Ultrasound and Microbubbles May Be Used to Treat Alzheimer’s Disease

Alzheimer’s disease, the most common form of dementia, is characterized by the buildup of toxic, sticky plaques inside the brain. These plaques are made of a protein called amyloid-beta. Although hundreds of drug candidates that try to remove amyloid-beta from the brain have been tested in clinical trials, these have been a resounding failure (see “Where’s our cure to Alzheimer’s disease?”). This has led scientists to try out new methods for treating the disease.

One of the most intriguing ideas for treating Alzheimer’s is to use ultrasound. Ultrasound uses high-frequency sound waves outside the range of human hearing. These sound waves can pass through soft tissues but bounce off of denser things such as bone, which is how ultrasound can generate the image of a fetus during pregnancy.

Ultrasound has many uses outside of imaging. One recent techniques involves injecting the patient with tiny “microbubbles.” When hit with an ultrasound pulse, the microbubbles expand and contract. This allows them to gently press against the blood vessel walls without damaging them.

The microbubble ultrasound technique has an interesting effect inside the blood-brain barrier (BBB). The BBB is a complex structure that surrounds blood vessels inside the brain. It prevents harmful toxins and pathogens from entering the brain, but can also make it difficult for waste products (including amyloid-beta) to be cleared away.

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The cells surrounding blood vessels in the brain, known as the blood-brain barrier, prevent large molecules from passing through. Image Source

When microbubbles inside the brain’s blood vessels expand, they can temporarily open the BBB. This not only allows for enhanced clearance of waste products, but also activates many immune pathway in the brain that further assist with this process.

Early experiments involving mice have been encouraging. In 2013, 2014, and 2015, three different research groups found that mice that were genetically engineered to develop Alzheimer’s disease showed improvements after ultrasound/microbubble treatments. This included reduced levels of amyloid-beta, improved spatial memory, and more newborn neurons inside the hippocampus, a part of the brain associated with memory.

Several human trials involving ultrasound are currently being planned or in progress. One small trial of five subjects found that the ultrasound device could safely and reversibly open the BBB. However, we still need to wait for more results to come out before we’ll know whether this strategy is effective for treating Alzheimer’s.

It also remains to be seen whether ultrasound may come with any unforeseen consequences. It’s possible that opening the BBB could allow certain immune cells or pathogens to enter the brain, creating an opportunity for autoimmune reactions or brain infections. Despite the potential risks, researchers remain hopeful that ultrasound could offer a noninvasive means for treating Alzheimer’s disease in the future.

 

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Why Are Women Twice as Likely to Get Alzheimer’s Disease?

Of the more than 5 million Americans living with Alzheimer’s disease, nearly 2/3 of them are women. A woman in her 60s has a 1 in 6 chance of later developing Alzheimer’s, compared to only 1 in 11 for a man. What is the cause for this sex imbalance?

A major player in this question is the APOE gene (see The Genetics of Alzheimer’s Disease for more detail). This gene comes in three different forms: APOE2, APOE3, and APOE4. Each of us inherits two copies of this gene (one from each parent). If you have one copy of APOE4, your risk of Alzheimer’s increases threefold, while having two copies of APOE4 increases your risk by fifteen times. For reasons that remain unclear, the APOE4 allele seems to be a stronger risk factor for women than men, which could help to explain the difference in Alzheimer’s prevalence.

Some lines of research suggest that sex hormones may also play a role. Specifically, reduced estrogen levels, which commonly occur during menopause, are associated with increased risk of Alzheimer’s. Several studies have shown that women with Alzheimer’s tend to have lower estrogen levels in their brains. Pregnancy also reduces lifetime exposure to estrogen, which may explain why women who have had biological children have a higher risk of dementia than women without biological children. Similarly, women who have had a hysterectomy or oophorectomy (removal of the uterus or ovaries), which can induce menopause at an earlier age, also have an increased risk of dementia.

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A woman’s estrogen levels decrease as they approach menopause, which may be linked to their increased risk for Alzheimer’s. Image Source

So if low estrogen is a risk factor for Alzheimer’s, could estrogen replacement therapy (ERT) combat this? ERT is commonly used as a treatment for menopausal symptoms such as hot flashes, as well as to reduce the risk of osteoperosis. Clinical trials investigating the effects of ERT on dementia have had mixed results. There is some evidence to suggest that it may only be protective if women begin treatment within the first few years of menopause. So far, the jury is still out on whether these therapies could be beneficial for preventing dementia. There are also some notable risks associated with ERT, including a higher chance of breast cancer.

What about male sex hormones? Similarly to women, men with Alzheimer’s disease tend to have lower levels of testosterone than normal. So if the loss of both sex hormones can increase the risk of Alzheimer’s, why do we see a much higher prevalence in women? One theory is that it relates to how quickly these hormones are lost. The menopause transition usually takes around four years, while male reproductive aging takes place gradually over several decades. Perhaps the abruptness of estrogen loss in menopause is responsible for the higher risk of dementia.

Another important difference between men and women lies in their risk for other dementia-related diseases. Women are more than twice as likely as men to have depression, and they also have a higher risk of insomnia and fragmented sleep. All of these conditions are linked to an increased risk of Alzheimer’s. In addition, women have historically been granted less access to education, employment, and physical exercise, which can be protective against dementia. This is particularly true for women who grew up in the mid-20th century and are now reaching their elderly years.

In conclusion, there’s still a lot we have to learn about why women are more prone to Alzheimer’s disease than men. In the meantime, both women and men can still greatly reduce their overall risk of Alzheimer’s through lifestyle changes. See 10 Tips to Reduce Your Dementia Risk to learn more.

 

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Why People with Down Syndrome are at High Risk for Alzheimer’s Disease

Down syndrome is a neurodevelopmental disorder caused by inheriting an extra copy of chromosome 21. The most common symptoms include intellectual disability, unusual facial features, and heart defects. About 1 in 700 babies is born with this condition.

The average lifespan for a person with Down syndrome is 60 years. Sadly, the last few years of their lives are often lost to Alzheimer’s disease. Nearly two-thirds of Down syndrome patients are diagnosed with Alzheimer’s before the age of 60. This is far higher than the general population, of whom less than 1% develop Alzheimer’s this early in life.

The reason for this greatly elevated risk of Alzheimer’s disease comes down to genetics. While chromosome 21 contains hundreds of different genes, a single gene is believed to cause Alzheimer’s disease in Down syndrome patients: APP. This gene encodes a protein called amyloid-beta. Amyloid-beta is a toxic, sticky protein that can clump together and accumulate inside the brain, which is believed to be a major contributing factor to Alzheimer’s disease.

Because of their extra copy of chromosome 21, people with Down syndrome produce more amyloid-beta than normal. Nearly 100% of Down syndrome patients start to develop amyloid-beta aggregates in their brains during their 40s. This puts them at a very high risk of developing Alzheimer’s at an early age.

After the practice of institutionalizing people with Down syndrome became less common, their life expectancy improved dramatically, up from only 25 in 1983 to 60 today. However, this means that more Down syndrome patients are living long enough to develop Alzheimer’s disease, which is a frightening prospect to these individuals and their families.

Despite the troubling statistics, there is hope for people with Down syndrome. Many neuroscientists believe that early intervention is key for preventing Alzheimer’s disease. However, ethical standards make it difficult to administer treatments to people before we know for sure that they’ll develop a disease, particularly if those treatments come with certain risks. This makes it challenging to test out new preventative therapies for Alzheimer’s disease.

Because of the very high rate of Alzheimer’s disease among Down syndrome patients, they may be an exception to this rule. New drug candidates can be tested on these individuals beginning early in life, which may prove to be a more effective strategy for preventing Alzheimer’s. While only time can tell whether these treatments will prove beneficial, many remain hopeful for the future of research.

 

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Interview with Alzheimer’s researcher, blogger, and advocate Maya Gosztyla

Check out Global Health Aging’s interview with AlzScience creator, Maya Gosztyla!

GLOBAL HEALTH AGING

Maya Gosztyla is the creator of AlzScience. Her passion for Alzheimer’s disease began at a young age when her grandmother was diagnosed with vascular dementia following a stroke. She currently works in a lab at the National Institutes of Health, where she’s researching a rare neurodegenerative disorder called Niemann-Pick Disease. In addition to her love of research, Maya has a passion for science writing and hopes to continue educating the public about the ways we can keep our brains healthy as we age. We are excited to interview Maya about her research, fighting Alzheimer’s and the role of diet in brain health.

Can you tell us about your journey in science?

I’ve pretty much always known that I wanted to be a scientist, but the exact field of science has varied quite a bit. For most of my high school, I wanted to be an astrophysicist. But then I took an…

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Neurons Changing their DNA Could Lead to Alzheimer’s Disease

A recent study finds that neurons can spontaneously change the sequence of a gene called APP, which is involved with Alzheimer’s disease.

In most cases, the DNA that you’re born with stays the same throughout your entire life. However, according to a paper recently published in Nature, neurons can randomly change their own DNA sequence, which may contribute to the development of Alzheimer’s disease.

The study was led by Dr. Jerold Chun’s research group at the University of California San Diego and the Sanford Burnham Prebys Medical Research Institute. Dr. Chun’s lab and others have previously shown that adult neurons can alter their own DNA sequence. As a result, different neurons inside your brain can have their own unique genomes, a phenomenon known as genomic mosaicism. This is distinct from epigenetic modifications, which can turn genes on or off but do not change the actual genetic sequence.

Genomic mosaicism, which occurs by a seemingly random process, can range in size from a single nucleotide to entire chromosomes. These changes tend to accumulate as we age, which led many scientists to wonder if they could be related to neurodegenerative diseases.

Our Mosaic Brains and Alzheimer’s Disease

In their recent Nature paper, Dr. Chun’s group investigated a single gene called Amyloid Precursor Protein, or APP for short. APP is the precursor to amyloid-beta, a toxic sticky protein that builds up in the brains of people with Alzheimer’s disease. The researchers were curious whether different forms of the APP gene could exist throughout the brain.

Using postmortem brain samples from five people with sporadic Alzheimer’s disease, as well as five age-matched controls, they extracted DNA from individual neurons and sequenced the APP gene. They found that more than 6,000 variants of APP existed across different neurons.

Interestingly, the Alzheimer’s brains had far greater diversity of genetic variants than the healthy brains. This suggests that these unusual APP variants could be related to the development of Alzheimer’s. When they took three of these variants and expressed them in a cell culture, two of them resulted in cell death. In addition, the Alzheimer’s brains had several APP variants that have been linked to familial Alzheimer’s disease (a rare, genetic form of early-onset Alzheimer’s), while none of the healthy brains contained these variants.

Next, the researchers wanted to understand how all these different APP variants might arise in neurons. They used a hamster cell culture that was made to express the human APP gene. When they used chemicals to induce DNA double-stranded breaks, the cells began producing unique APP variants, just like human neurons. The researchers also showed that this process relies on reverse transcription, which converts an RNA sequence to DNA.

Impacts for Alzheimer’s, AIDS, and Memory

This discovery is a major shift for Alzheimer’s researchers. Previous anti-APP drug candidates have generally only targeted one form of the gene, and this work shows that a huge array of genetic variants can exist in our brains. We will certainly need to reconsider our strategy for Alzheimer’s therapies moving forward.

In addition, the link between genomic mosaicism and reverse transcription has some intriguing implications for HIV. Previously studies have shown that people with HIV who are over age 65 have a lower rate of Alzheimer’s disease than the general population. One explanation could be the anti-retroviral drugs that they take. These drugs prevent the HIV multiplying by inhibiting reverse transcription, a process that the virus requires for replication. An unintended consequence of this could be that these people do not develop the APP variants that are linked to Alzheimer’s. If this turns out to be the case, anti-retroviral drugs could possibly be used as a preventative measure for Alzheimer’s.

So far, none of this has addressed the reason why neurons are so prone to developing different APP variants. In the Nature study, another Alzheimer’s-related gene called PSEN1 did not have such a wide variety, suggesting that the mechanism is specific to APP. In addition, non-neuronal cells did not develop all these APP variants. A possible explanation could be that this process is important for memory formation. The authors suggest that storing so many unique version of APP could be a mechanism for memory storage and recall at the molecular level. This idea remains speculative, but it does have a kind of poetic irony to it: the gene responsible for forming memories could also destroy those memories as we age.

 

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Interview with a Dementia Researcher: Rory Boyle, Cognitive Neuroscience Researcher

What areas of research are you currently pursuing?

My PhD research is focused on using machine learning to identify markers of cognitive ageing. Currently, I am working on a project which uses machine learning and MRI scans to create a model of normal or healthy brain ageing. This model can be used to estimate how well, or poorly, a person’s brain is ageing and this estimation is termed the brain-predicted age difference, or brainPAD.

It has already been shown that people who have high brainPAD scores (which means their brains are ‘older’ relative to their actual age) have a higher risk of early mortality and tend to perform worse on measures of physical functioning (such as grip strength, lung function, walking speed).

However, we don’t yet know whether brainPAD can be used as a measure of cognitive ageing. If people with high brainPAD scores are shown to perform worse on tests of cognitive function, then brainPAD could potentially be used as a way of identifying such people at a very early stage, before cognitive decline is noticed using standard cognitive tests.

The next project in my PhD will look at developing an objective measure of cognitive reserve. Some people whose brains have the hallmarks of Alzheimer’s disease or other dementias seem to be able to maintain normal cognitive function. This has led researchers to try and understand why some people might have a buffer or some form of protection against certain neurodegenerative diseases. One theory is that people who are able to tolerate such neurodegeneration have high levels of what is called ‘cognitive reserve’.

Cognitive reserve refers to an individual’s ability to use their brain irrespective of their brains’ structural health. It is proposed that life experiences, such as education, occupational attainment, engagement in social, leisure, and mentally stimulating activities, and physical activity contribute to cognitive reserve.

However, currently, cognitive reserve is typically measured by questionnaires and interviews which measure these same factors (education, occupational attainment, etc.). This means that we might not have the most accurate measures, as people might not fully remember all the details of their education or social activities and their answers might be affected by response bias!

My goal is to use neuroimaging to develop an objective and standardised measure of cognitive reserve so that people with low cognitive reserve can be identified. This would allow for interventions to be directed at these people and it would also help in studies evaluating strategies to improve cognitive reserve.

What are the big questions or theories currently being debated in your subfield?

There are a couple of big questions which people are trying to answer in relation to cognitive reserve. Can cognitive reserve be objectively measured, and if so, how? What is the neural basis of cognitive reserve? Hopefully my project will help to shed some light on these questions.

What is a common misconception related to dementia that you often encounter?

One common misconception is that there nothing we can do to reduce our risk of dementia. Given our knowledge of cognitive reserve, one way we could reduce our risk of dementia is by increasing cognitive reserve! There is more and more evidence that taking part in mentally stimulating activities, being socially active, and regularly exercising can lower the risk of dementia. More generally, there is evidence that having a healthy diet, particularly a Mediterranean diet, not smoking, and cutting down on alcohol can also reduce the risk of dementia.

What recommendations would you give to people wanting to reduce their risk of Alzheimer’s disease?

Like a lot of things, the best recommendations for reducing risk of Alzheimer’s disease or other dementias are to live a healthy and active life. Specifically, try to exercise three times a week, particularly aerobic exercise like brisk walking, swimming, cycling. As well as that, try to stick to a Mediterranean diet, which is rich in fruits and vegetables, whole grains, beans and nuts, olive oil and fish.

Be socially active, join a group or club. In Ireland, we have a really great initiative called Men’s Sheds were men can meet up and work together on hobbies and meaningful projects. This is a great example of how people can keep socially engaged. As well as that, take part in mentally stimulating activities like puzzles and Sudoku. If you have access to a PC, there are now thousands of free online courses on websites like Coursera or EdX. By signing up for these, you can challenge yourself and learn something new, all while keeping your brain stimulated!

How can non-scientists contribute to the fight against Alzheimer’s?

Non-scientists could help in the fight against Alzheimer’s by taking part in research. Research studies are always on the lookout for participants. People without Alzheimer’s disease are always needed as well to form control groups. Have a look online or at any nearby universities!

On top of that, there are now even easier ways to take part in research. For example, downloading and playing the SeaHero Quest app allows researchers to collect valuable information about how the brain navigates in space, which is a key skill that declines early on in dementia.

When do you believe a viable Alzheimer’s treatment will be available?

I’m not sure, but I am hopeful that with all of the new techniques we will be able to identify people likely to develop Alzheimer’s or other dementias, earlier than ever before. This will allow for any interventions that can help with Alzheimer’s to be implemented at the early stages of the disease, where interventions are likely to be most specific. It will also help researchers test and monitor the effects of new interventions and treatments.

Is there any other information you’d like to add?

My PhD research is funded by the Irish Research Council, in partnership with Altoida AG. I am very grateful for the support of both of these organisations. Altoida AG has developed an app that uses computerised and gamefied tests of cognitive performance to evaluate perceptual and memory function in older adults. This app may ultimately allow for early screening of mild cognitive impairment and identification of people who are at risk of developing Alzheimer’s disease. We have tested this app on a number of older adults here in Trinity College, and hopefully we will have some interesting data from these tests in the next year!

 

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Rory Boyle is a PhD candidate in the Whelan Lab in Trinity College Dublin. He graduated with a BSc in Psychology from Dublin City University in 2014, and an MSc in Brain Sciences from the University of Glasgow in 2016. His BSc research project compared the effects of aerobic exercise and caffeine consumption on measures of mood and cognitive performance. His MSc research project used EEG to investigate the age-related differences in the visual processing of faces. Specifically, his project examined whether there were differences in the information content of brain activity during the visual processing of faces.

 

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Interview with a Dementia Researcher: Dr. Aida Suarez Gonzalez, Clinical Neuropsychologist

What areas of research are you currently pursuing?

I am a clinical neuroscientist with a strong translational focus. I have a passion for non-pharmacological interventions and evidence-based services to help people to live well with dementia.

What are the big questions or theories currently being debated in your field?

The development of new multicomponent functional interventions in dementia (such as disease education, counselling, goal-setting, goal-oriented cognitive rehabilitation, coping strategies training, etc.) is a hot topic. These interventions have the potential to increase autonomy, quality of life, and mental health in patients and families.

Another big concept is the need to develop more suitable methods to produce high quality evidence in support of non-pharmacological interventions. The traditional methods used in classic drug trials do not always makes sense when applied to non-pharmacological approaches.

I am also interested in the introduction of a new generation of purpose-built assistive technologies (such as specific communication aids, adapted e-readers, memory aids, etc.). These tools are revolutionizing the way we provide support, so people can remain independent for longer. IDEAL and GREAT are two examples of programs that support the concept of living well with dementia.

What is a common misconception related to dementia that you often encounter?

There are two big misunderstandings that particularly trouble me because they produce undesirable consequences when a diagnosis of dementia is provided.

First, we always highlight that dementia is not a natural part of aging, that it is a disease. However, we usually forget to add that this is a very common disease in old age and that we, as longer-living societies, have lived with age-related diseases for centuries (and hey, here we are after all).

I don’t mean we should belittle the seriousness of dementia, but rather encourage more acceptance and reconciliation with life and trust in the resilience of what we human beings are capable of. I think this way of thinking moves the focus from the frustration of the current absence of a treatment to reflecting on what we can do to live well with the disease. And of course this way of seeing things is not incompatible with increasing research efforts towards finding a cure.

Secondly, calling the dementias “dementias” contributes the stigma and misunderstanding of the disease. In many societies across the world, the word dementia means losing yourself, your reasoning, judgement, understanding and contact with reality. And this is not true. This is a false and unfair misconception that every day strips millions of people around the world from their social roles and right to decide about their lives, and exposes them to patronization.

Of course, advanced stages of the disease do impair your thinking skills severely, but this is not the case in the early and even moderate stages (that can last for many years) and it also depends a lot on the dementia subtype that you have. With the right support, many people with progressive cognitive impairment can lead fairly independent lives for a long time.

Look for example at the UK Network of Dementia Voices, which is a community of 100 groups of people living with dementia that seeks to magnify their own views, make their voices being heard and pressure the public administration to include their advice in matters that affect them.

The same applies to the 3 Nations Dementia Working Group, who are a powerful group of people living with dementia transforming the way we perceive dementia and progressive cognitive impairment by making an extraordinary contribution to society through education and raising awareness. They do public speaking, provide input to public policy bodies and bring value, advice and information about what is like the experience of living with dementia. They have dementiayes, and also they are inspiring, powerful and they are transforming the world.

What recommendations would you give to people wanting to reduce their risk of Alzheimer’s disease?

There is quite a lot of scientific consensus around the main preventive measures: healthy diet, good control of vascular risk factors such as cholesterol, diabetes and hypertension, regular physical exercise, remaining mentally active, and maintaining strong and good quality social bonds and social networks.

How can non-scientists contribute to the fight against Alzheimer’s?

The lay public can make a powerful contribution by trying to educate themselves about dementia, understanding better the changes experienced by a person with the disease, and committing to contribute towards a more dementia-friendly society.

For example, if you run a fruit shop in a neighborhood with an aged population, it’s very likely that some of your clients may be living with memory problems. You can seek information to educate yourself to understand better what that means and place a sign in your shop window explaining that this is a “memory problems friendly shop” and that people can come and speak to you about how to better support them to continue doing their shopping safely and independently.

When do you believe a viable Alzheimer’s treatment will be available?

I wish I had a response for that and I wish that response was “soon.” However, it is possible that we still have to live with Alzheimer’s in our lives for a long time, so I would encourage researchers and policy-makers to double efforts on finding a treatment, but also on helping us having good, purposeful, meaningful and fulfilling lives even if carrying a diagnosis of Alzheimer’s. There is a lot of life beyond the diagnosis, let’s also embrace that and make the best of it.

Is there any other information you’d like to add?

I would like to encourage other scientists to join a movement for change that focuses more on people and less on the disease, at least in the case of the diseases for which a cure has not been found yet. We hardly have any relevant tools to use in clinical studies to measure the impact of non-pharmacological interventions on people’s real lives and this needs to change. Current methods in this area are so quantitatively constrained and disease-oriented that allow little flexibility and, their resulting scientific outputs are usually difficult to translate into clinically practice.

 

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Dr. Aida Suarez Gonzalez is a clinical neuropsychologist at University College London’s Dementia Research Centre. She earned her Masters degrees in Gerontology and Clinical Neuropsychology, as well as her PhD in Neuropsychology, from the University of Salmanca in Spain.

 

 

 

 

 

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