Definition of Alzheimer’s disease

Focused Ultrasound Therapy as A Means to Treat Alzheimer’s Disease

Introduction

Definition of Alzheimer’s disease

The Alzheimer’s Association defines Alzheimer’s disease as a type of dementia which leads to problems with memory, thinking as well as behavior (What is Alzheimer’s, n.d.). The term dementia is used to define deterioration in mental ability that is serious enough to obstruct a person’s daily life. The World Health Organization (WHO) reports that Alzheimer’s disease is the most common form of dementia and that 60-70% of dementia cases are due to Alzheimer’s (Dementia, 2017). The Centers for Disease Control and Prevention (CDC) further defines Alzheimer’s as a progressive disease which begins with slight memory loss and can probably result in the loss of the capability to have conversations. The disease affects the part of the brain that controls memory, thinking, and language (Alzheimer’s disease, n.d.). About 5.5 million Americans were diagnosed with the disease as of 2013 (Hebert, Weuve, Scherr, & Evans, 2013). The 2017 estimates placed this number at 5.5 million when it comes to the prevalence. The Alzheimer’s Association reports that this illness is the 6th leading cause of deaths in the US.  More facts show that the disease mostly affects those above the age of 65 and that over 60% of these cases are women. The figures also show that 1 in 10 of the elderly has the condition. When it comes to global figures, over 20 million had dementia by 2011, and most of these cases were due to Alzheimer’s (Reitz, Brayne & Mayeux, 2011). Epidemiology reports by WHO showed that 50 million people had dementia by the end of 2017 where most of these cases are also Alzheimer’s (WHO, 2017).

The Alzheimer’s Association reports ten significant signs and symptoms of the disorder. The principal sign is memory loss which causes victims to forget recently learned information. Problem-solving and planning also become a major challenge. Familiar tasks that are usually done daily also become difficult to complete such as recording a television show. The people affected also tend to lose track of time, dates, and seasons. The most common case is whereby they will forget where they are and how they got there. A problem also arises in the use of words both in speaking and writing. This symptom is easily reflected in trouble in following or joining in a conversation. A person affected by Alzheimer’s disease will, therefore, stop mid-conversation and have no idea how to continue. They might also repeat themselves. A problem might also arise in finding the right vocabulary, and this can lead to calling things by their wrong names. Another symptom is the difficulty in comprehending visual images. This can result in difficulty in reading as well as judging of distances. Driving for people with Alzheimer is, therefore, very problematic. Another significant symptom also is the misplacement of things and the lack of ability to retrace steps to find these things. They might, therefore, end up accusing others of stealing which does occur frequently. Another sign is the sudden withdrawal from social activities and also work as well. This is characterized by having trouble in keeping up with favorite things such as sports teams and hobbies. They may also develop anti-social behavior. There is also poor judgment or decision-making which can relay affect their rationale. Grooming becomes an issue as they do not keep themselves clean. A final sign is a change in mood and personality characterized by symptoms such as confusion, depression, fear, anxiety, and even acting suspiciously. Despite all these being signs and symptoms of Alzheimer’s, it is important to understand that some of these symptoms are typical age-related changes which can occur in the elderly. The concern should arise when these signs persist over a period but not when they occur once in a while (10 early signs, n.d.).

There isn’t a cure for Alzheimer’s currently. However, treatments exist which improve both behavioral and cognitive symptoms as more research continues in search of new treatments. Focused ultrasound therapy is one of these treatments, and is quite promising.

 

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Information about focused ultrasound therapy

Focused Ultrasound therapy is a non-invasive, early stage, and therapeutic technology that possesses the potential to improve the quality of Alzheimer’s patients and also decrease the cost that is associated with the disease. According to the Focused Ultrasound Foundation, this ultrasound technology focuses beams of ultrasonic energy accurately and precisely on targets found in the brain. This is done without harming the adjacent normal tissue. The beams converge at a given region in the brain, whereby the ultrasound produces a range of beneficial effects without any radiations and incisions (Alzheimer’s disease, 2018).

The history of focused ultrasound dates back to 1880 when the Curie brothers discovered piezoelectric effect in certain crystals which led to the evolution of techniques involving high-frequency echo-sounding. Following this in 1915, hydrophones were discovered, which were high-frequency ultrasonic devices. A great step occurred in 1935 when Gruetzmacher found that an ultrasound could be focused. The idea that ultrasound could be intensely focused on diseased tissue within the body surfaced in 1942. Lynn et al. had a view that such focusing would produce extreme heat and non-invasively destroy targeted diseased tissue. The year 1944 saw Lynn and Putcham achieve a milestone by destroying cerebral tissue in animals using focused ultrasound. The first therapeutic use of ultrasound was in 1950 when Leksell designed a specially adapted frame and ultrasound transducer which was applied for the treatment of psychiatric disorders. Another remarkable time in the history of ultrasound was in 1962 when Meyer and Fry used focused ultrasound to treat Parkinson’s disease. Since then, focused ultrasound has been used to treat thyroids, brain cancers, and brain tumors. More advancement has been made through time culminating in 2017 when the first clinical trial of focused ultrasound for Alzheimer’s began in Canada. Focused ultrasound is used in collaboration with Magnetic resonance imaging (MRI) to provide imaging which is important in guiding the ultrasound (Timeline of focused ultrasound,  n.d.).

The Cause of Alzheimer’s disease

Although the cause of Alzheimer’s disease is not yet entirely understood, it is widely agreed by scientists that it is caused by a mixture of various factors such as genetic, environmental, and lifestyle factors that affect the brain over time. Various risk factors have been put forward and are likely to lead to the Alzheimer’s disease. The risk factors of this illness include age, Down syndrome, family history and genetics, sex, mild cognitive impairment, lifestyle and the health of the heart, past head trauma, lifelong learning and social engagement. When it comes to genetics, the risk of developing Alzheimer’s is high if a first relative, whether a sibling or parent, has the condition. Three genes have been identified by scientists, and these are likely to mutate leading to Alzheimer’s. However, this has been found to be a rare cause. The ApoE4 gene, responsible for creating the apolipoprotein E4 protein has been found to be highly associated with the disease. This discovery is however not conclusive. Lifestyle factors that might increase the risk of developing Alzheimer’s include obesity, the lack of exercise, the exposure to smoking, high blood pressure, high blood cholesterol, poor diet, and poorly controlled type 2 diabetes (Reitz & Mayeux, 2014).

Increasing age has been recognized as the highest risk factor for Alzheimer’s, especially after the age of 65. Also, the extra chromosome that causes Down syndrome contains a gene that highly increases the risk of Alzheimer’s. When it comes to sex as a risk factor, women are more likely to develop Alzheimer as compared to men. This has been associated with the fact that women are more likely to live longer. People are also required to involve themselves in lifelong involvement in socially and mentally stimulating activities.

Biological cause of the disease

There are various biological changes that result from Alzheimer’s disease. The illness kills and harms brain cells. The result is lesser cells and much lesser connections among the surviving cells ultimately leading to brain shrinkage. Two abnormalities on the brain tissue can be observed under a microscope for this condition. These include plaques and tangles. These two have been revealed as the hallmarks of Alzheimer’s disease.

Plaques are described as abnormal clusters of beta-amyloid, which are chemically “sticky” proteins that build up in between nerve cells. The result of this protein build-up is the blocking of cell-to-cell signaling at the synapses. These plaques might also trigger an immune response leading to inflammation and the devouring of the disabled cells. Tangles, on the other hand, are twisted fibers of a protein referred to as tau which forms inside dying cells. Tau proteins are significant in the stabilizing of microtubules which are a part of the cytoskeleton and are an integral part of the transport system. These proteins are more common in the Central Nervous system. When tangles form, the twisted strands of tau affect the structure of the microtubules hence the transport of nutrients and other essential supplies through the cells. These cells, therefore, ultimately die. The formation of plaques and tangles has been found to begin in areas of the brain associated with memory and learning, before spreading to other regions (Selkoe, 2015).

 

Limitations of Drug and Antibody Therapies

Reasons to why these procedures are ineffective

The major treatments for Alzheimer’s at the present include medications for memory loss, whereby a few medications have been approved by the US Food and Drug Administration (FDA). These include memantine and cholinesterase inhibitors which treat cognitive symptoms of Alzheimer’s including confusion, memory loss, and reasoning problems. Antibodies therapy is also being developed for Alzheimer’s. These antibodies are targeted against the amyloid-β (Aβ) peptide which causes plaques. Also, treatments for behavioral changes include providing emotional comfort. These treatments have, however, been found not to be effective. They only help for a time with the symptoms (Schneider et al., 2006).

The major reason for this is that drugs and antibodies are unable to cross the naturally occurring blood-brain barrier which impedes the ability of the drugs the anti-amyloid antibodies to infuse into the central nervous system. This is the reason why focused ultrasound therapy is very promising as it has been able to open the blood-brain barrier in patients with Alzheimer’s disease (Montagne et al., 2015).

Biological reason to why these procedures have limitations

The blood-brain barrier (BBB) is the main challenge for Alzheimer treatment. It is a semi-permeable membrane barrier that is highly selective.  It is a term that describes the unique properties of the Central Nervous System (CNS) microvasculature or rather the smallest systems of blood vessels in the body. These vessels are continuous non-fenestrated vessels meaning that they lack pores in their endothelial cells. They also possess special properties that allow them to tightly regulate molecule, cell, and ion movement between the CNS and the blood. The BBB epithelial cells can tightly regulate the CNS homeostasis due to their highly restricting barrier capacity. These properties allow for the protection of the CNS from pathogens, toxins, injury, inflammation, and disease. It also allows for proper neuronal function. Neurological diseases such as multiple sclerosis, stroke, neurodegenerative disorders, and brain traumas can lead to the partial or full loss of these properties of the BBB. This loss is also a major contributor to the progression and pathology of CNS diseases. Dysfunction of the BBB can also lead to altered signaling homeostasis, ion dysregulation, and other processes that can lead to neuronal dysfunction and degeneration. It is therefore of utmost importance to find a completely safe way of opening up the BBB without leading to these complications (Montagne et al., 2015).

Benefits of Ultrasound Therapy

Reasons to why ultrasound therapy is more beneficial than previous procedures

Studies have shown that when it comes to drug and antibodies treatments, only about 0.1% of the therapeutic antibodies enter the brain due to the BBB. This translates to a very high cost of Alzheimer’s treatment due to the amount of medication required. Ultrasound sound therapy is beneficial in that it can be used to temporarily open the BBB, which increases the uptake of drugs or antibodies hence decreasing the number of expensive treatments. Ongoing research also shows that ultrasound therapy can potentially be used to target plaques and destroy them. Although these are ongoing studies, focused ultrasound therapy is still used to produce therapeutic effects in targeted areas in the brain without having to undergo the side effects that are caused by drug intake (Meng et al., 2017).

Pros and cons of this procedure

The advantages of Focused Ultrasound Therapy include the fact that it is non-invasive. The procedure involves no incisions, electrodes, or even holes in the skulls. The risk of infection and blood clots is therefore greatly reduced. The process also greatly minimizes any damage to the healthy brain that is non-targeted. This therapy can also complement drug therapy through temporary opening the blood-brain barrier. It is, therefore, more cost-effective compared to drug treatment. The cons of this procedure lie in the fact that it is still in its early phases of development. The safety of opening the BBB has not completely been assessed as the implications of repeatedly opening it (Meng et al., 2017).

Trials on Mouse Models

Researchers in Canada have undertaken experimental studies on mice to find out the feasibility of utilizing focused ultrasound therapy to open up the BBB. They used MRI-guided Focused Ultrasound targeting to the hippocampus, which is a brain structure highly relevant for Alzheimer’s, aimed at opening up the BB and improving pathologic abnormalities and behavior. The test was a success with spatial memory improvement being observed in a Tg mouse model of Alzheimer’s disease (Burgess et al., 2014). Furthermore, a report was submitted from the University of Toronto, Canada detailing another mouse model in 2016. The research was focused on the lifespan of one focused ultrasound-mediated BBB treatment in a mouse model of Alzheimer’s. Although this study was successful in imaging of the plaques, it failed to determine the lifespan of one focused ultrasound which is significant in determining the frequency of treatment required for Alzheimer’s disease (Poon & Hynynen, 2016).

 

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The Future of Ultrasound Therapy

Preclinical studies involving Focused ultrasound and microbubbles have been found to be promising as a big step towards the treatment of the Alzheimer’s disease. It has been found that a combination of focused ultrasound and microbubbles can potentially safely open the blood-brain barrier which can then facilitate and enhance the delivery of anti-amyloid antibodies to the brain. This can go a long way in improving cognition as well as reducing the number of plaques in Alzheimer’s disease models. Focused ultrasound and microbubbles alone in the absence of antibodies have also been found to have similar effects in two different Alzheimer’s models. These models have served as significant preclinical evidence. Clinical trials are therefore underway thus suggesting a promising future of ultrasound therapy and that of Alzheimer’s disease treatment (Miller & O’Callaghan, 2017).

Conclusion

Alzheimer’s disease is a leading cause of death globally due to its lack of a cure. The already existing drugs only treat the symptoms for a while and are therefore considered ineffective. Their ineffectiveness is due to the inability of drugs and antibodies to cross the blood-brain barrier and deliver the treatments. Focused Ultrasound therapy promises to address these shortcomings by being able to open the BBB for the treatments to pass through. Trials on mouse models have already proved successful in opening up the BBB. More tests are still being done on mouse models of Alzheimer’s disease to determine after how long the barrier remains open before human experimental studies are done. More research on the targeting of plaques through MRI-guided focused ultrasound is also recommended. For now, the biggest issue is the safety of the procedure. From the research conducted, MRI-guided Focused ultrasound therapy remains the greatest hope of attaining an effective treatment for Alzheimer’s disease.

References

Alzheimer’s disease, (2018). Retrieved from https://www.fusfoundation.org/diseases-and-conditions/neurological/alzheimers-disease

Alzheimer’s disease, (n.d.). Retrieved from https://www.cdc.gov/dotw/alzheimers/index.html

Burgess, A., Dubey, S., Yeung, S., Hough, O., Eterman, N., Aubert, I., & Hynynen, K. (2014). Alzheimer disease in a mouse model: MR imaging–guided focused ultrasound targeted to the hippocampus opens the blood-brain barrier and improves pathologic abnormalities and behavior. Radiology273(3), 736-745.

Dementia, (2017). Retrieved from http://www.who.int/mediacentre/factsheets/fs362/en/

Hebert, L. E., Weuve, J., Scherr, P. A., & Evans, D. A. (2013). Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology80(19), 1778-1783.

Meng, Y., Volpini, M., Black, S., Lozano, A. M., Hynynen, K., & Lipsman, N. (2017). Focused ultrasound as a novel strategy for Alzheimer disease therapeutics. Annals of neurology81(5), 611-617.

Miller, D. B., & O’Callaghan, J. P. (2017). New horizons for focused ultrasound (FUS)–therapeutic applications in neurodegenerative diseases. Metabolism-Clinical and Experimental69, S3-S7.

Poon, C., & Hynynen, K. (2016). LIFESPAN OF ONE FOCUSED ULTRASOUND MEDIATED BLOOD-BRAIN BARRIER TREATMENT IN A MOUSE MODEL OF ALZHEIMER’S DISEASE. Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association12(7), P180.

Reitz, C., Brayne, C., & Mayeux, R. (2011). Epidemiology of Alzheimer disease. Nature Reviews Neurology7(3), 137.

Reitz, C., & Mayeux, R. (2014). Alzheimer disease: epidemiology, diagnostic criteria, risk factors and biomarkers. Biochemical pharmacology88(4), 640-651.

Schneider, L. S., Tariot, P. N., Dagerman, K. S., Davis, S. M., Hsiao, J. K., Ismail, M. S., … & Sultzer, D. L. (2006). Effectiveness of atypical antipsychotic drugs in patients with Alzheimer’s disease. New England Journal of Medicine355(15), 1525-1538.

Selkoe, D. J. (2015). Alzheimer disease. In Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease (Fifth Edition) (pp. 753-768).

Timeline of focused ultrasound, (n.d.). Retrieved from https://www.fusfoundation.org/the-technology/timeline-of-focused-ultrasound

What is Alzheimer’s, (n.d.). What Is Alzheimer’s? Alzheimer’s association. Retrieved from https://www.alz.org/alzheimers_disease_what_is_alzheimers.asp

10 early signs, (n.d.) 10 Early Signs and Symptoms of Alzheimer’s. Alzheimer’s association. Retrieved from https://www.alz.org/10-signs-symptoms-alzheimers-dementia.asp

 

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