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--- group_1_presentation_2_-alzheimer_s_disease [2017/11/03 22:28]
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).
@@ Line 8: / Line 10: @@
 ===== Epidemiology =====
-Globally, the prevalence of Alzheimer’s disease is estimated to be 24 million, and is predicted to double every 20 years (Mayeux & Stern, 2012). North America’s population is aging, and as a result of this, there is an exponential rise of patients diagnosed with Alzheimer’s disease as seen in Figure 1 (Mayeux & Stern, 2012). The highest prevalence of Alzheimer’s is in North America, Western Europe, Latin America, and China (Reitz, Brayne & Mayeux, 2011). The average age when patients are affected is at 60 years (Reitz et al., 2011). The annual incident rates (per 1000) in these countries are 10.5 in North America, 8.8 in Western Europe, 9.2 in Latin America, and 8.0 in China (Reitz et al., 2011).
+<box 30% round left| > {{:screen_shot_2017-10-28_at_11.53.57_pm.png?300 |}} </box| Figure 1: The graph depicts the prevalence of AD across Europe, China, USA, and Brazil in the elderly population. >  <box 30% round right| > {{ :1-s2.0-s0022510x07004911-gr2.jpg|}}</box| Figure 2: The graph compares the incidence rates of AD in men and women in the same age groups. > Globally, the prevalence of Alzheimer’s disease is estimated to be 24 million, and is predicted to double every 20 years (Mayeux & Stern, 2012). North America’s population is aging, and as a result of this, there is an exponential rise of patients diagnosed with Alzheimer’s disease as seen in Figure 1 (Mayeux & Stern, 2012). The highest prevalence of Alzheimer’s is in North America, Western Europe, Latin America, and China (Reitz, Brayne & Mayeux, 2011). The average age when patients are affected is at 60 years (Reitz et al., 2011). The annual incident rates (per 1000) in these countries are 10.5 in North America, 8.8 in Western Europe, 9.2 in Latin America, and 8.0 in China (Reitz et al., 2011).
-{{ :screen_shot_2017-10-28_at_11.53.57_pm.png |}}
-**Figure 1:** The graph depicts the prevalence of AD across Europe, China, USA, and Brazil in the elderly population.
 Studies have shown that although advancing age is a risk factor, there is also a sex difference in incidence and prevalence rates (Bermejo-Pareja, Benito-León, Vega, Medrona, & Román, 2008). Research shows that women have a higher risk of developing AD in the population older than 85 years of age (Figure 2) (Bermejo-Pareja et al., 2008). Incidence figures increase with age in women, but decreased beyond age 90 in men.
-{{ :1-s2.0-s0022510x07004911-gr2.jpg |}}
-**Figure 2: ** The graph compares the incidence rates of AD in men and women in the same age groups.
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-**fMRI**: <box 32% round right | > {{ :23283481_2216140458411516_1439233055_n.png|}} </box| Figure 3: an fMRI image of an Alzheimer's patient. The image shows changes in local connectivity levels for the patient group (Stam, 2014). >
+**fMRI**: <box 45% round right | > {{ :23283481_2216140458411516_1439233055_n.png|}} </box| Figure 3: an fMRI image of an Alzheimer's patient. The image shows changes in local connectivity levels for the patient group (Stam, 2014). >
 Functional magnetic resonance imaging or fMRI is another non-invasive neuroimaging technique that helps detect changes in brain pattern and activities. It is widely used to better understand the changes in brain pathology of many disorders including Alzheimer's disease. It detects signal changes that are used to produce magnetic resonance imaging, implicating changes in neuronal brain activity (Gore, 2003). Specifically, fMRI detects blood oxygen dependant changes (BOLD) in the brain and uses it to visualize changes in neural brain activity (Gore, 2003). Therefore, fMRI provides functional information about the brain. It is also used to better understand functional changes in the brain of Alzheimer's patients. For example, fMRI images provides information on hippocampus alterations in patients with Alzheimer’s (Wang, et. al., 2005). Moreover, fMRIs show a decrease in brain activity when doing visual encoding tasks (Rombouts, et. al., 2005). It allows doctors to better understand changes in brain physiology patterns however, providing a clearer diagnosis. fMRI’s also allow to better compare the level of the disease and the functional brain patterns as well.
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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).
 **Pre-Clinical AD: Early Stage (7-20 years)**
@@ Line 63: / Line 52: @@
 **Early Stage Symptoms**:
     * Short-term memory loss
-    * Language problems characterised by a decreased vocabulary and word fluency but patient with AD can communicate basic ideas adequately
+    * Language problems characterised by a decreased vocabulary and word fluency but patient with AD can communicate basic ideas adequately<br>
+<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)**
-**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.
 **Mid-Stage Symptoms**:
@@ Line 77: / Line 66: @@
       * Mood changes
-**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).
@@ Line 87: / Line 76: @@
     * 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 =====
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 ==== 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 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). >
-{{ :app_protein.jpg?direct|}}
-**Figure **: 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).
-**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 121: / Line 109: @@
 ==== Aβ Peptide Immunization ====
-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).
-==== Base Inhibition ====
+==== BACE Inhibition ====
 The gene that encodes the beta-secretase, a popular protease of the APP protein, is known as the BACE protein (Roberds, et. al, 2001). Inhibiting the production of BACE is seen to reduce the levels of beta-secretase (Vassar, et. al, 1999). Future research is looking at the development of BACE inhibitors to reduce the onset of familial Alzheimer's (Vassar, et. al, 1999). For example, BACE knockout studies in mice show a reduction in beta-amylase production (Roberds, et. al, 2001). Moreover, knocking out BACE does not have any harmful physiological effects of phenotypic differences in the mice, indicating future therapeutics.
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 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 138: / 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).  >
-===== References =====
+===== 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.
+----
-Allan's References
+===== References =====
-References
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+Alzheimer's Disease and Related Dementias. (2016, August). Retrieved October 23, 2017, from
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+Bermejo-Pareja, F., Benito-León, J., Vega, S., Medrano, M., & Román, G. (2008). Incidence and subtypes of dementia in three elderly populations of central Spain. Journal of the Neurological Sciences, 264(1-2), 63-72. doi:10.1016/j.jns.2007.07.021
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+Citron, M. (2010). Alzheimer's disease: strategies for disease modification. Nature reviews Drug discovery, 9(5), 387-398.
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-(Ellis, 2005) (A5)
+Delacourte, A., & Defossez, A. (1986). Alzheimer's disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. Journal of the neurological sciences, 76(2), 173-186.
-http://jaoa.org/article.aspx?articleid=2093130#72960479
+DeMattos, R. B., Bales, K. R., Cummins, D. J., Dodart, J.-C., Paul, S. M., & Holtzman, D. M. (2001). Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer’s disease. Proceedings of the National Academy of Sciences of the United States of America, 98(15), 8850–8855. http://doi.org/10.1073/pnas.151261398
 Ellis, J. M. (2005). Cholinesterase inhibitors in the treatment of dementia. The Journal of the American Osteopathic Association, 105(3), 145–158. https://doi.org/10.7556/JAOA.2005.105.3.145
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+Hippius, H., & Neundörfer, G. (2003). The discovery of Alzheimer's disease. Dialogues in clinical    neuroscience, 5(1), 101.
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