factors for Alzheimer’s disease. Source: Xu et al., 2015.

Conclusion

It was once thought that we couldn’t change our brains after birth, but the discovery of neuroplasticity revolutionized the field by showing us that our daily actions can have enormous impacts on the structure and function of our brains. Similarly, the growing study of epigenetics (meaning “above genetics”) proves that we are not at the mercy of our genes. Though we are born with a set DNA sequence, the choices we make throughout our lives determine which genes are turned on or off, a process that can significantly influence our risk of disease. We may not be able to change the genetic risk coded into our DNA, but we can all help protect our brains from Alzheimer’s disease through simple lifestyle choices.

 

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Calcium Supplements May Increase Risk of Dementia in Women with Cardiovascular Disease

Background

To reduce the risk of osteoporosis, the NIH recommends that elderly people consume 1,000 to 1,200 mg of calcium per day. Since this is difficult to obtain from food alone (for reference, a glass of milk contains less than 300 mg), many people take calcium supplements to reach their daily minimum. However, this recommended daily intake has recently received some criticism from the scientific community, with several studies failing to find a relationship between calcium intake and bone density.

In fact, it’s possible that high calcium intake could be harmful to our health. A 2008 review found that hyperparathyroidism, a condition that causes abnormally high levels of calcium in the blood, can contribute to cardiovascular disease. Since hypertension, diabetes, and other cardiovascular problems increase the risk of both vascular dementia and Alzheimer’s disease, the results of this study raised the question of whether calcium supplements could play a role in dementia.

New Study

In a recent study published in the journal Neurology, researchers observed 700 Swedish women between the ages of 70 and 92, all of whom were initially dementia-free. At the beginning of the study, women who took calcium supplements did not differ significantly in age, scores on cognitive exams, or education level. After a five-year follow-up, the women taking calcium supplements were twice as likely to be diagnosed with any dementia and more than four times as likely to be diagnosed with vascular dementia. There was no association observed between calcium supplements and Alzheimer’s disease.

Future analysis of the data revealed that the increase in dementia risk among calcium supplement users only existed in women who had a history of stroke or who had white matter lesions (small regions of damaged brain tissue that can result from cardiovascular disease). Women without these conditions had the same dementia risk regardless of calcium consumption. Notably, women who took calcium supplements had only a 20% risk of experiencing a bone fracture during the course of the study, while those who did not take the supplements had a 40% risk of fractures.

The authors of this study offered several possible explanations for these results. One possibility is that high levels of calcium in the blood could increase the risk of neurons dying near the site of a stroke, as other studies have shown that calcium is involved with apoptosis and necrosis (two forms of cell death). Calcium could also be affecting the blood or vasculature directly. The authors also pointed out that dietary calcium does not lead to the same spikes in blood calcium levels as calcium supplements, so consuming calcium in our food instead of pills may avoid these possible cardiovascular risks.

This study has several important limitations. The analysis looked only at whether or not the women took calcium supplements and did not consider the amount of calcium consumed in food. The sample size was also fairly small, with only 98 dementia diagnoses in the cohort, of whom 14 took calcium supplements. Since only women were included, these results may not generalize to men. Finally, being an observational study, the results cannot establish a causal relationship between calcium and dementia (see How to Be a Smart Consumer of Science News), so further research utilizing randomized assignment is needed to determine whether calcium or a different factor caused the observed discrepancy in dementia incidence.

 

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Menstrual Pain-Relievers May Protect from Alzheimer’s Disease

Background

Non-steroidal anti-inflammatory drugs (NSAIDs) are a broad class of pain-relievers that includes ibuprofen, aspirin, and naproxen. NSAIDs work by decreasing the levels of pro-inflammatory hormones called prostaglandins. Interestingly, recent studies have found that NSAIDs may also be beneficial for reducing the risk of dementia. A 2015 meta-analysis found that short-term NSAID users had a 28% reduced incidence of Alzheimer’s disease, while long-term users had a 64% reduction. Notably, this effect was only significant in observational studies and not randomized controlled trials, so a conclusive link between NSAIDs and brain health remains elusive.

One possible mechanism for how NSAIDs could combat Alzheimer’s is by regulating inflammatory pathways outside of prostaglandins. Studies suggest that Alzheimer’s disease is closely linked to a complex inflammatory network called the NLRP3 inflammasome. If NSAIDs could inhibit this inflammasome, it may protect the brain from neurodegeneration.

New Study

In a study published last week in Nature Communications, researchers investigated whether a class of NSAIDs called fenamates could inhibit the NLRP3 inflammasome. Fenamate NSAIDs include mefanamic acid, a common medication used to treat menstrual pain. The researchers treated mouse cell cultures with fenmates and found that they selectively inhibited the NLRP3 inflammasome without interfering with other inflammatory pathways. The researchers then treated two animal models of Alzheimer’s disease (rats and mice) with mefanamic acid over an extended period of time. Memory tests administered to the rats showed reduced impairment when they were given the drug. Meanwhile, the mice’s brains showed that signs of neuroinflammation had been reduced to healthy levels.

A limitation of this study is that the NLRP3 inflammasome has still not been conclusively linked to Alzheimer’s in humans. It is also not clear how well these animal models simulate the neuroinflammatory aspects of the disease. Future studies will likely examine how fenamates and other NSAIDs affect inflammatory pathways in humans to determine their potential as therapy. If mefanamic acid is one day repurposed as an anti-dementia drug, it could avoid the lengthy pipeline for FDA approval and be available immediately to consumers.

 

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Cleveland Clinic Website Offers Free Brain Health Checkup

While browsing the web recently, I stumbled onto a fantastic resource that I wanted to share with you all. About a year ago, the Cleveland Clinic Lou Ruvo Center for Brain Health launched a new site called HealthyBrains. The website is centered around the six pillars of brain health: physical exercise, food/nutrition, medical health, sleep/relaxation, mental fitness, and social interaction. The goal of the site is to allow everyday people to take their brain health into their own hands. There are so many simple ways to incorporate small lifestyle changes that can dramatically reduce your risk of Alzheimer’s and other neurocognitive disorders.

One of my favorite parts about the site is the Brain Health Checkup, a free quiz that takes around 20 minutes to complete. It asks you a variety of questions about your lifestyle and medical history to calculate a Brain Health Index (BHI), a score between 0 and 100. The higher the score, the better your odds of minimizing your dementia risk based on the latest scientific research. After receiving your score, you can read personalized tips on how to improve your BHI. Your information is saved so that you can retake the checkup later and see how your brain health has improved. You can also take a memory test and see how your brain stacks up against others.

This is such an easy way to learn how to improve your brain health. I highly recommend that you check it out, no matter your age. Click here to visit the site!

 

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Dark Microglia: Strange Brain Cells with a Connection to Alzheimer’s Disease

Background

Our neurons communicate with each other via junctions called synapses. In neurodegenerative diseases like Alzheimer’s, the number of synapses in the brain decreases dramatically, contributing to cognitive decline. It’s believed that the mechanism for synapse loss involves brain cells called microglia, which engulf and destroy the synapse in a process known as phagocytosis.

A paper published earlier this year in the journal Glia announced the discovery of a new type of microglia in mice called dark microglia. These cells’ unusually dark color comes from oxidative stress that leads to condensing of fluids in the cell. They are relatively uncommon under normal conditions but become more prevalent in mice that are old, exposed to chronic stress, genetically predisposed to Alzheimer’s disease, or deficient in a microglia signaling molecule called fractalkine. Dark microglia are more phagocytically active than their normal counterparts, often devouring entire synapses whole. The authors suggested that these cells might be a future therapeutic target in Alzheimer’s disease.

New Results

Dr. Marie-Eve Tremblay, who led the team that discovered dark microglia, presented an update on her research at the recent Translational Neuroimmunology conference in Big Sky, Montana. She announced that they had identified dark microglia in human brains for the first time. Tremblay’s team examined the postmortem brain of a 45-year-old person who’d had early-onset Alzheimer’s disease. They found that there were around twice as many dark microglia compared to a healthy brain from a person of the same age.

It’s not clear yet what causes dark microglia to appear at higher concentrations, and further research is needed to determine whether they play a causative role in neurodegenerative diseases. Nonetheless, Tremblay’s team’s discovery opens the door to exciting new possibilities for the immunological mechanisms of Alzheimer’s and could one day lead to novel therapeutic approaches.

 

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