Dementia

"Dementia – a chronic or persistent disorder of the mental processes marked by memory disorders, personality changes, impaired reasoning, etc. due to brain disease or injury"

- Oxford Concise Dictionary

Nearly 18 million people in the world suffer from dementia, the majority resulting from general brain deterioration with old age and thus affecting one in twenty of people over sixty five and one in five people over eighty1. However dementia can also be obtained congenitally or through severe injury allowing it to prevail in those of young age as well. The human brain, which many scientists believe to be the most complex organ in the universe, is composed of an incredibly intricate design with separate regions of the brain accounting for different characteristics. The cerebellum has been associated with coordination and movement, the olfactory bulb with smell, the hippocampus with memory processing etc. For this reason the list of brain diseases is vast and always growing. In diagnosing dementia a neurologist looks for features which would affect an individual's lifestyle such as memory difficulties and impaired reasoning. Straightforward tests such as instructing a patient to remember a set of cards can be used to discover whether he/she is a sufferer. More recently, Dr. Andrew Blackwell, Sahakian and several colleagues of Cambridge University devised two simple tests which have been shown to be completely accurate in detecting dementia2. By combining the patient's age with two simple tests, physicians can now diagnose dementia earlier allowing ready treatment which can slow down the onset of neuro-degeneration. The causes of dementia are huge in number, spanning from the most common Alzheimer's disease to alcohol dementia. Since such a complex set of several systems is required to maintain the functions which are affected by dementia (e.g. memory and personality) an error in a single junction can result in massive adjustments to a person's abilities. One of the most commonly affected features of a person in dementia is memory. Although continuing evidence is helping us to understand the mechanisms of memory in the brain, there still remains much to be discovered. Memory's influence in shaping ones personality is enormous giving us our childhood memories as well as enhancing our chances of survival in a threatening situation. The arrangement of the brain in respect to memory is highly convoluted in that memory can be defined as so many different concepts. There is the notion of reminiscence of one's youth, ability to navigate around a familiar area, and even those memories which appeal to our senses; Smells can remind us of a place, sounds can help up recognise a voice, and even taste can cause to recall an occasion. To understand how causes of dementia affect our memory, one must first understand how memory is processed and stored in the brain. Biological foundation of memory

Still today neurological researchers are trying to understand the details of memory however many studies, some rather tragic, have demonstrated the significance of certain regions of the brain in forming our memories, both in processing and storage. One such case involved a patient, H.M.3 (remains anonymous), who suffered from epileptic seizures regularly. Neurosurgeons removed his medial temporal lobes which included the amygdala and hippocampus. The fact that H.M. could no longer form memories implied that the hippocampus was vital in developing memories. H.M.'s long term memories were still intact and could be recalled by him clearly suggesting that although memories may be processed by the hippocampus, they are stored in a different area. The role of the hippocampus has since been confirmed by positron emission topography (PET) and functional magnetic resonance imaging (fMRI). These brain images measure increases in the rate of blood flow to an area. When performing an action which involves a certain region of the brain, the rate at which neurons fire in that area increases which consequently increases blood flow. Thus the imaging techniques have confirmed that when people are memorising new information, the hippocampus is active. However where are memories stored? The fact that memory can take many different forms e.g. recognition of a human, finding one's way round or nostalgic reminiscence suggests that several areas of the brain would be involved in memory retrieval. Actually this is in some ways true. In a rare disease known as Capgras syndrome the individual can see perfectly but when approached by his parents, he immediately claims they are impostors. Analysis of the patient's brain shows no problem with the hippocampus but instead damage to the neurons connecting the fusiform gyrus and amygdala. The fusiform gyrus is concerned with the process of identification of the object/person being looked at. Once recognised the impulse is sent to the amygdala which informs you emotionally of what you are looking at. Thus one recognises ones parents but feels no emotions towards them causing them to think that these could only possibly be frauds. Capgras syndrome reveals how important a role emotion can play in memory.3 A similar connection has recently been studied by Kim Dalton4 who was analysing the fusiform gyrus as the source of autism's characteristic eye avoidance. She was surprised to find that in fact the amygdala, being overactive in autistics, may be at the root of the disorder suggesting that an abundance of emotions is causing this avoidance. There is also evidence that the areas of the hippocampus are involved in memory retrieval, particularly the aspect of navigation. Studies in rats have shown that when placed in area of familiarity certain neurons in the hippocampus, called place cells, begin to fire. On examining epileptics, these same place cells have been found in the hippocampus of humans leading neurologists to believe that the hippocampus constitutes our ability to find new shortcuts as well as steer ourselves on a return course5. However the notion of memories and learning has primarily been attributed to the synapses, gaps between nerve cells where chemicals known as neurotransmitters diffuse across to maintain a nerve impulse. The nerve which sends the impulse is known as the presynaptic cell and the receiving cell, the postsynaptic cell. During the transfer of an impulse, calcium channels in the presynaptic cell cause an influx of calcium ions. These ions encourage vesicles containing neurotransmitters to fuse with the synaptic membrane thus releasing the chemicals into the synapse. When the neurotransmitters reach the postsynaptic cell, receptors bind to the chemicals stimulating a release or uptake of ions.6 This causes a change in the potential across the membrane which can be short term or long term. In 1949 Donald Hebb, a Canadian psychologist, published The Organisation of the Brain in which he proposed the idea of synaptic plasticity. This theory states:

"Let us assume that the persistence or repetition of a reverberatory activity (or "trace") tends to induce lasting cellular changes that add to its stability.… When an axon of cell A is near enough to excite a cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A's efficiency, as one of the cells firing B, is increased."7

Evidence since Hebb has shown support of his theory and contributed to its understanding. However the mechanism of a neuron increasing its efficient involves complex . , distinguished neurologist and Nobel laureate, performed brain studies on marine snails which shed light on the formation of both short-term and long-term memory. In short term memory the stimulus is weak generating a short term change in trans-membrane potential and thus causing little change in synaptic function. In long term memory the strong stimulus generates a long term change in the potential across the membrane. These long term changes cause second messenger neurotransmitter to be released into the nerve cell's nucleus instigating protein synthesis. This production of messenger RNA induces changes in the structure of the neuron which make it more efficient hence synaptic plasticity and the storage of long-term memories. Kandel's research on memory also showed that the presence of phosphate groups facilitated the passing of calcium and other ions through the synapse in a process known as phosphorylation.8

Common Forms of Dementia

Alzheimer's disease

Around 55% of all people with dementia can be accounted as having Alzheimer's disease. First described by German psychiatrist Alois Alzheimer in 1906, the disease was initially thought to have affected only younger people and was often titled presenile dementia. This perhaps resulted from the belief that memory loss in the older patients was just a result of senility however we now know that early-onset Alzheimer's is very rare affecting less than 10% of Alzheimer's sufferers in the United States.9 The warning signs of Alzheimer's begin with mild difficulties in remembering new and straightforward information such as where one left one's glasses. Gradually the symptoms begin to worsen as the sufferer can no longer recall recent events or even what day of the week or month it is. The disease culminates into the patient becoming severely debilitated, no longer able to perform simple tasks such as eating. In the early studies of the disease it was found that all patients suffered from a deficiency in several neurotransmitters – serotonin, norepinephrine somatostatin and especially acetylcholine. Acetylcholine is an essential neurotransmitter which operates principally in the central nervous system and parasympathetic nervous system. This theory of acetylcholine insufficiency is known as the "cholinergic hypothesis" and gained strong popularity as the disease was initially studied. This led to the first Alzheimer's medications which sought to inhibit enzymes that catalyse the breakdown of acetylcholine (acetylcholinerases). There are two other prominent theories, one relating to the formation of beta plaques and other to tau proteins. Alzheimer's disease, being an amyloid disease, involves an accumulation of proteins in the brain. In this particular disorder the protein is amyloid beta which results from the catalysis performed by secretase enzymes on amyloid precursor protein (APP). The amyloid deposits are the root for the more intricately developed plaques. These senile plaques aggregate outside neurons inhibiting optimal performance. Then it is believed that the beta amyloid breaks into free radicals which attack the neurons. The protein may also generate channels in the neuron membranes allowing profuse amounts of calcium into the cell. Although synaptic plasticity has shown us the importance of calcium's role in the synapses, an excess of the chemical may destroy cells. There is also evidence that abnormal protein filaments, known as tau, amass in the neurons. Tau's usual function involves stabilising microtubules but here, because of an abnormal phosphorylation of the molecule, it collects in tangles, neuropil threads, and around amyloid plaques. It is not really known what the sole cause of Alzheimer's disease is, however it has since been suggested by researchers at the University of California, San Diego that nervous "traffic" may prompt the disease. They believe that the axons, which relay chemicals between neurons, become packed with cellular debris. This clogging up of the nerve transportation path may encourage the growth of amyloid plaques. The role of amyloid beta and tau protein in being the main cause of Alzheimer's disease has since been questioned because autopsies have shown that even people with high levels of both of these proteins may not exhibit any symptoms. Thus it has since been suggested that these tangles may even themselves be symptoms of the disease. Immunologist researchers at the University of California, Los Angeles have recently discovered that the source of Alzheimer's disease may involve the immune system. Dr. Milan Fiala, the head researcher, found that Alzheimer's patients suffered from a flaw in their immune system which makes their macrophages, immune system cells, incapable of "cleaning away" the accumulation of amyloid beta plaque. This has strong implications for treatment of the disease in forms such as hormones or inflammation-fighting drugs which could promote the health of the immune system of the sufferer. However with all the disappointments of drugs previously used to treat Alzheimer's such as acetylcholinerases, which only mildly moderated the symptoms, one may begin to think that it is necessary to focus on the prevention of the disease. Other than the belief that ibuprofen and aspirin may delay the disease's onset, there are studies showing that a good amount of both vitamin C and E massively reduces the chance of getting Alzheimer's. The science behind it is that vitamin E absorbs the free radicals which damage nerve cells while the vitamin c "recharges" the vitamin E, making it effective once again. Results show that an excess of vitamin E has a moderate effect in delaying Alzheimer's start while an excess of vitamin C has no effect. There is a long list of suggested preventive measures including eating fish, maintaining a low cholesterol level, assimilating more B vitamin folic acid and regular physical exercise but Alzheimer's inevitability strongly correlates with age meaning that its prevention is still far from our technological status.10

Lewy Bodies

While studying patients suffering from Parkinson's disease in 1914, Dr. Frederick Lewy, a colleague of Alois Alzheimer, came across a strange phenomenon. In several of the patients, the substantia nigra had spherical protein deposits in its cells. Now known as Lewy bodies, these filaments are made of alpha synuclein protein, the same protein which is thought to be the cause of Parkinson's disease. 15% of dementia victims have dementia with Lewy bodies. Its causes relate with Alzheimer's and Parkinson's very closely. Just as Parkinson's disease, patients endure the loss of dopamine-producing neurons which is thought to be linked with the characteristic deterioration of motor control in Parkinsonians. There is also a loss of acetycholine-producing neurons as in Alzheimer's disease. These are believed to account for the loss of cognitive thinking and emotional response. On analysis of an autopsy, one would often see in the brain of a person, affected by Dementia with Lewy Bodies (DLB), degeneration of the cortex of the cerebrum. There would also be striking similarities to the hippocampus between this patient and one with Alzheimer's disease. Tau protein, one of the culprits of Alzheimer's disease, would collect in neurofibrillary tangles because of its abnormally phosphorylated structure. One would see deposits of beta amyloid plaque as well. This is no surprise as two out of three patients with DLB will experience problems with memory. Not only this but also many other symptoms draw similarities to those of Parkinson's disease. The victim may suffer from spontaneous tremors and muscle rigidity. Parkinson's symptoms come from the deposits of alpha synuclein protein on the substantia nigra which consists of two parts, the pars compacta and pars reticulate. The pars compacta is comprised of the neurons which are responsible for the nerve impulses directed to the dopamine-producing neurons in the striatum, an area believed to account for the modulation of movement pathways and consisting of a direct pathway of movement which assists movement and the indirect pathway of movement which inhibits it. Dopamine hormone's functions have been linked to pleasure, drive, cognition, and overall stability but it also has a massive influence on physical movement as has been demonstrated by Parkinson's disease. The deficiency of dopamine results in the inhibition of the direct pathway of movement and encourages activation of the indirect pathway of movement. This ultimately leads to the muscles only being able to move slowly (hypokinesia) because the scarcity of dopamine inhibits the thalamus from performing its function best which is to relay nerve impulses in the brain. The second part, the pars reticulate consists also of dopamine neurons but mainly other neurons which produce gamma-aminobutyric acid (GABA). These neurons link to the thalamus, brainstem and sometimes even the dopamine neurons found in the pars compacta. Not much is known about how change in pars reticulate is expressed as a visible symptom of DLB but it has been asserted that it is one of the nuclei involved in orientation and the control of eye movement. With all of DLB's effects being so similar to Parkinson's and Alzheimer's disease, one may wonder as to how a physician makes a distinction between them without the inspection of an autopsy or brain image scan. Diagnosing a DLB patient improperly can have hugely adverse effects since their reaction to many drugs can be highly varied, sometimes even worsening the disease. Neuroleptics are antipsychotic drugs used most often on those suffering from schizophrenia, mania, or any other general character disorder. However prescribing them to DLB patients, will often result in effects seen in Parkinson's disease such as muscle rigidity and bradykinesia. In some rare cases, it may even lead to sudden death. With the difficulty in diagnosing DLB, expanding in the field of research has been complicated. Current studies are placing emphasis on the use of PET functional brain imaging to examine areas of interest especially the cholinesterase inhibitors but there ultimately remains much to be discovered about how DLB can be treated.11

Vascular Dementia

As the second most common form of dementia after Alzheimer's disease, vascular dementia accounts for 20% of all cases of dementia. The cause involves the circulation of blood to the brain and is usually triggered by a stroke or mini-stroke. Similar to a heart attack being caused by a clogged artery, strokes are a result of blocked vessels in the brain hence hypertension is often a good predictor of whether someone will suffer a stroke. The obstruction can come from build up of plaque in the artery walls as well as a blot clot. Cells in the vessel walls degenerate as these deposits cause rigidity and restricted blood flow. Brain tissues can also be starved of oxygen if there is a lack of blood flow (ischemia). Faults in the artery wall can also cause it to grow outward like a balloon (aneurysm) where it may burst (brain hemorrhage), thus depriving the cells of oxygen ultimately resulting in the death of brain tissue. Since all regions of brain are supplied with an interlacing system of blood vessels, strokes can occur in any area and thus cause a huge catalogue of symptoms. For example, if the stroke occurs in the insula cingulate the patient will not be able to experience pain – a condition known as pain asymbolia – or if the stroke occurs in the Broca's area, they would become mute. In vascular dementia, the stroke occurs in an area which is concerned with the symptoms of dementia i.e. a stroke occurring in the hippocampus would hinder the individual's ability to create new memories. Almost any stroke in the frontal lobe will result in dementia-like symptoms since this area is associated with mysterious qualities such as moral sense and ambition. The most frequent form of vascular dementia is multi-infarct dementia (MID), so called because victims suffer a persistent series of strokes known as transient ischemic attacks (TIA), with symptoms not usually lasting longer than two or three days. One is thus able to see the disease developing in a series of clear stages as each additional stroke causes subsequent damage. Signs of MID include difficulty in social communication, spontaneous laughter and emotional swings, and hallucinations but as mentioned previously, the strokes can occur anywhere and therefore have various different effects. Very rarely a person will suffer from a distinct form of MID known as Binswanger's disease where particular damage is done to the white-matter of the brain and is seen as deep lesions, a loss of axons and myelin sheaths, and extensive gliosis. Thus a diagnosis can be simply made on analysis of a Magnetic Resonance Image. Once again it is caused by insufficient blood flow, aneurysms and generally high blood pressure. Vascular dementia is very much preventable in the same way a heart attack is. One must avoid hypertension by eating low cholesterol food, keeping away from cigarettes and too much alcohol, physical activity, or taking blood pressure lowering drugs. If the disease has already initiated, then medicine to stop additional strokes is essential, as well as aspirin as a blood thinner to prevent the build up of clots in the vessels.12

Frontotemporal Lobar Degeneration (FTLD)

In explaining vascular dementia, one came across the enigma of the role of the frontal lobes in qualities which, in a sense, make us human such as our concept of morality and judgement as well as spontaneity and problem solving. In FTLD the damage is done to frontal lobe and often expands as far as the temporal lobes. The temporal lobe's functions include hearing, emotions, and certain aspects of visual perception. Thus when injury is done to these areas of the brain, a broad mixture of symptoms appear. Luckily the chances of dementia by FTLD are extremely low, occurring more seldom than dementia with Lewy bodies or Alzheimer's disease. FTLD manifests itself in three different forms – frontotemporal dementia, semantic dementia, and progressive nonfluent aphasia. In frontotemporal dementia, the deterioration of the frontal and temporal lobes results in such symptoms as personality change and loss of balance in movement. The most frequent arising form of frontotemporal dementia is known as Pick's disease, named after the German neurologist, Arnold Pick in 1892. Pick's Disease will have typical indicators of frontal lobe injury but in particular, sufferers will experience difficulty with speech and language. They may be unable to name objects, forget the meaning of words, or even become mute. This effect arises from spherical deposits of tau protein which will collect in parts of the temporal lobe associated with speech. One such area is the Wernicke's area which is situated at the junction between the temporal and parietal lobes. Carl Wernicke discovered that damage to this area resulted in aphasia, trouble in comprehending language and understanding syntax. Another possibly affected area could be the Broca's area, which is believed to account for producing speech and processing language. Injury to the Broca's area results in slightly different symptoms to those connected to the Wernicke's area. Broca's aphasia will render a patient incapable of articulating sentences with complex grammatical constructions. Both semantic dementia and progressive nonfluent aphasia belong to a group of disorders known as Primary Progressive Aphasia (PPA). The term aphasia implies an inability to communicate efficiently and can range from struggling to read and write as well as not being able to express oneself. Sufferers of PPA will be mentally stable in all respects except for their failure to communicate i.e. they will still be able to feed themselves and maintain an ordinary routine but will be incapable of having any social contact. Like frontotemporal dementia, patients with semantic dementia will express a lack of fluency and word meaning. In this case though, the effects will be from injury to components of long-term memory as this will be where the semantics of the sufferer's known languages are situated. This form of dementia has been useful in providing evidence in arguments concerning the diversity of language of various nations. In the Journal of Neuropsychiatry Dr. Mendez demonstrated through two case studies that an individual affected with semantic dementia was more prone to losing a firm grasp of word meaning in their second or third language. The research also supported the belief that semantics in the brain involves several separate regions. In particular it suggests that certain areas account for grammar, topics and modality i.e. whether something is spoken or written. On analysis of an MRI of these case study patients, atrophy of the left anterior temporal lobe was viewed. This is quite complementary as the left temporal lobe comprises of the Wernicke's area and Broca's area. The primary symptoms of the final type of FTLD dementia, progressive nonfluent aphasia (PNFA), are illustrated through difficulties in comprehending complex sentence structure and general loss of the ability to execute any form or understanding of speech. It has often been compared with Broca's aphasia because of the evidence that the regions affected by PNFA are situated within the vascular areas where Broca's aphasia is known to act – the left inferior frontal gyrus and anterior insula. Characteristic of a primary progressive aphasia disorder, PNFA patients will initially maintain all other cognitive functions. However as the disease progresses, cognitive deterioration will occur with noticeable spongiform developments on the surface of the cortex in the frontal and temporal lobe.13

Alcohol Dementia

Just as its name suggests, this type of dementia results from excessive intake of alcohol however this should not deter one from occasional drinks which in fact are believed to reduce the risk of Alzheimer's disease. Around 20 percent of cases of dementia are related to the abuse of alcohol but alcohol has not been linked to being a cause of Alzheimer's disease and indeed patients with alcohol dementia will not usually suffer from memory problems. Alcohol's role in causing dementia is still being debated. One possibility is that alcohol has a direct effect on the brain and acts as a central nervous system depressant. Alcohol is very quickly assimilated into the bloodstream and thus can reach the brain because of its polar structure. It is believed that alcohol operates on certain ion channels called BK channels which are calcium dependent potassium channels. The alcohol also obstructs synaptic firing because of a new abundance of calcium which creates an electrochemical imbalance in the gradient. As was said before about memory, calcium is essential in the continuation of a nerve impulse through synapses. Not only is the unusual electrochemical imbalance experienced by the neurons in the vicinity enough to cause them to die, but also calcium acts as an enzyme cofactor and activates proteases which can cause cell proteins to deteriorate. Alcohol could also have an indirect effect on the brain by causing cirrhosis of the liver and creating a deficiency of vitamins especially thiamine. Also known as Vitamin B1, thiamine is soluble in plasma but not in alcohol and therefore can not be transported around the body appropriately. It is an essential cofactor in glucose metabolism and its absence can cause an alcohol-related dementia known as Wernicke-Korsakoff syndrome to arise. Obviously this deficiency can easily be overcome by the patient taking additional supplementary thiamine however he/she must also be seeking to give up alcohol. Wernicke's encephalopathy is one of the most common forms of alcohol-dementia and causes a loss of short-term memory. The disorder is so called because it arises from damage to the Wernicke's area which was previously mentioned in frontal-lobar degeneration. In rare cases, the syndrome can cause coma but more commonly it manifests itself as confusion, paralysis of eye muscles (opthalmoplegia), and clumsy motion of muscles (ataxia.) The tragedy of Korsakoff's syndrome has been illustrated in many books, perhaps most notably Oliver Sacks' The Man Who Mistook His Wife for a Hat. In the chapter The Lost Mariner, the author tells us of a veteran of World War II who since the end of the war has no longer been able to form any new memories. The primary region affected in this disease is known as the mammillary bodies which are part of our memory and emotional hub, the limbic system. In the brain of a sufferer, one would notice haemorrhage of the mamillary bodies, atrophy and gliosis, production of supporting neurons in an area where damage has killed the cells. Sometimes a patient will have both Wernicke's encephalopathy and Korsakoff's syndrome, and this is classified as Wernicke-Korsakoff syndrome. Contrary to most forms of dementia, alcohol dementia is often treatable. If the disease has recently begun, then thiamine injections and an effort to stop drinking can reverse the effects of the dementia. However permanent damage can be done by it if it is not treated near its initiation.14

Diseases which often result in Dementia

Prion disease

While studying the Fore tribe in Papua New Guinea, Carleton Gajdusek noticed that a strange disease was spreading among the inhabitants, manifesting itself in some very demented symptoms. People would have speech impairments, difficulty in keeping balance and maintaining decent coordination, regularly suffering from seizures, and experiencing jerky movements. With the majority of the tribe's people suffering from the disease, Gajdusek didn't know what to make of it. He looked at the difference between the sufferers and the healthy and realised that the origin of the disease came from something as simple as diet. Upholding an ancient tradition, the Fore always ate deceased tribe members as a sign of respect. Diseases similar to this horrific affliction, termed kuru, would later appear in many different forms. On a quiet farm in England in 1984 a farmer noticed that one of his cows was behaving strangely. After the death of the cow, more and more cases appeared and in 1986 scientists diagnosed the first case of bovine spongiform encephalopathy. After being assured that mad cow disease could not affect humans, people began suffering from a new strain of disease – Creutzfeldt - Jakob disease. The cause of both CJD and kuru begins with misshaped proteins known as prions (short for proteinaceous infectious particle). These chemicals are responsible for the group of diseases known as transmissible spongiform encephalopathy (TSEs), so called because of the presence of large vacuoles in the cortex and cerebellum. Affecting both humans and animals, prions' effects can be seen in CJD and kuru as well as scrapie in sheep and the more obvious BSE in cows. The ability to surpass the boundary between humans and animals confused researchers while they were trying to identify the cause of TSEs. The delay in confirming prions as the source of disease arose from its disagreement with the central dogma of modern biology. Unlike the widespread belief that nucleic acids were required for reproduction, Stanley Prusiner, awarded the Nobel Prize for medicine in 1997, suggested that the prion protein was able to reproduce itself without the assistance of nucleic acids. Scientists judge that theories involving prions do not contradict the central dogma because the change in the shape of the protein is believed to alter the biological functions of the prion. Part of the protein's genetic structure accounts for shaping the core of the prion's structure. When several misfolded prion molecules come together, an amyloid fiber is formed, similar to that of Alzheimer's disease. The fiber's edges operate as a template for any available proteins which have a complementary sequence on their structure thus promoting the growth of the fiber. Many believe that this specificity of the protein is the reason that mad cow disease was able to transcend the boundary between species, expressing itself as CJD. Mutated prions also have a unique infection feature in that each time they come in contact with a healthy prion, they are able to contaminate it with the mutation, thus leading to a sort of exponential increase in the number of mutated prions. Prions are often referred to as "self-replicating rogue protein" but in fact they perform normal functions in some organisms. It has been discovered that in yeast prions are able to act as genetic material leading researchers to believe that these proteins may date back to before RNA viruses in the history of evolution. As a naturally-occurring substance in the body, normal prions have been linked to the role of sleep regulation and maintaining a circadian rhythm. To support this, researchers at the University of Zurich examined mice that were "prion knockout mice" as well as controls. They found that the knockout mice experienced insomniac episodes and had frequent issues in sleep fragmentation. This connection with sleep comes as no surprise, as a serious cause of dementia known as fatal familial insomnia, has been identified as a prion disease. Each night when we turn out our light to fall asleep, a region of our brain called the thalamus, which is essential for communication relaying between the brain and the body, becomes less efficient at transmitting the impulses giving us the characteristic drowsy state. In fatal familial insomnia, a mutation in our DNA alters the gene for the amino acid asparagine-178 into aspartic acid in prions thus changing the shape of the protein. As in CJD, this abnormal prion structure encourages the development of an amyloid fibre but, in this case, the strand collects in the thalamus initially causing insomnia. Although insomnia is not listed under dementia's many symptoms, the lack of sleep can result in a demented condition. As insomnia continues, the sufferer will begin to experience severe sweating, hallucinations and psychotic episodes followed by extreme weight loss and culminating in total insomnia. Ultimately this stress on the brain and body results in dementia and muteness. Sudden death may also occur, most likely relating to the evidence that as someone becomes more deprived of sleep, the number of white blood cells in the body decreases. In 1936, Josef Gerstmann, Ernst Straussler, and I. Scheinker described another prion disease which would later be known after their names as GSS syndrome. Affecting patients in their thirties to seventies, the disease consists of a mutation of the gene for proline into leucine in prion molecules. Starting signs of the disease involve difficulty in dysarthria (difficult in speaking) and ataxia (loss of balance and coordination of limb movements). The mutation in the genes of the prion results, as in other prion diseases, in the accumulation of amyloid plaques and neurofibrillary tangles. The tangles are believed, because of the ataxia, to deposit on areas of the cerebellum. The effects of prion diseases will continue to terrorise sufferers because of the difficulty in treating them. The only auspicious cure appearing is through the use of gene therapy however the procedure, being so complex, is a rarity and most patients will die within 1-5 years after illustrating the symptoms. More recently Dr. Neil Cashman of the University of Toronto has discovered that in mutated prions, a side chain in the genetic code is uncovered and can therefore be acted upon by antibodies. Usually the misfolded shape of the protein does not provoke attack by the immune system because of its maintained similarities to the structure of a healthy prion, but programming these antibodies to bind to the exposed genes results in breakdown of the diseased prion. Rigorous testing is still being performed on the technique but it will hopefully provide the method of curing TSEs both in humans and animals.15

Down Syndrome

Crowds cheered at the performance of the film Duo which told the story of Stephan and his struggles with his congenital disorder, Down syndrome. Praised with several awards, Duo had a massive influence in opening up the eyes of the public to the tragedy of Down syndrome. Characterised by decreased muscle tone, an asymmetrical skull, slanting eyes and a protruding forehead, around 40% of people aged 50 to 59 with Down syndrome will become demented. The chance of a baby being born with Down syndrome increases as the age of the mother's conception gets higher. In fact many older mothers will ask for a diagnostic test such as aminocentesis or chorionic villus sampling to see whether their baby will have Down syndrome. Down syndrome is the result of a mutation in chromosome 21 which leads to trisomy i.e. three chromosome 21s in each cell. The gene, which has the usual function of converting oxygen radicals to hydrogen peroxide and water, is over-expressed. Hence oxygen radicals are in abundance which can damage neurons and ultimately lead to Alzheimer's disease. However it is also believed that another gene on chromosome 21 might be responsible for the link between Down syndrome and Alzheimer's. The gene codes for what eventually becomes amyloid protein, one of the main culprits in Alzheimer's disease. The possibility of this is high since amyloid plaques and neurofibrillary tangles are observed on autopsies of Down syndrome patients' brains. Although a form of treatment has not yet been established for Down syndrome, life has improved for them thanks to current medical technology and social acceptance. The life expectancy in 1929 for a person with Down syndrome was nine years. This depressing figure has since gone up to over fifty. Also certain legislations like the American with Disabilities Act have given victims the chance to maintain jobs consistently and be treated as equals.16 Huntington's chorea

In 1872 George Huntington presented his research and deductions on chorea at Middleport, Ohio in the Meigs and Mason Academy of Medicine. His findings astonished and impressed the crowd of physicians so much that he decided to send them to the Medical and Surgical Reporter of Philadelphia. Some believe a disease has never been more vividly and completely explained than Huntington's chorea was by Dr. Huntington. The origin of the disease comes from a dominant allele of a gene located on chromosome 4. This gene accounts for the production of a cytoplasmic protein now known as huntingtin. Like amyloid proteins, mutated huntingtin builds up into aggregate on neurons particularly in the frontal lobes and basal ganglia thus causing cell death and shrunken size in these regions. There is as a result an inhibition of the neurotransmitters Acetylcholine (as in Alzheimer's disease) and GABA (Gamma-Aminobutyric Acid). Contrary to Parkinson's disease, dopamine is overactive thus the individual experiences chorea, spontaneous uncontrollable and rapid muscle jerks. They may also suffer from slurred speech, depression, deterioration of cognition, and swallowing difficulties. Taking it account the hyperactivity of dopamine-producing neurons in Huntington's chorea, it seems logical that dopamine receptor blockers would provide a suitable form of treatment to those affected however the benefits are not dramatic and offer only mild relief to the patient. Anti-depressants and sedatives help to control the chorea symptoms as well as keeping the person's emotional state stable. Recent studies include the belief that omega-III fatty acids can delay the development of the disease and may even reverse its progression. Huntington's chorea will be difficult to get rid of not only because of the disease's complexity but also the fact that its symptoms do not appear until around the age of 35 hence allowing the affected to have reproduced several offspring with the mutated gene. Steve Jones once said that since most of us our reproducing, modern evolution's impact is minute.17

Parkinson's disease

Boasting to be the greatest fighter of all time, Muhammad Ali was a three time world heavyweight champion and his popularity was unrivalled by any other boxer since. However in 1980 Ali was incorrectly diagnosed with thyroid problems which his doctor later rectified to be Parkinson's disease. He was immediately treated with levodopa, a dopamine agonist which helped to alleviate the symptoms of Parkinson's associated with the hyperactivity of dopamine-producing neurons. Luckily, Ali's condition is stable because of good response to his medication and he has encouraged the research of the disease by funding an organisation known as the Muhammad Ali Parkinson Research Center. In Parkinson's disease the genes believed to code for the disease are those involved with the production of alpha synuclein (the same as in dementia with Lewy bodies) and ones involved with the protein parkin. This relationship to dementia with Lewy bodies can be seen on viewing the substantia nigra using brain imaging. There are Lewy body aggregates on this region and in the locus coeruleus which is situated in the brainstem and has been linked to the processes concerned with our feeling of stress and panic. There may also be a strong role of free-radicals in causing Parkinson's disease. Thus some believe anti-oxidants, which may prevent the damaging oxidation caused by free-radicals, reduce the risk of Parkinson's disease. Free-radical development becomes more likely as age increases but environmental toxin exposure can also promote the making of free-radicals and inhibit dopamine-production. Symptoms of Parkinson's are caused by a reason similar to that of dementia with Lewy bodies. The destruction of dopamine-producing cells which lay out a path to the striatum leads to inhibition of the direct pathway of movement. Characteristic signs of Parkinson's such as spontaneous tremors and muscle rigidity are therefore very similar to DLB. However there are other more abstract indicators of Parkinson's disease. The Lewy body aggregates in the locus coeruleus may express themselves as anxiety or panic attacks in the patient. Other affected areas give rise to some distinctive signs such as oily skin, anosmia (loss of sense of smell), drooling, and micrographia (extremely small handwriting). Fortunately quite a few forms of treatment have appeared for sufferers of Parkinson's disease. In terms of drugs, levodopa has probably had the greatest impact easing a patient's bradykinesia and tremors. The dopamine agonist binds to dopamine receptors preventing a true dopamine from attaching thus reducing the effects of hyperactive dopamine-producing cells. Due to its success, many similar forms of the drug have been manufactured such as pergolide and bromocriptine. There is also use of drugs known as anticholinergics. In Parkinson's disease, neurons involved with the production of acetylcholine often display damage leading to an overproduction of the chemical. Anticholinergics are competitive inhibitors of the acetylcholine receptors thus preventing binding of the actual compound. However the form of treatment for Parkinson's disease which is gaining considerable popularity is the surgical implantation of brain electrodes in a process known as Deep brain stimulation (DBS). For a Parkinson's patient, the electrode is implanted into the thalamus, a nerve relay centre, or the basal ganglia, the centre of motor functions or anywhere the neurologist deems suitable. The location of the electrode is very much dependent upon the symptoms exhibited and this will usually be ascertained by means of an MRI or some form of brain imaging technique which will allow the doctor to identify the source of the symptom. In order to power the electrode, a neurostimulator powered by batteries is placed under the collar bone and is later programmed by a neurologist to ensure the best possible settings are established. Thus the electrical impulses emitted by the region affected with Parkinson's disease will be blocked or hindered by the electrode. Treatment for Parkinson's disease has improved massively in the last decade and further research is always being done to go a step further in removing the disease completely however with the diseases having possible links to mutated genes and occurring at quite a late stage of life like Huntington's chorea, Parkinson's disease will never be completely removed. Our only hope is to expand in the fields of DBS and drug treatment.18

Conclusion

At the end of this year, around 52,000 people will be diagnosed with dementia in Australia bringing the country to a total near 200,000. It has been estimated that by the year 2050 11.3 million to 16 million people will have Alzheimer's disease. Clearly treatment for dementia will prove a massive influence in medical research as we near the future.19 Professor Chris Dobson of Cambridge University who currently researches the biochemistry of amyloid diseases and how they operate in the brain believes that in curing diseases such as Parkinson's and Alzheimer's disease, one would be walking "in the footsteps of the alchemist" since these diseases are primarily "age diseases." In treating them we are reaching an apex of knowledge on the subject and coming within an arm's reach of immortality.20

Bibliography

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