alzheimers_presentation_2_.pptx

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Key Points:

• Worldwide, nearly 44 million people have Alzheimer’s or a related dementia.
• Only 1-in-4 people with Alzheimer’s disease have been diagnosed.
• Alzheimer’s and dementia is most common in Western Europe (North America is close behind).
• Alzheimer’s is least prevalent in Sub-Saharan Africa.
• Alzheimer’s and other dementias are the top cause for disabilities in later life. (Alzheimer’s Disease International, 2015)

Figure ## - Projected growth of Dementia in the world in several areas. (Alzheimer's Disease International, 2015)

The incidence of AD is approximately 5–8 for per thousand person, which represents half of new dementia cases each year are AD (Bermejo-Pareja et al, 2008). One of the primary risk factor for AD, where there is a correlation of the incidence rate of every five years after the age of 65, the risk of acquiring AD approximately doubles (Di Carlo et al, 2002). Furthermore, there is also higher incidence rates in women compared to men of developing AD particularly in the population older than 85 (Andersen et al, 1999). In the United States, Alzheimer prevalence was estimated to be 1.6% in 2000 both overall and in the 65–74 age group, with the rate increasing to 19% in the 75–84 group and to 42% in the greater than 84 group. (Hebert et al, 2003) Prevalence rates of AD is less in developed countries compared to developing countries (Ferri et al, 2006). AD accounts to 50-70% of all forms of dementia, making it the leading cause of this neurodegenerative disease (7). Furthermore, due to the rapid increase of dementia, individuals would also be at increased risk of AD. Another study estimated that in 2006, 0.40% of the world population were afflicted by AD, and that the prevalence rate would triple and the absolute number would quadruple by 2050. (Brookmeyer et al, 2007)

Figure ## - Deaths due to Alzheimer's in 2012 (Red indicating larger number of deaths compared to orange). (Wikipedia, 2013)

Figure ## - The prevalence and incidence rates in various areas compared to an age category. (Qiu, Kivipelto & Strauss, 2009)

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Breast Cancer is similar to other cancers in which abnormal cell growth can potentially invade and spread to other areas of the body. In normal cell growth, cells can divide as necessary and have functioning signals that can stop cell division. These cells stay attached and localized in their respective sites and do not spread or invade other areas. Normal cells can also undergo programmed cell death, which keeps a balance in the cell population and discards unnecessary cells (Hartwell & Kastan, 1994).

The P13K pathway is an example of one of the most important pathways that protect cells by controlling functions such as cell growth, differentiation, motility, survival, and proliferation. P13Ks are lipid kinases that phosphorylate phosphoinositides. The P13Ks involved in breast cancer are Class 1A, which are comprised of a regulatory subunit (p85) and a catalytic subunit (p110). The activation of the P13K is initiated from growth factor or ligand binding to its respective receptor tyrosine kinase (RTK). These receptors contain two important growth factor receptors; the human epidermal growth factor receptor (HER) family and the insulin-like growth factor 1 receptor (IGF-1R). Once activated by a receptor, the P13K heterodimer interacts with a portion of the p85. This binding removes the inhibitory effect of p85 on p1110 rendering the P13K pathway active. The activation leads to a cascade of events downstream of the pathway, resulting in diverse functions such as cellular metabolism, proliferation, differentiation and survival (Liang & Slingerland, 2003).

In breast cancer this pathway is aberrantly hyperactive, as shown in Figure __. This results from mutations in various parts of the pathway but most predominantly in PIK3CA, which encodes for the catalytic p110a subunit. Mutations in these promote downstream signaling elements such as Akt that increase enzymatic function. The overexpression of p110a subunit, therefore leads to robust activation of the pathway (Berns et al., 2007). P13K pathway also involves tumor suppressors such as PTEN, which turn off the pathway and induce cell death. However, in cases such as breast cancer, the PTEN protein may be mutated and unable to turn off the pathway. Therefore, there is excessive cell proliferation and the cell does not undergo programmed cell death. In this case, low expression of PTEN leads to excessive cell growth (Depowski, Rosenthal, & Ross, 2001).

Figure 5 - PTEN Pathway and Mutations Retrieved from: http://theoncologist.alphamedpress.org/content/16/suppl_1/12/F1.expansion

The ErbB is a family of receptor tyrosine kinases, which include the Her2 (ErbB2) receptor-tyrosine-protein kinase. Both the P13K/AKT pathway and Ras-Raf-MAPK pathway are important signalling routes for the ErbB protein. In normal cell activity, the ErbB protein forms homodimers and heterodimers upon activation by growth factor ligands. Upon dimerization these proteins become autophosphorylated and act as binding sites for intracellular signal activators. This triggers a signal cascade leading to increased cell proliferation and inhibition of apoptosis (cell death). Mutation in the HER2 gene leads to amplification of this oncogene and excessive ErbB signalling. Therefore, this increased signalling leads to aberrant cell proliferation and increased inhibition of cell apoptosis (Mitri, Constantine, & O’Regan, 2012).

Figure shows the various types of abnormalities that can result from abnormal cell growth. Ductal hyperplasia contains lesions in the breast that are not cancerous but have active growth and division in the breast tissue cells. Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ (DCIS) occurs when breast tissue is beginning to take an abnormal appearance, however the abnormal cells are still localized in within the tissue. In DCIS-microinvasion and Invasive ductal cancer, the excessive cell growth spreads outside of the tissue and invades other areas of the body (Hüsemann et al., 2008).

Figure 6 - Type of Abnormalities. (Da Silva, R. (2015) Module 3 Lecture 2: Breast Cancer[PowerPoint Slides]. Retrieved from McMaster University Health and Disease)

The spread of the tumour varies with different stages in breast cancer. Usually, the least progressive is when atypical cells are in the breast tissue and there are no signs of spread to lymph nodes. As the tumour size increases it begins to spread to lymph nodes and there is metastases in axillary lymph nodes. From here the tumours of any size may spread into the skin, chest wall, and eventually the cancer spreads to other organs and tissues (Hüsemann et al., 2008).

The cancer cells are able to spread to various areas of the body by penetrating the extracellular matrix and blood vessels. Cells are constrained in their respective organs by cell-cell adhesion and basement membrane. However, cancer cells can penetrate the basement membrane by using invadopodia. Invadopodia is the process in which cells form actin-rich protrusions in the plasma membrane and subsequently degrade the extracellular matrix. Genes involved in these protrusions and invasions are upregulated in malignant cancer cells, allowing increased cell invasion and motility. This way, some cells contained in the tumour can separate from their parent mass and enter vascular and lymphatic circulation (Linder, 2007).

There are many procedures to treat breast cancer ranging from invasive to non-invasive treatments. One of the least invasive treatments is a lumpectomy, which is considered breast conserving surgery. This form of treatment aims to remove any abnormal masses within the breast, without removing all breast tissue (Fisher et al, 1993). Along with the mass itself, a layer of surrounding tissue, specifically regions near the axillary nodes, are also extracted to ensure cancer has not spread to neighboring regions (Fisher et al, 1993). However, due to the conservation of most breast tissue, this method is most effectively used at the earliest stages of breast cancer, before it has spread to multiple layers of tissue.

One of the most commonly used treatments is a mastectomy. This is because a lot of breast cancer cases are reported late, after cancer has already spread to multiple layers of tissue. Using this method all of the breast tissue, including the nipple and areola is removed on the affected breast(s) (Canadian Cancer Society, 2017). Once removed, the skin is stitched closed with a temporary tube attached to an opening in the wound, allowing for any fluid post-surgery to be removed safely (Canadian Cancer Society, 2017). After surgery, a pathologist examines the removed tissue to determine the extent of cancer penetration, and detect whether it has spread to neighboring regions. Since the axillary nodes have the highest likelihood for cancer to spread from the breasts, a few lymph nodes are also removed during surgery for examination (Canadian Cancer Society, 2017). If cancer has appeared to spread to other regions, then other treatments may be used in conjunction with a mastectomy, such as radiation therapy, in order to kill all remaining cancer cells.

Radiation therapy is a form of treatment that targets specific suspected regions. This type of therapy uses high-energy X-rays to assist in targeting and killing cancer cells (Canadian Cancer Society, 2017). Due to its ability to target cells, this form of treatment is typically used post-surgery in order to kill any remaining cancer cells that were missed during surgical procedures. This form of treatment used alone is an option for those experiencing early stage breast cancer, when all the cancer cells are contained within a specific region. However, radiation therapy is also an option for individuals with more advanced breast cancer if used in combination with other forms of treatment such as surgery or chemotherapy (Canadian Cancer Society, 2017).

Majority of lumpectomy procedures are followed by radiation therapy to ensure the cancer is killed from remaining breast tissue (Fisher et al, 1993). By doing this it will lower the chance of breast cancer recurrence by 50 percent, along with death due to breast cancer events by approximately 20 percent (Fisher et al, 1993). In terms of a mastectomy, radiation therapy has not shown to be a beneficial post-procedure (Canadian Cancer Society, 2017). However, in rare cases when radiation therapy is used after mastectomy, its purpose is to treat neighboring regions that are highly susceptible to the spread of cancer, such as the chest wall and axillary nodes (Canadian Cancer Society, 2017).

One of the most common forms of treatment for general cancer cases is chemotherapy. During this form of treatment tumors are treated with high levels of radiation to kill the rapidly diving cells (Canadian Cancer Society, 2017). This form of treatment targets cells non-specifically, and is therefore highly invasive as it kills both healthy and cancerous cells within the body. The radiation from chemotherapy causes the cells within the body to remain in the metaphase-anaphase stage during cell division, leading to apoptosis instead of replication (Canadian Cancer Society, 2017). Due to the killing of these cells there are high toxicity levels associated with this form of treatment which cause side effects such as hair loss, fatigue and nausea (Canadian Cancer Society, 2017).

Chemotherapy is divided into two categories depending on when it is used. Chemotherapy done prior to surgery is referred to as Neoadjuvant therapy. This method is used to shrink large tumors before attempting surgery to increase the chances of successful lump extraction, preventing breast removal (Kuerer et al, 1999). Neoadjuvant therapy can also be used in those with larger tumors in need of a mastectomy. In this case it would be used to increase the chances of tumor shrinkage, and promote a lumpectomy breast conserving procedure instead. Treatment this way also monitors how the tumor responds to treatment, making it safer for tumor removal (Kuerer et al, 1999). Chemotherapy used post surgery is referred to as Adjuvant therapy. This method is given to those who have no current evidence of containing cancer cells in their body (Kuerer et al, 1999). The purpose of adjuvant therapy is to kill the cancer cells that may potentially have been left behind or have metastasized, to reduce the risk of recurrence.

Patients who have been diagnosed with estrogen-receptor positive tumors often experience beneficial results from undergoing endocrine therapy (Lumachi et al, 2011). This type of therapy is usually done through oral contraceptives containing specific estrogen-receptor modulators (SERMs) (Lumachi et al, 2011). A few of the most commonly used SERMs are aromatase inhibitors, GnRH agonists and tamoxifen. Aromatase inhibitors decrease estrogen levels, whereas tamoxifen blocks estrogen receptors, both of which aim to either decrease the tumor’s size or delay its growth (Lumachi et al, 2011). Since endocrine therapy is used amongst those with estrogen-receptor positive tumors, women are classified as premenopausal or postmenopausal in order to determine which method of treatment to undergo. Women in the premenopausal stage who have the estrogen/progesterone receptor are normally treated with tamoxifen for a length of five years (Lumachi et al, 2011). This drug’s ability to block estrogen receptors lowers the risk of breast cancer recurrence by approximately 50 percent (Lumachi et al, 2011). Alternatively, women who are postmenopausal and estrogen-receptor positive have higher beneficial rates from adjuvant therapy, using an aromatase inhibitor (Lumachi et al, 2011). Since postmenopausal women still produce low levels of estrogen in specific fatty tissues, such as the breast tissue, this estrogen-lowering drug reduces the amounts of hormones which contribute to breast cancer growth.

To continue declining mortality rates, some future treatments and screening technologies that are in the process of being introduced, focus on more micro areas of the disease. A new screening technology called Scintimammography, which is molecular breast imaging, uses a radioactive drug called Tracer which is injected into the patient. The drug travels to the breasts via circulation and attaches to breast tissue cells (American Cancer Society, 2016). The radioactive substance is then detected by a special camera called a cadmium-zinc-tullerida gamma camera. The significance of this piece of technology is its beneficial detection of small tumours which other current screening technologies lack in advancement (Rhodes, 2005). This screening technology is able to give an early diagnosis to certain cases that show no symptoms of the disease in earlier stages, leading to declines of mortality rates. (Rhodes, 2005).

Future treatments are underway. These specific treatments are called target therapies and are a group of drugs which target specific changes in genes of cancer cells, a preventative measure in cancer cell proliferation. Some of these target therapies include PARP inhibitors. PARP inhibitors target the BRCA mutations (American Cancer Society, 2016). These target drugs have shown success in some types of breast cancers and are further being studies to determine exactly when these drugs have their highest potential to be helpful in treatment. Another target therapy in current research is anti-angiogenesis drugs, which refers to the blocking process of angiogenesis. Fast growing cancer cells require blood cells to nourish their cell bodies. Therefore preventing the proliferation and rapid growth of the cancer cells, blocking angiogenesis may be helpful in slowing down the disease (American Cancer Society, 2016).

Figure 7 - (Zetter, 2008)

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