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--- group_1_presentation_2_-alzheimer_s_disease [2017/11/03 23:34]
muthura
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 ======== Alzheimer's Disease ========
+Presentation File: {{::alzheimer.pdf|}}
 ===== Introduction =====
 Alzheimer’s disease (AD) is an irreversible brain disorder that is characterized by a progressive decline in cognitive function, which typically begins with deterioration in memory (Alzheimer’s Disease, 2016). Alzheimer’s is the most common neurodegenerative disorder, and is the sixth leading cause of death in the United States (Alzheimer’s Disease, 2016). The greatest known risk factor is increasing age, however Alzheimer’s is not a normal part of aging as one can also develop early-onset Alzheimer’s in their 40s or 50s of age (Alzheimer’s Disease, 2016). Alzheimer’s disease is a degeneration of neurons in the brain, starting in the temporal lobe and spreads to parietal, and frontal lobe(Alzheimer’s Disease, 2016)). The overall mass of the brain is reduced as a result of cell death, and the degeneration of neurons (Alzheimer’s Disease, 2016)). Alzheimer’s disease is progressive, and has three stages : early, mild to moderate, and severe (Alzheimer’s Disease, 2016)). In the earlier stages, memory loss is mild compared to the late stages, where the ability to carry a conversation and respond to the environment is completely impaired, resulting in complete dependence on others for care (Alzheimer’s Disease, 2016). There is no cure for Alzheimer’s that stops the progression completely, however treatments are available for the symptoms and can temporarily slow the worsening of the symptoms, and improve quality of life (Alzheimer’s Disease, 2016).
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 Figure three: A FDG-PET scan outlining the endophenotype typical of an Alzheimer’s patient in the mild to moderate stage of AD. The precuneus, lateral parietal, lateral temporal, and medial temporal lobes have slowly decreased in neuronal mass over time thus displaying decreased glucose metabolism.
 ===== Signs, Stages & Symptoms =====
-Alzheimer’s disease is progressive and composed of different stages, characterized by different symptoms that also worsen over time (Alzheimer’s Disease, 2016).
+ <box 26% round left | > {{ :23226818_2216187875073441_894752928_n.jpg?300|}} </box| Figure 4: Visualization of Alzheimer patient's brain in the Early Stage.>  Alzheimer’s disease is progressive and composed of different stages, characterized by different symptoms that also worsen over time (Alzheimer’s Disease, 2016).
-<box 26% round left | > {{::23226818_2216187875073441_894752928_n.jpg?300|}} </box| Figure 4: Visualization of Alzheimer patient's brain in the Early Stage.> **Pre-Clinical AD: Early Stage (7-20 years)**
+**Pre-Clinical AD: Early Stage (7-20 years)**
 Changes may start to happen as long as twenty years or more before a clinical diagnosis, such as the slow formation of plaques and tangles causing short-term memory loss (Alzheimer’s Association, n.d). Also known as the pre-dementia stage or mild-cognitive impairment (MCI), patients may experience a hinderance in both learning new information and their ability to access the semantic memory system (Förstl & Kurz, 1999).  As such, the patient may slowly forget familiar words, colours, material they just read, misplace valuable objects and have trouble planning and organizing (Alzheimer’s Association, n.d). Also at this stage, clinically, there is no differentiation between the early stages of Alzheimer’s Disease (AD) and other non-AD memory impairments that may be benign and/or reversible, causing unreliability in detecting and providing treatment as early as possible (Arlt, 2013). The brain areas affected in this stage can be seen in Figure 3 and are the entorhinal cortex and the hippocampus, in charge of thinking/planning, and learning/memory respectively. Some alternate distinctive changes that may be seen are short term memory loss and the shrinkage of the amygdala (Alzheimer’s Association, n.d).
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     * Short-term memory loss
     * Language problems characterised by a decreased vocabulary and word fluency but patient with AD can communicate basic ideas adequately<br>
-<box 26% round left | > {{::23201936_2216190225073206_740873072_n.png?300|}} </box| Figure 5: Visualization of Alzheimer patient's brain in the Mid-Stage.>  **Mild to Moderate AD: Mid-Stage (2-4 years)**
+<box 26% round right | > {{::23201936_2216190225073206_740873072_n.png?300|}} </box| Figure 5: Visualization of Alzheimer patient's brain in the Mid-Stage.>  **Mild to Moderate AD: Mid-Stage (2-4 years)**
 Also known as the mild to moderate dementia stage, most AD patients are diagnosed in this stage. There is an observed increase in plaques and tangles found in the hippocampus and frontal lobe, causing memory hinderance serious enough to interfere with work or social life (Alzheimer’s Association, n.d). Moreover, plaques and tangles will spread to the speaking/understanding speech as well as the spatial orientation areas of the brain, resulting in the shrinkage of the cortical area, shrinkage of hippocampus and moderately enlarged ventricles (Alzheimer’s Association, n.d). In the early parts of this stage, patients may be able to live independently, however as the disease progresses, patients tend to “live in the past”, language, reading and writing skills worsen and patients gradually lose insight into their own condition— so close supervision is necessary (Förstl & Kurz, 1999). As Alzheimer's progresses, individuals may experience changes in personality and behaviour as well, resulting in trouble recognizing family members (Alzheimer’s Association, n.d). Due to this, family support seems to diminish due to restlessness, aggression, disorientation and involuntary urinary excretion (Förstl & Kurz, 1999). At the later times of this stage, closer to the Severe Stage, the parietal, frontal and temporal lobes will all be affected with this disease.
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       * Mood changes
-<box 26% round left | > {{::23316244_2216190375073191_249889212_n.png?300|}} </box| Figure 6: Visualization of Alzheimer patient's brain in the Late Stage.> **Severe AD: Late Stage (~3 years)**
+<box 26% round right | > {{::23316244_2216190375073191_249889212_n.png?300|}} </box| Figure 6: Visualization of Alzheimer patient's brain in the Late Stage.> **Severe AD: Late Stage (~3 years)**
 In this stage, almost all cognitive functions are severely impaired, while the brain has decreased in mass significantly due to widespread cell death (Alzheimer’s Association, n.d). Moreover, the extreme shrinkage particularly in the cerebral cortex and hippocampus is accompanied by a large increase in the ventricles of the brain (Alzheimer’s Association, n.d). The language of patients is severely reduced to simple phrases, however emotions can still be broadcasted or received (Förstl & Kurz, 1999). Nursing support is also disrupted due to many reasons. One being the patient's inability to understand nursing interventions, leading to angered experiences, along with displays of apathy and exhaustion (Förstl & Kurz, 1999). Also, due to impaired motor functions (chewing and swallowing) and large disturbances, nurses may have a harder time feeding AD patients (Förstl & Kurz, 1999). Moreover, plaques and tangles are widespread throughout the brain now, and severe dementia, and weight loss due to bed-riddance are often observed in the Severe AD stage (Alzheimer’s Association, n.d).
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     * Loss of mobility
     * Weight loss
-{{ :screen_shot_2017-10-29_at_12.33.48_am.png |}}**Figure 3:** The stage by stage progression of Alzheimer's and its spatial and temporal infection patterns in the brain.
+<box 50% round centre | > {{ :screen_shot_2017-10-29_at_12.33.48_am.png |}} </box| Figure 7: The stage by stage progression of Alzheimer's and its spatial and temporal infection patterns in the brain.>
 ===== Pathophysiology =====
@@ Line 80: / Line 84: @@
 ==== Tau Proteins ====
+<box 77% round right | > {{ :screen_shot_2017-10-28_at_8.50.10_am.png |}} </box| Figure 8: Mechanisms by which Tau proteins and microtubules react to allow transport of nutrients across axon.>
-{{ :screen_shot_2017-10-28_at_8.50.10_am.png |}}Tau proteins are microtubule-associated proteins (MAPs) found on the surface of microtubules in a neuronal cell. They stabilize the microtubules and prevent depolymerization to allow for the transportation of essential nutrients across the axon (Delacourte & Defossez, 1986). Tau proteins allow for normal axonal growth and maintenance of the internal structure of the neuronal transport system. Protein kinases such as GSK3 and CDK5 are involved in the phosphorylation of Tau proteins. The kinases cause Tau proteins to detach from the microtubules to allow cargo to move across the axon. After the cargo has safely transported across the axon, a dephosphorylation reaction occurs by which phosphatases reattach Tau proteins to the microtubules (Ballatore et al., 2007).
+Tau proteins are microtubule-associated proteins (MAPs) found on the surface of microtubules in a neuronal cell. They stabilize the microtubules and prevent depolymerization to allow for the transportation of essential nutrients across the axon (Delacourte & Defossez, 1986). Tau proteins allow for normal axonal growth and maintenance of the internal structure of the neuronal transport system. Protein kinases such as GSK3 and CDK5 are involved in the phosphorylation of Tau proteins. The kinases cause Tau proteins to detach from the microtubules to allow cargo to move across the axon. After the cargo has safely transported across the axon, a dephosphorylation reaction occurs by which phosphatases reattach Tau proteins to the microtubules (Ballatore et al., 2007).
 Hyperphosphorylation of Tau proteins results in the formation of neurofibrillary tangles (NFTs). When Tau proteins are hyperphosphorylated, they dissociate from microtubules, thus destabilizing them (Ballatore et al., 2007). The structure of the microtubules deteriorates such that they can no longer actively participate in the neuronal transport system. Free roaming Tau proteins aggregate to form NFTs which usually begin to form at the temporal lobe of the brain. Tau proteins can no longer be dephosphorylated to reattach to the degraded microtubules and the neuronal cell is ultimately destroyed (Ballatore et al., 2007). Research shows that the location and density of NFTs play a critical role in the pathophysiology and progression of AD. The direction of progression can vary and thus initial symptoms of AD vary between individuals (Ballatore et al., 2007).
 ==== Amyloid Precursor Protein ====
-<box 20% round right | > {{:23192938_2216168488408713_1466559488_n.jpg?200 |}} </box| Figure 4: The Amyloid precursor protein has four domains. Three domains are found on the surface of the cell. The fourth domain is a peptide that expands the surface of the membrane (Goodsell, 2006). >
+<box 20% round right | > {{:23192938_2216168488408713_1466559488_n.jpg?200 |}} </box| Figure 9: The Amyloid precursor protein has four domains. Three domains are found on the surface of the cell. The fourth domain is a peptide that expands the surface of the membrane (Goodsell, 2006). >
 The amyloid precursor protein is a large membrane protein found on the surface of cells and is said to be associated with the growth and repair of neural cells (Goodsell, 2006). It is made up of four domains, three of which that can extend on the surface of cells and one peptide that expands the length of the entire membrane (Goodsell, 2006). As an intact protein, the APP can act as a G protein receptor and can bind to other structural molecules such as heparin and laminin (Goodsell, 2006). The APP can also be broken down by proteases known as secretases into small and large pieces (Goodsell, 2006). The larger pieces help with neural growth once released to the outside surface. On the other hand, the smaller pieces have also been implicated with Alzheimer's disease (Goodsell, 2006).
-<box 20% round left | > {{ :23283485_2216169541741941_2027891156_n.jpg?200|}} </box| Figure 5: Amyloid beta pepttide leads to formation of dimers trimers and plaques in the brain of an Alzheimer's patient (O'Brien, 2015). >  **Histopathological features of the Alzheimer’s brain:**
+<box 20% round left | > {{ :23283485_2216169541741941_2027891156_n.jpg?200|}} </box| Figure 10: Amyloid beta pepttide leads to formation of dimers trimers and plaques in the brain of an Alzheimer's patient (O'Brien, 2015). >  **Histopathological features of the Alzheimer’s brain:**
 The formation of plaques from the proteolytic cleavage of the APP protein has played a central role in the pathogenesis of Alzheimer’s disease (Janus, et. al, 2000). The plaques are formed from 40-42 amino acid B-amyloid peptide chains and are found on the surface of the cells  (Roberds, et. al, 2001). This AB peptide is cleaved from the APP protein via secretase enzymes such as the beta secretase which cleaves the APP from the N terminus. Moreover, spinal fluid concentrations of patients with Alzheimer’s show anywhere between 500-900ng/ml of AB plaques (Seeman and Seeman, 2011). This concentration is generally much lower in the plasma suggesting the presence of receptors on neurons and glial cells (Seeman and Seeman, 2011). These are suggested to be damaging to the neurons and glial cells (Seeman and Seeman, 2011). Moreover, the presence of B-amyloid are correlated with the formation of plaques (Seeman and Seeman, 2011) since single molecules of Beta amyloid tend to form dimers and trimers, leading to the formation of plaques (Seeman and Seeman, 2011).
@@ Line 104: / Line 109: @@
 ==== Aβ Peptide Immunization ====
-<box 20% round right | > {{ :23201626_2031121397118456_1487395403_n.jpg?200|}} </box| Figure 6: Cleavage of the APP protein from beta and gamma secretase (Prostek, Barnea, Yaish, Zharhary, 2004). > A study conducted by Janus and colleagues looked at the effects of immunization of AB peptides in murine models of Alzheimer’s disease (Janus, et. al, 2000). Evidence suggests that there was a reduction in amyloid plaques, reducing cognitive dysfunction in the murine models (Janus, et. al, 2000). The team began by injecting a mutated APP transgene in the murine models. For three months, the mices cognitive function and brain physiology were monitored showing both spatial deficits and an increase in the amount of AB plaques (Janus, et. al, 2000). The mice were vaccinated with AB42 or an islet-associated polypeptide known as IAPP at different time frames (Janus, et. al, 2000). After vaccination, the mice were tested in spatial memory using the Morris water maze test (Janus, et. al, 2000). AB42 immunized mice on average performed better than IAPP immunized mice(Janus, et. al, 2000). Moreover, there was a 50% reduction in AB plaques in the mice vaccinated by the AB42 vaccination(Janus, et. al, 2000).
+<box 20% round right | > {{ :23201626_2031121397118456_1487395403_n.jpg?200|}} </box| Figure 11: Cleavage of the APP protein from beta and gamma secretase (Prostek, Barnea, Yaish, Zharhary, 2004). > A study conducted by Janus and colleagues looked at the effects of immunization of AB peptides in murine models of Alzheimer’s disease (Janus, et. al, 2000). Evidence suggests that there was a reduction in amyloid plaques, reducing cognitive dysfunction in the murine models (Janus, et. al, 2000). The team began by injecting a mutated APP transgene in the murine models. For three months, the mices cognitive function and brain physiology were monitored showing both spatial deficits and an increase in the amount of AB plaques (Janus, et. al, 2000). The mice were vaccinated with AB42 or an islet-associated polypeptide known as IAPP at different time frames (Janus, et. al, 2000). After vaccination, the mice were tested in spatial memory using the Morris water maze test (Janus, et. al, 2000). AB42 immunized mice on average performed better than IAPP immunized mice(Janus, et. al, 2000). Moreover, there was a 50% reduction in AB plaques in the mice vaccinated by the AB42 vaccination(Janus, et. al, 2000).
 ==== BACE Inhibition ====
@@ Line 114: / Line 119: @@
 Tau is a soluble microtubule-binding protein. One of the functions of Tau is to stabilize microtubules in axons for axonal transport, and as cytoskeletal elements for growth (Citron, 2010). One of the characteristics observed in AD neurons consist of hyperphosphorylated, aggregated insoluble tau (Citron, 2010). This leads to direct toxic effects such as a loss of axonal transport as tau can be detached from microtubules leading to the formation of soluble tau aggregates forming neurofibrillary tangles (Citron, 2010). Current therapeutic strategies focus on the inhibition of tau aggregation, and to block tau hyperphosphorylation (Citron, 2010). One of these strategies is to design kinase inhibitors, which would prevent hyperphosphorylation, and design aggregation inhibitors that would block the soluble tau aggregates and formation of tangles (Citron, 2010). Tau toxicity can also be prevented by enhancing clearance of tau, and degradation of tau aggregates (Citron, 2010).
-{{ :screen_shot_2017-10-29_at_1.10.29_am.png |}}
+<box 65% round centre | > {{ :screen_shot_2017-10-29_at_1.10.29_am.png |}} </box| Figure 12: Tau pathology and therapeutic approaches such as designing kinase inhibitors and aggregation inhibitors to prevent the formation of tau tangles (Citron, 2010). >
 ----
@@ Line 121: / Line 126: @@
 Over the past few years, amyloid-β (Aβ) immunotherapy have become a fascinating area of research in AD. Research in this field was initiated after the publication of the first immunization paper from Elan that reported that amyloid pathology was reduced in an APP transgenic mouse model after vaccination with aggregated Aβ (Citron, 2010). Three hypotheses have been proposed regarding Aβ immunotherapy mechanism. The first mechanism (Figure A) is based on microglial activation and phagocytosis. In this mechanism, amyloid-specific antibodies are administered and reach the central nervous system, bind to amyloid deposits (plaque), and trigger microglia to phaocytose the amyloid (Citron, 2010). The second mechanism (Figure B) is a direct interact interaction of amyloid-specific antibodies with the amyloid deposits. The antibodies are able to resolve the  in vitro aggregated Aβ, however research is still being done on how the amounts of antibody administered can dissolve the existing insoluble fibrils in the brain (Citron, 2010). A follow-up mechanism was proposed, in which peripheral amyloid-specific antibodies act as a sink (Figure C), and pull soluble Aβ into periphery where it is cleared (Citron, 2010). In vivo studies identified an efficient receptor-mediated transport mechanism for Aβ at the blood brain barrier, where Aβ is transported from CNS to plasma, and from plasma to CNS (Demattos, Bales, Cummins, Dodart, Paul & Holtzman, 2001). Research data suggests that to alter the CNS Aβ levels, increase efflux of Aβ from CNS to plasma and/or decrease efflux of Aβ from plasma to CNS is needed (Demattos et al., 2001). The experiment demonstrated that the  Aβ monoclonal antibody 266 (m266) showed affinity to soluble Aβ, and did not bind to plaques (Demattos et al., 2001). This reduced the amyloid levels upon administration. It was concluded that sufficient antibody concentrations were required to produce noticeable levels of cerebrospinal fluid capture needed to capture soluble Aβ, and produce a net flux of Aβ from the CNS to periphery, leading to decreased amyloid levels (Citron, 2010). Although peripheral administration of m266 reduced Aβ deposition, m266 did not bind to the deposits (Demattos et al., 2001). Hence, m266 appears to reduce brain Aβ burden by altering the CNS and plasma Aβ clearance (Demattos et al., 2001).
-{{ ::screen_shot_2017-10-29_at_1.18.26_am.png |}}
+<box 65% round centre | > {{ ::screen_shot_2017-10-29_at_1.18.26_am.png |}} </box| Figure 13: Four models of antibody-mediated amyloid clearance proposed as a future therapeutic to clear amyloid-beta plaques (Citron, 2010).  >
+===== Conclusion =====
+Alzheimer’s disease is a very common form of dementia that has significant implications to future health research, and well-being of elderly. There are two cases of Alzheimer’s disease, sporadic and familial, with sporadic being the most common and associated with late-onset Alzheimer’s. Sporadic cases occur because of the common variant allele, E4 of the apolipoprotein altering the normal functions, and resulting in amyloid-beta aggregation. Epidemiology research shows that age is one of the  risk factors for Alzheimer’s, but Alzheimer’s is not a normal part of aging. There are many symptoms, which can all be attributed to a loss of cognitive function, and memory decline, and these symptoms progress through the various stages of Alzheimer’s : early, mild-moderate, severe. This puzzling and debilitating disease has no forms of prevention and cure. The treatments for Alzheimer’s that are offered are only able to alleviate the symptoms and slow the progression, but do not cure the disease completely. Future therapeutics are focusing on more specific ways to target tau tangles, and amyloid-beta plaques in a more effective manner as these two have been found to be the indicator of Alzheimer’s in most cases.
+----
 ===== References =====
-Allan's References
-References
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