The Beta-Amyloid Hypothesis of Alzheimer's Disease

Currently there are limited treatments for Alzheimer's that only address the symptoms or slow down progression.  For example, people with Alzheimer's have been found to have a shortage of acetylcholine in their brain so drugs such as Reminyl work by maintaining existing supplies of acetyl choline, by acting as enzyme inhibitors of acetylcholinesterase. To form better treatments focus on the root causes of AD and brain pathology are necessary. I found it interesting to note that there are 100 billion nerve cells in an adult brain with branches connecting at over 100 trillion points, called the 'neurone forest'. Signals travelling through the neurone forest form the basis of memories, thoughts and feelings. Alzheimer's causes cell death and tissue loss, so a brain affected by Alzheimer's has fewer synapses and nerve cells. It seems that the most likely explanation is the amyloid hypothesis and more research into this could lead to treatments that tackle the underlying cause of Alzheimer's.

The amyloid precursor protein (APP) is found widely throughout the body. Little is known about it's function although it is speculated that it may bind to the surface of cells and help them attach to one another. A fault with the processing of the APP in the brain leads to production of a short chain of APP called beta-amyloid. The hypothesis is that the fault may lie within the overproduction of beta-amyloid or the mechanism that removes it from the brain or both. Production of this sticky protein fragment forms clumps called amyloid plaques which triggers the destruction and disruption of the nerve cells in the brain, causing Alzheimer's.

APP is made of up to 771 amino acids and beta-amyloid is produced when betascretase and gammasecretase enzymes break the chain, forming beta-amyloid of 38, 40 or 42 amino acids long. The chain which is 42 amino acids long is chemically stickier and more likely to form plaques. There are three genetic faults, which alter the role of gammasecretase, leading to increased production of beta amyloid 42.

The plaques build up in spaces between nerve cells affecting neurotransmission, and also damage neurones. This in turn causes an inflammatory response as the brain tries to repair itself. It is also thought to cause the formation of neurofibrillary tangles, which are twisted fibres of another protein called tau, that builds up inside cells. 

There is lots of evidence that beta-amyloid causes AD and destruction of nerve cells. For example beta-amyloid killed nerve cells cultured in a laboratory. Mice with human Alzheimer's genes inserted in their DNA developed proteins plaques and showed decreases in their memory and learning skills (measured by use of tests such as a water maze which requires memory). Of those mice, the ones given anti-amyloid vaccine developed the condition more slowly. Despite this evidence that amyloid is key to damage in Alzheimer's disease, the question still remains of exactly how the damage done. It seems that there are ingredients that are directly toxic to nerve cells, formed when the first few strands of protein stick together. Most damage is done during early stages, when the clumps are small and thus more mobile, enabling them to affect more nerve cells.

As neurones die throughout the brain, the affected regions begin to shrink in a process called brain atrophy. In the final stages of AD damage is widespread and brain tissue has shrunk significantly.

Treatments under development and testing aim to remove beta-amyloid or disrupt it's production from APP in the first instant.

Researchers are trying to develop drugs which prevent production of beta-amyloid from APP, by acting as inhibitors to the enzymes gamma and betasecretase. Several drugs which interfere with gamma-secretase have had some success and reached phase III trials.

Immunotherapy could be used, whereby an active vaccine is used to trigger a process that uses the immune system to clear away deposits or plaques of amyloid in the brain. After animal models were successful, human treatments were developed. In a trial in 2000, a vaccine caused 12 out of 360 to develop serious inflammation in the brain after the immune system overreacted to the treatment. This particular method of vaccine was less successful and had to be halted, however in post mortem examinations it was revealed that participants had fewer plaques than expected. If a safe vaccine can be developed this route of treatment could be very promising.

Dementia

Dementia has been at the top of the political agenda for many years now as politicians realise that they need to take action to tackle a disease that will soon affect one million people across the country. The Alzheimer's society has been working with authorities to create the worlds first dementia-friendly parliament.

Volunteering at a care home first brought about my interest into this topic, after which I read a book called, 'Contented Dementia'. This book taught me a lot about how you should care for people with dementia. Putting yourself in their shoes is crucial. Although there are common symptoms, it is not a universal disease; we are all individuals and it affects people in different ways.

Dementia is the umbrella term for a chronic or persistent disorder of the mental processes caused by brain disease. It is marked by memory disorders, personality changes and impaired reasoning. There are many forms of dementia and here is a brief overview of the most common forms being, dementia with Lewy bodies, Frontotemporal dementia, vascular dementia and Alzheimers.

Alzheimer's
This is the most common form of dementia and with the ageing population it is becoming an increasing problem and is a condition that healthcare professionals will need to really understand in order to provide good care.
Causes
Researchers are unsure of where the progressive nature of Alzheimer's starts from, however sufferers have been found to have abnormal amounts of amyloid plaques (protein), fibres (tau tangles) and acetyl choline in the brain. This reduces effectiveness of nerve cells and destroys them gradually- that is why it is progressive in nature. Over time it spreads to areas of the brain such as, grey matter (responsible for thought processing) and hippocampus (responsible for memory). In my next post I will delve deeper into amyloid hypothesis.
Symptoms
Whilst there are common symptoms, it's vital to remember that everyone is unique and it will affect each person in different ways. Common symptoms include mood swings, feeling sad, angry, scared frustrated at their increasing memory loss, more withdrawn due to loss of confidence. They have difficulty with everyday activities and will need more and more support as it progresses.


Dementia with Lewy Bodies (DLB)
Causes
Unsurprisingly, this form of dementia is caused by Lewy bodies. Lewy bodies are tiny deposits of proteins in nerve cells. named after the doctor who discovered them. Researchers do not yet understand how they appear in the brain or contribute to dementia. However their presence is linked to low levels of acetyl choline and dopamine (chemical messengers) which leads to a loss of connection in nerve cells. It is progressive and leads to death of nerve cells and brain tissue. Lewy bodies are also the underlying cause of Parkinson's disease, collectively called Lewy body disorders.
Symptoms

This type of dementia shares symptoms with Alzheimer's and Parkinson's disease. Symptoms partly depend on where the Lewy bodies are in the brain. Lewy bodies at the base of the brain are linked to problems with movement (motor symptoms) - the main feature of Parkinson's disease. Lewy bodies on the outer layers of the brain link to problems with mental abilities (cognitive symptoms), characteristic of DBL. These symptoms can both occur together. 1/3 of people with Parkinson's develop dementia, whilst 2/3 of people with DBL develop motor symptoms. 

Symtoms unique to DBL can include convincing visual hallucinations and less common auditory hallucinations, which can be very distressing. Delusions such as ideas that strangers live in the house or that a spouse has been replaced with an identical impostor can be distressing for carers and relatives.

Later stages include problems with speech or swallowing, leading to chest infections and risk of choking. This requires extensive nursing care. On average a person may live eight years after first symptoms.

Who is affected
It is thought that Lewy bodies accounts for 10% of all dementia cases but is under-diagnosed and mistaken for other diseases, so only accounts for 4% of recorded dementia. It is particularly important to have an accurate diagnosis of DBL because sufferers can react well to some medications but badly to others. There is equal chances of both men and women developing dementia and it is more common in people over 65. There are very few risk factors identified to increase chances of developing DBL.


Vascular Dementia 
Causes
Brain cells are killed due to reduced oxygen supply to the brain as blood vessels to the brain narrow or become blocked. This can occur gradually after damage to blood vessels deep in the brain, after a series of small strokes or suddenly after a large stroke. Symptoms overlap with  with the most common form of dementia, that is, Alzheimer's. It is not uncommon for people to have mixed dementia, such as both Alzheimer's and vascular dementia.
Factors that increase risk are the same as those which increase the risk of cardiovascular disease (makes sense). Risk factors are anything which causes damage to the vascular system, including high blood pressure, high cholesterol diabetes and heart problems.
Symptoms
Typically symptoms appear suddenly after a stroke or in a step progression, where it will stay at a constant level then suddenly deteriorate. Symptoms are similar to Alzheimer's but symptoms particular to vascular dementia include problems with concentration, communication, speed of thinking, and memory. Seizures could occur, periods of acute confusion, symptoms of stroke such as weakness of paralysis. Hallucinations, misperceptions, behavioural changes, difficulty walking and unsteadiness can also occur. These, however may not be directly as a consequence of the disease, but other factors play a part. For example behavioural changes could be as a result of care needs not being wholly met.


Frontotemporal Dementia 
Causes 
This is a less common form of dementia but is the significant cause of dementia in under 65s. The cause is not yet known, but it is assumed to be caused by a mixture of genetic and lifestyle factors. It occurs to due death of nerve cells in the frontal and temporal lobes. Frontal lobes situated behind the forehead- on the right side they control behaviour and emotions and language on the left. Temporal lobes on either side of the brain have many roles such as understanding of words on the left side. The death of nerve cells is linked to lumps of abnormal proteins inside cells. These build up and become toxic causing brain cells to die and the lobes to shrink over time. A mutation in the tau gene can cause frontotemporal dementia, leading to a build up of the protein which usually is involved in transporting chemical messengers between nerve cells. It can also be caused by the progranulin gene or a recently discovered gene called c9orf72 that can also cause motor neurone disease.
Symptoms
This is hard to diagnose because it is not associated with memory loss in the early stages. In addition this dementia can occur in middle aged people which is unusual. Brain damage leads to changes in behaviour, personality and difficulty with language.

With dementia becoming so prevalent in society today, more needs to be done amongst us all to create communities which are aware and supports the needs of those living with dementia. This is what the Dementia Friends campaign is all about. Anybody can become a dementia friend and if you are interested, here is a short video about it: https://dementiafriends.org.uk/

Book Review: Bad Science by Ben Goldacre

Ben Goldacre's engaging and comical style writing persuades you to join his view of science. His thorough research and facts support a strong argument against all groups who present 'Bad Science' in research.

He particularly shuns homeopaths as he believes they are no better than placebo stating that they 'cherry pick' trials. Whilst this may well be true, it contradicts claims in the book I have read called, 'What the Drug Companies Wont Tell You and You're Doctor Doesn't Know',  by Michael T Murray, claiming that the trial methods are all included and accuse drug companies of paying scientists to 'cherry pick' the results and not homeopaths. For me, it is easier to believe Ben Goldacre's claims, as he takes a more unbiased approach, by highlighting 'Bad Science', in both mainstream and alternative drug industries.

From this I have learnt to be critical in all investigations that you do first hand, which is so important in modern day evidence-based medicine. There are so many factors to control in investigations and in this book I learned the importance of randomisation and double blind trials. A particular topic that grabbed my attention was placebos. I also found it interesting to note that the method of placebo used can affect how effective the placebo is. For example an injection of salt water is more effective as a placebo than a sugar pill because the injection is a far more dramatic event. The manner of the doctor can also alter the placebo effect. Patients report better improvements in their health, when prescribed the same treatment from a more warm, empathetic and reassuring doctor, than doctor who is cold and less reassuring. This makes me reflect on the kind of doctor that I would want to be. It also highlights why double blind trials are vitally important in investigations.

I feel as a prospective doctor it is important to know about the science behind the medicine, rather than prescribing drugs blindly to patients. The drug companies are the base of the healthcare system and without them there would be next to no treatments. In order to advance the field medicine, scientists need to be precise and critical with their investigations. In addition it is important not to waste money on unnecessary research. For example, utilising tools such as Meta-analysis, whereby you collate results from trials, each too small to be conclusive. After all, information can save lives.

Miscarriages

My interest into the topic of miscarriages came about through work experience at Broomfield Hospital, where I spent time with woman going through a miscarraige, caused by an immune response, which was heartbreaking for the couple, who had experienced it a number of times before. It struck me how a such a devastating experience so big, could stem from something so small, on a molecular level. Miscarriages are very common occurrence with around 30% of pregnancies ending up unsuccessful. This was a shocking statistic for me to see, as I had not realised how prevalent they were in society.

Most early miscarriages are caused by a random genetic problem in the foetus, causing the mothers body to reject the foetus, as it may have too many or not enough chromosomes. They can also be caused by problems with the development of the placenta, that links the mother's blood supply with that of the baby's.This type is non-reccurent and most people who experience this can then go on to have a normal healthy pregnancy. 

On the other hand some recurrent miscarriages are caused by other issues which is obviously upsetting and frustrating for the potential mother. Causes of recurrent miscarriages are:

• anatomical, such as a misshaped uterus, large fibroids, dramatic scarring within the uterus or a weakened cervix. This is when the muscle opens too early during pregnancy causing a miscarriage and can be treated with a "cervical stitch" and removed near the end of pregnancy.
• genetic defects in the egg or sperm, which is more common in men and women over 35.
• blood clotting in the uterus which can leave the placenta cut off so the foetus receives no nutrients or oxygen.
• high homocysteine levels (Sulfur-containing amino acids) causes hypercoagulability where your blood clots more easily, putting you and the baby at risk
• This can lead to hormone imbalances in the womb.
• Immunological disorders.

Immunological disorders as a cause of miscarriage

Some people with autoimmune diseases such as lupus, are at higher risk of a miscarriage. This is a poorly understood condition where, for reasons not clearly known, the immune system attacks healthy tissue. This means that when you get pregnant, antibodies fight off the developing pregnancy tissue as if it was foreign, therefore causing a recurrent miscarriages to occur.

Ebola Virus Disease

This virus has recently taken over science and medically related news pages, due to fears of an impending outbreak in the UK. With no licensed treatment or vaccine, an outbreak has already occurred in Sierra Leone and as a result they have had to announce a four day lock down. Overall over 2000 people have died already.

Ebola Virus Disease (EVD), formally known as Ebola haemorrhagic fever, is a severe or fatal illness with a fatality rate of up to 90%, with the current outbreak having a mortality rate of 55%. Outbreaks occur as the virus is transmitted from wild animals to people and then continues to spread via human-to-human transmission, through direct contact with bodily fluids. Fruit bats are the natural host of the virus. Infections have also been known to come from chimpanzees, gorillas, monkeys, forest antelope and porcupines.

Genus Ebolavirus is composed of five distinct species:

1. Bundibugyo ebolavirus (BDBV)

2. Zaire ebolavirus (EBOV)

3. Reston ebolavirus (RESTV)

4. Sudan ebolavirus (SUDV)

5. Tai Forest ebolavirus (TAFV)

BDBV, EBOV and SUDV are the species that have caused the large outbreaks. On the other hand RESTV species are found in the Philippines and can infect humans without causing illness or death, as known so far.

The problem is that symptoms may only show from 2 to 21 days from initial contraction. During this period you are unknowingly contagious leaving the virus open to spread to people close to you. In addition, after someone has recovered they can still be contagious. Men can transmit the disease by their semen for up to seven weeks after they have recovered from the illness. This is why WHO are encouraging educational health messages to be put out to prevent and control the disease. They focus on reducing the risk of transmission by telling people not to handle animals with bare skin or eat raw meat. People should avoid close physical contact and wear gloves when caring for patients at home, as well as regular hand washing. 

Symptoms

It is a severe viral illness, characterised by sudden onset of fever, intense weakness, sore throat, muscle pain and headache. This is then followed by rash, vomiting and diarrhoea, impaired liver and kidney function. In some cases there is internal and external bleeding. There is also central nervous system damage. Labs find that there's low platelet and white blood cell count and elevated liver enzymes.

Current Treatments
This sudden outbreak has caused researchers to concentrate their efforts on finding a suitable vaccine. The trouble is that, like HIV and influenza, Ebola's genetic code is a strand of RNA. Therefore the Ebola virus has a high rate of mutation and with mutation comes the possibility of adapting. 

Nevertheless WHO have announced that a vaccines could be in use in November. This is after, 150 experts have been investigating how to fast-track experimental drugs to make them available for use in West Africa. If proved safe they may be in use by November for use in West Africa. Unfortunately there would be limited supply of the drugs and to increase production could take several months by which time the disease would be much more widespread.

Fortunately, very recently the World Health Organisation have announced that an Ebola survivor's blood can be used to treat patients with Ebola. Antibodies produced in the survivors blood should be used and transferred to a patient. They cannot be sure of effectiveness just yet. From the 1995 outbreak in the Democratic Republic of Congo seven out of eight people survived who were given the therapy.

Volunteering at a Carehome

Having volunteered for a week last summer, I decided to go back to Anisha Grange Care Home for the elderly for another week this summer, having enjoyed the experience of helping the elderly, sometimes just by talking to them.

I learned a lot through this experience. One thing I in particular was the importance of treating each one as an individual and getting to know how to approach each person is important. I learned about the complexities of dementia which is becoming an increasing problem for the ageing population of Britain.   It was important to recognise that this illness is a very personal to the individual it affects. It can develop causing residents to be very different from how they would usually behave or magnify how they would normally act. All residents are at different stages of the illness. Taking all this into consideration, understanding and compassion are vital in how you should treat residents with dementia.

For example we were potting flowers whilst drinking tea when a resident confused a gardening shear for a spoon and began to stir her tea with it. Seeing this I explained I would get her a new cup of tea and a spoon, and upon prizing the shears away she was very angry and confused which was understandable. It is important not to run out of patience.

In addition last year I remember going on a ward round with the nurses on the dementia floor (called The Primrose Community). This was far more challenging than I thought it would be. They had to check some peoples blood pressure everyday and many of the residents were very resistant to it, as they didn't understand who/why/what was going on. It takes a lot of necessary patience and understanding. Some nurses had scratches and cuts up there arms and face from frightened residents, so it was a shocking eye opener to Alzheimer's disease.   

It can still be rewarding. A lovely moment with resident was when she was distressed as she kept muttering her husband's name and asking where he was. Music was playing in the background and having remembered that she liked dancing previously, I commented on the music and about how it is a great dance number. She immediately got distracted and broke out of her trance and talked about how she loved dancing. 

Another resident, who was brought into the home by the social services two days a week, talked for a long time about her situation at home with her son. She talked about how she wanted to stay at the care home and dreaded going back. She enjoyed her two days a week just by being able to talk to other residents, staff and volunteers. She told her me story over and over again but at least it helped her to have somebody to talk to. She was slow and frail but when it came to knitting, her speed was worthy of a gold at the olympics and she thoroughly enjoyed teaching me. 

I gained a lot from the week of volunteering and will organise to go back for a few hours every week, so I can continue to see the residents. 

It is perceived that most people send their elderly relatives to a carehome where they live the last few months of their life peacefully. However the main thing I learnt is that the residents do not go into the home to die, but rather, to live.

Tomorrow's Doctors

The General Medical Council's aim is to protect patients. They have published a number of documents which act as guidelines by which doctors should follow. 

The Tomorrow’s Doctors document created by the General Medical Council states the roles of the NHS, doctors, medical students and outcomes for graduates. The Good Medical Practice document expands on the duties of doctors that should be second nature to them.

It ensures that the "Tomorrow's Doctors" (Like me hopefully!) can enter and maintain a good healthcare service in the UK. 

A doctor's primary concern is the care of the patients, by keeping knowledge up to date with fast changing technology, creating good relationships with patients and colleagues, acting with integrity and being honest. They are required to offer leadership and work with others in changing systems to benefit patients. This forms the basis of patient-centred care that we have in the NHS.

From reading the documents you can see that the role of a doctor is also wide ranging from being willing and able to teach medical students and communicating effectively with patients and their families and working as a team with colleagues. At work experience I was able to see how crucial it was for doctors to have good relationships with nurses, as well as other doctors for a professional smooth running health service. I also shadowed an FY2 doctor who showed enthusiasm in fulfilling a teaching role, which I enjoyed, as he explained simple procedures to me, such as inserting cannulas and showed me CT scans.

Case study

From reading the document I observed that the doctor must deal with many wide-ranging complex and uncertain situations:

.      "If patients are at risk because of inadequate premises, equipment or other resources, policies or systems, you should put the matter right if that is possible."
"Good Medical Practice (2013)", paragraph 25b

At work experience at Broomfield Hospital I observed an issue regarding lack of resources, which is becoming a prevalent issue in the NHS. A patient who had travelled for 2 hours arrived at the gynecology ward with a lack of beds available. The nurses and doctors had to communicate considerately and effectively and explain the difficult situation at the hospital which means they must be sent home. Therefore some aspects of the job are frustrating when you want to help but some factors are limited beyond your control.

Challenges

Whilst prospective doctors just to help people, they must bear in mind that things can go wrong:

 "55  You must be open and honest with patients if things go wrong. If a patient under your care has suffered harm or distress, you should:

53. 1. a  put matters right (if that is possible)
       
    2. b  offer an apology
       
    3. c  explain fully and promptly what has happened and the likely short-term and long-term effects."
       "Good Medical Practice (2013)"
54. 
    
55. This is especially important as a junior doctor where you will be carrying out new procedures under pressure and you must be prepared to make mistakes, respond appropriately, learn and move on. However things can even go wrong with a doctor having twenty years of experience so it is just part of the profession. It is something to bear in mind but not necessarily be discouraged by.

Three Outcomes of Graduates

In accordance with Good Medical Practice undergraduates are trained to provide and improve health and care of patients as scholars and scientists, practitioners and professionals. 

1) The Doctor as a Scholar and Scientist

This requires being able to apply knowledge gained to medical practice.

2) The Doctor as a Practitioner

This includes being able to carry out a consultation with a patient.
Difficulties in this include when doctors must assess patients capacity to make a particular decision in accordance with legal requirements (Gillick competence for under 16s)
You must provide an explanation, advice, reassurance, whilst staying honest.

3) The Doctor as a Professional 

This is behaving in accordance with ethical and legal principles. 

It includes reflecting, learning and teaching others: being a doctor includes lifelong learning academically and socially (something I would enjoy).


Finally...

Peter Rubin (chair of GMC) states that we will see huge changes in medical practice with continuing developments, new health priorities and rising expectations. Learning about the complexities and difficulties of being a doctor, whilst slightly daunting, makes me more excited to rise to the challenge in the ever-changing field of medicine.