Monday, July 14, 2008
Metalosis Maligna reference
Metalosis Maligna :is one of the most impressive and powerful diseases the human body has ever being capable of development, a virus called STREPTOCOCCCUS METALOMALIGNA is the responsible for this impressive disorder involving the human tissue and the metal implant.
Symtoms: you start feeling itchy and are forced to use a metal object to scratch your back.
Cure: Theres is no cure or treatment for this disease.
Saturday, July 12, 2008
AIDS reference
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome (AIDS or Aids) is a set of symptoms and infections resulting from the damage to the human immune system caused by the human immunodeficiency virus (HIV).[1] This condition progressively reduces the effectiveness of the immune system and leaves individuals susceptible to opportunistic infections and tumors. HIV is transmitted through direct contact of a mucous membrane or the bloodstream with a bodily fluid containing HIV, such as blood, semen, vaginal fluid, preseminal fluid, and breast milk.[2][3] This transmission can involve anal, vaginal or oral sex, blood transfusion, contaminated hypodermic needles, exchange between mother and baby during pregnancy, childbirth, or breastfeeding, or other exposure to one of the above bodily fluids.
AIDS is now a pandemic.[4] In 2007, an estimated 33.2 million people lived with the disease worldwide, and it killed an estimated 2.1 million people, including 330,000 children.[5] Over three-quarters of these deaths occurred in sub-Saharan Africa,[5] retarding economic growth and destroying human capital.[6] Most researchers believe that HIV originated in sub-Saharan Africa during the twentieth century.[7] The disease was first identified by the U.S. Centers for Disease Control and Prevention in 1981 and its cause identified by American and French scientists in the late 1980s.[8]
Although treatments for AIDS and HIV can slow the course of the disease, there is currently no vaccine or cure. Antiretroviral treatment reduces both the mortality and the morbidity of HIV infection, but these drugs are expensive and routine access to antiretroviral medication is not available in all countries.[9] Due to the difficulty in treating HIV infection, preventing infection is a key aim in controlling the AIDS epidemic, with health organizations promoting safe sex and needle-exchange programmes in attempts to slow the spread of the virus.
The symptoms of AIDS are primarily the result of conditions that do not normally develop in individuals with healthy immune systems. Most of these conditions are infections caused by bacteria, viruses, fungi and parasites that are normally controlled by the elements of the immune system that HIV damages. Opportunistic infections are common in people with AIDS.[10] HIV affects nearly every organ system. People with AIDS also have an increased risk of developing various cancers such as Kaposi's sarcoma, cervical cancer and cancers of the immune system known as lymphomas. Additionally, people with AIDS often have systemic symptoms of infection like fevers, sweats (particularly at night), swollen glands, chills, weakness, and weight loss.[11][12] The specific opportunistic infections that AIDS patients develop depend in part on the prevalence of these infections in the geographic area in which the patient lives.
Pulmonary infections
X-ray of Pneumocystis jirovecii caused pneumonia. There is increased white (opacity) in the lower lungs on both sides, characteristic of Pneumocystis pneumonia
X-ray of Pneumocystis jirovecii caused pneumonia. There is increased white (opacity) in the lower lungs on both sides, characteristic of Pneumocystis pneumonia
Pneumocystis pneumonia (originally known as Pneumocystis carinii pneumonia, and still abbreviated as PCP, which now stands for Pneumocystis pneumonia) is relatively rare in healthy, immunocompetent people, but common among HIV-infected individuals. It is caused by Pneumocystis jirovecii. Before the advent of effective diagnosis, treatment and routine prophylaxis in Western countries, it was a common immediate cause of death. In developing countries, it is still one of the first indications of AIDS in untested individuals, although it does not generally occur unless the CD4 count is less than 200 cells per µL of blood.[13]
Tuberculosis (TB) is unique among infections associated with HIV because it is transmissible to immunocompetent people via the respiratory route, is easily treatable once identified, may occur in early-stage HIV disease, and is preventable with drug therapy. However, multidrug resistance is a potentially serious problem. Even though its incidence has declined because of the use of directly observed therapy and other improved practices in Western countries, this is not the case in developing countries where HIV is most prevalent. In early-stage HIV infection (CD4 count >300 cells per µL), TB typically presents as a pulmonary disease. In advanced HIV infection, TB often presents atypically with extrapulmonary (systemic) disease a common feature. Symptoms are usually constitutional and are not localized to one particular site, often affecting bone marrow, bone, urinary and gastrointestinal tracts, liver, regional lymph nodes, and the central nervous system.[14]
Gastrointestinal infections
Esophagitis is an inflammation of the lining of the lower end of the esophagus (gullet or swallowing tube leading to the stomach). In HIV infected individuals, this is normally due to fungal (candidiasis) or viral (herpes simplex-1 or cytomegalovirus) infections. In rare cases, it could be due to mycobacteria.
Unexplained chronic diarrhea in HIV infection is due to many possible causes, including common bacterial (Salmonella, Shigella, Listeria or Campylobacter) and parasitic infections; and uncommon opportunistic infections such as cryptosporidiosis, microsporidiosis, Mycobacterium avium complex (MAC) and viruses,[16] astrovirus, adenovirus, rotavirus and cytomegalovirus, (the latter as a course of colitis). In some cases, diarrhea may be a side effect of several drugs used to treat HIV, or it may simply accompany HIV infection, particularly during primary HIV infection. It may also be a side effect of antibiotics used to treat bacterial causes of diarrhea (common for Clostridium difficile). In the later stages of HIV infection, diarrhea is thought to be a reflection of changes in the way the intestinal tract absorbs nutrients, and may be an important component of HIV-related wasting.[17]
Neurological and psychiatric involvement
HIV infection may lead to a variety of neuropsychiatric sequelae, either by infection of the now susceptible nervous system by organisms, or as a direct consequence of the illness itself.
Toxoplasmosis is a disease caused by the single-celled parasite called Toxoplasma gondii; it usually infects the brain causing toxoplasma encephalitis but it can infect and cause disease in the eyes and lungs.[18] Cryptococcal meningitis is an infection of the meninx (the membrane covering the brain and spinal cord) by the fungus Cryptococcus neoformans. It can cause fevers, headache, fatigue, nausea, and vomiting. Patients may also develop seizures and confusion; left untreated, it can be lethal.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease, in which the gradual destruction of the myelin sheath covering the axons of nerve cells impairs the transmission of nerve impulses. It is caused by a virus called JC virus which occurs in 70% of the population in latent form, causing disease only when the immune system has been severely weakened, as is the case for AIDS patients. It progresses rapidly, usually causing death within months of diagnosis.[19]
AIDS dementia complex (ADC) is a metabolic encephalopathy induced by HIV infection and fueled by immune activation of HIV infected brain macrophages and microglia which secrete neurotoxins of both host and viral origin.[20] Specific neurological impairments are manifested by cognitive, behavioral, and motor abnormalities that occur after years of HIV infection and is associated with low CD4+ T cell levels and high plasma viral loads. Prevalence is 10–20% in Western countries[21] but only 1–2% of HIV infections in India.[22][23] This difference is possibly due to the HIV subtype in India. AIDS related mania is sometimes seen in patients with advanced HIV illness; it presents with more irritability and cognitive impairment and less euphoria than a manic episode associated with true bipolar disorder. Unlike the latter condition, it may have a more chronic course. This syndrome is less often seen with the advent of multi-drug therapy.
Tumors and malignancies
Kaposi's sarcoma
Patients with HIV infection have substantially increased incidence of several malignant cancers. This is primarily due to co-infection with an oncogenic DNA virus, especially Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV), and human papillomavirus (HPV).[24][25]
Kaposi's sarcoma (KS) is the most common tumor in HIV-infected patients. The appearance of this tumor in young homosexual men in 1981 was one of the first signals of the AIDS epidemic. Caused by a gammaherpes virus called Kaposi's sarcoma-associated herpes virus (KSHV), it often appears as purplish nodules on the skin, but can affect other organs, especially the mouth, gastrointestinal tract, and lungs.
High-grade B cell lymphomas such as Burkitt's lymphoma, Burkitt's-like lymphoma, diffuse large B-cell lymphoma (DLBCL), and primary central nervous system lymphoma present more often in HIV-infected patients. These particular cancers often foreshadow a poor prognosis. In some cases these lymphomas are AIDS-defining. Epstein-Barr virus (EBV) or KSHV cause many of these lymphomas.
Cervical cancer in HIV-infected women is considered AIDS-defining. It is caused by human papillomavirus (HPV).[26]
In addition to the AIDS-defining tumors listed above, HIV-infected patients are at increased risk of certain other tumors, such as Hodgkin's disease and anal and rectal carcinomas. However, the incidence of many common tumors, such as breast cancer or colon cancer, does not increase in HIV-infected patients. In areas where HAART is extensively used to treat AIDS, the incidence of many AIDS-related malignancies has decreased, but at the same time malignant cancers overall have become the most common cause of death of HIV-infected patients.[27]
Other opportunistic infections
AIDS patients often develop opportunistic infections that present with non-specific symptoms, especially low-grade fevers and weight loss. These include infection with Mycobacterium avium-intracellulare and cytomegalovirus (CMV). CMV can cause colitis, as described above, and CMV retinitis can cause blindness. Penicilliosis due to Penicillium marneffei is now the third most common opportunistic infection (after extrapulmonary tuberculosis and cryptococcosis) in HIV-positive individuals within the endemic area of Southeast Asia.[28]
AIDS is the most severe acceleration of infection with HIV. HIV is a retrovirus that primarily infects vital organs of the human immune system such as CD4+ T cells (a subset of T cells), macrophages and dendritic cells. It directly and indirectly destroys CD4+ T cells.[29] Once HIV has killed so many CD4+ T cells that there are fewer than 200 of these cells per microliter (µL) of blood, cellular immunity is lost. Acute HIV infection progresses over time to clinical latent HIV infection and then to early symptomatic HIV infection and later to AIDS, which is identified either on the basis of the amount of CD4+ T cells remaining in the blood, and/or the presence of certain infections, as noted above.[30]
In the absence of antiretroviral therapy, the median time of progression from HIV infection to AIDS is nine to ten years, and the median survival time after developing AIDS is only 9.2 months.[31] However, the rate of clinical disease progression varies widely between individuals, from two weeks up to 20 years. Many factors affect the rate of progression. These include factors that influence the body's ability to defend against HIV such as the infected person's general immune function.[32][33] Older people have weaker immune systems, and therefore have a greater risk of rapid disease progression than younger people. Poor access to health care and the existence of coexisting infections such as tuberculosis also may predispose people to faster disease progression.[31][34][35] The infected person's genetic inheritance plays an important role and some people are resistant to certain strains of HIV. An example of this is people with the homozygous CCR5-Δ32 variation are resistant to infection with certain strains of HIV.[36] HIV is genetically variable and exists as different strains, which cause different rates of clinical disease progression.[37][38][39]
Sexual transmission
Sexual transmission occurs with the contact between sexual secretions of one person with the rectal, genital or oral mucous membranes of another. Unprotected receptive sexual acts are riskier than unprotected insertive sexual acts, and the risk for transmitting HIV through unprotected anal intercourse is greater than the risk from vaginal intercourse or oral sex. However, oral sex is not entirely safe, as HIV can be transmitted through both insertive and receptive oral sex.[40] The risk of HIV transmission from exposure to saliva is considerably smaller than the risk from exposure to semen, one would have to swallow liters of saliva from a carrier to run a significant risk of becoming infected.[41] Sexual assault greatly increases the risk of HIV transmission as protection is rarely employed and physical trauma to the vagina frequently occurs, facilitating the transmission of HIV.[42]
Other sexually transmitted infections (STI) increase the risk of HIV transmission and infection, because they cause the disruption of the normal epithelial barrier by genital ulceration and/or microulceration; and by accumulation of pools of HIV-susceptible or HIV-infected cells (lymphocytes and macrophages) in semen and vaginal secretions. Epidemiological studies from sub-Saharan Africa, Europe and North America suggest that genital ulcers, such as those caused by syphilis and/or chancroid, increase the risk of becoming infected with HIV by about four-fold. There is also a significant although lesser increase in risk from STIs such as gonorrhea, Chlamydial infection and trichomoniasis, which all cause local accumulations of lymphocytes and macrophages.[43]
Transmission of HIV depends on the infectiousness of the index case and the susceptibility of the uninfected partner. Infectivity seems to vary during the course of illness and is not constant between individuals. An undetectable plasma viral load does not necessarily indicate a low viral load in the seminal liquid or genital secretions. However, each 10-fold increase in the level of HIV in the blood is associated with an 81% increased rate of HIV transmission.[43][44] Women are more susceptible to HIV-1 infection due to hormonal changes, vaginal microbial ecology and physiology, and a higher prevalence of sexually transmitted diseases.[45][46] People who have been infected with one strain of HIV can still be infected later on in their lives by other, more virulent strains.
Infection is unlikely in a single encounter. High rates of infection have been linked to a pattern of overlapping long-term romantic relationships. This allows the virus to quickly spread to multiple partners who in turn infect their partners. A pattern of serial monogamy or occasional casual encounters is associated with lower rates of infection.[47]
Exposure to blood-borne pathogens
CDC poster from 1989 highlighting the threat of AIDS associated with drug use
CDC poster from 1989 highlighting the threat of AIDS associated with drug use
This transmission route is particularly relevant to intravenous drug users, hemophiliacs and recipients of blood transfusions and blood products. Sharing and reusing syringes contaminated with HIV-infected blood represents a major risk for infection with HIV. Needle sharing is the cause of one third of all new HIV-infections in North America, China, and Eastern Europe. The risk of being infected with HIV from a single prick with a needle that has been used on an HIV-infected person is thought to be about 1 in 150 (see table above). Post-exposure prophylaxis with anti-HIV drugs can further reduce this risk.[48] This route can also affect people who give and receive tattoos and piercings. Universal precautions are frequently not followed in both sub-Saharan Africa and much of Asia because of both a shortage of supplies and inadequate training. The WHO estimates that approximately 2.5% of all HIV infections in sub-Saharan Africa are transmitted through unsafe healthcare injections.[49] Because of this, the United Nations General Assembly has urged the nations of the world to implement precautions to prevent HIV transmission by health workers.[50]
The risk of transmitting HIV to blood transfusion recipients is extremely low in developed countries where improved donor selection and HIV screening is performed. However, according to the WHO, the overwhelming majority of the world's population does not have access to safe blood and between 5% and 10% of the world's HIV infections come from transfusion of infected blood and blood products.[51]
Perinatal transmission
The transmission of the virus from the mother to the child can occur in utero during the last weeks of pregnancy and at childbirth. In the absence of treatment, the transmission rate between a mother and her child during pregnancy, labor and delivery is 25%. However, when the mother takes antiretroviral therapy and gives birth by caesarean section, the rate of transmission is just 1%.[52] The risk of infection is influenced by the viral load of the mother at birth, with the higher the viral load, the higher the risk. Breastfeeding also increases the risk of transmission by about 4 %.[53]
Misconceptions
A number of misconceptions have arisen surrounding HIV/AIDS. Three of the most common are that AIDS can spread through casual contact, that sexual intercourse with a virgin will cure AIDS, and that HIV can infect only homosexual men and drug users. Other misconceptions are that any act of anal intercourse between gay men can lead to AIDS infection, and that open discussion of homosexuality and HIV in schools will lead to increased rates of homosexuality and AIDS.
Cells affected
The virus, entering through which ever route, acts primarily on the following cells:[61]
1. Lymphoreticular system:
1. CD4+ T-Helper cells
2. CD4+ Macrophages
3. CD4+ Monocytes
4. B-lymphocytes
2. Certain endothelial cells
3. Central nervous system:
1. Microglia of the nervous system
2. Astrocytes
3. Oligodendrocytes
4. Neurones - indirectly by the action of cytokines and the gp-120
The effect
The virus has cytopathic effects but how it does it is still not quite clear. It can remain inactive in these cells for long periods, though. This effect is hypothesized to be due to the CD4-gp120 interaction.
* The most prominent effect of the HIV virus is its T-helper cell suppression and lysis. The cell is simply killed off or deranged to the point of being function-less (they do not respond to foreign antigens). The infected B-cells can not produce enough antibodies either. Thus the immune system collapses leading to the familiar AIDS complications, like infections and neoplasms (vide supra).
* Infection of the cells of the CNS cause acute aseptic meningitis, subacute encephalitis, vacuolar myelopathy and peripheral neuropathy. Later it leads to even AIDS dementia complex.
* The CD4-gp120 interaction (vide supra) is also permissive to other viruses like Cytomegalovirus, Hepatitis virus, Herpes simplex virus, etc. These viruses lead to further cell damage i.e. cytopathy.
Molecular basis
For details, see:
* Structure and genome of HIV,
* HIV replication cycle
* HIV tropism
Diagnosis
The diagnosis of AIDS in a person infected with HIV is based on the presence of certain signs or symptoms. Since June 5, 1981, many definitions have been developed for epidemiological surveillance such as the Bangui definition and the 1994 expanded World Health Organization AIDS case definition. However, clinical staging of patients was not an intended use for these systems as they are neither sensitive, nor specific. In developing countries, the World Health Organization staging system for HIV infection and disease, using clinical and laboratory data, is used and in developed countries, the Centers for Disease Control (CDC) Classification System is used.
In 1990, the World Health Organization (WHO) grouped these infections and conditions together by introducing a staging system for patients infected with HIV-1.[63] An update took place in September 2005. Most of these conditions are opportunistic infections that are easily treatable in healthy people.
* Stage I: HIV infection is asymptomatic and not categorized as AIDS
* Stage II: includes minor mucocutaneous manifestations and recurrent upper respiratory tract infections
* Stage III: includes unexplained chronic diarrhea for longer than a month, severe bacterial infections and pulmonary tuberculosis
* Stage IV: includes toxoplasmosis of the brain, candidiasis of the esophagus, trachea, bronchi or lungs and Kaposi's sarcoma; these diseases are indicators of AIDS.
CDC classification system
There are two main definitions for AIDS, both produced by the Centers for Disease Control and Prevention (CDC). The older definition is to referring to AIDS using the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus.[64][65] In 1993, the CDC expanded their definition of AIDS to include all HIV positive people with a CD4+ T cell count below 200 per µL of blood or 14% of all lymphocytes.[66] The majority of new AIDS cases in developed countries use either this definition or the pre-1993 CDC definition. The AIDS diagnosis still stands even if, after treatment, the CD4+ T cell count rises to above 200 per µL of blood or other AIDS-defining illnesses are cured.
HIV test
Many people are unaware that they are infected with HIV.[67] Less than 1% of the sexually active urban population in Africa has been tested, and this proportion is even lower in rural populations. Furthermore, only 0.5% of pregnant women attending urban health facilities are counseled, tested or receive their test results. Again, this proportion is even lower in rural health facilities.[67] Therefore, donor blood and blood products used in medicine and medical research are screened for HIV.
HIV tests are usually performed on venous blood. Many laboratories use fourth generation screening tests which detect anti-HIV antibody (IgG and IgM) and the HIV p24 antigen. The detection of HIV antibody or antigen in a patient previously known to be negative is evidence of HIV infection. Individuals whose first specimen indicates evidence of HIV infection will have a repeat test on a second blood sample to confirm the results. The window period (the time between initial infection and the development of detectable antibodies against the infection) can vary since it can take 3–6 months to seroconvert and to test positive. Detection of the virus using polymerase chain reaction (PCR) during the window period is possible, and evidence suggests that an infection may often be detected earlier than when using a fourth generation EIA screening test. Positive results obtained by PCR are confirmed by antibody tests.[68] Routinely used HIV tests for infection in neonates, born to HIV-positive mothers, have no value because of the presence of maternal antibody to HIV in the child's blood. HIV infection can only be diagnosed by PCR, testing for HIV pro-viral DNA in the children's lymphocytes
Sexual contact
The majority of HIV infections are acquired through unprotected sexual relations between partners, one of whom has HIV. The primary mode of HIV infection worldwide is through sexual contact between members of the opposite sex.[78][79][80] During a sexual act, only male or female condoms can reduce the chances of infection with HIV and other STDs and the chances of becoming pregnant. The best evidence to date indicates that typical condom use reduces the risk of heterosexual HIV transmission by approximately 80% over the long-term, though the benefit is likely to be higher if condoms are used correctly on every occasion.[81] The male latex condom, if used correctly without oil-based lubricants, is the single most effective available technology to reduce the sexual transmission of HIV and other sexually transmitted infections. Manufacturers recommend that oil-based lubricants such as petroleum jelly, butter, and lard not be used with latex condoms, because they dissolve the latex, making the condoms porous. If necessary, manufacturers recommend using water-based lubricants. Oil-based lubricants can however be used with polyurethane condoms.[82]
The female condom is an alternative to the male condom and is made from polyurethane, which allows it to be used in the presence of oil-based lubricants. They are larger than male condoms and have a stiffened ring-shaped opening, and are designed to be inserted into the vagina. The female condom contains an inner ring, which keeps the condom in place inside the vagina – inserting the female condom requires squeezing this ring. However, at present availability of female condoms is very low and the price remains prohibitive for many women. Preliminary studies suggest that, where female condoms are available, overall protected sexual acts increase relative to unprotected sexual acts, making them an important HIV prevention strategy.[83]
Studies on couples where one partner is infected show that with consistent condom use, HIV infection rates for the uninfected partner are below 1% per year.[84] Prevention strategies are well-known in developed countries, however, recent epidemiological and behavioral studies in Europe and North America have suggested that a substantial minority of young people continue to engage in high-risk practices and that despite HIV/AIDS knowledge, young people underestimate their own risk of becoming infected with HIV.[85]
Randomized controlled trials have shown that male circumcision lowers the risk of HIV infection among heterosexual men by up to 60%.[86] It is expected that this procedure will be actively promoted in many of the countries affected by HIV, although doing so will involve confronting a number of practical, cultural and attitudinal issues. Some experts fear that a lower perception of vulnerability among circumcised men may result in more sexual risk-taking behavior, thus negating its preventive effects.[87]
Exposure to infected body fluids
Health care workers can reduce exposure to HIV by employing precautions to reduce the risk of exposure to contaminated blood. These precautions include barriers such as gloves, masks, protective eyeware or shields, and gowns or aprons which prevent exposure of the skin or mucous membranes to blood borne pathogens. Frequent and thorough washing of the skin immediately after being contaminated with blood or other bodily fluids can reduce the chance of infection. Finally, sharp objects like needles, scalpels and glass, are carefully disposed of to prevent needlestick injuries with contaminated items.[88] Since intravenous drug use is an important factor in HIV transmission in developed countries, harm reduction strategies such as needle-exchange programmes are used in attempts to reduce the infections caused by drug abuse.
Mother-to-child transmission (MTCT)
Current recommendations state that when replacement feeding is acceptable, feasible, affordable, sustainable and safe, HIV-infected mothers should avoid breast-feeding their infant. However, if this is not the case, exclusive breast-feeding is recommended during the first months of life and discontinued as soon as possible.[91]
Treatment
Abacavir – a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
Abacavir – a nucleoside analog reverse transcriptase inhibitors (NARTIs or NRTIs)
The chemical structure of Abacavir
The chemical structure of Abacavir
There is currently no vaccine or cure for HIV or AIDS. The only known methods of prevention are based on avoiding exposure to the virus or, failing that, an antiretroviral treatment directly after a highly significant exposure, called post-exposure prophylaxis (PEP).[92] PEP has a very demanding four week schedule of dosage. It also has very unpleasant side effects including diarrhea, malaise, nausea and fatigue.[93]
Antiviral therapy
Current treatment for HIV infection consists of highly active antiretroviral therapy, or HAART.[94] This has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available.[9] Current optimal HAART options consist of combinations (or "cocktails") consisting of at least three drugs belonging to at least two types, or "classes," of antiretroviral agents. Typical regimens consist of two nucleoside analogue reverse transcriptase inhibitors (NARTIs or NRTIs) plus either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor (NNRTI). Because HIV disease progression in children is more rapid than in adults, and laboratory parameters are less predictive of risk for disease progression, particularly for young infants, treatment recommendations are more aggressive for children than for adults.[95] In developed countries where HAART is available, doctors assess the viral load, rapidity in CD4 decline, and patient readiness while deciding when to recommend initiating treatment.[96]
HAART allows the stabilization of the patient’s symptoms and viremia, but it neither cures the patient of HIV, nor alleviates the symptoms, and high levels of HIV-1, often HAART resistant, return once treatment is stopped.[97][98] Moreover, it would take more than the lifetime of an individual to be cleared of HIV infection using HAART.[99] Despite this, many HIV-infected individuals have experienced remarkable improvements in their general health and quality of life, which has led to the plummeting of HIV-associated morbidity and mortality. In the absence of HAART, progression from HIV infection to AIDS occurs at a median of between nine to ten years and the median survival time after developing AIDS is only 9.2 months. HAART is thought to increase survival time by between 4 and 12 years.
For some patients, which can be more than fifty percent of patients, HAART achieves far less than optimal results, due to medication intolerance/side effects, prior ineffective antiretroviral therapy and infection with a drug-resistant strain of HIV. Non-adherence and non-persistence with therapy are the major reasons why some people do not benefit from HAART.[105] The reasons for non-adherence and non-persistence are varied. Major psychosocial issues include poor access to medical care, inadequate social supports, psychiatric disease and drug abuse. HAART regimens can also be complex and thus hard to follow, with large numbers of pills taken frequently.[106][107][108] Side effects can also deter people from persisting with HAART, these include lipodystrophy, dyslipidaemia, diarrhoea, insulin resistance, an increase in cardiovascular risks and birth defects.[109] Anti-retroviral drugs are expensive, and the majority of the world's infected individuals do not have access to medications and treatments for HIV and AIDS.
Future research
It has been postulated that only a vaccine can halt the pandemic because a vaccine would possibly cost less, thus being affordable for developing countries, and would not require daily treatments. However, even after almost 30 years of research, HIV-1 remains a difficult target for a vaccine.
Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining the best sequence of regimens to manage drug resistance. A number of studies have shown that measures to prevent opportunistic infections can be beneficial when treating patients with HIV infection or AIDS. Vaccination against hepatitis A and B is advised for patients who are not infected with these viruses and are at risk of becoming infected.[111] Patients with substantial immunosuppression are also advised to receive prophylactic therapy for Pneumocystis jiroveci pneumonia (PCP), and many patients may benefit from prophylactic therapy for toxoplasmosis and Cryptococcus meningitis as well.[93]
Alternative medicine
Various forms of alternative medicine have been used to treat symptoms or alter the course of the disease.[112] Acupuncture has been used to alleviate some symptoms, such peripheral neuropathy, but cannot cure the HIV infection.[113] Several randomized clinical trials testing the effect of herbal medicines have shown that there is no evidence that these herbs have any effect on the progression of the disease, but may instead produce serious side-effects.[114]
Some data suggest that multivitamin and mineral supplements might reduce HIV disease progression in adults, although there is no conclusive evidence on if they reduce mortality among people with good nutritional status.[115] Vitamin A supplementation in children probably has some benefit.[115] Daily doses of selenium can suppress HIV viral burden with an associated improvement of the CD4 count. Selenium can be used as an adjunct therapy to standard antiviral treatments, but cannot itself reduce mortality and morbidity.[116]
Current studies indicate that that alternative medicine therapies have little effect on the mortality or morbidity of the disease, but may improve the quality of life of individuals afflicted with AIDS. The psychological benefits of these therapies are the most important use.
Epidemiology
Estimated prevalence of HIV among young adults (15-49) per country at the end of 2005
The AIDS pandemic can also be seen as several epidemics of separate subtypes; the major factors in its spread are sexual transmission and vertical transmission from mother to child at birth and through breast milk.[4] Despite recent, improved access to antiretroviral treatment and care in many regions of the world, the AIDS pandemic claimed an estimated 2.1 million (range 1.9–2.4 million) lives in 2007 of which an estimated 330,000 were children under 15 years.[5] Globally, an estimated 33.2 million people lived with HIV in 2007, including 2.5 million children. An estimated 2.5 million (range 1.8–4.1 million) people were newly infected in 2007, including 420,000 children.[5]
Sub-Saharan Africa remains by far the worst affected region. In 2007 it contained an estimated 68% of all people living with AIDS and 76% of all AIDS deaths, with 1.7 million new infections bringing the number of people living with HIV to 22.5 million, and with 11.4 million AIDS orphans living in the region. Unlike other regions, most people living with HIV in sub-Saharan Africa in 2007 (61%) were women. Adult prevalence in 2007 was an estimated 5.0%, and AIDS continued to be the single largest cause of mortality in this region.[5] South Africa has the largest population of HIV patients in the world, followed by Nigeria and India.[117] South & South East Asia are second worst affected; in 2007 this region contained an estimated 18% of all people living with AIDS, and an estimated 300,000 deaths from AIDS.[5] India has an estimated 2.5 million infections and an estimated adult prevalence of 0.36%.[5] Life expectancy has fallen dramatically in the worst-affected countries; for example, in 2006 it was estimated that it had dropped from 65 to 35 years in Botswana.[4]
Prognosis
Without treatment, the net median survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype,[5] and the median survival rate after diagnosis of AIDS in resource-limited settings where treatment is not available ranges between 6 and 19 months, depending on the study.[118] In areas where it is widely available, the development of HAART as effective therapy for HIV infection and AIDS reduced the death rate from this disease by 80%, and raised the life expectancy for a newly-diagnosed HIV-infected person to about 20 years.
As new treatments continue to be developed and because HIV continues to evolve resistance to treatments, estimates of survival time are likely to continue to change. Without antiretroviral therapy, death normally occurs within a year. Most patients die from opportunistic infections or malignancies associated with the progressive failure of the immune system.[120] The rate of clinical disease progression varies widely between individuals and has been shown to be affected by many factors such as host susceptibility and immune function health care and co-infections,[ as well as which particular strain of the virus is involved.
History
AIDS was first reported June 5, 1981, when the U.S. Centers for Disease Control and Prevention recorded a cluster of Pneumocystis carinii pneumonia (now still classified as PCP but known to be caused by Pneumocystis jirovecii) in five homosexual men in Los Angeles.[123] In the beginning, the Centers for Disease Control and Prevention (CDC) did not have an official name for the disease, often referring to it by way of the diseases that were associated with it, for example, lymphadenopathy, the disease after which the discoverers of HIV originally named the virus.[64][65] They also used Kaposi's Sarcoma and Opportunistic Infections, the name by which a task force had been set up in 1981.[124] In the general press, the term GRID, which stood for Gay-related immune deficiency, had been coined.[125] The CDC, in search of a name, and looking at the infected communities coined “the 4H disease,” as it seemed to single out Haitians, homosexuals, hemophiliacs, and heroin users.[126] However, after determining that AIDS was not isolated to the homosexual community,[124] the term GRID became misleading and AIDS was introduced at a meeting in July 1982.[127] By September 1982 the CDC started using the name AIDS, and properly defined the illness.[128]
A more controversial theory known as the OPV AIDS hypothesis suggests that the AIDS epidemic was inadvertently started in the late 1950s in the Belgian Congo by Hilary Koprowski's research into a poliomyelitis vaccine.[129][130] According to scientific consensus, this scenario is not supported by the available evidence.[131][132][133]
A recent study states that HIV probably moved from Africa to Haiti and then entered the United States around 1969.
Society and culture
Stigma
Ryan White became a poster child for HIV after being expelled from school because of his infection.
Ryan White became a poster child for HIV after being expelled from school because of his infection.
AIDS stigma exists around the world in a variety of ways, including ostracism, rejection, discrimination and avoidance of HIV infected people; compulsory HIV testing without prior consent or protection of confidentiality; violence against HIV infected individuals or people who are perceived to be infected with HIV; and the quarantine of HIV infected individuals.[135] Stigma-related violence or the fear of violence prevents many people from seeking HIV testing, returning for their results, or securing treatment, possibly turning what could be a manageable chronic illness into a death sentence and perpetuating the spread of HIV.
AIDS stigma has been further divided into the following three categories:
* Instrumental AIDS stigma—a reflection of the fear and apprehension that are likely to be associated with any deadly and transmissible illness.[137]
* Symbolic AIDS stigma—the use of HIV/AIDS to express attitudes toward the social groups or lifestyles perceived to be associated with the disease.[137]
* Courtesy AIDS stigma—stigmatization of people connected to the issue of HIV/AIDS or HIV- positive people.[138]
Often, AIDS stigma is expressed in conjunction with one or more other stigmas, particularly those associated with homosexuality, bisexuality, promiscuity, and intravenous drug use.
In many developed countries, there is an association between AIDS and homosexuality or bisexuality, and this association is correlated with higher levels of sexual prejudice such as anti-homosexual attitudes.[139] There is also a perceived association between AIDS and all male-male sexual behavior, including sex between uninfected men.[137]
Economic impact
Changes in life expectancy in some hard-hit African countries. Botswana Zimbabwe Kenya South Africa Uganda
Changes in life expectancy in some hard-hit African countries. Botswana Zimbabwe Kenya South Africa Uganda
HIV and AIDS affects economic growth by reducing the availability of human capital.[6] Without proper nutrition, health care and medicine that is available in developed countries, large numbers of people are falling victim to AIDS. They will not only be unable to work, but will also require significant medical care. The forecast is that this will likely cause a collapse of economies and societies in countries with a significant AIDS populationi. In some heavily infected areas, the epidemic has left behind many orphans cared for by elderly grandparents.
The increased mortality in this region will result in a smaller skilled population and labor force. This smaller labor force will be predominantly young people, with reduced knowledge and work experience leading to reduced productivity. An increase in workers’ time off to look after sick family members or for sick leave will also lower productivity. Increased mortality will also weaken the mechanisms that generate human capital and investment in people, through loss of income and the death of parents. By killing off mainly young adults, AIDS seriously weakens the taxable population, reducing the resources available for public expenditures such as education and health services not related to AIDS resulting in increasing pressure for the state's finances and slower growth of the economy. This results in a slower growth of the tax base, an effect that will be reinforced if there are growing expenditures on treating the sick, training (to replace sick workers), sick pay and caring for AIDS orphans. This is especially true if the sharp increase in adult mortality shifts the responsibility and blame from the family to the government in caring for these orphans.[140]
On the level of the household, AIDS results in both the loss of income and increased spending on healthcare by the household. The income effects of this lead to spending reduction as well as a substitution effect away from education and towards healthcare and funeral spending. A study in Côte d'Ivoire showed that households with an HIV/AIDS patient spent twice as much on medical expenses as other households.[141]
AIDS denialism
A small group of activists, including several scientists who do not study HIV/AIDS, question the connection between HIV and AIDS,[142] the existence of HIV itself,[143] or the validity of current testing and treatment methods. Though these claims have been examined and thoroughly rejected by the scientific community,[144] they continue to be promulgated through the Internet[145] and have had a significant political impact, particularly in South Africa, where President Thabo Mbeki's embrace of AIDS denialism has been blamed for an ineffective response to that country's AIDS epidemic.
allergies reference
Allergy is a disorder of the immune system often also referred to as atopy. Allergic reactions occur to environmental substances known as allergens; these reactions are acquired, predictable and rapid. Strictly, allergy is one of four forms of hypersensitivity and is called type I (or immediate) hypersensitivity. It is characterized by excessive activation of certain white blood cells called mast cells and basophils by a type of antibody known as IgE, resulting in an extreme inflammatory response. Common allergic reactions include eczema, hives, hay fever, asthma, food allergies, and reactions to the venom of stinging insects such as wasps and bees.[1]
Mild allergies like hay fever are highly prevalent in the human population and cause symptoms such as allergic conjunctivitis, itchiness, and runny nose. Allergies can play a major role in conditions such as asthma. In some people, severe allergies to environmental or dietary allergens or to medication may result in life-threatening anaphylactic reactions and potentially death.
A variety of tests now exist to diagnose allergic conditions; these include testing the skin for responses to known allergens or analyzing the blood for the presence and levels of allergen-specific IgE. Treatments for allergies include allergen avoidance, use of anti-histamines, steroids or other oral medications, immunotherapy to desensitize the response to allergen, and targeted therapy.
Classification and history
The concept "allergy" was originally introduced in 1906 by the Viennese pediatrician Clemens von Pirquet, after he noted that some of his patients were hypersensitive to normally innocuous entities such as dust, pollen, or certain foods.[2] Pirquet called this phenomenon "allergy" from the Greek words allos meaning "other" and ergon meaning "work".[3] Historically, all forms of hypersensitivity were classified as allergies, and all were thought to be caused by an improper activation of the immune system. Later, it became clear that several different disease mechanisms were implicated, with the common link to a disordered activation of the immune system. In 1963, a new classification scheme was designed by Philip Gell and Robin Coombs that described four types of hypersensitivity reactions, known as Type I to Type IV hypersensitivity.[4] With this new classification, the word "allergy" was restricted to only type I hypersensitivities (also called immediate hypersensitivity), which are characterized as rapidly developing reactions.
A major breakthrough in understanding the mechanisms of allergy was the discovery of the antibody class labeled immunoglobulin E (IgE) - Kimishige Ishizaka and co-workers were the first to isolate and describe IgE in the 1960s.
Cause
Risk factors for allergy can be placed in two general categories, namely host and environmental factors. Host factors include heredity, sex, race, and age, with heredity being by far the most significant. There have been recent increases in the incidence of allergic disorders, however, that cannot be explained by genetic factors alone. The four main environmental candidates are alterations in exposure to infectious diseases during early childhood, environmental pollution, allergen levels, and dietary changes.[14]
Genetic basis
Allergic diseases are strongly familial: identical twins are likely to have the same allergic diseases about 70% of the time; the same allergy occurs about 40% of the time in non-identical twins.[15] Allergic parents are more likely to have allergic children,[16] and their allergies are likely to be more severe than those from non-allergic parents. Some allergies, however, are not consistent along genealogies; parents who are allergic to peanuts may have children who are allergic to ragweed. It seems that the likelihood of developing allergies is inherited and related to an irregularity in the immune system, but the specific allergen is not.[16]
The risk of allergic sensitization and the development of allergies varies with age, with young children most at risk.[17] Several studies have shown that IgE levels are highest in childhood and fall rapidly between the ages of 10 and 30 years.[17] The peak prevalence of hay fever is highest in children and young adults and the incidence of asthma is highest in children under 10.[18] Overall, boys have a higher risk of developing allergy than girls,[16] although for some diseases, namely asthma in young adults, females are more likely to be affected.[19] Sex differences tend to decrease in adulthood.[16] Ethnicity may play a role in some allergies, however racial factors have been difficult to separate from environmental influences and changes due to migration.[16] Interestingly, it has been suggested that different genetic loci are responsible for asthma, specifically, in people of Caucasian, Hispanic, Asian, and African origins.[20]
Environmental factors
International differences have been associated with the number of individuals within a population that suffer from allergy. Allergic diseases are more common in industrialized countries than in countries that are more traditional or agricultural, and there is a higher rate of allergic disease in urban populations versus rural populations, although these differences are becoming less defined.[21]
Exposure to allergens, especially in early life, is an important risk factor for allergy. Alterations in exposure to microorganisms is the most plausible explanation, at present, for the increase in atopic allergy.[14] Since children that live in large families or overcrowded households, or attend day care, have a reduced incidence of allergic disease, a relationship has been proposed between exposures to bacteria and viruses during childhood, and protection against the development of allergy, which has been called – the "hygiene hypothesis".[21] Exposure to endotoxin and other components of bacteria may reduce atopic diseases.[22] Endotoxin exposure reduces release of inflammatory cytokines such as TNF-α, IFNγ, interleukin-10, and interleukin-12 from white blood cells (leukocytes) that circulate in the blood.[23] Certain microbe-sensing proteins, known as Toll-like receptors, found on the surface of cells in the body are also thought to be involved in these processes.[24]
Gutworms and similar parasites are present in untreated drinking water in developing countries, and were present in the water of developed countries until the routine chlorination and purification of drinking water supplies.[25] Recent research has shown that some common parasites, such as intestinal worms (e.g. hookworms), secrete chemicals into the gut wall (and hence the bloodstream) that suppress the immune system and prevent the body from attacking the parasite.[26] This gives rise to a new slant on the hygiene hypothesis theory — that co-evolution of man and parasites has led to an immune system that only functions correctly in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive.[27] In particular, research suggests that allergies may coincide with the delayed establishment of gut flora in infants.[28] However, the research to support this theory is conflicting, with some studies performed in China and Ethiopia showing an increase in allergy in people infected with intestinal worms.[21] Clinical trials have been initiated to test the effectiveness of certain worms in treating some allergies.[29] It may be that the term 'parasite' could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work.[29] For more information on this topic, see Helminthic therapy.
Pathophysiology
The pathophysiology of allergic responses can be divided into two phases. The first is an acute response that occurs immediately after exposure to an allergen. This phase can either subside or progress into a "late phase reaction" which can substantially prolong the symptoms of a response, and result in tissue damage.
Acute response
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
In the early stages of allergy, a type I hypersensitivity reaction against an allergen, encountered for the first time, causes a response in a type of immune cell called a TH2 lymphocyte, which belongs to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells, whose role is production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage are sensitized to the allergen.[14]
If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule, and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system and eczema is localized to the dermis.[14]
Late-phase response
After the chemical mediators of the acute response subside, late phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils and macrophages to the initial site. The reaction is usually seen 2-24 hours after the original reaction.[30] Cytokines from mast cells may also play a role in the persistence of long-term effects. Late phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils, and are still dependent on activity of TH2 cells.[31]
Diagnosis
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base
Before a diagnosis of allergic disease can be confirmed, the other possible causes of the presenting symptoms should be carefully considered.[32] Vasomotor rhinitis, for example, is one of many maladies that shares symptoms with allergic rhinitis, underscoring the need for professional differential diagnosis.[33] Once a diagnosis of asthma, rhinitis, anaphylaxis, or other allergic disease has been made, there are several methods for discovering the causative agent of that allergy.
Skin testing
Skin Testing
For assessing the presence of allergen-specific IgE antibodies, allergy skin testing is preferred over blood allergy tests because it is more sensitive and specific, simpler to use, and less expensive.[34] Skin testing is also known as "puncture testing" and "prick testing" due to the series of tiny puncture or pricks made into the patient's skin. Small amounts of suspected allergens and/or their extracts (pollen, grass, mite proteins, peanut extract, etc.) are introduced to sites on the skin marked with pen or dye (the ink/dye should be carefully selected, lest it cause an allergic response itself). A small plastic or metal device is used to puncture or prick the skin. Sometimes, the allergens are injected "intradermally" into the patient's skin, with a needle and syringe. Common areas for testing include the inside forearm and the back. If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from slight reddening of the skin to a full-blown hive (called "wheal and flare") in more sensitive patients. Interpretation of the results of the skin prick test is normally done by allergists on a scale of severity, with +/- meaning borderline reactivity, and 4+ being a large reaction. Increasingly, allergists are measuring and recording the diameter of the wheal and flare reaction. Interpretation by well-trained allergists is often guided by relevant literature.[35] Some patients may believe they have determined their own allergic sensitivity from observation, but a skin test has been shown to be much better than patient observation to detect allergy.[36]
If a serious life threatening anaphylactic reaction has brought a patient in for evaluation, some allergists will prefer an initial blood test prior to performing the skin prick test. Skin tests may not be an option if the patient has widespread skin disease or has taken antihistamines sometime the last several days.
Blood testing
Various blood allergy testing methods are also available for detecting allergy to specific substances. This kind of testing measures a "total IgE level" - an estimate of IgE contained within the patient's serum. This can be determined through the use of radiometric and colormetric immunoassays. Radiometric assays include the radioallergosorbent test (RAST) test method, which uses IgE-binding (anti-IgE) antibodies labeled with radioactive isotopes for quantifying the levels of IgE antibody in the blood.[34] Other newer methods use colorimetric or fluorometric technology in the place of radioactive isotopes. Some "screening" test methods are intended to provide qualitative test results, giving a "yes" or "no" answer in patients with suspected allergic sensitization. One such method has a sensitivity of about 70.8% and a positive predictive value of 72.6% according to a large study.[37]
A low total IgE level is not adequate to rule out sensitization to commonly inhaled allergens. Statistical methods, such as ROC curves, predictive value calculations, and likelihood ratios have been used to examine the relationship of various testing methods to each other. These methods have shown that patients with a high total IgE have a high probability of allergic sensitization, but further investigation with specific allergy tests for a carefully chosen allergens is often warranted.
Pharmacotherapy
Several antagonistic drugs are used to block the action of allergic mediators, or to prevent activation of cells and degranulation processes. These include antihistamines, cortisone, dexamethasone, hydrocortisone, epinephrine (adrenaline), theophylline and cromolyn sodium. Anti-leukotrienes, such as Montelukast (Singulair) or Zafirlukast (Accolate), are FDA approved for treatment of allergic diseases.[citation needed] Anti-cholinergics, decongestants, mast cell stabilizers, and other compounds thought to impair eosinophil chemotaxis, are also commonly used. These drugs help to alleviate the symptoms of allergy, and are imperative in the recovery of acute anaphylaxis, but play little role in chronic treatment of allergic disorders.
Immunotherapy
Desensitization or hyposensitization is a treatment in which the patient is gradually vaccinated with progressively larger doses of the allergen in question. This can either reduce the severity or eliminate hypersensitivity altogether. It relies on the progressive skewing of IgG antibody production, to block excessive IgE production seen in atopys. In a sense, the person builds up immunity to increasing amounts of the allergen in question. Studies have demonstrated the long-term efficacy and the preventive effect of immunotherapy in reducing the development of new allergy.[40] Meta-analyses have also confirmed efficacy of the treatment in allergic rhinitis in children and in asthma.[citation needed] A review by the Mayo Clinic in Rochester confirmed the safety and efficacy of allergen immunotherapy for allergic rhinitis and conjunctivitis, allergic forms of asthma, and stinging insect based on numerous well-designed scientific studies.[41] Additionally, national and international guidelines confirm the clinical efficacy of injection immunotherapy in rhinitis and asthma, as well as the safety, provided that recommendations are followed.[42]
A second form of immunotherapy involves the intravenous injection of monoclonal anti-IgE antibodies. These bind to free and B-cell associated IgE; signalling their destruction. They do not bind to IgE already bound to the Fc receptor on basophils and mast cells, as this would stimulate the allergic inflammatory response. The first agent of this class is Omalizumab. While this form of immunotherapy is very effective in treating several types of atopy, it should not be used in treating the majority of people with food allergies.[citation needed]
A third type, Sublingual immunotherapy, is an orally-administered therapy which takes advantage of oral immune tolerance to non-pathogenic antigens such as foods and resident bacteria. This therapy currently accounts for 40 percent of allergy treatment in Europe.[citation needed] In the United States, sublingual immunotherapy is gaining support among traditional allergists and is endorsed by doctors who treat allergy.[citation needed]
Unproven or ineffective treatments
An experimental treatment, enzyme potentiated desensitization (EPD), has been tried for decades but is not generally accepted as effective.[43] EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes are supposed to respond by favouring desensitization, or down-regulation, rather than sensitization. EPD has also been tried for the treatment of autoimmune diseases but again is not FDA approved or of proven effectiveness.[43]
In alternative medicine, a number of allergy treatments are described by its practitioners, particularly naturopathic, herbal medicine, homeopathy, traditional Chinese medicine and kinesiology. Systematic literature searches conducted by the Mayo Clinic through 2006, involving hundreds of articles studying multiple conditions, including asthma and upper respiratory tract infection showed no effectiveness of any alternative treatments, and no difference compared with placebo. The authors concluded that, based on rigorous clinical trials of all types of homeopathy for childhood and adolescence ailments, there is no convincing evidence that supports the use of alternative treatments.[44]
Epidemiology
Many diseases related to inflammation such as type 1 diabetes, rheumatoid arthritis and allergic diseases—hay fever and asthma—have increased in the Western world over the past 2-3 decades.[45] Rapid increases in allergic asthma and other atopic disorders in industrialized nations probably began in the 1960s and 1970s, with further increases occurring during the 1980s and 1990s,[46] although some suggest that a steady rise in sensitization has been occurring since the 1920s.[47] The incidence of atopy in developing countries has generally remained much lower.
Mild allergies like hay fever are highly prevalent in the human population and cause symptoms such as allergic conjunctivitis, itchiness, and runny nose. Allergies can play a major role in conditions such as asthma. In some people, severe allergies to environmental or dietary allergens or to medication may result in life-threatening anaphylactic reactions and potentially death.
A variety of tests now exist to diagnose allergic conditions; these include testing the skin for responses to known allergens or analyzing the blood for the presence and levels of allergen-specific IgE. Treatments for allergies include allergen avoidance, use of anti-histamines, steroids or other oral medications, immunotherapy to desensitize the response to allergen, and targeted therapy.
Classification and history
The concept "allergy" was originally introduced in 1906 by the Viennese pediatrician Clemens von Pirquet, after he noted that some of his patients were hypersensitive to normally innocuous entities such as dust, pollen, or certain foods.[2] Pirquet called this phenomenon "allergy" from the Greek words allos meaning "other" and ergon meaning "work".[3] Historically, all forms of hypersensitivity were classified as allergies, and all were thought to be caused by an improper activation of the immune system. Later, it became clear that several different disease mechanisms were implicated, with the common link to a disordered activation of the immune system. In 1963, a new classification scheme was designed by Philip Gell and Robin Coombs that described four types of hypersensitivity reactions, known as Type I to Type IV hypersensitivity.[4] With this new classification, the word "allergy" was restricted to only type I hypersensitivities (also called immediate hypersensitivity), which are characterized as rapidly developing reactions.
A major breakthrough in understanding the mechanisms of allergy was the discovery of the antibody class labeled immunoglobulin E (IgE) - Kimishige Ishizaka and co-workers were the first to isolate and describe IgE in the 1960s.
Cause
Risk factors for allergy can be placed in two general categories, namely host and environmental factors. Host factors include heredity, sex, race, and age, with heredity being by far the most significant. There have been recent increases in the incidence of allergic disorders, however, that cannot be explained by genetic factors alone. The four main environmental candidates are alterations in exposure to infectious diseases during early childhood, environmental pollution, allergen levels, and dietary changes.[14]
Genetic basis
Allergic diseases are strongly familial: identical twins are likely to have the same allergic diseases about 70% of the time; the same allergy occurs about 40% of the time in non-identical twins.[15] Allergic parents are more likely to have allergic children,[16] and their allergies are likely to be more severe than those from non-allergic parents. Some allergies, however, are not consistent along genealogies; parents who are allergic to peanuts may have children who are allergic to ragweed. It seems that the likelihood of developing allergies is inherited and related to an irregularity in the immune system, but the specific allergen is not.[16]
The risk of allergic sensitization and the development of allergies varies with age, with young children most at risk.[17] Several studies have shown that IgE levels are highest in childhood and fall rapidly between the ages of 10 and 30 years.[17] The peak prevalence of hay fever is highest in children and young adults and the incidence of asthma is highest in children under 10.[18] Overall, boys have a higher risk of developing allergy than girls,[16] although for some diseases, namely asthma in young adults, females are more likely to be affected.[19] Sex differences tend to decrease in adulthood.[16] Ethnicity may play a role in some allergies, however racial factors have been difficult to separate from environmental influences and changes due to migration.[16] Interestingly, it has been suggested that different genetic loci are responsible for asthma, specifically, in people of Caucasian, Hispanic, Asian, and African origins.[20]
Environmental factors
International differences have been associated with the number of individuals within a population that suffer from allergy. Allergic diseases are more common in industrialized countries than in countries that are more traditional or agricultural, and there is a higher rate of allergic disease in urban populations versus rural populations, although these differences are becoming less defined.[21]
Exposure to allergens, especially in early life, is an important risk factor for allergy. Alterations in exposure to microorganisms is the most plausible explanation, at present, for the increase in atopic allergy.[14] Since children that live in large families or overcrowded households, or attend day care, have a reduced incidence of allergic disease, a relationship has been proposed between exposures to bacteria and viruses during childhood, and protection against the development of allergy, which has been called – the "hygiene hypothesis".[21] Exposure to endotoxin and other components of bacteria may reduce atopic diseases.[22] Endotoxin exposure reduces release of inflammatory cytokines such as TNF-α, IFNγ, interleukin-10, and interleukin-12 from white blood cells (leukocytes) that circulate in the blood.[23] Certain microbe-sensing proteins, known as Toll-like receptors, found on the surface of cells in the body are also thought to be involved in these processes.[24]
Gutworms and similar parasites are present in untreated drinking water in developing countries, and were present in the water of developed countries until the routine chlorination and purification of drinking water supplies.[25] Recent research has shown that some common parasites, such as intestinal worms (e.g. hookworms), secrete chemicals into the gut wall (and hence the bloodstream) that suppress the immune system and prevent the body from attacking the parasite.[26] This gives rise to a new slant on the hygiene hypothesis theory — that co-evolution of man and parasites has led to an immune system that only functions correctly in the presence of the parasites. Without them, the immune system becomes unbalanced and oversensitive.[27] In particular, research suggests that allergies may coincide with the delayed establishment of gut flora in infants.[28] However, the research to support this theory is conflicting, with some studies performed in China and Ethiopia showing an increase in allergy in people infected with intestinal worms.[21] Clinical trials have been initiated to test the effectiveness of certain worms in treating some allergies.[29] It may be that the term 'parasite' could turn out to be inappropriate, and in fact a hitherto unsuspected symbiosis is at work.[29] For more information on this topic, see Helminthic therapy.
Pathophysiology
The pathophysiology of allergic responses can be divided into two phases. The first is an acute response that occurs immediately after exposure to an allergen. This phase can either subside or progress into a "late phase reaction" which can substantially prolong the symptoms of a response, and result in tissue damage.
Acute response
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
Degranulation process in allergy.1 - antigen; 2 - IgE antibody; 3 - FcεRI receptor; 4 - preformed mediators (histamine, proteases, chemokines, heparine); 5 - granules; 6 - mast cell; 7 - newly formed mediators (prostaglandins, leukotrienes, thromboxanes, PAF)
In the early stages of allergy, a type I hypersensitivity reaction against an allergen, encountered for the first time, causes a response in a type of immune cell called a TH2 lymphocyte, which belongs to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). These TH2 cells interact with other lymphocytes called B cells, whose role is production of antibodies. Coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of other kinds of immune cells called mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells, at this stage are sensitized to the allergen.[14]
If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule, and activates the sensitized cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucous secretion, nerve stimulation and smooth muscle contraction. This results in rhinorrhea, itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be system-wide (classical anaphylaxis), or localized to particular body systems; asthma is localized to the respiratory system and eczema is localized to the dermis.[14]
Late-phase response
After the chemical mediators of the acute response subside, late phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils and macrophages to the initial site. The reaction is usually seen 2-24 hours after the original reaction.[30] Cytokines from mast cells may also play a role in the persistence of long-term effects. Late phase responses seen in asthma are slightly different from those seen in other allergic responses, although they are still caused by release of mediators from eosinophils, and are still dependent on activity of TH2 cells.[31]
Diagnosis
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base
An allergy testing machine being operated in the diagnostic immunology lab at Lackland Air Force Base
Before a diagnosis of allergic disease can be confirmed, the other possible causes of the presenting symptoms should be carefully considered.[32] Vasomotor rhinitis, for example, is one of many maladies that shares symptoms with allergic rhinitis, underscoring the need for professional differential diagnosis.[33] Once a diagnosis of asthma, rhinitis, anaphylaxis, or other allergic disease has been made, there are several methods for discovering the causative agent of that allergy.
Skin testing
Skin Testing
For assessing the presence of allergen-specific IgE antibodies, allergy skin testing is preferred over blood allergy tests because it is more sensitive and specific, simpler to use, and less expensive.[34] Skin testing is also known as "puncture testing" and "prick testing" due to the series of tiny puncture or pricks made into the patient's skin. Small amounts of suspected allergens and/or their extracts (pollen, grass, mite proteins, peanut extract, etc.) are introduced to sites on the skin marked with pen or dye (the ink/dye should be carefully selected, lest it cause an allergic response itself). A small plastic or metal device is used to puncture or prick the skin. Sometimes, the allergens are injected "intradermally" into the patient's skin, with a needle and syringe. Common areas for testing include the inside forearm and the back. If the patient is allergic to the substance, then a visible inflammatory reaction will usually occur within 30 minutes. This response will range from slight reddening of the skin to a full-blown hive (called "wheal and flare") in more sensitive patients. Interpretation of the results of the skin prick test is normally done by allergists on a scale of severity, with +/- meaning borderline reactivity, and 4+ being a large reaction. Increasingly, allergists are measuring and recording the diameter of the wheal and flare reaction. Interpretation by well-trained allergists is often guided by relevant literature.[35] Some patients may believe they have determined their own allergic sensitivity from observation, but a skin test has been shown to be much better than patient observation to detect allergy.[36]
If a serious life threatening anaphylactic reaction has brought a patient in for evaluation, some allergists will prefer an initial blood test prior to performing the skin prick test. Skin tests may not be an option if the patient has widespread skin disease or has taken antihistamines sometime the last several days.
Blood testing
Various blood allergy testing methods are also available for detecting allergy to specific substances. This kind of testing measures a "total IgE level" - an estimate of IgE contained within the patient's serum. This can be determined through the use of radiometric and colormetric immunoassays. Radiometric assays include the radioallergosorbent test (RAST) test method, which uses IgE-binding (anti-IgE) antibodies labeled with radioactive isotopes for quantifying the levels of IgE antibody in the blood.[34] Other newer methods use colorimetric or fluorometric technology in the place of radioactive isotopes. Some "screening" test methods are intended to provide qualitative test results, giving a "yes" or "no" answer in patients with suspected allergic sensitization. One such method has a sensitivity of about 70.8% and a positive predictive value of 72.6% according to a large study.[37]
A low total IgE level is not adequate to rule out sensitization to commonly inhaled allergens. Statistical methods, such as ROC curves, predictive value calculations, and likelihood ratios have been used to examine the relationship of various testing methods to each other. These methods have shown that patients with a high total IgE have a high probability of allergic sensitization, but further investigation with specific allergy tests for a carefully chosen allergens is often warranted.
Pharmacotherapy
Several antagonistic drugs are used to block the action of allergic mediators, or to prevent activation of cells and degranulation processes. These include antihistamines, cortisone, dexamethasone, hydrocortisone, epinephrine (adrenaline), theophylline and cromolyn sodium. Anti-leukotrienes, such as Montelukast (Singulair) or Zafirlukast (Accolate), are FDA approved for treatment of allergic diseases.[citation needed] Anti-cholinergics, decongestants, mast cell stabilizers, and other compounds thought to impair eosinophil chemotaxis, are also commonly used. These drugs help to alleviate the symptoms of allergy, and are imperative in the recovery of acute anaphylaxis, but play little role in chronic treatment of allergic disorders.
Immunotherapy
Desensitization or hyposensitization is a treatment in which the patient is gradually vaccinated with progressively larger doses of the allergen in question. This can either reduce the severity or eliminate hypersensitivity altogether. It relies on the progressive skewing of IgG antibody production, to block excessive IgE production seen in atopys. In a sense, the person builds up immunity to increasing amounts of the allergen in question. Studies have demonstrated the long-term efficacy and the preventive effect of immunotherapy in reducing the development of new allergy.[40] Meta-analyses have also confirmed efficacy of the treatment in allergic rhinitis in children and in asthma.[citation needed] A review by the Mayo Clinic in Rochester confirmed the safety and efficacy of allergen immunotherapy for allergic rhinitis and conjunctivitis, allergic forms of asthma, and stinging insect based on numerous well-designed scientific studies.[41] Additionally, national and international guidelines confirm the clinical efficacy of injection immunotherapy in rhinitis and asthma, as well as the safety, provided that recommendations are followed.[42]
A second form of immunotherapy involves the intravenous injection of monoclonal anti-IgE antibodies. These bind to free and B-cell associated IgE; signalling their destruction. They do not bind to IgE already bound to the Fc receptor on basophils and mast cells, as this would stimulate the allergic inflammatory response. The first agent of this class is Omalizumab. While this form of immunotherapy is very effective in treating several types of atopy, it should not be used in treating the majority of people with food allergies.[citation needed]
A third type, Sublingual immunotherapy, is an orally-administered therapy which takes advantage of oral immune tolerance to non-pathogenic antigens such as foods and resident bacteria. This therapy currently accounts for 40 percent of allergy treatment in Europe.[citation needed] In the United States, sublingual immunotherapy is gaining support among traditional allergists and is endorsed by doctors who treat allergy.[citation needed]
Unproven or ineffective treatments
An experimental treatment, enzyme potentiated desensitization (EPD), has been tried for decades but is not generally accepted as effective.[43] EPD uses dilutions of allergen and an enzyme, beta-glucuronidase, to which T-regulatory lymphocytes are supposed to respond by favouring desensitization, or down-regulation, rather than sensitization. EPD has also been tried for the treatment of autoimmune diseases but again is not FDA approved or of proven effectiveness.[43]
In alternative medicine, a number of allergy treatments are described by its practitioners, particularly naturopathic, herbal medicine, homeopathy, traditional Chinese medicine and kinesiology. Systematic literature searches conducted by the Mayo Clinic through 2006, involving hundreds of articles studying multiple conditions, including asthma and upper respiratory tract infection showed no effectiveness of any alternative treatments, and no difference compared with placebo. The authors concluded that, based on rigorous clinical trials of all types of homeopathy for childhood and adolescence ailments, there is no convincing evidence that supports the use of alternative treatments.[44]
Epidemiology
Many diseases related to inflammation such as type 1 diabetes, rheumatoid arthritis and allergic diseases—hay fever and asthma—have increased in the Western world over the past 2-3 decades.[45] Rapid increases in allergic asthma and other atopic disorders in industrialized nations probably began in the 1960s and 1970s, with further increases occurring during the 1980s and 1990s,[46] although some suggest that a steady rise in sensitization has been occurring since the 1920s.[47] The incidence of atopy in developing countries has generally remained much lower.
Alzheimer's disease reference
Alzheimer's disease (AD), also called Alzheimer disease or simply Alzheimer's, is the most common cause of dementia. Alzheimer's is a degenerative and terminal disease for which there is no known cure. In its most common form, it afflicts individuals over 65 years old, although a less prevalent early-onset form also exists. It is estimated that 26.6 million people worldwide were afflicted by AD in 2006, which could quadruple by 2050,[1] although estimations vary greatly.[2]
Each individual experiences the symptoms of AD in unique ways.[3] The symptoms of Alzheimer's disease are generally reported to a physician when memory loss becomes apparent. If AD is suspected as the cause, the physician or healthcare specialist will confirm the diagnosis with behavioral assessments and cognitive tests, often followed by a brain scan, if available.[4] A prognosis for Alzheimer's is hard to make, as the duration of the disease varies per individual, and the disease can develop for an indeterminate time before becoming fully apparent, sometimes escaping diagnosis for years. Generally, life with Alzheimer's disease lasts between 5 and 20 years.[5][6] In the early stages, the most commonly recognised symptom is memory loss, such as the difficulty to remember recently learned facts. Earliest occurring symptoms are often mistaken as being noncritical age-related complaints, or forms of stress.[7] As the disease advances, progressive symptoms include confusion, anger, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as his or her senses decline.[7][8] Gradually, minor and major bodily functions are lost, leading ultimately to death.[9]
The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain.[10] No treatment has been found to stop or reverse the disease, and it is not known whether current treatments slow the progression, or simply manage the symptoms. Many preventive measures have been suggested for Alzheimer's disease, but their value is unproven in reducing the course and severity of the disease. Mental stimulation, exercise and a balanced diet are often recommended, both as a possible prevention and as a sensible way of managing the disease
Characteristics
The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment expressed during each stage.
Predementia
Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria of diagnosis.[16] These early symptoms can have an effect on the most complex daily living activities.[17] The most noticeable deficit is memory loss , shown as a difficulty to remember recently learned facts and an inability to acquire new information.[18][19] In addition, subtle executive function problems (attention, planning, flexibility, abstraction...) or impairments in semantic memory (memory of meanings and concept relationships) can also occur.[20][21] Apathy can be observed at this stage, and is the most common and persistent neuropsychiatric symptom throughout the course of the disease.[22][23][24] This stage of the disease has also been termed mild cognitive impairment,[25] but there is still a debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.[26]
Early dementia
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.
In most people with the disease the increasing impairments in learning and memory will lead to diagnosis, while in a small proportion of them difficulties with language, executive functions, recognition of perceptions (agnosia) or execution of movements (apraxia) will be more salient.[27] Nevertheless, memory problems do not affect all memory subcapacities equally. Older memories of the patient's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a much lesser degree than the capacities needed to learn new facts or make new memories.[28][29] Language problems are mainly characterised by a shrinking vocabulary and a decreased word fluency which leads to a general impoverishment of oral and written language. The Alzheimer's patient is usually capable of adequately communicating basic ideas.] While performing fine motor tasks such as writing, drawing or dressing, certain visoconstructional difficulties, or apraxia, may be present, which may appear as clumsiness. As the disease progresses to the middle stage, patients might still be able to live and perform tasks independently for most of the time, but may need assistance or supervision with the most complicated activities.[27]
Moderate dementia
In the early stage, people with Alzheimer's can usually care for themselves. At the moderate stage, progressive deterioration seriously hinders the possibility of independence.[27]
Speech difficulties become clearly noticeable: due to difficulties in finding words the person makes frequent incorrect substitutions (paraphasias) , and content is poor. Reading and writing are also progressively forgotten.[30][34] As time passes, complex motor sequences become less coordinated, costing the patient most of their daily-living abilities.[35] Memory problems worsen, and the person may not recognize close relatives.[36] Long-term memory, which was previously left intact, is now also impaired.[37] At this stage, behavior changes are the norm. Common neuropsychiatric manifestations in this stage are irritability and labile affect, leading to crying or outbursts of unpremeditated aggression and physical violence, even in patients whose life-long behavior has been peaceful. Approximately 30% of the patients also develop illusionary misidentifications and other delusional symptoms.[22][38] Often urinary incontinence develops.[39] Because of the communication deficit along with delusions, patients often resist when caregivers attempt to provide care.[40] It is important to prevent escalation of resistiveness to care into combativeness when patient might strike out. All these symptoms create stress for relatives and caretakers, increasing the likelihood of moving the patient from home care to other long-term care facilities.[27][41]
Advanced
In the last stage of Alzheimer's disease the subject with the disease is fully dependent. Language is reduced to simple phrases or even single words before being lost altogether.[30] Nevertheless many patients can receive and return emotional signals long after the loss of verbal language.[42] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common.[27] Patients will ultimately not be able to perform even the most simple tasks independently. Finally, deterioration of muscle and mobility will develop, leading the patient to become bedridden,[43] and to lose the ability to feed oneself,[44] if death from some external cause, such as infection due to pressure ulcers or pneumonia, does not occur first.[45][46]
Causes
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the cholinergic hypothesis and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. However, the medications that treat acetylcholine deficiency only affect symptoms of the disease and neither halt nor reverse it.[47] The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,[48] leading to generalised neuroinflammation.[49]
In 1991 the amyloid hypothesis was proposed,[50] while research after 2000 is also centered on tau proteins. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other states that amyloid beta (Aβ) deposits are the causative factor in the disease.[51]
The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques does not correlate well with neuron loss.[52] In this model, hyperphosphorylated tau begins to pair with other threads of tau and they become tangled up together inside nerve cell bodies in masses known as neurofibrillary tangles.[53] When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.[54]
A majority of researchers support the alternative hypothesis that Aβ is the primary causative agent.[51] The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on chromosome 21, and patients with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age. It should be noted further that APOE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.[57] It is known that some types of inherited AD involve only mutations in the APP gene (although this is not the most common type—others involve genes for "pre-senilin" proteins which process APP and may also have still-unknown functions).[58] However, another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop fibrillar amyloid plaques.[59]
Pathophysiology
Main article: Biochemistry of Alzheimer's disease
Neuropathology
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.
At a macroscopic level, AD is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[49]
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.[10] Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.[60]
Biochemical characteristics
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.[61] Plaques are made of a small peptide (39 to 43 amino acid residues) called beta-amyloid (also A-beta or Aβ), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). APP is a transmembrane protein; which means that it sticks through the neuron's membrane; and is believed to help neurons grow, survive and repair themselves after injury.[62][63] In AD, something causes APP to be divided by enzymes through a mechanism called proteolysis.[64] One of these fragments is beta-amyloid. Beta-amyloid fragments (amyloid fibrils) outside the cell form clumps that deposit outside neurons in dense formations known as senile plaques.[65][10]
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Healthy neurons have an internal support structure, or cytoskeleton, partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A protein called tau makes the microtubules stable when phosphorylated, and is therefore called a microtubule-associated protein.[66] In AD, tau is changed chemically, becoming phosphate saturated (hyperphosphorylated).
Disease mechanism
If the production and aggregation of the amyloid beta peptide plays a key role in AD, the exact mechanism has not been elucidated.[67] The traditional formulation of the amyloid hypothesis points to the accumulation of beta-amyloid peptides as the central event triggering neurons degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces apoptosis (programmed cell death).[68] It is also known that Aβ selectively builds up in the cells mitochondria of brains with AD and inhibits certain enzyme functions and the utilization of glucose by neurons. This process may also lead to the formation of damaging reactive oxygen species, calcium influx, and apoptosis.[69]
Various inflammatory processes and inflammatory cytokines may also have a role in the pathology of Alzheimer's disease. However, these are general markers of tissue damage in any disease, and may also be either secondary causes of tissue damage in AD, or else bystander "marker" effects.
Genetic
While earlier disease familial onset is mainly explained by three genes, later age of disease onset representing most cases of AD has yet to be explained by a purely genetic model. In the second case the APOE gene is the strongest genetic risk factor discovered but it is far from explaining all occurrences of the disease.[71]
Only 10% of AD cases occurring before 60 years of age are due to autosomal dominant (familial) mutations, which represents less than 0,01 of all patients.[71][72] These mutations have been discovered in three different genes: amyloid precursor protein or APP,[73] and presenilins 1,[74] and 2[75]. Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta42, which is the main component of senile plaques in brains of AD patients.[76]
Most cases of Alzheimer's disease do not exhibit familial inheritance. In this case genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). This gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer's.[77] Genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer's disease.[71] Over 400 genes have been tested for association with late-onset sporadic AD.[78]
Diagnosis
Dementia is by definition a clinical condition but not an exact diagnosis. Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.[79][80] Advanced medical imaging with CT or MRI, and with SPECT or PET are generally used to help to diagnose the subtype of dementia and exclude other cerebral pathology.[81] Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia.[82] Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians. Sometimes the diagnosis can be confirmed or made at postmortem when brain material is available and can be examined histologically and histochemically.[83]
Diagnostic criteria
The diagnostic criteria for Alzheimer of the NINCDS-ADRDA (NINCDS and the ADRDA) are among the most used.[84] These criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD while they need histopathologic confirmation (microscopic examination of brain tissue) for the definitive diagnosis. They have shown good reliability and validity.[85] They specify as well eight cognitive domains that may be impaired in AD (i.e., memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities). Similar to the NINCDS-ADRDA Alzheimer's Criteria are the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria published by the American Psychiatric Association.[86][87]
Diagnostic tools
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.
Neuropsychological screening tests such as the Mini mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis, but more comprehensive tests arrays are necessary for high reliability by this method, especially in the earliest stages of the disease.[88][89] Neurological examination in early AD will usually be normal, independent of cognitive impairment; but for many of the other dementing disorders is key for diagnosis. Therefore, neurological examination is crucial in the differential diagnosis of Alzheimer and other diseases.[82] In addition, interviews with family members are also utilized in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease over time of the patient's mental function.[90] This is especially important since a patient with AD is commonly unaware of his or her own deficits (anosognosia).[91] Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.[92] Finally, supplemental testing provides extra information on some features of the disease or are used to rule out other diagnoses. Examples are blood tests, which can identify other causes for dementia different than AD,[82] which rarely may even be reversible;[93] or psychological tests for depression, as depression can both co-occur with AD or, on the contrary, be at the origin of the patient's cognitive impairment.[94][95]
Increasingly, the functional neuroimaging modalities of single photon emission computed tomography (SPECT) and positron emission tomography (PET) are being used to diagnose Alzheimer's, as they have shown similar ability to diagnose Alzheimer's disease as methods involving mental status examination.[96] Furthermore, the ability of SPECT to differentiate Alzheimer's disease from other possible causes, in a patient already known to be suffering from dementia, appears to be superior to attempts to differentiate the cause of dementia cause by mental testing and history.[97] A new technique known as "PiB PET" has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a contrasting tracer that binds selectively to the Abeta deposits.[98][99][100] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.[101] Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.[84][82]
Prevention
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
At present contradictory results in global studies, incapacity to prove causal relationships between risk factors and the disease, and possible secondary effects indicate a lack of specific measures to prevent or delay the onset of AD.[102] Different epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether, in fact, these factors can help to prevent AD.[103]
The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. Vitamins B and C, or folic acid have appeared to be related to a reduced risk of AD, but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important secondary effects.[106] Curcumin in curry has shown some effectiveness in preventing brain damage in mouse models.
Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[108][109] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[110][111] However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.[112] Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia,[113][114] and a 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on dementia or cognitive impairment.[115]
Intellectual activities such as playing chess, completing crossword puzzles or regular social interaction, may also delay the onset or reduce the severity of Alzheimer's disease.[116][117] Bilingualism is also related to a later onset of Alzheimer.[118]
Some studies have shown a positive relationship between risk of developing AD and different occupational exposures such as magnetic field exposure,[119][120], metals intake and specifically aluminium,[121][122] or solvents.[123] The quality of some of these studies has been criticized,[124] and other research does not confirm this link.[125][126] [127][128]
[edit] Management
There is no known cure for Alzheimer's disease. Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.
Pharmaceutical
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms
Four medications, to treat the cognitive manifestations of AD, are currently approved by regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.
Because reduction in the activity of the cholinergic neurons in the disease is well known, acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down and so to increase the concentration of ACh in the brain, thereby combatting the loss of ACh caused by the death of the cholinergin neurons.[130] Cholinesterase inhibitors currently approved include donepezil (brand name Aricept),[131] galantamine (Razadyne),[132] and rivastigmine (branded as Exelon,[133] and Exelon Patch[134]). There is also evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,[135] and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.[136] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.[137] Most common side effects include nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately ten to twenty percent of users and are mild to moderate in severity. Less common secondary effects include muscle cramps; decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid.[138][139][140][141]
Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.[142] Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),[143] is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA glutamate receptors and inhibits their overstimulation by glutamate.[142] Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer’s disease. Its effects in the initial stages are unknown.[144] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[145] Memantine used in combination with donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[146]
Neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with behavioural problems are modestly useful in reducing aggression and psychosis, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use.[147][148][149]
Psychosocial intervention
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia
Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior, emotion, cognition or stimulation oriented approaches. Research on efficacy is unavailable and rarely specific to the disease, focusing instead on dementia.[150]
Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in the overall functioning of patients,[151] but can help to reduce some specific problem behaviors, such as incontinence.[152] There is still a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.[153][154]
Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration or snoezelen, and simulated presence therapy. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired patients adjust to their illness.[150] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT it may be beneficial for cognition and mood.[155] Simulated presence therapy (SPT) is based on attachment theories and is normally carried out playing a recording with voices of the closest relatives of the patient. There is preliminary evidence indicating that SPT may reduce anxiety and challenging behaviors.[156][157] Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate senses. There is little evidence to support the usefulness of these therapies.[158][159]
The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining is the restoration of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities,[160][161] although in some works these effects were transient and negative effects, such as frustration, have also been reported.[150]
Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities for patients. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the improvement in the patient daily life routine they suppose.[150]
Caregiving
Further information: Caregiving and dementia
Since there is no cure for Alzheimer's, caregiving is an essential part of the treatment. Due to the eventual inability for the sufferer to self-care, Alzheimer's has to be carefully care-managed. Home care in the familiar surroundings of home may delay onset of some symptoms and delay or eliminate the need for more professional and costly levels of care.[162] Many family members choose to look after their relatives,[12] but two-thirds of nursing home residents have dementias.[163]
Modifications to the living environment and lifestyle of the Alzheimer's patient can improve functional performance and ease caretaker burden. Assessment by an occupational therapist is often indicated. Adherence to simplified routines and labeling of household items to cue the patient can aid with activities of daily living, while placing safety locks on cabinets, doors, and gates and securing hazardous chemicals can prevent accidents and wandering. Changes in routine or environment can trigger or exacerbate agitation, whereas well-lit rooms, adequate rest, and avoidance of excess stimulation all help prevent such episodes.[164][165] Appropriate social and visual stimulation can improve function by increasing awareness and orientation. For instance, boldly colored tableware aids those with severe AD, helping people overcome a diminished sensitivity to visual contrast to increase food and beverage intake.[166]
Prognosis
As the disease progresses, the patient will advance from mild cognitive impairment, when the suspected underlying pathology may or may not yet have been diagnosed, to mild and advanced stages of dementia, finally reaching a severe stage of dementia.[27] Once Alzheimer's has been diagnosed, the average life expectancy is approximately seven years, while less than three percent of the patients live more than fourteen years.
History
Auguste D, first described patient with AD by Alöis Alzheimer in 1901
Although the concept of dementia goes as far back as the ancient Greek and Roman philosophers and physicians,[179] it was in 1901 when Alöis Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alöis Alzheimer followed her until she died in 1906, when he first reported the case publicly.[180] In the following five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[179] The official consideration of the disease as a distinctive entity is attributed to Emil Kraepelin, who included Alzheimer’s disease or presenile dementia as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.[181]
For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility of different etiologies.[182] This eventually led to the use of Alzheimer's disease independently of onset age of the disease.[183] The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.[184]
Society and culture
Social costs
Because the median age of the industrialised world's population is gradually increasing, AD is a public health challenge. The World Health Organization estimates that globally the total disability adjusted life years (DALYs) for AD and other dementias exceeded eleven million in 2005, with a projected 3.4% annual increase.[185] The DALYs are a measure for the overall disease burden that quantifies the impact of premature death and disability on a population by combining them into a single measure.
The solvency of governmental social safety nets will be impacted by the increased aged population which may develop Alzheimer's in the same proportions as earlier generations
Each individual experiences the symptoms of AD in unique ways.[3] The symptoms of Alzheimer's disease are generally reported to a physician when memory loss becomes apparent. If AD is suspected as the cause, the physician or healthcare specialist will confirm the diagnosis with behavioral assessments and cognitive tests, often followed by a brain scan, if available.[4] A prognosis for Alzheimer's is hard to make, as the duration of the disease varies per individual, and the disease can develop for an indeterminate time before becoming fully apparent, sometimes escaping diagnosis for years. Generally, life with Alzheimer's disease lasts between 5 and 20 years.[5][6] In the early stages, the most commonly recognised symptom is memory loss, such as the difficulty to remember recently learned facts. Earliest occurring symptoms are often mistaken as being noncritical age-related complaints, or forms of stress.[7] As the disease advances, progressive symptoms include confusion, anger, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as his or her senses decline.[7][8] Gradually, minor and major bodily functions are lost, leading ultimately to death.[9]
The cause and progression of Alzheimer's disease are not well understood. Research indicates that the disease is associated with plaques and tangles in the brain.[10] No treatment has been found to stop or reverse the disease, and it is not known whether current treatments slow the progression, or simply manage the symptoms. Many preventive measures have been suggested for Alzheimer's disease, but their value is unproven in reducing the course and severity of the disease. Mental stimulation, exercise and a balanced diet are often recommended, both as a possible prevention and as a sensible way of managing the disease
Characteristics
The disease course is divided into four stages, with a progressive pattern of cognitive and functional impairment expressed during each stage.
Predementia
Detailed neuropsychological testing can reveal mild cognitive difficulties up to eight years before a person fulfills the clinical criteria of diagnosis.[16] These early symptoms can have an effect on the most complex daily living activities.[17] The most noticeable deficit is memory loss , shown as a difficulty to remember recently learned facts and an inability to acquire new information.[18][19] In addition, subtle executive function problems (attention, planning, flexibility, abstraction...) or impairments in semantic memory (memory of meanings and concept relationships) can also occur.[20][21] Apathy can be observed at this stage, and is the most common and persistent neuropsychiatric symptom throughout the course of the disease.[22][23][24] This stage of the disease has also been termed mild cognitive impairment,[25] but there is still a debate on whether this term corresponds to a different diagnostic entity by itself or just a first step of the disease.[26]
Early dementia
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.
In 1994 the former United States president R. Reagan informed the country of his AD diagnosis via a hand-written letter. Writing is usually affected in the first stages of the disease.
In most people with the disease the increasing impairments in learning and memory will lead to diagnosis, while in a small proportion of them difficulties with language, executive functions, recognition of perceptions (agnosia) or execution of movements (apraxia) will be more salient.[27] Nevertheless, memory problems do not affect all memory subcapacities equally. Older memories of the patient's life (episodic memory), facts learned (semantic memory), and implicit memory (the memory of the body on how to do things, such as using a fork to eat) are affected to a much lesser degree than the capacities needed to learn new facts or make new memories.[28][29] Language problems are mainly characterised by a shrinking vocabulary and a decreased word fluency which leads to a general impoverishment of oral and written language. The Alzheimer's patient is usually capable of adequately communicating basic ideas.] While performing fine motor tasks such as writing, drawing or dressing, certain visoconstructional difficulties, or apraxia, may be present, which may appear as clumsiness. As the disease progresses to the middle stage, patients might still be able to live and perform tasks independently for most of the time, but may need assistance or supervision with the most complicated activities.[27]
Moderate dementia
In the early stage, people with Alzheimer's can usually care for themselves. At the moderate stage, progressive deterioration seriously hinders the possibility of independence.[27]
Speech difficulties become clearly noticeable: due to difficulties in finding words the person makes frequent incorrect substitutions (paraphasias) , and content is poor. Reading and writing are also progressively forgotten.[30][34] As time passes, complex motor sequences become less coordinated, costing the patient most of their daily-living abilities.[35] Memory problems worsen, and the person may not recognize close relatives.[36] Long-term memory, which was previously left intact, is now also impaired.[37] At this stage, behavior changes are the norm. Common neuropsychiatric manifestations in this stage are irritability and labile affect, leading to crying or outbursts of unpremeditated aggression and physical violence, even in patients whose life-long behavior has been peaceful. Approximately 30% of the patients also develop illusionary misidentifications and other delusional symptoms.[22][38] Often urinary incontinence develops.[39] Because of the communication deficit along with delusions, patients often resist when caregivers attempt to provide care.[40] It is important to prevent escalation of resistiveness to care into combativeness when patient might strike out. All these symptoms create stress for relatives and caretakers, increasing the likelihood of moving the patient from home care to other long-term care facilities.[27][41]
Advanced
In the last stage of Alzheimer's disease the subject with the disease is fully dependent. Language is reduced to simple phrases or even single words before being lost altogether.[30] Nevertheless many patients can receive and return emotional signals long after the loss of verbal language.[42] Although aggressiveness can still be present, extreme apathy and exhaustion are much more common.[27] Patients will ultimately not be able to perform even the most simple tasks independently. Finally, deterioration of muscle and mobility will develop, leading the patient to become bedridden,[43] and to lose the ability to feed oneself,[44] if death from some external cause, such as infection due to pressure ulcers or pneumonia, does not occur first.[45][46]
Causes
Three major competing hypotheses exist to explain the cause of the disease. The oldest, on which most currently available drug therapies are based, is known as the cholinergic hypothesis and suggests that AD is due to reduced biosynthesis of the neurotransmitter acetylcholine. However, the medications that treat acetylcholine deficiency only affect symptoms of the disease and neither halt nor reverse it.[47] The cholinergic hypothesis has not maintained widespread support in the face of this evidence, although cholinergic effects have been proposed to initiate large-scale aggregation,[48] leading to generalised neuroinflammation.[49]
In 1991 the amyloid hypothesis was proposed,[50] while research after 2000 is also centered on tau proteins. The two positions differ with one stating that the tau protein abnormalities initiate the disease cascade, while the other states that amyloid beta (Aβ) deposits are the causative factor in the disease.[51]
The tau hypothesis is supported by the long-standing observation that deposition of amyloid plaques does not correlate well with neuron loss.[52] In this model, hyperphosphorylated tau begins to pair with other threads of tau and they become tangled up together inside nerve cell bodies in masses known as neurofibrillary tangles.[53] When this happens, the microtubules disintegrate, collapsing the neuron's transport system. This may result first in malfunctions in communication between neurons and later in the death of the cells.[54]
A majority of researchers support the alternative hypothesis that Aβ is the primary causative agent.[51] The amyloid hypothesis is compelling because the gene for the amyloid beta precursor (APP) is located on chromosome 21, and patients with trisomy 21 (Down Syndrome) who thus have an extra gene copy almost universally exhibit AD-like disorders by 40 years of age. It should be noted further that APOE4, the major genetic risk factor for AD, leads to excess amyloid build-up in the brain before AD symptoms arise. Thus, Aβ deposition precedes clinical AD.[57] It is known that some types of inherited AD involve only mutations in the APP gene (although this is not the most common type—others involve genes for "pre-senilin" proteins which process APP and may also have still-unknown functions).[58] However, another strong support for the amyloid hypothesis, which looks at Aβ as the common initiating factor for Alzheimer's disease, is that transgenic mice solely expressing a mutant human APP gene develop fibrillar amyloid plaques.[59]
Pathophysiology
Main article: Biochemistry of Alzheimer's disease
Neuropathology
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.
MRI images of a normal aged brain (right) and an Alzheimer's patient's brain (left). In the Alzheimer brain, atrophy is clearly seen.
At a macroscopic level, AD is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus.[49]
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in AD brains.[10] Plaques are dense, mostly insoluble deposits of amyloid-beta protein and cellular material outside and around neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. Though many older people develop some plaques and tangles, the brains of AD patients have them to a much greater extent and in different brain locations.[60]
Biochemical characteristics
Alzheimer's disease has been identified as a protein misfolding disease, or proteopathy, due to the accumulation of abnormally folded A-beta and tau proteins in the brains of AD patients.[61] Plaques are made of a small peptide (39 to 43 amino acid residues) called beta-amyloid (also A-beta or Aβ), a protein fragment snipped from a larger protein called amyloid precursor protein (APP). APP is a transmembrane protein; which means that it sticks through the neuron's membrane; and is believed to help neurons grow, survive and repair themselves after injury.[62][63] In AD, something causes APP to be divided by enzymes through a mechanism called proteolysis.[64] One of these fragments is beta-amyloid. Beta-amyloid fragments (amyloid fibrils) outside the cell form clumps that deposit outside neurons in dense formations known as senile plaques.[65][10]
AD is also considered a tauopathy due to abnormal aggregation of the tau protein. Healthy neurons have an internal support structure, or cytoskeleton, partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. A protein called tau makes the microtubules stable when phosphorylated, and is therefore called a microtubule-associated protein.[66] In AD, tau is changed chemically, becoming phosphate saturated (hyperphosphorylated).
Disease mechanism
If the production and aggregation of the amyloid beta peptide plays a key role in AD, the exact mechanism has not been elucidated.[67] The traditional formulation of the amyloid hypothesis points to the accumulation of beta-amyloid peptides as the central event triggering neurons degeneration. Accumulation of aggregated amyloid fibrils, which are believed to be the toxic form of the protein responsible for disrupting the cell's calcium ion homeostasis, induces apoptosis (programmed cell death).[68] It is also known that Aβ selectively builds up in the cells mitochondria of brains with AD and inhibits certain enzyme functions and the utilization of glucose by neurons. This process may also lead to the formation of damaging reactive oxygen species, calcium influx, and apoptosis.[69]
Various inflammatory processes and inflammatory cytokines may also have a role in the pathology of Alzheimer's disease. However, these are general markers of tissue damage in any disease, and may also be either secondary causes of tissue damage in AD, or else bystander "marker" effects.
Genetic
While earlier disease familial onset is mainly explained by three genes, later age of disease onset representing most cases of AD has yet to be explained by a purely genetic model. In the second case the APOE gene is the strongest genetic risk factor discovered but it is far from explaining all occurrences of the disease.[71]
Only 10% of AD cases occurring before 60 years of age are due to autosomal dominant (familial) mutations, which represents less than 0,01 of all patients.[71][72] These mutations have been discovered in three different genes: amyloid precursor protein or APP,[73] and presenilins 1,[74] and 2[75]. Most mutations in the APP and presenilin genes increase the production of a small protein called Abeta42, which is the main component of senile plaques in brains of AD patients.[76]
Most cases of Alzheimer's disease do not exhibit familial inheritance. In this case genes may act as risk factors. The best known genetic risk factor is the inheritance of the ε4 allele of the apolipoprotein E (APOE). This gene is regarded as a risk factor for development of up to 50% of late-onset sporadic Alzheimer's.[77] Genetic experts agree that there are other risk and protective factor genes that influence the development of late onset Alzheimer's disease.[71] Over 400 genes have been tested for association with late-onset sporadic AD.[78]
Diagnosis
Dementia is by definition a clinical condition but not an exact diagnosis. Alzheimer's disease is usually diagnosed clinically from the patient history, collateral history from relatives, and clinical observations, based on the presence of characteristic neurological and neuropsychological features and the absence of alternative conditions.[79][80] Advanced medical imaging with CT or MRI, and with SPECT or PET are generally used to help to diagnose the subtype of dementia and exclude other cerebral pathology.[81] Neuropsychological evaluation including memory testing and assessment of intellectual functioning can further characterize the dementia.[82] Medical organizations have created diagnostic criteria to ease and standardize the process for practicing physicians. Sometimes the diagnosis can be confirmed or made at postmortem when brain material is available and can be examined histologically and histochemically.[83]
Diagnostic criteria
The diagnostic criteria for Alzheimer of the NINCDS-ADRDA (NINCDS and the ADRDA) are among the most used.[84] These criteria require that the presence of cognitive impairment and a suspected dementia syndrome be confirmed by neuropsychological testing for a clinical diagnosis of possible or probable AD while they need histopathologic confirmation (microscopic examination of brain tissue) for the definitive diagnosis. They have shown good reliability and validity.[85] They specify as well eight cognitive domains that may be impaired in AD (i.e., memory, language, perceptual skills, attention, constructive abilities, orientation, problem solving and functional abilities). Similar to the NINCDS-ADRDA Alzheimer's Criteria are the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) criteria published by the American Psychiatric Association.[86][87]
Diagnostic tools
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.
Neuropsychological screening tests can help in the diagnosis of AD. In them patients have to copy drawings similar to the one shown in the picture, remember words, read or sum.
Neuropsychological screening tests such as the Mini mental state examination (MMSE) are widely used to evaluate the cognitive impairments needed for diagnosis, but more comprehensive tests arrays are necessary for high reliability by this method, especially in the earliest stages of the disease.[88][89] Neurological examination in early AD will usually be normal, independent of cognitive impairment; but for many of the other dementing disorders is key for diagnosis. Therefore, neurological examination is crucial in the differential diagnosis of Alzheimer and other diseases.[82] In addition, interviews with family members are also utilized in the assessment of the disease. Caregivers can supply important information on the daily living abilities, as well as on the decrease over time of the patient's mental function.[90] This is especially important since a patient with AD is commonly unaware of his or her own deficits (anosognosia).[91] Many times families also have difficulties in the detection of initial dementia symptoms and in adequately communicating them to a physician.[92] Finally, supplemental testing provides extra information on some features of the disease or are used to rule out other diagnoses. Examples are blood tests, which can identify other causes for dementia different than AD,[82] which rarely may even be reversible;[93] or psychological tests for depression, as depression can both co-occur with AD or, on the contrary, be at the origin of the patient's cognitive impairment.[94][95]
Increasingly, the functional neuroimaging modalities of single photon emission computed tomography (SPECT) and positron emission tomography (PET) are being used to diagnose Alzheimer's, as they have shown similar ability to diagnose Alzheimer's disease as methods involving mental status examination.[96] Furthermore, the ability of SPECT to differentiate Alzheimer's disease from other possible causes, in a patient already known to be suffering from dementia, appears to be superior to attempts to differentiate the cause of dementia cause by mental testing and history.[97] A new technique known as "PiB PET" has been developed for directly and clearly imaging beta-amyloid deposits in vivo using a contrasting tracer that binds selectively to the Abeta deposits.[98][99][100] Another recent objective marker of the disease is the analysis of cerebrospinal fluid for amyloid beta or tau proteins.[101] Both advances (neuroimaging and cerebrospinal fluid analysis) have led to the proposal of new diagnostic criteria.[84][82]
Prevention
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
Intellectual activities such as playing chess or regular social interaction have been linked to a reduced risk of AD in epidemiological studies, although no causal relationship has been found.
At present contradictory results in global studies, incapacity to prove causal relationships between risk factors and the disease, and possible secondary effects indicate a lack of specific measures to prevent or delay the onset of AD.[102] Different epidemiological studies have proposed relationships between certain modifiable factors, such as diet, cardiovascular risk, pharmaceutical products, or intellectual activities among others, and a population's likelihood of developing AD. Only further research, including clinical trials, will reveal whether, in fact, these factors can help to prevent AD.[103]
The components of a Mediterranean diet, which include fruit and vegetables, bread, wheat and other cereals, olive oil, fish, and red wine, may all individually or together reduce the risk and course of Alzheimer's disease. Vitamins B and C, or folic acid have appeared to be related to a reduced risk of AD, but other studies indicate that they do not have any significant effect on the onset or course of the disease and may have important secondary effects.[106] Curcumin in curry has shown some effectiveness in preventing brain damage in mouse models.
Although cardiovascular risk factors, such as hypercholesterolemia, hypertension, diabetes, and smoking, are associated with a higher risk of onset and course of AD,[108][109] statins, which are cholesterol lowering drugs, have not been effective in preventing or improving the course of the disease.[110][111] However long-term usage of non-steroidal anti-inflammatory drug (NSAIDs), is associated with a reduced likelihood of developing AD in some individuals.[112] Other pharmaceutical therapies such as female hormone replacement therapy are no longer thought to prevent dementia,[113][114] and a 2007 systematic review concluded that there was inconsistent and unconvincing evidence that ginkgo has any positive effect on dementia or cognitive impairment.[115]
Intellectual activities such as playing chess, completing crossword puzzles or regular social interaction, may also delay the onset or reduce the severity of Alzheimer's disease.[116][117] Bilingualism is also related to a later onset of Alzheimer.[118]
Some studies have shown a positive relationship between risk of developing AD and different occupational exposures such as magnetic field exposure,[119][120], metals intake and specifically aluminium,[121][122] or solvents.[123] The quality of some of these studies has been criticized,[124] and other research does not confirm this link.[125][126] [127][128]
[edit] Management
There is no known cure for Alzheimer's disease. Available treatments offer relatively small symptomatic benefit but remain palliative in nature. Current treatments can be divided into pharmaceutical, psychosocial and caregiving.
Pharmaceutical
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
3d molecular spacefill of donepezil, an acetylcholinesterase inhibitor used in the treatment of AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms
Molecular structure of memantine, a medication approved for advanced AD symptoms
Four medications, to treat the cognitive manifestations of AD, are currently approved by regulatory agencies, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Three are acetylcholinesterase inhibitors and the other is memantine, an NMDA receptor antagonist. No drug has an indication for delaying or halting the progression of the disease.
Because reduction in the activity of the cholinergic neurons in the disease is well known, acetylcholinesterase inhibitors are employed to reduce the rate at which acetylcholine (ACh) is broken down and so to increase the concentration of ACh in the brain, thereby combatting the loss of ACh caused by the death of the cholinergin neurons.[130] Cholinesterase inhibitors currently approved include donepezil (brand name Aricept),[131] galantamine (Razadyne),[132] and rivastigmine (branded as Exelon,[133] and Exelon Patch[134]). There is also evidence for the efficacy of these medications in mild to moderate Alzheimer’s disease,[135] and some evidence for their use in the advanced stage. Only donepezil is approved for treatment of advanced AD dementia.[136] The use of these drugs in mild cognitive impairment has not shown any effect in a delay of the onset of AD.[137] Most common side effects include nausea and vomiting, both of which are linked to cholinergic excess. These side effects arise in approximately ten to twenty percent of users and are mild to moderate in severity. Less common secondary effects include muscle cramps; decreased heart rate (bradycardia), decreased appetite and weight, and increased gastric acid.[138][139][140][141]
Glutamate is a useful excitatory neurotransmitter of the nervous system, although excessive amounts in the brain can lead to cell death through a process called excitotoxicity which consists of the overstimulation of glutamate receptors. Excitotoxicity occurs not only in Alzheimer's disease, but also in other neurological diseases such as Parkinson's disease and multiple sclerosis.[142] Memantine (brand names Akatinol, Axura, Ebixa/Abixa, Memox and Namenda),[143] is a noncompetitive NMDA receptor antagonist first used as an anti-influenza agent. It acts on the glutamatergic system by blocking NMDA glutamate receptors and inhibits their overstimulation by glutamate.[142] Memantine has been shown to be moderately efficacious in the treatment of moderate to severe Alzheimer’s disease. Its effects in the initial stages are unknown.[144] Reported adverse events with memantine are infrequent and mild, including hallucinations, confusion, dizziness, headache and fatigue.[145] Memantine used in combination with donepezil has been shown to be "of statistically significant but clinically marginal effectiveness".[146]
Neuroleptic anti-psychotic drugs commonly given to Alzheimer's patients with behavioural problems are modestly useful in reducing aggression and psychosis, but are associated with serious adverse effects, such as cerebrovascular events, movement difficulties or cognitive decline, that do not permit their routine use.[147][148][149]
Psychosocial intervention
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia
A specifically designed room for sensory integration therapy, or snoezelen; an emotion-oriented psychosocial intervention for people with dementia
Psychosocial interventions are used as an adjunct to pharmaceutical treatment and can be classified within behavior, emotion, cognition or stimulation oriented approaches. Research on efficacy is unavailable and rarely specific to the disease, focusing instead on dementia.[150]
Behavioral interventions attempt to identify and reduce the antecedents and consequences of problem behaviors. This approach has not shown success in the overall functioning of patients,[151] but can help to reduce some specific problem behaviors, such as incontinence.[152] There is still a lack of high quality data on the effectiveness of these techniques in other behavior problems such as wandering.[153][154]
Emotion-oriented interventions include reminiscence therapy, validation therapy, supportive psychotherapy, sensory integration or snoezelen, and simulated presence therapy. Supportive psychotherapy has received little or no formal scientific study, but some clinicians find it useful in helping mildly impaired patients adjust to their illness.[150] Reminiscence therapy (RT) involves the discussion of past experiences individually or in group, many times with the aid of photographs, household items, music and sound recordings, or other familiar items from the past. Although there are few quality studies on the effectiveness of RT it may be beneficial for cognition and mood.[155] Simulated presence therapy (SPT) is based on attachment theories and is normally carried out playing a recording with voices of the closest relatives of the patient. There is preliminary evidence indicating that SPT may reduce anxiety and challenging behaviors.[156][157] Finally, validation therapy is based on acceptance of the reality and personal truth of another's experience, while sensory integration is based on exercises aimed to stimulate senses. There is little evidence to support the usefulness of these therapies.[158][159]
The aim of cognition-oriented treatments, which include reality orientation and cognitive retraining is the restoration of cognitive deficits. Reality orientation consists in the presentation of information about time, place or person in order to ease the understanding of the person about its surroundings and his place in them. On the other hand cognitive retraining tries to improve impaired capacities by exercitation of mental abilities. Both have shown some efficacy improving cognitive capacities,[160][161] although in some works these effects were transient and negative effects, such as frustration, have also been reported.[150]
Stimulation-oriented treatments include art, music and pet therapies, exercise, and any other kind of recreational activities for patients. Stimulation has modest support for improving behavior, mood, and, to a lesser extent, function. Nevertheless, as important as these effects are, the main support for the use of stimulation therapies is the improvement in the patient daily life routine they suppose.[150]
Caregiving
Further information: Caregiving and dementia
Since there is no cure for Alzheimer's, caregiving is an essential part of the treatment. Due to the eventual inability for the sufferer to self-care, Alzheimer's has to be carefully care-managed. Home care in the familiar surroundings of home may delay onset of some symptoms and delay or eliminate the need for more professional and costly levels of care.[162] Many family members choose to look after their relatives,[12] but two-thirds of nursing home residents have dementias.[163]
Modifications to the living environment and lifestyle of the Alzheimer's patient can improve functional performance and ease caretaker burden. Assessment by an occupational therapist is often indicated. Adherence to simplified routines and labeling of household items to cue the patient can aid with activities of daily living, while placing safety locks on cabinets, doors, and gates and securing hazardous chemicals can prevent accidents and wandering. Changes in routine or environment can trigger or exacerbate agitation, whereas well-lit rooms, adequate rest, and avoidance of excess stimulation all help prevent such episodes.[164][165] Appropriate social and visual stimulation can improve function by increasing awareness and orientation. For instance, boldly colored tableware aids those with severe AD, helping people overcome a diminished sensitivity to visual contrast to increase food and beverage intake.[166]
Prognosis
As the disease progresses, the patient will advance from mild cognitive impairment, when the suspected underlying pathology may or may not yet have been diagnosed, to mild and advanced stages of dementia, finally reaching a severe stage of dementia.[27] Once Alzheimer's has been diagnosed, the average life expectancy is approximately seven years, while less than three percent of the patients live more than fourteen years.
History
Auguste D, first described patient with AD by Alöis Alzheimer in 1901
Although the concept of dementia goes as far back as the ancient Greek and Roman philosophers and physicians,[179] it was in 1901 when Alöis Alzheimer, a German psychiatrist, identified the first case of what became known as Alzheimer's disease in a fifty-year-old woman he called Auguste D. Alöis Alzheimer followed her until she died in 1906, when he first reported the case publicly.[180] In the following five years, eleven similar cases were reported in the medical literature, some of them already using the term Alzheimer's disease.[179] The official consideration of the disease as a distinctive entity is attributed to Emil Kraepelin, who included Alzheimer’s disease or presenile dementia as a subtype of senile dementia in the eighth edition of his Textbook of Psychiatry, published in 1910.[181]
For most of the twentieth century, the diagnosis of Alzheimer's disease was reserved for individuals between the ages of 45 and 65 who developed symptoms of dementia. The terminology changed after 1977 when a conference concluded that the clinical and pathological manifestations of presenile and senile dementia were almost identical, although the authors also added that this did not rule out the possibility of different etiologies.[182] This eventually led to the use of Alzheimer's disease independently of onset age of the disease.[183] The term senile dementia of the Alzheimer type (SDAT) was used for a time to describe the condition in those over 65, with classical Alzheimer's disease being used for those younger. Eventually, the term Alzheimer's disease was formally adopted in medical nomenclature to describe individuals of all ages with a characteristic common symptom pattern, disease course, and neuropathology.[184]
Society and culture
Social costs
Because the median age of the industrialised world's population is gradually increasing, AD is a public health challenge. The World Health Organization estimates that globally the total disability adjusted life years (DALYs) for AD and other dementias exceeded eleven million in 2005, with a projected 3.4% annual increase.[185] The DALYs are a measure for the overall disease burden that quantifies the impact of premature death and disability on a population by combining them into a single measure.
The solvency of governmental social safety nets will be impacted by the increased aged population which may develop Alzheimer's in the same proportions as earlier generations
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