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| - | ====== Kidney Transplants ====== | + | ==========Alzheimer's Disease========= |
| - | {{:messages_image_1546672056_.png|}} | + | |
| - | ''"1 in 10 Canadians have kidney disease and millions more are at risk."<sup>[15]</sup>'' | + | ======Origin and Background====== |
| - | ===== General Information ===== | + | |
| - | ==== Kidneys ==== | + | |
| - | <style float-right> | + | |
| - | {{:messages_image_207363904_.png|}} | + | |
| + | In 1906, a German psychiatrist and neuropathologist by the name of Alois Alzheimer was drawn to the case of a woman showing unusual symptoms. Post mortem analysis of the brain tissue of the woman started the journey of Dr. Alzheimer’s description of the neurodegenerative disease (Hippius, 2013). Alzheimer disease is an incurable disorder of cognitive and behavioural impairment with a long and progressive timeline. 75% of patients with dementia are thought to have genetically based Alzheimer’s, however the incidence can also be sporadic (Chapman et al, 2006). In Alzheimer’s, misfolded amino acid aggregates known as plaques develop in brain areas and impact and impede neuronal communication causing brain cell atrophy. This neurodegeneration begins in the hippocampus, then spreads to the rest of the brain over time and increasing severity of the disease. The affected region of the brain is the reduction of the memory encoding hippocampus, along with associated regions of the cerebral cortex involved in thinking, decision making, and planning (Purohit et al, 1998) | ||
| - | ''Figure 1: Anatomical Location of Kidneys'' | + | ======Epidemiology====== |
| - | </style> | + | |
| - | The kidneys are two-bean shaped organs located at the back of the abdominal cavity (also known as the retroperitoneal space)<sup>[15]</sup>. The kidney is a vital organ that carries out numerous essential functions in our body that are required to sustain life. There are three main functions that the kidneys are involved in: an excretory function, homeostatic function and endocrine function. In particular, the kidneys are responsible to filter blood and remove waste products. The kidneys can filter about 180 L of plasma per day. This means that your entire body gets filtered approximately 20 to 25 times a day<sup>[15]</sup>! Kidneys also play a role in maintaining our internal balance. For instance, the kidneys regulate water balance and acid-base balance, in addition to blood pressure levels. Kidneys also play a huge role in producing, activating, and secreting essential hormones and vitamins in the body such as vitamin D, as well as proteins such as erythropoietin (EPO). EPO is required for the production of red blood cells<sup>[15]</sup>. | + | 46 million people live with dementia worldwide, and most of these cases are attributed to Alzheimer’s disease. This number is expected to increase due to the elderly being the most rapidly growing portion of Canada and US populations (Abbott, 2011). As the population ages, Alzheimer’s disease is expected to become increasingly prevalent. Within the next 25 years, the number of people with Alzheimer’s disease in the US will triple (Kandel et al, 2013). It is important that enough research is being devoted to Alzheimer’s disease. Most funding is allocated to other research related to the main causes of death, but because the course of Alzheimer’s is between 7-10+ years whereas cancer for example is about 4 months, there are less deaths compared to cancer and this may be overridden (Leading causes of death, by sex (Both sexes), 2015). Due to the longer course, dementia and thus Alzheimer’s disease incurs more costs, even though there is not as much investment compared to other leading causes of death (Abbott, 2011). |
| - | ==== Kidney Disease ==== | + | {{:alzchart.jpg|}} |
| - | <style float-left> | + | |
| - | {{:messages_image_384999235_.png|}} | + | |
| - | ''Figure 2: Healthy Kidney vs. Diseased Kidney'' | + | **Figure 1:**This figure shows that dementia has the largest economic burden in the UK, but receives the lowest funding. (Abbott, 2011). |
| - | </style> | + | |
| - | Consequently, damage to the kidneys results in decreased levels of kidney function. Kidney damage and kidney disease may not be easily identifiable in individuals without undergoing specific diagnostic tests. For this reason kidney disease is often referred to as a 'silent' disease. Kidney damage can be an acute or chronic problem. Chronic kidney disease, commonly referred to as CKD, is the gradual loss of kidney function over a period of time (months, years)<sup>[4]</sup>. In order for an individual to be diagnosed with CKD they will need to have a gradual loss of kidney function over a minimum period of at least three months. Further, CKD is diagnosed in 5 stages. Each stage is characterized by a marker of kidney function called the estimated glomerular filtration rate (eGFR). A decrease in eGFR levels corresponds to decreasing levels of kidney function. The last stage of kidney disease, stage five, is called end-stage renal disease (ESRD) or end-stage kidney failure (ESKF). At this stage the eGFR is less than 15 mL/minute. In normal healthy individuals, eGFR would be greater than 90 mL/min<sup>[4]</sup>. | + | |
| - | ==== Prevalence of Kidney Disease ==== | + | |
| - | <style float-right> | + | |
| - | {{:messages_image_673158543_.png|}} | + | |
| - | '' | + | {{:alzdeathcause.jpg|}} |
| - | Figure 3: Projected Growth of CKD in the US Population'' | + | |
| - | <sup>[15]</sup> | + | |
| - | </style> | + | |
| - | Kidney damage, and in particular, kidney failure is becoming an increasing issue, especially in North America. The number of individuals with CKD is growing and continues to grow each year. According to Collins et al. (2003) the projected growth rate of CKD is 5% per year in the United States. These rates are comparable to the Canadian population. In fact, the number of Canadians with kidney failure have tripled over the last 20 years<sup>[15]</sup>. This constant rise in the prevalence of chronic kidney disease (and kidney failure) is partly due to the aging population. However, rising obesity rates, as well as rising rates of diabetes and hypertension are also responsible for this increase. In fact, the most common causes of CKD are history of diabetes and hypertension. Other causes of renal failure include glomerular diseases such as glomerulonephritis, and the use of certain medications and toxins including tobacco<sup>[15]</sup>. | + | |
| - | ==== Renal Replacement Therapy ==== | + | **Figure 2:**This figure shows the leading causes of death by sex (2015). Since Alzheimer's disease is not one of the leading causes of death due to its long course, not as much funding is allocated to it (Statistics Canada Leading causes of death, by sex (Both sexes) 2015). |
| - | Individuals with end-stage kidney failure will require renal replacement therapy. There are two primary treatments for renal replacement therapy: dialysis and renal transplants<sup>[15]</sup>. Dialysis is a treatment that removes wastes and excess fluids from your blood. There are two types of dialysis treatments: hemodialysis, which cleans the blood through an artificial kidney hooked up to a machine, and peritoneal dialysis, which removes waste products and excess fluids by using the body's peritoneal as a filter. On the other hand, a kidney transplant is an operation to replace a damaged kidney with a donated kidney. The best and most effective replacement therapy would be kidney transplants<sup>[15]</sup>. | + | |
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| - | ===== Kidney Transplantation ===== | + | ===== Symptoms ===== |
| + | At first, language, strength, reflexes, sensory capacities and motor skills are spared. Memory loss increases as the disease progresses, often leading to confusion. Cognitive abilities such as problem solving, language, calculation and visuospatial skills are compromised with progression of the disease (Kandel et al, 2013). Due to the loss of cognitive abilities, experiencing psychotic symptoms are common such as hallucinations and delusions. Mental functions and the ability to carry out usual daily activities become impaired (Kandel et al, 2013). The late stages of Alzheimer's are related to becoming mute, loss of autonomic functions and eventually becoming bedridden, relying completely on a caregiver (Kandel et al, 2013). Because shrinkage of the amygdala is also a hallmark of Alzheimer’s, it is associated with mood changes. | ||
| + | {{:alzbrain.jpg|}} | ||
| + | **Figure 3:**This figure illustrates the comparison between a pre-clinical and severe Alzheimer's brain (Neergaard, 2016). | ||
| + | ======Disease Progression====== | ||
| - | ==== Types of Kidney Donors ==== | + | Mild: Patients with Alzheimer's may show physiological changes in the brain 10- 20 years prior to showing any symptoms. Shrinkage of the amygdala brings about symptoms of emotional outbursts and mood changes (Purohit et al, 1998) |
| - | <style float-right> | + | Moderate: Memory loss at this stage advances to confusion of location in familiar places and poor judgement, mood changes, increased anxiety and language impairment (Hippius, 2013). |
| - | {{:messages_image_2896089175_.png|}} | + | |
| - | ''Figure 4: Kidney Transplant'' | + | Severe: Plaques and tangles become widespread, memory loss advances to severe dementia and atrophy of other brain regions leads to progressive loss of autonomic functions (Hippius, 2013). |
| - | </style> | + | |
| - | There are two types of kidney donors (transplants): deceased-donor kidney transplant and living-donor kidney transplant<sup>[15]</sup>. Living-donor transplants are generally better for the recipient. These individuals have to wait less time for a donor, regain normal kidney functions faster than deceased-donor kidney transplant recipients, and regain normal kidney functions faster. In fact, living-donor recipients have a 90-95% success rate in the first year in comparison to a 85-90% success rate in deceased-donor recipients. Similarly, living-donor kidneys last approximately 15-20 years in comparison to deceased-donor kidneys that last 10-15 years <sup>[15]</sup>. | + | |
| - | ==== Procedure ==== | + | {{:alzprogress.png|}} |
| - | <style float-left> {{:heterotopi.png|}} | + | **Figure 4:**This figure illustrates the progressive impact of the neurodegenerative disease. |
| - | ''Figure 5: Anatomical Location of a Transplanted Kidney'' | + | ====== Etiology ====== |
| - | </style> Kidney transplants are a common procedure in medical practice nowadays. The first kidney transplant in Canada took place in 1950<sup>[4]</sup>. The technical aspects of the procedure have not greatly changed since the 1970s. A kidney transplant is a heterotopic transplant. This means that the native or diseased kidney is not removed during the transplant and is left in place. The donor kidney is implanted in the pelvic area below the native kidneys. Donor kidneys are one of the least sensitive organs with respect to organ preservation and ischemia tolerance levels. In fact, donor kidneys can last for about 24 to 36 hours prior to transplantation<sup>[2]</sup>. They are kept in preservation fluids and ice to reduce tissue damage and prevent ischemia. | + | |
| - | A typical kidney transplant is about two to three hours on average. The recipient is monitored in the hospital for three to seven days on average, patients who acquire complications will usually stay longer. The donor kidneys may take three to fifteen years to reach normal kidney functioning levels; living-donor transplants are usually on the lower end of this spectrum<sup>[15]</sup>. | + | |
| - | [[https://www.youtube.com/watch?v=ou8CC4XN9wk]] | + | |
| - | === Advantages === | + | |
| - | Kidney transplants are usually the best course of treatment for renal failure, especially in comparison to dialysis treatment. Dialysis can put a huge strain on the body and the individual's lifestyle. Unfortunately, dialysis only carries out ten percent of the functions that a normal, healthy kidney would. On the contrary, individuals who receive a kidney transplant have a longer life expectancy, have less expenses to deal with, and face fewer complications<sup>[15]</sup>. Individuals living with a kidney transplant generally have a better quality of life with less diet-restrictions. They feel healthier, more energetic, and have less nutrient deficiency problems. | + | **Sporadic cases:** |
| - | === Disadvantages === | + | The greatest risk factor for Alzheimer’s is aging, but Alzheimer’s is not a normal part of aging. The most common form of Alzheimer’s disease is called sporadic Alzheimer’s disease, meaning it has no specific family link (Understanding Genetics and Alzheimer's Disease, 2016). Sporadic Alzheimer’s is associated with late-onset Alzheimer’s disease, which includes individuals older than 60 years of age. A certain form of a protein called apolipoprotein E (ApoE), has been found to increase the risk for sporadic Alzheimer’s (Kandel et al, 2013). The specific allele of the ApoE gene is ApoE4. This gene is expressed as three alleles, ApoE2, ApoE3, and ApoE4 (Kandel et al, 2013). The normal function of the ApoE protein is to carry cholesterol and other lipids in the blood. It also plays a fundamental role in the maintenance and repair of neurons, and it binds amyloid beta (Mahley, 2006). However, isoforms may bind amyloid beta differently, which may influence aggregation, deposition and clearance of amyloid beta (Kandel et al, 2013). In this case, ApoE4 is the poorest at binding to and clearing amyloid beta from the bloodstream, so amyloid beta continues to aggregate and the cascade of events, including neuronal injury, follows (Kandel et al, 2013). The exact mechanism through which ApoE4 works is unknown, but some studies have shown features of Alzheimer's pathology in transgenic mice expressing the human ApoE4 allele in neurons (Mahley, 2006). The features included reduced numbers of presynaptic terminals, increased phosphorylation of tau, increased plaque deposition and impaired learning and memory, found by testing mice in a water maze (Mahley, 2006). |
| - | There are some contraindications with a renal transplant; these include: pulmonary, cardiac and hepatic insufficiency, history of metastatic cancer, and morbid obesity. Emotional and psychological well-being of the recipient is also taken into consideration prior to a transplant. Currently, there are more than 3,000 Canadians waiting for a kidney transplant<sup>[13]</sup>. Difficulties finding a match, and the long waiting lists are two primary concerns with regards to kidney transplants. Canada's transplant system puts "geography in front of needs" of patients, putting the more vulnerable patients at risk. In fact, it can four to six years on average for an individual to be matched with a kidney in Ontario and British Colombia <sup>[12]</sup>. The possibility of rejection post-transplant is also a concern, however, rejection is less of a problem nowadays due to immunosuppressant medications. | + | |
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| + | {{:alzdiseaserisk.jpg|}} | ||
| - | ===== Kidney Transplant Rejection ===== | + | **Figure 5:**This graph shows that the ApoE4 allele is a risk factor for sporadic Alzheimer's disease. It appears that ApoE2 and ApoE3 lower the risk for Alzheimer's disease (Kandel et al, 2013). |
| - | ==== Minimizing Risks of Rejection ==== | + | **Familial Cases** |
| - | Human Leukocyte Antigen (HLA) is the human version of the commonly studied Major Histocompatibility Complex (HMC), highly involved in immunological reactions. This HLA molecule is expressed on the surface of all cells in the human body, presenting randomly generated peptides from the interior[20]. This allows for the immune system to monitor whether cells are healthy or infected, as well as whether an immune response needs to be mounted. To prevent the immune system from recognizing the newly transplanted graft as foreign, the donor and recipient both have their HLA genes checked using high-resolution DNA typing techniques[20]. The HLA system has loci across chromosome 6, expressing 3 classes of HLA[20]. When matching HLA between the donor and recipient, HLA –A, –B, and –DR are checked for similarities[20]. There are a vast number of alleles for these genes (>800 type –A and –B, >400 type –DR), adding to the complexity of matching donors and recipients appropriately to minimize risk of rejection[20]. | + | The familial, or inherited form of Alzheimer’s is associated with early-onset Alzheimer’s, which includes individuals 60 years of age or younger. Mutations in three genes are associated with this form of Alzheimer’s; APP, presinilin-1 and presinilin-2 (Kandel et al, 2013). The mutations influence the cleavage of APP, increasing the production of amyloid beta peptides, or increasing the ratio of the more toxic amyloid beta 42 kind. Some APP mutations are amino acid substitutions within the amyloid beta region (Kandel et al, 2013). Cells with this mutation secrete more amyloid beta peptides compared to wildtype APP. Another APP mutation influences gamma-secretase to selectively produce amyloid beta 42 instead of amyloid beta 40 (Kandel et al, 2013). The presinilin mutants are similar, as they produce mutant gamma-secretase as well, causing over activity of gamma-secretase, and again generating a higher ratio of amyloid beta 42 (Kanel et al, 2013). The mutations in APP or presinilin genes lead to a gain of function for overproducing amyloid beta 42. |
| - | <style float-right> | + | ======Pathophysiology===== |
| - | {{:chromosome_6.jpg|}} | + | |
| - | ''Figure 6: Chromsome 6 Expresses 3 Classes of HLA'' | + | Dementia is defined as a group of symptoms including memory loss and other mental abilities. Investigators have learned that Alzheimer's disease is the most common causes of dementia. It accounts for about 60 - 80% of all dementia related cases (Seeman & Seeman, 2011). One of the prominent features of Alzheimer's is the loss of connections between cells. This results in diminished cell function or cell death. At this point, no one knows what exactly causes Alzheimer's disease but it appears that the damage to the brain starts at least 10 years before the issues become obvious. The classic biological hallmarks of the disease are β-amyloid plaques and neurofibrillary tangles, which are made of misfolded proteins (Seeman & Seeman, 2011). |
| - | </style> | + | |
| - | Internationally, HLA matching between donors and recipients differ by the acceptability of mismatches[20]. Countries with organ transplant systems regulate the amount of HLA mismatch they deem is acceptable in order for the transplant to be viable[20]. In the United States, because the majority of organ donors belong to Caucasian ancestry, the HLA alleles are skewed towards certain populations[20]. This puts recipients of differing ancestral backgrounds at a disadvantage when an organ transplant is vital for their health, such as in the case of end-stage renal diseases[20]. | + | {{:alzmicroscope.jpg|}} |
| - | Maximizing the similarity of HLA between the donor and recipient not only minimizes the risks of transplant rejection, but also minimizes the probability of graft versus host disease[20]. This is a case when the immune cells present from the transplanted graft recognize the new host as foreign, and proceed to mount an immunological attack[20]. HLA matching also presents dualistic effects; matching may improve the outcome of the kidney transplant, but may also enhance the cellular immune mechanisms leading to further graft dysfunction[20]. | + | **Figure 6:** The histopathological features of the Alzheimer's Brain, where the * indicates plaques and the < indicates tangles (Del Cerro & C. Triarhou, 2006). |
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| - | ==== Allorecognition ==== | ||
| - | In many cases of renal transplantation, the recipient’s immune system is able to recognize that the transplanted kidney is a foreign organ, by a process termed allorecognition. This allows the immune system to prime T-cells to recognize and launch an immune response against the new organ [3]. There are 3 main ways via which allorecognition occurs: | ||
| - | - Direct allorecognition occurs when donor dendritic cells (or other antigen-presenting cells) from the graft present a graft peptide to T-cells of the recipient’s immune system. This usually results in immediate rejection, but the response becomes less likely to occur over time due to the decrease in donor dendritic cell count [3]. | + | ===β-Amyloid Plaques=== |
| - | - Indirect allorecognition occurs when recipient antigen-presenting cells display a graft antigen to the recipient T-cells. This is the most common occurrence that is responsible for chronic rejections [3]. | + | In the cell membrane the amyloid precursor protein (APP) helps neurons grow and repair themselves. Scientists have identified 3 enzymes responsible for cleaving APP (Lieff, 2015). These enzymes are called α-secretase, γ-secretase and β-secretase. Normally, APP is sliced by a α-secretase to generate a sliced-APP (sAPP) and a C83 carboxy-terminal fragment. The presence of sAPP is associated with normal synaptic signaling and result in synaptic plasticity, learning and memory, emotional behaviours and neuronal survival (Lieff, 2015). A small APP fragment remains tethered to the membrane but is later cleaved by γ-secretase. It is then released into the space outside the neuron where it eventually dissolves (Lieff, 2015). The brain of an individual with Alzheimer's disease follows a much different path. β-secretase replaces α-secretase, which then teams up with γ-secretase to cause a mutation that disrupts the function of APP. This mutation does not allow the β-amyloid peptide to breakdown resulting in small, soluble aggregates of two, three, four, or even up to a dozen beta-amyloid peptides called oligomers (Lieff, 2015). It is likely that some oligomers are cleared from the brain. Those that cannot be cleared clump together with more beta-amyloid peptides. As the process continues, oligomers grow larger, becoming entities called protofibrils and fibrils. Eventually, other proteins and cellular material are added, and these increasingly insoluble entities combine to become the well-known β-amyloid plaques (Lieff, 2015). |
| - | - Semi-direct allorecognition occurs when recipient antigen-presenting cells “capture” donor MHC complexes with an antigen from the graft and presenting it to T-cells of the recipient’s immune system. The function of semi-direct allorecognition has not yet been elucidated [3]. | + | |
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| - | <style float-left> | + | {{:alzplaques.jpg|}} |
| - | {{:allorecognition.jpg?300x200}} | + | |
| - | ''Figure 7: Allorecognition in Renal Transplants'' | + | **Figure 7:** An animated image depicting the harmful pathway that results in β-amyloid plaques for individuals with Alzheimer's disease (Patterson et al., 2008). |
| - | </style> | + | |
| - | ==== Types of Rejection ==== | ||
| - | Before performing a kidney transplantation, physicians ensure that the donor kidney is a match to the recipient [20]. Often times, even when an HLA antigen match has occurred, the recipient’s immune system may still detect the donor organ has foreign; triggering a severe immune response. There are three types of rejection: | + | ===Neurofibrillary Tangles=== |
| + | Tangles are abnormal collections of twisted protein threads found inside nerve cells. The main component of tangles is a protein called tau. Healthy neurons are internally supported in part by structures called microtubules, which help transport nutrients and other cellular components, such as neurotransmitter containing vesicles, from the cell body down the axon (Lieff, 2015). Tau, which usually has a certain number of phosphate molecules attached to it, binds to microtubules and appears to stabilize them. The brain of an individual with Alzheimer's disease has an abnormally large number of additional phosphate molecules attach to tau resulting in hyperphosphorylation. GSK-3 and CDK5 are the kinases primarily responsible for phosphorylation of Tau (PKC, PKA and Erk2 are also involved) (Lieff, 2015). The hyperphosphorylation of tau protein results in microtubule destabilization that disrupts the transportation of motor proteins. The disengaged tau tangle with the other tau proteins resulting in neurofibrillary tangles. Current research suggests that the beta amyloid plaques that build up outside the neuron initiates pathways inside the neuron, which leads to the hyperphosphorylation of tau (Lieff, 2015). | ||
| - | * **Hyper Acute Rejection:** This is the most rapidly elicited form of kidney transplant rejection. Hyper acute rejection occurs a few minutes after the transplant has taken place and is the result of mismatched ABO blood types; triggering a humoral immune response. For example, this would occur if the recipient had type A blood and the donor had type B blood. In this case, the donor organ tissue must be removed right away to prevent death of the recipient [3]. | + | {{:alzdegen.jpg|}} |
| - | * **Acute Rejection**: Acute rejection takes at least a week to occur and is modulated by cytotoxic T cells; signifying the involvement of the immune system. In this case, the recipient has circulating antibodies in their blood before the transplant occurs. The T cells produce cytokines that then recruit other inflammatory mediators leading to the eventual death of the kidney tissue [3]. | + | **Figure 8:** An animated image depicting the harmful pathway that results in neurofibrillary tangles for individuals with Alzheimer's disease (Patterson et al., 2008). |
| - | * **Chronic Rejection:** Chronic rejection describes long-term dysfunction of the donated organ [3]. In most patients, chronic rejection takes several months to elicit. It is the most prevalent cause of renal dysfunction, usually characterized by a gradual loss of kidney function, coupled with hypertension and excess protein in the urine. Chronic rejection initially develops in tissue grafts that are prone to continuous damage as a result of indirect recognition of alloantigens [3]. In this case, the immune modulators destroy the endothelium of blood vessels, depleting the donor organ tissue of blood. | ||
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| - | **Signs of Rejection:** | + | =====Diagnosis===== |
| + | It is suggested that the pathophysiological process of Alzheimer’s disease (AD) begins about 10-15 years before the diagnosis of clinical dementia (Sperling et al, 2011). Diagnosing AD in the early stages is difficult because the initial symptoms such as memory impairment and neuronal loss are part of normal age-related cognitive decline. Diagnosis of AD can only be confirmed with an autopsy by examining brain tissues (Kandel et al, 2013). Studies using new neuroimaging techniques and fluid biomarkers suggest that Alzheimer's disease pathology can be detected preclinically using different techniques. Amyloid plaques and neurofibrillary tangles are hallmarks of AD (Kandel et al, 2013). This also includes inflammation and neuronal, axonal and synaptic loss and dysfunction and ultimately neuronal death. However, these changes in the brain are seen before any cognitive declines (Kandel et al, 2013). | ||
| - | * Fatigue | ||
| - | * Fever or flu-like symptoms | ||
| - | * Elevated protein levels in urine (proteinuria) | ||
| - | * Elevated granzyme and perforin levels in urine | ||
| - | * Elevated creatine levels | ||
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| - | ==== Mechanisms of Rejection ==== | + | **Figure 9:** Plaques, neurofibrillary tangles, synaptic and neuronal loss appear in the brain prior to significant cognitive decline (Abbott, 2011). |
| - | Overall, allorecognition leads to the priming of T-cells, activating them to respond to the presenting antigen. In most cases, dendritic cells or other antigen-presenting cells are exposed to these peptides first, resulting in their activation and migration to the thymus. In the thymus, the antigen is presenting via MHC to T-cells, allowing for their maturation and ability to launch an immune response [20]. Recently, it has been elucidated that T-cells do not necessarily need to become activated at the Thymus, but can also be activated directly at the graft via interactions with the endothelial cell lining of the transplant [20]. The microenvironment where T-cells become activated leads to the differentiation of T-cells, varying in their cytokine signatures and functionalities (CD8+ T-cells versus CD4+ T-cells). This differentiation depends on the expression of a master transcription factor, determining the final subset of cytotoxic T-cells (CD8+) and T-helper cells (CD4+). During renal transplants, there are many factors that can affect the microenvironment post-transplant [20]: | + | ===Technique 1: Physical, neurological and neuropsychological examination=== |
| + | This technique measures motor and neurological skills to see if there is a cognitive decline. The problem with testing psychological traits is that there is nothing to compare these traits to (Kandel et al, 2013). It unknown whether this is a recent decline in memory or not. Memory decline is normal with old age, so a longitudinal study would be needed to compare the performance of an individual (Kandel et al, 2013). | ||
| - | <style float-right> | + | ===Technique 2- MRI and fMRI=== |
| - | {{:rejection_mech.png?300x200}} | + | An MRI is used to view structural changes such as enlargement of cerebral ventricles, cortical thinning, and shrinkage of hippocampus and medial temporal lobe (Kandel et al, 2013). Functional magnetic resonance imaging (fMRI) is believed to provide a measure of synaptic activity, and this technique appears to show hypoactivation of the medial temporal lobe memory system in the clinical stages of the disease (Perrin et al, 2009). Due to neuronal loss, many other cortical regions also show evidence of decreased glucose metabolism in patients with Alzheimer’s (Perrin et al, 2009). |
| - | ''Figure 8: Mechanisms of Rejection'' | + | ===Technique 3- PET=== |
| - | </style> | + | Amyloid plaques can be visualized using Positron Emission Tomography (PET) using a new radioactive compound called Pittsburgh compound B (PIB) that binds with high affinity to amyloid beta or tau (Kandel et al, 2013). PIB is injected into the bloodstream. In Alzheimer’s, PIB is retained specifically in areas with amyloid deposition (Kandel et al, 2013). Other PET labelling agents have been developed to image inflammation as reflected by activated microglia and reactive astrocytes that surround plaques (Kandel et al, 2013). |
| - | * Immune status of the recipient at the time of transplant | + | {{:alzpetpib.jpg|}} |
| - | * Degree of ischemia-reperfusion | + | |
| - | * Degree of donor-recipient HLA mismatch | + | |
| - | * Current immunosuppressive regime | + | |
| - | CD8+ T-cells, also known as cytotoxic T-cells, are typically activated after forming a three-cell cluster between itself, a CD4+ T-cell, and an antigen-presenting cell [20]. It can directly destroy graft cells by expressing perforin to disrupt their membrane and injecting granzyme in to the cell to destroy crucial proteins via the release of cytotoxic granules. FasL released by the cytotoxic T-cell can bind to FasR on the target cell, resulting in the triggering of apoptosis of the graft cell by triggering various cascades [20]. CD4+ T-cells release cytokines that result in inflammation, and can attract other immune cells towards the location of the graft. Recent studies indicate that CD4+ T-cells can result in graft rejection by themselves, although the exact mechanism is not clear [20]. | ||
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| - | ===== Tolerance ===== | ||
| - | ==== Pharmacotherapy ==== | ||
| - | The aim of pharmacotherapy in kidney transplantation is to avoid graft rejection, minimize side effects and prevent metabolic complications. The leading drugs that allow for successful graft transplants are immunosuppressants. Immunosuppressants fall under a class of drugs that decrease the strength of the immune system. Immunosuppressants are also known as anti-rejection drugs. In kidney transplant, anti-rejection drugs suppress the body's ability in detecting a foreign organ and consequently rejecting it <sup>[9]</sup>. | + | **Figure 10:**This image clearly shows PIB retained in brain areas associated with amyloid deposition. There is a lot more PIB in the brain on the right, the Alzheimer's brain, compared with the healthy brain on the left (Kandel et al, 2013). |
| - | Immunosuppressants are currently the leading cause of success in acute allograft acceptance. There are two classes of anti-rejection drugs used, depending on the time surpassed since the transplantation procedure: induction drugs and maintenance drugs <sup>[9]</sup>. | + | ===Technique 4- Fluid Biomarkers=== |
| + | Longitudinal measurements of the levels of amyloid beta 42 rather than amyloid beta 40 are used because amyloid 42 is more hydrophobic and more prone to fibril formation and thus is the predominant form found in cerebral plaques (Kandel et al, 2013). This technique also looks at concentration of tau. This may allow clinicians to monitor and possibly even predict the progression of Alzheimer’s throughout its course (Kandel et al, 2013). In Alzheimer’s, it is expected that amyloid beta 42 levels will be lower in the cerebrospinal fluid versus the control (Kandel et al, 2013). This is due to the fact that amyloid beta 42 aggregates more easily and is cleared poorly, thus less amyloid beta 42 will be found in the cerebrospinal fluid. Tau is also a good biomarker because it is normally found in the intracellular fluid compartment of a neuron (Kandel et al, 2013). In Alzheimer’s, high concentrations of tau are found in the cerebrospinal fluid. This is due to the fact that when cells break apart, the plasma membrane breaks and thus tau is released into cerebrospinal fluid from neuronal injury and death (Kandel et al, 2013). | ||
| - | Induction drugs are used at the time of the transplantation. The ultimate aim of induction drugs is to avoid acute rejection during the early stages of post-transplatnation by administering a high potency of immunosuppression. Induction immunosuppressive agents include monoclonal agents (such as alemtuzumab, daclizumab, muromonab-CD3) or polyclonal agents. This includes antithymocyte globulin [rabbit]) antibodies or antithymocyte globulin [equine] <sup>[6]</sup>. | ||
| - | Maintenance drugs are used for long-term medication after the procedure. Such drugs include calcineurin inhibitors, corticosteroids, mTor inhibitors and anti-proliferative agents. It is common for an immunosuppression regime to include a combination of multiple drugs <sup>[14]</sup>. | + | {{:alzexperimentplot.jpg|}} |
| - | **Corticosteroids** | + | **Figure 11:** Using fluid biomarkers as a method to detect Alzheimer's. On the left, there are lower concentrations of amyloid beta 42 in cerebrospinal fluid compared to the control due to the aggregation of amyloid beta 42. On the right, there are higher concentrations of tau in the cerebrospinal fluid compared to the control, due to the cell death releasing tau (Kandel et al, 2013). |
| - | Corticosteroids, such as oral prednisolone and IV methylprednisolone, can be used as induction and maintenance drugs. These drugs halt cytokine production and vasoactive substances. These immunosuppressants are alkylating agents, which interfere with DNA replication by cross-linking nucleotides. In addition, corticosteroids act as glucocorticoid receptor agonists. Prednisolone is metabolized in the liver and then excreted as an inactive metabolite by the kidney. The common interactions with corticosteroids include P450 inhibitors <sup>[5]</sup>. | ||
| - | **Mammalian Target of Rapamycin (mTOR) Inhibitors** | + | =====Treatments===== |
| - | Sirolimus (a rapamycin) is a microbial product of a soil fungus, Streptomyces hygroscopicus, located on the Easter Island. This agent is used for both chronic rejection and maintenance immunosuppression. The mode of action includes preventing IL-2 activation and proliferation, however it does not inhibit calcineurin <sup>[7]</sup>. | + | Currently Alzheimer’s has no cure but there are current treatments available that can slow down the worsening of the symptoms and as a result improving individual’s quality of life. |
| - | Due to the prolonged half-life, multiple drug interactions are quite possible. Concomitant use with strong CYP3A4/P-gp inducers or inhibitors fluctuates the sirolimus concentrations. When cyclosporine is used simultaneously with mTOR inhibitors, there is an increase in the maximum concentration of the drug (Cmax) and area-under-the-curve (AUC) for both compounds. Thus, if both drugs are to be administered, it is recommended to have a 4 hour gap between the administration of cyclosporine and mTOR inhibitors. | + | {{:alztreatments.jpg|}} |
| - | Adverse effects from the use of mTOR inhibitors include hyperlipidemia, thrombocytopenia, anemia, pneumonitis, oral ulcers, and diarrhea. These agents can also hinder the healing process of wounds and dehiscence production of lymphoceles. When used concomitantly with calcineurin inhibitors, sirolimus heightens the nephrotoxicity of calcineurin <sup>[1]</sup>. | + | |
| - | \\ | + | |
| - | \\ | + | |
| - | ==== Calcineurin Inhibitors ==== | + | **Figure 12:** Table showing treatments according to severity. Image from Alzheimer's Association, 2016. |
| - | Calcineurin Inhibitors (CNIs) are commonly known as the golden standard of care in modern immunosuppression. Calcineurin is a protein phosphatase that activates the T-cells by cleaving off a phosphate group. As a result, inhibitors of calcineurin inactivate the proliferation of T-cells. The two popular CNIs used commonly for the prevention of allograft rejections are Cyclosporine and Tacrolimus <sup>[13]</sup>. | + | ====Drug Treatment==== |
| + | |||
| + | ===Mild to moderate stages=== | ||
| + | A main drug treatment for Alzheimer’s that targets memory loss are cholinesterase inhibitors (donepezil, rivastigmine and galantamine). For mild to moderate stages, individuals are prescribed drugs that are cholinesterase inhibitors. These inhibitors treat symptoms that relate to memory, thinking, language, judgment and all other thought processes (Alzheimer's Association, 2016). Acetylcholine is a chemical messenger important for learning and memory. It is cholinesterase inhibitors that prevent the breakdown of acetylcholine and keep the levels high (Alzheimer's Association, 2016). | ||
| + | |||
| + | ===Moderate to severe stages=== | ||
| + | Individuals that experiences moderate to severe stages are normally prescribed a second type of drug called memantine. Memantine is aimed to improve memory, attention, reason, language and the ability to perform simple tasks (Alzheimer's Association, 2016). It regulates the activity of glutamate, which is a different chemical messenger responsible for learning and memory (Alzheimer's Association, 2016). Another drug used to treat moderate to severe stages is Namzaric. Namzaric is a combination of memantine and donepezil. Some studies have shown that those who take a cholinesterase inhibitor such as donepezil with a combination of memantine can benefit more from it, however it is only prescribed to individuals experiencing moderate to severe stages of Alzheimer’s | ||
| - | **Cyclosporine** | + | ====Alternative Treatments==== |
| - | <style float-right> | + | ===Environment=== |
| - | {{:fungi.png?200x220}} | + | A safe and supportive environment is critical to any treatment plan. As memory demanding tasks may be difficult for individuals with Alzheimer's it is important to establish and strengthen routine habits and minimizing memory demanding tasks to make daily living more convenient to the individual (Mayo Clinic, 2015). Some examples that support individuals with Alzheimer's needs are to always place keys; wallets and phones in the same place at home so the error of misplacing valuable items does not occur. Also it can help reduce the number of mirrors in the home as the images in mirrors can confuse or frighten those with Alzheimer's. Making sure appointments that are regular are on the same day at the same time if possible to make life much easier. |
| - | ''Figure 9: Cyclosporine from a Fungal Origin'' | + | ===Exercise and Nutrition=== |
| - | </style> | + | Exercise is used as a treatment for Alzheimer’s as it is associated with a lower risk of cognitive decline (Riordan, 2016). Physical activity increase the blood flow to the brain and body, thus providing additional nourishment that can reduce risk factors associated with Alzheimer patients such as high blood pressure, diabetes and high cholesterol (Riordan, 2016). Small activities such as walking can improve both mental and physical health as it may improve the quality of life for individuals in all stages of the condition. It is important to note that depression is very common risk associated with individuals experiencing Alzheimer’s disease and exercise is typically recommended as a treatment for such secondary symptoms. There are certain nutritional supplements that are available to specifically treat Alzheimer's disease to maintain a balanced diet. Also avoiding caffeine can prevent interference with sleep and increased restlessness. |
| + | |||
| + | ===Alternative medicine=== | ||
| + | There are many supplements that promote support for cognitive health or delay Alzheimer's but currently there is no strong evidence that this form of therapy slows down progression of cognitive decline. The following treatments, herbs and vitamins support this idea: Omega-3 fatty acids, curcumin, Ginkgo, Vitamin (Mayo Clinic, 2015). However it should be noted that dietary supplements could have serious interactions with current prescribed medication therefore it may not be practical for every patient. | ||
| - | The calcineurin inhibitor, cyclosporine, has been employed as an immunosuppressant in transplantation for around 4 decades. It is also used for both induction and maintenance immunosuppression. The molecule comprises a 11 amino acid polypeptide chain from a fungal origin, which inhibits calcineurin phosphatase and T-cell activation through dephosphorylation of inactive nuclear factor of activated T-cells <sup>[13]</sup>. Thus, it prevents IL-2 via calcineurin inhibition production. The inhibition of IL-2 activation cycle prevent the proliferation of T-cells and thus rendering an effective adaptive immune response. The adverse side effects of cyclosporin include nephrotoxicity, nausea, diarrhea, vomiting, hyperkalemia, and hypomagnesemia <sup>[13]</sup>. | + | ====Future Treatments & Prevention==== |
| + | |||
| + | Researchers are currently looking for new treatments for Alzheimer's disease specifically pertaining to studies that test new drugs to show that they can slow the progression of the disease from getting worse or at least improve the symptoms such as memory (Smith et al, 2016). Researchers are also looking for a way to diagnose Alzheimer's earlier prior to the symptoms appearing therefore these results can help with starting treatment sooner. Preventive measures are living a healthy lifestyle. However, there are many ongoing studies at the moment, such as a clinical study conducted by the Dominantly Inherited Alzheimer Network (DIAN). This study is testing if antibodies to beta-amyloid can reduce the accumulation of beta amyloid plaque in the brains of people who have the genetic mutation (Smith et al, 2016). This study allows researchers to create antibodies that reduce delays and prevent symptoms (Smith et al, 2016). | ||
| - | **Tacrolimus** | + | =====Current Clinical Trials on Potential Drug Treatments===== |
| - | Tacrolimus prevents the production of IL-2 through calcineurin inhibition by binding to the tacrolimus binding protein (TBP). This macrolide antibiotic is active against T-helper cells. The tacrolimus FKBP12 active complex inhibits calcineurin with a stronger potency than the corresponding cyclosporine complex. This drug is used particularly for maintenance immunosuppression and during the refractory rejection under cyclosporine-based therapy (known as rescue therapy). Adverse effects are similar to the calcineurin inhibitor, cyclosporine, but with a lower occurrence of hypertension, hyperlipidemia, hirsutism, gum hyperplasia and skin changes. However, it is reported that Tacrolimus has a lower occurrence of acute-rejections and less-pronounced adverse effects. In addition, Tacrolimus can cause reverse alopecia <sup>[13]</sup>. | + | ===Solanezumab=== |
| - | \\ | + | |
| - | \\ | + | |
| - | ==== Future Treatments ==== | + | {{:alzdrug.jpg|}} |
| - | **Rituximab** | + | **Figure 13:** Pharmacodynamics of Solezumab. |
| - | A new drug that is being investigated recently is Rituximab, which effectively depletes B cells and decreases the concentration of antibodies. Rituximab binds to CD20 at the precursor and mature B cell surface, thus inhibiting B-cell proliferation and causing cellular apoptosis. B-cells are responsible for producing antibodies; therefore the inhibition of B-cell proliferation prevents antibodies from attacking antigens (and rejecting the kidney) <sup>[2]</sup>. | + | Solanezumab is a humanized monoclonal IgG1 antibody that selectively binds to the soluble form of Beta-amyloid (which aggregate and form plaques in the brain) (Farlow et al, 2012). Once this binding occurs, there is a resulting efflux of Beta-amyloid protein peptides away from the Central Nervous System to the blood plasma, ultimately leading to a slowing-down of the progression of the disease. |
| - | **Intravenous Immunoglobulin** | + | In a randomized, double-blind, placebo-controlled clinical trial, 52 patients with AD received either a placebo treatment or the antibody/Solanezumab treatment (dosage: 100 mg every 4 weeks, 100 mg weekly, 400 mg every 4 weeks or 400 mg weekly) for 12 weeks. Safety and biomarker measurements continued until 1 year after randomization, and Magnetic Resonance Imaging and cerebrospinal fluid examinations were carried out at baseline as well as after the treatment period. The Beta-amyloid protein concentrations were measured in blood plasma as well as in the cerebrospinal fluid, and the Alzheimer’s Disease Assessment Scale – cognition (ADAS-cog; a test of cognitive performance on 11 tasks) was then delivered. Results show that the total (both bound to antibody and unbound forms) amount of Beta-amyloid in blood plasma is positively correlated with antibody/Solanezumab dosage. The total amount of Beta-amyloid in the cerebrospinal fluid also increased with the antibody treatment; however, the treatment decreased the unbound form of the protein and increased the bound form of the protein in a dose-dependent manner. These results show consistency with the pharmacodynamics of Solanezumab: clearing these amyloid proteins away from the central nervous system and essentially dumping them into the systemic circulation for later excretion. In terms of clinical effects on cognition as measured by ADAS-cog, there was no significant differences between the two treatment groups. This was expected because there would be no measurable change in cognitive performance after only 12 weeks into the treatment (note that during this time, there was no decline in the placebo group as well, showing that in the normal progression of the disease, cognitive impairment is not evident at this point just yet) (Farlow et al, 2012). |
| - | IVIG (intravenous immunoglobulin) causes alloantibody inhibition through the induced apoptosis of B cells. IVIG blocks T cell and B cell activation through Fc receptor-mediated interaction with antigen-presenting cells. | + | Recently, the results of a phase 3 trial of this new drug were presented at the Alzheimer’s Association International Conference 2015. The trial consisted only of individuals diagnosed with the mild form of AD. Results show that solanezumab was efficient in slowing down the progressive decline in memory and cognition with time in these patients, therefore slowing down the progression of the disease. |
| - | **3D-Prints of Kidneys** | + | ===Carbonic Anhydrase Activators (CAAs)=== |
| - | <style float-left> | + | Carbonic Anhydrases are a family of enzymes that catalyze the interconversion of CO2 and H2O to bicarbonate and protons; this biochemical process is critical in the maintenance of an organism’s physiological acid-base balance, as well as in the removal of carbon dioxide from tissues (Sun & Alkon, 2001). The inhibition/activation of Carbonic Anhydrases have been widely investigated in terms of their various therapeutic applications. For instance, CAAs are a new revolutionary approach towards the treatment of Alzheimer’s disease, as well as other neurodegenerative disorders that require memory therapy. Some examples of CAAs are Phenylalanine and imidazole. Carbonic Anhydrase 1 (CA1) were recorded from pyramidal cells in sections of a rat hippocampus. Application of CAAs, coupled with stimulation of cholinergic inputs from the stratum oriens and GABA-ergic inputs from stratum pyramidale at low intensities, switched the hyperpolarizing GABA-mediated inhibitory postsynaptic potentials into depolarizing postsynaptic responses, presumably due to the generation of protons as the CAAs shift the bicarbonate buffer system equation to the right. On the other hand, in the absence of CAAs, the same stimulation were not adequate to trigger the synaptic switch into depolarizing potentials. Administration of these CAAs into the intralateral ventricles triggered the rats to demonstrate an enhanced learning of the Morris water maze task; this shows that the synaptic switch is important for gating the synaptic plasticity underlying spatial memory. These findings imply that increased Carbonic Anhydrase activity through CAAs might also enhance other cognitive processes such as perception and the processing and storing of temporally associated signals. This might lead to the creation of a drug design/diagnostic tools (i.e. memory therapy) for the enhancement of synaptic efficacy, spatial learning and memory, thus potentially alleviating the memory-loss symptoms associated with Alzheimer’s disease (Sun & Alkon, 2001). |
| - | {{:3d2.png?371x265}} | + | |
| - | ''Figure 10: 3D Print Technology for Customizing Organs'' | ||
| - | </style> | ||
| - | An exciting form of tolerance to kidney transplant rejections are 3D-Prints of Kidneys, using the host's cells. The goal of 3D-Prints is to construct organs with the patient’s cells. Through this approach, graft rejections will not be an issue (as the organ is constructed through the host's cells) and the use of immunosuppressants will not be required. | + | ===The A4 Study (Anti-Amyloid Treatment in Asymptomatic Alzheimer’s)=== |
| - | <sup>[18]</sup> | + | |
| - | The steps of 3D-Prints include the following: | + | {{:alzpetscan.jpg|}} |
| - | **1.** Obtain biopsy of the replaced organ. | + | **Figure 14:** PET scans of the diseased patients. |
| - | **2.** Isolate cells of regenerative capabilities and keep within a mixture of nutrients and oxygen. | + | The study is targeted towards individuals between 65-85 years old who are determined to be at risk for AD-related memory loss, but who have not yet significantly shown signs of the disease (Houston, 2015). Thus, this treatment is more of a preventative measure for those at risk. Positron Emission Tomography (PET) scans demonstrate that the Beta-amyloid plaque formation begins about 10-20 years before the initial AD symptoms start to manifest. Therefore, detecting this initial Beta-amyloid overexpression with PET scans in individuals predisposed to Alzheimer’s can then proceed to Solanezumab treatments in order to lower amyloid levels. In addition, it has been hypothesized that the accumulation of the amyloid protein may have a role in the eventual memory loss induced by AD, through an excess production of an abnormal form of the brain protein tau. This abnormal tau forms neurofibrillatory tangles that destroy nervous tissue, therefore propagating brain damage. There appears to be a point in the progression of AD where the removal of Beta-amyloid is not anymore sufficient in reversing or halting the disease development, because a critically high amount of tau has already been generated by this point. Hence, it is also crucial to use PET scans to measure the amount of abnormal tau present in the brain (Houston, 2015). |
| - | **3.** Place the mixture in a printer cartridge. The printer cartridge shall "print" the organ of desire. | ||
| - | **4.** Customize the organ based on anthropometric measurements of the patient (through medical scans). | ||
| - | 3D-Prints is a relatively new application that is being used to print many organs such as the heart, kidneys and other crucial organs <sup>[18]</sup>. | + | ======References====== |
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| + | Alzheimer's Association. (2016). Latest Medication for Memory Loss. Retrieved September 21, 2016, from http://www.alz.org/alzheimers_disease_standard_prescriptions.asp) | ||
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