0100000101101100011110100110100001100101011010010110110101100101011100100010011101110011001000000110010001101001011 1001101100101011000010111001101100101001110100010000001100001001000000111000001110010011011110110011101110010011001 0101110011011100110110100101110110011001010010000001100110011011110111001001101101001000000110111101100110001000000 1110000011100100110010101110011011001010110111001101001011011000110010100100000011001000110010101101101011001010110 1110011101000110100101100001001000000111010001101000011000010111010000100000011010010111001100100000011100110110100 1011011010110100101101100011000010111001000100000011101000110111100100000011100110110010101101110011010010110110001 1001010010000001100100011001010110110101100101011011100111010001101001011000010010000001100101011110000110001101100 1010111000001110100001000000111010001101000011000010111010000100000011010010111010000100000011101010111001101110101 0110000101101100011011000111100100100000011100110111010001100001011100100111010001110011001000000110100101101110001 0000001110100011010000110010100100000001101000011000001110011001000000110111101110010001000000011010100110000011100 1100111011001000000110011001101001011100100111001101110100001000000111001101111001011011010111000001110100011011110 1101101011100110010000001100001011100100110010100100000011010010110110101110000011000010110100101110010011001010110 0100001000000110110101100101011011010110111101110010011110010010000001110111011010000110100101100011011010000010000 0011010010111001100100000011001100110111101101100011011000110111101110111011001010110010000100000011000100111100100 1000000110100101101101011100000110000101101001011100100110010101100100001000000111010001101000011011110111010101100 1110110100001110100001000000110000101101110011001000010000001110011011100000110010101100101011000110110100000100000 0110000101101110011001000010000001100110011010010110111001100001011011000110110001111001001000000110001101101111011 0110101110000011011000110010101110100011001010010000001101000011001010110110001110000011011000110010101110011011100 1101101110011001010111001101110011 010000010110110001111010011010000110010101101001011011010110010101110010001001110 1110011001000000110010001101001011100110110010101100001011100110110010100111010001000000110000100100000011100000111 0010011011110110011101110010011001010111001101110011011010010111011001100101001000000110011001101111011100100110110 1001000000110111101100110001000000111000001110010011001010111001101100101011011100110100101101100011001010010000001 1001000110010101101101011001010110111001110100011010010110000100100000011101000110100001100001011101000010000001101 0010111001100100000011100110110100101101101011010010110110001100001011100100010000001110100011011110010000001110011 0110010101101110011010010110110001100101001000000110010001100101011011010110010101101110011101000110100101100001001 0000001100101011110000110001101100101011100000111010000100000011101000110100001100001011101000010000001101001011101 0000100000011101010111001101110101011000010110110001101100011110010010000001110011011101000110000101110010011101000 1110011001000000110100101101110001000000111010001101000011001010010000000110100001100000111001100100000011011110111 0010001000000011010100110000011100110011101100100000011001100110100101110010011100110111010000100000011100110111100 1011011010111000001110100011011110110110101110011001000000110000101110010011001010010000001101001011011010111000001 1000010110100101110010011001010110010000100000011011010110010101101101011011110111001001111001001000000111011101101 0000110100101100011011010000010000001101001011100110010000001100110011011110110110001101100011011110111011101100101 0110010000100000011000100111100100100000011010010110110101110000011000010110100101110010011001010110010000100000011 1010001101000011011110111010101100111011010000111010000100000011000010110111001100100001000000111001101110000011001 0101100101011000110110100000100000011000010110111001100100001000000110011001101001011011100110000101101100011011000 1111001001000000110001101101111011011010111000001101100011001010111010001100101001000000110100001100101011011000111 00000110110001100101011100110111001101101110011001010111001101110011 01000001011011000111101001101000011001010110100 1011011010110010101110010001001110111001100100000011001000110100101110011011001010110000101110011011001010011101000 1000000110000100100000011100000111001001101111011001110111001001100101011100110111001101101001011101100110010100100 0000110011001101111011100100110110100100000011011110110011000100000011100000111001001100101011100110110010101101110 0110100101101100011001010010000001100100011001010110110101100101011011100111010001101001011000010010000001110100011 0100001100001011101000010000001101001011100110010000001110011011010010110110101101001011011000110000101110010001000 0001110100011011110010000001110011011001010110111001101001011011000110010100100000011001000110010101101101011001010 1101110011101000110100101100001001000000110010101111000011000110110010101110000011101000010000001110100011010000110 0001011101000010000001101001011101000010000001110101011100110111010101100001011011000110110001111001001000000111001 1011101000110000101110010011101000111001100100000011010010110111000100000011101000110100001100101001000000011010000 1100000111001100100000011011110111001000100000001101010011000001110011001110110010000001100110011010010111001001110 0110111010000100000011100110111100101101101011100000111010001101111011011010111001100100000011000010111001001100101 0010000001101001011011010111000001100001011010010111001001100101011001000010000001101101011001010110110101101111011 1001001111001001000000111011101101000011010010110001101101000001000000110100101110011001000000110011001101111011011 0001101100011011110111011101100101011001000010000001100010011110010010000001101001011011010111000001100001011010010 1110010011001010110010000100000011101000110100001101111011101010110011101101000011101000010000001100001011011100110 0100001000000111001101110000011001010110010101100011011010000010000001100001011011100110010000100000011001100110100 1011011100110000101101100011011000111100100100000011000110110111101101101011100000110110001100101011101000110010100 100000011010000110010101101100011100000110110001100101011100110111001101101110011001010111001101110011 0100000101101 1000111101001101000011001010110100101101101011001010111001000100111011100110010000001100100011010010111001101100101 0110000101110011011001010011101000100000011000010010000001110000011100100110111101100111011100100110010101110011011 1001101101001011101100110010100100000011001100110111101110010011011010010000001101111011001100010000001110000011100 1001100101011100110110010101101110011010010110110001100101001000000110010001100101011011010110010101101110011101000 1101001011000010010000001110100011010000110000101110100001000000110100101110011001000000111001101101001011011010110 1001011011000110000101110010001000000111010001101111001000000111001101100101011011100110100101101100011001010010000 0011001000110010101101101011001010110111001110100011010010110000100100000011001010111100001100011011001010111000001 1 1101000010000001110100011010000110000101110100001000000110100101110100001000000111010101110011011101010110000101101 1000110110001111001001000000111001101110100011000010111001001110100011100110010000001101001011011100010000001110100 0110100001100101001000000011010000110000011100110010000001101111011100100010000000110101001100000111001100111011001 0000001100110011010010111001001110011011101000010000001110011011110010110110101110000011101000110111101101101011100
2
3
4
Contents
5
Alzheimer’s disease An introduction to the disease and its history
7
The Brain How the Brain works.
9
What’s happening? The science behind Alzheimer’s disease.
11
The Genome The link between our genetic makeup and the disease
17
Insulin & Alzheimer’s Insulin and its increasingly more obvious relationship with Alzheimer’s disease.
20
The Body’s own defense Your body’s defense against the disease.
22
The search for a cure New research and emerging miracle cures
24
References Further reading and information
28
5
6
Alzheimer’s disease
Alzheimer’s disease is an irreversible, progressive brain disease that slowly destroys memory and thinking skills and, eventually, even the ability to carry out the simplest tasks of daily living. In most people with Alzheimer’s, symptoms first appear after age 60 and Alzheimer’s disease is the most common cause of dementia among older people in our society today. The disease is named after Dr. Alois Alzheimer. In 1906, Alzheimer noticed changes in the brain tissue of a woman who had died of an unusual and unknown mental illness. Her symptoms included memory loss, language problems, and unpredictable behaviour. After she died, he examined her brain and found many abnormal clumps and tangled bundles of fibres (now known as Amyloid plaques and neurofibrillary tangles). Plaques and tangles in the brain are two of the main features of Alzheimer’s disease. The third is the loss of connections between nerve cells in the brain.
7
8
The Brain
In a healthy human brain information travels down millions of nerve cells. The information jumps from cell to cell via tiny microscopic gaps between connecting filaments that are part of these cells: ‘Synapses’.
9
Healthy
Alzheimer’s
APP APP
Beta Amyloid
Cell membrane
Alpha-secretase
Gamma-secretase
Cell membrane
Cell membrane
Gamma-secretase
Cell membrane
10
Beta-secretase
What’s Happening
In a healthy cell membrane, proteins are produced and cut by special enzymes. Alpha-secretase usually cuts the first part of these protein strings off forming Amyloid Precursor Protein or ‘APP’. Then another enzyme, called Gamma-secretase, cuts APP in another place. For convenience we will call these enzymes ‘Alpha’ and ‘Gamma’. These released fragments are thought to be beneficial to the workings of the brain. In a brain suffering with Alzheimers, instead of Alpha doing its usual job, an enzyme called Beta-secretase now makes the first cut. This, coupled with the Gamma enzyme doing its usual job, results in fragments of this APP protein being released into the brain. These fragments are called Beta Amyloid. The become tangled together becoming toxic and disrupting the normal functions of the synapses and killing cells. These clumps grow in size and become insoluble eventually forming Beta Amyloid plaques.
11
12
Beta Amyloid plaques 13
14
Neurofibrillary tangles are made when a protein called Tau is modified. In normal brain cells Tau stabilises structures critical to the cells internal transport system. Nutrients and other cargo are transported up and down structures called microtubules to all parts of the neuron. In Alzheimer’s disease abnormal Tau separates from the microtubules causing them to fall apart. Strands of this Tau combine to create tangles inside the neuron disabling the transport system and ultimately destroying the cell. As this continues cells in the brain die causing the tell tale signs of the disease and causing the brain to physically shrink in size. 15
16
Our genes dictate who we are and how we are different from other human beings. Our ‘genetic code’ is contained in our human DNA, which is made up of about 30,000 genes that dictate everything from our eye colour to the size of our big toe and even our propensity to suffer from certain specific illnesses during our life time. Illnesses can be caused by slight alterations to our genetic code that come about by mutations in a sequence which can cause abnormal proteins to be made. Build-ups of these abnormal proteins can lead to disease. Scientists have identified two forms of Alzheimer’s: early onset, which is caused by a rare genetic mutation, and the more common late onset form where the genetics is less clear. Early onset is believed to be caused by an inherited gene mutation and often occurs between the ages of 40 and 60. In terms of proportion this is about 5% of all cases.
The Genome
Late onset is the more common cause and is just one of the forms of dementia that has historically come with growing old. It is generally seen as caused by both environmental and genetic risk factors. The age of onset is commonly from the age of 60 onwards but the majority of cases are 70 or older. This group account for 95% of Alzheimer’s sufferers. The risks of genetically inheriting the disease are thought to be down to what are named by researchers as ‘susceptibility factors’. Each susceptibility factor does very little on its own and doesn’t raise the risk hugely. But if an individual has several susceptibility factors and they are significant then their risk may be increased: Put enough significant risks together and it increases the chances of developing the disease substantially.
17
A susceptibility gene for late-onset Alzheimer’s is a gene called ApoE which has been identified and is known to be involved with mediating cholesterol. It’s genetically variable so there can be different variants of ApoE just like different eye colours. Increasing levels of Cholesterol in the blood are a known risk for heart disease. The TA variant of the same gene has also been studied of late for its role in Alzheimer’s disease. Defects in ApoE have been associated with greater risk of Alzheimer’s. ApoE has been called ‘the poster child’ for the susceptibility factor concept: It’s a gene we all have, you can grow old with the bad form and be fine, but your risk of contracting the disease is increased As you grow into old age the risk of getting Alzheimer’s gets higher and higher. If you had a parent that had Alzheimer’s in their early 80s, that’s probably not that atypical, and you can probably assume that maybe they didn’t have that many susceptibility genes, and correspondingly you won’Wt have that many. Scientists reckon that, If you are lucky, and there is no family history of Alzheimer’s then there’s approximately a 10% lifetime risk of developing the disease; history among your close relatives can elevate the risk to 20%.
18
19
Insulin & Alzheimer’s
You may not know that Insulin has an important role to play in the body. It is required for the Brain to function and it is also associated with ageing of the brain as well as ageing of the body.
Glucose
The Pancreas creates insulin, a type of small protein called a Peptide, in response to glucose, which is a primary fuel for cells in the body and in the brain. Glucose needs insulin in order to transport it into the cells to do its work. Too much glucose results in a build up of insulin outside cells of the body, which leads to ‘insulin resistance’. Diabetes is the disease that affects us when Glucose levels exceed a certain level. Insulin resistance leads to a whole series of life effecting diseases; diabetes, cardiovascular disease, small stroke, and hypertension. Scientists have now also identified that all these diseases also contribute to the risk of contracting Alzheimer’s. 4. Approximately 25-30% of adults over 60 have insulin resistance; called VSA. With the rise in obesity and sedentary life style, insulin resistance and diabetes are becoming more and more prevalent in todays society. Most people have no idea they have insulin resistance. Glucose levels can be within normal levels but medical practitioners don’t test insulin resistance; there is no standard test. Treating insulin resistance can be done in a number of ways; the most potent of which is aerobic exercise. One small bout of exercise improves insulin function for 24 hours. Good diet is also important. Visceral fat which is the fat found around the body’s organs is bad for the body function. Subcutaneous fat, which lies under the skin, is more beneficial for the body. In a test it was shown just how bad for the body a high fat high sugar diet was, vs. a low fat low sugar diet. It showed that on the high fat and sugar diet more Beta Amyloid (the toxic protein fragments associated with Alzheimer’s sufferers brains we highlighted earlier), was found in the spinal fluid. The low fat diet led to lower insulin and lower Beta Amyloid. 20
Glycogen
glucose transporter 1. 3. glucose transporter
insulin receptor
2.
6.
Pyruvate 5. Fatty acids
Insulin promotes Glucose take up in the Hippocampus which affects memory. It is thought to strengthen connections through brain cells, which is thought to underlie the formation of memories. A memory is just a pattern of connections between neurons, so anything that effects this or modulates it will have an impact on memories. In tests diabetics and unhealthy older people tend to have the most effect on memory. New treatments are currently being trialled around insulin resistance. An example is a study to correct insulin resistance, which is being carried out by administering insulin through an ‘intranasal process’, sending the insulin straight to the brain with less affect on the rest of the body.
21
The key protagonist in Alzheimer’s, Beta Amyloid, is seen by the body as abnormal and attacked by the body’s immune system which causes ‘inflammation’. Inflammation is the system the body uses to rid itself of ‘alien invaders’ such as bacteria and viruses. A build up of Beta Amyloid in the brain causes the immune system to go on the attack to get rid of this excess protein. The inflammatory cells in the brain that attack this Beta Amyloid are called ‘Microglia’. Researchers believe that whilst this process may well be working in Alzheimer’s patients it may not be working well enough.
22
The body’s own defence
Beta Amyloid is a ‘tough assignment’ for the Microglia because it is very insoluble and difficult to break down. A flood of inflammatory cells attack the Beta Amyloid but they can also destroy healthy tissue, as collateral damage, so any treatments that involve use of these cells need to be handled very carefully. Researchers have managed to grow brain cells in the laboratory. These form lots of networks between cells, which are very similar to what is happening in the brain. When Beta Amyloid is introduced these networks start to breakdown. When tests were carried out on the brains of mice that had been genetically engineered to have Alzheimer’s, researchers were able to show that when they introduced inflammatory cells these links between nerve cells were broken. This shows that part of the decline in brain function is formed by the natural clearing process of the body. This opens doors for experimenting with existing anti-inflammatory drugs as inflammation is a process we already understand and can, to an extent, control.
23
An exciting potential new therapy being tested by scientists as a treatment for Alzheimer’s disease involves an experimental helmet which delivers low levels of infra-red light, which researchers at the University of Sunderland, believe may stimulate the growth of brain cells. Trial participants wear the helmet for 10 minutes a day and tests in mice have showed that it improved learning ability. The infra-red therapy was first developed to treat cold sores.
As cells age they lose the ability to repair and regenerate them selves, which in the brain leads to loss of memory. Currently all that can be achieved with dementia is to slow down the rate of decay and it’s hoped that the new process will not only stop that rate of decay but partially reverse it. The Alzheimer’s Society has commented positively stating, “A treatment that reverses the effects of dementia rather than just temporarily halting its symptoms could change the lives of the hundreds of thousands of people who live with this devastating condition. We look forward to further research to determine whether it could help improve cognition in humans. Only then can we begin to investigate whether near infra-red could benefit people with dementia.”
24
The search for a cure
Based on the results of work done by Dr Gordon Dougal, a GP and director of Virulite, a medical research company based in County Durham, tests in people with dementia using infra-red lasers, showed an improvement in cognitive ability in eight out of nine people tested. The helmet was developed in order to safely deliver the treatment through the scalp. The helmet bathes the brain in low levels of infra-red light and only needs to be worn for 10 minutes a day. Trials of 100 people with age-related memory problems will look to see if the beneficial results seen in previous test on mice, which showed beneficial results, can be replicated in humans.
Terry Pratchett – trialling an experimnetal infra-red light helmet
25
Many of these remedies have no proven benefits to Alzheimer sufferers. However there are some remedies that do appear to have some benefits and these are the ones that scientists are studying more closely to try and fully understand how they help. There is some evidence, for example, that regular use of anti oxidants can have some beneficial effects. Scientists know that oxidative damage to cells increases with Alzheimer’s patients. Oxidative damage is a by-product of the brain using oxygen. There is some inefficiency in the way brain cells use oxygen which causes oxidative damage or injures molecules, proteins lipids and nucleic acid. This damage causes them to dysfunction. Oxidative damage to cells can be seen as the molecular equivalent to rust on metal.
26
Dietary studies have been carried out using aged dogs as the patients because its easier to feed a dog a very controlled diet over the 3 years of the study. Dogs also suffer from cognitive decline in the same way humans do. The group of dogs was fed an antioxidant enriched diet and their cognition was studied for 3 years. The results of the study showed that antioxidants looked to rejuvenate and improve cognitive performance in the dogs. It is also believed that exercise may be beneficial because it raises levels of brain derived neurotropic factor; BDNF. This is a protein found in the brain that acts something like a growth fertilizer for brain cells and scientists have identified that BDNF is also vulnerable in Alzheimer’s sufferers. Again, using the results of a study using animals, it has been possible to see benefits from exercise. Two groups of mice were studied. The first group lived just in their cages with no access to a running gym or any other form of execrcise. The second group had access to a running gym which they use mainly at night. The cognitive test involved a water maze where the mice are put in the water and have to find their way out using repetitive markings as a guide to help. The results were better for the mice with the exercise wheel implying greater cognitive powers as a result of frequent excercise. Sadly the benefits of exercise may well delay the onset of Alzheimer’s disease but it doesn’t necessarily stop it.
27
20% Likelihood with a family history of Alzheimer’s.
28
Following its discovery in 1906 and the general increase in life expectancy, particularly in the latter half of the 20th century, Alzheimer’s has more and more become the affliction of the elderly and the disease to be feared, almost as much as the big ‘C’.
You have a 1 in 10 likelihood of developing Alzheimer’s in your late 70’s or - early 80’s.
The up side to this increased profile for the disease is that more money has been poured into research and so the progress in our knowledge over the last 20 years has been significant. Scientist now know much about the disease; what it is, how it works, what its causes are and correspondingly what life style changes can reduce our risk of developing the disease and what we can do to restrict its progress once diagnosed. Today our chances of suffering from Alzheimer’s in old age, the most prevalent form of the disease, are one in ten, if there is no family history, but double that if there is. Advances in science however may give those in their 30’s and 40’s today the hope that this disease will be far less of a menace when they reach their 60’s. Maybe the success story of Polio in the first part of the 21st century will be the Alzheimer’s story of the next generation.
29
30
Terry Pratchett Living with Alzheimers: part 1 and part 2 A BBC docomentary following the life of Terry Pratchett, a famous science fiction author, as he copes with the onset of Alzheimer’s disease. The Alzheimer’s Association www.alz.org
References
The Alzheimer’s society www.alzheimers.org.uk Alzheimer’s Research UK www.alzheimersresearchuk.org Louis Theroux Extreme Love: Dementia A documentary in which Louis Theroux travels to America to and spends time with Alzheimer’s sufferers with varying stages of the disease. The Alzheimer’s Project www.hbo.com/alzheimers
31
32
33
0100000101101100011110100110100001100101011010010110110101100101011100100010011101110011001000000110010001101001011 1001101100101011000010111001101100101001110100010000001100001001000000111000001110010011011110110011101110010011001 0101110011011100110110100101110110011001010010000001100110011011110111001001101101001000000110111101100110001000000 1110000011100100110010101110011011001010110111001101001011011000110010100100000011001000110010101101101011001010110 1110011101000110100101100001001000000111010001101000011000010111010000100000011010010111001100100000011100110110100 1011011010110100101101100011000010111001000100000011101000110111100100000011100110110010101101110011010010110110001 1001010010000001100100011001010110110101100101011011100111010001101001011000010010000001100101011110000110001101100 1010111000001110100001000000111010001101000011000010111010000100000011010010111010000100000011101010111001101110101 0110000101101100011011000111100100100000011100110111010001100001011100100111010001110011001000000110100101101110001 0000001110100011010000110010100100000001101000011000001110011001000000110111101110010001000000011010100110000011100 1100111011001000000110011001101001011100100111001101110100001000000111001101111001011011010111000001110100011011110 1101101011100110010000001100001011100100110010100100000011010010110110101110000011000010110100101110010011001010110 0100001000000110110101100101011011010110111101110010011110010010000001110111011010000110100101100011011010000010000 0011010010111001100100000011001100110111101101100011011000110111101110111011001010110010000100000011000100111100100 1000000110100101101101011100000110000101101001011100100110010101100100001000000111010001101000011011110111010101100 1110110100001110100001000000110000101101110011001000010000001110011011100000110010101100101011000110110100000100000 0110000101101110011001000010000001100110011010010110111001100001011011000110110001111001001000000110001101101111011 0110101110000011011000110010101110100011001010010000001101000011001010110110001110000011011000110010101110011011100 1101101110011001010111001101110011 010000010110110001111010011010000110010101101001011011010110010101110010001001110 1110011001000000110010001101001011100110110010101100001011100110110010100111010001000000110000100100000011100000111 0010011011110110011101110010011001010111001101110011011010010111011001100101001000000110011001101111011100100110110 1001000000110111101100110001000000111000001110010011001010111001101100101011011100110100101101100011001010010000001 1001000110010101101101011001010110111001110100011010010110000100100000011101000110100001100001011101000010000001101 0010111001100100000011100110110100101101101011010010110110001100001011100100010000001110100011011110010000001110011 0110010101101110011010010110110001100101001000000110010001100101011011010110010101101110011101000110100101100001001 0000001100101011110000110001101100101011100000111010000100000011101000110100001100001011101000010000001101001011101 0000100000011101010111001101110101011000010110110001101100011110010010000001110011011101000110000101110010011101000 1110011001000000110100101101110001000000111010001101000011001010010000000110100001100000111001100100000011011110111 0010001000000011010100110000011100110011101100100000011001100110100101110010011100110111010000100000011100110111100 1011011010111000001110100011011110110110101110011001000000110000101110010011001010010000001101001011011010111000001 1000010110100101110010011001010110010000100000011011010110010101101101011011110111001001111001001000000111011101101 0000110100101100011011010000010000001101001011100110010000001100110011011110110110001101100011011110111011101100101 0110010000100000011000100111100100100000011010010110110101110000011000010110100101110010011001010110010000100000011 1010001101000011011110111010101100111011010000111010000100000011000010110111001100100001000000111001101110000011001 0101100101011000110110100000100000011000010110111001100100001000000110011001101001011011100110000101101100011011000 1111001001000000110001101101111011011010111000001101100011001010111010001100101001000000110100001100101011011000111 00000110110001100101011100110111001101101110011001010111001101110011 01000001011011000111101001101000011001010110100 1011011010110010101110010001001110111001100100000011001000110100101110011011001010110000101110011011001010011101000 1000000110000100100000011100000111001001101111011001110111001001100101011100110111001101101001011101100110010100100 0000110011001101111011100100110110100100000011011110110011000100000011100000111001001100101011100110110010101101110 0110100101101100011001010010000001100100011001010110110101100101011011100111010001101001011000010010000001110100011 0100001100001011101000010000001101001011100110010000001110011011010010110110101101001011011000110000101110010001000 0001110100011011110010000001110011011001010110111001101001011011000110010100100000011001000110010101101101011001010 1101110011101000110100101100001001000000110010101111000011000110110010101110000011101000010000001110100011010000110 0001011101000010000001101001011101000010000001110101011100110111010101100001011011000110110001111001001000000111001 1011101000110000101110010011101000111001100100000011010010110111000100000011101000110100001100101001000000011010000 1100000111001100100000011011110111001000100000001101010011000001110011001110110010000001100110011010010111001001110 0110111010000100000011100110111100101101101011100000111010001101111011011010111001100100000011000010111001001100101 0010000001101001011011010111000001100001011010010111001001100101011001000010000001101101011001010110110101101111011 1001001111001001000000111011101101000011010010110001101101000001000000110100101110011001000000110011001101111011011 0001101100011011110111011101100101011001000010000001100010011110010010000001101001011011010111000001100001011010010 1110010011001010110010000100000011101000110100001101111011101010110011101101000011101000010000001100001011011100110 0100001000000111001101110000011001010110010101100011011010000010000001100001011011100110010000100000011001100110100 1011011100110000101101100011011000111100100100000011000110110111101101101011100000110110001100101011101000110010100 100000011010000110010101101100011100000110110001100101011100110111001101101110011001010111001101110011 0100000101101 1000111101001101000011001010110100101101101011001010111001000100111011100110010000001100100011010010111001101100101 0110000101110011011001010011101000100000011000010010000001110000011100100110111101100111011100100110010101110011011 1001101101001011101100110010100100000011001100110111101110010011011010010000001101111011001100010000001110000011100 1001100101011100110110010101101110011010010110110001100101001000000110010001100101011011010110010101101110011101000 1101001011000010010000001110100011010000110000101110100001000000110100101110011001000000111001101101001011011010110 1001011011000110000101110010001000000111010001101111001000000111001101100101011011100110100101101100011001010010000 0011001000110010101101101011001010110111001110100011010010110000100100000011001010111100001100011011001010111000001 34 1101000010000001110100011010000110000101110100001000000110100101110100001000000111010101110011011101010110000101101 1000110110001111001001000000111001101110100011000010111001001110100011100110010000001101001011011100010000001110100 0110100001100101001000000011010000110000011100110010000001101111011100100010000000110101001100000111001100111011001 0000001100110011010010111001001110011011101000010000001110011011110010110110101110000011101000110111101101101011100